CK Murthy

current good manufacturing practices
pharmaceutical validation: volume I general processes



compiled by
compiled by
c k moorthy
c k moorthy
Published by: Center for GMP 509 Block C Godavari NCL Complex Pipeline Road, Petbashirabad Jeedimetla PO Hyderabad 500 055 eMail: ckm@cgxp.org; cgmp@vsnl.com URL: www.cgxp.org Standard edition Printed in India
Published by: Center for GMP 509 Block C Godavari NCL Complex Pipeline Road, Petbashirabad Jeedimetla PO Hyderabad 500 055 eMail: ckm@cgxp.org; cgmp@vsnl.com URL: www.cgxp.org Standard edition Printed in India
All rights reserved. No part of this work may be copied, reproduced, adapted, abridged or translated, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior written permission of the publisher.
All rights reserved. No part of this work may be copied, reproduced, adapted, abridged or translated, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior written permission of the publisher.
The frontiers of knowledge are constantly changing, ever expanding. As information becomes available, changes in design approach, procedures, equipment and their use become necessary. The author and publisher have, as far as it is possible, taken care to ensure that the information given in the text is both accurate and current. However, readers are strongly advised to confirm that the information, especially with regard to drug and device manufacture, complies with current regulatory and compendial expectations, legislations and standards of practice.
The frontiers of knowledge are constantly changing, ever expanding. As information becomes available, changes in design approach, procedures, equipment and their use become necessary. The author and publisher have, as far as it is possible, taken care to ensure that the information given in the text is both accurate and current. However, readers are strongly advised to confirm that the information, especially with regard to drug and device manufacture, complies with current regulatory and compendial expectations, legislations and standards of practice.
acknowledgement
acknowledgement
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aterial presented here has been collated, compiled and reproduced with permission from sources listed below. Our contribution is restricted to organising it in such a maner as to serve your needs, whether novice or veteran; in nonsterile formulations or in API maufacture. We have sought to facilitate comprehension and appreciation of regulatory expectations in letter and spirit, as well as their implemetation for compliance. We have endeavoured to provide documents updated as we go to press, and have therefore included the Draft Guidance on Process Validation. WHO TRS 937 Annexure 4: 2006 Department of Health and Human Services, USFDA, CPG 7132c.08 European Agency for the Evaluation of Medicinal Products Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-operation Scheme o International Conference on Harmonisation: Q7A o Active Pharmaceutical Ingredients Committee at CEFIC o Health Products and Food Branch Inspectorate, Canada
M
o o o o
aterial presented here has been collated, compiled and reproduced with permission from sources listed below. Our contribution is restricted to organising it in such a maner as to serve your needs, whether novice or veteran; in nonsterile formulations or in API maufacture. We have sought to facilitate comprehension and appreciation of regulatory expectations in letter and spirit, as well as their implemetation for compliance. We have endeavoured to provide documents updated as we go to press, and have therefore included the Draft Guidance on Process Validation. WHO TRS 937 Annexure 4: 2006 Department of Health and Human Services, USFDA, CPG 7132c.08 European Agency for the Evaluation of Medicinal Products Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-operation Scheme o International Conference on Harmonisation: Q7A o Active Pharmaceutical Ingredients Committee at CEFIC o Health Products and Food Branch Inspectorate, Canada
contents
contents
Process Validation - General Principles & Practices (Draft Guidance Document, November 2008) Qualification and Validation USFDA compliance policy guide 2004 Canadian guide 0029: 2004 WHO guide: TRS 937: 2006 ICH Q7A Chapter 12 EC guide to GMP Volume 4 Annexure 15: 2004 PIC/PICS guide Cleaning validation Canadian guide for cleaning validation
Process Validation - General Principles & Practices (Draft Guidance Document, November 2008) Qualification and Validation
35 45 63 139 155 167
USFDA compliance policy guide 2004 Canadian guide 0029: 2004 WHO guide: TRS 937: 2006 ICH Q7A Chapter 12 EC guide to GMP Volume 4 Annexure 15: 2004 PIC/PICS guide Cleaning validation
35 45 63 139 155 167
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Canadian guide for cleaning validation
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WHO guide for cleaning validation APIC guide for cleaning validation Analytical methods validation USFDA guide for analytical methods validation WHO guide for analytical methods validation Analytical method validation Computers and software validation USFDA guide for software validation EC guide to GMP Volume 4 Annexure 11 Computers: 2004 EC guide to GMP Volume 4 Annexure 11 proposed changes WHO guide for computer systems validation Examples and tips Validating a synthetic API process Integrated approach to validation: a case study Pure water system qualification Prerequisites for successful validation Templates for drafting qualification protocols
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WHO guide for cleaning validation APIC guide for cleaning validation Analytical methods validation
209 223
299 339 347
USFDA guide for analytical methods validation WHO guide for analytical methods validation Analytical method validation Computers and software validation
299 339 347
381 439 445 451
USFDA guide for software validation EC guide to GMP Volume 4 Annexure 11 Computers: 2004 EC guide to GMP Volume 4 Annexure 11 proposed changes WHO guide for computer systems validation Examples and tips
381 439 445 451
461 487 529 539 549
Validating a synthetic API process Integrated approach to validation: a case study Pure water system qualification Prerequisites for successful validation Templates for drafting qualification protocols
461 487 529 539 549
Guidance for Industry
Guidance for Industry
Process Validation: General Principles and Practices

DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document contact Brian Hasselbalch or Grace McNally (CDER) 301-796-3286 or 301-796-3279, Christopher Joneckis (CBER) 301-827-0373, or Dennis Bensley (CVM) 301-827-6956.
Process Validation: General Principles and Practices

DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document contact Brian Hasselbalch or Grace McNally (CDER) 301-796-3286 or 301-796-3279, Christopher Joneckis (CBER) 301-827-0373, or Dennis Bensley (CVM) 301-827-6956.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine (CVM) November 2008 Current Good Manufacturing Practices (CGMP)
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine (CVM) November 2008 Current Good Manufacturing Practices (CGMP)
GUIDANCE FOR INDUSTRY PROCESS VALIDATION: GENERAL PRINCIPLES AND PRACTICES

Additional copies are available from: Office of Training and Communication Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Avenue Building 51, Room 2201 Silver Spring, MD 20993-0002 (Tel) 301-796-3400 http://www.fda.gov/cder/guidance/index.htm and/or Office of Communication, Training and Manufacturers Assistance, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike Rockville, MD 20852-1448 (Tel) 800-835-4709 or 301-827-1800 http://www.fda.gov/cber/guidelines.htm and/or
GUIDANCE FOR INDUSTRY PROCESS VALIDATION: GENERAL PRINCIPLES AND PRACTICES

Additional copies are available from: Office of Training and Communication Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Avenue Building 51, Room 2201 Silver Spring, MD 20993-0002 (Tel) 301-796-3400 http://www.fda.gov/cder/guidance/index.htm and/or Office of Communication, Training and Manufacturers Assistance, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike Rockville, MD 20852-1448 (Tel) 800-835-4709 or 301-827-1800 http://www.fda.gov/cber/guidelines.htm and/or
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Communications Staff, HFV-12 Center for Veterinary Medicine Food and Drug Administration 7519 Standish Place, Rockville, MD 20855 (Tel) 240-276-9300 http://www.fda.gov/cvm/guidance/published.htm
Communications Staff, HFV-12 Center for Veterinary Medicine Food and Drug Administration 7519 Standish Place, Rockville, MD 20855 (Tel) 240-276-9300 http://www.fda.gov/cvm/guidance/published.htm
process validation :general principles and practices - draft guidance (november 2008)
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Guidance for Industry1
Guidance for Industry1
PROCESS VALIDATION: GENERAL PRINCIPLES AND PRACTICES

This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. I. INTRODUCTION This guidance outlines the general principles and approaches that FDA considers to be appropriate elements of process validation for the manufacture of human and animal drug and biological products, including active pharmaceutical ingredients (API or drug substance), collectively referred to in this guidance as drugs or products . This guidance incorporates principles and approaches that all manufacturers can use in validating a manufacturing process. This guidance aligns process validation activities with the product lifecycle concept and with existing FDA guidance. 2 The lifecycle concept links product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production. This guidance promotes modern manufacturing principles, process improvement, innovation, and sound science. The following categories of drugs are within the scope of this guidance: Human drugs Veterinary drugs Biological and biotechnology products Finished products and active pharmaceutical ingredients (API or drug substance)3 The drug constituent of a combination (drug & medical device) product
PROCESS VALIDATION: GENERAL PRINCIPLES AND PRACTICES

This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. I. INTRODUCTION This guidance outlines the general principles and approaches that FDA considers to be appropriate elements of process validation for the manufacture of human and animal drug and biological products, including active pharmaceutical ingredients (API or drug substance), collectively referred to in this guidance as drugs or products . This guidance incorporates principles and approaches that all manufacturers can use in validating a manufacturing process. This guidance aligns process validation activities with the product lifecycle concept and with existing FDA guidance. 2 The lifecycle concept links product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production. This guidance promotes modern manufacturing principles, process improvement, innovation, and sound science. The following categories of drugs are within the scope of this guidance: Human drugs Veterinary drugs Biological and biotechnology products Finished products and active pharmaceutical ingredients (API or drug substance)3 The drug constituent of a combination (drug & medical device) product
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The following categories of products are not covered by this guidance: Type A medicated articles and medicated feed Medical devices Dietary supplements Human tissues intended for transplantation regulated under section 361 of the Public Health 46 Service Act4 This guidance does not specify what information should be included as part of a regulatory submission. Interested persons can refer to the appropriate guidance or contact the appropriate Center in determining what information should be included in a submission. This guidance also does not specifically discuss the validation of automated process control systems (i.e., computer hardware and software interfaces), which are commonly integrated into modern drug manufacturing equipment. This guidance is relevant, however, to the validation of processes that include automated equipment in processing. FDAs guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. II. BACKGROUND In the Federal Register of May 11, 1987 (52 FR 17638), FDA issued a notice announcing the availability of a guidance entitled Guideline on General Principles of Process Validation (the 1987 guidance).5 Since then, we have obtained additional experience through our regulatory oversight that allows us to update our recommendations to industry on this topic. This revised guidance conveys FDAs current thinking on process validation and is consistent with basic principles first introduced in the 1987 guidance. This guidance also provides recommendations that reflect some of the goals of FDAs initiative entitled Pharmaceutical CGMPs for the 21st Century A Risk-Based Approach, particularly with regard to the use of technological advances in pharmaceutical manufacturing, as well as implementation of modern risk management and quality system
The following categories of products are not covered by this guidance: Type A medicated articles and medicated feed Medical devices Dietary supplements Human tissues intended for transplantation regulated under section 361 of the Public Health 46 Service Act4 This guidance does not specify what information should be included as part of a regulatory submission. Interested persons can refer to the appropriate guidance or contact the appropriate Center in determining what information should be included in a submission. This guidance also does not specifically discuss the validation of automated process control systems (i.e., computer hardware and software interfaces), which are commonly integrated into modern drug manufacturing equipment. This guidance is relevant, however, to the validation of processes that include automated equipment in processing. FDAs guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. II. BACKGROUND In the Federal Register of May 11, 1987 (52 FR 17638), FDA issued a notice announcing the availability of a guidance entitled Guideline on General Principles of Process Validation (the 1987 guidance).5 Since then, we have obtained additional experience through our regulatory oversight that allows us to update our recommendations to industry on this topic. This revised guidance conveys FDAs current thinking on process validation and is consistent with basic principles first introduced in the 1987 guidance. This guidance also provides recommendations that reflect some of the goals of FDAs initiative entitled Pharmaceutical CGMPs for the 21st Century A Risk-Based Approach, particularly with regard to the use of technological advances in pharmaceutical manufacturing, as well as implementation of modern risk management and quality system
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tools and concepts. When finalized, this guidance will replace the 1987 guidance. FDA has the authority and responsibility to inspect and evaluate process validation performed by manufacturers. The CGMP regulations for validating pharmaceutical (drug) manufacturing require that drug products be produced with a high degree of assurance of meeting all the attributes they are intended to possess (21 CFR 211.100(a) and 211.110(a)). Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug should be produced that is fit for its intended use; this principle incorporates the understanding that the following conditions exist: Quality, safety, and efficacy are designed or built into the product. Quality cannot be adequately assured merely by in-process and finished-product inspection or testing. Each step of a manufacturing process is controlled to assure that the finished product meets all design characteristics and quality attributes including specifications. For purposes of this guidance, process validation is defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products. Process validation involves a series of activities taking place over the lifecycle of the product and process. This guidance describes the process validation activities in three stages. Stage 1 Process Design: The commercial process is defined during this stage based on knowledge gained through development and scaleup activities. Stage 2 Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing. Stage 3 Continued Process Verification: Ongoing assurance is gained during routine 106 production that the process remains in a state of control. This guidance describes activities typical in each stage, but in practice, some activities in different stages might overlap.
tools and concepts. When finalized, this guidance will replace the 1987 guidance. FDA has the authority and responsibility to inspect and evaluate process validation performed by manufacturers. The CGMP regulations for validating pharmaceutical (drug) manufacturing require that drug products be produced with a high degree of assurance of meeting all the attributes they are intended to possess (21 CFR 211.100(a) and 211.110(a)). Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug should be produced that is fit for its intended use; this principle incorporates the understanding that the following conditions exist: Quality, safety, and efficacy are designed or built into the product. Quality cannot be adequately assured merely by in-process and finished-product inspection or testing. Each step of a manufacturing process is controlled to assure that the finished product meets all design characteristics and quality attributes including specifications. For purposes of this guidance, process validation is defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products. Process validation involves a series of activities taking place over the lifecycle of the product and process. This guidance describes the process validation activities in three stages. Stage 1 Process Design: The commercial process is defined during this stage based on knowledge gained through development and scaleup activities. Stage 2 Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing. Stage 3 Continued Process Verification: Ongoing assurance is gained during routine 106 production that the process remains in a state of control. This guidance describes activities typical in each stage, but in practice, some activities in different stages might overlap.
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Before any batch from the process is commercially distributed for use by consumers, a manufacturer should have gained a high degree of assurance in the performance of the manufacturing process such that it will consistently produce APIs and drug products meeting those attributes relating to identity, strength, quality, purity, and potency. The assurance should be obtained from objective information and data from laboratory-, pilot-, and/or commercial- scale studies. Information and data should demonstrate that the commercial manufacturing process is capable of consistently producing acceptable quality products within commercial manufacturing conditions, including those conditions that pose a high risk of process failure. A successful validation program depends upon information and knowledge from product and process development. This knowledge and understanding is the basis for establishing an approach to control that is appropriate for the manufacturing process. Manufacturers should: understand the sources of variation detect the presence and degree of variation understand the impact of variation on the process and ultimately on product attributes control the variation in a manner commensurate with the risk it represents to the process and product Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify commercial distribution of the product. Focusing on qualification efforts without understanding the manufacturing process may not lead to adequate assurance of quality. After establishing and confirming the process, manufacturers must maintain the process in a state of control over the life of the process, even as materials, equipment, production environment, personnel, and manufacturing procedures change.6 III. STATUTORY AND REGULATORY REQUIREMENTS FOR PROCESS VALIDATION Process validation for drugs (finished pharmaceuticals and components) is a legally enforceable requirement under section 501(a)(2)(B) of the Act, which states the following:
Before any batch from the process is commercially distributed for use by consumers, a manufacturer should have gained a high degree of assurance in the performance of the manufacturing process such that it will consistently produce APIs and drug products meeting those attributes relating to identity, strength, quality, purity, and potency. The assurance should be obtained from objective information and data from laboratory-, pilot-, and/or commercial- scale studies. Information and data should demonstrate that the commercial manufacturing process is capable of consistently producing acceptable quality products within commercial manufacturing conditions, including those conditions that pose a high risk of process failure. A successful validation program depends upon information and knowledge from product and process development. This knowledge and understanding is the basis for establishing an approach to control that is appropriate for the manufacturing process. Manufacturers should: understand the sources of variation detect the presence and degree of variation understand the impact of variation on the process and ultimately on product attributes control the variation in a manner commensurate with the risk it represents to the process and product Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify commercial distribution of the product. Focusing on qualification efforts without understanding the manufacturing process may not lead to adequate assurance of quality. After establishing and confirming the process, manufacturers must maintain the process in a state of control over the life of the process, even as materials, equipment, production environment, personnel, and manufacturing procedures change.6 III. STATUTORY AND REGULATORY REQUIREMENTS FOR PROCESS VALIDATION Process validation for drugs (finished pharmaceuticals and components) is a legally enforceable requirement under section 501(a)(2)(B) of the Act, which states the following:
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A drug . . . shall be deemed to be adulterated . . . if . . . the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess. FDA regulations describing current good manufacturing practice (CGMP) are provided in 21 CFR parts 210 and 211. Process validation is required, in both general and specific terms, by the CGMP regulations in parts 210 and 211. The foundation for process validation is provided in 211.100(a), which states that [t]here shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess (emphasis added). This regulation requires that manufacturers design a process including operations and controls that will result in a product meeting these attributes. Product quality in the context of process validation means that product performance is consistent from batch-to-batch and unit-to-unit. Many products are single-source or involve complicated processes to manufacture. Validation also offers assurance that a process is reasonably safeguarded from sources of variability affecting production output, the loss of which can cause supply problems, thereby negatively affecting public health. Other CGMP regulations define the various aspects of validation. Section 211.110(a), Sampling and testing of in-process materials and drug products, requires that control procedures . . . be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product (emphasis added). This regulation establishes the requirement that even well-designed processes must include in-process control procedures to assure final product quality. CGMP regulations require that batch samples represent the batch under analysis (see, e.g., 211.160(b)(3)) and that the sampling plan result in statistical confidence ( 211.165(c) and (d)) that the batch meets its predetermined specifications ( 211.165(a)). Section 211.110(b) provides
A drug . . . shall be deemed to be adulterated . . . if . . . the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess. FDA regulations describing current good manufacturing practice (CGMP) are provided in 21 CFR parts 210 and 211. Process validation is required, in both general and specific terms, by the CGMP regulations in parts 210 and 211. The foundation for process validation is provided in 211.100(a), which states that [t]here shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess (emphasis added). This regulation requires that manufacturers design a process including operations and controls that will result in a product meeting these attributes. Product quality in the context of process validation means that product performance is consistent from batch-to-batch and unit-to-unit. Many products are single-source or involve complicated processes to manufacture. Validation also offers assurance that a process is reasonably safeguarded from sources of variability affecting production output, the loss of which can cause supply problems, thereby negatively affecting public health. Other CGMP regulations define the various aspects of validation. Section 211.110(a), Sampling and testing of in-process materials and drug products, requires that control procedures . . . be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product (emphasis added). This regulation establishes the requirement that even well-designed processes must include in-process control procedures to assure final product quality. CGMP regulations require that batch samples represent the batch under analysis (see, e.g., 211.160(b)(3)) and that the sampling plan result in statistical confidence ( 211.165(c) and (d)) that the batch meets its predetermined specifications ( 211.165(a)). Section 211.110(b) provides
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two principles to follow when establishing in-process specifications. The first principle is that . . . in-process specifications for such characteristics [of in-process material and the drug product] shall be consistent with drug product final specifications . . . . Accordingly, in-process material should be controlled to assure that the final drug product will meet its quality requirements. The second principle in this regulation further requires that in-process specifications . . . shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate. This requirement, in part, establishes the need for manufacturers to analyze process performance and control batch-to-batch variability.7 The CGMP regulations also describe and define activities connected with process design, development, and maintenance. Section 211.180(e) requires that information and data about product performance and manufacturing experience be periodically reviewed to determine whether any changes to the established process are warranted. Ongoing feedback about product performance is an essential feature of process maintenance. In addition, the CGMP regulations require that facilities in which drugs are manufactured be of suitable size, construction, and location to facilitate proper operations (21 CFR 211.42). Equipment must be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use (21 CFR 211.63). Automated, mechanical, and electronic equipment must be calibrated, inspected, or checked according to a written program designed to 198 assure proper performance (21 CFR 211.68). In summary, the CGMP regulations require that manufacturing processes be designed and controlled to assure that in-process materials and the finished product meet predetermined quality requirements and do so consistently and reliably. IV. RECOMMENDATIONS A. General Considerations for Process Validation In all stages of the product lifecycle, good project management and good archiving that capture scientific knowledge will make the process validation program more effective and efficient. These practices should
two principles to follow when establishing in-process specifications. The first principle is that . . . in-process specifications for such characteristics [of in-process material and the drug product] shall be consistent with drug product final specifications . . . . Accordingly, in-process material should be controlled to assure that the final drug product will meet its quality requirements. The second principle in this regulation further requires that in-process specifications . . . shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate. This requirement, in part, establishes the need for manufacturers to analyze process performance and control batch-to-batch variability.7 The CGMP regulations also describe and define activities connected with process design, development, and maintenance. Section 211.180(e) requires that information and data about product performance and manufacturing experience be periodically reviewed to determine whether any changes to the established process are warranted. Ongoing feedback about product performance is an essential feature of process maintenance. In addition, the CGMP regulations require that facilities in which drugs are manufactured be of suitable size, construction, and location to facilitate proper operations (21 CFR 211.42). Equipment must be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use (21 CFR 211.63). Automated, mechanical, and electronic equipment must be calibrated, inspected, or checked according to a written program designed to 198 assure proper performance (21 CFR 211.68). In summary, the CGMP regulations require that manufacturing processes be designed and controlled to assure that in-process materials and the finished product meet predetermined quality requirements and do so consistently and reliably. IV. RECOMMENDATIONS A. General Considerations for Process Validation In all stages of the product lifecycle, good project management and good archiving that capture scientific knowledge will make the process validation program more effective and efficient. These practices should
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ensure uniform collection and assessment of information about the process, reduce the chance for redundant information gathering and analysis, and enhance the accessibility of such information later in the product lifecycle. We recommend an integrated8 team approach to process validation that includes expertise from a variety of disciplines, including process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance. Project plans, along with the full support of senior management, are essential elements for success. Throughout the product lifecycle, various studies can be initiated to discover, observe, correlate, or confirm information about the product and process. All studies should be planned and conducted according to sound scientific principles, appropriately documented, and should be approved in accordance with the established procedure appropriate for the stage of the lifecycle. B. Specific Stages and Activities of Process Validation in the Product Lifecycle The following subsections describe the recommended stages and specific activities. 1. Stage 1 Process Design a. Building and Capturing Process Knowledge and Understanding Process design is the activity of defining the commercial manufacturing process that will be reflected in the master production and control records. The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its critical quality attributes. Generally, early process design experiments do not need to be performed under CGMP conditions. They should, however, be conducted in accordance with sound scientific methods and principles, including good documentation practices. This recommendation is consistent with ICH guidance for industry, Q10 Pharmaceutical Quality System.9 Decisions and justification of the controls should be sufficiently documented and internally reviewed to verify and preserve their value for use later in the lifecycle of the process and product.
ensure uniform collection and assessment of information about the process, reduce the chance for redundant information gathering and analysis, and enhance the accessibility of such information later in the product lifecycle. We recommend an integrated8 team approach to process validation that includes expertise from a variety of disciplines, including process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance. Project plans, along with the full support of senior management, are essential elements for success. Throughout the product lifecycle, various studies can be initiated to discover, observe, correlate, or confirm information about the product and process. All studies should be planned and conducted according to sound scientific principles, appropriately documented, and should be approved in accordance with the established procedure appropriate for the stage of the lifecycle. B. Specific Stages and Activities of Process Validation in the Product Lifecycle The following subsections describe the recommended stages and specific activities. 1. Stage 1 Process Design a. Building and Capturing Process Knowledge and Understanding Process design is the activity of defining the commercial manufacturing process that will be reflected in the master production and control records. The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its critical quality attributes. Generally, early process design experiments do not need to be performed under CGMP conditions. They should, however, be conducted in accordance with sound scientific methods and principles, including good documentation practices. This recommendation is consistent with ICH guidance for industry, Q10 Pharmaceutical Quality System.9 Decisions and justification of the controls should be sufficiently documented and internally reviewed to verify and preserve their value for use later in the lifecycle of the process and product.
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There are exceptions, however. For example, viral and impurity clearance studies have a direct impact on drug safety and should be performed under CGMP conditions, even when performed at small scale. The quality unit should be involved with these studies as is typical during commercial production. Product-development activities provide key inputs to the design stage, such as the intended dosage form, the quality attributes, and a general manufacturing pathway. Process information available from the productdevelopment stage can be leveraged in the process-design stage. However, the full spectrum of input variability typical of commercial production is not generally known at this stage. The functionality and limitations of commercial manufacturing equipment should be considered, as well as the contributions of variability by different component lots, production operators, environmental conditions, and measurement systems in the production setting. Laboratory or pilot-scale models designed to be representative of the commercial process can be used to estimate variability. However, it is not a regulatory expectation that the process be developed and tested until it fails, but rather that a process be controlled within commercial manufacturing conditions, including those combinations of conditions posing a high risk of process failure. Designing an efficient process with an effective process control approach is dependent on the process knowledge and understanding obtained. Design of Experiment (DOE) studies can help develop process knowledge by revealing relationships, including multifactorial interactions, between the variable inputs (e.g., component10 characteristics or processing parameters) and the resulting outputs (e.g., in-process material, intermediates, or the final product). Risk analysis tools can be used to screen potential variables for DOE studies to minimize the total number of experiments conducted while maximizing knowledge gained. The results of DOE studies can provide justification for establishing ranges of incoming component quality, equipment parameters, and in-process material quality attributes. Other activities, such as experiments or demonstrations at laboratory or pilot scale, allow evaluation of certain conditions and prediction of performance of the commercial process. These activities also provide information that can be used to model or simulate the commercial process. Computer-based or virtual simulations of certain unit operations or
There are exceptions, however. For example, viral and impurity clearance studies have a direct impact on drug safety and should be performed under CGMP conditions, even when performed at small scale. The quality unit should be involved with these studies as is typical during commercial production. Product-development activities provide key inputs to the design stage, such as the intended dosage form, the quality attributes, and a general manufacturing pathway. Process information available from the productdevelopment stage can be leveraged in the process-design stage. However, the full spectrum of input variability typical of commercial production is not generally known at this stage. The functionality and limitations of commercial manufacturing equipment should be considered, as well as the contributions of variability by different component lots, production operators, environmental conditions, and measurement systems in the production setting. Laboratory or pilot-scale models designed to be representative of the commercial process can be used to estimate variability. However, it is not a regulatory expectation that the process be developed and tested until it fails, but rather that a process be controlled within commercial manufacturing conditions, including those combinations of conditions posing a high risk of process failure. Designing an efficient process with an effective process control approach is dependent on the process knowledge and understanding obtained. Design of Experiment (DOE) studies can help develop process knowledge by revealing relationships, including multifactorial interactions, between the variable inputs (e.g., component10 characteristics or processing parameters) and the resulting outputs (e.g., in-process material, intermediates, or the final product). Risk analysis tools can be used to screen potential variables for DOE studies to minimize the total number of experiments conducted while maximizing knowledge gained. The results of DOE studies can provide justification for establishing ranges of incoming component quality, equipment parameters, and in-process material quality attributes. Other activities, such as experiments or demonstrations at laboratory or pilot scale, allow evaluation of certain conditions and prediction of performance of the commercial process. These activities also provide information that can be used to model or simulate the commercial process. Computer-based or virtual simulations of certain unit operations or
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dynamics can provide process understanding and avoid problems at commercial scale. It is important to understand the degree to which models represent the commercial process, including any differences that might exist, as this may have an impact on the relevance of information derived from the studies. It is essential that activities and studies resulting in product understanding be documented. Documentation should reflect the basis for decisions made about the process. For example, manufacturers should document the variables studied for a unit operation and the rationale for those variables identified as significant. This information is useful during the process qualification and continued process verification stages, including when the design is revised or the strategy for control is refined or changed. b. Establishing a Strategy for Process Control Process knowledge and understanding is the basis for establishing an approach to process control for each unit operation and the process overall. Strategies for process control can be designed to reduce input variation, adjust for input variation during manufacturing (and so reduce its impact on the output), or combine both approaches. Process controls address variability to assure quality of the product. Controls can consist of material analysis and equipment monitoring at significant processing points designed to assure that the operation remains on target and in control with respect to output quality. Special attention to control of the process through operational limits and in-process monitoring is essential (1) where the product attribute is not readily measurable due to limitations of sampling or detectability (e.g., viral clearance or microbial contamination), or (2) when intermediates and products cannot be highly characterized and well-defined quality attributes cannot be identified. These controls are included in the master production and control records (see 21 CFR 211.186(a) and (b)(9)). More advanced strategies, such as process analytical technology (PAT), use timely analysis and control loops to adjust the processing conditions so that the output remains constant. Manufacturing systems of this type can provide a higher degree of process control. In the case of PAT strategy, the approach to process qualification will be different from that for other process designs. Further information on PAT processes can be found in
dynamics can provide process understanding and avoid problems at commercial scale. It is important to understand the degree to which models represent the commercial process, including any differences that might exist, as this may have an impact on the relevance of information derived from the studies. It is essential that activities and studies resulting in product understanding be documented. Documentation should reflect the basis for decisions made about the process. For example, manufacturers should document the variables studied for a unit operation and the rationale for those variables identified as significant. This information is useful during the process qualification and continued process verification stages, including when the design is revised or the strategy for control is refined or changed. b. Establishing a Strategy for Process Control Process knowledge and understanding is the basis for establishing an approach to process control for each unit operation and the process overall. Strategies for process control can be designed to reduce input variation, adjust for input variation during manufacturing (and so reduce its impact on the output), or combine both approaches. Process controls address variability to assure quality of the product. Controls can consist of material analysis and equipment monitoring at significant processing points designed to assure that the operation remains on target and in control with respect to output quality. Special attention to control of the process through operational limits and in-process monitoring is essential (1) where the product attribute is not readily measurable due to limitations of sampling or detectability (e.g., viral clearance or microbial contamination), or (2) when intermediates and products cannot be highly characterized and well-defined quality attributes cannot be identified. These controls are included in the master production and control records (see 21 CFR 211.186(a) and (b)(9)). More advanced strategies, such as process analytical technology (PAT), use timely analysis and control loops to adjust the processing conditions so that the output remains constant. Manufacturing systems of this type can provide a higher degree of process control. In the case of PAT strategy, the approach to process qualification will be different from that for other process designs. Further information on PAT processes can be found in
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FDAs guidance for industry on PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (available on the Internet at http://www.fda.gov/cder/guidance/index.htm). The planned commercial production and control records, which contain the operational limits and overall strategy for process control, should be carried forward to the next stage for confirmation. 2. Stage 2 Process Qualification During the process qualification stage of process validation, the process design is confirmed as being capable of reproducible commercial manufacture. This stage has two elements: (1) design of the facility and qualification of the equipment and utilities, and (2) performance qualification (PQ). During this stage, CGMP-compliant procedures must be followed and successful completion of this stage is necessary before commercial distribution.11 Products manufactured during this stage, if acceptable, can be released. a. Design of a Facility and Qualification of Utilities and Equipment Proper design of a manufacturing facility is required under 21 CFR part 211, subpart C, of the CGMP regulations on Buildings and Facilities. It is essential that activities performed to assure proper facility design and commissioning precede PQ. Activities undertaken to demonstrate that utilities and pieces of equipment are suitable for their intended use and perform properly is referred to in this guidance as qualification. These activities necessarily precede manufacturing products at the commercial scale. Qualification of utilities and equipment generally includes the following activities: Selecting utilities and equipment construction materials, operating principles, and performance characteristics based on whether they are appropriate for their specific use. Verifying that utility systems and equipment are built and installed in compliance with the design specifications (e.g., built as designed with proper materials, capacity, and functions, and properly connected and calibrated).
FDAs guidance for industry on PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (available on the Internet at http://www.fda.gov/cder/guidance/index.htm). The planned commercial production and control records, which contain the operational limits and overall strategy for process control, should be carried forward to the next stage for confirmation. 2. Stage 2 Process Qualification During the process qualification stage of process validation, the process design is confirmed as being capable of reproducible commercial manufacture. This stage has two elements: (1) design of the facility and qualification of the equipment and utilities, and (2) performance qualification (PQ). During this stage, CGMP-compliant procedures must be followed and successful completion of this stage is necessary before commercial distribution.11 Products manufactured during this stage, if acceptable, can be released. a. Design of a Facility and Qualification of Utilities and Equipment Proper design of a manufacturing facility is required under 21 CFR part 211, subpart C, of the CGMP regulations on Buildings and Facilities. It is essential that activities performed to assure proper facility design and commissioning precede PQ. Activities undertaken to demonstrate that utilities and pieces of equipment are suitable for their intended use and perform properly is referred to in this guidance as qualification. These activities necessarily precede manufacturing products at the commercial scale. Qualification of utilities and equipment generally includes the following activities: Selecting utilities and equipment construction materials, operating principles, and performance characteristics based on whether they are appropriate for their specific use. Verifying that utility systems and equipment are built and installed in compliance with the design specifications (e.g., built as designed with proper materials, capacity, and functions, and properly connected and calibrated).
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Verifying that the utility system and equipment operate in accordance with the process requirements in all anticipated operating ranges. This should include challenging the equipment or system functions while under load comparable to that expected during routine production. It should also include the performance of interventions, stoppage, and start-up as is expected during routine production. Operating ranges should be shown capable of being held as long as would be necessary during routine production. Qualification of utilities and equipment can be covered under individual plans or as part of an overall project plan. The plan should consider the requirements of use and can incorporate risk management to prioritize certain activities and to identify a level of effort in both the performance and documentation of qualification activities. The plan should identify (1) the studies or tests to use, (2) the criteria appropriate to assess outcomes, (3) the timing of qualification activities, (4) responsibilities, and (5) the procedures for documenting and approving the qualification. It should also include the firms requirements for the evaluation of changes. Qualification activities should be documented and summarized in a report with conclusions that address criteria in the plan. The quality control unit must review and approve the qualification plan and report (21 367 CFR 211.22). b. Performance Qualification Approach The PQ is the second element of stage 2, process qualification. The PQ combines the actual facility, utilities, equipment (each now qualified), and the trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches. A successful PQ will confirm the process design and demonstrate that the commercial manufacturing process performs as expected. Success at this stage signals an important milestone in the product lifecycle and needs to be completed before a manufacturer commences commercial distribution of the drug product.12 The decision to begin commercial distribution should be supported by data from commercial batches. Data from laboratory and pilot studies can provide additional assurance.
Verifying that the utility system and equipment operate in accordance with the process requirements in all anticipated operating ranges. This should include challenging the equipment or system functions while under load comparable to that expected during routine production. It should also include the performance of interventions, stoppage, and start-up as is expected during routine production. Operating ranges should be shown capable of being held as long as would be necessary during routine production. Qualification of utilities and equipment can be covered under individual plans or as part of an overall project plan. The plan should consider the requirements of use and can incorporate risk management to prioritize certain activities and to identify a level of effort in both the performance and documentation of qualification activities. The plan should identify (1) the studies or tests to use, (2) the criteria appropriate to assess outcomes, (3) the timing of qualification activities, (4) responsibilities, and (5) the procedures for documenting and approving the qualification. It should also include the firms requirements for the evaluation of changes. Qualification activities should be documented and summarized in a report with conclusions that address criteria in the plan. The quality control unit must review and approve the qualification plan and report (21 367 CFR 211.22). b. Performance Qualification Approach The PQ is the second element of stage 2, process qualification. The PQ combines the actual facility, utilities, equipment (each now qualified), and the trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches. A successful PQ will confirm the process design and demonstrate that the commercial manufacturing process performs as expected. Success at this stage signals an important milestone in the product lifecycle and needs to be completed before a manufacturer commences commercial distribution of the drug product.12 The decision to begin commercial distribution should be supported by data from commercial batches. Data from laboratory and pilot studies can provide additional assurance.
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The approach to PQ should be based on sound science and the manufacturers overall level of product and process understanding. The cumulative data from all relevant studies (e.g., designed experiments; laboratory, pilot, and commercial batches) should be used to establish the manufacturing conditions in the PQ. For example, to have sufficient understanding of the commercial process, the manufacturer will need to consider the effects of scale; however, it is not typically necessary to explore the entire operating range at commercial scale if assurance can be provided by other data. Previous credible experience with sufficiently similar products and processes can also be considered. In addition, we strongly recommend firms employ objective measures (e.g., statistical metrics), wherever feasible and meaningful to achieve adequate assurance. In most cases, PQ will have a higher level of sampling, additional testing, and greater scrutiny of process performance. The level of monitoring and testing should be sufficient to confirm uniform product quality throughout the batch during processing. This greater scrutiny accompanied by a higher level of sampling should continue through the process verification stage, as appropriate. The extent to which some materials, such as column resins or molecular filtration media, can be re-used without adversely affecting product quality can be assessed in relevant laboratory studies, and their usable lifetime should be confirmed by an ongoing PQ protocol during commercial manufacture. A manufacturing process that uses PAT may warrant a different PQ approach. Such a process is one that is designed to measure in real time the attributes of an in-process material and then adjust the process in a timely control loop so the process maintains the desired quality of the output material. The process design stage and the process qualification stage should have as a focus the measurement system and control loop. Regardless, the goal remains the same: establishing scientific evidence that the process is reproducible and will consistently deliver quality products.
The approach to PQ should be based on sound science and the manufacturers overall level of product and process understanding. The cumulative data from all relevant studies (e.g., designed experiments; laboratory, pilot, and commercial batches) should be used to establish the manufacturing conditions in the PQ. For example, to have sufficient understanding of the commercial process, the manufacturer will need to consider the effects of scale; however, it is not typically necessary to explore the entire operating range at commercial scale if assurance can be provided by other data. Previous credible experience with sufficiently similar products and processes can also be considered. In addition, we strongly recommend firms employ objective measures (e.g., statistical metrics), wherever feasible and meaningful to achieve adequate assurance. In most cases, PQ will have a higher level of sampling, additional testing, and greater scrutiny of process performance. The level of monitoring and testing should be sufficient to confirm uniform product quality throughout the batch during processing. This greater scrutiny accompanied by a higher level of sampling should continue through the process verification stage, as appropriate. The extent to which some materials, such as column resins or molecular filtration media, can be re-used without adversely affecting product quality can be assessed in relevant laboratory studies, and their usable lifetime should be confirmed by an ongoing PQ protocol during commercial manufacture. A manufacturing process that uses PAT may warrant a different PQ approach. Such a process is one that is designed to measure in real time the attributes of an in-process material and then adjust the process in a timely control loop so the process maintains the desired quality of the output material. The process design stage and the process qualification stage should have as a focus the measurement system and control loop. Regardless, the goal remains the same: establishing scientific evidence that the process is reproducible and will consistently deliver quality products.
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c. Performance Qualification Protocol A written protocol that specifies the manufacturing conditions, controls, testing, and expected outcomes is essential for this stage of process validation. We recommend that the protocol discuss: The manufacturing conditions including operating parameters, processing limits, and component (raw material) inputs. The data to be collected and when and how it will be evaluated. Tests to be performed (in-process, release, characterization) and acceptance criteria for each significant processing step. The sampling plan including sampling points, number of samples, and the frequency of sampling for each unit operation and attribute. The number of samples should be adequate to provide sufficient statistical confidence of quality both within a batch and between batches. The confidence level selected can be based on risk analysis as it relates to the particular attribute under examination. Sampling during this stage should be more extensive than is typical during routine production. Criteria that provide for a rational conclusion of whether the process consistently produces quality products. The criteria should include: o A description of the statistical methods to be used in analyzing all collected data (e.g., statistical metrics defining both intra-batch and inter-batch variability). o Provision for addressing deviations from expected conditions and handling of nonconforming data. Data should not be excluded from further consideration in terms of PQ without a documented, sciencebased justification. Design of facilities and the qualification of utilities and equipment, personnel training and qualification, and verification of material sources (components and container/closures), if not previously accomplished. Status of the validation of analytical methods used in measuring the process, in-process materials, and the product. Review and approval by appropriate departments and the quality unit.
c. Performance Qualification Protocol A written protocol that specifies the manufacturing conditions, controls, testing, and expected outcomes is essential for this stage of process validation. We recommend that the protocol discuss: The manufacturing conditions including operating parameters, processing limits, and component (raw material) inputs. The data to be collected and when and how it will be evaluated. Tests to be performed (in-process, release, characterization) and acceptance criteria for each significant processing step. The sampling plan including sampling points, number of samples, and the frequency of sampling for each unit operation and attribute. The number of samples should be adequate to provide sufficient statistical confidence of quality both within a batch and between batches. The confidence level selected can be based on risk analysis as it relates to the particular attribute under examination. Sampling during this stage should be more extensive than is typical during routine production. Criteria that provide for a rational conclusion of whether the process consistently produces quality products. The criteria should include: o A description of the statistical methods to be used in analyzing all collected data (e.g., statistical metrics defining both intra-batch and inter-batch variability). o Provision for addressing deviations from expected conditions and handling of nonconforming data. Data should not be excluded from further consideration in terms of PQ without a documented, sciencebased justification. Design of facilities and the qualification of utilities and equipment, personnel training and qualification, and verification of material sources (components and container/closures), if not previously accomplished. Status of the validation of analytical methods used in measuring the process, in-process materials, and the product. Review and approval by appropriate departments and the quality unit.
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d. Protocol Execution and Report Protocol execution should not begin until the protocol has been reviewed and approved by all appropriate departments, including the quality unit. Departure from the established protocol must be made according to established procedure or provisions in the protocol. Such departures must be justified and approved by all appropriate departments and the quality unit before implementation ( 211.100). The commercial manufacturing process and routine procedures must be followed ( 211.100(b) and 211.110(a)). The PQ lots should be manufactured under normal conditions by personnel expected to routinely perform each step of each unit operation in the process. Normal operating conditions should cover the utility systems (e.g., air handling and water purification), material, personnel, environment, and manufacturing procedures. A report documenting and assessing adherence to the written protocol should be prepared in a timely manner after the completion of the protocol. This report should: Discuss and cross-reference all aspects of the protocol. Summarize data collected and analyze the data, as specified by the protocol. Evaluate any unexpected observations and additional data not specified in the protocol. Summarize and discuss all manufacturing nonconformances such as deviations, aberrant test results, or other information that has bearing on the validity of process. Describe in sufficient detail any corrective actions or changes that should be made to existing procedures and controls. State a clear conclusion as to whether the data indicates the process met the conditions established in the protocol and whether the process is considered to be in a sufficient state of control. If not, the report should state what should be accomplished before such a conclusion can be reached. This conclusion should be based on a documented justification for the approval of the process, and release of lots produced by it to the market in consideration of the entire compilation of
d. Protocol Execution and Report Protocol execution should not begin until the protocol has been reviewed and approved by all appropriate departments, including the quality unit. Departure from the established protocol must be made according to established procedure or provisions in the protocol. Such departures must be justified and approved by all appropriate departments and the quality unit before implementation ( 211.100). The commercial manufacturing process and routine procedures must be followed ( 211.100(b) and 211.110(a)). The PQ lots should be manufactured under normal conditions by personnel expected to routinely perform each step of each unit operation in the process. Normal operating conditions should cover the utility systems (e.g., air handling and water purification), material, personnel, environment, and manufacturing procedures. A report documenting and assessing adherence to the written protocol should be prepared in a timely manner after the completion of the protocol. This report should: Discuss and cross-reference all aspects of the protocol. Summarize data collected and analyze the data, as specified by the protocol. Evaluate any unexpected observations and additional data not specified in the protocol. Summarize and discuss all manufacturing nonconformances such as deviations, aberrant test results, or other information that has bearing on the validity of process. Describe in sufficient detail any corrective actions or changes that should be made to existing procedures and controls. State a clear conclusion as to whether the data indicates the process met the conditions established in the protocol and whether the process is considered to be in a sufficient state of control. If not, the report should state what should be accomplished before such a conclusion can be reached. This conclusion should be based on a documented justification for the approval of the process, and release of lots produced by it to the market in consideration of the entire compilation of
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knowledge and information gained from the design stage through the process qualification stage. Include all appropriate department and quality unit review and approvals. 3. Stage 3 Continued Process Verification The goal of the third validation stage is to continually assure that the process remains in a state of control (the validated state) during commercial manufacture. A system or systems for detecting unplanned departures from the process as designed is essential to accomplish this goal. Adherence to the CGMP requirements, specifically including the collection and evaluation of information and data about the performance of the process (see below), will allow detection of process drift. The evaluation should determine whether action must be taken to prevent the process from drifting out of control ( 211.180(e)). An ongoing program to collect and analyze product and process data that relate to product quality must be established ( 211.180(e)). The data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products. The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the critical quality attributes are being controlled throughout the process. We recommend that a statistician or person with adequate training in statistical process control techniques develop the data collection plan and statistical methods and procedures used in measuring and evaluating process stability and process capability. Procedures should describe how trending and calculations are to be performed. Procedures should guard against overreaction to individual events as well as against failure to detect process drift. Production data should be collected to evaluate process stability and capability. The quality unit should review this information. If done properly, these efforts can identify variability in the process and/ or product; this information can be used to alert the manufacturer that the process should be improved. Good process design and development should anticipate significant sources of variability and establish appropriate detection, control, and/or mitigation strategies, as well as appropriate alert and action limits. However, a process
knowledge and information gained from the design stage through the process qualification stage. Include all appropriate department and quality unit review and approvals. 3. Stage 3 Continued Process Verification The goal of the third validation stage is to continually assure that the process remains in a state of control (the validated state) during commercial manufacture. A system or systems for detecting unplanned departures from the process as designed is essential to accomplish this goal. Adherence to the CGMP requirements, specifically including the collection and evaluation of information and data about the performance of the process (see below), will allow detection of process drift. The evaluation should determine whether action must be taken to prevent the process from drifting out of control ( 211.180(e)). An ongoing program to collect and analyze product and process data that relate to product quality must be established ( 211.180(e)). The data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products. The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the critical quality attributes are being controlled throughout the process. We recommend that a statistician or person with adequate training in statistical process control techniques develop the data collection plan and statistical methods and procedures used in measuring and evaluating process stability and process capability. Procedures should describe how trending and calculations are to be performed. Procedures should guard against overreaction to individual events as well as against failure to detect process drift. Production data should be collected to evaluate process stability and capability. The quality unit should review this information. If done properly, these efforts can identify variability in the process and/ or product; this information can be used to alert the manufacturer that the process should be improved. Good process design and development should anticipate significant sources of variability and establish appropriate detection, control, and/or mitigation strategies, as well as appropriate alert and action limits. However, a process
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is likely to encounter sources of variation that were not previously detected or to which the process was not previously exposed. Many tools and techniques, some statistical and others more qualitative, can be used to detect variation, characterize it, and determine the root cause. We recommend that the manufacturer use quantitative, statistical methods whenever feasible. We also recommend that it scrutinize intra-batch as well as inter-batch variation as part of a comprehensive continued process verification program. We recommend continued monitoring and/or sampling at the level established during the process qualification stage until sufficient data is available to generate significant variability estimates. Once the variability is known, sampling and/or monitoring should be adjusted to a statistically appropriate and representative level. Process variability should be periodically assessed and sampling and/or monitoring adjusted accordingly. Variation can also be detected by the timely assessment of defect complaints, out-of-specification findings, process deviation reports, process yield variations, batch records, incoming raw material records, and adverse event reports. Production line operators and quality unit staff should be encouraged to provide feedback on process performance. Operator errors should also be tracked to measure the quality of the training program; to identify operator performance issues; and to look for potential batch record, procedural, and/or process improvements that could help to reduce operator error. We recommend that the quality unit meet periodically with production staff to evaluate data, discuss possible trends or drifts in the process, and coordinate any correction or follow-up actions by production. Data gathered during this stage might suggest ways to improve and/or optimize the process by altering some aspect of the process or product such as the operating conditions (ranges and set-points), process controls, component, or in-process material characteristics. A description of the planned change, a well-justified rationale for the change, an implementation plan, and quality unit approval before implementation must be documented (21 CFR 211.100). Depending on the significance to product quality, modifications may warrant performing additional process design and process qualification activities.13
is likely to encounter sources of variation that were not previously detected or to which the process was not previously exposed. Many tools and techniques, some statistical and others more qualitative, can be used to detect variation, characterize it, and determine the root cause. We recommend that the manufacturer use quantitative, statistical methods whenever feasible. We also recommend that it scrutinize intra-batch as well as inter-batch variation as part of a comprehensive continued process verification program. We recommend continued monitoring and/or sampling at the level established during the process qualification stage until sufficient data is available to generate significant variability estimates. Once the variability is known, sampling and/or monitoring should be adjusted to a statistically appropriate and representative level. Process variability should be periodically assessed and sampling and/or monitoring adjusted accordingly. Variation can also be detected by the timely assessment of defect complaints, out-of-specification findings, process deviation reports, process yield variations, batch records, incoming raw material records, and adverse event reports. Production line operators and quality unit staff should be encouraged to provide feedback on process performance. Operator errors should also be tracked to measure the quality of the training program; to identify operator performance issues; and to look for potential batch record, procedural, and/or process improvements that could help to reduce operator error. We recommend that the quality unit meet periodically with production staff to evaluate data, discuss possible trends or drifts in the process, and coordinate any correction or follow-up actions by production. Data gathered during this stage might suggest ways to improve and/or optimize the process by altering some aspect of the process or product such as the operating conditions (ranges and set-points), process controls, component, or in-process material characteristics. A description of the planned change, a well-justified rationale for the change, an implementation plan, and quality unit approval before implementation must be documented (21 CFR 211.100). Depending on the significance to product quality, modifications may warrant performing additional process design and process qualification activities.13
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Maintenance of the facility, utilities, and equipment is another important aspect of ensuring that a process remains in control. Once established, qualification status must be maintained through routine monitoring, maintenance, and calibration procedures and schedules (21 CFR part 211, subparts C and D). The data should be assessed periodically to determine whether re-qualification should be performed and the extent of that requalification. Maintenance and calibration frequency should be adjusted based on feedback from these activities. V. CONCURRENT RELEASE OF PERFORMANCE QUALIFICATION BATCHES In most cases, the PQ protocol needs to be completed before the commercial distribution of a product. In special situations, the PQ protocol can be designed to release a PQ batch for distribution before completion of the protocol. The conclusions about the manufacturing process should be made when the protocol is completed and the data is fully evaluated. FDA expects that concurrent release will be used rarely. Concurrent release might be appropriate for processes used infrequently because of limited demand for the product (e.g., orphan drugs), processes with necessarily low production volume per batch (e.g., radiopharmaceuticals, including positron emission tomography drugs), and processes manufacturing medically necessary drugs to alleviate a short supply, which should be coordinated with the Agency. When warranted and used, concurrent release should be accompanied by a system for careful oversight of the distributed batch to facilitate rapid customer feedback. For example, customer complaints and defect reports should be rapidly assessed to determine root cause and whether the process should be improved or changed. We recommend that each batch in a concurrent release program also undergo stability testing and that this test data be promptly evaluated to ensure rapid detection and correction of any problems. VI. DOCUMENTATION Documentation at each stage of the process validation lifecycle is essential for effective communication in complex, lengthy, and multidisciplinary projects. Documentation is important so that knowledge gained about a
Maintenance of the facility, utilities, and equipment is another important aspect of ensuring that a process remains in control. Once established, qualification status must be maintained through routine monitoring, maintenance, and calibration procedures and schedules (21 CFR part 211, subparts C and D). The data should be assessed periodically to determine whether re-qualification should be performed and the extent of that requalification. Maintenance and calibration frequency should be adjusted based on feedback from these activities. V. CONCURRENT RELEASE OF PERFORMANCE QUALIFICATION BATCHES In most cases, the PQ protocol needs to be completed before the commercial distribution of a product. In special situations, the PQ protocol can be designed to release a PQ batch for distribution before completion of the protocol. The conclusions about the manufacturing process should be made when the protocol is completed and the data is fully evaluated. FDA expects that concurrent release will be used rarely. Concurrent release might be appropriate for processes used infrequently because of limited demand for the product (e.g., orphan drugs), processes with necessarily low production volume per batch (e.g., radiopharmaceuticals, including positron emission tomography drugs), and processes manufacturing medically necessary drugs to alleviate a short supply, which should be coordinated with the Agency. When warranted and used, concurrent release should be accompanied by a system for careful oversight of the distributed batch to facilitate rapid customer feedback. For example, customer complaints and defect reports should be rapidly assessed to determine root cause and whether the process should be improved or changed. We recommend that each batch in a concurrent release program also undergo stability testing and that this test data be promptly evaluated to ensure rapid detection and correction of any problems. VI. DOCUMENTATION Documentation at each stage of the process validation lifecycle is essential for effective communication in complex, lengthy, and multidisciplinary projects. Documentation is important so that knowledge gained about a
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product and process is accessible and comprehensible to others involved in each stage of the lifecycle. In addition to being a fundamental tenet of following the scientific method, information transparency and accessibility are essential so that organizational units responsible and accountable for the process can make informed, science-based decisions that ultimately support the release of a product to commerce. The degree and type of documentation required by CGMP is greatest during stage 2, process qualification, and stage 3, continued process verification. Studies during these stages must conform to CGMPs and must be approved by the quality unit in accordance with the regulations (see 21 CFR 211.22 and 211.100). Viral and impurity clearance studies, even when performed at small scale, also require full quality unit oversight as is necessary during routine commercial production. CGMP documents for commercial manufacturing (i.e., the initial commercial master batch production and control record (21 CFR 211.186) and supporting procedures) are key outputs of stage 1, process design. We recommend that firms diagram the process flow for the full-scale process. Process flow diagrams should describe each unit operation, its placement in the overall process, monitoring and control points, and the component, as well as other processing material inputs (e.g., processing aids) and expected outputs (i.e., in-process materials and finished product). It is also useful to generate and preserve process flow diagrams of the various scales as the process design progresses to facilitate comparison and decision making about their comparability. VII. ANALYTICAL METHODOLOGY Process knowledge is dependent on accurate and precise measuring techniques that are used to test and examine the quality of drug components, in-process materials, and finished products. For data to have value in predicting process outcomes, it is essential that the analytical tests be scientifically sound (as required under 21 CFR 211.160). While validated analytical methods are not required during product- and processdevelopment activities, methods should be scientifically sound (e.g., specific, sensitive, and accurate), suitable, and reliable for the specified purpose. There should be assurance of proper equipment function for laboratory experiments.Procedures for analytical method and equipment maintenance, documentation practices, and calibration practices supporting
product and process is accessible and comprehensible to others involved in each stage of the lifecycle. In addition to being a fundamental tenet of following the scientific method, information transparency and accessibility are essential so that organizational units responsible and accountable for the process can make informed, science-based decisions that ultimately support the release of a product to commerce. The degree and type of documentation required by CGMP is greatest during stage 2, process qualification, and stage 3, continued process verification. Studies during these stages must conform to CGMPs and must be approved by the quality unit in accordance with the regulations (see 21 CFR 211.22 and 211.100). Viral and impurity clearance studies, even when performed at small scale, also require full quality unit oversight as is necessary during routine commercial production. CGMP documents for commercial manufacturing (i.e., the initial commercial master batch production and control record (21 CFR 211.186) and supporting procedures) are key outputs of stage 1, process design. We recommend that firms diagram the process flow for the full-scale process. Process flow diagrams should describe each unit operation, its placement in the overall process, monitoring and control points, and the component, as well as other processing material inputs (e.g., processing aids) and expected outputs (i.e., in-process materials and finished product). It is also useful to generate and preserve process flow diagrams of the various scales as the process design progresses to facilitate comparison and decision making about their comparability. VII. ANALYTICAL METHODOLOGY Process knowledge is dependent on accurate and precise measuring techniques that are used to test and examine the quality of drug components, in-process materials, and finished products. For data to have value in predicting process outcomes, it is essential that the analytical tests be scientifically sound (as required under 21 CFR 211.160). While validated analytical methods are not required during product- and processdevelopment activities, methods should be scientifically sound (e.g., specific, sensitive, and accurate), suitable, and reliable for the specified purpose. There should be assurance of proper equipment function for laboratory experiments.Procedures for analytical method and equipment maintenance, documentation practices, and calibration practices supporting
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process-development efforts should be documented or described. Analytical methods supporting clinical supply production, particularly stage 2 and 3 studies, must follow appropriate CGMPs in parts 210 and 211. REFERENCES FDA, 1987 (CDER, CBER, and Center for Devices and Radiological Health (CDRH)), Guideline on General Principles of Process Validation, guidance for industry, May 1987. FDA, 2002 (CBER), Validation of Procedures for Processing of Human Tissues Intended for Transplantation, guidance for industry, May 2002. FDA, 2004 (CDER, CVM, and ORA), PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, guidance for industry, September 2004. FDA, 2006 (CDER, CBER, CVM, and ORA), Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, guidance for industry, September 2006. FDA/Global Harmonization Task Force (GHTF; medical devices), 2004, Quality Management Systems Process Validation, edition 2, guidance, January 2004. FDA/ICH, 2001 (CDER and CBER), Q7A Good Manufacturing Practice, Guidance for Active Pharmaceutical Ingredients, ICH guidance for industry, August 2001. FDA/ICH, 2006 (CDER and CBER), Q8A Pharmaceutical Development, ICH guidance for industry, May 2006. FDA/ICH, 2006 (CDER and CBER), Q9A Quality Risk Management, ICH guidance for industry, June 2006. FDA/ICH (CDER and CBER) Q10 Quality Systems, ICH draft guidance for industry, May 2007 (when finalized, this guidance will convey FDAs current thinking on this topic). Footnotes
1
process-development efforts should be documented or described. Analytical methods supporting clinical supply production, particularly stage 2 and 3 studies, must follow appropriate CGMPs in parts 210 and 211. REFERENCES FDA, 1987 (CDER, CBER, and Center for Devices and Radiological Health (CDRH)), Guideline on General Principles of Process Validation, guidance for industry, May 1987. FDA, 2002 (CBER), Validation of Procedures for Processing of Human Tissues Intended for Transplantation, guidance for industry, May 2002. FDA, 2004 (CDER, CVM, and ORA), PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, guidance for industry, September 2004. FDA, 2006 (CDER, CBER, CVM, and ORA), Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, guidance for industry, September 2006. FDA/Global Harmonization Task Force (GHTF; medical devices), 2004, Quality Management Systems Process Validation, edition 2, guidance, January 2004. FDA/ICH, 2001 (CDER and CBER), Q7A Good Manufacturing Practice, Guidance for Active Pharmaceutical Ingredients, ICH guidance for industry, August 2001. FDA/ICH, 2006 (CDER and CBER), Q8A Pharmaceutical Development, ICH guidance for industry, May 2006. FDA/ICH, 2006 (CDER and CBER), Q9A Quality Risk Management, ICH guidance for industry, June 2006. FDA/ICH (CDER and CBER) Q10 Quality Systems, ICH draft guidance for industry, May 2007 (when finalized, this guidance will convey FDAs current thinking on this topic). Footnotes This guidance has been prepared by the Division of Manufacturing and Product Quality, Center for Drug Evaluation and Research (CDER), in cooperation with the Center for Biologics Evaluation and Research (CBER) and the Center for Veterinary Medicine (CVM) at the Food and
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This guidance has been prepared by the Division of Manufacturing and Product Quality, Center for Drug Evaluation and Research (CDER), in cooperation with the Center for Biologics Evaluation and Research (CBER) and the Center for Veterinary Medicine (CVM) at the Food and
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Drug Administration. FDAs Office of Regulatory Affairs (ORA) also contributed significantly to the development of this guidance.
2
Drug Administration. FDAs Office of Regulatory Affairs (ORA) also contributed significantly to the development of this guidance.
2
See the FDA/International Conference on Harmonisation (ICH) guidances for industry: Q8 Pharmaceutical Development, Q9 Quality Risk Management, and when finalized, Q10 Pharmaceutical Quality System (a notice of availability for the May 2007 ICH draft guidance, Q10 Pharmaceutical Quality System, published in the Federal Register on July 13, 2007 (72 FR 38604)). We update guidance documents periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page at http://www.fda.gov/cder/guidance/index.htm, the CBER guidance page at http://www.fda.gov/cber/guidelines.htm, or the CVM guidance page at http://www.fda.gov/cvm/Guidance/published.htm.
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See the FDA/International Conference on Harmonisation (ICH) guidances for industry: Q8 Pharmaceutical Development, Q9 Quality Risk Management, and when finalized, Q10 Pharmaceutical Quality System (a notice of availability for the May 2007 ICH draft guidance, Q10 Pharmaceutical Quality System, published in the Federal Register on July 13, 2007 (72 FR 38604)). We update guidance documents periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page at http://www.fda.gov/cder/guidance/index.htm, the CBER guidance page at http://www.fda.gov/cber/guidelines.htm, or the CVM guidance page at http://www.fda.gov/cvm/Guidance/published.htm.
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Separate current good manufacturing practice (CGMP) regulations for drug components such as APIs (drug substances) and intermediates have not published as of the date of this guidance, but these components are subject to the statutory CGMP requirements of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 351(a)(2)(B)). Process validation for APIs is discussed in the FDA/ICH guidance for industry, Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH Q7A), available on the Internet at http://www.fda.gov/cder/guidance/index.htm. Section XII of ICH Q7A describes in detail the principles to be followed in validating API processes.
Separate current good manufacturing practice (CGMP) regulations for drug components such as APIs (drug substances) and intermediates have not published as of the date of this guidance, but these components are subject to the statutory CGMP requirements of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 351(a)(2)(B)). Process validation for APIs is discussed in the FDA/ICH guidance for industry, Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH Q7A), available on the Internet at http://www.fda.gov/cder/guidance/index.htm. Section XII of ICH Q7A describes in detail the principles to be followed in validating API processes.
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See the FDA guidance for industry, Validation of Procedures for Processing of Human Tissues Intended for Transplantation, available on the Internet at http://www.fda.gov/cber/guidelines.htm. The 1987 guidance was prepared by a working group that included representation from the Center for Devices and Radiological Health (CDRH). Since that time, CDRH elected to publish its own process validation guidance through the Global Harmonization Task Force. The principles and recommendations in that document, Quality Management Systems Process Validation, edition 2 (available on the Internet at http:/ /www.ghtf.org/sg3/sg3-final.html), are also useful to consider for drug manufacturing processes.
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See the FDA guidance for industry, Validation of Procedures for Processing of Human Tissues Intended for Transplantation, available on the Internet at http://www.fda.gov/cber/guidelines.htm.
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The 1987 guidance was prepared by a working group that included representation from the Center for Devices and Radiological Health (CDRH). Since that time, CDRH elected to publish its own process validation guidance through the Global Harmonization Task Force. The principles and recommendations in that document, Quality Management Systems Process Validation, edition 2 (available on the Internet at http:/ /www.ghtf.org/sg3/sg3-final.html), are also useful to consider for drug manufacturing processes.
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The statute and regulations described in section III of this guidance explain the requirement that the methods and facilities used for the
The statute and regulations described in section III of this guidance explain the requirement that the methods and facilities used for the
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manufacturing of drugs be operated and maintained under control sufficient to assure that the identity, strength, purity, and quality of a drug are as they purport or are represented to possess. In the Federal Register of September 29, 1978 (43 FR 45013 at 45052), FDA published a final rule on Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding (available on the Internet at http://www.fda.gov/cder/dmpq/preamble.txt). In the preamble of the final rule, the Agency further explains this principle.
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manufacturing of drugs be operated and maintained under control sufficient to assure that the identity, strength, purity, and quality of a drug are as they purport or are represented to possess. In the Federal Register of September 29, 1978 (43 FR 45013 at 45052), FDA published a final rule on Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding (available on the Internet at http://www.fda.gov/cder/dmpq/preamble.txt). In the preamble of the final rule, the Agency further explains this principle.
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This concept is discussed in more detail in FDAs guidance for industry, Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, available on the Internet at http:// www.fda.gov/cder/guidance/index.htm. A notice of availability for this draft ICH guidance published in the Federal Register on July 13, 2007 (72 FR 38604). When finalized, this guidance will represent FDAs current thinking on this topic. Component means any ingredient [raw material] intended for use in the manufacture of a drug product, including those that may not appear in such drug product (21 CFR 210.3(b)(3)).
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This concept is discussed in more detail in FDAs guidance for industry, Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, available on the Internet at http:// www.fda.gov/cder/guidance/index.htm.
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A notice of availability for this draft ICH guidance published in the Federal Register on July 13, 2007 (72 FR 38604). When finalized, this guidance will represent FDAs current thinking on this topic.
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Component means any ingredient [raw material] intended for use in the manufacture of a drug product, including those that may not appear in such drug product (21 CFR 210.3(b)(3)). As discussed in section III of this guidance, process validation (including process qualification) is legally enforceable under section 501(a)(2)(B) of the Act. FDA regulations require that process validation procedures be established and followed (21 CFR 211.100) before a batch can be distributed (21 CFR 211.22 and 211.165). See section III of this guidance, Statutory and Regulatory Requirements for Process Validation. Certain manufacturing changes may call for a formal notification to the Agency before implementation, as directed by existing regulations and filing guidance (i.e., documents that describe procedures for filing information to an application).
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As discussed in section III of this guidance, process validation (including process qualification) is legally enforceable under section 501(a)(2)(B) of the Act. FDA regulations require that process validation procedures be established and followed (21 CFR 211.100) before a batch can be distributed (21 CFR 211.22 and 211.165). See section III of this guidance, Statutory and Regulatory Requirements for Process Validation. Certain manufacturing changes may call for a formal notification to the Agency before implementation, as directed by existing regulations and filing guidance (i.e., documents that describe procedures for filing information to an application).
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SEC. 490.100
SEC. 490.100
Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval
CPG 7132c.08
Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval
CPG 7132c.08
NOTE: This compliance policy guide (CPG) also applies to pre-market approval applications submitted to the Center for Veterinary Medicine (NADAs or ANADAs). The CPG reference may be found at Sec. 638.100 (7125.38). Issued: 08/30/1993 Revised: 03/12/2004 This guidance document represents the Food and Drug Administrations (FDA) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute and regulations.
NOTE: This compliance policy guide (CPG) also applies to pre-market approval applications submitted to the Center for Veterinary Medicine (NADAs or ANADAs). The CPG reference may be found at Sec. 638.100 (7125.38). Issued: 08/30/1993 Revised: 03/12/2004 This guidance document represents the Food and Drug Administrations (FDA) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute and regulations.
BACKGROUND
This Compliance Policy Guide (CPG) explains the Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), and Center for Veterinary Medicine (CVM) enforcement policy regarding the timing of the completion of certain process validation activities for the products covered by this CPG. This policy guide covers sterile as well as non-sterile manufacturing processes, but it does not address the methods and controls designed to ensure product sterility (e.g., aseptic fill validation). New drug applications for sterile products include information about the intended sterilization or aseptic processing procedures. The Centers evaluate this information as part of the application review process. CDER, CBER, and CVM may also issue assignments to district offices to audit and assess the filed information as well as any additional information that demonstrates the adequacy of the sterile process. This CPG does not address products approved by a Biologics License Application (BLA) or recombinant protein drug products submitted in a New Drug Application (NDA).
BACKGROUND
This Compliance Policy Guide (CPG) explains the Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), and Center for Veterinary Medicine (CVM) enforcement policy regarding the timing of the completion of certain process validation activities for the products covered by this CPG. This policy guide covers sterile as well as non-sterile manufacturing processes, but it does not address the methods and controls designed to ensure product sterility (e.g., aseptic fill validation). New drug applications for sterile products include information about the intended sterilization or aseptic processing procedures. The Centers evaluate this information as part of the application review process. CDER, CBER, and CVM may also issue assignments to district offices to audit and assess the filed information as well as any additional information that demonstrates the adequacy of the sterile process. This CPG does not address products approved by a Biologics License Application (BLA) or recombinant protein drug products submitted in a New Drug Application (NDA).
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Validation of manufacturing processes is a requirement of the Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals (21 CFR 211.100 and 211.110), and is considered an enforceable element of current good manufacturing practice for active pharmaceutical ingredients (APIs) under the broader statutory CGMP provisions of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act. A validated manufacturing process has a high level of scientific assurance that it will reliably produce acceptable product. The proof of validation is obtained through rational experimental design and the evaluation of data, preferably beginning from the process development phase and continuing through the commercial production phase. Refer also to the Guideline of General Principles of Process Validation (May 1987, originally published by CDER, CBER, and CDRH and presently recognized by CDER, CBER, and CVM). (Note: The guideline is under revision as of the date of this CPG.) Before commercial distribution begins, a manufacturer is expected to have accumulated enough data and knowledge about the commercial production process to support post-approval product distribution. Normally, this is achieved after satisfactory product and process development, scale-up studies, equipment and system qualification, and the successful completion of the initial conformance batches. Conformance batches (sometimes referred to as validation batches and demonstration batches) are prepared to demonstrate that, under normal conditions and defined ranges of operating parameters, the commercial scale process appears to make acceptable product. Prior to the manufacture of the conformance batches the manufacturer should have identified and controlled all critical sources of variability.
Validation of manufacturing processes is a requirement of the Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals (21 CFR 211.100 and 211.110), and is considered an enforceable element of current good manufacturing practice for active pharmaceutical ingredients (APIs) under the broader statutory CGMP provisions of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act. A validated manufacturing process has a high level of scientific assurance that it will reliably produce acceptable product. The proof of validation is obtained through rational experimental design and the evaluation of data, preferably beginning from the process development phase and continuing through the commercial production phase. Refer also to the Guideline of General Principles of Process Validation (May 1987, originally published by CDER, CBER, and CDRH and presently recognized by CDER, CBER, and CVM). (Note: The guideline is under revision as of the date of this CPG.) Before commercial distribution begins, a manufacturer is expected to have accumulated enough data and knowledge about the commercial production process to support post-approval product distribution. Normally, this is achieved after satisfactory product and process development, scale-up studies, equipment and system qualification, and the successful completion of the initial conformance batches. Conformance batches (sometimes referred to as validation batches and demonstration batches) are prepared to demonstrate that, under normal conditions and defined ranges of operating parameters, the commercial scale process appears to make acceptable product. Prior to the manufacture of the conformance batches the manufacturer should have identified and controlled all critical sources of variability.
POLICY
Conformance batches New drug applications may be approved by the Center prior to the completion of the initial conformance batch phase of process validation. The manufacture of the initial conformance batches should be successfully completed prior to commercial distribution, except as identified below.
POLICY
Conformance batches New drug applications may be approved by the Center prior to the completion of the initial conformance batch phase of process validation. The manufacture of the initial conformance batches should be successfully completed prior to commercial distribution, except as identified below.
process validation guidance: CPG 7132c.08 (revised: 2004)
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Inspection of validation activities during a pre-approval inspection: If a pre-approval inspection is performed, the inspection team should audit and assess any available process validation protocols, activities, data, and information, whether or not completed, and report to the firm any deficiencies. The district should recommend withholding approval of an application if any completed validation efforts include data of questionable integrity or demonstrate that the process is not under control and the firm has not committed to making appropriate changes. Refer also to the Center pre-approval inspection compliance programs for additional guidance. If during a pre-approval inspection, process validation activities are found significantly deficient for an approved product made by a process similar to that of the subject of the pre-approval inspection and for which a warning letter or regulatory action will be proposed, the district should recommend withholding approval of the application. Inspection of validation activities during a post-approval inspection: If the initial conformance batch validation activities for a particular approved product were not substantially inspected and found satisfactory during the pre-approval inspection, the district should cover this activity for the approved application or a substantially similar process/product during the next routine CGMP inspection (see Compliance Programs 7356.002 for human drugs, and 7371.001 for animal drugs). The district should inspect the firms validation activities for the new product within the first year of manufacture at commercial scale (if not inspected during the pre-approval inspection) if any of the following conditions apply: O the new drug is the first produced by the manufacturing site; O the firm has had previous problems validating a similar process for another product; O the product is manufactured by equipment or process that is substantially different from equipment or processes previously used by this firm; or, O the product is made by a process involving inherently variable unit operations or complex operations or procedures (see Compliance
Inspection of validation activities during a pre-approval inspection: If a pre-approval inspection is performed, the inspection team should audit and assess any available process validation protocols, activities, data, and information, whether or not completed, and report to the firm any deficiencies. The district should recommend withholding approval of an application if any completed validation efforts include data of questionable integrity or demonstrate that the process is not under control and the firm has not committed to making appropriate changes. Refer also to the Center pre-approval inspection compliance programs for additional guidance. If during a pre-approval inspection, process validation activities are found significantly deficient for an approved product made by a process similar to that of the subject of the pre-approval inspection and for which a warning letter or regulatory action will be proposed, the district should recommend withholding approval of the application. Inspection of validation activities during a post-approval inspection: If the initial conformance batch validation activities for a particular approved product were not substantially inspected and found satisfactory during the pre-approval inspection, the district should cover this activity for the approved application or a substantially similar process/product during the next routine CGMP inspection (see Compliance Programs 7356.002 for human drugs, and 7371.001 for animal drugs). The district should inspect the firms validation activities for the new product within the first year of manufacture at commercial scale (if not inspected during the pre-approval inspection) if any of the following conditions apply: O the new drug is the first produced by the manufacturing site; O the firm has had previous problems validating a similar process for another product; O the product is manufactured by equipment or process that is substantially different from equipment or processes previously used by this firm; or, O the product is made by a process involving inherently variable unit operations or complex operations or procedures (see Compliance
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Programs 7356.002 for human drugs, and 7371.001 for animal drugs; and consult further with the Centers reviewing office for the product being inspected and/or the Office of Compliance subject contact for further guidance). If none of the above conditions apply, the district should evaluate validation activities for new products during the next routine CGMP program inspection (7356.002). Alternatively, for sites with a history of successful validation efforts for related products made by similar processes the district may request the process validation protocol and report to be sent to the district office for audit and assessment. Based on the review of this information, additional on-site inspection, evaluation, and documentation of the information received may, or may not be conducted at the districts discretion unless directed otherwise. If a firms validation activities for the new product are found to have significant deficiencies (e.g., the initial conformance batch phase was not completed, the protocol was not followed or is inadequate, or validation data indicates process is not adequate), and one or more batches have been distributed, the district office should recommend regulatory action. Seizure of distributed batches should be considered when there are significant deficiencies with validation or the evidence demonstrates the product does not comply with specifications. Injunction should be considered when there are significant deficiencies or data demonstrating the process is not capable of producing product meeting the established specifications. Completion of initial conformance batch manufacture prior to commercial distribution: For some products, the completion of the initial conformance batch phase of process validation before the distribution of any one batch would require the manufacture of unneeded batches (e.g., certain orphan drug products), which would not be in the interest of public health. In addition, the completion of multiple batches before first distribution may also be impractical for a product with a very short shelf-life or that is intended for limited use (e.g., some radiopharmaceuticals). Therefore, the need to manufacture multiple conformance batches in advance of initial product distribution may not be needed under these circumstances. In such cases,
Programs 7356.002 for human drugs, and 7371.001 for animal drugs; and consult further with the Centers reviewing office for the product being inspected and/or the Office of Compliance subject contact for further guidance). If none of the above conditions apply, the district should evaluate validation activities for new products during the next routine CGMP program inspection (7356.002). Alternatively, for sites with a history of successful validation efforts for related products made by similar processes the district may request the process validation protocol and report to be sent to the district office for audit and assessment. Based on the review of this information, additional on-site inspection, evaluation, and documentation of the information received may, or may not be conducted at the districts discretion unless directed otherwise. If a firms validation activities for the new product are found to have significant deficiencies (e.g., the initial conformance batch phase was not completed, the protocol was not followed or is inadequate, or validation data indicates process is not adequate), and one or more batches have been distributed, the district office should recommend regulatory action. Seizure of distributed batches should be considered when there are significant deficiencies with validation or the evidence demonstrates the product does not comply with specifications. Injunction should be considered when there are significant deficiencies or data demonstrating the process is not capable of producing product meeting the established specifications. Completion of initial conformance batch manufacture prior to commercial distribution: For some products, the completion of the initial conformance batch phase of process validation before the distribution of any one batch would require the manufacture of unneeded batches (e.g., certain orphan drug products), which would not be in the interest of public health. In addition, the completion of multiple batches before first distribution may also be impractical for a product with a very short shelf-life or that is intended for limited use (e.g., some radiopharmaceuticals). Therefore, the need to manufacture multiple conformance batches in advance of initial product distribution may not be needed under these circumstances. In such cases,
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product distribution may have occurred concurrently with the release (or approval for release) of each conformance batch. The agencys evaluation of a firms decision to release batches concurrent with the manufacture of the initial conformance batches should include review and/or audit and assessment of: O the firms basis for justifying the distribution of individual batches prior to completion of the initial conformance batches (to include review of the product/process development effort); O the firms protocol/plan and available data to verify that there are adequate batch controls and testing prior to release for distribution of each batch, and provides for adequate and timely assessment of the validity of the process once all initial conformance batches have been manufactured; and, O the firms program for monitoring distributed batches and provisions for a rapid response to information suggesting the process is not under control (e.g., subsequent batch failures, production problems related to process design or equipment performance, complaints). Advanced pharmaceutical science and engineering principles and manufacturing control technologies can provide a high level of process understanding and control capability. Use of these advanced principles and control technologies can provide a high assurance of quality by continuously monitoring, evaluating, and adjusting every batch using validated in-process measurements, tests, controls, and process endpoints. For manufacturing processes developed and controlled in such a manner, it may not be necessary for a firm to manufacture multiple conformance batches prior to initial distribution. Agency staff (field and Center) should discuss the need for conformance batches prior to distribution with the designated agency contacts when inspecting firms employing these advanced pharmaceutical science and engineering principles and control technologies. The district should consult with the appropriate agency contact before initiating regulatory action based on insufficient validation under the above circumstances.
product distribution may have occurred concurrently with the release (or approval for release) of each conformance batch. The agencys evaluation of a firms decision to release batches concurrent with the manufacture of the initial conformance batches should include review and/or audit and assessment of: O the firms basis for justifying the distribution of individual batches prior to completion of the initial conformance batches (to include review of the product/process development effort); O the firms protocol/plan and available data to verify that there are adequate batch controls and testing prior to release for distribution of each batch, and provides for adequate and timely assessment of the validity of the process once all initial conformance batches have been manufactured; and, O the firms program for monitoring distributed batches and provisions for a rapid response to information suggesting the process is not under control (e.g., subsequent batch failures, production problems related to process design or equipment performance, complaints). Advanced pharmaceutical science and engineering principles and manufacturing control technologies can provide a high level of process understanding and control capability. Use of these advanced principles and control technologies can provide a high assurance of quality by continuously monitoring, evaluating, and adjusting every batch using validated in-process measurements, tests, controls, and process endpoints. For manufacturing processes developed and controlled in such a manner, it may not be necessary for a firm to manufacture multiple conformance batches prior to initial distribution. Agency staff (field and Center) should discuss the need for conformance batches prior to distribution with the designated agency contacts when inspecting firms employing these advanced pharmaceutical science and engineering principles and control technologies. The district should consult with the appropriate agency contact before initiating regulatory action based on insufficient validation under the above circumstances.
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Active Pharmaceutical Ingredients: Under the broader statutory CGMP provisions of section 501(a)(2)(B) of the Act, process validation, including the manufacture of initial conformance batches, is also expected for Active Pharmaceutical Ingredients (APIs), but the specific expectations differ somewhat from those required for dosage form products. Refer to the Guidance for Industry, Q7A, GMP Guidance for Active Pharmaceutical Ingredients, issued August, 2001, for details. If the API for an application under review is already used in other approved or marketed dosage form products, and is being made by substantially the same process and scale as for the application under consideration for approval, the inspection should cover full process validation data and activities (including conformance batches), unless covered during a previous inspection of the API manufacturer. If validation is covered and significant deficiencies are found, the district is to recommend withholding approval of the dosage form application and consider proposing action to address the use of that API in other dosage form products. If the API for an application under review is a new molecular entity or is being manufactured by a process substantially new in design or scale to the site of manufacture, approval of the dosage form incorporating the API is not to be delayed by the performance of initial conformance batches for the API. However, the inspection team is to audit and assess any available process validation protocols, activities, data, and information whether or not completed, and report to the firm any deficiencies. The district should recommend withholding approval of an application if any completed API validation efforts include data of questionable integrity or demonstrate that the API process is not under control and the firm has not committed to making appropriate changes. Some biotech NDAs include information about the validation of the manufacturing process for the API, and this information is reviewed in conjunction with the other chemistry, manufacturing, and controls information in the application. In these cases, the inspection team should audit the accuracy and completeness of the data and information submitted to the application. Potentially objectionable findings should
Active Pharmaceutical Ingredients: Under the broader statutory CGMP provisions of section 501(a)(2)(B) of the Act, process validation, including the manufacture of initial conformance batches, is also expected for Active Pharmaceutical Ingredients (APIs), but the specific expectations differ somewhat from those required for dosage form products. Refer to the Guidance for Industry, Q7A, GMP Guidance for Active Pharmaceutical Ingredients, issued August, 2001, for details. If the API for an application under review is already used in other approved or marketed dosage form products, and is being made by substantially the same process and scale as for the application under consideration for approval, the inspection should cover full process validation data and activities (including conformance batches), unless covered during a previous inspection of the API manufacturer. If validation is covered and significant deficiencies are found, the district is to recommend withholding approval of the dosage form application and consider proposing action to address the use of that API in other dosage form products. If the API for an application under review is a new molecular entity or is being manufactured by a process substantially new in design or scale to the site of manufacture, approval of the dosage form incorporating the API is not to be delayed by the performance of initial conformance batches for the API. However, the inspection team is to audit and assess any available process validation protocols, activities, data, and information whether or not completed, and report to the firm any deficiencies. The district should recommend withholding approval of an application if any completed API validation efforts include data of questionable integrity or demonstrate that the API process is not under control and the firm has not committed to making appropriate changes. Some biotech NDAs include information about the validation of the manufacturing process for the API, and this information is reviewed in conjunction with the other chemistry, manufacturing, and controls information in the application. In these cases, the inspection team should audit the accuracy and completeness of the data and information submitted to the application. Potentially objectionable findings should
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be handled consistent with the applicable compliance program and include consultation with the Center reviewer and/or compliance officer before making any formal objection to the firm. If during a pre-approval inspection of the API manufacturer, process validation activities are found significantly deficient for an API made by a process similar to that of the API under inspection and for which a warning letter or other regulatory action will be proposed, the district should recommend withholding approval of the dosage form application. The district should also recommend withholding approval if the API firm has not established or is not following an adequate initial conformance batch validation plan/protocol or when the process is not under control as demonstrated by repeated batch failures due to manufacturing process variability. If batches have been distributed, the district should consider recommending an appropriate regulatory action.
be handled consistent with the applicable compliance program and include consultation with the Center reviewer and/or compliance officer before making any formal objection to the firm. If during a pre-approval inspection of the API manufacturer, process validation activities are found significantly deficient for an API made by a process similar to that of the API under inspection and for which a warning letter or other regulatory action will be proposed, the district should recommend withholding approval of the dosage form application. The district should also recommend withholding approval if the API firm has not established or is not following an adequate initial conformance batch validation plan/protocol or when the process is not under control as demonstrated by repeated batch failures due to manufacturing process variability. If batches have been distributed, the district should consider recommending an appropriate regulatory action.
canadian guide - 0029
canadian guide - 0029
validation guidelines for pharmaceutical dosage forms
validation guidelines for pharmaceutical dosage forms
Supersedes: May 1st, 2000 Date issued: August 15, 2004 Date of implementation: October 1st, 2004
Supersedes: May 1st, 2000 Date issued: August 15, 2004 Date of implementation: October 1st, 2004
1.0 Scope This Guidance document has been prepared to provide guidance to the pharmaceutical industry in dealing with validation issues for sterile and non-sterile dosage forms, biologicals, and radiopharmaceuticals. It should be noted that additional guidance related to sterile products and not contained in this document should also be considered. These requirements may be found in the five supplemental process validation guidelines available on the Inspectorates website. The five documents pertain to the following specific processes: Moist Heat Sterilization for Pharmaceuticals Aseptic Processes for Pharmaceuticals Form-Fill-Seal for Pharmaceuticals Irradiation Sterilization for Pharmaceuticals Gaseous Sterilization for Pharmaceuticals It is expected that importers and distributors of drug products have documented evidence that their vendors meet validation requirements. 2.0 Introduction This document provides guidance on issues and topics related to systems, equipment qualification, product and process validation for sterile and non-sterile dosage forms. These topics reflect an area in pharmaceutical, biological, and, radiopharmaceuticals manufacture that is noted as being important by both the Inspectorate and the pharmaceutical industry. These guidelines have been prepared to provide guidance to inspectors, evaluators and the industry in dealing with issues related to validation. Utilization of this information should facilitate compliance with Division 2, Part C of the Regulations to the Food and Drugs Act. It is not intended that the recommendations made in these guidelines become requirements under all circumstances. Information provided in the Interpretation section for limits to be applied in defined circumstances, as well as the number of batches to be utilized for validation studies are for guidance purposes only. Inspectors, evaluators and the industry may consider other alternate means if proposed and documented with appropriate scientific justification.
1.0 Scope This Guidance document has been prepared to provide guidance to the pharmaceutical industry in dealing with validation issues for sterile and non-sterile dosage forms, biologicals, and radiopharmaceuticals. It should be noted that additional guidance related to sterile products and not contained in this document should also be considered. These requirements may be found in the five supplemental process validation guidelines available on the Inspectorates website. The five documents pertain to the following specific processes: Moist Heat Sterilization for Pharmaceuticals Aseptic Processes for Pharmaceuticals Form-Fill-Seal for Pharmaceuticals Irradiation Sterilization for Pharmaceuticals Gaseous Sterilization for Pharmaceuticals It is expected that importers and distributors of drug products have documented evidence that their vendors meet validation requirements. 2.0 Introduction This document provides guidance on issues and topics related to systems, equipment qualification, product and process validation for sterile and non-sterile dosage forms. These topics reflect an area in pharmaceutical, biological, and, radiopharmaceuticals manufacture that is noted as being important by both the Inspectorate and the pharmaceutical industry. These guidelines have been prepared to provide guidance to inspectors, evaluators and the industry in dealing with issues related to validation. Utilization of this information should facilitate compliance with Division 2, Part C of the Regulations to the Food and Drugs Act. It is not intended that the recommendations made in these guidelines become requirements under all circumstances. Information provided in the Interpretation section for limits to be applied in defined circumstances, as well as the number of batches to be utilized for validation studies are for guidance purposes only. Inspectors, evaluators and the industry may consider other alternate means if proposed and documented with appropriate scientific justification.
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3.0 Purpose These guidelines outline the general principles that the Inspectorate considers to be acceptable elements of validation which may be used by fabricators, packagers/labellers for drug products. The Guidelines on Good Manufacturing Practices (GMP), Division 2, Part C of the Food and Drug Regulations require that: all critical production processes be validated validation studies are conducted in accordance with pre-defined protocols. Written reports summarizing recorded results and conclusions are prepared, evaluated, approved and maintained changes to production processes, operating parameters, equipment or materials that may affect product quality and/or the reproducibility of the process are also to be validated prior to implementation. These guidelines are not intended to specify how validation is to be conducted, but are indicators of what is expected to be covered by fabricators, packagers/labellers. The elements of validation presented in these guidelines are not intended to be all-encompassing. The particular requirements of validation may vary according to factors such as the nature of drug products eg. sterile, nonsterile, biologicals, and the complexity of the process. The concepts provided in these guidelines have general applicability and provide an acceptable framework for establishing a comprehensive approach to validation. 4.0 Definitions CHANGE CONTROL (contrle des changements): A written procedure that describes the action to be taken if a change is proposed (a) to facilities, materials, equipment, and/or processes used in the fabrication, packaging, and testing of drugs, or (b) that may affect the operation of the quality or support system. CLEANING VALIDATION (validation des procds de nettoyage): The documented act of demonstrating that cleaning procedures for the equipment used in fabricating/packaging will reduce to an acceptable level all residues
3.0 Purpose These guidelines outline the general principles that the Inspectorate considers to be acceptable elements of validation which may be used by fabricators, packagers/labellers for drug products. The Guidelines on Good Manufacturing Practices (GMP), Division 2, Part C of the Food and Drug Regulations require that: all critical production processes be validated validation studies are conducted in accordance with pre-defined protocols. Written reports summarizing recorded results and conclusions are prepared, evaluated, approved and maintained changes to production processes, operating parameters, equipment or materials that may affect product quality and/or the reproducibility of the process are also to be validated prior to implementation. These guidelines are not intended to specify how validation is to be conducted, but are indicators of what is expected to be covered by fabricators, packagers/labellers. The elements of validation presented in these guidelines are not intended to be all-encompassing. The particular requirements of validation may vary according to factors such as the nature of drug products eg. sterile, nonsterile, biologicals, and the complexity of the process. The concepts provided in these guidelines have general applicability and provide an acceptable framework for establishing a comprehensive approach to validation. 4.0 Definitions CHANGE CONTROL (contrle des changements): A written procedure that describes the action to be taken if a change is proposed (a) to facilities, materials, equipment, and/or processes used in the fabrication, packaging, and testing of drugs, or (b) that may affect the operation of the quality or support system. CLEANING VALIDATION (validation des procds de nettoyage): The documented act of demonstrating that cleaning procedures for the equipment used in fabricating/packaging will reduce to an acceptable level all residues
HPFBI 0029: validation guidelines for pharmaceutical dosage forms (2004)
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(products/cleaning agents) and to demonstrate that routine cleaning and storage of equipment does not allow microbial proliferation. CONCURRENT VALIDATION (validation concomitante): A process where current production batches are used to monitor processing parameters. It gives assurance of the present batch being studied, and offers limited assurance regarding consistency of quality from batch to batch. CRITICAL PROCESS PARAMETER (paramtre critique du procd): A parameter which if not controlled will contribute to the variability of the end product. EQUIPMENT QUALIFICATION (qualification de lquipement): Studies which establish with confidence that the process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. The studies must include equipment specifications, installation qualification, and operational qualification of all major equipment to be used in the manufacture of commercial scale batches. Equipment Qualification should simulate actual production conditions, including worst case/ stressed conditions. INSTALLATION QUALIFICATION (qualification dinstallation): The documented act of demonstrating that process equipment and ancillary systems are appropriately selected and correctly installed. MAJOR EQUIPMENT (quipement principal): A piece of equipment which performs significant processing steps in the sequence of operations required for fabrication/packaging of drug products. Some examples of major equipment include tablet compression machines, mills, blenders, fluid bed dryers, heaters, drying ovens, tablet coaters, encapsulators, fermentors, centrifuges, etc. MASTER PRODUCTION DOCUMENT (document-type de production): A document that includes specifications for raw material, for packaging material and for packaged dosage form, master formula, sampling procedures, and critical processing related SOPs, whether or not these SOPs are specifically referenced in the master formula. MEASURING DEVICES (instruments de mesure): A device used in monitoring or measuring process parameters.
(products/cleaning agents) and to demonstrate that routine cleaning and storage of equipment does not allow microbial proliferation. CONCURRENT VALIDATION (validation concomitante): A process where current production batches are used to monitor processing parameters. It gives assurance of the present batch being studied, and offers limited assurance regarding consistency of quality from batch to batch. CRITICAL PROCESS PARAMETER (paramtre critique du procd): A parameter which if not controlled will contribute to the variability of the end product. EQUIPMENT QUALIFICATION (qualification de lquipement): Studies which establish with confidence that the process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. The studies must include equipment specifications, installation qualification, and operational qualification of all major equipment to be used in the manufacture of commercial scale batches. Equipment Qualification should simulate actual production conditions, including worst case/ stressed conditions. INSTALLATION QUALIFICATION (qualification dinstallation): The documented act of demonstrating that process equipment and ancillary systems are appropriately selected and correctly installed. MAJOR EQUIPMENT (quipement principal): A piece of equipment which performs significant processing steps in the sequence of operations required for fabrication/packaging of drug products. Some examples of major equipment include tablet compression machines, mills, blenders, fluid bed dryers, heaters, drying ovens, tablet coaters, encapsulators, fermentors, centrifuges, etc. MASTER PRODUCTION DOCUMENT (document-type de production): A document that includes specifications for raw material, for packaging material and for packaged dosage form, master formula, sampling procedures, and critical processing related SOPs, whether or not these SOPs are specifically referenced in the master formula. MEASURING DEVICES (instruments de mesure): A device used in monitoring or measuring process parameters.
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OPERATIONAL QUALIFICATION (qualification oprationelle): The documented action of demonstrating that process equipment and ancillary systems work correctly and operate consistently in accordance with established specifications. PROCESS CAPABILITY (capacit du procd): Studies conducted to identify the critical process parameters that yield a resultant quality, and their acceptable specification ranges, based on the established +/- 3 sigma deviations of the process, under stressed conditions but when free of any assignable causes. PROCESS QUALIFICATION (qualification du procd): The phase of validation dealing with sampling and testing at various stages of the manufacturing process to ensure that product specifications are met. PROCESS RE-VALIDATION (revalidation du procd): Required when there is a change in any of the critical process parameters, formulation, primary packaging components, raw material fabricators, major equipment or premises. Failure to meet product and process specifications in sequential batches would also require process re-validation. PROCESS VALIDATION (validation du procd): Establishing documented evidence with a high degree of assurance, that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics. Process validation may take the form of Prospective, Concurrent or Retrospective Validation and Process Qualification or Re-validation. PROSPECTIVE VALIDATION (validation prospective): Conducted prior to the distribution of either a new product or a product made under a modified production process, where the modifications are significant and may affect the products characteristics. It is a pre-planned scientific approach and includes the initial stages of formulation development, process development, setting of process specifications, developing inprocess tests, sampling plans, designing of batch records, defining raw material specifications, completion of pilot runs, transfer of technology from scale-up batches to commercial size batches, listing major process equipment and environmental controls. RETROSPECTIVE VALIDATION (validation rtrospective): Conducted for a product already being marketed, and is based on extensive data
OPERATIONAL QUALIFICATION (qualification oprationelle): The documented action of demonstrating that process equipment and ancillary systems work correctly and operate consistently in accordance with established specifications. PROCESS CAPABILITY (capacit du procd): Studies conducted to identify the critical process parameters that yield a resultant quality, and their acceptable specification ranges, based on the established +/- 3 sigma deviations of the process, under stressed conditions but when free of any assignable causes. PROCESS QUALIFICATION (qualification du procd): The phase of validation dealing with sampling and testing at various stages of the manufacturing process to ensure that product specifications are met. PROCESS RE-VALIDATION (revalidation du procd): Required when there is a change in any of the critical process parameters, formulation, primary packaging components, raw material fabricators, major equipment or premises. Failure to meet product and process specifications in sequential batches would also require process re-validation. PROCESS VALIDATION (validation du procd): Establishing documented evidence with a high degree of assurance, that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics. Process validation may take the form of Prospective, Concurrent or Retrospective Validation and Process Qualification or Re-validation. PROSPECTIVE VALIDATION (validation prospective): Conducted prior to the distribution of either a new product or a product made under a modified production process, where the modifications are significant and may affect the products characteristics. It is a pre-planned scientific approach and includes the initial stages of formulation development, process development, setting of process specifications, developing inprocess tests, sampling plans, designing of batch records, defining raw material specifications, completion of pilot runs, transfer of technology from scale-up batches to commercial size batches, listing major process equipment and environmental controls. RETROSPECTIVE VALIDATION (validation rtrospective): Conducted for a product already being marketed, and is based on extensive data
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accumulated over several lots and over time. Retrospective Validation may be used for older products which were not validated by the fabricator at the time that they were first marketed, and which are now to be validated to conform to the requirements of Division 2, Part C of the Regulations to the Food and Drugs Act. VALIDATION (validation): The documented act of demonstrating that any procedure, process, and activity will consistently lead to the expected results. Includes the qualification of systems and equipment. VALIDATION MASTER PLAN (plan matre de validation): An approved written plan of objectives and actions stating how and when a company will achieve compliance with the GMP requirements regarding validation. VALIDATION PROTOCOL (protocole de validation): A written plan of actions stating how process validation will be conducted; it will specify who will conduct the various tasks and define testing parameters; sampling plans, testing methods and specifications; will specify product characteristics, and equipment to be used. It must specify the minimum number of batches to be used for validation studies; it must specify the acceptance criteria and who will sign/approve/ disapprove the conclusions derived from such a scientific study. VALIDATION TEAM (quipe de validation): A multi-disciplinary team of personnel primarily responsible for conducting and/or supervising validation studies. Such studies may be conducted by person(s) qualified by training and experience in a relevant discipline. WORST CASE CONDITION (condition de la pire ventualit): The highest and /or lowest value of a given parameter actually evaluated in the validation exercise. 5.0 Phases of Validation The activities relating to validation studies may be classified into three phases: Phase 1: Pre-Validation Phase or the Qualification Phase, which covers all activities relating to product research and development, formulation, pilot batch studies, scale-up studies, transfer of technology to commercial scale
accumulated over several lots and over time. Retrospective Validation may be used for older products which were not validated by the fabricator at the time that they were first marketed, and which are now to be validated to conform to the requirements of Division 2, Part C of the Regulations to the Food and Drugs Act. VALIDATION (validation): The documented act of demonstrating that any procedure, process, and activity will consistently lead to the expected results. Includes the qualification of systems and equipment. VALIDATION MASTER PLAN (plan matre de validation): An approved written plan of objectives and actions stating how and when a company will achieve compliance with the GMP requirements regarding validation. VALIDATION PROTOCOL (protocole de validation): A written plan of actions stating how process validation will be conducted; it will specify who will conduct the various tasks and define testing parameters; sampling plans, testing methods and specifications; will specify product characteristics, and equipment to be used. It must specify the minimum number of batches to be used for validation studies; it must specify the acceptance criteria and who will sign/approve/ disapprove the conclusions derived from such a scientific study. VALIDATION TEAM (quipe de validation): A multi-disciplinary team of personnel primarily responsible for conducting and/or supervising validation studies. Such studies may be conducted by person(s) qualified by training and experience in a relevant discipline. WORST CASE CONDITION (condition de la pire ventualit): The highest and /or lowest value of a given parameter actually evaluated in the validation exercise. 5.0 Phases of Validation The activities relating to validation studies may be classified into three phases: Phase 1: Pre-Validation Phase or the Qualification Phase, which covers all activities relating to product research and development, formulation, pilot batch studies, scale-up studies, transfer of technology to commercial scale
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batches, establishing stability conditions, storage and handling of inprocess and finished dosage forms, Equipment Qualification, Installation Qualification, master production documents, Operational Qualification, Process Capability. Phase 2: Process Validation Phase (Process Qualification phase) designed to verify that all established limits of the Critical Process Parameters are valid and that satisfactory products can be produced even under the worst case conditions. Phase 3: Validation Maintenance Phase requiring frequent review of all process related documents, including validation audit reports to assure that there have been no changes, deviations, failures, modifications to the production process, and that all SOPs have been followed, including Change Control procedures. At this stage the Validation Team also assures that there have been no changes/ deviations that should have resulted in Requalification and Revalidation. 6.0 Interpretation General Concepts: Quality, safety and effectiveness must be built into the product. This requires careful attention to a number of factors such as the selection of quality materials/components, product and process design, control of processes, in-process control, and end-product testing. Due to the complexity of the drug products, routine end-product testing alone is not sufficient due to several reasons. Furthermore, quality cannot be tested into the finished drug product but rather be built in the manufacturing processes and these processes should be controlled in order that the finished product meets all quality specifications. A careful design and validation of systems and process controls can establish a high degree of confidence that all lots or batches produced will meet their intended specifications.
batches, establishing stability conditions, storage and handling of inprocess and finished dosage forms, Equipment Qualification, Installation Qualification, master production documents, Operational Qualification, Process Capability. Phase 2: Process Validation Phase (Process Qualification phase) designed to verify that all established limits of the Critical Process Parameters are valid and that satisfactory products can be produced even under the worst case conditions. Phase 3: Validation Maintenance Phase requiring frequent review of all process related documents, including validation audit reports to assure that there have been no changes, deviations, failures, modifications to the production process, and that all SOPs have been followed, including Change Control procedures. At this stage the Validation Team also assures that there have been no changes/ deviations that should have resulted in Requalification and Revalidation. 6.0 Interpretation General Concepts: Quality, safety and effectiveness must be built into the product. This requires careful attention to a number of factors such as the selection of quality materials/components, product and process design, control of processes, in-process control, and end-product testing. Due to the complexity of the drug products, routine end-product testing alone is not sufficient due to several reasons. Furthermore, quality cannot be tested into the finished drug product but rather be built in the manufacturing processes and these processes should be controlled in order that the finished product meets all quality specifications. A careful design and validation of systems and process controls can establish a high degree of confidence that all lots or batches produced will meet their intended specifications.
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Validation protocol A written plan stating how validation will be conducted, including test parameters, product characteristics, production and packaging equipment, and decision points on what constitutes acceptable test results. This document should give details of critical steps of the manufacturing process that should be measured, the allowable range of variability and the manner in which the system will be tested. The validation protocol provides a synopsis of what is hoped to be accomplished. The protocol should list the selected process and control parameters, state the number of batches to be included in the study, and specify how the data, once assembled, will be treated for relevance. The date of approval by the validation team should also be noted. In the case where a protocol is altered or modified after its approval, appropriate reasoning for such a change must be documented. The validation protocol should be numbered, signed and dated, and should contain as a minimum the following information: objectives, scope of coverage of the validation study validation team membership, their qualifications and responsibilities type of validation: prospective, concurrent, retrospective, re-validation number and selection of batches to be on the validation study a list of all equipment to be used; their normal and worst case operating parameters outcome of IQ, OQ for critical equipment requirements for calibration of all measuring devices critical process parameters and their respective tolerances description of the processing steps: copy of the master documents for the product sampling points, stages of sampling, methods of sampling, sampling plans statistical tools to be used in the analysis of data training requirements for the processing operators validated test methods to be used in in-process testing and for the finished product
Validation protocol A written plan stating how validation will be conducted, including test parameters, product characteristics, production and packaging equipment, and decision points on what constitutes acceptable test results. This document should give details of critical steps of the manufacturing process that should be measured, the allowable range of variability and the manner in which the system will be tested. The validation protocol provides a synopsis of what is hoped to be accomplished. The protocol should list the selected process and control parameters, state the number of batches to be included in the study, and specify how the data, once assembled, will be treated for relevance. The date of approval by the validation team should also be noted. In the case where a protocol is altered or modified after its approval, appropriate reasoning for such a change must be documented. The validation protocol should be numbered, signed and dated, and should contain as a minimum the following information: objectives, scope of coverage of the validation study validation team membership, their qualifications and responsibilities type of validation: prospective, concurrent, retrospective, re-validation number and selection of batches to be on the validation study a list of all equipment to be used; their normal and worst case operating parameters outcome of IQ, OQ for critical equipment requirements for calibration of all measuring devices critical process parameters and their respective tolerances description of the processing steps: copy of the master documents for the product sampling points, stages of sampling, methods of sampling, sampling plans statistical tools to be used in the analysis of data training requirements for the processing operators validated test methods to be used in in-process testing and for the finished product
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specifications for raw and packaging materials and test methods forms and charts to be used for documenting results format for presentation of results, documenting conclusions and for approval of study results. Validation Master Plan A validation master plan is a document that summarises the companys overall philosophy, intentions and approaches to be used for establishing performance adequacy. The Validation Master Plan should be agreed upon by management. Validation in general requires meticulous preparation and careful planning of the various steps in the process. In addition, all work should be carried out in a structured way according to formally authorised standard operating procedures. All observations must be documented and where possible must be recorded as actual numerical results. The validation master plan should provide an overview of the entire validation operation, its organizational structure, its content and planning. The main elements of it being the list/inventory of the items to be validated and the planning schedule. All validation activities relating to critical technical operations, relevant to product and process controls within a firm should be included in the validation master plan. It should comprise all prospective, concurrent and retrospective validations as well as revalidation. The Validation Master Plan should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but should refer to existing documents such as policy documents, SOPs and validation protocols and reports. The format and content should include: introduction: validation policy, scope, location and schedule organizational structure: personnel responsibilities plant/ process /product description: rational for inclusions or exclusions and extent of validation specific process considerations that are critical and those requiring extra attention
specifications for raw and packaging materials and test methods forms and charts to be used for documenting results format for presentation of results, documenting conclusions and for approval of study results. Validation Master Plan A validation master plan is a document that summarises the companys overall philosophy, intentions and approaches to be used for establishing performance adequacy. The Validation Master Plan should be agreed upon by management. Validation in general requires meticulous preparation and careful planning of the various steps in the process. In addition, all work should be carried out in a structured way according to formally authorised standard operating procedures. All observations must be documented and where possible must be recorded as actual numerical results. The validation master plan should provide an overview of the entire validation operation, its organizational structure, its content and planning. The main elements of it being the list/inventory of the items to be validated and the planning schedule. All validation activities relating to critical technical operations, relevant to product and process controls within a firm should be included in the validation master plan. It should comprise all prospective, concurrent and retrospective validations as well as revalidation. The Validation Master Plan should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but should refer to existing documents such as policy documents, SOPs and validation protocols and reports. The format and content should include: introduction: validation policy, scope, location and schedule organizational structure: personnel responsibilities plant/ process /product description: rational for inclusions or exclusions and extent of validation specific process considerations that are critical and those requiring extra attention
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list of products/ processes/ systems to be validated, summarized in a matrix format, validation approach re-validation activities, actual status and future planning key acceptance criteria documentation format reference to the required SOPs time plans of each validation project and sub-project. Installation and Operational Qualification The detail and scope of a qualification exercise is in many respects related to the complexity of the equipment involved and the critical nature of that equipment with respect to the quality of the final product. Installation and Operational Qualification exercises assure through appropriate performance tests and related documentation that equipment, ancillary systems and sub-systems have been commissioned correctly. The end results are that all future operations will be reliable and within prescribed operating limits. The basic principles are: equipment be correctly installed in accordance with an installation plan requirements for calibration, maintenance and cleaning be covered in approved SOPs tests be conducted to assure that equipment is operating correctly, under normal and worst case conditions operator training requirements pertaining to new equipment be conducted and documented. At various stages in a validation exercise there is need for protocols, documentation, procedures, equipment, specifications and acceptance criteria for test results. All these need to be reviewed, checked and authorised. It would be expected that representatives from the appropriate professional disciplines, eg. Engineering , Research and Development, Manufacturing, Quality Control and Quality Assurance be actively involved in these undertakings with the final authorisation given by a validation team or the Quality Assurance representative.
list of products/ processes/ systems to be validated, summarized in a matrix format, validation approach re-validation activities, actual status and future planning key acceptance criteria documentation format reference to the required SOPs time plans of each validation project and sub-project. Installation and Operational Qualification The detail and scope of a qualification exercise is in many respects related to the complexity of the equipment involved and the critical nature of that equipment with respect to the quality of the final product. Installation and Operational Qualification exercises assure through appropriate performance tests and related documentation that equipment, ancillary systems and sub-systems have been commissioned correctly. The end results are that all future operations will be reliable and within prescribed operating limits. The basic principles are: equipment be correctly installed in accordance with an installation plan requirements for calibration, maintenance and cleaning be covered in approved SOPs tests be conducted to assure that equipment is operating correctly, under normal and worst case conditions operator training requirements pertaining to new equipment be conducted and documented. At various stages in a validation exercise there is need for protocols, documentation, procedures, equipment, specifications and acceptance criteria for test results. All these need to be reviewed, checked and authorised. It would be expected that representatives from the appropriate professional disciplines, eg. Engineering , Research and Development, Manufacturing, Quality Control and Quality Assurance be actively involved in these undertakings with the final authorisation given by a validation team or the Quality Assurance representative.
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Installation Qualification (IQ): I.Q. is the method of establishing with confidence that all major processing, packaging equipment and ancillary systems are in conformance with installation specifications, equipment manuals, schematics and engineering drawings. This stage of validation includes examination of equipment design, determination of calibration, maintenance and adjustment requirements. For complicated or large pieces of equipment, a pharmaceutical manufacturer may elect to undertake a predelivery check of the equipment at the suppliers assembly facility. This pre-delivery check cannot substitute for the Installation Qualification. However, it is acknowledged that the checks conducted and documented at this stage may duplicate a number of the checks conducted at the I.Q. stage, thus leading to a reduction in the scope of the I.Q. checks. All equipment, gauges and services should be adequately identified and should be given a serial number or other reference number. This number should appear in the reports for the equipment validation studies conducted. Installation qualification requires a formal and systematic check of all installed equipment against the equipment suppliers specifications and additional criteria identified by the user as part of the purchase specifications. These checks, tests and challenges should be repeated a significant number of times to assure reliable and meaningful results. At the I.Q. stage the company should document preventive maintenance requirements for installed equipment. The preventive maintenance schedule should be incorporated into the routine maintenance schedule. NOTE: There will be cases where installation of the equipment had not been qualified at the time of installation, and the engineering drawings and manuals for the equipment are no longer available at the manufacturing site. However, the equipment in place operates for a lengthy period of time without any problem or modifications of its design since it was first installed. In such situations, the Inspectorate considers that it may be appropriate for those specific cases to verify a limited number of the most critical parameters demonstrating that the equipment had been adequately installed. Thereafter,
Installation Qualification (IQ): I.Q. is the method of establishing with confidence that all major processing, packaging equipment and ancillary systems are in conformance with installation specifications, equipment manuals, schematics and engineering drawings. This stage of validation includes examination of equipment design, determination of calibration, maintenance and adjustment requirements. For complicated or large pieces of equipment, a pharmaceutical manufacturer may elect to undertake a predelivery check of the equipment at the suppliers assembly facility. This pre-delivery check cannot substitute for the Installation Qualification. However, it is acknowledged that the checks conducted and documented at this stage may duplicate a number of the checks conducted at the I.Q. stage, thus leading to a reduction in the scope of the I.Q. checks. All equipment, gauges and services should be adequately identified and should be given a serial number or other reference number. This number should appear in the reports for the equipment validation studies conducted. Installation qualification requires a formal and systematic check of all installed equipment against the equipment suppliers specifications and additional criteria identified by the user as part of the purchase specifications. These checks, tests and challenges should be repeated a significant number of times to assure reliable and meaningful results. At the I.Q. stage the company should document preventive maintenance requirements for installed equipment. The preventive maintenance schedule should be incorporated into the routine maintenance schedule. NOTE: There will be cases where installation of the equipment had not been qualified at the time of installation, and the engineering drawings and manuals for the equipment are no longer available at the manufacturing site. However, the equipment in place operates for a lengthy period of time without any problem or modifications of its design since it was first installed. In such situations, the Inspectorate considers that it may be appropriate for those specific cases to verify a limited number of the most critical parameters demonstrating that the equipment had been adequately installed. Thereafter,
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the company could pass directly to the operational qualification (O.Q.) stage if there is sufficient documented evidence that these units have always been well maintained and calibrated according to an adequate preestablished schedule. Operational Qualification (OQ): The conduct of an Operational Qualification should follow an authorised protocol. The critical operating parameters for the equipment and systems should be identified at the O.Q. stage. The plans for the O.Q. should identify the studies to be undertaken on the critical variables, the sequence of those studies and the measuring equipment to be used and the acceptance criteria to be met. Studies on the critical variables should include a condition or a set of conditions encompassing upper and lower processing and operating limits referred to as worst-case conditions. The completion of a successful O.Q. should allow the finalisation of operating procedures and operator instructions documentation for the equipment. This information should be used as the basis for training of operators in the requirements for satisfactory operation of the equipment. The completion of satisfactory I.Q. and O.Q. exercises should permit a formal release of the equipment for the next stage in the process validation exercise as long as calibration, cleaning, preventive maintenance and operator training requirements have been finalised and documented. Re-Qualification: Modifications to, or relocation of equipment should follow satisfactory review and authorization of the documented change proposal through the change control procedure. This formal review should include consideration of re-qualification of the equipment. Minor changes or changes having no direct impact on final or in-process product quality should be handled through the documentation system of the preventative maintenance program. Process Validation: It would normally be expected that process validation be completed prior to the distribution of a finished product that is intended for sale (Prospective Validation). Where this is not possible, it may be necessary to validate
the company could pass directly to the operational qualification (O.Q.) stage if there is sufficient documented evidence that these units have always been well maintained and calibrated according to an adequate preestablished schedule. Operational Qualification (OQ): The conduct of an Operational Qualification should follow an authorised protocol. The critical operating parameters for the equipment and systems should be identified at the O.Q. stage. The plans for the O.Q. should identify the studies to be undertaken on the critical variables, the sequence of those studies and the measuring equipment to be used and the acceptance criteria to be met. Studies on the critical variables should include a condition or a set of conditions encompassing upper and lower processing and operating limits referred to as worst-case conditions. The completion of a successful O.Q. should allow the finalisation of operating procedures and operator instructions documentation for the equipment. This information should be used as the basis for training of operators in the requirements for satisfactory operation of the equipment. The completion of satisfactory I.Q. and O.Q. exercises should permit a formal release of the equipment for the next stage in the process validation exercise as long as calibration, cleaning, preventive maintenance and operator training requirements have been finalised and documented. Re-Qualification: Modifications to, or relocation of equipment should follow satisfactory review and authorization of the documented change proposal through the change control procedure. This formal review should include consideration of re-qualification of the equipment. Minor changes or changes having no direct impact on final or in-process product quality should be handled through the documentation system of the preventative maintenance program. Process Validation: It would normally be expected that process validation be completed prior to the distribution of a finished product that is intended for sale (Prospective Validation). Where this is not possible, it may be necessary to validate
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processes during routine production (Concurrent Validation). Processes which have been in use for some time without any significant changes may also be validated according to an approved protocol (Retrospective Validation). a) Prospective Validation: In Prospective Validation, the validation protocol is executed before the process is put into commercial use. During the product development phase the production process should be broken down into individual steps. Each step should be evaluated on the basis of experience or theoretical considerations to determine the critical parameters that may affect the quality of the finished product. A series of experiments should be designed to determine the criticality of these factors. Each experiment should be planned and documented fully in an authorised protocol. All equipment, production environment and the analytical testing methods to be used should have been fully validated. Master batch documents can be prepared only after the critical parameters of the process have been identified and machine settings, component specifications and environmental conditions have been determined. Using this defined process a series of batches should be produced. In theory, the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, giving product of the desired quality would constitute a proper validation of the process. In practice, it may take some considerable time to accumulate these data. Some considerations should be exercised when selecting the process validation strategy. Amongst these should be the use of different lots of active raw materials and major excipients, batches produced on different shifts, the use of different equipment and facilities dedicated for commercial production, operating range of the critical processes, and a thorough analysis of the process data in case of Requalification and Revalidation. During the processing of the validation batches, extensive sampling and testing should be performed on the product at various stages, and should
processes during routine production (Concurrent Validation). Processes which have been in use for some time without any significant changes may also be validated according to an approved protocol (Retrospective Validation). a) Prospective Validation: In Prospective Validation, the validation protocol is executed before the process is put into commercial use. During the product development phase the production process should be broken down into individual steps. Each step should be evaluated on the basis of experience or theoretical considerations to determine the critical parameters that may affect the quality of the finished product. A series of experiments should be designed to determine the criticality of these factors. Each experiment should be planned and documented fully in an authorised protocol. All equipment, production environment and the analytical testing methods to be used should have been fully validated. Master batch documents can be prepared only after the critical parameters of the process have been identified and machine settings, component specifications and environmental conditions have been determined. Using this defined process a series of batches should be produced. In theory, the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, giving product of the desired quality would constitute a proper validation of the process. In practice, it may take some considerable time to accumulate these data. Some considerations should be exercised when selecting the process validation strategy. Amongst these should be the use of different lots of active raw materials and major excipients, batches produced on different shifts, the use of different equipment and facilities dedicated for commercial production, operating range of the critical processes, and a thorough analysis of the process data in case of Requalification and Revalidation. During the processing of the validation batches, extensive sampling and testing should be performed on the product at various stages, and should
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be documented comprehensively. Detailed testing should also be done on the final product in its package. Upon completion of the review, recommendations should be made on the extent of monitoring and the inprocess controls necessary for routine production. These should be incorporated into the Batch manufacturing and packaging record or into appropriate standard operating procedures. Limits, frequencies and actions to be taken in the event of the limits being exceeded should be specified. Matrix or Family approaches to prospective process validation: It may be possible and acceptable in particular circumstances for a manufacturer that uses the same process for several related products to develop a scientifically sound validation plan for that process rather than different plans for each product manufactured by that process. The matrix approach generally means a plan to conduct process validation on different strengths of the same product, whereas the family approach means a plan to conduct process validation on different products manufactured with the same processes using the same equipment. The validation process using these approaches must include batches of different strengths or products which should be selected to represent the worst case conditions or scenarios to demonstrate that the process is consistent for all strengths or products involved. b) Concurrent Validation: Unconditional use of this approach is not encouraged by the Inspectorate and is not acceptable as being the norm. In using this approach there is always the risk of having to modify process parameters or specifications over a period of time. This situation often leads to questions regarding disposition of the batches that had already been released for sale, subsequently known to have undesired quality characteristics. Concurrent validation may be the practical approach under certain circumstances. Examples of these may be: when a previously validated process is being transferred to a third party contract manufacturer or to another manufacturing site
be documented comprehensively. Detailed testing should also be done on the final product in its package. Upon completion of the review, recommendations should be made on the extent of monitoring and the inprocess controls necessary for routine production. These should be incorporated into the Batch manufacturing and packaging record or into appropriate standard operating procedures. Limits, frequencies and actions to be taken in the event of the limits being exceeded should be specified. Matrix or Family approaches to prospective process validation: It may be possible and acceptable in particular circumstances for a manufacturer that uses the same process for several related products to develop a scientifically sound validation plan for that process rather than different plans for each product manufactured by that process. The matrix approach generally means a plan to conduct process validation on different strengths of the same product, whereas the family approach means a plan to conduct process validation on different products manufactured with the same processes using the same equipment. The validation process using these approaches must include batches of different strengths or products which should be selected to represent the worst case conditions or scenarios to demonstrate that the process is consistent for all strengths or products involved. b) Concurrent Validation: Unconditional use of this approach is not encouraged by the Inspectorate and is not acceptable as being the norm. In using this approach there is always the risk of having to modify process parameters or specifications over a period of time. This situation often leads to questions regarding disposition of the batches that had already been released for sale, subsequently known to have undesired quality characteristics. Concurrent validation may be the practical approach under certain circumstances. Examples of these may be: when a previously validated process is being transferred to a third party contract manufacturer or to another manufacturing site
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where the product is a different strength of a previously validated product with the same ratio of active / inactive ingredients when the number of lots evaluated under the Retrospective Validation were not sufficient to obtain a high degree of assurance demonstrating that the process is fully under control when the number of batches produced are limited (e.g. orphan drugs). It is important in these cases however, that the systems and equipment to be used have been fully validated previously. The justification for conducting concurrent validation must be documented and the protocol must be approved by the Validation Team. A report should be prepared and approved prior to the sale of each batch and a final report should be prepared and approved after the completion of all concurrent batches. It is generally considered acceptable that a minimum of three consecutive batches within the finally agreed parameters, giving the product the desired quality would constitute a proper validation of the process. c) Retrospective Validation: In many establishments, processes that are stable and in routine use have not undergone a formally documented validation process. Historical data may be utilized to provide necessary documentary evidence that the processes are validated. The steps involved in this type of validation still require the preparation of a protocol, the reporting of the results of the data review, leading to a conclusion and recommendation. Retrospective validation is only acceptable for well established detailed processes that include operational limits for each critical step of the process and will be inappropriate where there have been recent changes in the formulation of the product, operating procedures, equipment and facility. The source of data for retrospective validation should include amongst others, batch documents, process control charts, maintenance log books, process capability studies, finished product test results, including trend analyses, and stability results. For the purpose of retrospective validation studies, it is considered acceptable that data from a minimum of ten consecutive batches produced
where the product is a different strength of a previously validated product with the same ratio of active / inactive ingredients when the number of lots evaluated under the Retrospective Validation were not sufficient to obtain a high degree of assurance demonstrating that the process is fully under control when the number of batches produced are limited (e.g. orphan drugs). It is important in these cases however, that the systems and equipment to be used have been fully validated previously. The justification for conducting concurrent validation must be documented and the protocol must be approved by the Validation Team. A report should be prepared and approved prior to the sale of each batch and a final report should be prepared and approved after the completion of all concurrent batches. It is generally considered acceptable that a minimum of three consecutive batches within the finally agreed parameters, giving the product the desired quality would constitute a proper validation of the process. c) Retrospective Validation: In many establishments, processes that are stable and in routine use have not undergone a formally documented validation process. Historical data may be utilized to provide necessary documentary evidence that the processes are validated. The steps involved in this type of validation still require the preparation of a protocol, the reporting of the results of the data review, leading to a conclusion and recommendation. Retrospective validation is only acceptable for well established detailed processes that include operational limits for each critical step of the process and will be inappropriate where there have been recent changes in the formulation of the product, operating procedures, equipment and facility. The source of data for retrospective validation should include amongst others, batch documents, process control charts, maintenance log books, process capability studies, finished product test results, including trend analyses, and stability results. For the purpose of retrospective validation studies, it is considered acceptable that data from a minimum of ten consecutive batches produced
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be utilized. When less than ten batches are available, it is considered that the data are not sufficient to demonstrate retrospectively that the process is fully under control. In such cases the study should be supplemented with data generated with concurrent or prospective validation. Some of the essential elements for Retrospective Validation are: Batches manufactured for a defined period (minimum of 10 last consecutive batches) Number of lots released per year Batch size/strength/manufacturer/year/period Master manufacturing/packaging documents Current specifications for active materials/finished products List of process deviations, corrective actions and changes to manufacturing documents Data for stability testing for several batches Trend analyses including those for quality related complaints Process Re-Validation: Re-validation provides the evidence that changes in a process and /or the process environment that are introduced do not adversely affect process characteristics and product quality. Documentation requirements will be the same as for the initial validation of the process. Periodic review and trend analysis should be carried out at scheduled intervals. Re-validation becomes necessary in certain situations. The following are examples of some of the planned or unplanned changes that may require re-validation: Changes in raw materials (physical properties such as density, viscosity, particle size distribution, and moisture, etc., that may affect the process or product). Changes in the source of active raw material manufacturer Changes in packaging material (primary container/closure system). Changes in the process (e.g., mixing time, drying temperatures and batch size) Changes in the equipment (e.g. addition of automatic detection system). Changes of equipment which involve the replacement of equipment on a
be utilized. When less than ten batches are available, it is considered that the data are not sufficient to demonstrate retrospectively that the process is fully under control. In such cases the study should be supplemented with data generated with concurrent or prospective validation. Some of the essential elements for Retrospective Validation are: Batches manufactured for a defined period (minimum of 10 last consecutive batches) Number of lots released per year Batch size/strength/manufacturer/year/period Master manufacturing/packaging documents Current specifications for active materials/finished products List of process deviations, corrective actions and changes to manufacturing documents Data for stability testing for several batches Trend analyses including those for quality related complaints Process Re-Validation: Re-validation provides the evidence that changes in a process and /or the process environment that are introduced do not adversely affect process characteristics and product quality. Documentation requirements will be the same as for the initial validation of the process. Periodic review and trend analysis should be carried out at scheduled intervals. Re-validation becomes necessary in certain situations. The following are examples of some of the planned or unplanned changes that may require re-validation: Changes in raw materials (physical properties such as density, viscosity, particle size distribution, and moisture, etc., that may affect the process or product). Changes in the source of active raw material manufacturer Changes in packaging material (primary container/closure system). Changes in the process (e.g., mixing time, drying temperatures and batch size) Changes in the equipment (e.g. addition of automatic detection system). Changes of equipment which involve the replacement of equipment on a
like for like basis would not normally require a re-validation except that this new equipment must be qualified. Changes in the plant/facility. Variations revealed by trend analysis (e.g. process drifts) A decision not to perform re-validation studies must be fully justified and documented. Change Control: Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component, process equipment, process environment, processing site, method of production or testing or any other change that may affect product quality or support system operations. All changes must be formally requested, documented and accepted by the Validation Team. The likely impact / risk of the change on the product must be assessed and the need for the extent of re-validation should be determined. Commitment of the company to control all changes to premises, supporting utilities, systems, materials, equipment and processes used in the fabrication/ packaging of pharmaceutical dosage forms is essential to ensure a continued validation status of the systems concerned. The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorised. Products made by processes subjected to changes should not be released for sale without full awareness and consideration of the change by the Validation Team. The Team should decide if a re-validation must be conducted prior to implementing the proposed change. 7.0 References 1. Guidelines on General Principles of Process Validation, CDER, US-FDA 1987 2. Pharmaceutical Process Validation; 2nd edition, Editors: I. R. Berry and R.A. Nash, 1993 3. Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation, PIC/S, August 2001
like for like basis would not normally require a re-validation except that this new equipment must be qualified. Changes in the plant/facility. Variations revealed by trend analysis (e.g. process drifts) A decision not to perform re-validation studies must be fully justified and documented. Change Control: Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component, process equipment, process environment, processing site, method of production or testing or any other change that may affect product quality or support system operations. All changes must be formally requested, documented and accepted by the Validation Team. The likely impact / risk of the change on the product must be assessed and the need for the extent of re-validation should be determined. Commitment of the company to control all changes to premises, supporting utilities, systems, materials, equipment and processes used in the fabrication/ packaging of pharmaceutical dosage forms is essential to ensure a continued validation status of the systems concerned. The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorised. Products made by processes subjected to changes should not be released for sale without full awareness and consideration of the change by the Validation Team. The Team should decide if a re-validation must be conducted prior to implementing the proposed change. 7.0 References 1. Guidelines on General Principles of Process Validation, CDER, US-FDA 1987 2. Pharmaceutical Process Validation; 2nd edition, Editors: I. R. Berry and R.A. Nash, 1993 3. Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation, PIC/S, August 2001
World Health Organization WHO Technical Report Series, No. 937, 2006
Annex 4 Supplementary guidelines on good manufacturing practices: validation
1. INTRODUCTION
Validation is an essential part of good manufacturing practices (GMP). It is, therefore, an element of the quality assurance programme associated with a particular product or process. The basic principles of quality assurance have as their goal the production of products that are fit for their intended use. These principles are as follows: Quality, safety and efficacy must be designed and built into the product. Quality cannot be inspected or tested into the product. Each critical step of the manufacturing process must be validated. Other steps in the process must be under control to maximize the probability that the finished product consistently and predictably meets all quality and design specifications. Validation of processes and systems is fundamental to achieving these goals. It is by design and validation that a manufacturer can establish confidence that the manufactured products will consistently meet their product specifications. Documentation associated with validation includes: standard operating procedures (SOPs) specifications validation master plan (VMP) qualification protocols and reports validation protocols and reports.
1. INTRODUCTION
Validation is an essential part of good manufacturing practices (GMP). It is, therefore, an element of the quality assurance programme associated with a particular product or process. The basic principles of quality assurance have as their goal the production of products that are fit for their intended use. These principles are as follows: Quality, safety and efficacy must be designed and built into the product. Quality cannot be inspected or tested into the product. Each critical step of the manufacturing process must be validated. Other steps in the process must be under control to maximize the probability that the finished product consistently and predictably meets all quality and design specifications. Validation of processes and systems is fundamental to achieving these goals. It is by design and validation that a manufacturer can establish confidence that the manufactured products will consistently meet their product specifications. Documentation associated with validation includes: standard operating procedures (SOPs) specifications validation master plan (VMP) qualification protocols and reports validation protocols and reports.
The implementation of validation work requires considerable resources such as: Time: generally validation work is subject to rigorous time schedules. Financial: validation often requires the time of specialized personnel and expensive technology. Human: validation requires the collaboration of experts from various disciplines (e.g. a multidisciplinary team, comprising quality assurance,
The implementation of validation work requires considerable resources such as: Time: generally validation work is subject to rigorous time schedules. Financial: validation often requires the time of specialized personnel and expensive technology. Human: validation requires the collaboration of experts from various disciplines (e.g. a multidisciplinary team, comprising quality assurance,
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engineering, manufacturing and other disciplines, depending on the product and process to be validated). These guidelines aim to give guidance to inspectors of pharmaceutical manufacturing facilities and manufacturers of pharmaceutical products on the requirements for validation. The main part covers the general principles of validation and qualification. In addition to the main part, appendices on validation and qualification (e.g. cleaning, computer and computerized systems, equipment, utilities and systems, and analytical methods) are included.
engineering, manufacturing and other disciplines, depending on the product and process to be validated). These guidelines aim to give guidance to inspectors of pharmaceutical manufacturing facilities and manufacturers of pharmaceutical products on the requirements for validation. The main part covers the general principles of validation and qualification. In addition to the main part, appendices on validation and qualification (e.g. cleaning, computer and computerized systems, equipment, utilities and systems, and analytical methods) are included.
2. SCOPE
2.1 These guidelines focus mainly on the overall concept of validation and are intended as a basic guide for use by GMP inspectors and manufacturers. It is not the intention to be prescriptive in specific validation requirements. This document serves as general guidance only, and the principles may be considered useful in its application in the manufacture and control of active pharmaceutical ingredients (APIs) and finished pharmaceutical products. Validation of specific processes and products, for example in sterile product manufacture, requires much more consideration and a detailed approach that is beyond the scope of this document. 2.2 There are many factors affecting the different types of validation and it is, therefore, not intended to define and address all aspects related to one particular type of validation here. 2.3 Manufacturers should plan validation in a manner that will ensure regulatory compliance and ensuring that product quality, safety and consistency are not compromised. 2.4 The general text in the main part of these guidelines may be applicable to validation and qualification of premises, equipment, utilities and systems, and processes and procedures. More specific principles of qualification and validation are addressed in the appendices. Semi-
2. SCOPE
2.1 These guidelines focus mainly on the overall concept of validation and are intended as a basic guide for use by GMP inspectors and manufacturers. It is not the intention to be prescriptive in specific validation requirements. This document serves as general guidance only, and the principles may be considered useful in its application in the manufacture and control of active pharmaceutical ingredients (APIs) and finished pharmaceutical products. Validation of specific processes and products, for example in sterile product manufacture, requires much more consideration and a detailed approach that is beyond the scope of this document. 2.2 There are many factors affecting the different types of validation and it is, therefore, not intended to define and address all aspects related to one particular type of validation here. 2.3 Manufacturers should plan validation in a manner that will ensure regulatory compliance and ensuring that product quality, safety and consistency are not compromised. 2.4 The general text in the main part of these guidelines may be applicable to validation and qualification of premises, equipment, utilities and systems, and processes and procedures. More specific principles of qualification and validation are addressed in the appendices. Semi-
process validation guidance: WHO TRS 937 (2006)
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automatic or fully automatic clean-in-place (CIP) systems and other special cases should be treated separately.
automatic or fully automatic clean-in-place (CIP) systems and other special cases should be treated separately.
3. GLOSSARY
The definitions given below apply to the terms used in these guidelines. They may have different meanings in other contexts. calibration The set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring (for example, weight, temperature and pH), recording, and controlling, or the values represented by a material measure, and the corresponding known values of a reference standard. Limits for acceptance of the results of measuring should be established. computer validation Documented evidence which provides a high degree of assurance that a computerized system analyses, controls and records data correctly and that data processing complies with predetermined specifications. commissioning The setting up, adjustment and testing of equipment or a system to ensure that it meets all the requirements, as specified in the user requirement specification, and capacities as specified by the designer or developer. Commissioning is carried out before qualification and validation. concurrent validation Validation carried out during routine production of products intended for sale. cleaning validation Documented evidence to establish that cleaning procedures are removing residues to predetermined levels of acceptability, taking into consideration factors such as batch size, dosing, toxicology and equipment size.
3. GLOSSARY
The definitions given below apply to the terms used in these guidelines. They may have different meanings in other contexts. calibration The set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring (for example, weight, temperature and pH), recording, and controlling, or the values represented by a material measure, and the corresponding known values of a reference standard. Limits for acceptance of the results of measuring should be established. computer validation Documented evidence which provides a high degree of assurance that a computerized system analyses, controls and records data correctly and that data processing complies with predetermined specifications. commissioning The setting up, adjustment and testing of equipment or a system to ensure that it meets all the requirements, as specified in the user requirement specification, and capacities as specified by the designer or developer. Commissioning is carried out before qualification and validation. concurrent validation Validation carried out during routine production of products intended for sale. cleaning validation Documented evidence to establish that cleaning procedures are removing residues to predetermined levels of acceptability, taking into consideration factors such as batch size, dosing, toxicology and equipment size.
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design qualification (DQ) Documented evidence that the premises, supporting systems, utilities, equipment and processes have been designed in accordance with the requirements of GMP. good engineering practices (GEP) Established engineering methods and standards that are applied throughout the project life-cycle to deliver appropriate, cost-effective solutions. installation qualification (IQ) The performance of tests to ensure that the installations (such as machines, measuring devices, utilities and manufacturing areas) used in a manufacturing process are appropriately selected and correctly installed and operate in accordance with established specifications. operational qualification (OQ) Documented verification that the system or subsystem performs as intended over all anticipated operating ranges. performance qualification (PQ) Documented verification that the equipment or system operates consistently and gives reproducibility within defined specifications and parameters for prolonged periods. (In the context of systems, the term process validation may also be used.) process validation Documented evidence which provides a high degree of assurance that a specific process will consistently result in a product that meets its predetermined specifications and quality characteristics. prospective validation Validation carried out during the development stage on the basis of a risk analysis of the production process, which is broken down into individual
design qualification (DQ) Documented evidence that the premises, supporting systems, utilities, equipment and processes have been designed in accordance with the requirements of GMP. good engineering practices (GEP) Established engineering methods and standards that are applied throughout the project life-cycle to deliver appropriate, cost-effective solutions. installation qualification (IQ) The performance of tests to ensure that the installations (such as machines, measuring devices, utilities and manufacturing areas) used in a manufacturing process are appropriately selected and correctly installed and operate in accordance with established specifications. operational qualification (OQ) Documented verification that the system or subsystem performs as intended over all anticipated operating ranges. performance qualification (PQ) Documented verification that the equipment or system operates consistently and gives reproducibility within defined specifications and parameters for prolonged periods. (In the context of systems, the term process validation may also be used.) process validation Documented evidence which provides a high degree of assurance that a specific process will consistently result in a product that meets its predetermined specifications and quality characteristics. prospective validation Validation carried out during the development stage on the basis of a risk analysis of the production process, which is broken down into individual
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steps; these are then evaluated on the basis of past experience to determine whether they may lead to critical situations. qualification Action of proving and documenting that any premises, systems and equipment are properly installed, and/or work correctly and lead to the expected results. Qualification is often a part (the initial stage) of validation, but the individual qualification steps alone do not constitute process validation. retrospective validation Involves the evaluation of past experience of production on the condition that composition, procedures, and equipment remain unchanged. revalidation Repeated validation of an approved process (or a part thereof) to ensure continued compliance with established requirements. standard operating procedure (SOP) An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material but of a more general nature (e.g. equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control; sampling and inspection). Certain SOPs may be used to supplement product-specific master batch production documentation. validation Action of proving and documenting that any process, procedure or method actually and consistently leads to the expected results. validation protocol (or plan) (VP) A document describing the activities to be performed in a validation, including the acceptance criteria for the approval of a manufacturing process or a part thereof for routine use.
steps; these are then evaluated on the basis of past experience to determine whether they may lead to critical situations. qualification Action of proving and documenting that any premises, systems and equipment are properly installed, and/or work correctly and lead to the expected results. Qualification is often a part (the initial stage) of validation, but the individual qualification steps alone do not constitute process validation. retrospective validation Involves the evaluation of past experience of production on the condition that composition, procedures, and equipment remain unchanged. revalidation Repeated validation of an approved process (or a part thereof) to ensure continued compliance with established requirements. standard operating procedure (SOP) An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material but of a more general nature (e.g. equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control; sampling and inspection). Certain SOPs may be used to supplement product-specific master batch production documentation. validation Action of proving and documenting that any process, procedure or method actually and consistently leads to the expected results. validation protocol (or plan) (VP) A document describing the activities to be performed in a validation, including the acceptance criteria for the approval of a manufacturing process or a part thereof for routine use.
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validation report (VR) A document in which the records, results and evaluation of a completed validation programme are assembled and summarized. It may also contain proposals for the improvement of processes and/or equipment. validation master plan (VMP) The VMP is a high-level document that establishes an umbrella validation plan for the entire project and summarizes the manufacturers overall philosophy and approach, to be used for establishing performance adequacy. It provides information on the manufacturers validation work programme and defines details of and timescales for the validation work to be performed, including a statement of the responsibilities of those implementing the plan. verification The application of methods, procedures, tests and other evaluations, in addition to monitoring, to determine compliance with the GMP principles. worst case A condition or set of conditions encompassing the upper and lower processing limits for operating parameters and circumstances, within SOPs, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily include product or process failure.
validation report (VR) A document in which the records, results and evaluation of a completed validation programme are assembled and summarized. It may also contain proposals for the improvement of processes and/or equipment. validation master plan (VMP) The VMP is a high-level document that establishes an umbrella validation plan for the entire project and summarizes the manufacturers overall philosophy and approach, to be used for establishing performance adequacy. It provides information on the manufacturers validation work programme and defines details of and timescales for the validation work to be performed, including a statement of the responsibilities of those implementing the plan. verification The application of methods, procedures, tests and other evaluations, in addition to monitoring, to determine compliance with the GMP principles. worst case A condition or set of conditions encompassing the upper and lower processing limits for operating parameters and circumstances, within SOPs, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily include product or process failure.
4. RELATIONSHIP BETWEEN VALIDATION AND QUALIFICATION

Validation and qualification are essentially components of the same concept. The term qualification is normally used for equipment, utilities and systems, and validation for processes. In this sense, qualification is part of validation.
4. RELATIONSHIP BETWEEN VALIDATION AND QUALIFICATION

Validation and qualification are essentially components of the same concept. The term qualification is normally used for equipment, utilities and systems, and validation for processes. In this sense, qualification is part of validation.
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5. VALIDATION
5. VALIDATION
5.1 Approaches to validation

5.1.1 There are two basic approaches to validation one based on evidence obtained through testing (prospective and concurrent validation), and one based on the analysis of accumulated (historical) data (retrospective validation). Whenever possible, prospective validation is preferred. Retrospective validation is no longer encouraged and is, in any case, not applicable to the manufacturing of sterile products. 5.1.2 Both prospective and concurrent validation, may include: extensive product testing, which may involve extensive sample testing (with the estimation of confidence limits for individual results) and the demonstration of intra- and inter-batch homogeneity; simulation process trials; challenge/worst case tests, which determine the robustness of the process; and control of process parameters being monitored during normal production runs to obtain additional information on the reliability of the process.
5.1 Approaches to validation

5.1.1 There are two basic approaches to validation one based on evidence obtained through testing (prospective and concurrent validation), and one based on the analysis of accumulated (historical) data (retrospective validation). Whenever possible, prospective validation is preferred. Retrospective validation is no longer encouraged and is, in any case, not applicable to the manufacturing of sterile products. 5.1.2 Both prospective and concurrent validation, may include: extensive product testing, which may involve extensive sample testing (with the estimation of confidence limits for individual results) and the demonstration of intra- and inter-batch homogeneity; simulation process trials; challenge/worst case tests, which determine the robustness of the process; and control of process parameters being monitored during normal production runs to obtain additional information on the reliability of the process.
5.2 Scope of validation

5.2.1 There should be an appropriate and sufficient system including organizational structure and documentation infrastructure, sufficient personnel and financial resources to perform validation tasks in a timely manner. Management and persons responsible for quality assurance should be involved. 5.2.2 Personnel with appropriate qualifications and experience should be responsible for performing validation. They should represent different departments depending on the validation work to be performed. 5.2.3 There should be proper preparation and planning before validation is performed. There should be a specific programme for validation activities.
5.2 Scope of validation

5.2.1 There should be an appropriate and sufficient system including organizational structure and documentation infrastructure, sufficient personnel and financial resources to perform validation tasks in a timely manner. Management and persons responsible for quality assurance should be involved. 5.2.2 Personnel with appropriate qualifications and experience should be responsible for performing validation. They should represent different departments depending on the validation work to be performed. 5.2.3 There should be proper preparation and planning before validation is performed. There should be a specific programme for validation activities.
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5.2.4 Validation should be performed in a structured way according to the documented procedures and protocols. 5.2.5 Validation should be performed: for new premises, equipment, utilities and systems, and processes and procedures; at periodic intervals; and when major changes have been made. (Periodic revalidation or periodic requalification may be substituted, where appropriate, with periodic evaluation of data and information to establish whether requalification or revalidation is required.) 5.2.6 Validation should be performed in accordance with written protocols. A written report on the outcome of the validation should be produced. 5.2.7 Validation should be done over a period of time, e.g. at least three consecutive batches (full production scale) should be validated, to demonstrate consistency. Worst case situations should be considered. 5.2.8 There should be a clear distinction between in-process controls and validation. In-process tests are performed during the manufacture of each batch according to specifications and methods devised during the development phase. Their objective is to monitor the process continuously. 5.2.9 When a new manufacturing formula or method is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to result in the consistent yield of a product of the required quality. 5.2.10 Manufacturers should identify what validation work is needed to prove that critical aspects of their operations are appropriately controlled. Significant changes to the facilities or the equipment, and processes that may affect the quality of the product should be validated. A risk assessment approach should be used to determine the scope and extent of validation required.
5.2.4 Validation should be performed in a structured way according to the documented procedures and protocols. 5.2.5 Validation should be performed: for new premises, equipment, utilities and systems, and processes and procedures; at periodic intervals; and when major changes have been made. (Periodic revalidation or periodic requalification may be substituted, where appropriate, with periodic evaluation of data and information to establish whether requalification or revalidation is required.) 5.2.6 Validation should be performed in accordance with written protocols. A written report on the outcome of the validation should be produced. 5.2.7 Validation should be done over a period of time, e.g. at least three consecutive batches (full production scale) should be validated, to demonstrate consistency. Worst case situations should be considered. 5.2.8 There should be a clear distinction between in-process controls and validation. In-process tests are performed during the manufacture of each batch according to specifications and methods devised during the development phase. Their objective is to monitor the process continuously. 5.2.9 When a new manufacturing formula or method is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to result in the consistent yield of a product of the required quality. 5.2.10 Manufacturers should identify what validation work is needed to prove that critical aspects of their operations are appropriately controlled. Significant changes to the facilities or the equipment, and processes that may affect the quality of the product should be validated. A risk assessment approach should be used to determine the scope and extent of validation required.
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6. QUALIFICATION
6.1 Qualification should be completed before process validation is performed. The process of qualification should be a logical, systematic process and should start from the design phase of the premises, equipment, utilities and equipment. 6.2 Depending on the function and operation of the equipment, utility or system, only installation qualification (IQ) and operational qualification (OQ) may be required, as the correct operation of the equipment, utility or system could be considered to be a sufficient indicator of its performance (refer to Section 11 for IQ, OQ and performance qualification (PQ)). (The equipment, utility and system should then be maintained, monitored and calibrated according to a regular schedule.) 6.3 Major equipment and critical utilities and systems, however, require IQ, OQ and PQ.
6. QUALIFICATION
6.1 Qualification should be completed before process validation is performed. The process of qualification should be a logical, systematic process and should start from the design phase of the premises, equipment, utilities and equipment. 6.2 Depending on the function and operation of the equipment, utility or system, only installation qualification (IQ) and operational qualification (OQ) may be required, as the correct operation of the equipment, utility or system could be considered to be a sufficient indicator of its performance (refer to Section 11 for IQ, OQ and performance qualification (PQ)). (The equipment, utility and system should then be maintained, monitored and calibrated according to a regular schedule.) 6.3 Major equipment and critical utilities and systems, however, require IQ, OQ and PQ.
7. CALIBRATION AND VERIFICATION

7.1 Calibration and verification of equipment, instruments and other devices, as applicable, used in production and quality control, should be performed at regular intervals. 7.2 Personnel who carry out calibration and preventive maintenance should have appropriate qualifications and training. 7.3 A calibration programme should be available and should provide information such as calibration standards and limits, responsible persons, calibration intervals, records and actions to be taken when problems are identified. 7.4 There should be traceability to standards (e.g. national, regional or international standards) used in the calibration. 7.5 Calibrated equipment, instruments and other devices should be labelled, coded or otherwise identified to indicate the status of calibration and the date on which recalibration is due.
7. CALIBRATION AND VERIFICATION

7.1 Calibration and verification of equipment, instruments and other devices, as applicable, used in production and quality control, should be performed at regular intervals. 7.2 Personnel who carry out calibration and preventive maintenance should have appropriate qualifications and training. 7.3 A calibration programme should be available and should provide information such as calibration standards and limits, responsible persons, calibration intervals, records and actions to be taken when problems are identified. 7.4 There should be traceability to standards (e.g. national, regional or international standards) used in the calibration. 7.5 Calibrated equipment, instruments and other devices should be labelled, coded or otherwise identified to indicate the status of calibration and the date on which recalibration is due.
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7.6 When the equipment, instruments and other devices have not been used for a certain period of time, their function and calibration status should be verified and shown to be satisfactory before use.
7.6 When the equipment, instruments and other devices have not been used for a certain period of time, their function and calibration status should be verified and shown to be satisfactory before use.
8. VALIDATION MASTER PLAN

The validation master plan (VMP) should reflect the key elements of the validation programme. It should be concise and clear and contain at least the following: a validation policy organizational structure of validation activities summary of facilities, systems, equipment and processes validated and to be validated documentation format (e.g. protocol and report format) planning and scheduling change control references to existing documents.

The validation master plan (VMP) should reflect the key elements of the validation programme. It should be concise and clear and contain at least the following: a validation policy organizational structure of validation activities summary of facilities, systems, equipment and processes validated and to be validated documentation format (e.g. protocol and report format) planning and scheduling change control references to existing documents.
9. QUALIFICATION AND VALIDATION PROTOCOLS

9.1 There should be qualification and validation protocols describing the qualification and validation study to be performed. 9.2 As a minimum the protocols should include the following significant background information: the objectives of the study the site of the study the responsible personnel description of SOPs to be followed equipment to be used; standards and criteria for the relevant products and processes the type of validation the processes and/or parameters sampling, testing and monitoring requirements
9. QUALIFICATION AND VALIDATION PROTOCOLS

9.1 There should be qualification and validation protocols describing the qualification and validation study to be performed. 9.2 As a minimum the protocols should include the following significant background information: the objectives of the study the site of the study the responsible personnel description of SOPs to be followed equipment to be used; standards and criteria for the relevant products and processes the type of validation the processes and/or parameters sampling, testing and monitoring requirements
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predetermined acceptance criteria for drawing conclusions. 9.3 There should be a description of the way in which the results will be analysed. 9.4 The protocol should be approved prior to use. Any changes to a protocol should be approved prior to implementation of the change.
predetermined acceptance criteria for drawing conclusions. 9.3 There should be a description of the way in which the results will be analysed. 9.4 The protocol should be approved prior to use. Any changes to a protocol should be approved prior to implementation of the change.
10. QUALIFICATION AND VALIDATION REPORTS

10.1 There should be written reports on the qualification and validation performed. 10.2 Reports should reflect the protocols followed and include at least the title and objective of the study; reference to the protocol; details of material, equipment, programmes and cycles used; procedures and test methods. 10.3 The results should be evaluated, analysed and compared against the pre-determined acceptance criteria. The results should meet the acceptance criteria; deviations and out-of-limit results should be investigated. If these deviations are accepted, this should be justified. Where necessary further studies should be performed. 10.4 The departments responsible for the qualification and validation work should approve the completed report. 10.5 The conclusion of the report should state whether or not the outcome of the qualification and/or validation was considered successful. 10.6 The quality assurance department should approve the report after the final review. The criteria for approval should be in accordance with the companys quality assurance system. 10.7 Any deviations found during the validation process should be acted upon and documented as such. Corrective actions may be required.
10. QUALIFICATION AND VALIDATION REPORTS

10.1 There should be written reports on the qualification and validation performed. 10.2 Reports should reflect the protocols followed and include at least the title and objective of the study; reference to the protocol; details of material, equipment, programmes and cycles used; procedures and test methods. 10.3 The results should be evaluated, analysed and compared against the pre-determined acceptance criteria. The results should meet the acceptance criteria; deviations and out-of-limit results should be investigated. If these deviations are accepted, this should be justified. Where necessary further studies should be performed. 10.4 The departments responsible for the qualification and validation work should approve the completed report. 10.5 The conclusion of the report should state whether or not the outcome of the qualification and/or validation was considered successful. 10.6 The quality assurance department should approve the report after the final review. The criteria for approval should be in accordance with the companys quality assurance system. 10.7 Any deviations found during the validation process should be acted upon and documented as such. Corrective actions may be required.
11. QUALIFICATION STAGES

11.1 There are four stages of qualification: design qualification (DQ);
11. QUALIFICATION STAGES

11.1 There are four stages of qualification: design qualification (DQ);
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installation qualification (IQ); operational qualification (OQ); and performance qualification (PQ). 11.2 All SOPs for operation, maintenance and calibration should be prepared during qualification. 11.3. Training should be provided to operators and training records should be maintained.
installation qualification (IQ); operational qualification (OQ); and performance qualification (PQ). 11.2 All SOPs for operation, maintenance and calibration should be prepared during qualification. 11.3. Training should be provided to operators and training records should be maintained.
Design qualification
11.4 Design qualification should provide documented evidence that the design specifications were met.
11.4 Design qualification should provide documented evidence that the design specifications were met.
Installation qualification
11.5 Installation qualification should provide documented evidence that the installation was complete and satisfactory. 11.6 The purchase specifications, drawings, manuals, spare parts lists and vendor details should be verified during installation qualification. 11.7 Control and measuring devices should be calibrated.
Installation qualification
11.5 Installation qualification should provide documented evidence that the installation was complete and satisfactory. 11.6 The purchase specifications, drawings, manuals, spare parts lists and vendor details should be verified during installation qualification. 11.7 Control and measuring devices should be calibrated.
Operational qualification
11.8 Operational qualification should provide documented evidence that utilities, systems or equipment and all its components operate in accordance with operational specifications. 11.9 Tests should be designed to demonstrate satisfactory operation over the normal operating range as well as at the limits of its operating conditions (including worst case conditions). 11.10 Operation controls, alarms, switches, displays and other operational components should be tested.
Operational qualification
11.8 Operational qualification should provide documented evidence that utilities, systems or equipment and all its components operate in accordance with operational specifications. 11.9 Tests should be designed to demonstrate satisfactory operation over the normal operating range as well as at the limits of its operating conditions (including worst case conditions). 11.10 Operation controls, alarms, switches, displays and other operational components should be tested.
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11.11 Measurements made in accordance with a statistical approach should be fully described.
11.11 Measurements made in accordance with a statistical approach should be fully described.
Performance qualification
11.12 Performance qualification should provide documented evidence that utilities, systems or equipment and all its components can consistently perform in accordance with the specifications under routine use. 11.13 Test results should be collected over a suitable period of time to prove consistency.
Performance qualification
11.12 Performance qualification should provide documented evidence that utilities, systems or equipment and all its components can consistently perform in accordance with the specifications under routine use. 11.13 Test results should be collected over a suitable period of time to prove consistency.
Requalification
11.14 Requalification should be done in accordance with a defined schedule. The frequency of requalification may be determined on the basis of factors such as the analysis of results relating to calibration, verification and maintenance. 11.15 There should be periodic requalification, as well as requalification after changes (such as changes to utilities, systems, equipment; maintenance work; and movement). (See also point 5.2.5 above and section 12 below.) 11.16 Requalification should be considered as part of the change control procedure.
Requalification
11.14 Requalification should be done in accordance with a defined schedule. The frequency of requalification may be determined on the basis of factors such as the analysis of results relating to calibration, verification and maintenance. 11.15 There should be periodic requalification, as well as requalification after changes (such as changes to utilities, systems, equipment; maintenance work; and movement). (See also point 5.2.5 above and section 12 below.) 11.16 Requalification should be considered as part of the change control procedure.
Revalidation
11.17 Processes and procedures should be revalidated to ensure that they remain capable of achieving the intended results. 11.18 There should be periodic revalidation, as well as revalidation after changes. (See also points 5.2.5 above, point 11.21 below and section 12 below.) 11.19 Revalidation should be done in accordance with a defined schedule.
Revalidation
11.17 Processes and procedures should be revalidated to ensure that they remain capable of achieving the intended results. 11.18 There should be periodic revalidation, as well as revalidation after changes. (See also points 5.2.5 above, point 11.21 below and section 12 below.) 11.19 Revalidation should be done in accordance with a defined schedule.
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11.20 The frequency and extent of revalidation should be determined using a risk-based approach together with a review of historical data.
11.20 The frequency and extent of revalidation should be determined using a risk-based approach together with a review of historical data.
Periodic revalidation
11.21 Periodic revalidation should be performed to assess process changes that may occur gradually over a period of time, or because of wear of equipment. 11.22 The following should be considered when periodic revalidation is performed: master formulae and specifications; SOPs; records (e.g. of calibration, maintenance and cleaning); and analytical methods.
Periodic revalidation
11.21 Periodic revalidation should be performed to assess process changes that may occur gradually over a period of time, or because of wear of equipment. 11.22 The following should be considered when periodic revalidation is performed: master formulae and specifications; SOPs; records (e.g. of calibration, maintenance and cleaning); and analytical methods.
Revalidation after change

11.23 Revalidation should be performed following a change that could have an effect on the process, procedure, quality of the product and/or the product characteristics. Revalidation should be considered as part of the change control procedure. 11.24 The extent of revalidation will depend on the nature and significance of the change(s). 11.25 Changes should not adversely affect product quality or process characteristics. 11.26 Changes requiring revalidation should be defined in the validation plan and may include: changes in starting materials (including physical properties, such as density, viscosity or particle size distribution that may affect the process or product); change of starting material manufacturer;
Revalidation after change

11.23 Revalidation should be performed following a change that could have an effect on the process, procedure, quality of the product and/or the product characteristics. Revalidation should be considered as part of the change control procedure. 11.24 The extent of revalidation will depend on the nature and significance of the change(s). 11.25 Changes should not adversely affect product quality or process characteristics. 11.26 Changes requiring revalidation should be defined in the validation plan and may include: changes in starting materials (including physical properties, such as density, viscosity or particle size distribution that may affect the process or product); change of starting material manufacturer;
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transfer of processes to a different site (including change of facilities and installations which infl uence the process); changes of primary packaging material (e.g. substituting plastic for glass); changes in the manufacturing process (e.g. mixing times or drying temperatures); changes in the equipment (e.g. addition of automatic detection systems, installation of new equipment, major revisions to machinery or apparatus and breakdowns); production area and support system changes (e.g. rearrangement of areas, or a new water treatment method); appearance of negative quality trends; appearance of new findings based on current knowledge, e.g. new technology; support system changes. Changes of equipment which involve the replacement of equipment on a like-for-like basis would not normally require a revalidation. For example, installation of a new centrifugal pump to replace an older model would not necessarily require revalidation.
transfer of processes to a different site (including change of facilities and installations which infl uence the process); changes of primary packaging material (e.g. substituting plastic for glass); changes in the manufacturing process (e.g. mixing times or drying temperatures); changes in the equipment (e.g. addition of automatic detection systems, installation of new equipment, major revisions to machinery or apparatus and breakdowns); production area and support system changes (e.g. rearrangement of areas, or a new water treatment method); appearance of negative quality trends; appearance of new findings based on current knowledge, e.g. new technology; support system changes. Changes of equipment which involve the replacement of equipment on a like-for-like basis would not normally require a revalidation. For example, installation of a new centrifugal pump to replace an older model would not necessarily require revalidation.
12. CHANGE CONTROL

12.1 Changes should be controlled in accordance with a SOP as changes may have an impact on a qualified utility, system or piece of equipment, and a validated process and/or procedure. 12.2 The procedure should describe the actions to be taken, including the need for and extent of qualification or validation to be done. 12.3 Changes should be formally requested, documented and approved before implementation. Records should be maintained.
12. CHANGE CONTROL

12.1 Changes should be controlled in accordance with a SOP as changes may have an impact on a qualified utility, system or piece of equipment, and a validated process and/or procedure. 12.2 The procedure should describe the actions to be taken, including the need for and extent of qualification or validation to be done. 12.3 Changes should be formally requested, documented and approved before implementation. Records should be maintained.
13. PERSONNEL
13.1 Personnel should demonstrate that they are appropriately qualified, where relevant. 13.2 Personnel requiring qualification include, for example: laboratory analysts; personnel following critical procedures; personnel doing data entry in computerized systems; and risk assessors.
13. PERSONNEL
13.1 Personnel should demonstrate that they are appropriately qualified, where relevant. 13.2 Personnel requiring qualification include, for example: laboratory analysts; personnel following critical procedures; personnel doing data entry in computerized systems; and risk assessors.
Appendix 1
VALIDATION OF HEATING, VENTILATION AND AIRCONDITIONING SYSTEMS
1. General 2. Commissioning 3. Qualification 4. Reference
Appendix 1
VALIDATION OF HEATING, VENTILATION AND AIRCONDITIONING SYSTEMS
1. General 2. Commissioning 3. Qualification 4. Reference
1. General
1.1 The heating, ventilation and air-conditioning (HVAC) system plays an important role in the protection of the product, the personnel and the environment. 1.2 For all HVAC installation components, subsystems or parameters, critical parameters and non-critical parameters should be determined. 1.3 Some of the parameters of a typical HVAC system that should be qualified include: room temperature and humidity; supply air and return air quantities; room pressure, air change rate, flow patterns, particle count and cleanup rates; and unidirectional flow velocities and HEPA filter penetration tests.
1. General
1.1 The heating, ventilation and air-conditioning (HVAC) system plays an important role in the protection of the product, the personnel and the environment. 1.2 For all HVAC installation components, subsystems or parameters, critical parameters and non-critical parameters should be determined. 1.3 Some of the parameters of a typical HVAC system that should be qualified include: room temperature and humidity; supply air and return air quantities; room pressure, air change rate, flow patterns, particle count and cleanup rates; and unidirectional flow velocities and HEPA filter penetration tests.
2. Commissioning
2.1 Commissioning should involve the setting up, balancing, adjustment and testing of the entire HVAC system, to ensure that the system meets all the requirements, as specified in the user requirement specification, and capacities as specified by the designer or developer. 2.2 The installation records of the system should provide documented evidence of all measured capacities of the system.
2. Commissioning
2.1 Commissioning should involve the setting up, balancing, adjustment and testing of the entire HVAC system, to ensure that the system meets all the requirements, as specified in the user requirement specification, and capacities as specified by the designer or developer. 2.2 The installation records of the system should provide documented evidence of all measured capacities of the system.
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2.3 The data should include items such as the design and measured figures for airflows, water flows, system pressures and electrical amperages. These should be contained in the operating and maintenance manuals (O & M manuals). 2.4 Acceptable tolerances for all system parameters should be specified prior to commencing the physical installation. 2.5 Training should be provided to personnel after installation of the system, and should include how to perform operation and maintenance. 2.6 O & M manuals, schematic drawings, protocols and reports should be maintained as reference documents for any future changes and upgrades to the system. 2.7 Commissioning should be a precursor to system qualification and validation.
2.3 The data should include items such as the design and measured figures for airflows, water flows, system pressures and electrical amperages. These should be contained in the operating and maintenance manuals (O & M manuals). 2.4 Acceptable tolerances for all system parameters should be specified prior to commencing the physical installation. 2.5 Training should be provided to personnel after installation of the system, and should include how to perform operation and maintenance. 2.6 O & M manuals, schematic drawings, protocols and reports should be maintained as reference documents for any future changes and upgrades to the system. 2.7 Commissioning should be a precursor to system qualification and validation.
3. Qualification
3.1 Manufacturers should qualify HVAC systems using a risk-based approach. The basic concepts of qualification of HVAC systems are set out in Fig. 1 below.
3. Qualification
3.1 Manufacturers should qualify HVAC systems using a risk-based approach. The basic concepts of qualification of HVAC systems are set out in Fig. 1 below.
Figure 1 Qualification is a part of validation Equip 1 Equip 2 Equip 3 Equip 4 Equip 5 Equip 6 Equip 7 Equip 1
Figure 1 Qualification is a part of validation Equip 2 Equip 3 Equip 4 Equip 5 Equip 6 Equip 7
System 1
System 2
System 1
System 2
Process
Process
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3.2 The qualification of the HVAC system should be described in a validation master plan (VMP). 3.3 The validation master plan should define the nature and extent of testing and the test procedures and protocols to be followed. 3.4 Stages of the qualification of the HVAC system should include design qualification (DQ), installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). 3.5 Critical and non-critical parameters for all HVAC installation components, subsystems and controls should be determined by means of a risk analysis. 3.6 Any parameter that may affect the quality of the pharmaceutical product should be considered a critical parameter. 3.7 All critical parameters should be included in the qualification process. Note: A realistic approach to differentiating between critical and noncritical parameters is required, to avoid making the validation process unnecessarily complex. Example: The humidity of the room where the product is exposed should be considered a critical parameter when a humidity-sensitive product is being manufactured. The humidity sensors and the humidity monitoring system should, therefore, be qualified. The heat transfer system, chemical drier or steam humidifier, which is producing the humidity-controlled air, is further removed from the product and may not require operational qualification. A room cleanliness classification is a critical parameter and, therefore, the room air-change rates and high-efficiency particulate air (HEPA) filters should be critical parameters and require qualification. Items such as the fan generating the airflow and the primary and secondary filters are non-critical parameters, and may not require operational qualification.
3.2 The qualification of the HVAC system should be described in a validation master plan (VMP). 3.3 The validation master plan should define the nature and extent of testing and the test procedures and protocols to be followed. 3.4 Stages of the qualification of the HVAC system should include design qualification (DQ), installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). 3.5 Critical and non-critical parameters for all HVAC installation components, subsystems and controls should be determined by means of a risk analysis. 3.6 Any parameter that may affect the quality of the pharmaceutical product should be considered a critical parameter. 3.7 All critical parameters should be included in the qualification process. Note: A realistic approach to differentiating between critical and noncritical parameters is required, to avoid making the validation process unnecessarily complex. Example: The humidity of the room where the product is exposed should be considered a critical parameter when a humidity-sensitive product is being manufactured. The humidity sensors and the humidity monitoring system should, therefore, be qualified. The heat transfer system, chemical drier or steam humidifier, which is producing the humidity-controlled air, is further removed from the product and may not require operational qualification. A room cleanliness classification is a critical parameter and, therefore, the room air-change rates and high-efficiency particulate air (HEPA) filters should be critical parameters and require qualification. Items such as the fan generating the airflow and the primary and secondary filters are non-critical parameters, and may not require operational qualification.
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3.8 Non-critical systems and components should be subject to good engineering practice (GEP) and may not necessarily require full qualification. 3.9 A change control procedure should be followed when changes are planned to the HVAC system, its components, and controls, that may affect critical parameters. 3.10 Acceptance criteria and limits should be defined during the design stage. 3.11 The manufacturer should define design conditions, normal operating ranges, operating ranges, and alert and action limits. 3.12 Design condition and normal operating ranges should be identified and set to realistically achievable parameters. 3.13 All parameters should fall within the design condition range during system operational qualification. Conditions may go out of the design condition range during normal operating procedures but they should remain within the operating range. 3.14 Out-of-limit results (e.g. action limit deviations) should be recorded and form part of the batch manufacturing records.
3.8 Non-critical systems and components should be subject to good engineering practice (GEP) and may not necessarily require full qualification. 3.9 A change control procedure should be followed when changes are planned to the HVAC system, its components, and controls, that may affect critical parameters. 3.10 Acceptance criteria and limits should be defined during the design stage. 3.11 The manufacturer should define design conditions, normal operating ranges, operating ranges, and alert and action limits. 3.12 Design condition and normal operating ranges should be identified and set to realistically achievable parameters. 3.13 All parameters should fall within the design condition range during system operational qualification. Conditions may go out of the design condition range during normal operating procedures but they should remain within the operating range. 3.14 Out-of-limit results (e.g. action limit deviations) should be recorded and form part of the batch manufacturing records.
Figure 2 Action limit System operating ranges Alarm limit Alarm limit Action limit Action limit
Figure 2 System operating ranges Alarm limit Alarm limit Action limit
Design condition Normal operating range Operating range - validated acceptance criteria
Design condition Normal operating range Operating range - validated acceptance criteria
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3.15 The relationships between design conditions, operating range and qualified acceptance criteria are given in Figure 2. 3.16 A narrow range of relative humidities coupled with a wide range of temperatures is unacceptable as changes in temperature will automatically give rise to variations in the relative humidity. 3.17 Some of the typical HVAC system parameters that should be qualified for a pharmaceutical facility may include: temperature relative humidity supply air quantities for all diffusers return air or exhaust air quantities room air-change rates room pressures (pressure differentials) room airflow patterns unidirectional flow velocities containment system velocities HEPA filter penetration tests room particle counts room clean-up rates microbiological air and surface counts where appropriate operation of de-dusting warning/alarm systems where applicable.
3.15 The relationships between design conditions, operating range and qualified acceptance criteria are given in Figure 2. 3.16 A narrow range of relative humidities coupled with a wide range of temperatures is unacceptable as changes in temperature will automatically give rise to variations in the relative humidity. 3.17 Some of the typical HVAC system parameters that should be qualified for a pharmaceutical facility may include: temperature relative humidity supply air quantities for all diffusers return air or exhaust air quantities room air-change rates room pressures (pressure differentials) room airflow patterns unidirectional flow velocities containment system velocities HEPA filter penetration tests room particle counts room clean-up rates microbiological air and surface counts where appropriate operation of de-dusting warning/alarm systems where applicable.
3.18 The maximum time interval between tests should be defined by the manufacturer. The type of facility under test and the product level of protection should be considered. Note: Table 1 gives intervals for reference purposes only. The actual test periods may be more or less frequent, depending on the product and process. 3.19 Periodic requalification of parameters should be done at regular intervals, e.g. annually. 3.20 Requalification should also be done when any change, which could affect system performance, takes place.
3.18 The maximum time interval between tests should be defined by the manufacturer. The type of facility under test and the product level of protection should be considered. Note: Table 1 gives intervals for reference purposes only. The actual test periods may be more or less frequent, depending on the product and process. 3.19 Periodic requalification of parameters should be done at regular intervals, e.g. annually. 3.20 Requalification should also be done when any change, which could affect system performance, takes place.
Table 1 Strategic tests (for reference purposes only)

Test parameter Schedule of tests to demonstrate continuing compliance Clean area Max. time Test procedure class interval All classes 6 months Dust particle counts to be carried out and printouts of results produced. No. of readings and positions of tests to be in accordance with ISO 14644-1 Annex B Log of pressure differential readings to be produced or critical plants should be logged daily, preferably continuously. A 15 Pa pressure differential between different zones is recommended. In accordance with ISO 14644-3 Annex B5 Airfl ow readings for supply air and return air grilles to be measured and air change rates to be calculated. In accordance with ISO 14644-3 Annex B13 Air velocities for containment systems and unidirectional fl ow protection systems to be measured. In accordance with ISO 14644-3 Annex B4 Test parameter
Table 1 Strategic tests (for reference purposes only)

Schedule of tests to demonstrate continuing compliance Clean area Max. time Test procedure class interval All classes 6 months Dust particle counts to be carried out and printouts of results produced. No. of readings and positions of tests to be in accordance with ISO 14644-1 Annex B Log of pressure differential readings to be produced or critical plants should be logged daily, preferably continuously. A 15 Pa pressure differential between different zones is recommended. In accordance with ISO 14644-3 Annex B5 Airfl ow readings for supply air and return air grilles to be measured and air change rates to be calculated. In accordance with ISO 14644-3 Annex B13 Air velocities for containment systems and unidirectional fl ow protection systems to be measured. In accordance with ISO 14644-3 Annex B4
Particle count test (verifi cation of cleanliness)
Particle count test (verifi cation of cleanliness)
Air pressure All classes difference (To verify absence of crosscontamination) Airfl ow volume (To verify air change rates) All classes
12 months
Air pressure All classes difference (To verify absence of crosscontamination) Airfl ow volume (To verify air change rates) All classes
12 months
12 months
12 months
Airfl ow velocity All classes 12 months (To verify unidirectional fl ow or containment conditions) Source: ISO 14644 Standard, given for reference purposes only.
Airfl ow velocity All classes 12 months (To verify unidirectional fl ow or containment conditions) Source: ISO 14644 Standard, given for reference purposes only.
3.21 Clean-up times normally relate to the time it takes to clean up the room from one condition to another, e.g. the relationship between atrest and operational conditions in the clean area may be used as the criteria for clean-up tests. Therefore, the clean-up time can be expressed as the time taken to change from an operational condition to an atrest condition.
3.21 Clean-up times normally relate to the time it takes to clean up the room from one condition to another, e.g. the relationship between atrest and operational conditions in the clean area may be used as the criteria for clean-up tests. Therefore, the clean-up time can be expressed as the time taken to change from an operational condition to an atrest condition.
4. Reference
1. Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2006 (WHO Technical Report Series, No. 937), Annex 2.
4. Reference
1. Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2006 (WHO Technical Report Series, No. 937), Annex 2.
Appendix 2
VALIDATION OF WATER SYSTEMS FOR PHARMACEUTICAL USE
1. General 2. Start-up and commissioning of water systems 3. Qualification 4. Reference
Appendix 2
VALIDATION OF WATER SYSTEMS FOR PHARMACEUTICAL USE
1. General 2. Start-up and commissioning of water systems 3. Qualification 4. Reference
1. General
1.1 All water-treatment systems should be subject to planned maintenance, validation and monitoring. 1.2 Validation of water systems should consist of at least three phases: Phase 1: investigational phase; Phase 2: short-term control; and Phase 3: long-term control. 1.3 During the period following phase 3 (typically running for one year) the objective should be to demonstrate that the system is under control over a long period of time. Sampling may be reduced from, e.g. daily to weekly. 1.4 The validation performed and revalidation requirements should be included in the Water quality manual.
1. General
1.1 All water-treatment systems should be subject to planned maintenance, validation and monitoring. 1.2 Validation of water systems should consist of at least three phases: Phase 1: investigational phase; Phase 2: short-term control; and Phase 3: long-term control. 1.3 During the period following phase 3 (typically running for one year) the objective should be to demonstrate that the system is under control over a long period of time. Sampling may be reduced from, e.g. daily to weekly. 1.4 The validation performed and revalidation requirements should be included in the Water quality manual.
2. Start-up and commissioning of water systems

2.1 Planned, well-defined, successful and well-documented commissioning is an essential precursor to successful validation of water systems. The commissioning work should include setting to work, system set-up, controls, loop tuning and recording of all system performance parameters. If it is intended to use or refer to commissioning data within the validation work then the quality of the commissioning work and associated data and
2. Start-up and commissioning of water systems

2.1 Planned, well-defined, successful and well-documented commissioning is an essential precursor to successful validation of water systems. The commissioning work should include setting to work, system set-up, controls, loop tuning and recording of all system performance parameters. If it is intended to use or refer to commissioning data within the validation work then the quality of the commissioning work and associated data and
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documentation must be commensurate with the validation plan requirements.
documentation must be commensurate with the validation plan requirements.
3. Qualification
3.1 Water for pharmaceutical use (WPU), purified water (PW), highly purified water (HPW) and water for injections (WFI) systems are all considered to be direct impact, quality critical systems that should be qualified. The qualification should follow the validation convention of design review or design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ). 3.2 This guidance does not define the standard requirements for the conventional validation stages DQ, IQ and OQ, but concentrates on the particular PQ approach that should be used for WPU systems to demonstrate their consistent and reliable performance. A three-phase approach should be used to satisfy the objective of proving the reliability and robustness of the system in service over an extended period. Phase 1 A test period of 24 weeks should be spent monitoring the system intensively. During this period the system should operate continuously without failure or performance deviation. The following procedures should be included in the testing approach. Undertake chemical and microbiological testing in accordance with a defined plan. Sample the incoming feed-water to verify its quality. Sample after each step in the purification process daily. Sample at each point of use and at other defined sampling points daily. Develop appropriate operating ranges. Develop and finalize operating, cleaning, sanitizing and maintenance procedures.
3. Qualification
3.1 Water for pharmaceutical use (WPU), purified water (PW), highly purified water (HPW) and water for injections (WFI) systems are all considered to be direct impact, quality critical systems that should be qualified. The qualification should follow the validation convention of design review or design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ). 3.2 This guidance does not define the standard requirements for the conventional validation stages DQ, IQ and OQ, but concentrates on the particular PQ approach that should be used for WPU systems to demonstrate their consistent and reliable performance. A three-phase approach should be used to satisfy the objective of proving the reliability and robustness of the system in service over an extended period. Phase 1 A test period of 24 weeks should be spent monitoring the system intensively. During this period the system should operate continuously without failure or performance deviation. The following procedures should be included in the testing approach. Undertake chemical and microbiological testing in accordance with a defined plan. Sample the incoming feed-water to verify its quality. Sample after each step in the purification process daily. Sample at each point of use and at other defined sampling points daily. Develop appropriate operating ranges. Develop and finalize operating, cleaning, sanitizing and maintenance procedures.
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Demonstrate production and delivery of product water of the required quality and quantity. Use and refine the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting. Verify provisional alert and action levels. Develop and refine the test-failure procedure. Phase 2 A further test period of 24 weeks should be spent carrying out further intensive monitoring while deploying all the refined SOPs after the satisfactory completion of phase 1. The sampling scheme should be generally the same as in phase 1. Water can be used for manufacturing purposes during this phase. The approach should also: demonstrate consistent operation within established ranges; and demonstrate consistent production and delivery of water of the required quantity and quality when the system is operated in accordance with the SOPs. Phase 3 Phase 3 typically runs for one year after the satisfactory completion of phase 2. Water can be used for manufacturing purposes during this phase which has the following objectives and features: Demonstrate extended reliable performance. Ensure that seasonal variations are evaluated. The sample locations, sampling frequencies and tests should be reduced to the normal routine pattern based on established procedures proven during phases 1 and 2.
Demonstrate production and delivery of product water of the required quality and quantity. Use and refine the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting. Verify provisional alert and action levels. Develop and refine the test-failure procedure. Phase 2 A further test period of 24 weeks should be spent carrying out further intensive monitoring while deploying all the refined SOPs after the satisfactory completion of phase 1. The sampling scheme should be generally the same as in phase 1. Water can be used for manufacturing purposes during this phase. The approach should also: demonstrate consistent operation within established ranges; and demonstrate consistent production and delivery of water of the required quantity and quality when the system is operated in accordance with the SOPs. Phase 3 Phase 3 typically runs for one year after the satisfactory completion of phase 2. Water can be used for manufacturing purposes during this phase which has the following objectives and features: Demonstrate extended reliable performance. Ensure that seasonal variations are evaluated. The sample locations, sampling frequencies and tests should be reduced to the normal routine pattern based on established procedures proven during phases 1 and 2.
Reference
1. WHO good manufacturing practices: water for pharmaceutical use. Geneva, World Health Organization 2005 (WHO Technical Report Series, No. 929), Annex 3.
Reference
1. WHO good manufacturing practices: water for pharmaceutical use. Geneva, World Health Organization 2005 (WHO Technical Report Series, No. 929), Annex 3.
Appendix 6
QUALIFICATION OF SYSTEMS AND EQUIPMENT
1. Principle 2. Scope 3. General 4. Design qualification 5. Installation qualification 6. Operational qualification 7. Performance qualification 8. Requalification 9. Qualification of in use systems and equipment
Appendix 6
QUALIFICATION OF SYSTEMS AND EQUIPMENT
1. Principle 2. Scope 3. General 4. Design qualification 5. Installation qualification 6. Operational qualification 7. Performance qualification 8. Requalification 9. Qualification of in use systems and equipment
1. Principle
1.1 Systems and equipment should be appropriately designed, located, installed, operated and maintained to suit their intended purpose. 1.2 Critical systems, i.e. those whose consistent performance may have an impact on the quality of products, should be qualified. These may include, where appropriate, water purification systems, air-handling systems, compressed air systems and steam systems. 1.3 The continued suitable performance of equipment is important to ensure batch-to-batch consistency. Critical equipment should therefore be qualified.
1. Principle
1.1 Systems and equipment should be appropriately designed, located, installed, operated and maintained to suit their intended purpose. 1.2 Critical systems, i.e. those whose consistent performance may have an impact on the quality of products, should be qualified. These may include, where appropriate, water purification systems, air-handling systems, compressed air systems and steam systems. 1.3 The continued suitable performance of equipment is important to ensure batch-to-batch consistency. Critical equipment should therefore be qualified.
2. Scope
2.1 These guidelines describe the general aspects of qualification for systems and equipment. 2.2 Normally qualification would be applicable to critical systems and equipment whose performance may have an impact on the quality of the product.
2. Scope
2.1 These guidelines describe the general aspects of qualification for systems and equipment. 2.2 Normally qualification would be applicable to critical systems and equipment whose performance may have an impact on the quality of the product.
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3. General
3.1 The manufacturer should have a qualification policy for systems and equipment. 3.2 Equipment (including instruments) used in production and quality control should be included in the qualification policy and programme. 3.3 New systems and equipment should pass through all stages of qualification including design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ) as appropriate (Fig. 1). 3.4 In some cases, not all stages of qualification may be required. See also the guidelines on the qualification of water purification systems in Appendix 2 and heating, ventilation and air-conditioning (HVAC) in Appendix 1.
3. General
3.1 The manufacturer should have a qualification policy for systems and equipment. 3.2 Equipment (including instruments) used in production and quality control should be included in the qualification policy and programme. 3.3 New systems and equipment should pass through all stages of qualification including design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ) as appropriate (Fig. 1). 3.4 In some cases, not all stages of qualification may be required. See also the guidelines on the qualification of water purification systems in Appendix 2 and heating, ventilation and air-conditioning (HVAC) in Appendix 1.
Figure 1 Stages of qualification
Figure 1 Stages of qualification
Change control
Design qualification Installation qualification Operational qualification Performance qualification

Change control
Installation qualification Operational qualification Performance qualification
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3.5 Systems should be qualified before equipment. 3.6 Equipment should be qualified prior to being brought into routine use to provide documented evidence that the equipment is fit for its intended purpose. 3.7 Systems and equipment should undergo periodic requalification, as well as requalification after change. 3.8 Certain stages of the equipment qualification may be done by the supplier or a third party. 3.9 The relevant documentation associated with qualification including standard operating procedures (SOPs), specifications and acceptance criteria, certificates and manuals should be maintained. 3.10 Qualification should be done in accordance with predetermined and approved qualification protocols. The results of the qualification should be recorded and reflected in qualification reports. 3.11 The extent of the qualification should be based on the criticality of a system or equipment (e.g. blenders, autoclaves or computerized systems)
3.5 Systems should be qualified before equipment. 3.6 Equipment should be qualified prior to being brought into routine use to provide documented evidence that the equipment is fit for its intended purpose. 3.7 Systems and equipment should undergo periodic requalification, as well as requalification after change. 3.8 Certain stages of the equipment qualification may be done by the supplier or a third party. 3.9 The relevant documentation associated with qualification including standard operating procedures (SOPs), specifications and acceptance criteria, certificates and manuals should be maintained. 3.10 Qualification should be done in accordance with predetermined and approved qualification protocols. The results of the qualification should be recorded and reflected in qualification reports. 3.11 The extent of the qualification should be based on the criticality of a system or equipment (e.g. blenders, autoclaves or computerized systems)
4. Design qualification
Note: see also Supplementary guidelines on good manufacturing practices (GMP): validation. 4.1 User requirements should be considered when deciding on the specific design of a system or equipment. 4.2 A suitable supplier should be selected for the appropriate system or equipment (approved vendor).
4. Design qualification
Note: see also Supplementary guidelines on good manufacturing practices (GMP): validation. 4.1 User requirements should be considered when deciding on the specific design of a system or equipment. 4.2 A suitable supplier should be selected for the appropriate system or equipment (approved vendor).
5. Installation qualification
Note: see also Supplementary guidelines on good manufacturing practices (GMP): validation.
5. Installation qualification
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5.1 Systems and equipment should be correctly installed in accordance with an installation plan and installation qualification protocol. 5.2 Requirements for calibration, maintenance and cleaning should be drawn up during installation. 5.3 Installation qualification should include identification and verification of all system elements, parts, services, controls, gauges and other components. 5.4 Measuring, control and indicating devices should be calibrated against appropriate national or international standards, which are traceable. 5.5 There should be documented records for the installation (installation qualification report) to indicate the satisfactoriness of the installation, which should include the details of the supplier and manufacturer, system or equipment name, model and serial number, date of installation, spare parts, relevant procedures and certificates.
5.1 Systems and equipment should be correctly installed in accordance with an installation plan and installation qualification protocol. 5.2 Requirements for calibration, maintenance and cleaning should be drawn up during installation. 5.3 Installation qualification should include identification and verification of all system elements, parts, services, controls, gauges and other components. 5.4 Measuring, control and indicating devices should be calibrated against appropriate national or international standards, which are traceable. 5.5 There should be documented records for the installation (installation qualification report) to indicate the satisfactoriness of the installation, which should include the details of the supplier and manufacturer, system or equipment name, model and serial number, date of installation, spare parts, relevant procedures and certificates.
6. Operational qualification
Note: see also Supplementary guidelines on good manufacturing practices (GMP): validation. 6.1 Systems and equipment should operate correctly and their operation should be verified in accordance with an operational qualification protocol. 6.2 Critical operating parameters should be identified. Studies on the critical variables should include conditions encompassing upper and lower operating limits and circumstances (also referred to as worst case conditions). 6.3 Operational qualification should include verification of operation of all system elements, parts, services, controls, gauges and other components. 6.4 There should be documented records for the verification of operation (operational qualification report) to indicate the satisfactory operation. 6.5 Standard operating procedures for the operation should be finalized and approved.
6. Operational qualification
Note: see also Supplementary guidelines on good manufacturing practices (GMP): validation. 6.1 Systems and equipment should operate correctly and their operation should be verified in accordance with an operational qualification protocol. 6.2 Critical operating parameters should be identified. Studies on the critical variables should include conditions encompassing upper and lower operating limits and circumstances (also referred to as worst case conditions). 6.3 Operational qualification should include verification of operation of all system elements, parts, services, controls, gauges and other components. 6.4 There should be documented records for the verification of operation (operational qualification report) to indicate the satisfactory operation. 6.5 Standard operating procedures for the operation should be finalized and approved.
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Format for an installation qualification protocol & reporta

Validation protocol _________ Installation Qualification _________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Validation Protocol # ____________________________IQ Protocol number: ______ Title: ___________________________________________________________________________ Protocol written by: _________________________________ Protocol approved by: ______________________________ Date: __________________ QA Approval: _____________________________________Date:__________________ Objective To ensure that _________________ (system/equipment) installed conforms to the purchase specifications and the manufacturer details and literature, and to document the information that _______________________ (system/equipment) meets its specifications. Equipment inventory number: _______________________________________________ Scope To perform installation qualification as described in this IQ protocol at the time of installation, modification and relocation. Responsibility
Format for an installation qualification protocol & reporta

Validation protocol _________ Installation Qualification _________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Validation Protocol # ____________________________IQ Protocol number: ______ Title: ___________________________________________________________________________ Protocol written by: _________________________________ Protocol approved by: ______________________________ Date: __________________ QA Approval: _____________________________________Date:__________________ Objective To ensure that _________________ (system/equipment) installed conforms to the purchase specifications and the manufacturer details and literature, and to document the information that _______________________ (system/equipment) meets its specifications. Equipment inventory number: _______________________________________________ Scope To perform installation qualification as described in this IQ protocol at the time of installation, modification and relocation. Responsibility
________________ (post/person) overseeing the installation will perform the qualification and records results. ________________(post/person) will verify results and write the report. Quality Assurance will review and approve the IQ protocol and report. This format is used for training purposes and reflects some of the possible contents for an installation qualification protocol.
a
________________ (post/person) overseeing the installation will perform the qualification and records results. ________________(post/person) will verify results and write the report. Quality Assurance will review and approve the IQ protocol and report. This format is used for training purposes and reflects some of the possible contents for an installation qualification protocol.
a
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Format for an installation qualification protocol & reporta (continued)

Validation protocol _________ Installation Qualification _________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________

Validation protocol _________ Installation Qualification _________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________
System/Equipment ________________Code no.: __________________

a. Description of the system/equipment being installed: general description of the function and the main components. _______________________________________________________________________________ _______________________________________________________________________________ _______________ b. List of the main components: 1. _________________________________ Code no.: _____________________________ 2. _________________________________ Code no.: _____________________________ 3. _________________________________ Code no.: _____________________________ 4. _________________________________ Code no.: _____________________________ c. Description of supporting utilities (e.g. piping, connections, water supply) 1. _________________________________ Code no.: _____________________________ 2. _________________________________ Code no.: _____________________________ 3. _________________________________ Code no.: _____________________________ 4. _________________________________ Code no.: _____________________________ Procedure 1. Prepare a checklist of all components and parts, including spare parts according to the purchase order and manufacturers specifications. 2. Record the information for each actual part, component, item of auxiliary equipment, supporting facilities, and compare with the manufacturers specifications. 3. Record any deviations to the system/equipment. 4. Prepare a deviation report including justification of acceptance and impact on the function. 5. Prepare an IQ report.b 6. Submit the report to QA for review and approval.
a
System/Equipment ________________Code no.: __________________

a. Description of the system/equipment being installed: general description of the function and the main components. _______________________________________________________________________________ _______________________________________________________________________________ _______________ b. List of the main components: 1. _________________________________ Code no.: _____________________________ 2. _________________________________ Code no.: _____________________________ 3. _________________________________ Code no.: _____________________________ 4. _________________________________ Code no.: _____________________________ c. Description of supporting utilities (e.g. piping, connections, water supply) 1. _________________________________ Code no.: _____________________________ 2. _________________________________ Code no.: _____________________________ 3. _________________________________ Code no.: _____________________________ 4. _________________________________ Code no.: _____________________________ Procedure 1. Prepare a checklist of all components and parts, including spare parts according to the purchase order and manufacturers specifications. 2. Record the information for each actual part, component, item of auxiliary equipment, supporting facilities, and compare with the manufacturers specifications. 3. Record any deviations to the system/equipment. 4. Prepare a deviation report including justification of acceptance and impact on the function. 5. Prepare an IQ report.b 6. Submit the report to QA for review and approval.
a
This format is used for training purposes and reflects some of the possible contents for an installation qualification protocol. b As a minimum, the IQ report should include the date of initiation of the study, date completed, observations made, problems encountered, completeness of information collected, summary of deviation report, results of any tests, sample data (if appropriate), location of original data, other information relevant to the study, and the conclusion on the validity of the installation.
This format is used for training purposes and reflects some of the possible contents for an installation qualification protocol. b As a minimum, the IQ report should include the date of initiation of the study, date completed, observations made, problems encountered, completeness of information collected, summary of deviation report, results of any tests, sample data (if appropriate), location of original data, other information relevant to the study, and the conclusion on the validity of the installation.
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Validation protocol _________ Installation Qualification _________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Checklist for component no. ______________________ Name: ______________________________________Code no.: ____________________ Component function: _______________________________________________________ Require/order 1 2 3 4 5 6 7 Model/serial no. Specification Manual Drawing Wiring/cabling Power, fusing SOP (operation) SOP (maintenance) SOP (calibration) 8 9 10 11 12 13 Input/output control Environment Test equipment or instruments Utilities and service Spare parts list, part number and supplier Other Actual Deviations

Validation protocol _________ Installation Qualification _________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Checklist for component no. ______________________ Name: ______________________________________Code no.: ____________________ Component function: _______________________________________________________ Require/order 1 2 3 4 5 6 7 Model/serial no. Specification Manual Drawing Wiring/cabling Power, fusing SOP (operation) SOP (maintenance) SOP (calibration) 8 9 10 11 12 13 Input/output control Environment Test equipment or instruments Utilities and service Spare parts list, part number and supplier Other Actual Deviations
Performed by: ______________________________Date: _______________________ Deviations: ________________________________ Date: _______________________ Verified by: ________________________________ Date: _______________________ This format is used for training purposes and reflects some of the possible contents for an installation qualification protocol.
a
Performed by: ______________________________Date: _______________________ Deviations: ________________________________ Date: _______________________ Verified by: ________________________________ Date: _______________________
a
This format is used for training purposes and reflects some of the possible contents for an installation qualification protocol.
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Validation protocol _________ Installation Qualification _________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Deviation report Deviations: ________________________________________________________________________________ __________________________________________________________________________________________________ __________________________________________________________________________________________________ _________________________________________________________________________________________________ _________________________________________________________________________________________________ Justification for acceptance __________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________ Impact on operation: ____________________________________________________________________________________________________ ____________________________________________________________________________________________________ ____________________________________________________________________________________________________ ____________________________________________________________________________________________________ Report written by: __________________________ Date: _______________________ This format is used for training purposes and reflects some of the possible contents for an installation qualification protocol.
a

Validation protocol _________ Installation Qualification _________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Deviation report Deviations: ________________________________________________________________________________ __________________________________________________________________________________________________ __________________________________________________________________________________________________ _________________________________________________________________________________________________ _________________________________________________________________________________________________ Justification for acceptance __________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________ Impact on operation: ____________________________________________________________________________________________________ ____________________________________________________________________________________________________ ____________________________________________________________________________________________________ ____________________________________________________________________________________________________ Report written by: __________________________ Date: _______________________
a This format is used for training purposes and reflects some of the possible contents for an installation qualification protocol.
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Validation protocol _________ Installation Qualification _________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Installation qualification report Results: ________________________________________________________________________________ _________________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________________ Conclusions: __________________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________________ ________________________________________________________________________________ ________________________________________________________________________________ Report written by: __________________________ Date: _______________________ QA approved by: ____________________________Date: _______________________
a This format is used for training purposes and reflects some of the possible contents for an installation qualification protocol.

Validation protocol _________ Installation Qualification _________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Installation qualification report Results: ________________________________________________________________________________ _________________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________________ Conclusions: __________________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________________ ________________________________________________________________________________ ________________________________________________________________________________ Report written by: __________________________ Date: _______________________ QA approved by: ____________________________Date: _______________________
a
This format is used for training purposes and reflects some of the possible contents for an installation qualification protocol.
6.6 Training of operators for the systems and equipment should be provided, and training records maintained. 6.7 Systems and equipment should be released for routine use after completion of operational qualification, provided that all calibration, cleaning, maintenance, training and related tests and results were found to be acceptable.
6.6 Training of operators for the systems and equipment should be provided, and training records maintained. 6.7 Systems and equipment should be released for routine use after completion of operational qualification, provided that all calibration, cleaning, maintenance, training and related tests and results were found to be acceptable.
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7. Performance qualification
7. Performance qualification
Format for an operational qualification protocol & reporta

Validation protocol ________ Operational Qualification _________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Validation Protocol # __________________Operational Qualification _______________ Title ____________________________________________________________________________ ________________________________________________________________________________ Protocol written by _______________________________________________________ Departmental Approval by ________________________________ Date ____________ QA Approval by ________________________________________ Date ____________ Objective To determine that the system/equipment operates according to specifications, and to record all relevant information and data to demonstrate that the system/equipment functions as expected. Scope To be performed after installation, modification or relocation, after the Installation Qualification has been completed. Responsibility Person responsible for operating the system/equipment will perform the qualification and record the information. The supervisor will supervise the study, verify the completion of the records, write the deviation report and the Operational Qualification (OQ) Report. Qualify Assurance will review and approve the OQ protocol and report.
a
Format for an operational qualification protocol & reporta

Validation protocol ________ Operational Qualification _________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Validation Protocol # __________________Operational Qualification _______________ Title ____________________________________________________________________________ ________________________________________________________________________________ Protocol written by _______________________________________________________ Departmental Approval by ________________________________ Date ____________ QA Approval by ________________________________________ Date ____________ Objective To determine that the system/equipment operates according to specifications, and to record all relevant information and data to demonstrate that the system/equipment functions as expected. Scope To be performed after installation, modification or relocation, after the Installation Qualification has been completed. Responsibility Person responsible for operating the system/equipment will perform the qualification and record the information. The supervisor will supervise the study, verify the completion of the records, write the deviation report and the Operational Qualification (OQ) Report. Qualify Assurance will review and approve the OQ protocol and report.
a
This format is used for training purposes and reflects some of the possible contents for an operational qualification protocol.
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Format for an operational qualification protocol & reporta (continued)

Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Materials, Equipment, Documents List of calibration equipment required (Chart 1). Materials or supplies needed to perform the Operational Qualification 1 2 3 4 5 6 ____________________________________________________Code # __________ ____________________________________________________Code # __________ ____________________________________________________ Code # __________ ____________________________________________________ Code # __________ ___________________________________________________ Code # __________ ____________________________________________________ Code # __________

Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Materials, Equipment, Documents List of calibration equipment required (Chart 1). Materials or supplies needed to perform the Operational Qualification 1 2 3 4 5 6 ____________________________________________________Code # __________ ____________________________________________________Code # __________ ____________________________________________________ Code # __________ ____________________________________________________ Code # __________ ___________________________________________________ Code # __________ ____________________________________________________ Code # __________
SOPs and datasheets for normal operations of the system under test (Chart 2). Training records documenting that operators have been trained (Chart 2). Manuals for equipment (Chart 2). Procedure Test and record calibration data for calibrating apparatus and instruments (Chart 1). Test and record operative condition of control points and alarms (Chart 3). Test and record outputs (Chart 4). List of calibration requirements for the system under test and records of the calibration of the system (Chart 5). Measure and record the results of specific challenge to the system in normal and worst case situation where appropriate (Chart 6). Record any deviations to the procedures performed. Prepare a Deviation Report including the justification of acceptance and impact on the operation. Prepare an Operational Qualification Report. This should include date study initiated; date completed; observations made; problems encountered; completeness of information collected; summary of deviation report; results of control/alarm tests; sample data if appropriate; location of original data; other information relevant to the study; and conclusions on the validity of the equipment/system operations. Submit QA for review and approval.
a This format is used for training purposes and reflects some of the possible contents for an operational qualification protocol.
SOPs and datasheets for normal operations of the system under test (Chart 2). Training records documenting that operators have been trained (Chart 2). Manuals for equipment (Chart 2). Procedure Test and record calibration data for calibrating apparatus and instruments (Chart 1). Test and record operative condition of control points and alarms (Chart 3). Test and record outputs (Chart 4). List of calibration requirements for the system under test and records of the calibration of the system (Chart 5). Measure and record the results of specific challenge to the system in normal and worst case situation where appropriate (Chart 6). Record any deviations to the procedures performed. Prepare a Deviation Report including the justification of acceptance and impact on the operation. Prepare an Operational Qualification Report. This should include date study initiated; date completed; observations made; problems encountered; completeness of information collected; summary of deviation report; results of control/alarm tests; sample data if appropriate; location of original data; other information relevant to the study; and conclusions on the validity of the equipment/system operations. Submit QA for review and approval.
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Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Preparation Chart 1: Calibrating apparatus and instruments. Apparatus/Instrument Calibration method Calibration date

Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Preparation Chart 1: Calibrating apparatus and instruments. Apparatus/Instrument Calibration method Calibration date
_____________________ ________________________ _______________________ _____________________ ________________________ _______________________ _____________________ ________________________ _______________________ _____________________ ________________________ _______________________ _____________________ ________________________ _______________________ _____________________ ________________________ _______________________ _____________________ ________________________ _______________________ _____________________ ________________________ _______________________ _____________________ ________________________ _______________________ _____________________ ________________________ _______________________ Performed by: _______________________________________Date ____________ Deviations: ___________________________________________________________ _______________________________________________________________________________ _______________________________________________________________________________ _______________________________________________________________________________ Verified by: _________________________________________Date ____________
_____________________ ________________________ _______________________ _____________________ ________________________ _______________________ _____________________ ________________________ _______________________ _____________________ ________________________ _______________________ _____________________ ________________________ _______________________ _____________________ ________________________ _______________________ _____________________ ________________________ _______________________ _____________________ ________________________ _______________________ _____________________ ________________________ _______________________ _____________________ ________________________ _______________________ Performed by: _______________________________________Date ____________ Deviations: ___________________________________________________________ _______________________________________________________________________________ _______________________________________________________________________________ _______________________________________________________________________________ Verified by: _________________________________________Date ____________
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Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Preparation Chart 2: Document check SOP Title and number ___________________ ___________________ ___________________ ___________________ File location ___________________________ ___________________________ ___________________________ ___________________________ QA/QC approval date _______________________ _______________________ _______________________ _______________________

Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Preparation Chart 2: Document check SOP Title and number ___________________ ___________________ ___________________ ___________________ File location ___________________________ ___________________________ ___________________________ ___________________________ QA/QC approval date _______________________ _______________________ _______________________ _______________________
___________________ ___________________________ _______________________ Training Records Course on SOP # ______________ ______________ ______________ ______________ Staff name Date ______________ ______________ ______________ ______________
___________________ ___________________________ _______________________ Training Records Course on SOP # ______________ ______________ ______________ ______________ Staff name Date ______________ ______________ ______________ ______________
_________________________________________ _________________________________________ _________________________________________ _________________________________________
_________________________________________ _________________________________________ _________________________________________ _________________________________________
______________ _________________________________________ ______________ Equipment Make and Model Manual Available
______________ _________________________________________ ______________ Equipment Make and Model Manual Available
__________________________________________________ Y [ ] N [ ] __________________________________________________ Y [ ] N [ ] __________________________________________________ Y [ ] N [ ] Performed by: ______________________________________ Date ____________ Deviations: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _______________________________________________________________________________ Verified by: ________________________________________ Date ____________
__________________________________________________ Y [ ] N [ ] __________________________________________________ Y [ ] N [ ] __________________________________________________ Y [ ] N [ ] Performed by: ______________________________________ Date ____________ Deviations: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _______________________________________________________________________________ Verified by: ________________________________________ Date ____________
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Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Results Chart 3: Control points and alarms. Control point/Alarm Results Date

Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Results Chart 3: Control points and alarms. Control point/Alarm Results Date
___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________
___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________ ___________________ ___________________________________ _______________
Performed by:_________________________________________ Date ____________ Deviations: _____________________________________________________________ _______________________________________________________________________________ _______________________________________________________________________________ Verified by: __________________________________________ Date ____________
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Performed by:_________________________________________ Date ____________ Deviations: _____________________________________________________________ _______________________________________________________________________________ _______________________________________________________________________________ Verified by: __________________________________________ Date ____________
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Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Results Chart 4: Outputs Outputs Results Date

Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Results Chart 4: Outputs Outputs Results Date
_____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________
_____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________
Performed by: ________________________________________ Date ____________ Deviations: _____________________________________________________________ _______________________________________________________________________________ _______________________________________________________________________________ Verified by: __________________________________________ Date ____________
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Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Results Chart 5: Calibration of Equipment/System Calibration SOP (short title and #) Result Date

Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Results Chart 5: Calibration of Equipment/System Calibration SOP (short title and #) Result Date
_____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ Performed by: _________________________________________ Date ____________ Deviations: ____________________________________________________________ _______________________________________________________________________________ _______________________________________________________________________________ Verified by:___________________________________________ Date ____________
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_____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ _____________________ _________________________________ _______________ Performed by: _________________________________________ Date ____________ Deviations: ____________________________________________________________ _______________________________________________________________________________ _______________________________________________________________________________ Verified by:___________________________________________ Date ____________
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Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Results Chart 6: Specific challenge of the equipment or system Test in normal conditions:

Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Results Chart 6: Specific challenge of the equipment or system Test in normal conditions:
Test of worst case situation: (e.g. start-up after shutdown, temperature recovery time, centrifuge imbalance)
Test of worst case situation: (e.g. start-up after shutdown, temperature recovery time, centrifuge imbalance)
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Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Deviation Report Deviation(s):

Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Deviation Report Deviation(s):
Justification for acceptance:
Impact on operation:
Impact on operation:
Written by: ___________________________________________ Date ____________

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Written by: ___________________________________________ Date ____________

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Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Operational Qualification Report Results:

Validation protocol _________ Operational Qualification_________ Page __ of _____ Title: ______________ Name and address of site: _____________________________ ________________________________________________________________________________ Operational Qualification Report Results:
Conclusions:
Conclusions:
Written by: ___________________________________________ Date ____________ QA approved by: _______________________________________ Date ____________ This format is used for training purposes and reflects some of the possible contents for an operational qualification protocol.
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Written by: ___________________________________________ Date ____________ QA approved by: _______________________________________ Date ____________
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7.1 Systems and equipment should consistently perform in accordance with design specifications. The performance should be verified in accordance with a performance qualification protocol. 7.2 There should be documented records for the verification of performance (performance qualification report) to indicate the satisfactory performance over a period of time. Manufacturers should justify the selected period over which performance qualification is done.
7.1 Systems and equipment should consistently perform in accordance with design specifications. The performance should be verified in accordance with a performance qualification protocol. 7.2 There should be documented records for the verification of performance (performance qualification report) to indicate the satisfactory performance over a period of time. Manufacturers should justify the selected period over which performance qualification is done.
8. Requalification
Note: see also Supplementary guidelines on good manufacturing practices (GMP): validation. 8.1 Requalification of systems and equipment should be done in accordance with a defined schedule. The frequency of requalification may be determined on the basis of factors such as the analysis of results relating to calibration, verification and maintenance. 8.2 There should be periodic requalification. 8.3 There should be requalification after changes. The extent of requalification after the change should be justified based on a riskassessment of the change. Requalification after change should be considered as part of the change control procedure.
8. Requalification
Note: see also Supplementary guidelines on good manufacturing practices (GMP): validation. 8.1 Requalification of systems and equipment should be done in accordance with a defined schedule. The frequency of requalification may be determined on the basis of factors such as the analysis of results relating to calibration, verification and maintenance. 8.2 There should be periodic requalification. 8.3 There should be requalification after changes. The extent of requalification after the change should be justified based on a riskassessment of the change. Requalification after change should be considered as part of the change control procedure.
9. Qualification of in-use systems and equipment

9.1 There should be data to support and verify the suitable operation and performance of systems and equipment that have been in use for a period of time, and which had not been subjected to installation and or operational qualification. 9.2 These should include operating parameters and limits for critical variables, calibration, maintenance and preventive maintenance, standard operating procedures (SOPs) and records.
9. Qualification of in-use systems and equipment

9.1 There should be data to support and verify the suitable operation and performance of systems and equipment that have been in use for a period of time, and which had not been subjected to installation and or operational qualification. 9.2 These should include operating parameters and limits for critical variables, calibration, maintenance and preventive maintenance, standard operating procedures (SOPs) and records.
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Format for a performance qualification protocola

Validation protocol _______ Performance Qualification ______ Page _____ of _____ Title: ______________________ Name of facility: _____________________________ _________________________________________________________________________________ Validation Protocol # ________________ Performance Qualification number ________ Title __________________________________________________________________ ________________________________________________________________________________ Protocol written by _______________________________________________________ Departmental Approval by _________________________________ Date ____________ QA Approval by _________________________________________ Date ____________ Objective To determine that the systems/equipment perform as intended by repeatedly running the system on its intended schedules and recording all relevant information and data. Results must demonstrate that performance consistently meets pre-determined specifications under normal conditions, and where appropriate for worst case situations. Scope To be performed after the Installation and Operational Qualification have been completed and approved. To be performed after installation, modification or relocation and for re-validation at appropriate intervals. Each piece of equipment must be validated before it serves another piece of equipment/ system during validation of the latter (e.g. water system before steam generator; steam generator before autoclave).

Validation protocol _______ Performance Qualification ______ Page _____ of _____ Title: ______________________ Name of facility: _____________________________ _________________________________________________________________________________ Validation Protocol # ________________ Performance Qualification number ________ Title __________________________________________________________________ ________________________________________________________________________________ Protocol written by _______________________________________________________ Departmental Approval by _________________________________ Date ____________ QA Approval by _________________________________________ Date ____________ Objective To determine that the systems/equipment perform as intended by repeatedly running the system on its intended schedules and recording all relevant information and data. Results must demonstrate that performance consistently meets pre-determined specifications under normal conditions, and where appropriate for worst case situations. Scope To be performed after the Installation and Operational Qualification have been completed and approved. To be performed after installation, modification or relocation and for re-validation at appropriate intervals. Each piece of equipment must be validated before it serves another piece of equipment/ system during validation of the latter (e.g. water system before steam generator; steam generator before autoclave).
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(continued)
Validation protocol _______ Performance Qualification ______ Page _____ of _____ Title: ______________________ Name of facility: _____________________________ _________________________________________________________________________________ Responsibility Person responsible for operating the system or equipment will perform the qualification and record the information. The supervisor will supervise the study, verify the completion of the records and write the Deviation Report and the Performance Qualification Report. Qualify Assurance will review and approve the Performance Qualification Protocol and Report. Materials, Equipment, Documents SOPs for normal operations of the equipment or system under test (including data record forms, charts, diagrams materials and equipment needed). Attach copies. SOP list: ________________________________________________________________________________ ________________________________________________________________________________ ________________________________________________________________________________ ________________________________________________________________________________ ________________________________________________________________________________ ________________________________________________________________________________ SOPs specific for performance tests (including data record forms, charts, diagrams, materials and equipment needed, calculations and statistical analyses to be performed, and predetermined specifications and acceptance criteria). Attach copies. SOP list: ________________________________________________________________________________ ________________________________________________________________________________ ________________________________________________________________________________ ________________________________________________________________________________ ________________________________________________________________________________
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(continued)
Validation protocol _______ Performance Qualification ______ Page _____ of _____ Title: ______________________ Name of facility: _____________________________ _________________________________________________________________________________ Responsibility Person responsible for operating the system or equipment will perform the qualification and record the information. The supervisor will supervise the study, verify the completion of the records and write the Deviation Report and the Performance Qualification Report. Qualify Assurance will review and approve the Performance Qualification Protocol and Report. Materials, Equipment, Documents SOPs for normal operations of the equipment or system under test (including data record forms, charts, diagrams materials and equipment needed). Attach copies. SOP list: ________________________________________________________________________________ ________________________________________________________________________________ ________________________________________________________________________________ ________________________________________________________________________________ ________________________________________________________________________________ ________________________________________________________________________________ SOPs specific for performance tests (including data record forms, charts, diagrams, materials and equipment needed, calculations and statistical analyses to be performed, and predetermined specifications and acceptance criteria). Attach copies. SOP list: ________________________________________________________________________________ ________________________________________________________________________________ ________________________________________________________________________________ ________________________________________________________________________________ ________________________________________________________________________________
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(continued)
Validation protocol _______ Performance Qualification ______ Page _____ of _____ Title: ______________________ Name of facility: ___________________________ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Procedure Equipment: Run normal procedure three times for each use (configuration or load) and record all required data and any deviations to the procedure. Systems: Run for 20 consecutive working days, recording all required data and any deviations to the procedure. Prepare the Summary Data Record Form(Chart 1).

(continued)
Validation protocol _______ Performance Qualification ______ Page _____ of _____ Title: ______________________ Name of facility: ___________________________ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Procedure Equipment: Run normal procedure three times for each use (configuration or load) and record all required data and any deviations to the procedure. Systems: Run for 20 consecutive working days, recording all required data and any deviations to the procedure. Prepare the Summary Data Record Form(Chart 1).
Evaluation Attach all completed, signed data record forms. Complete the Summary Data Record Form (Chart 1). Perform all required calculations and statistical analyses (Chart 2). Compare to acceptance criteria (Chart 3). Prepare Deviation Report including the justification of acceptance and impact on the performance. Prepare a Performance Qualification Report: This should include: date study initiated; date completed; observations made; problems encountered; completeness of information collected; summary of deviation report; results of any tests; do results meet acceptance criteria; location of original data; other information relevant to the study; and conclusions on the validity of the equipment/system. Submit Performance Qualification Document to QA for review and approval.
Evaluation Attach all completed, signed data record forms. Complete the Summary Data Record Form (Chart 1). Perform all required calculations and statistical analyses (Chart 2). Compare to acceptance criteria (Chart 3). Prepare Deviation Report including the justification of acceptance and impact on the performance. Prepare a Performance Qualification Report: This should include: date study initiated; date completed; observations made; problems encountered; completeness of information collected; summary of deviation report; results of any tests; do results meet acceptance criteria; location of original data; other information relevant to the study; and conclusions on the validity of the equipment/system. Submit Performance Qualification Document to QA for review and approval.
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(continued)
Validation protocol _______ Performance Qualification ______ Page _____ of _____ Title: ______________________ Name of facility: ___________________________ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Chart 1: Summary Data Record (To be prepared for the specific procedure being tested)

(continued)
Validation protocol _______ Performance Qualification ______ Page _____ of _____ Title: ______________________ Name of facility: ___________________________ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Chart 1: Summary Data Record (To be prepared for the specific procedure being tested)
Performed by: ________________________________________ Date ____________ Verified by: __________________________________________ Date ____________
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Validation protocol _______ Performance Qualification ______ Page _____ of _____ Title: ______________________ Name of facility: ___________________________ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Chart 2: Calculations and Statistical Analyses

(continued)
Validation protocol _______ Performance Qualification ______ Page _____ of _____ Title: ______________________ Name of facility: ___________________________ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Chart 2: Calculations and Statistical Analyses
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Validation protocol _______ Performance Qualification ______ Page _____ of _____ Title: ______________________ Name of facility: ___________________________ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Chart 3: Acceptance Criteria vs. Performance Test Results Criteria Results Pass/Fail

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Validation protocol _______ Performance Qualification ______ Page _____ of _____ Title: ______________________ Name of facility: ___________________________ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Chart 3: Acceptance Criteria vs. Performance Test Results Criteria Results Pass/Fail
____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ Performed by: ________________________________________ Date ____________ Verified by: __________________________________________ Date ____________
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____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ ____________________ ____________________________________ _____________ Performed by: ________________________________________ Date ____________ Verified by: __________________________________________ Date ____________
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Validation protocol _______ Performance Qualification ______ Page _____ of _____ Title: ______________________ Name of facility: ___________________________ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Deviation Report Deviation(s):

(continued)
Validation protocol _______ Performance Qualification ______ Page _____ of _____ Title: ______________________ Name of facility: ___________________________ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Deviation Report Deviation(s):
Impact on operation, function or process:
Impact on operation, function or process:
Written by: ________________________________________ Date ____________ Verified by: ________________________________________ Date ____________
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Validation protocol _______ Performance Qualification ______ Page _____ of _____ Title: ______________________ Name of facility: ___________________________ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Performance Qualification Report Results:

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Validation protocol _______ Performance Qualification ______ Page _____ of _____ Title: ______________________ Name of facility: ___________________________ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Performance Qualification Report Results:
Conclusions:
Conclusions:
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10. Reference
A WHO guide to good manufacturing practice (GMP) requirements. Part 2: Validation. Geneva, Global Programme for Vaccines and Immunization, Vaccine Supply and Quality, Global Training Network, World Health Organization, 1997 (WHO/VSQ/97.02)
10. Reference
A WHO guide to good manufacturing practice (GMP) requirements. Part 2: Validation. Geneva, Global Programme for Vaccines and Immunization, Vaccine Supply and Quality, Global Training Network, World Health Organization, 1997 (WHO/VSQ/97.02)
Appendix 7
NON-STERILE PROCESS VALIDATION
1. Principle 2. Scope 3. General 4. Prospective validation 5. Concurrent validation 6. Retrospective validation 7. Revalidation 8. Change control
Appendix 7
NON-STERILE PROCESS VALIDATION
1. Principle 2. Scope 3. General 4. Prospective validation 5. Concurrent validation 6. Retrospective validation 7. Revalidation 8. Change control
1. Principle
1.1 Process validation provides documented evidence that a process is capable of reliably and repeatedly rendering a product of the required quality. 1.2 The principles of planning, organizing and performing process validation are similar to those for qualification. It should be done in accordance with process validation protocols, data should be collected and reviewed against predetermined acceptance criteria, and reflected in process validation reports.
1. Principle
1.1 Process validation provides documented evidence that a process is capable of reliably and repeatedly rendering a product of the required quality. 1.2 The principles of planning, organizing and performing process validation are similar to those for qualification. It should be done in accordance with process validation protocols, data should be collected and reviewed against predetermined acceptance criteria, and reflected in process validation reports.
2. Scope
2.1 These guidelines describe the general aspects of process validation for the manufacture of non-sterile finished products. 2.2 Normally process validation should cover at least the critical steps and parameters (e.g. those that may have an impact on the quality of the product) in the process of manufacturing a pharmaceutical product.
2. Scope
2.1 These guidelines describe the general aspects of process validation for the manufacture of non-sterile finished products. 2.2 Normally process validation should cover at least the critical steps and parameters (e.g. those that may have an impact on the quality of the product) in the process of manufacturing a pharmaceutical product.
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3. General
3.1 The policy and approach to process validation should be documented, e.g. in a validation master plan, and should include the critical process steps and parameters. 3.2 Process validation should normally begin only once qualification of support systems and equipment is completed. In some cases process validation may be conducted concurrently with performance qualification. 3.3 Process validation should normally be completed prior to the manufacture of finished product that is intended for sale (prospective validation). Process validation during routine production may also be acceptable (concurrent validation).
3. General
3.1 The policy and approach to process validation should be documented, e.g. in a validation master plan, and should include the critical process steps and parameters. 3.2 Process validation should normally begin only once qualification of support systems and equipment is completed. In some cases process validation may be conducted concurrently with performance qualification. 3.3 Process validation should normally be completed prior to the manufacture of finished product that is intended for sale (prospective validation). Process validation during routine production may also be acceptable (concurrent validation).
4. Prospective validation
4.1 Critical factors or parameters that may affect the quality of the finished product should be identified during product development. To achieve this, the production process should be broken down into individual steps, and each step should be evaluated (e.g. on the basis of experience or theoretical considerations). 4.2 The criticality of these factors should be determined through a worstcase challenge where possible. 4.3 Prospective validation should be done in accordance with a validation protocol. The protocol should include: a description of the process; a description of the experiment; details of the equipment and/or facilities to be used (including measuring or recording equipment) together with its calibration status; the variables to be monitored; the samples to be taken where, when, how, how many and how much (sample size);
4. Prospective validation
4.1 Critical factors or parameters that may affect the quality of the finished product should be identified during product development. To achieve this, the production process should be broken down into individual steps, and each step should be evaluated (e.g. on the basis of experience or theoretical considerations). 4.2 The criticality of these factors should be determined through a worstcase challenge where possible. 4.3 Prospective validation should be done in accordance with a validation protocol. The protocol should include: a description of the process; a description of the experiment; details of the equipment and/or facilities to be used (including measuring or recording equipment) together with its calibration status; the variables to be monitored; the samples to be taken where, when, how, how many and how much (sample size);
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the product performance characteristics/attributes to be monitored, together with the test methods; the acceptable limits; time schedules; personnel responsibilities; and details of methods for recording and evaluating results, including statistical analysis. 4.4 All equipment, the production environment and analytical testing methods to be used should have been fully validated (e.g. during installation qualification and operational qualification). 4.5 Personnel participating in the validation work should have been appropriately trained. 4.6 Batch manufacturing documentation to be used should be prepared after these critical parameters of the process have been identified, and machine settings, component specifications and environmental conditions have been determined and specified. 4.7 A number of batches of the final product should then be produced. The number of batches produced in this validation exercise should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation. 4.8 Data within the finally agreed parameters, from at least three consecutive batches, giving product of the desired quality may be considered to constitute a proper validation of the process. 4.9 The batches should be of the same size, and should be the same as the batch size intended in full-scale production. Where this is not possible, the reduced batch size should be considered in the design of the protocol and when full-scale production starts, the validity of any assumptions made should be demonstrated. 4.10 Extensive testing should be performed on the product at various stages during the manufacturing process of the batches, including on the final product and its package.
the product performance characteristics/attributes to be monitored, together with the test methods; the acceptable limits; time schedules; personnel responsibilities; and details of methods for recording and evaluating results, including statistical analysis. 4.4 All equipment, the production environment and analytical testing methods to be used should have been fully validated (e.g. during installation qualification and operational qualification). 4.5 Personnel participating in the validation work should have been appropriately trained. 4.6 Batch manufacturing documentation to be used should be prepared after these critical parameters of the process have been identified, and machine settings, component specifications and environmental conditions have been determined and specified. 4.7 A number of batches of the final product should then be produced. The number of batches produced in this validation exercise should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation. 4.8 Data within the finally agreed parameters, from at least three consecutive batches, giving product of the desired quality may be considered to constitute a proper validation of the process. 4.9 The batches should be of the same size, and should be the same as the batch size intended in full-scale production. Where this is not possible, the reduced batch size should be considered in the design of the protocol and when full-scale production starts, the validity of any assumptions made should be demonstrated. 4.10 Extensive testing should be performed on the product at various stages during the manufacturing process of the batches, including on the final product and its package.
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4.11 The results should be documented in the validation report. As a minimum, the report should include: a description of the process: batch/packaging document, including details of critical steps; a detailed summary of the results obtained from in-process and final testing, including data from failed tests. When raw data are not included, reference should be made to the sources used and where it can be found; any work done in addition to that specified in the protocol, or any deviations from the protocol should be formally noted along with an explanation; a review and comparison of the results with those expected; and formal acceptance or rejection of the work by the team or persons designated as being responsible for the validation, after completion of any corrective action or repeated work. 4.12 A conclusion and recommendation should be made on the extent of monitoring and the in-process controls necessary for routine production, on the basis of the results obtained. 4.13 The conclusion and recommendation should be incorporated into the batch manufacturing and batch packaging documents and/or standard operating procedures (SOPs) for routine use. Limits and frequencies of testing and monitoring should be specified. Actions to be taken in the event of the limits being exceeded should be specified. 4.14 Batches manufactured as part of the validation exercise, and intended to be sold or supplied, should have been manufactured under conditions that comply fully with the requirements of good manufacturing practice and the marketing authorization (where applicable).
4.11 The results should be documented in the validation report. As a minimum, the report should include: a description of the process: batch/packaging document, including details of critical steps; a detailed summary of the results obtained from in-process and final testing, including data from failed tests. When raw data are not included, reference should be made to the sources used and where it can be found; any work done in addition to that specified in the protocol, or any deviations from the protocol should be formally noted along with an explanation; a review and comparison of the results with those expected; and formal acceptance or rejection of the work by the team or persons designated as being responsible for the validation, after completion of any corrective action or repeated work. 4.12 A conclusion and recommendation should be made on the extent of monitoring and the in-process controls necessary for routine production, on the basis of the results obtained. 4.13 The conclusion and recommendation should be incorporated into the batch manufacturing and batch packaging documents and/or standard operating procedures (SOPs) for routine use. Limits and frequencies of testing and monitoring should be specified. Actions to be taken in the event of the limits being exceeded should be specified. 4.14 Batches manufactured as part of the validation exercise, and intended to be sold or supplied, should have been manufactured under conditions that comply fully with the requirements of good manufacturing practice and the marketing authorization (where applicable).
5. Concurrent validation
5.1 In certain cases, it may be appropriate to validate a process during routine production, e.g. where the product is a different strength of a previously validated product, a different tablet shape or where the process is well understood.
5. Concurrent validation
5.1 In certain cases, it may be appropriate to validate a process during routine production, e.g. where the product is a different strength of a previously validated product, a different tablet shape or where the process is well understood.
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5.2 The decision to carry out concurrent validation should be made by appropriately authorized personnel. 5.3 It is essential that the premises and equipment to be used during concurrent validation have been previously qualified. 5.4 Prospective validation should be done in accordance with a validation protocol. 5.5 The results should be documented in the validation report.
5.2 The decision to carry out concurrent validation should be made by appropriately authorized personnel. 5.3 It is essential that the premises and equipment to be used during concurrent validation have been previously qualified. 5.4 Prospective validation should be done in accordance with a validation protocol. 5.5 The results should be documented in the validation report.
6. Retrospective validation
6.1 Retrospective validation is based on a comprehensive review of historical data to provide the necessary documentary evidence that the process is doing what it is believed to do. This type of validation also requires the preparation of a protocol, the reporting of the results of the data review, a conclusion and a recommendation. 6.2 Retrospective validation is not the preferred method of validation and should be used in exceptional cases only. It is acceptable only for wellestablished processes and will be inappropriate where there have been changes in the composition of the product, operating procedures or equipment. 6.3 Sufficient data should be reviewed to provide a statistically significant conclusion. 6.4 When the results of retrospective validation are considered satisfactory, this should serve only as an indication that the process does not need to be subjected to validation in the immediate future.
6. Retrospective validation
6.1 Retrospective validation is based on a comprehensive review of historical data to provide the necessary documentary evidence that the process is doing what it is believed to do. This type of validation also requires the preparation of a protocol, the reporting of the results of the data review, a conclusion and a recommendation. 6.2 Retrospective validation is not the preferred method of validation and should be used in exceptional cases only. It is acceptable only for wellestablished processes and will be inappropriate where there have been changes in the composition of the product, operating procedures or equipment. 6.3 Sufficient data should be reviewed to provide a statistically significant conclusion. 6.4 When the results of retrospective validation are considered satisfactory, this should serve only as an indication that the process does not need to be subjected to validation in the immediate future.
7. Revalidation
Note: see main text on Validation. The need for periodic revalidation of non-sterile processes is considered to be a lower priority than for sterile processes.
7. Revalidation
Note: see main text on Validation. The need for periodic revalidation of non-sterile processes is considered to be a lower priority than for sterile processes.
7.1 In the case of standard processes using conventional equipment, a data review similar to that which would be required for retrospective validation may provide an adequate assurance that the process continues to be under control. The following points should also be considered: the occurrence of any changes in the master formula, methods, starting material manufacturer, equipment and/or instruments; equipment calibrations and preventive maintenance carried out; standard operating procedures (SOPs); and cleaning and hygiene programme.
7.1 In the case of standard processes using conventional equipment, a data review similar to that which would be required for retrospective validation may provide an adequate assurance that the process continues to be under control. The following points should also be considered: the occurrence of any changes in the master formula, methods, starting material manufacturer, equipment and/or instruments; equipment calibrations and preventive maintenance carried out; standard operating procedures (SOPs); and cleaning and hygiene programme.
8. Change control
Note: see main text on Validation. 8.1 Products manufactured by processes that have been subjected to changes should not be released for sale without full awareness and consideration of the change and its impact on the process validation. 8.2 Changes that are likely to require revalidation may include: changes in the manufacturing process (e.g. mixing times, drying temperatures); changes in the equipment (e.g. addition of automatic detection systems); production area and support system changes (e.g. rearrangement of areas or a new water treatment method); transfer of processes to another site; and unexpected changes (e.g. those observed during self-inspection or during routine analysis of process trend data).
8. Change control
Note: see main text on Validation. 8.1 Products manufactured by processes that have been subjected to changes should not be released for sale without full awareness and consideration of the change and its impact on the process validation. 8.2 Changes that are likely to require revalidation may include: changes in the manufacturing process (e.g. mixing times, drying temperatures); changes in the equipment (e.g. addition of automatic detection systems); production area and support system changes (e.g. rearrangement of areas or a new water treatment method); transfer of processes to another site; and unexpected changes (e.g. those observed during self-inspection or during routine analysis of process trend data).
WHO
GOOD MANUFACTURING PRACTICES
WHO
GOOD MANUFACTURING PRACTICES
validation of api manufacturing processes

Introduction These guidelines do not constitute additional requirements in the area of good manufacturing practices (GMP). The purpose of this Annex is to explain and promote the concept of validation, and to assist in establishing priorities and selecting approaches when a validation programme is being developed. Since the WHO guide on GMP (1) is applicable essentially to the manufacture of pharmaceutical dosage forms, this text is also concerned with the production of such finished forms. However, the general principles of process validation outlined here are relevant mainly to the manufacture of active ingredients. While the emphasis is on the production processes, many recommendations are also valid for supporting operations, such as cleaning. Analytical validation is not discussed here. Further advice is given in Validation of analytical procedures used in the examination of pharmaceutical materials (2). The guide on GMP for pharmaceutical products (section 5) (1, page 27) requires the validation of critical processes as well as of changes in the manufacturing process which may affect product quality. Experience shows that few manufacturing processes do not contain steps which are critical that may cause variations in final product quality. A prudent manufacturer would therefore normally validate all production processes and supporting activities, including cleaning operations. The term critical process in this context indicates a process, operation or step that requires particularly close attention, e.g. sterilization, where the effect on product quality is crucial. It may be noted that certain GMP guides, e.g. that of the European Community (3), do not distinguish between critical and non-critical processes from the point of view of validation.
validation of api manufacturing processes

Introduction These guidelines do not constitute additional requirements in the area of good manufacturing practices (GMP). The purpose of this Annex is to explain and promote the concept of validation, and to assist in establishing priorities and selecting approaches when a validation programme is being developed. Since the WHO guide on GMP (1) is applicable essentially to the manufacture of pharmaceutical dosage forms, this text is also concerned with the production of such finished forms. However, the general principles of process validation outlined here are relevant mainly to the manufacture of active ingredients. While the emphasis is on the production processes, many recommendations are also valid for supporting operations, such as cleaning. Analytical validation is not discussed here. Further advice is given in Validation of analytical procedures used in the examination of pharmaceutical materials (2). The guide on GMP for pharmaceutical products (section 5) (1, page 27) requires the validation of critical processes as well as of changes in the manufacturing process which may affect product quality. Experience shows that few manufacturing processes do not contain steps which are critical that may cause variations in final product quality. A prudent manufacturer would therefore normally validate all production processes and supporting activities, including cleaning operations. The term critical process in this context indicates a process, operation or step that requires particularly close attention, e.g. sterilization, where the effect on product quality is crucial. It may be noted that certain GMP guides, e.g. that of the European Community (3), do not distinguish between critical and non-critical processes from the point of view of validation.
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Glossary The definitions given below apply to the terms used in these guidelines. They may have different meanings in other contexts. calibration The performance of tests and retests to ensure that measuring equipment (e.g. for temperature, weight, pH) used in a manufacturing process or analytical procedure (in production or quality control) gives measurements that are correct within established limits. certification The final review and formal approval of a validation or revalidation, followed by approval of a process for routine use. challenge tests/worst case A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, that pose the greatest chance of process or product failure when compared with ideal conditions. installation qualification The performance of tests to ensure that the installations (such as machines, measuring devices, utilities, manufacturing areas) used in a manufacturing process are appropriately selected and correctly installed and operate in accordance with established specifications. manufacturing process (For the purpose of these guidelines, manufacturing process is used as a synonym of production process. ) The transformation of starting materials into finished products (drug substances or pharmaceutical dosage forms) through a single operation or a sequence of operations involving installations, personnel, documentation and environment. operational qualification Documented verification that the system or subsystem performs as intended over all anticipated operating ranges.
Glossary The definitions given below apply to the terms used in these guidelines. They may have different meanings in other contexts. calibration The performance of tests and retests to ensure that measuring equipment (e.g. for temperature, weight, pH) used in a manufacturing process or analytical procedure (in production or quality control) gives measurements that are correct within established limits. certification The final review and formal approval of a validation or revalidation, followed by approval of a process for routine use. challenge tests/worst case A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, that pose the greatest chance of process or product failure when compared with ideal conditions. installation qualification The performance of tests to ensure that the installations (such as machines, measuring devices, utilities, manufacturing areas) used in a manufacturing process are appropriately selected and correctly installed and operate in accordance with established specifications. manufacturing process (For the purpose of these guidelines, manufacturing process is used as a synonym of production process. ) The transformation of starting materials into finished products (drug substances or pharmaceutical dosage forms) through a single operation or a sequence of operations involving installations, personnel, documentation and environment. operational qualification Documented verification that the system or subsystem performs as intended over all anticipated operating ranges.
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qualification of equipment The act of planning, carrying out and recording the results of tests on equipment to demonstrate that it will perform as intended. Measuring instruments and systems must be calibrated. revalidation Repeated validation of an approved process (or a part thereof) to ensure continued compliance with established requirements. validation The collection and evaluation of data, beginning at the process development stage and continuing through the production phase, which ensure that the manufacturing processes - including equipment, buildings, personnel and materials - are capable of achieving the intended results on a consistent and continuous basis. Validation is the establishment of documented evidence that a system does what it is supposed to do. Other definitions also exist, e.g. that given in the guidelines on GMP for pharmaceutical products (1, page 22). validation protocol (or plan) A document describing the activities to be performed in a validation, including the acceptance criteria for the approval of a manufacturing process - or a part thereof - for routine use. validation report A document in which the records, results and evaluation of a completed validation programme are assembled. It may also contain proposals for the improvement of processes and/or equipment. General Validation is an integral part of quality assurance, but the use of this term in connection with manufacturing often gives rise to difficulties. As defined above, it involves the systematic study of systems, facilities and processes aimed at determining whether they perform their intended functions adequately and consistently as specified. A validated operation is one which has been demonstrated to provide a high degree of assurance that uniform batches will be produced that meet the required specifications, and has therefore been formally approved.
qualification of equipment The act of planning, carrying out and recording the results of tests on equipment to demonstrate that it will perform as intended. Measuring instruments and systems must be calibrated. revalidation Repeated validation of an approved process (or a part thereof) to ensure continued compliance with established requirements. validation The collection and evaluation of data, beginning at the process development stage and continuing through the production phase, which ensure that the manufacturing processes - including equipment, buildings, personnel and materials - are capable of achieving the intended results on a consistent and continuous basis. Validation is the establishment of documented evidence that a system does what it is supposed to do. Other definitions also exist, e.g. that given in the guidelines on GMP for pharmaceutical products (1, page 22). validation protocol (or plan) A document describing the activities to be performed in a validation, including the acceptance criteria for the approval of a manufacturing process - or a part thereof - for routine use. validation report A document in which the records, results and evaluation of a completed validation programme are assembled. It may also contain proposals for the improvement of processes and/or equipment. General Validation is an integral part of quality assurance, but the use of this term in connection with manufacturing often gives rise to difficulties. As defined above, it involves the systematic study of systems, facilities and processes aimed at determining whether they perform their intended functions adequately and consistently as specified. A validated operation is one which has been demonstrated to provide a high degree of assurance that uniform batches will be produced that meet the required specifications, and has therefore been formally approved.
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Unlike many other requirements of GMP, validation in itself does not improve processes. It can only confirm (or not, as the case may be) that the process has been properly developed and is under control. Ideally, any development activity in the later stages should be finalized by a validation phase. This includes, in particular, the manufacture of investigational products and the scaling up of processes from pilot plant to production unit. In this event, GMP as manufacturing practice may only be concerned with revalidation, e.g. when processes are transferred from development to production, after modifications are introduced (in starting materials, equipment, etc.) or when periodic revalidation is performed. (It may be noted that in some countries data on process validation are required at the preregistration stage (in the submission of, or application for, marketing authorizations)). However, it cannot be assumed that all processes in the pharmaceutical industry worldwide have been properly validated at the development stage. Consequently, validation is discussed here in a broader context as an activity which is initiated in development and is continued until the stage of full-scale production is reached. In fact, it is in the course of development that critical processes, steps or unit operations are identified. Good validation practice requires the close collaboration of departments such as those concerned with development, production, engineering, quality assurance and control. This is most important when processes go into routine full-scale production following pharmaceutical development and pilot-plant operations. With a view to facilitating subsequent validation and its assessment in the course of quality audits or regulatory inspections, it is recommended that all documentation reflecting such transfers be kept together in a separate file (technology transfer document). Adequate validation may be beneficial for the manufacturer in many ways: It deepens the understanding of processes, decreases the risks of processing problems, and thus assures the smooth running of the process. It decreases the risks of defect costs. It decreases the risks of regulatory non-compliance.
Unlike many other requirements of GMP, validation in itself does not improve processes. It can only confirm (or not, as the case may be) that the process has been properly developed and is under control. Ideally, any development activity in the later stages should be finalized by a validation phase. This includes, in particular, the manufacture of investigational products and the scaling up of processes from pilot plant to production unit. In this event, GMP as manufacturing practice may only be concerned with revalidation, e.g. when processes are transferred from development to production, after modifications are introduced (in starting materials, equipment, etc.) or when periodic revalidation is performed. (It may be noted that in some countries data on process validation are required at the preregistration stage (in the submission of, or application for, marketing authorizations)). However, it cannot be assumed that all processes in the pharmaceutical industry worldwide have been properly validated at the development stage. Consequently, validation is discussed here in a broader context as an activity which is initiated in development and is continued until the stage of full-scale production is reached. In fact, it is in the course of development that critical processes, steps or unit operations are identified. Good validation practice requires the close collaboration of departments such as those concerned with development, production, engineering, quality assurance and control. This is most important when processes go into routine full-scale production following pharmaceutical development and pilot-plant operations. With a view to facilitating subsequent validation and its assessment in the course of quality audits or regulatory inspections, it is recommended that all documentation reflecting such transfers be kept together in a separate file (technology transfer document). Adequate validation may be beneficial for the manufacturer in many ways: It deepens the understanding of processes, decreases the risks of processing problems, and thus assures the smooth running of the process. It decreases the risks of defect costs. It decreases the risks of regulatory non-compliance.
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A fully validated process may require less in-process control and endproduct testing. 1. Types of process validation Depending on when it is performed in relation to production, validation can be prospective, concurrent, retrospective or revalidation (repeated validation). Prospective validation is carried out during the development stage by means of a risk analysis of the production process, which is broken down into individual steps; these are then evaluated on the basis of past experience to determine whether they might lead to critical situations. Where possible critical situations are identified, the risk is evaluated, the potential causes are investigated and assessed for probability and extent, the trial plans are drawn up, and the priorities set. The trials are then performed and evaluated, and an overall assessment is made. If, at the end, the results are acceptable, the process is satisfactory. Unsatisfactory processes must be modified and improved until a validation exercise proves them to be satisfactory. This form of validation is essential in order to limit the risk of errors occurring on the production scale, e.g. in the preparation of injectable products. Concurrent validation is carried out during normal production. This method is effective only if the development stage has resulted in a proper understanding of the fundamentals of the process. The first three production-scale batches must be monitored as comprehensively as possible. (This careful monitoring of the first three production batches is sometimes regarded as prospective validation.) The nature and specifications of subsequent in-process and final tests are based on the evaluation of the results of such monitoring. Concurrent validation together with a trend analysis including stability should be carried out to an appropriate extent throughout the life of the product. Retrospective validation involves the examination of past experience of production on the assumption that composition, procedures, and equipment remain unchanged; such experience and the results of inprocess and final control tests are then evaluated. Recorded difficulties and failures in production are analysed to determine the limits of
A fully validated process may require less in-process control and endproduct testing. 1. Types of process validation Depending on when it is performed in relation to production, validation can be prospective, concurrent, retrospective or revalidation (repeated validation). Prospective validation is carried out during the development stage by means of a risk analysis of the production process, which is broken down into individual steps; these are then evaluated on the basis of past experience to determine whether they might lead to critical situations. Where possible critical situations are identified, the risk is evaluated, the potential causes are investigated and assessed for probability and extent, the trial plans are drawn up, and the priorities set. The trials are then performed and evaluated, and an overall assessment is made. If, at the end, the results are acceptable, the process is satisfactory. Unsatisfactory processes must be modified and improved until a validation exercise proves them to be satisfactory. This form of validation is essential in order to limit the risk of errors occurring on the production scale, e.g. in the preparation of injectable products. Concurrent validation is carried out during normal production. This method is effective only if the development stage has resulted in a proper understanding of the fundamentals of the process. The first three production-scale batches must be monitored as comprehensively as possible. (This careful monitoring of the first three production batches is sometimes regarded as prospective validation.) The nature and specifications of subsequent in-process and final tests are based on the evaluation of the results of such monitoring. Concurrent validation together with a trend analysis including stability should be carried out to an appropriate extent throughout the life of the product. Retrospective validation involves the examination of past experience of production on the assumption that composition, procedures, and equipment remain unchanged; such experience and the results of inprocess and final control tests are then evaluated. Recorded difficulties and failures in production are analysed to determine the limits of
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process parameters. A trend analysis may be conducted to determine the extent to which the process parameters are within the permissible range. Retrospective validation is obviously not a quality assurance measure in itself, and should never be applied to new processes or products. It may be considered in special circumstances only, e.g. when validation requirements are first introduced in a company. Retrospective validation may then be useful in establishing the priorities for the validation programme. If the results of a retrospective validation are positive, this indicates that the process is not in need of immediate attention and may be validated in accordance with the normal schedule. For tablets which have been compressed under individual pressuresensitive cells, and with qualified equipment, retrospective validation is the most comprehensive test of the overall manufacturing process of this dosage form. On the other hand, it should not be applied in the manufacture of sterile products. Revalidation is needed to ensure that changes in the process and/or in the process environment, whether intentional or unintentional, do not adversely affect process characteristics and product quality. Revalidation may be divided into two broad categories: Revalidation after any change having a bearing on product quality. Periodic revalidation carried out at scheduled intervals. Revalidation after changes. Revalidation must be performed on introduction of any changes affecting a manufacturing and/or standard procedure having a bearing on the established product performance characteristics. Such changes may include those in starting material, packaging material, manufacturing processes, equipment, in-process controls, manufacturing areas, or support systems (water, steam, etc.). Every such change requested should be reviewed by a qualified validation group, which will decide whether it is significant enough to justify revalidation and, if so, its extent. Revalidation after changes may be based on the performance of the same tests and activities as those used during the original validation, including tests on subprocesses and on the equipment concerned. Some typical changes which require revalidation include the following:
process parameters. A trend analysis may be conducted to determine the extent to which the process parameters are within the permissible range. Retrospective validation is obviously not a quality assurance measure in itself, and should never be applied to new processes or products. It may be considered in special circumstances only, e.g. when validation requirements are first introduced in a company. Retrospective validation may then be useful in establishing the priorities for the validation programme. If the results of a retrospective validation are positive, this indicates that the process is not in need of immediate attention and may be validated in accordance with the normal schedule. For tablets which have been compressed under individual pressuresensitive cells, and with qualified equipment, retrospective validation is the most comprehensive test of the overall manufacturing process of this dosage form. On the other hand, it should not be applied in the manufacture of sterile products. Revalidation is needed to ensure that changes in the process and/or in the process environment, whether intentional or unintentional, do not adversely affect process characteristics and product quality. Revalidation may be divided into two broad categories: Revalidation after any change having a bearing on product quality. Periodic revalidation carried out at scheduled intervals. Revalidation after changes. Revalidation must be performed on introduction of any changes affecting a manufacturing and/or standard procedure having a bearing on the established product performance characteristics. Such changes may include those in starting material, packaging material, manufacturing processes, equipment, in-process controls, manufacturing areas, or support systems (water, steam, etc.). Every such change requested should be reviewed by a qualified validation group, which will decide whether it is significant enough to justify revalidation and, if so, its extent. Revalidation after changes may be based on the performance of the same tests and activities as those used during the original validation, including tests on subprocesses and on the equipment concerned. Some typical changes which require revalidation include the following:
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Changes in the starting material(s). Changes in the physical properties, such as density, viscosity, particle size distribution, and crystal type and modification, of the active ingredients or excipients may affect the mechanical properties of the material; as a consequence, they may adversely affect the process or the product. Changes in the packaging material, e.g. replacing plastics by glass, may require changes in the packaging procedure and therefore affect product stability. Changes in the process, e.g. changes in mixing time, drying temperature and cooling regime, may affect subsequent process steps and product quality. Changes in equipment, including measuring instruments, may affect both the process and the product; repair and maintenance work, such as the replacement of major equipment components, may affect the process. Changes in the production area and support system, e.g. the rearrangement of manufacturing areas and/or support systems, may result in changes in the process. The repair and maintenance of support systems, such as ventilation, may change the environmental conditions and, as a consequence, revalidation/requalification may be necessary, mainly in the manufacture of sterile products. Unexpected changes and deviations may be observed during selfinspection or audit, or during the continuous trend analysis of process data. Periodic revalidation. It is well known that process changes may occur gradually even if experienced operators work correctly according to established methods. Similarly, equipment wear may also cause gradual changes. Consequently, revalidation at scheduled times is advisable even if no changes have been deliberately made. The decision to introduce periodic revalidation should be based essentially on a review of historical data, i.e. data generated during inprocess and finished product testing after the latest validation, aimed at verifying that the process is under control. During the review of such historical data, any trend in the data collected should be evaluated.
Changes in the starting material(s). Changes in the physical properties, such as density, viscosity, particle size distribution, and crystal type and modification, of the active ingredients or excipients may affect the mechanical properties of the material; as a consequence, they may adversely affect the process or the product. Changes in the packaging material, e.g. replacing plastics by glass, may require changes in the packaging procedure and therefore affect product stability. Changes in the process, e.g. changes in mixing time, drying temperature and cooling regime, may affect subsequent process steps and product quality. Changes in equipment, including measuring instruments, may affect both the process and the product; repair and maintenance work, such as the replacement of major equipment components, may affect the process. Changes in the production area and support system, e.g. the rearrangement of manufacturing areas and/or support systems, may result in changes in the process. The repair and maintenance of support systems, such as ventilation, may change the environmental conditions and, as a consequence, revalidation/requalification may be necessary, mainly in the manufacture of sterile products. Unexpected changes and deviations may be observed during selfinspection or audit, or during the continuous trend analysis of process data. Periodic revalidation. It is well known that process changes may occur gradually even if experienced operators work correctly according to established methods. Similarly, equipment wear may also cause gradual changes. Consequently, revalidation at scheduled times is advisable even if no changes have been deliberately made. The decision to introduce periodic revalidation should be based essentially on a review of historical data, i.e. data generated during inprocess and finished product testing after the latest validation, aimed at verifying that the process is under control. During the review of such historical data, any trend in the data collected should be evaluated.
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In some processes, such as sterilization, additional process testing is required to complement the historical data. The degree of testing required will be apparent from the original validation. Additionally, the following points should be checked at the time of a scheduled revalidation: Have any changes in master formula and methods, batch size, etc., occurred? If so, has their impact on the product been assessed? Have calibrations been made in accordance with the established programme and time schedule? Has preventive maintenance been performed in accordance with the programme and time schedule? Have the standard operating procedures (SOPs) been properly updated? Have the SOPs been implemented? Have the cleaning and hygiene programmes been carried out? Have any changes been made in the analytical control methods? 2. Prerequisites for process validation Before process validation can be started, manufacturing equipment and control instruments, as well as the formulation, must be qualified. The formulation of a pharmaceutical product should be studied in detail and qualified at the development stage, i.e. before the application for the marketing authorization is submitted. This involves preformulation studies, studies on the compatibility of active ingredients and excipients, and of final drug product and packaging material, stability studies, etc. Other aspects of manufacture must be validated, including critical services (water, air, nitrogen, power supply, etc.), and supporting operations, such as equipment cleaning and sanitation of premises. Proper training and motivation of personnel are prerequisites to successful validation.
In some processes, such as sterilization, additional process testing is required to complement the historical data. The degree of testing required will be apparent from the original validation. Additionally, the following points should be checked at the time of a scheduled revalidation: Have any changes in master formula and methods, batch size, etc., occurred? If so, has their impact on the product been assessed? Have calibrations been made in accordance with the established programme and time schedule? Has preventive maintenance been performed in accordance with the programme and time schedule? Have the standard operating procedures (SOPs) been properly updated? Have the SOPs been implemented? Have the cleaning and hygiene programmes been carried out? Have any changes been made in the analytical control methods? 2. Prerequisites for process validation Before process validation can be started, manufacturing equipment and control instruments, as well as the formulation, must be qualified. The formulation of a pharmaceutical product should be studied in detail and qualified at the development stage, i.e. before the application for the marketing authorization is submitted. This involves preformulation studies, studies on the compatibility of active ingredients and excipients, and of final drug product and packaging material, stability studies, etc. Other aspects of manufacture must be validated, including critical services (water, air, nitrogen, power supply, etc.), and supporting operations, such as equipment cleaning and sanitation of premises. Proper training and motivation of personnel are prerequisites to successful validation.
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3. Approaches Two basic approaches to the validation of the process itself exist (apart from the qualification of equipment used in production, the calibration of control and measurement instruments, the evaluation of environmental factors, etc.), namely the experimental approach and the approach based on the analysis of historical data. The experimental approach, which is applicable to both prospective and concurrent validation, may involve: Extensive product testing. Simulation process trials. Challenge/worst case trials. Controls of process parameters (mostly physical). One of the most practical forms of process validation, mainly for nonsterile products, is the final testing of the product to an extent greater than that required in routine quality control. It may involve extensive sampling, far beyond that called for in routine quality control and testing to normal quality control specifications, and often for certain parameters only. Thus, for instance, several hundred tablets per batch may be weighed to determine unit dose uniformity. The results are then treated statistically to verify the normality of the distribution, and to determine the standard deviation from the average weight. Confidence limits for individual results and for batch homogeneity are also estimated. Strong assurance is provided that samples taken at random will meet regulatory requirements if the confidence limits are well within compendial specifications. Similarly, extensive sampling and testing may be performed with regard to any quality requirements. In addition, intermediate stages may be validated in the same way, e.g. dozens of samples may be assayed individually to validate mixing or granulation stages of lowdose tablet production by using the content uniformity test. Products (intermediate or final) may occasionally be tested for non-routine characteristics. Thus, subvisual particulate matter in parenteral preparations may be determined by means of electronic devices, or tablets/capsules tested for dissolution profile if such tests are not performed on every batch.
3. Approaches Two basic approaches to the validation of the process itself exist (apart from the qualification of equipment used in production, the calibration of control and measurement instruments, the evaluation of environmental factors, etc.), namely the experimental approach and the approach based on the analysis of historical data. The experimental approach, which is applicable to both prospective and concurrent validation, may involve: Extensive product testing. Simulation process trials. Challenge/worst case trials. Controls of process parameters (mostly physical). One of the most practical forms of process validation, mainly for nonsterile products, is the final testing of the product to an extent greater than that required in routine quality control. It may involve extensive sampling, far beyond that called for in routine quality control and testing to normal quality control specifications, and often for certain parameters only. Thus, for instance, several hundred tablets per batch may be weighed to determine unit dose uniformity. The results are then treated statistically to verify the normality of the distribution, and to determine the standard deviation from the average weight. Confidence limits for individual results and for batch homogeneity are also estimated. Strong assurance is provided that samples taken at random will meet regulatory requirements if the confidence limits are well within compendial specifications. Similarly, extensive sampling and testing may be performed with regard to any quality requirements. In addition, intermediate stages may be validated in the same way, e.g. dozens of samples may be assayed individually to validate mixing or granulation stages of lowdose tablet production by using the content uniformity test. Products (intermediate or final) may occasionally be tested for non-routine characteristics. Thus, subvisual particulate matter in parenteral preparations may be determined by means of electronic devices, or tablets/capsules tested for dissolution profile if such tests are not performed on every batch.
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Simulation process trials are used mainly to validate the aseptic filling of parenteral products that cannot be terminally sterilized. This involves filling ampoules with culture media under normal conditions, followed by incubation and control of microbial growth. In the past, a level of contamination of less than 0.3% was considered to be acceptable; however, the current target level should not exceed 0.1%. Challenge experiments are performed to determine the robustness of the process, i.e. its capacity to operate smoothly when parameters approach acceptable limits. The use of ranges of parameters for the quality of the starting materials in experimental batches may make it possible to estimate the extent to which the process is still capable of producing an end-product that meets the specifications. The physical parameters of the process are monitored in normal production runs to obtain additional information on the process and its reliability. Extra temperature-sensitive devices installed in an autoclave or dry-heat sterilizer (in addition to probes used routinely) will permit an in-depth study of the heat distribution for several loads. Heatpenetration measurements are recommended for injectable products of higher viscosity or with volumes larger than 5 ml. A tableting press equipped with pressure-sensitive cells will be helpful in collecting statistical data on the uniformity of die-fill and therefore on mass uniformity. In the approach based on the analysis of historical data, no experiments are performed in retrospective validation, but instead all available historical data concerning a number of batches are combined and jointly analysed. If production is proceeding smoothly during the period preceding validation, the data from in-process inspection and final testing of the product are combined and treated statistically. The results, including the outcome of process capability studies, trend analysis, etc., will indicate whether the process is under control or not. Quality control charts may be used for retrospective validation. A total of 10 - 25 batches or more are used for this purpose, preferably processed over a period of no longer than 12 months, and reviewed together. (Batches rejected during routine quality control are not included in this review since they belong to a different population, but failure investigations are performed separately.) A critical quality parameter of the end-product is selected, e.g. the assay value or potency,
Simulation process trials are used mainly to validate the aseptic filling of parenteral products that cannot be terminally sterilized. This involves filling ampoules with culture media under normal conditions, followed by incubation and control of microbial growth. In the past, a level of contamination of less than 0.3% was considered to be acceptable; however, the current target level should not exceed 0.1%. Challenge experiments are performed to determine the robustness of the process, i.e. its capacity to operate smoothly when parameters approach acceptable limits. The use of ranges of parameters for the quality of the starting materials in experimental batches may make it possible to estimate the extent to which the process is still capable of producing an end-product that meets the specifications. The physical parameters of the process are monitored in normal production runs to obtain additional information on the process and its reliability. Extra temperature-sensitive devices installed in an autoclave or dry-heat sterilizer (in addition to probes used routinely) will permit an in-depth study of the heat distribution for several loads. Heatpenetration measurements are recommended for injectable products of higher viscosity or with volumes larger than 5 ml. A tableting press equipped with pressure-sensitive cells will be helpful in collecting statistical data on the uniformity of die-fill and therefore on mass uniformity. In the approach based on the analysis of historical data, no experiments are performed in retrospective validation, but instead all available historical data concerning a number of batches are combined and jointly analysed. If production is proceeding smoothly during the period preceding validation, the data from in-process inspection and final testing of the product are combined and treated statistically. The results, including the outcome of process capability studies, trend analysis, etc., will indicate whether the process is under control or not. Quality control charts may be used for retrospective validation. A total of 10 - 25 batches or more are used for this purpose, preferably processed over a period of no longer than 12 months, and reviewed together. (Batches rejected during routine quality control are not included in this review since they belong to a different population, but failure investigations are performed separately.) A critical quality parameter of the end-product is selected, e.g. the assay value or potency,
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unit dose uniformity, disintegration time, or extent of dissolution. The analytical results for this parameter for the batches under review are extracted from past batch release documentation and pooled together, while the results from each batch are treated as subgroups. The grand average (process average) and control limits are calculated and plotted on graphs or charts in accordance with the instructions given in numerous publications on control charts. A careful review of the charts will enable the reliability of the process to be estimated. A process may be considered reliable if the plotted data are within the control limits and the variability of individual results is stable or tends to decrease. Otherwise, an investigation and possibly an improvement are needed. (It may be noted that, once control charts for past batches have been prepared, they become a powerful tool for prospective quality management. Data for new batches are plotted on the same charts and, for every result outside control limits, a reason, that is a new factor affecting the process, is sought and, when found, eliminated. By consistently applying this approach over a period of time the process may be considerably improved.) In addition, information on product-related problems is also analysed. The reliability of the process is demonstrated if, for a considerable time, there are no rejections, complaints, returns, unaccountable adverse reactions, etc. The process may be certified as retrospectively validated if the results of statistical analysis are positive and the absence of serious problems is documented. However, it should be emphasized that this approach is not applicable to the manufacture of sterile products. 4. Organization Several possible methods of organizing validation are available, one of which is the establishment of a validation group. For this purpose, the management appoints a person responsible for validation (validation officer), who then forms the group (team, committee). This is headed by a group leader, and represents all major departments: development, production, engineering, quality assurance and control. The composition of the group should be changed from time to time to give opportunities to other people to generate new ideas and to gain experience. The validation group then prepares a programme, which determines the scope of its work, its priorities, the time-schedule, the resources needed, etc. The programme
unit dose uniformity, disintegration time, or extent of dissolution. The analytical results for this parameter for the batches under review are extracted from past batch release documentation and pooled together, while the results from each batch are treated as subgroups. The grand average (process average) and control limits are calculated and plotted on graphs or charts in accordance with the instructions given in numerous publications on control charts. A careful review of the charts will enable the reliability of the process to be estimated. A process may be considered reliable if the plotted data are within the control limits and the variability of individual results is stable or tends to decrease. Otherwise, an investigation and possibly an improvement are needed. (It may be noted that, once control charts for past batches have been prepared, they become a powerful tool for prospective quality management. Data for new batches are plotted on the same charts and, for every result outside control limits, a reason, that is a new factor affecting the process, is sought and, when found, eliminated. By consistently applying this approach over a period of time the process may be considerably improved.) In addition, information on product-related problems is also analysed. The reliability of the process is demonstrated if, for a considerable time, there are no rejections, complaints, returns, unaccountable adverse reactions, etc. The process may be certified as retrospectively validated if the results of statistical analysis are positive and the absence of serious problems is documented. However, it should be emphasized that this approach is not applicable to the manufacture of sterile products. 4. Organization Several possible methods of organizing validation are available, one of which is the establishment of a validation group. For this purpose, the management appoints a person responsible for validation (validation officer), who then forms the group (team, committee). This is headed by a group leader, and represents all major departments: development, production, engineering, quality assurance and control. The composition of the group should be changed from time to time to give opportunities to other people to generate new ideas and to gain experience. The validation group then prepares a programme, which determines the scope of its work, its priorities, the time-schedule, the resources needed, etc. The programme
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is sent for review and approval to the departments and functions concerned. The final review and approval are the responsibility of the validation officer.
Table 1. Example of priorities for a process validation programme
is sent for review and approval to the departments and functions concerned. The final review and approval are the responsibility of the validation officer.
Table 1. Example of priorities for a process validation programme
Type of process New
Validation requirements Every new process must be validated before approval for routine production All processes affecting sterility and manufacturing environment must be validated; the most important is the sterilization stage Low-dose tablets and capsules containing highly active substances: validation of mixing and granulation in relation to content uniformity Other tablets and capsules: validation of tablet compressing and capsule filling in relation to uniformity of mass
Type of process New
Validation requirements Every new process must be validated before approval for routine production All processes affecting sterility and manufacturing environment must be validated; the most important is the sterilization stage Low-dose tablets and capsules containing highly active substances: validation of mixing and granulation in relation to content uniformity Other tablets and capsules: validation of tablet compressing and capsule filling in relation to uniformity of mass
Existing: Processes designed to render a product sterile
Existing: Processes designed to render a product sterile
Non-sterile production
Non-sterile production
5. Scope of a process validation programme Suggested priorities for a validation programme are listed in Table 1. For new processes, it is recommended that the first few full-scale production batches (e.g. three batches) should not be released from quarantine after approval by the quality control department until the validation has been completed, the results presented and reviewed, and the process approved (certified).
5. Scope of a process validation programme Suggested priorities for a validation programme are listed in Table 1. For new processes, it is recommended that the first few full-scale production batches (e.g. three batches) should not be released from quarantine after approval by the quality control department until the validation has been completed, the results presented and reviewed, and the process approved (certified).
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6. Validation protocol and report A suggested scheme for the validation protocol and subsequent report concerning a particular process is shown below: Part 1. Purpose (the validation) and prerequisites Part 2. Presentation of the entire process and subprocesses, flow diagram, critical steps/risks Part 3. Validation protocol, approval Part 4. Installation qualification, drawings Part 5. Qualification protocol/report 5.1 Subprocess 1 5.1.1 Purpose 5.1.2 Methods/procedures, list of manufacturing methods, SOPs, and written procedures, as applicable 5.1.3 Sampling and testing procedures, acceptance criteria (detailed description of, or reference to, established procedures, as described in pharmacopoeias) 5.1.4 Reporting 5.1.4.1 Calibration of test equipment used in the production process 5.1.4.2 Test data (raw data) 5.1.4.3 Results (summary) 5.1.5 Approval and requalification procedure 5.2 Subprocess 2 (same as for Subprocess 1) 5.n Subprocess n Part 6. Product characteristics, test data from validation batches Part 7. Evaluation, including comparison with the acceptance criteria and recommendations (including frequency of revalidation/ requalification) Part 8. Certification (approval) Part 9. If applicable, preparation of an abbreviated version of the validation report for external use, for example by the regulatory authority
6. Validation protocol and report A suggested scheme for the validation protocol and subsequent report concerning a particular process is shown below: Part 1. Purpose (the validation) and prerequisites Part 2. Presentation of the entire process and subprocesses, flow diagram, critical steps/risks Part 3. Validation protocol, approval Part 4. Installation qualification, drawings Part 5. Qualification protocol/report 5.1 Subprocess 1 5.1.1 Purpose 5.1.2 Methods/procedures, list of manufacturing methods, SOPs, and written procedures, as applicable 5.1.3 Sampling and testing procedures, acceptance criteria (detailed description of, or reference to, established procedures, as described in pharmacopoeias) 5.1.4 Reporting 5.1.4.1 Calibration of test equipment used in the production process 5.1.4.2 Test data (raw data) 5.1.4.3 Results (summary) 5.1.5 Approval and requalification procedure 5.2 Subprocess 2 (same as for Subprocess 1) 5.n Subprocess n Part 6. Product characteristics, test data from validation batches Part 7. Evaluation, including comparison with the acceptance criteria and recommendations (including frequency of revalidation/ requalification) Part 8. Certification (approval) Part 9. If applicable, preparation of an abbreviated version of the validation report for external use, for example by the regulatory authority
The validation protocol and report may also include copies of the product stability report or a summary of it, validation documentation on cleaning, and analytical methods. References 1. Good manufacturing practices for pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1992:1479 (WHO Technical Report Series, No. 823). 2. Validation of analytical procedures used in the examination of pharmaceutical materials. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1992:117121 (WHO Technical Report Series, No. 823). 3. Good manufacturing practice for medicinal products in the European Community. Brussels, Commission of the European Communities, 1992.
The validation protocol and report may also include copies of the product stability report or a summary of it, validation documentation on cleaning, and analytical methods. References 1. Good manufacturing practices for pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1992:1479 (WHO Technical Report Series, No. 823). 2. Validation of analytical procedures used in the examination of pharmaceutical materials. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1992:117121 (WHO Technical Report Series, No. 823). 3. Good manufacturing practice for medicinal products in the European Community. Brussels, Commission of the European Communities, 1992.
Q7A: good manufacturing practice guidance for active pharmaceutical ingredients1,2 with APICs interpretation
Q7A: good manufacturing practice guidance for active pharmaceutical ingredients1,2 with APICs interpretation
This guidance was developed within the Expert Working Group (Q7A) of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2000. At Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States.
2 Arabic numbers in subheadings reflect the organizational breakdown in the document endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2000.
This guidance was developed within the Expert Working Group (Q7A) of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2000. At Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States.
2
Arabic numbers in subheadings reflect the organizational breakdown in the document endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2000. This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.
XII. VALIDATION (12)

A. Validation Policy (12.1) The companys overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems, and persons responsible for design, review, approval, and documentation of each validation phase, should be documented. The critical parameters/attributes should normally be identified during the development stage or from historical data, and the necessary ranges for the reproducible operation should be defined. This should include: Defining the API in terms of its critical product attributes Identifying process parameters that could affect the critical quality attributes of the API Determining the range for each critical process parameter expected to be used during routine manufacturing and process control Validation should extend to those operations determined to be critical to the quality and purity of the API.
XII. VALIDATION (12)

A. Validation Policy (12.1) The companys overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems, and persons responsible for design, review, approval, and documentation of each validation phase, should be documented. The critical parameters/attributes should normally be identified during the development stage or from historical data, and the necessary ranges for the reproducible operation should be defined. This should include: Defining the API in terms of its critical product attributes Identifying process parameters that could affect the critical quality attributes of the API Determining the range for each critical process parameter expected to be used during routine manufacturing and process control Validation should extend to those operations determined to be critical to the quality and purity of the API.
APIC INTERPRETATION
12.10 Overall Policy The company should document clear and unambiguous policy related to all validation activities. Qualification activities are considered to be an integral part of validation. The policy should clearly show a companies rationale towards validation and detail how it will approach each key activity. Responsible Person Detail on responsibility during validation should be documented to ensure that commitment is made at the appropriate level. 12.11 Critical Parameters/Attributes
APIC INTERPRETATION
12.10 Overall Policy The company should document clear and unambiguous policy related to all validation activities. Qualification activities are considered to be an integral part of validation. The policy should clearly show a companies rationale towards validation and detail how it will approach each key activity. Responsible Person Detail on responsibility during validation should be documented to ensure that commitment is made at the appropriate level. 12.11 Critical Parameters/Attributes
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A risk assessment should be performed to map out critical parameter attributes prior to validation. These parameters need careful consideration as they will form the basis for assessing the system to be validated. Ranges used for each critical parameter should be well defined and supported by development data and or historical data. The parameters, if not adequately controlled, could affect the critical quality attributes of the product. Further details on critical parameters can be found in ISPE guideline Qualification and Commissioning. 12.12 Validation should extend to those operations deemed to be critical. Protocols used in validation should encompass those operations deemed to be critical. Non-critical operations need not form part of the validation study, for example material transfer in closed systems. Manufacturers should refrain from thinking they have to validate all operations. Validation of only critical operations will prove to be more cost effective and is scientifically sound. B. Validation Documentation (12.2) A written validation protocol should be established that specifies how validation of a particular process will be conducted. The protocol should be reviewed and approved by the quality unit(s) and other designated units. The validation protocol should specify critical process steps and acceptance criteria as well as the type of validation to be conducted (e.g., retrospective, prospective, concurrent) and the number of process runs. A validation report that cross-references the validation protocol should be prepared, summarizing the results obtained, commenting on any deviations observed, and drawing the appropriate conclusions, including recommending changes to correct deficiencies. Any variations from the validation protocol should be documented with appropriate justification.
A risk assessment should be performed to map out critical parameter attributes prior to validation. These parameters need careful consideration as they will form the basis for assessing the system to be validated. Ranges used for each critical parameter should be well defined and supported by development data and or historical data. The parameters, if not adequately controlled, could affect the critical quality attributes of the product. Further details on critical parameters can be found in ISPE guideline Qualification and Commissioning. 12.12 Validation should extend to those operations deemed to be critical. Protocols used in validation should encompass those operations deemed to be critical. Non-critical operations need not form part of the validation study, for example material transfer in closed systems. Manufacturers should refrain from thinking they have to validate all operations. Validation of only critical operations will prove to be more cost effective and is scientifically sound. B. Validation Documentation (12.2) A written validation protocol should be established that specifies how validation of a particular process will be conducted. The protocol should be reviewed and approved by the quality unit(s) and other designated units. The validation protocol should specify critical process steps and acceptance criteria as well as the type of validation to be conducted (e.g., retrospective, prospective, concurrent) and the number of process runs. A validation report that cross-references the validation protocol should be prepared, summarizing the results obtained, commenting on any deviations observed, and drawing the appropriate conclusions, including recommending changes to correct deficiencies. Any variations from the validation protocol should be documented with appropriate justification.
ICH Q7A guidelines together with APIC interpretation
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APIC INTERPRETATION
12.20 Review and Approval Review and approval of protocols needs to come from personnel who are competent and have the authority to support the validation. 12.21 Acceptance Criteria Acceptance criteria are established in validation protocols in order to allow the measurement of success or failure of a particular validation. Acceptance criteria should be identified from previous experience and need to reflect the key parameters that are measured during validation. For example, for process validation levels of impurities need to be controlled in line with any registered specification. Meeting the limits for these impurities consistently would be a key acceptance criteria. 12.22 Deviations Observed Deviations during validation should be fully explained in the validation report. Conclusions and corrective actions need to be described. Significant deviations that impact product quality or reject batches that fail specification should be fully explained in the validation report. When API quality is jeopardised the validation should be evaluated as to whether it is best to stop the validation or amend the protocol to manufacture additional batches. Careful consideration is required before this decision is made as the underlying reason for the failure should be fully understood and acted on. C. Qualification (12.3) Before initiating process validation activities, appropriate qualification of critical equipment and ancillary systems should be completed. Qualification is usually carried out by conducting the following activities, individually or combined: Design Qualification (DQ): documented verification that the proposed design of the facilities, equipment, or systems is suitable for the intended purpose Installation Qualification (IQ): documented verification that the equipment or systems, as installed or modified, comply with the
APIC INTERPRETATION
12.20 Review and Approval Review and approval of protocols needs to come from personnel who are competent and have the authority to support the validation. 12.21 Acceptance Criteria Acceptance criteria are established in validation protocols in order to allow the measurement of success or failure of a particular validation. Acceptance criteria should be identified from previous experience and need to reflect the key parameters that are measured during validation. For example, for process validation levels of impurities need to be controlled in line with any registered specification. Meeting the limits for these impurities consistently would be a key acceptance criteria. 12.22 Deviations Observed Deviations during validation should be fully explained in the validation report. Conclusions and corrective actions need to be described. Significant deviations that impact product quality or reject batches that fail specification should be fully explained in the validation report. When API quality is jeopardised the validation should be evaluated as to whether it is best to stop the validation or amend the protocol to manufacture additional batches. Careful consideration is required before this decision is made as the underlying reason for the failure should be fully understood and acted on. C. Qualification (12.3) Before initiating process validation activities, appropriate qualification of critical equipment and ancillary systems should be completed. Qualification is usually carried out by conducting the following activities, individually or combined: Design Qualification (DQ): documented verification that the proposed design of the facilities, equipment, or systems is suitable for the intended purpose Installation Qualification (IQ): documented verification that the equipment or systems, as installed or modified, comply with the
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approved design, the manufacturers recommendations and/or user requirements Operational Qualification (OQ): documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges Performance Qualification (PQ): documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications
approved design, the manufacturers recommendations and/or user requirements Operational Qualification (OQ): documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges Performance Qualification (PQ): documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications
APIC INTERPRETATION
12.30 Definition: Design Qualification constitutes the documented assurance that the premises, supporting utilities, equipment, systems and processes have been designed in accordance with the user and regulatory requirements. Design qualification is the documented verification that the design of the systems is in compliance with the cGMP related user requirements. Typical deliverables of DQ are: - verification that each GMP-relevant URS statement is met by the design - verification that GMP critical system components are defined in the design document. Also: o DQ is a regulatory expectation (ICHQ7a); o DQ must be applied to all quality critical systems (new and modified); o DQ is helpful for the following qualification processes; o DQ procedures should be in place; o DQ is an important instrument to avoid mistakes and failure of the system in later steps of the implementation; o Detailed Design phase must be performed before the equipment is purchased or implemented in the field;
APIC INTERPRETATION
12.30 Definition: Design Qualification constitutes the documented assurance that the premises, supporting utilities, equipment, systems and processes have been designed in accordance with the user and regulatory requirements. Design qualification is the documented verification that the design of the systems is in compliance with the cGMP related user requirements. Typical deliverables of DQ are: - verification that each GMP-relevant URS statement is met by the design - verification that GMP critical system components are defined in the design document. Also: o DQ is a regulatory expectation (ICHQ7a); o DQ must be applied to all quality critical systems (new and modified); o DQ is helpful for the following qualification processes; o DQ procedures should be in place; o DQ is an important instrument to avoid mistakes and failure of the system in later steps of the implementation; o Detailed Design phase must be performed before the equipment is purchased or implemented in the field;
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Critical systems A critical system is a structural, mechanical or electrical system that can impact the processing parameters and critical quality attributes of the product. (ISPE Baseline Volume5 Commissioning & qualification: Definitions) A direct impact system is expected to have a direct impact on product quality. These systems must be designed and commissioned in line with Good Engineering Practice In addition, they are subject to Qualification Practices. An impact assessment will determine the quality criticality of the equipment, system ect. The practice of the impact assessment is described ISPE Baseline Volume 5 Chapter 3.
Critical systems A critical system is a structural, mechanical or electrical system that can impact the processing parameters and critical quality attributes of the product. (ISPE Baseline Volume5 Commissioning & qualification: Definitions) A direct impact system is expected to have a direct impact on product quality. These systems must be designed and commissioned in line with Good Engineering Practice In addition, they are subject to Qualification Practices. An impact assessment will determine the quality criticality of the equipment, system ect. The practice of the impact assessment is described ISPE Baseline Volume 5 Chapter 3.
Design Qualification Flow Scheme
Design Qualification Flow Scheme
1) URS 2) Conceptual Design & Documentation Functional Design of review used as Documentation Including part of the protocol 3) Risk assessment & = 5) DQ Protocol GMP Review Step 1 Step 1 Basis for 4)Detailed Design & Documentation Design Specification of review used as Documentation Including part of the protocol 3) Risk assessment & = 5) DQ Protocol GMP Review Step 2 Step 2 The level of detail in the two steps depends on the system characteristics, for example commercial equipment can require a deeper documentation compared to lab equipment. 6) DQ Report Installation
1) URS 2) Conceptual Design & Documentation Functional Design of review used as Documentation Including part of the protocol 3) Risk assessment & = 5) DQ Protocol GMP Review Step 1 Step 1 Basis for 4)Detailed Design & Documentation Design Specification of review used as Documentation Including part of the protocol 3) Risk assessment & = 5) DQ Protocol GMP Review Step 2 Step 2 The level of detail in the two steps depends on the system characteristics, for example commercial equipment can require a deeper documentation compared to lab equipment. 6) DQ Report Installation
Change Control
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A design qualification is the best way to prepare for further qualification activities. It is in the interest of all to reveal design or specification problems through a rigorous, structured, and appropriate review process early in he project, rather than discover them later at the IQ or OQ stages, where a remedy might involve significant delay and expense. (ISPE Baseline 5 Chapter 7). Explanation of sub-headings of the flow scheme 1) User Requirement Specification A document, which captures the owners basic intent for the equipment, utility, system, facility or process, and outlines the general parameters used to develop the detailed design documents. It focuses on what the system should be capable of, without already specifying how (design) the system should achieve this. 2) Conceptual Design & Functional Design Provides details of the initial functional requirement to meet the user requirement. The design at this point may be subject to change. 3) Risk Assessment & GMP Review The purpose of the risk assessment (from a quality perspective) and GMP review is to highlight those items/systems, which are deemed critical. The URS will be challenged against the applicable GMPs to assure that they meet and include all predicate regulatory requirements. The process and related systems will be subject to a risk assessment in order to identify which (sub) system, components and/or functions are GMP critical. 4) Design Specifications A specification that defines the design of a system or system component. (ISPE Baseline Volume 1) 5) DQ Protocol A protocol approved by the QUALITY UNIT that details the design information. This document can cross reference items such as drawings and specifications. 6) DQ Report A report confirming the detailed design meets all user requirements complies with cGMP and identifies critical components. Requirements not met by the design should be reported and evaluated.
A design qualification is the best way to prepare for further qualification activities. It is in the interest of all to reveal design or specification problems through a rigorous, structured, and appropriate review process early in he project, rather than discover them later at the IQ or OQ stages, where a remedy might involve significant delay and expense. (ISPE Baseline 5 Chapter 7). Explanation of sub-headings of the flow scheme 1) User Requirement Specification A document, which captures the owners basic intent for the equipment, utility, system, facility or process, and outlines the general parameters used to develop the detailed design documents. It focuses on what the system should be capable of, without already specifying how (design) the system should achieve this. 2) Conceptual Design & Functional Design Provides details of the initial functional requirement to meet the user requirement. The design at this point may be subject to change. 3) Risk Assessment & GMP Review The purpose of the risk assessment (from a quality perspective) and GMP review is to highlight those items/systems, which are deemed critical. The URS will be challenged against the applicable GMPs to assure that they meet and include all predicate regulatory requirements. The process and related systems will be subject to a risk assessment in order to identify which (sub) system, components and/or functions are GMP critical. 4) Design Specifications A specification that defines the design of a system or system component. (ISPE Baseline Volume 1) 5) DQ Protocol A protocol approved by the QUALITY UNIT that details the design information. This document can cross reference items such as drawings and specifications. 6) DQ Report A report confirming the detailed design meets all user requirements complies with cGMP and identifies critical components. Requirements not met by the design should be reported and evaluated.
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Responsibilities in Design Qualification A list of typical participants with their responsibilities. This list represents only a guide of DQ responsibilities management: Engineering manager Initiates start-up, execution and documentation of the process (invitation, minutes of the meeting), control of implementation Discipline Engineers Provides drafts of lay-out (P&IDs, HVAC- plans, installation plans) including intended materials, operation ranges with respect of pressure and temperature, sanitary construction (if required), cleanability; Suppliers of detail - information (in contact with contractors or suppliers) Has to prepare a statement to critical aspects of the design Representative(s) from operation / production/R&D Definition of process and requirements Review of operability, quality, compliance Review of risk assessment Representative(s) from maintenance / technical services Review of Maintainability, availability Representative of SHE (safety, Health, environment) if required Topics concerned with safety, and environmental issues Representative of validation or named qualified group Reviewing and approving of DQ protocol and report QUALITY UNIT Reviewing and approving the final set of required documentation (URS, functional and detailed specification). Approval of changes to GMP requirements, and topics concerning regulatory affairs Approval of the GMP risk assessment and the DQ protocol. Project manager Supplier of the User Requirement Specification (URS)
Responsibilities in Design Qualification A list of typical participants with their responsibilities. This list represents only a guide of DQ responsibilities management: Engineering manager Initiates start-up, execution and documentation of the process (invitation, minutes of the meeting), control of implementation Discipline Engineers Provides drafts of lay-out (P&IDs, HVAC- plans, installation plans) including intended materials, operation ranges with respect of pressure and temperature, sanitary construction (if required), cleanability; Suppliers of detail - information (in contact with contractors or suppliers) Has to prepare a statement to critical aspects of the design Representative(s) from operation / production/R&D Definition of process and requirements Review of operability, quality, compliance Review of risk assessment Representative(s) from maintenance / technical services Review of Maintainability, availability Representative of SHE (safety, Health, environment) if required Topics concerned with safety, and environmental issues Representative of validation or named qualified group Reviewing and approving of DQ protocol and report QUALITY UNIT Reviewing and approving the final set of required documentation (URS, functional and detailed specification). Approval of changes to GMP requirements, and topics concerning regulatory affairs Approval of the GMP risk assessment and the DQ protocol. Project manager Supplier of the User Requirement Specification (URS)
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Stakeholder of the client, therefore also responsible for the approval of the design (signs together with QUALITY UNIT) A review has to be performed by persons, who can evaluate the design from a technical point of view as adequately addressing each requirement (see ISPE Baseline guide Volume 5 Commissioning and qualification page 79- 80). In practice, therefore the team that is outlined in the validation master plan (at least Engineering manager, project manager, Representative(s) from operation / production, Representative(s) from maintenance / technical services, QUALITY UNIT) has to discuss the proposed design. Project manager and QUALITY UNIT formally approve the laid down decisions. D. Approaches to Process Validation (12.4) Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes. There are three approaches to validation. Prospective validation is the preferred approach, but there are situations where the other approaches can be used. These approaches and their applicability are discussed here. Prospective validation should normally be performed for all API processes as defined in 12.1. Prospective validation of an API process should be completed before the commercial distribution of the final drug product manufactured from that API. Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of API batches have been produced, API batches are produced infrequently, or API batches are produced by a validated process that has been modified. Prior to the completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches. An exception can be made for retrospective validation of wellestablished processes that have been used without significant changes
Stakeholder of the client, therefore also responsible for the approval of the design (signs together with QUALITY UNIT) A review has to be performed by persons, who can evaluate the design from a technical point of view as adequately addressing each requirement (see ISPE Baseline guide Volume 5 Commissioning and qualification page 79- 80). In practice, therefore the team that is outlined in the validation master plan (at least Engineering manager, project manager, Representative(s) from operation / production, Representative(s) from maintenance / technical services, QUALITY UNIT) has to discuss the proposed design. Project manager and QUALITY UNIT formally approve the laid down decisions. D. Approaches to Process Validation (12.4) Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes. There are three approaches to validation. Prospective validation is the preferred approach, but there are situations where the other approaches can be used. These approaches and their applicability are discussed here. Prospective validation should normally be performed for all API processes as defined in 12.1. Prospective validation of an API process should be completed before the commercial distribution of the final drug product manufactured from that API. Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of API batches have been produced, API batches are produced infrequently, or API batches are produced by a validated process that has been modified. Prior to the completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches. An exception can be made for retrospective validation of wellestablished processes that have been used without significant changes
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to API quality due to changes in raw materials, equipment, systems, facilities, or the production process. This validation approach may be used where: 1. Critical quality attributes and critical process parameters have been identified 2. Appropriate in-process acceptance criteria and controls have been established 3. There have not been significant process/product failures attributable to causes other than operator error or equipment failures unrelated to equipment suitability 4. Impurity profiles have been established for the existing API Batches selected for retrospective validation should be representative of all batches produced during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Retained samples can be tested to obtain data to retrospectively validate the process.
to API quality due to changes in raw materials, equipment, systems, facilities, or the production process. This validation approach may be used where: 1. Critical quality attributes and critical process parameters have been identified 2. Appropriate in-process acceptance criteria and controls have been established 3. There have not been significant process/product failures attributable to causes other than operator error or equipment failures unrelated to equipment suitability 4. Impurity profiles have been established for the existing API Batches selected for retrospective validation should be representative of all batches produced during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Retained samples can be tested to obtain data to retrospectively validate the process.
APIC INTERPRETATION
12.40 Process Validation The purpose of process validation is to demonstrate that a particular process can perform effectively in a robust and consistent manner to produce material that meets predetermined specifications and quality attributes. 12.43 Concurrent validation Concurrent validation is a particular form of prospective validation, in which the batch or batches produced are released, based on more extensive testing, before the entire validation study is complete. 12.45 Retrospective Validation Retrospective validation requires a protocol that covers in detail the acceptance criteria and batch information that will form the basis for validation. Batches that fail to meet specification or are out of trend needs to be discussed.
APIC INTERPRETATION
12.40 Process Validation The purpose of process validation is to demonstrate that a particular process can perform effectively in a robust and consistent manner to produce material that meets predetermined specifications and quality attributes. 12.43 Concurrent validation Concurrent validation is a particular form of prospective validation, in which the batch or batches produced are released, based on more extensive testing, before the entire validation study is complete. 12.45 Retrospective Validation Retrospective validation requires a protocol that covers in detail the acceptance criteria and batch information that will form the basis for validation. Batches that fail to meet specification or are out of trend needs to be discussed.
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The number of batches chosen should be statistically based. Guidance on the number of batches chosen can be found in United States vs. Barr Laboratories [812 F.Supp. 458, 474-475, 477 (D.N.J. 1993)]. The general rule from the above judgement is that between 20-30 batches is required, but a firm can depart from this number provided it can support any such departure with statistical or other evidence that supports validation. E. Process Validation Program (12.5) The number of process runs for validation should depend on the complexity of the process or the magnitude of the process change being considered. For prospective and concurrent validation, three consecutive successful production batches should be used as a guide, but there may be situations where additional process runs are warranted to prove consistency of the process (e.g., complex API processes or API processes with prolonged completion times). For retrospective validation, generally data from 10 to 30 consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified. Critical process parameters should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in the process validation. Process validation should confirm that the impurity profile for each API is within the limits specified. The impurity profile should be comparable to, or better than, historical data and, where applicable, the profile determined during process development or for batches used for pivotal clinical and toxicological studies. F. Periodic Review of Validated Systems (12.6) Systems and processes should be periodically evaluated to verify that they are still operating in a valid manner. Where no significant changes have been made to the system or process, and a quality review confirms
The number of batches chosen should be statistically based. Guidance on the number of batches chosen can be found in United States vs. Barr Laboratories [812 F.Supp. 458, 474-475, 477 (D.N.J. 1993)]. The general rule from the above judgement is that between 20-30 batches is required, but a firm can depart from this number provided it can support any such departure with statistical or other evidence that supports validation. E. Process Validation Program (12.5) The number of process runs for validation should depend on the complexity of the process or the magnitude of the process change being considered. For prospective and concurrent validation, three consecutive successful production batches should be used as a guide, but there may be situations where additional process runs are warranted to prove consistency of the process (e.g., complex API processes or API processes with prolonged completion times). For retrospective validation, generally data from 10 to 30 consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified. Critical process parameters should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in the process validation. Process validation should confirm that the impurity profile for each API is within the limits specified. The impurity profile should be comparable to, or better than, historical data and, where applicable, the profile determined during process development or for batches used for pivotal clinical and toxicological studies. F. Periodic Review of Validated Systems (12.6) Systems and processes should be periodically evaluated to verify that they are still operating in a valid manner. Where no significant changes have been made to the system or process, and a quality review confirms
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that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation.
that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation.
APIC INTERPRETATION
12.60 Revalidation Product Quality Reviews (see 2.5) should assess the requirement for revalidation. Significant changes made to systems/processes or significant changes in product quality (see chapter 13) will require evaluation for revalidation. G. Cleaning Validation (12.7) Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent purification steps. Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability. The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labeled. Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning.
APIC INTERPRETATION
12.60 Revalidation Product Quality Reviews (see 2.5) should assess the requirement for revalidation. Significant changes made to systems/processes or significant changes in product quality (see chapter 13) will require evaluation for revalidation. G. Cleaning Validation (12.7) Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent purification steps. Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability. The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labeled. Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning.
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Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers). Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The methods attainable recovery level should be established. Residue limits should be practical, achievable, verifiable, and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component. Equipment cleaning/sanitation studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products). Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routine production. Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Visual inspection can allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis. H. Validation of Analytical Methods (12.8) Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognized standard reference. The suitability of all testing methods used should nonetheless be verified under actual conditions of use and documented. Methods should be validated to include consideration of characteristics included within the ICH guidances on validation of analytical methods. The degree of analytical validation performed
Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers). Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The methods attainable recovery level should be established. Residue limits should be practical, achievable, verifiable, and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component. Equipment cleaning/sanitation studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products). Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routine production. Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Visual inspection can allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis. H. Validation of Analytical Methods (12.8) Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognized standard reference. The suitability of all testing methods used should nonetheless be verified under actual conditions of use and documented. Methods should be validated to include consideration of characteristics included within the ICH guidances on validation of analytical methods. The degree of analytical validation performed
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should reflect the purpose of the analysis and the stage of the API production process. Appropriate qualification of analytical equipment should be considered before initiating validation of analytical methods. Complete records should be maintained of any modification of a validated analytical method. Such records should include the reason for the modification and appropriate data to verify that the modification produces results that are as accurate and reliable as the established method.
should reflect the purpose of the analysis and the stage of the API production process. Appropriate qualification of analytical equipment should be considered before initiating validation of analytical methods. Complete records should be maintained of any modification of a validated analytical method. Such records should include the reason for the modification and appropriate data to verify that the modification produces results that are as accurate and reliable as the established method.
APIC INTERPRETATION
Analytical methods used directly from recognised standard references (e.g. Pharmacopoeia) need only to be demonstrated suitable for use. System suitability tests can be found in European Pharmacopoeia. If modified pharmacopoeia methods or in-house methods (non-pharmacopoeia) are applied for compendia APIs equivalence with the relevant pharmacopoeia method has to be demonstrated and a report has to be made available on request. The level of the validation required for in-process controls should be evaluated depending on the influence on the final API quality. Guidance on the levels of analytical method validation can be found in ICH Q2a and Q2b. 12.82 Appropriate qualification Qualification can be performed in house or provided by the equipment supplier. If supplier qualification information is used it should be approved by the Quality Unit as suitable for its intended use. 12.83 Modification needs to be covered by a change control system.
APIC INTERPRETATION
Analytical methods used directly from recognised standard references (e.g. Pharmacopoeia) need only to be demonstrated suitable for use. System suitability tests can be found in European Pharmacopoeia. If modified pharmacopoeia methods or in-house methods (non-pharmacopoeia) are applied for compendia APIs equivalence with the relevant pharmacopoeia method has to be demonstrated and a report has to be made available on request. The level of the validation required for in-process controls should be evaluated depending on the influence on the final API quality. Guidance on the levels of analytical method validation can be found in ICH Q2a and Q2b. 12.82 Appropriate qualification Qualification can be performed in house or provided by the equipment supplier. If supplier qualification information is used it should be approved by the Quality Unit as suitable for its intended use. 12.83 Modification needs to be covered by a change control system.
The rules governing medicinal products in the European Union
VOLUME 4
VOLUME 4
good manufacturing practices
medicinal products for human and veterinary use

1998 EDITION
update of legal references in August 2004 EUROPEAN COMMISSION Enterprise Directorate-General Pharmaceuticals: Regulatory Framework and Market Authorisations

1998 EDITION
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EUGGMP Annexure 14: qualification and validation
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ANNEX 15: QUALIFICATION AND VALIDATION

Principle 1. This Annex describes the principles of qualification and validation which are applicable to the manufacture of medicinal products. It is a requirement of GMP that manufacturers identify what validation work is needed to prove control of the critical aspects of their particular operations. Significant changes to the facilities, the equipment and the processes, which may affect the quality of the product, should be validated. A risk assessment approach should be used to determine the scope and extent of validation. PLANNING FOR VALIDATION 2. All validation activities should be planned. The key elements of a validation programme should be clearly defined and documented in a validation master plan (VMP) or equivalent documents. 3. The VMP should be a summary document which is brief, concise and clear. 4. The VMP should contain data on at least the following: (a) validation policy; (b) organisational structure of validation activities; (c) summary of facilities, systems, equipment and processes to be validated; (d) documentation format: the format to be used for protocols and reports; (e) planning and scheduling; (f) change control; (g) reference to existing documents. 5. In case of large projects, it may be necessary to create separate validation master plans. DOCUMENTATION 6. A written protocol should be established that specifies how qualification and validation will be conducted. The protocol should be reviewed and approved.
ANNEX 15: QUALIFICATION AND VALIDATION

Principle 1. This Annex describes the principles of qualification and validation which are applicable to the manufacture of medicinal products. It is a requirement of GMP that manufacturers identify what validation work is needed to prove control of the critical aspects of their particular operations. Significant changes to the facilities, the equipment and the processes, which may affect the quality of the product, should be validated. A risk assessment approach should be used to determine the scope and extent of validation. PLANNING FOR VALIDATION 2. All validation activities should be planned. The key elements of a validation programme should be clearly defined and documented in a validation master plan (VMP) or equivalent documents. 3. The VMP should be a summary document which is brief, concise and clear. 4. The VMP should contain data on at least the following: (a) validation policy; (b) organisational structure of validation activities; (c) summary of facilities, systems, equipment and processes to be validated; (d) documentation format: the format to be used for protocols and reports; (e) planning and scheduling; (f) change control; (g) reference to existing documents. 5. In case of large projects, it may be necessary to create separate validation master plans. DOCUMENTATION 6. A written protocol should be established that specifies how qualification and validation will be conducted. The protocol should be reviewed and approved.
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The protocol should specify critical steps and acceptance criteria. 7. A report that cross-references the qualification and/or validation protocol should be prepared, summarising the results obtained, commenting on any deviations observed, and drawing the necessary conclusions, including recommending changes necessary to correct deficiencies. Any changes to the plan as defined in the protocol should be documented with appropriate justification. 8. After completion of a satisfactory qualification, a formal release for the next step in qualification and validation should be made as a written authorisation. QUALIFICATION Design qualification 9. The first element of the validation of new facilities, systems or equipment could be design qualification (DQ). 10. The compliance of the design with GMP should be demonstrated and documented. Installation qualification 11. Installation qualification (IQ) should be performed on new or modified facilities, systems and equipment. 12. IQ should include, but not be limited to the following: (a) installation of equipment, piping, services and instrumentation checked to current engineering drawings and specifications; (b) collection and collation of supplier operating and working instructions and maintenance requirements; (c) calibration requirements; (d) verification of materials of construction. Operational qualification 13. Operational qualification (OQ) should follow Installation qualification. 14. OQ should include, but not be limited to the following:
The protocol should specify critical steps and acceptance criteria. 7. A report that cross-references the qualification and/or validation protocol should be prepared, summarising the results obtained, commenting on any deviations observed, and drawing the necessary conclusions, including recommending changes necessary to correct deficiencies. Any changes to the plan as defined in the protocol should be documented with appropriate justification. 8. After completion of a satisfactory qualification, a formal release for the next step in qualification and validation should be made as a written authorisation. QUALIFICATION Design qualification 9. The first element of the validation of new facilities, systems or equipment could be design qualification (DQ). 10. The compliance of the design with GMP should be demonstrated and documented. Installation qualification 11. Installation qualification (IQ) should be performed on new or modified facilities, systems and equipment. 12. IQ should include, but not be limited to the following: (a) installation of equipment, piping, services and instrumentation checked to current engineering drawings and specifications; (b) collection and collation of supplier operating and working instructions and maintenance requirements; (c) calibration requirements; (d) verification of materials of construction. Operational qualification 13. Operational qualification (OQ) should follow Installation qualification. 14. OQ should include, but not be limited to the following:
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(a) tests that have been developed from knowledge of processes, systems and equipment; (b) tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as worst case conditions. 15. The completion of a successful Operational qualification should allow the finalisation of calibration, operating and cleaning procedures, operator training and preventative maintenance requirements. It should permit a formal release of the facilities, systems and equipment. Performance qualification 16. Performance qualification (PQ) should follow successful completion of Installation qualification and Operational qualification. 17. PQ should include, but not be limited to the following: (a) tests, using production materials, qualified substitutes or simulated product, that have been developed from knowledge of the process and the facilities, systems or equipment; (b) tests to include a condition or set of conditions encompassing upper and lower operating limits. 18. Although PQ is described as a separate activity, it may in some cases be appropriate to perform it in conjunction with OQ. Qualification of established (in-use) facilities, systems and equipment 19. Evidence should be available to support and verify the operating parameters and limits for the critical variables of the operating equipment. Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures and records should be documented. PROCESS VALIDATION General 20. The requirements and principles outlined in this chapter are applicable to the manufacture of pharmaceutical dosage forms. They cover the initial
(a) tests that have been developed from knowledge of processes, systems and equipment; (b) tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as worst case conditions. 15. The completion of a successful Operational qualification should allow the finalisation of calibration, operating and cleaning procedures, operator training and preventative maintenance requirements. It should permit a formal release of the facilities, systems and equipment. Performance qualification 16. Performance qualification (PQ) should follow successful completion of Installation qualification and Operational qualification. 17. PQ should include, but not be limited to the following: (a) tests, using production materials, qualified substitutes or simulated product, that have been developed from knowledge of the process and the facilities, systems or equipment; (b) tests to include a condition or set of conditions encompassing upper and lower operating limits. 18. Although PQ is described as a separate activity, it may in some cases be appropriate to perform it in conjunction with OQ. Qualification of established (in-use) facilities, systems and equipment 19. Evidence should be available to support and verify the operating parameters and limits for the critical variables of the operating equipment. Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures and records should be documented. PROCESS VALIDATION General 20. The requirements and principles outlined in this chapter are applicable to the manufacture of pharmaceutical dosage forms. They cover the initial
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validation of new processes, subsequent validation of modified processes and re-validation. 21. Process validation should normally be completed prior to the distribution and sale of the medicinal product (prospective validation). In exceptional circumstances, where this is not possible, it may be necessary to validate processes during routine production (concurrent validation). Processes in use for some time should also be validated (retrospective validation). 22. Facilities, systems and equipment to be used should have been qualified and analytical testing methods should be validated. Staff taking part in the validation work should have been appropriately trained. 23. Facilities, systems, equipment and processes should be periodically evaluated to verify that they are still operating in a valid manner. Prospective validation 24. Prospective validation should include, but not be limited to the following: (a) short description of the process; (b) summary of the critical processing steps to be investigated; (c) list of the equipment/facilities to be used (including measuring/ monitoring/recording equipment) together with its calibration status (d) finished product specifications for release; (e) list of analytical methods, as appropriate; (f) proposed in-process controls with acceptance criteria; (g) additional testing to be carried out, with acceptance criteria and analytical validation, as appropriate; (h) sampling plan; (i) methods for recording and evaluating results (j) functions and responsibilities; (k) proposed timetable. 25. Using this defined process (including specified components) a series of batches of the final product may be produced under routine conditions. In theory the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation. It is generally
validation of new processes, subsequent validation of modified processes and re-validation. 21. Process validation should normally be completed prior to the distribution and sale of the medicinal product (prospective validation). In exceptional circumstances, where this is not possible, it may be necessary to validate processes during routine production (concurrent validation). Processes in use for some time should also be validated (retrospective validation). 22. Facilities, systems and equipment to be used should have been qualified and analytical testing methods should be validated. Staff taking part in the validation work should have been appropriately trained. 23. Facilities, systems, equipment and processes should be periodically evaluated to verify that they are still operating in a valid manner. Prospective validation 24. Prospective validation should include, but not be limited to the following: (a) short description of the process; (b) summary of the critical processing steps to be investigated; (c) list of the equipment/facilities to be used (including measuring/ monitoring/recording equipment) together with its calibration status (d) finished product specifications for release; (e) list of analytical methods, as appropriate; (f) proposed in-process controls with acceptance criteria; (g) additional testing to be carried out, with acceptance criteria and analytical validation, as appropriate; (h) sampling plan; (i) methods for recording and evaluating results (j) functions and responsibilities; (k) proposed timetable. 25. Using this defined process (including specified components) a series of batches of the final product may be produced under routine conditions. In theory the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation. It is generally
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considered acceptable that three consecutive batches/runs within the finally agreed parameters, would constitute a validation of the process. 26. Batches made for process validation should be the same size as the intended industrial scale batches. 27. If it is intended that validation batches be sold or supplied, the conditions under which they are produced should comply fully with the requirements of Good Manufacturing Practice, including the satisfactory outcome of the validation exercise, and with the marketing authorisation. Concurrent validation 28. In exceptional circumstances it may be acceptable not to complete a validation programme before routine production starts. 29. The decision to carry out concurrent validation must be justified, documented and approved by authorised personnel. 30. Documentation requirements for concurrent validation are the same as specified for prospective validation. Retrospective validation 31. Retrospective validation is only acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedures or equipment. 32. Validation of such processes should be based on historical data. The steps involved require the preparation of a specific protocol and the reporting of the results of the data review, leading to a conclusion and a recommendation. 33. The source of data for this validation should include, but not be limited to batch processing and packaging records, process control charts, maintenance log books, records of personnel changes, process capability studies, finished product data, including trend cards and storage stability results. 34. Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Additional testing of retained samples
considered acceptable that three consecutive batches/runs within the finally agreed parameters, would constitute a validation of the process. 26. Batches made for process validation should be the same size as the intended industrial scale batches. 27. If it is intended that validation batches be sold or supplied, the conditions under which they are produced should comply fully with the requirements of Good Manufacturing Practice, including the satisfactory outcome of the validation exercise, and with the marketing authorisation. Concurrent validation 28. In exceptional circumstances it may be acceptable not to complete a validation programme before routine production starts. 29. The decision to carry out concurrent validation must be justified, documented and approved by authorised personnel. 30. Documentation requirements for concurrent validation are the same as specified for prospective validation. Retrospective validation 31. Retrospective validation is only acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedures or equipment. 32. Validation of such processes should be based on historical data. The steps involved require the preparation of a specific protocol and the reporting of the results of the data review, leading to a conclusion and a recommendation. 33. The source of data for this validation should include, but not be limited to batch processing and packaging records, process control charts, maintenance log books, records of personnel changes, process capability studies, finished product data, including trend cards and storage stability results. 34. Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Additional testing of retained samples
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may be needed to obtain the necessary amount or type of data to retrospectively validate the process. 35. For retrospective validation, generally data from ten to thirty consecutive batches should be examined to assess process consistency, but fewer batches may be examined if justified. CLEANING VALIDATION 36. Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure. The rationale for selecting limits of carry over of product residues, cleaning agents and microbial contamination should be logically based on the materials involved. The limits should be achievable and verifiable. 37. Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. 38. Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to noncontact parts. The intervals between use and cleaning as well as cleaning and reuse should be validated. Cleaning intervals and methods should be determined. 39. For cleaning procedures for products and processes which are similar, it is considered acceptable to select a representative range of similar products and processes. A single validation study utilising a worst case approach can be carried out which takes account of the critical issues. 40. Typically three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. 41. Test until clean. is not considered an appropriate alternative to cleaning validation. 42. Products which simulate the physicochemical properties of the substances to be removed may exceptionally be used instead of the substances themselves, where such substances are either toxic or hazardous.
may be needed to obtain the necessary amount or type of data to retrospectively validate the process. 35. For retrospective validation, generally data from ten to thirty consecutive batches should be examined to assess process consistency, but fewer batches may be examined if justified. CLEANING VALIDATION 36. Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure. The rationale for selecting limits of carry over of product residues, cleaning agents and microbial contamination should be logically based on the materials involved. The limits should be achievable and verifiable. 37. Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. 38. Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to noncontact parts. The intervals between use and cleaning as well as cleaning and reuse should be validated. Cleaning intervals and methods should be determined. 39. For cleaning procedures for products and processes which are similar, it is considered acceptable to select a representative range of similar products and processes. A single validation study utilising a worst case approach can be carried out which takes account of the critical issues. 40. Typically three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. 41. Test until clean. is not considered an appropriate alternative to cleaning validation. 42. Products which simulate the physicochemical properties of the substances to be removed may exceptionally be used instead of the substances themselves, where such substances are either toxic or hazardous.
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CHANGE CONTROL 43. Written procedures should be in place to describe the actions to be taken if a change is proposed to a starting material, product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or reproducibility of the process. Change control procedures should ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality, consistent with the approved specifications. 44. All changes that may affect product quality or reproducibility of the process should be formally requested, documented and accepted. The likely impact of the change of facilities, systems and equipment on the product should be evaluated, including risk analysis. The need for, and the extent of, requalification and re-validation should be determined. REVALIDATION 45. Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation. GLOSSARY Definitions of terms relating to qualification and validation which are not given in the glossary of the current EC Guide to GMP, but which are used in this Annex, are given below. Change Control A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect the validated status of facilities, systems, equipment or processes. The intent is to determine the need for action that would ensure and document that the system is maintained in a validated state. Cleaning Validation Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products.
CHANGE CONTROL 43. Written procedures should be in place to describe the actions to be taken if a change is proposed to a starting material, product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or reproducibility of the process. Change control procedures should ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality, consistent with the approved specifications. 44. All changes that may affect product quality or reproducibility of the process should be formally requested, documented and accepted. The likely impact of the change of facilities, systems and equipment on the product should be evaluated, including risk analysis. The need for, and the extent of, requalification and re-validation should be determined. REVALIDATION 45. Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation. GLOSSARY Definitions of terms relating to qualification and validation which are not given in the glossary of the current EC Guide to GMP, but which are used in this Annex, are given below. Change Control A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect the validated status of facilities, systems, equipment or processes. The intent is to determine the need for action that would ensure and document that the system is maintained in a validated state. Cleaning Validation Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products.
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Concurrent Validation Validation carried out during routine production of products intended for sale. Design qualification (DQ) The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose. Installation Qualification (IQ) The documented verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturers recommendations. Operational Qualification (OQ) The documented verification that the facilities, systems and equipment, as installed or modified, perform as intended throughout the anticipated operating ranges. Performance Qualification (PQ) The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and reproducibly, based on the approved process method and product specification. Process Validation The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes. Prospective Validation Validation carried out before routine production of products intended for sale. Retrospective Validation Validation of a process for a product which has been marketed based upon accumulated manufacturing, testing and control batch data. Re-Validation A repeat of the process validation to provide an assurance that changes in the process/equipment introduced in accordance with change control procedures do not adversely affect process characteristics and product quality.
Concurrent Validation Validation carried out during routine production of products intended for sale. Design qualification (DQ) The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose. Installation Qualification (IQ) The documented verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturers recommendations. Operational Qualification (OQ) The documented verification that the facilities, systems and equipment, as installed or modified, perform as intended throughout the anticipated operating ranges. Performance Qualification (PQ) The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and reproducibly, based on the approved process method and product specification. Process Validation The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes. Prospective Validation Validation carried out before routine production of products intended for sale. Retrospective Validation Validation of a process for a product which has been marketed based upon accumulated manufacturing, testing and control batch data. Re-Validation A repeat of the process validation to provide an assurance that changes in the process/equipment introduced in accordance with change control procedures do not adversely affect process characteristics and product quality.
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Risk analysis Method to assess and characterise the critical parameters in the functionality of an equipment or process. Simulated Product A material that closely approximates the physical and, where practical, the chemical characteristics (e.g. viscosity, particle size, pH etc.) of the product under validation. In many cases, these characteristics may be satisfied by a placebo product batch. System A group of equipment with a common purpose. Worst Case A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.
Risk analysis Method to assess and characterise the critical parameters in the functionality of an equipment or process. Simulated Product A material that closely approximates the physical and, where practical, the chemical characteristics (e.g. viscosity, particle size, pH etc.) of the product under validation. In many cases, these characteristics may be satisfied by a placebo product batch. System A group of equipment with a common purpose. Worst Case A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.
PHARMACEUTICAL INSPECTION CONVENTION/ PHARMACEUTICAL INSPECTION COOPERATION SCHEME
PHARMACEUTICAL INSPECTION CONVENTION/ PHARMACEUTICAL INSPECTION COOPERATION SCHEME
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PIC guideline for validation
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VALIDATION MASTER PLAN

Introduction Qualification and Validation should establish and provide documentary evidence that: - the premises, the supporting utilities, the equipment and the processes have been designed in accordance with the requirements of GMP. This constitutes Design Qualification or DQ. - the premises, supporting utilities and the equipment have been built and installed in compliance with their design specifications. This constitutes Installation Qualification or IQ. - the premises, supporting utilities and the equipment operate in accordance with their design specifications. This constitutes Operational Qualification or OQ. - a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. This constitutes Process Validation or PV. The term Performance Qualification or PQ may be used also. Any aspect of, including significant changes to, the premises, the facilities, the equipment or the processes, which may affect the quality of the product, directly or indirectly, should be qualified and validated. It is a requirement of GMP that each pharmaceutical company identifies what qualification and validation work is required to prove control of the critical aspects of their particular operation. Common sense and an understanding of pharmaceutical processing go a long way towards determining what aspects of an operation are critical. The key elements of a qualification and validation programme of a company should be clearly defined and documented in a Validation Master Plan. Qualification and validation can not be considered once-off exercises, for example, the start-up of a new manufacturing operation. An ongoing programme should follow its first implementation.
VALIDATION MASTER PLAN

Introduction Qualification and Validation should establish and provide documentary evidence that: - the premises, the supporting utilities, the equipment and the processes have been designed in accordance with the requirements of GMP. This constitutes Design Qualification or DQ. - the premises, supporting utilities and the equipment have been built and installed in compliance with their design specifications. This constitutes Installation Qualification or IQ. - the premises, supporting utilities and the equipment operate in accordance with their design specifications. This constitutes Operational Qualification or OQ. - a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. This constitutes Process Validation or PV. The term Performance Qualification or PQ may be used also. Any aspect of, including significant changes to, the premises, the facilities, the equipment or the processes, which may affect the quality of the product, directly or indirectly, should be qualified and validated. It is a requirement of GMP that each pharmaceutical company identifies what qualification and validation work is required to prove control of the critical aspects of their particular operation. Common sense and an understanding of pharmaceutical processing go a long way towards determining what aspects of an operation are critical. The key elements of a qualification and validation programme of a company should be clearly defined and documented in a Validation Master Plan. Qualification and validation can not be considered once-off exercises, for example, the start-up of a new manufacturing operation. An ongoing programme should follow its first implementation.
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Commitment of the company to control change to premises, supporting utilities, materials, equipment and processes used in the manufacture of medicinal products is essential to ensure a continued validation status of the systems concerned. This commitment should be stated in the relevant company documentation, for example, the Quality Manual, Quality Policy Documents or the Validation Master Plan. As part of its Quality Management System the company should have a defined and formalised Change Control Procedure. While the GMP Guide specifically identifies the responsibility of the Production and Quality Control departments, in practice, other departments, like Engineering and Research and Development as well as Contractors are usually involved in the programme. It is the responsibility of the pharmaceutical company to define the respective responsibilities of its personnel and of external contractors in the qualification and validation programme. This should form part of the Validation Master Plan. However, the Quality Assurance function of a company should normally have a critical role in overseeing the whole qualification and validation process. It is recommended that the validation programme be actively co-ordinated and managed by the company. To this end, validation teams are often formed with specific roles identified and assigned to individual team members. It is imperative that the most senior level of management within the company understands the personnel, time and financial resources required to execute a qualification and validation programme and commits the necessary resources to the work.
Commitment of the company to control change to premises, supporting utilities, materials, equipment and processes used in the manufacture of medicinal products is essential to ensure a continued validation status of the systems concerned. This commitment should be stated in the relevant company documentation, for example, the Quality Manual, Quality Policy Documents or the Validation Master Plan. As part of its Quality Management System the company should have a defined and formalised Change Control Procedure. While the GMP Guide specifically identifies the responsibility of the Production and Quality Control departments, in practice, other departments, like Engineering and Research and Development as well as Contractors are usually involved in the programme. It is the responsibility of the pharmaceutical company to define the respective responsibilities of its personnel and of external contractors in the qualification and validation programme. This should form part of the Validation Master Plan. However, the Quality Assurance function of a company should normally have a critical role in overseeing the whole qualification and validation process. It is recommended that the validation programme be actively co-ordinated and managed by the company. To this end, validation teams are often formed with specific roles identified and assigned to individual team members. It is imperative that the most senior level of management within the company understands the personnel, time and financial resources required to execute a qualification and validation programme and commits the necessary resources to the work.

1.1. Principle 1.1.1. Validation requires a meticulous preparation and careful planning of the various steps in the process. All work involved should be carried out in a structured way according to formally authorised standardised working procedures. Validation is characterised by: - a multidisciplinary approach: validation requires the collaboration of experts of various disciplines such as pharmacists, technologists,

1.1. Principle 1.1.1. Validation requires a meticulous preparation and careful planning of the various steps in the process. All work involved should be carried out in a structured way according to formally authorised standardised working procedures. Validation is characterised by: - a multidisciplinary approach: validation requires the collaboration of experts of various disciplines such as pharmacists, technologists,
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metrologists, chemical analysts, microbiologists, engineers, experts on Q.A. validation etc.. - time constraints: validation work is submitted to rigorous time schedules. These studies are always the last stage prior to taking new processes, facilities into routine operation, - costs: Validation studies are costly as they require time of highly specialised personnel and expensive technology. The above factors require a well organised and structured approach that should be adequately described in a Validation Master Plan (VMP). 1.2 Purpose and Definition 1.2.1. The VMP should present an overview of the entire validation operation, its organisational structure, its content and planning. The core of the VMP being the list / inventory of the items to be validated and the planning schedule. 1.2.2. A Validation Master Plan is a document that summarises the firms overall philosophy, intentions and approach to be used for establishing performance adequacy. 1.3. Scope 1.3.1. All validation activities relating to critical technical operations, relevant to product and process controls within a firm should be included in a VMP. This includes qualification of critical manufacturing and control equipment. 1.3.2. The VMP should comprise all Prospective, Concurrent, Retrospective Validations as well as Re-validations. 1.3.3. In case of large projects like the construction of a new facility, often the best approach is to create a separate VMP. (In such situations the VMP should be part of the total project management.) 1.4. Format and Content 1.4.1. The VMP should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but refer to existing documents such as policy documents, SOPs and validation protocols/reports. The VMP should be agreed by management and requires regular updating.
metrologists, chemical analysts, microbiologists, engineers, experts on Q.A. validation etc.. - time constraints: validation work is submitted to rigorous time schedules. These studies are always the last stage prior to taking new processes, facilities into routine operation, - costs: Validation studies are costly as they require time of highly specialised personnel and expensive technology. The above factors require a well organised and structured approach that should be adequately described in a Validation Master Plan (VMP). 1.2 Purpose and Definition 1.2.1. The VMP should present an overview of the entire validation operation, its organisational structure, its content and planning. The core of the VMP being the list / inventory of the items to be validated and the planning schedule. 1.2.2. A Validation Master Plan is a document that summarises the firms overall philosophy, intentions and approach to be used for establishing performance adequacy. 1.3. Scope 1.3.1. All validation activities relating to critical technical operations, relevant to product and process controls within a firm should be included in a VMP. This includes qualification of critical manufacturing and control equipment. 1.3.2. The VMP should comprise all Prospective, Concurrent, Retrospective Validations as well as Re-validations. 1.3.3. In case of large projects like the construction of a new facility, often the best approach is to create a separate VMP. (In such situations the VMP should be part of the total project management.) 1.4. Format and Content 1.4.1. The VMP should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but refer to existing documents such as policy documents, SOPs and validation protocols/reports. The VMP should be agreed by management and requires regular updating.
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1.4.2. A VMP should contain data on the following subjects / proposed chapters: (a) an introduction: the firms validation policy, general description of the scope of those operations covered by the VMP, location and schedule (including priorities); (b) the organisational structure of all validation activities: personnel responsibility for the VMP, protocols of individual validation projects, validation work, report and document preparation and control, approval/ authorisation of validation protocols and reports in all stages of validation processes, tracking system for reference and review, training needs in support of validation; (c) plant / process / product description: provides a cross reference to other documents. A rationale for the inclusion or exclusion of validations, for the validation approach, the extent of validation and any challenge and or worst case situation should be included. Consideration can be given to the grouping of products / processes for the purpose of validating worst case situations. Where worst case situations cannot be simulated, the rationale for the groupings made should be defined; (d) specific process considerations: characteristics / requirements of the plant / process etc. that are critical for yielding a quality product and need extra attention may be briefly outlined here; (e) list of products / processes / systems to be validated: all validation activities comprised in the VMP should be summarised and compiled in a matrix format . Such matrix should provide an overview and contain: - all items covered by the VMP that are subject to validation describing the extent of validation required [i.e. IQ, OQ and/or PQ]. It should include validation of analytical techniques which are to be used in determining the validation status of other processes or systems, - the validation approach, i.e. prospective, retrospective or concurrent, - the re-validation activities, - actual status and future planning; (f) key acceptance criteria: a general statement on key acceptance criteria for the items listed above;
1.4.2. A VMP should contain data on the following subjects / proposed chapters: (a) an introduction: the firms validation policy, general description of the scope of those operations covered by the VMP, location and schedule (including priorities); (b) the organisational structure of all validation activities: personnel responsibility for the VMP, protocols of individual validation projects, validation work, report and document preparation and control, approval/ authorisation of validation protocols and reports in all stages of validation processes, tracking system for reference and review, training needs in support of validation; (c) plant / process / product description: provides a cross reference to other documents. A rationale for the inclusion or exclusion of validations, for the validation approach, the extent of validation and any challenge and or worst case situation should be included. Consideration can be given to the grouping of products / processes for the purpose of validating worst case situations. Where worst case situations cannot be simulated, the rationale for the groupings made should be defined; (d) specific process considerations: characteristics / requirements of the plant / process etc. that are critical for yielding a quality product and need extra attention may be briefly outlined here; (e) list of products / processes / systems to be validated: all validation activities comprised in the VMP should be summarised and compiled in a matrix format . Such matrix should provide an overview and contain: - all items covered by the VMP that are subject to validation describing the extent of validation required [i.e. IQ, OQ and/or PQ]. It should include validation of analytical techniques which are to be used in determining the validation status of other processes or systems, - the validation approach, i.e. prospective, retrospective or concurrent, - the re-validation activities, - actual status and future planning; (f) key acceptance criteria: a general statement on key acceptance criteria for the items listed above;
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(g) documentation format: the format to be used for protocols and reports should be described or referred to; (h) required SOPs: a list of relevant SOPs should be presented; (i) planning & scheduling: an estimate of staffing (including training needs), equipment and other specific requirements to complete the validation effort,.a time plan of the project with detailed planning of subprojects. This time plan could be included in the above mentioned matrix; (j) change control: a statement of the companys commitment to controlling critical changes to materials, facilities, equipment or processes (including analytical techniques), should be included.
(g) documentation format: the format to be used for protocols and reports should be described or referred to; (h) required SOPs: a list of relevant SOPs should be presented; (i) planning & scheduling: an estimate of staffing (including training needs), equipment and other specific requirements to complete the validation effort,.a time plan of the project with detailed planning of subprojects. This time plan could be included in the above mentioned matrix; (j) change control: a statement of the companys commitment to controlling critical changes to materials, facilities, equipment or processes (including analytical techniques), should be included.
2. DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION

2.1. Principle 2.1.1. A very important step within qualification is the correct design of equipment and ancillary systems for the intended use. Therefore qualification starts with the documented verification of the user requirements for an equipment and its ancillary systems. This process is called Design Qualification or DQ. 2.1.2. After the initial Design Qualification, Installation and Operational Qualification exercises assure through appropriate performance tests and related documentation and records that equipment and ancillary systems or sub-systems have been commissioned correctly and that all future operations will be reliable and within prescribed or specified operating limits. 2.1.3. These guidelines outline the principles and basic requirements for the Installation and Operational Qualification of systems or subsystems (equipment) including support systems used in the manufacture of all pharmaceutical products, including active pharmaceutical ingredients (APIs). The recommendations are intended to cover installation and operation of new or modified systems or sub-systems. 2.1.4. The detail and scope of a qualification exercise is in many respects related to the complexity of the equipment involved and the critical nature of that equipment with respect to the quality of the final product.
2. DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION

2.1. Principle 2.1.1. A very important step within qualification is the correct design of equipment and ancillary systems for the intended use. Therefore qualification starts with the documented verification of the user requirements for an equipment and its ancillary systems. This process is called Design Qualification or DQ. 2.1.2. After the initial Design Qualification, Installation and Operational Qualification exercises assure through appropriate performance tests and related documentation and records that equipment and ancillary systems or sub-systems have been commissioned correctly and that all future operations will be reliable and within prescribed or specified operating limits. 2.1.3. These guidelines outline the principles and basic requirements for the Installation and Operational Qualification of systems or subsystems (equipment) including support systems used in the manufacture of all pharmaceutical products, including active pharmaceutical ingredients (APIs). The recommendations are intended to cover installation and operation of new or modified systems or sub-systems. 2.1.4. The detail and scope of a qualification exercise is in many respects related to the complexity of the equipment involved and the critical nature of that equipment with respect to the quality of the final product.
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Nevertheless, the basic principles should be adhered to whether it is the installation and operation of a simple piece of equipment or an autoclave. 2.1.5. The basic principles are as follows: (a) The equipment should be correctly installed in accordance with an installation plan, as per supplier and any special (purchaser) requirements, (b) The requirements for calibration, maintenance and cleaning developed as draft procedures should be reviewed and finally issued as authorised standard operating procedures (SOPs) as part of the SOP programme of the company, (c) Operating requirements should be established and tests conducted to assure equipment is operating correctly, under normal and worst case conditions, (d) Operator training requirements pertaining to the new equipment should be finalised and documented. 2.1.6. At various stages in a validation exercise there is need for protocols, documentation, procedures, equipment, specifications, acceptance criteria for test results to be reviewed, checked and authorised.It would be expected that representatives of the main professional disciplines, e.g. Engineering, Research & Development, Manufacturing, Quality Control and Quality Assurance, involved in manufacture are actively involved in these undertakings with the final authorisation given by a validation committee or the Quality Assurance representative. 2.2. Installation Qualification (l.Q.) - Overview Statement 2.2.1. Installation Qualification is an essential step preceding the Process Validation exercise. It is normally executed by the Engineering group. The installation of equipment, piping, services and instrumentation is undertaken and checked to engineering drawings Piping & Instrument Diagrams, (P&IDs) and Plant Functional Specifications developed during the project planning stage. During the project planning stage, Installation Qualification should involve the identification of all system elements, service conduits and gauges and the preparation of a documented record that all installed equipment satisfies the planned requirements. 2.2.2. Identification and documenting of maintenance requirements for each installed item and the collection and collation of supplier operating and
Nevertheless, the basic principles should be adhered to whether it is the installation and operation of a simple piece of equipment or an autoclave. 2.1.5. The basic principles are as follows: (a) The equipment should be correctly installed in accordance with an installation plan, as per supplier and any special (purchaser) requirements, (b) The requirements for calibration, maintenance and cleaning developed as draft procedures should be reviewed and finally issued as authorised standard operating procedures (SOPs) as part of the SOP programme of the company, (c) Operating requirements should be established and tests conducted to assure equipment is operating correctly, under normal and worst case conditions, (d) Operator training requirements pertaining to the new equipment should be finalised and documented. 2.1.6. At various stages in a validation exercise there is need for protocols, documentation, procedures, equipment, specifications, acceptance criteria for test results to be reviewed, checked and authorised.It would be expected that representatives of the main professional disciplines, e.g. Engineering, Research & Development, Manufacturing, Quality Control and Quality Assurance, involved in manufacture are actively involved in these undertakings with the final authorisation given by a validation committee or the Quality Assurance representative. 2.2. Installation Qualification (l.Q.) - Overview Statement 2.2.1. Installation Qualification is an essential step preceding the Process Validation exercise. It is normally executed by the Engineering group. The installation of equipment, piping, services and instrumentation is undertaken and checked to engineering drawings Piping & Instrument Diagrams, (P&IDs) and Plant Functional Specifications developed during the project planning stage. During the project planning stage, Installation Qualification should involve the identification of all system elements, service conduits and gauges and the preparation of a documented record that all installed equipment satisfies the planned requirements. 2.2.2. Identification and documenting of maintenance requirements for each installed item and the collection and collation of supplier operating and
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working instructions, maintenance and cleaning requirements, should form the minimum documentation for a satisfactory Installation Qualification. 2.3. Installation Qualification - Essential Elements Installation of Equipment 2.3.1. The installation of equipment singularly or as a group (plant) should follow well defined plans. The plans will have been developed and finalised following progression through a number of design stages. The plans will normally be available and documented as Equipment Specifications, Plant Functional Specifications and Piping & Instrument Diagrams (P&IDs). During the design stage, an effective Change Management procedure should be in place. All changes to the original design criteria should be documented and after that, appropriate modifications made to Equipment Specifications, Plant Functional Specifications and Piping & Instrument Diagrams (P&IDs). 2.3.2. During the final phases of the design stage the facilities and equipment necessary for calibration requirements will need to be identified. Calibration Requirements 2.3.3. (a) confirmation of calibration of calibrating equipment with reference to the appropriate national standard, (b) calibration of measuring devices utilised in the Operational Qualification stage, where confirmation of calibration is unavailable, (c) calibration of measuring devices related to installed equipment, (d) identification of calibration requirements for measuring devices for the future use of the equipment. Checking of Suppliers 2.3.4. For complicated or large pieces of equipment, a pharmaceutical manufacturer may elect to undertake a pre-delivery check of the equipment at the suppliers assembly facility, this pre-delivery check cannot substitute for the Installation Qualification. However, it is acknowledged that the checks conducted and documented at this stage may duplicate a number of the checks conducted at the Installation Qualification stage, hence, there could be a reduction in the scope of the Installation Qualification checks. If part of the Installation Qualification is performed by the supplier, the user should participate
working instructions, maintenance and cleaning requirements, should form the minimum documentation for a satisfactory Installation Qualification. 2.3. Installation Qualification - Essential Elements Installation of Equipment 2.3.1. The installation of equipment singularly or as a group (plant) should follow well defined plans. The plans will have been developed and finalised following progression through a number of design stages. The plans will normally be available and documented as Equipment Specifications, Plant Functional Specifications and Piping & Instrument Diagrams (P&IDs). During the design stage, an effective Change Management procedure should be in place. All changes to the original design criteria should be documented and after that, appropriate modifications made to Equipment Specifications, Plant Functional Specifications and Piping & Instrument Diagrams (P&IDs). 2.3.2. During the final phases of the design stage the facilities and equipment necessary for calibration requirements will need to be identified. Calibration Requirements 2.3.3. (a) confirmation of calibration of calibrating equipment with reference to the appropriate national standard, (b) calibration of measuring devices utilised in the Operational Qualification stage, where confirmation of calibration is unavailable, (c) calibration of measuring devices related to installed equipment, (d) identification of calibration requirements for measuring devices for the future use of the equipment. Checking of Suppliers 2.3.4. For complicated or large pieces of equipment, a pharmaceutical manufacturer may elect to undertake a pre-delivery check of the equipment at the suppliers assembly facility, this pre-delivery check cannot substitute for the Installation Qualification. However, it is acknowledged that the checks conducted and documented at this stage may duplicate a number of the checks conducted at the Installation Qualification stage, hence, there could be a reduction in the scope of the Installation Qualification checks. If part of the Installation Qualification is performed by the supplier, the user should participate
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to the writing and implementing of the protocol and should get all the results at the end of the tests. Checking at Users 2.3.5. Installation Qualification requires a formal and systematic check of all installed equipment against the equipment suppliers specifications and additional criteria identified by the user as part of the purchase specifications. At the Installation Qualification, all equipment, gauges and services should be given a serial (or other reference) number and a check conducted that the installed equipment (or plant) has been installed in accord with the current (approved) version of the Piping & Instrument Diagram (P&ID). 2.3.6. Confirmation of compliance of the operating criteria for the equipment, as installed, with the Plant Functional Specifications and Process Flow Diagrams should be documented. Installation Qualification 2.3.7. At the Installation Qualification stage the company should document preventative maintenance requirements for installed equipment. At this stage new equipment and the preventative maintenance requirements should be added to the preventative maintenance schedule of the pharmaceutical manufacturer. Cleaning, including sanitisation and/or sterilisation requirements for the equipment, should be developed in draft documentation form from equipment supplier specifications and operating procedures. The draft cleaning documentation should be finalised following experience and observation at the Operational Qualification stage and then verified at the Performance Qualification stage. 2.4. Operational Qualification (O.Q) - Overview Statement 2.4.1. Operational Qualification is an exercise oriented to the engineering function, generally referred to as commissioning. Studies on the critical variables (parameters) of the operation of the equipment or systems will define the critical characteristics for operation of the system or sub-system. All testing equipment should be identified and calibrated before use. Test methods should be authorised, implemented and resulting data collected and evaluated.
to the writing and implementing of the protocol and should get all the results at the end of the tests. Checking at Users 2.3.5. Installation Qualification requires a formal and systematic check of all installed equipment against the equipment suppliers specifications and additional criteria identified by the user as part of the purchase specifications. At the Installation Qualification, all equipment, gauges and services should be given a serial (or other reference) number and a check conducted that the installed equipment (or plant) has been installed in accord with the current (approved) version of the Piping & Instrument Diagram (P&ID). 2.3.6. Confirmation of compliance of the operating criteria for the equipment, as installed, with the Plant Functional Specifications and Process Flow Diagrams should be documented. Installation Qualification 2.3.7. At the Installation Qualification stage the company should document preventative maintenance requirements for installed equipment. At this stage new equipment and the preventative maintenance requirements should be added to the preventative maintenance schedule of the pharmaceutical manufacturer. Cleaning, including sanitisation and/or sterilisation requirements for the equipment, should be developed in draft documentation form from equipment supplier specifications and operating procedures. The draft cleaning documentation should be finalised following experience and observation at the Operational Qualification stage and then verified at the Performance Qualification stage. 2.4. Operational Qualification (O.Q) - Overview Statement 2.4.1. Operational Qualification is an exercise oriented to the engineering function, generally referred to as commissioning. Studies on the critical variables (parameters) of the operation of the equipment or systems will define the critical characteristics for operation of the system or sub-system. All testing equipment should be identified and calibrated before use. Test methods should be authorised, implemented and resulting data collected and evaluated.
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2.4.2. It is important at this stage to assure all operational test data conform with pre-determined acceptance criteria for the studies undertaken. 2.4.3. It is expected that during the Operational Qualification stage the manufacturer should develop draft standard operating procedures (SOPs) for the equipment and services operation, cleaning activities, maintenance requirements and calibration schedules. 2.4.4. An effective change control procedure should be operational and encompass the whole project from the pre-planning stage through to the final acceptance of the Process Validation exercise. 2.5. Operational Qualification - Essential Elements 2.5.1. The conduct of an Operational Qualification should follow an authorised protocol. The critical operating parameters for the equipment or the plant should be identified at the Operational Qualification stage. The plans for the Operational Qualification should identify the studies to be undertaken on the critical variables, the sequence of those studies and the measuring equipment to be used and the acceptance criteria to be met. Studies on the critical variables should incorporate specific details and tests that have been developed from specialist knowledge of the process and how the equipment will work (defined in design criteria and specifications). 2.5.2. Where applicable, simulated product may be used to conduct the Operational Qualification. Studies on the critical variables should include a condition or a set of conditions encompassing upper and lower processing or operating limits and circumstances; commonly referred to as worst case conditions. Such conditions should not necessarily induce product or process failure. 2.5.3. The completion of a successful Operational Qualification should allow the finalisation of operating procedures and operator instructions documentation for the equipment. This information should be used as the basis for training of operators in the requirements for satisfactory operation of the equipment. 2.5.4. Draft cleaning procedures developed at the lnstallation Qualification stage should be finalised after a satisfactory Operational Qualification exercise and issued as standard operating procedures (SOPs). Where applicable, these procedures should be validated as part of the Performance Qualification phase.
2.4.2. It is important at this stage to assure all operational test data conform with pre-determined acceptance criteria for the studies undertaken. 2.4.3. It is expected that during the Operational Qualification stage the manufacturer should develop draft standard operating procedures (SOPs) for the equipment and services operation, cleaning activities, maintenance requirements and calibration schedules. 2.4.4. An effective change control procedure should be operational and encompass the whole project from the pre-planning stage through to the final acceptance of the Process Validation exercise. 2.5. Operational Qualification - Essential Elements 2.5.1. The conduct of an Operational Qualification should follow an authorised protocol. The critical operating parameters for the equipment or the plant should be identified at the Operational Qualification stage. The plans for the Operational Qualification should identify the studies to be undertaken on the critical variables, the sequence of those studies and the measuring equipment to be used and the acceptance criteria to be met. Studies on the critical variables should incorporate specific details and tests that have been developed from specialist knowledge of the process and how the equipment will work (defined in design criteria and specifications). 2.5.2. Where applicable, simulated product may be used to conduct the Operational Qualification. Studies on the critical variables should include a condition or a set of conditions encompassing upper and lower processing or operating limits and circumstances; commonly referred to as worst case conditions. Such conditions should not necessarily induce product or process failure. 2.5.3. The completion of a successful Operational Qualification should allow the finalisation of operating procedures and operator instructions documentation for the equipment. This information should be used as the basis for training of operators in the requirements for satisfactory operation of the equipment. 2.5.4. Draft cleaning procedures developed at the lnstallation Qualification stage should be finalised after a satisfactory Operational Qualification exercise and issued as standard operating procedures (SOPs). Where applicable, these procedures should be validated as part of the Performance Qualification phase.
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2.5.5. The completion of satisfactory lnstallation Qualification and Operational Qualification exercises should permit a formal release of the equipment/ plant for the next stage in the validation exercise (Process Validation). The release should not proceed unless calibration, cleaning, preventative maintenance and operator training requirements have been finalised and documented. The release should take the form of written authorisations for both Installation Qualification and Operational Qualification. 2.6. Re-Qualification 2.6.1. Modifications to, or relocation of, equipment should only follow satisfactory review and authorisation of the documented change proposal through the change control procedure. Part of the review procedure should include consideration of re-qualification of the equipment. Minor changes should be handled through the documentation system of the preventative maintenance programme. 2.7. Qualification of Established (in-use) Equipment 2.7.1. While it is not possible to undertake the details of an Installation Qualification for established equipment nor the detailed approach for an Operational Qualification, nevertheless there should be data available that support and verify the operating parameters and limits for the critical variables of the operating equipment. Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures for the use of the equipment should be documented and in use as standard operating procedures (SOPs).
2.5.5. The completion of satisfactory lnstallation Qualification and Operational Qualification exercises should permit a formal release of the equipment/ plant for the next stage in the validation exercise (Process Validation). The release should not proceed unless calibration, cleaning, preventative maintenance and operator training requirements have been finalised and documented. The release should take the form of written authorisations for both Installation Qualification and Operational Qualification. 2.6. Re-Qualification 2.6.1. Modifications to, or relocation of, equipment should only follow satisfactory review and authorisation of the documented change proposal through the change control procedure. Part of the review procedure should include consideration of re-qualification of the equipment. Minor changes should be handled through the documentation system of the preventative maintenance programme. 2.7. Qualification of Established (in-use) Equipment 2.7.1. While it is not possible to undertake the details of an Installation Qualification for established equipment nor the detailed approach for an Operational Qualification, nevertheless there should be data available that support and verify the operating parameters and limits for the critical variables of the operating equipment. Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures for the use of the equipment should be documented and in use as standard operating procedures (SOPs).
3. NON-STERILE PROCESS VALIDATION

3.1. Principle Process Validation is the means of ensuring, and providing documentary evidence that processes (within their specified design parameters) are capable of repeatedly and reliably producing a finished product of the required quality. The requirements and principles outlined in these guidelines are applicable to the manufacture and packaging of non-sterile pharmaceutical dosage forms. They cover the initial validation of new processes, subsequent validation of modified processes and Re-validation.
3. NON-STERILE PROCESS VALIDATION

3.1. Principle Process Validation is the means of ensuring, and providing documentary evidence that processes (within their specified design parameters) are capable of repeatedly and reliably producing a finished product of the required quality. The requirements and principles outlined in these guidelines are applicable to the manufacture and packaging of non-sterile pharmaceutical dosage forms. They cover the initial validation of new processes, subsequent validation of modified processes and Re-validation.
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3.2. General 3.2.1. Any manufacturing or packaging process will involve a number of factors that may affect product quality. These factors will be identified during the development of a product and will facilitate process optimisation studies. On completion of development and optimisation, Process Validation provides a structured way of assessing methodically the factors that impact on the final product. 3.2.2. It would normally be expected that Process Validation be completed prior to the manufacture of finished product that is intended for sale (Prospective Validation). Where this is not possible, it may be necessary to validate processes during routine production (Concurrent Validation). Processes which have been in use for some time should also be validated (Retrospective Validation). 3.2.3. In theory a validation exercise should only need to be carried out once for any given process. In practice however the process rarely remains static. Changes occur in components (raw materials and packaging materials), equipment is modified and the process environment cannot be assumed to remain as during the initial validation. A regular programme of re-validation is essential. 3.2.4. The companys policy and approach to Process Validation should be clearly defined. 3.3. Prospective Validation 3.3.1. During product development the production process should be broken down into individual steps. Each step should be evaluated on the basis of experience or theoretical considerations to determine the critical factors/ parameters that may affect the quality of the finished product. 3.3.2. A series of experiments should be devised to determine the criticality of these factors. Representatives from production, QC/QA, engineering, and in some cases research and development will normally be involved in this process. These experiments may incorporate a challenge element to determine the robustness of the process. Such a challenge is generally referred to as a worst case exercise. The use of starting materials on the extremes of the specification may indicate the ability of the process to continue producing finished product to the required specification.
3.2. General 3.2.1. Any manufacturing or packaging process will involve a number of factors that may affect product quality. These factors will be identified during the development of a product and will facilitate process optimisation studies. On completion of development and optimisation, Process Validation provides a structured way of assessing methodically the factors that impact on the final product. 3.2.2. It would normally be expected that Process Validation be completed prior to the manufacture of finished product that is intended for sale (Prospective Validation). Where this is not possible, it may be necessary to validate processes during routine production (Concurrent Validation). Processes which have been in use for some time should also be validated (Retrospective Validation). 3.2.3. In theory a validation exercise should only need to be carried out once for any given process. In practice however the process rarely remains static. Changes occur in components (raw materials and packaging materials), equipment is modified and the process environment cannot be assumed to remain as during the initial validation. A regular programme of re-validation is essential. 3.2.4. The companys policy and approach to Process Validation should be clearly defined. 3.3. Prospective Validation 3.3.1. During product development the production process should be broken down into individual steps. Each step should be evaluated on the basis of experience or theoretical considerations to determine the critical factors/ parameters that may affect the quality of the finished product. 3.3.2. A series of experiments should be devised to determine the criticality of these factors. Representatives from production, QC/QA, engineering, and in some cases research and development will normally be involved in this process. These experiments may incorporate a challenge element to determine the robustness of the process. Such a challenge is generally referred to as a worst case exercise. The use of starting materials on the extremes of the specification may indicate the ability of the process to continue producing finished product to the required specification.
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3.3.3. Each experiment should be planned and documented fully in an authorised protocol. This document will have the following elements: (a) a description of the process, (b) a description of the experiment, (c) details of the equipment/facilities to be used (including measuring/ monitoring/recording equipment) together with its calibration status, (d) the variables to be monitored, (e) the samples to be taken - where, when, how and how many, (f) the product performance characteristics/attributes to be monitored, together with the test methods, (g) the acceptable limits , (h) time schedules, (i) personnel responsibilities, (j) details of methods for recording and evaluating results, including statistical analysis. 3.3.4. All equipment, the production environment and analytical testing methods to be used should have been fully validated, (Installation/ Operational Qualification). Staff taking part in the validation work should have been appropriately trained. In practice, Operational Qualification may be carried out using batches of actual product. This work may also fulfil the requirements of Prospective Validation. This approach to validation should not be adopted as a standard practice however. 3.3.5. Master Batch Documentation can be prepared only after the critical parameters of the process have been identified and machine settings, component specifications and environmental conditions have been determined. 3.3.6. Using this defined process (including specified components) a series of batches of the final product should be produced. In theory the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, giving product of the desired quality would constitute a proper validation of the process. In practice, it may take some considerable time to accumulate this data.
3.3.3. Each experiment should be planned and documented fully in an authorised protocol. This document will have the following elements: (a) a description of the process, (b) a description of the experiment, (c) details of the equipment/facilities to be used (including measuring/ monitoring/recording equipment) together with its calibration status, (d) the variables to be monitored, (e) the samples to be taken - where, when, how and how many, (f) the product performance characteristics/attributes to be monitored, together with the test methods, (g) the acceptable limits , (h) time schedules, (i) personnel responsibilities, (j) details of methods for recording and evaluating results, including statistical analysis. 3.3.4. All equipment, the production environment and analytical testing methods to be used should have been fully validated, (Installation/ Operational Qualification). Staff taking part in the validation work should have been appropriately trained. In practice, Operational Qualification may be carried out using batches of actual product. This work may also fulfil the requirements of Prospective Validation. This approach to validation should not be adopted as a standard practice however. 3.3.5. Master Batch Documentation can be prepared only after the critical parameters of the process have been identified and machine settings, component specifications and environmental conditions have been determined. 3.3.6. Using this defined process (including specified components) a series of batches of the final product should be produced. In theory the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, giving product of the desired quality would constitute a proper validation of the process. In practice, it may take some considerable time to accumulate this data.
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3.3.7. It is preferred that the batches made should be the same size as the intended batch size for full scale production. This may not always be practical due to a shortage of available starting materials and in such cases the effect of the reduced batch size should be considered in the design of the protocol. A reduced batch size should correspond to at least 10 % of the intended batch size for full scale production. When full scale production starts, the validity of any assumptions made should be demonstrated. 3.3.8. During the processing of the batch/run, extensive testing should be performed on the product at various stages. Detailed testing should also be done on the final product and its package. 3.3.9. The batches/runs under validation should be documented comprehensively. The following items should be included in the validation report: (a) a description of the process Batch Processing/Packaging Records, including details of critical steps, (b) a detailed summary of the results obtained from in-process and final testing, including data from failed tests. When raw data are not included reference should be made to the sources used and where it can be found, (c) any work done in addition to that specified in the protocol or any deviations from the protocol should be formally noted along with an explanation, (d) a review and comparison of the results with those expected, (e) formal acceptance/rejection of the work by the team/persons designated as being responsible for the validation, after completion of any corrective action or repeated work. 3.3.10. Upon completion of the review, recommendations should be made on the extent of monitoring and the in-process controls necessary for routine production. These should be incorporated into the Manufacturing Formula and Processing Instructions or the Packaging Instructions or into appropriate standard operating procedures (SOPs). Limits, frequencies and actions to be taken in the event of the limits being exceeded should be specified. 3.3.11. If it is intended that validation batches be sold or supplied, the conditions under which they are produced should comply fully with the requirements of Good Manufacturing Practice and the Marketing
3.3.7. It is preferred that the batches made should be the same size as the intended batch size for full scale production. This may not always be practical due to a shortage of available starting materials and in such cases the effect of the reduced batch size should be considered in the design of the protocol. A reduced batch size should correspond to at least 10 % of the intended batch size for full scale production. When full scale production starts, the validity of any assumptions made should be demonstrated. 3.3.8. During the processing of the batch/run, extensive testing should be performed on the product at various stages. Detailed testing should also be done on the final product and its package. 3.3.9. The batches/runs under validation should be documented comprehensively. The following items should be included in the validation report: (a) a description of the process Batch Processing/Packaging Records, including details of critical steps, (b) a detailed summary of the results obtained from in-process and final testing, including data from failed tests. When raw data are not included reference should be made to the sources used and where it can be found, (c) any work done in addition to that specified in the protocol or any deviations from the protocol should be formally noted along with an explanation, (d) a review and comparison of the results with those expected, (e) formal acceptance/rejection of the work by the team/persons designated as being responsible for the validation, after completion of any corrective action or repeated work. 3.3.10. Upon completion of the review, recommendations should be made on the extent of monitoring and the in-process controls necessary for routine production. These should be incorporated into the Manufacturing Formula and Processing Instructions or the Packaging Instructions or into appropriate standard operating procedures (SOPs). Limits, frequencies and actions to be taken in the event of the limits being exceeded should be specified. 3.3.11. If it is intended that validation batches be sold or supplied, the conditions under which they are produced should comply fully with the requirements of Good Manufacturing Practice and the Marketing
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Authorisation (if applicable). The premises used should be named on a Manufacturing Authorisation and this Authorisation should allow the manufacture/assembly of the particular type of product. The batch must be formally certified by a Qualified Person before release. 3.4. Concurrent Validation 3.4.1. In certain circumstances it may not be possible to complete a validation programme before routine production starts. In these cases it will be known in advance that the finished product will be for sale or supply. Circumstances where this is likely are, for example, when a process is being transferred to a third party contract manufacturer/assembler. 3.4.2. In addition there are many instances when it is appropriate to validate a process during routine production. Such instances are, for example, where the product is a different strength of a previously validated product, a different tablet shape or where the process is well defined. 3.4.3. It is important in these cases however, that the premises and equipment to be used have been validated previously and that the decision to carry out Concurrent Validation is made by appropriately authorised people. 3.4.4. Documentation requirements are the same as specified for Prospective Validation and the testing to be carried out in-process and on the finished product will be as specified in approved protocols. The completed protocols and reports should be reviewed and approved before product is released for sale or supply. 3.5. Retrospective Validation 3.5.1. There are many processes in routine use in many companies that have not undergone a formally documented validation process. 3.5.2. Validation of these processes is possible, using historical data to provide the necessary documentary evidence that the process is doing what it is believed to do. The steps involved in this type of validation still require the preparation of a specific protocol, the reporting of the results of the data review, leading to a conclusion and recommendation. 3.5.3. This type of validation exercise is only acceptable for well established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedures or equipment.
Authorisation (if applicable). The premises used should be named on a Manufacturing Authorisation and this Authorisation should allow the manufacture/assembly of the particular type of product. The batch must be formally certified by a Qualified Person before release. 3.4. Concurrent Validation 3.4.1. In certain circumstances it may not be possible to complete a validation programme before routine production starts. In these cases it will be known in advance that the finished product will be for sale or supply. Circumstances where this is likely are, for example, when a process is being transferred to a third party contract manufacturer/assembler. 3.4.2. In addition there are many instances when it is appropriate to validate a process during routine production. Such instances are, for example, where the product is a different strength of a previously validated product, a different tablet shape or where the process is well defined. 3.4.3. It is important in these cases however, that the premises and equipment to be used have been validated previously and that the decision to carry out Concurrent Validation is made by appropriately authorised people. 3.4.4. Documentation requirements are the same as specified for Prospective Validation and the testing to be carried out in-process and on the finished product will be as specified in approved protocols. The completed protocols and reports should be reviewed and approved before product is released for sale or supply. 3.5. Retrospective Validation 3.5.1. There are many processes in routine use in many companies that have not undergone a formally documented validation process. 3.5.2. Validation of these processes is possible, using historical data to provide the necessary documentary evidence that the process is doing what it is believed to do. The steps involved in this type of validation still require the preparation of a specific protocol, the reporting of the results of the data review, leading to a conclusion and recommendation. 3.5.3. This type of validation exercise is only acceptable for well established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedures or equipment.
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3.5.4. The source of data for this validation may include batch documents, process control charts, maintenance log books, records of personnel changes, process capability studies (reflected in a CpK), finished product data, including trend cards, and storage stability results. 3.6. Re-validation 3.6.1. Re-validation provides the evidence that changes in a process and/or the process environment, introduced either intentionally or unintentionally, do not adversely affect process characteristics and product quality. 3.6.2. There are two basic categories of Re-validation: (a) Re-validation in cases of known change (including transfer of processes from one company to another or from one site to another), (b) Periodic Re-validation carried out at scheduled intervals, which are justified. 3.6.3. A system should be in place (refer to Validation Master Plan requirements) to ensure both situations are addressed. Documentation requirements will be the same as for the initial validation of the process, and in many cases similar protocols can be employed. 3.6.4. The definition of what constitutes a change to a process or process environment needs to be agreed. Guidance on this is given below. 3.6.5. The need for periodic Re-validation of non-sterile processes is considered to be a lower priority than for sterile processes. In the case of standard processes on conventional equipment a data review similar to what would be required for Retrospective Validation may provide an adequate assurance that the process continues under control. In addition the following points should also be considered: (a) the occurrence of any changes in the master formula, methods or starting material manufacturer, (b) equipment calibrations carried out according to the established programme, (c) preventative maintenance carried out according to the programme, (d) standard operating procedures (SOPs) up to date and being followed, (e) cleaning and hygiene programme still appropriate, (f) unplanned changes or maintenance to equipment or instruments.
3.5.4. The source of data for this validation may include batch documents, process control charts, maintenance log books, records of personnel changes, process capability studies (reflected in a CpK), finished product data, including trend cards, and storage stability results. 3.6. Re-validation 3.6.1. Re-validation provides the evidence that changes in a process and/or the process environment, introduced either intentionally or unintentionally, do not adversely affect process characteristics and product quality. 3.6.2. There are two basic categories of Re-validation: (a) Re-validation in cases of known change (including transfer of processes from one company to another or from one site to another), (b) Periodic Re-validation carried out at scheduled intervals, which are justified. 3.6.3. A system should be in place (refer to Validation Master Plan requirements) to ensure both situations are addressed. Documentation requirements will be the same as for the initial validation of the process, and in many cases similar protocols can be employed. 3.6.4. The definition of what constitutes a change to a process or process environment needs to be agreed. Guidance on this is given below. 3.6.5. The need for periodic Re-validation of non-sterile processes is considered to be a lower priority than for sterile processes. In the case of standard processes on conventional equipment a data review similar to what would be required for Retrospective Validation may provide an adequate assurance that the process continues under control. In addition the following points should also be considered: (a) the occurrence of any changes in the master formula, methods or starting material manufacturer, (b) equipment calibrations carried out according to the established programme, (c) preventative maintenance carried out according to the programme, (d) standard operating procedures (SOPs) up to date and being followed, (e) cleaning and hygiene programme still appropriate, (f) unplanned changes or maintenance to equipment or instruments.
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3.7. Change Control 3.7.1. Change control is an important element in any Quality Assurance system. Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or support system operation. 3.7.2. All changes should be formally requested, documented and accepted by representatives of Production, QC/QA, R&D, Engineering and Regulatory Affairs as appropriate. The likely impact (risk assessment) of the change on the product should be evaluated and the need for, and the extent of Revalidation discussed. The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorised. 3.7.3. Change control procedures should ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality, consistent with the approved specification. Significant changes to processes which are likely to impact on product quality may need regulatory authority approval and the appropriate supporting data, obtained through re-validation, should be submitted by way of variation to the marketing authorisation. Products made by processes subjected to changes should not be released for sale without full awareness and consideration of the change by responsible staff, including the Qualified Person. 3.7.4. Changes that are likely to require Re-validation and might need to be submitted for Quality Assurance pre-approval and subsequently for regulatory approval, are as follows: (a) changes of raw materials (physical properties such as density, viscosity, particle size distribution may affect the process or product), (b) change of starting material manufacturer, (c) changes of packaging material (e.g. substituting plastic for glass), (d) changes in the process (e.g. mixing times, drying temperatures), (e) changes in the equipment (e.g. addition of automatic detection systems). Changes of equipment which involve the replacement of equipment on a like for like basis would not normally require a Revalidation,
3.7. Change Control 3.7.1. Change control is an important element in any Quality Assurance system. Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or support system operation. 3.7.2. All changes should be formally requested, documented and accepted by representatives of Production, QC/QA, R&D, Engineering and Regulatory Affairs as appropriate. The likely impact (risk assessment) of the change on the product should be evaluated and the need for, and the extent of Revalidation discussed. The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorised. 3.7.3. Change control procedures should ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality, consistent with the approved specification. Significant changes to processes which are likely to impact on product quality may need regulatory authority approval and the appropriate supporting data, obtained through re-validation, should be submitted by way of variation to the marketing authorisation. Products made by processes subjected to changes should not be released for sale without full awareness and consideration of the change by responsible staff, including the Qualified Person. 3.7.4. Changes that are likely to require Re-validation and might need to be submitted for Quality Assurance pre-approval and subsequently for regulatory approval, are as follows: (a) changes of raw materials (physical properties such as density, viscosity, particle size distribution may affect the process or product), (b) change of starting material manufacturer, (c) changes of packaging material (e.g. substituting plastic for glass), (d) changes in the process (e.g. mixing times, drying temperatures), (e) changes in the equipment (e.g. addition of automatic detection systems). Changes of equipment which involve the replacement of equipment on a like for like basis would not normally require a Revalidation,
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(f) production area and support system changes (e.g. rearrangement of areas, new water treatment method), (g) transfer of processes to another site
(f) production area and support system changes (e.g. rearrangement of areas, new water treatment method), (g) transfer of processes to another site
4. CLEANING VALIDATION
4.1. Principle 4.1.1. Pharmaceutical products and active pharmaceutical ingredients (APIs) can be contaminated by other pharmaceutical products or APIs, by cleaning agents, by micro-organisms or by other material (e.g. air-borne particles, dust, lubricants, raw materials, intermediates, auxiliaries). In many cases, the same equipment may be used for processing different products. To avoid contamination of the following pharmaceutical product, adequate cleaning procedures are essential. 4.1.2. Cleaning procedures must strictly follow carefully established and validated methods of execution. In any case, manufacturing processes have to be designed and carried out in a way that contamination is reduced to a pre-determined level. 4.1.3. Cleaning Validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing of pharmaceutical products. 4.1.4. Objective of the Cleaning Validation is the confirmation of a reliable cleaning procedure so that the analytical monitoring may be reduced to a minimum in the routine phase. 4.2. Purpose and Scope 4.2.1. These guidelines describe the validation of cleaning procedures for the removal of contaminants associated with the previous products, residues of cleaning agents as well as the control of potential microbial contaminants. 4.2.2. These guidelines apply to the manufacture of pharmaceutical products (final dosage forms). 4.3. General 4.3.1. Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to
4. CLEANING VALIDATION
4.1. Principle 4.1.1. Pharmaceutical products and active pharmaceutical ingredients (APIs) can be contaminated by other pharmaceutical products or APIs, by cleaning agents, by micro-organisms or by other material (e.g. air-borne particles, dust, lubricants, raw materials, intermediates, auxiliaries). In many cases, the same equipment may be used for processing different products. To avoid contamination of the following pharmaceutical product, adequate cleaning procedures are essential. 4.1.2. Cleaning procedures must strictly follow carefully established and validated methods of execution. In any case, manufacturing processes have to be designed and carried out in a way that contamination is reduced to a pre-determined level. 4.1.3. Cleaning Validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing of pharmaceutical products. 4.1.4. Objective of the Cleaning Validation is the confirmation of a reliable cleaning procedure so that the analytical monitoring may be reduced to a minimum in the routine phase. 4.2. Purpose and Scope 4.2.1. These guidelines describe the validation of cleaning procedures for the removal of contaminants associated with the previous products, residues of cleaning agents as well as the control of potential microbial contaminants. 4.2.2. These guidelines apply to the manufacture of pharmaceutical products (final dosage forms). 4.3. General 4.3.1. Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to
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noncontact parts into which product may migrate. For example premises, seals, flanges, mixing shaft, fans of ovens, heating elements etc. 4.3.2. Cleaning procedures for product changeover should be fully validated. 4.3.3. Generally in case of batch-to-batch production it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined. 4.3.4. Several questions should be addressed when evaluating the cleaning process. For example: (a) at what point does a piece of equipment or system become clean? (b) what does visually clean mean? (c) does the equipment need to be scrubbed by hand? (e) what is accomplished by hand scrubbing rather than just a solvent wash? (f) how variable are manual cleaning processes from batch to batch and product to product? (g) what is the most appropriate solvent or detergent? (h) are different cleaning processes required for different products in contact with a piece of equipment? (i) how many times need a cleaning process be applied to ensure adequate cleaning of each piece of equipment? 4.3.5. Cleaning procedures for products and processes which are very similar, do not need to be individually validated. It is considered acceptable to select a representative range of similar products and processes concerned and to justify a validation programme which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the worst case can then be carried out which takes account of the relevant criteria. This practice is termed Bracketing. 4.3.6. At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. 4.3.7. Raw materials sourced from different suppliers may have different physical properties and impurity profiles. Such differences should be considered when designing cleaning procedures, as the materials may behave differently.
noncontact parts into which product may migrate. For example premises, seals, flanges, mixing shaft, fans of ovens, heating elements etc. 4.3.2. Cleaning procedures for product changeover should be fully validated. 4.3.3. Generally in case of batch-to-batch production it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined. 4.3.4. Several questions should be addressed when evaluating the cleaning process. For example: (a) at what point does a piece of equipment or system become clean? (b) what does visually clean mean? (c) does the equipment need to be scrubbed by hand? (e) what is accomplished by hand scrubbing rather than just a solvent wash? (f) how variable are manual cleaning processes from batch to batch and product to product? (g) what is the most appropriate solvent or detergent? (h) are different cleaning processes required for different products in contact with a piece of equipment? (i) how many times need a cleaning process be applied to ensure adequate cleaning of each piece of equipment? 4.3.5. Cleaning procedures for products and processes which are very similar, do not need to be individually validated. It is considered acceptable to select a representative range of similar products and processes concerned and to justify a validation programme which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the worst case can then be carried out which takes account of the relevant criteria. This practice is termed Bracketing. 4.3.6. At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. 4.3.7. Raw materials sourced from different suppliers may have different physical properties and impurity profiles. Such differences should be considered when designing cleaning procedures, as the materials may behave differently.
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4.3.8. Control of change to validated cleaning procedures is required. Revalidation should be considered under the following circumstances: (a) re-validation in cases of changes to premises, equipment, products or processes, (b) periodic re-validation at defined intervals. 4.3.9. Manual methods should be reassessed at more frequent intervals than clean-in-place (CIP) systems. 4.3.10. It is usually not considered acceptable to test until clean. This concept involves cleaning, sampling and testing, with repetition of this sequence until an acceptable residue limit is attained. For the system or equipment with a validated cleaning process, this practice of test until clean should not be required. The practice of test until clean is not considered to replace the need to validate cleaning procedures. 4.3.11. Products which simulate the physicochemical properties of the substance to be removed may be used exceptionally instead of the substances themselves, where such substances are either toxic or hazardous. 4.4. Documentation 4.4.1. A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: (a) the objective of the validation process, (b) responsibilities for performing and approving the validation study, (c) description of the equipment to be used, (d) the interval between the end of production and the beginning of the cleaning procedures, (e) cleaning procedures to be used for each product, each manufacturing system or each piece of equipment, (f) the number of cleaning cycles to be performed consecutively, (g) any routine monitoring requirement, (h) sampling procedures, including the rationale for why a certain sampling method is used, (i) clearly defined sampling locations, (j) data on recovery studies where appropriate,
4.3.8. Control of change to validated cleaning procedures is required. Revalidation should be considered under the following circumstances: (a) re-validation in cases of changes to premises, equipment, products or processes, (b) periodic re-validation at defined intervals. 4.3.9. Manual methods should be reassessed at more frequent intervals than clean-in-place (CIP) systems. 4.3.10. It is usually not considered acceptable to test until clean. This concept involves cleaning, sampling and testing, with repetition of this sequence until an acceptable residue limit is attained. For the system or equipment with a validated cleaning process, this practice of test until clean should not be required. The practice of test until clean is not considered to replace the need to validate cleaning procedures. 4.3.11. Products which simulate the physicochemical properties of the substance to be removed may be used exceptionally instead of the substances themselves, where such substances are either toxic or hazardous. 4.4. Documentation 4.4.1. A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: (a) the objective of the validation process, (b) responsibilities for performing and approving the validation study, (c) description of the equipment to be used, (d) the interval between the end of production and the beginning of the cleaning procedures, (e) cleaning procedures to be used for each product, each manufacturing system or each piece of equipment, (f) the number of cleaning cycles to be performed consecutively, (g) any routine monitoring requirement, (h) sampling procedures, including the rationale for why a certain sampling method is used, (i) clearly defined sampling locations, (j) data on recovery studies where appropriate,
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(k) analytical methods including the limit of detection and the limit of quantitation of those methods, (l) the acceptance criteria, including the rationale for setting the specific limits, (m) other products, processes, and equipment for which the planned validation is valid according to a bracketing concept, (n) when Re-validation will be required. 4.4.2. The Cleaning Validation Protocol should be formally approved by the Plant Management, to ensure that aspects relating to the work defined in the protocol, for example personnel resources, are known and accepted by the management. Quality Assurance should be involved in the approval of protocols and reports. 4.4.3. A Final Validation Report should be prepared. The conclusions of this report should state if the cleaning process has been validated successfully. Limitations that apply to the use of the validated method should be defined (for example, the analytical limit at which cleanliness can be determined). The report should be approved by the Plant Management. 4.4.4. The cleaning process should be documented in an SOP. 4.5. Records should be kept of cleaning performed in such a way that the following information is readily available: (a) the area or piece of equipment cleaned, (b) the person who carried out the cleaning, (c) when the cleaning was carried out, (d) the SOP defining the cleaning process, (e) the product which was previously processed on the equipment being cleaned. 4.4.6. The cleaning record should be signed by the operator who performed the cleaning and by the person responsible for Production and should be reviewed by Quality Assurance. 4.5. Personnel 4.5.1. Operators who perform cleaning routinely should be trained in the application of validated cleaning procedures. Training records should be available for all training carried out.
(k) analytical methods including the limit of detection and the limit of quantitation of those methods, (l) the acceptance criteria, including the rationale for setting the specific limits, (m) other products, processes, and equipment for which the planned validation is valid according to a bracketing concept, (n) when Re-validation will be required. 4.4.2. The Cleaning Validation Protocol should be formally approved by the Plant Management, to ensure that aspects relating to the work defined in the protocol, for example personnel resources, are known and accepted by the management. Quality Assurance should be involved in the approval of protocols and reports. 4.4.3. A Final Validation Report should be prepared. The conclusions of this report should state if the cleaning process has been validated successfully. Limitations that apply to the use of the validated method should be defined (for example, the analytical limit at which cleanliness can be determined). The report should be approved by the Plant Management. 4.4.4. The cleaning process should be documented in an SOP. 4.5. Records should be kept of cleaning performed in such a way that the following information is readily available: (a) the area or piece of equipment cleaned, (b) the person who carried out the cleaning, (c) when the cleaning was carried out, (d) the SOP defining the cleaning process, (e) the product which was previously processed on the equipment being cleaned. 4.4.6. The cleaning record should be signed by the operator who performed the cleaning and by the person responsible for Production and should be reviewed by Quality Assurance. 4.5. Personnel 4.5.1. Operators who perform cleaning routinely should be trained in the application of validated cleaning procedures. Training records should be available for all training carried out.
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4.5.2. It is difficult to validate a manual, i.e. an inherently variable/cleaning procedure. Therefore, operators carrying out manual cleaning procedures should be supervised at regular intervals. 4.6. Equipment 4.6.1. The design of the equipment should be carefully examined. Critical areas (those hardest to clean) should be identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place (CIP) systems. 4.6.2. Dedicated equipment should be used for products which are difficult to remove (e.g. tarry or gummy residues in the bulk manufacturing), for equipment which is difficult to clean (e.g. bags for fluid bed dryers), or for products with a high safety risk (e.g. biologicals or products of high potency which may be difficult to detect below an acceptable limit). 4.7. Microbiological Aspects 4.7.1. The existence of conditions favourable to reproduction of micro organisms (e.g. moisture, temperature, crevices and rough surfaces) and the time of storage should be considered. The aim should be to prevent excessive microbial contamination. 4.7.2. The period and when appropriate, the conditions of storage of equipment before and after cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation. 4.7.3. In general, equipment should be stored dry, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations. 4.8. Sampling 4.8.1. Samples should be drawn according to the Cleaning Validation Protocol. 4.8.2. There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods is generally the
4.5.2. It is difficult to validate a manual, i.e. an inherently variable/cleaning procedure. Therefore, operators carrying out manual cleaning procedures should be supervised at regular intervals. 4.6. Equipment 4.6.1. The design of the equipment should be carefully examined. Critical areas (those hardest to clean) should be identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place (CIP) systems. 4.6.2. Dedicated equipment should be used for products which are difficult to remove (e.g. tarry or gummy residues in the bulk manufacturing), for equipment which is difficult to clean (e.g. bags for fluid bed dryers), or for products with a high safety risk (e.g. biologicals or products of high potency which may be difficult to detect below an acceptable limit). 4.7. Microbiological Aspects 4.7.1. The existence of conditions favourable to reproduction of micro organisms (e.g. moisture, temperature, crevices and rough surfaces) and the time of storage should be considered. The aim should be to prevent excessive microbial contamination. 4.7.2. The period and when appropriate, the conditions of storage of equipment before and after cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation. 4.7.3. In general, equipment should be stored dry, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations. 4.8. Sampling 4.8.1. Samples should be drawn according to the Cleaning Validation Protocol. 4.8.2. There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods is generally the
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most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling. a. Direct Surface Sampling The suitability of the material to be used for sampling and of the sampling medium should be determined. The ability to recover samples accurately may be affected by the choice of sampling material. It is important to ensure that the sampling medium and solvent are satisfactory and can be readily used. b. Rinse Samples Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant and the appropriate volume of the samples. A direct measurement of the product residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process. 4.9. Detergents 4.9.1. The efficiency of cleaning procedures for the removal of detergent residues should be evaluated. Acceptable limits should be defined for levels of detergent after cleaning. Ideally, there should be no residues detected. The possibility of detergent breakdown should be considered when validating cleaning procedures. 4.9.2. The composition of detergents should be known to the manufacturer. If such information is not available, alternative detergents should be selected whose composition can be defined. As a guide, food regulations may be consulted. The manufacturer should ensure, either by a written commitment or by a contract, that he is notified by the detergent supplier of any critical changes in the formulation of the detergent. 4.10. Analytical Methods 4.10.1. The analytical methods should be validated before the Cleaning Validation Study is carried out.
most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling. a. Direct Surface Sampling The suitability of the material to be used for sampling and of the sampling medium should be determined. The ability to recover samples accurately may be affected by the choice of sampling material. It is important to ensure that the sampling medium and solvent are satisfactory and can be readily used. b. Rinse Samples Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant and the appropriate volume of the samples. A direct measurement of the product residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process. 4.9. Detergents 4.9.1. The efficiency of cleaning procedures for the removal of detergent residues should be evaluated. Acceptable limits should be defined for levels of detergent after cleaning. Ideally, there should be no residues detected. The possibility of detergent breakdown should be considered when validating cleaning procedures. 4.9.2. The composition of detergents should be known to the manufacturer. If such information is not available, alternative detergents should be selected whose composition can be defined. As a guide, food regulations may be consulted. The manufacturer should ensure, either by a written commitment or by a contract, that he is notified by the detergent supplier of any critical changes in the formulation of the detergent. 4.10. Analytical Methods 4.10.1. The analytical methods should be validated before the Cleaning Validation Study is carried out.
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4.10.2. The analytical methods used to detect residuals or contaminants should be specific for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable by the company. 4.10.3. The analytical methods should be challenged in combination with the sampling methods used, to show that the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery. This is necessary before any conclusions can be made based on the sample results. A negative result may also be the result of poor sampling techniques. 4.11. Establishment of Limits 4.11.1. The pharmaceutical companys rationale for selecting limits for product residues should be logically based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable. 4.11.2. The approach for setting limits can be: (a) product specific Cleaning Validation for all products, (b) grouping into product families and choosing a worst case product, (c) grouping into groups of risk (e.g. very soluble products, similar potency, highly toxic products, difficult to detect). 4.11.3. Carry-over of product residues should meet defined criteria, for example the most stringent of the following criteria: (a) no more than 0.1% of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product, (b) no more than 10 ppm of any product will appear in another product, (c) no quantity of residue should be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible, (d) for certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products.
4.10.2. The analytical methods used to detect residuals or contaminants should be specific for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable by the company. 4.10.3. The analytical methods should be challenged in combination with the sampling methods used, to show that the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery. This is necessary before any conclusions can be made based on the sample results. A negative result may also be the result of poor sampling techniques. 4.11. Establishment of Limits 4.11.1. The pharmaceutical companys rationale for selecting limits for product residues should be logically based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable. 4.11.2. The approach for setting limits can be: (a) product specific Cleaning Validation for all products, (b) grouping into product families and choosing a worst case product, (c) grouping into groups of risk (e.g. very soluble products, similar potency, highly toxic products, difficult to detect). 4.11.3. Carry-over of product residues should meet defined criteria, for example the most stringent of the following criteria: (a) no more than 0.1% of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product, (b) no more than 10 ppm of any product will appear in another product, (c) no quantity of residue should be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible, (d) for certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products.
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4.11.4. One cannot ensure that the contaminate will be uniformly distributed throughout the system. It is also an invalid conclusion to make the assumption that a residual contaminant would be worn off the equipment surface uniformly or that the contamination might only occur at the beginning of the batch. 4.11.5. In establishing residual limits, it may not be adequate to focus only on the principal reactant since chemical variations (active decomposition materials) may be more difficult to remove.
4.11.4. One cannot ensure that the contaminate will be uniformly distributed throughout the system. It is also an invalid conclusion to make the assumption that a residual contaminant would be worn off the equipment surface uniformly or that the contamination might only occur at the beginning of the batch. 4.11.5. In establishing residual limits, it may not be adequate to focus only on the principal reactant since chemical variations (active decomposition materials) may be more difficult to remove.
GLOSSARY
Definitions of terms relating to qualification and validation which are not given in the glossary of the current EC Guide to GMP, but which are used in this Annex, are given below. Change Control A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status. The intent is to determine the need for action that would ensure and document that the system is maintained in a validated state. Change Management A less formal approach to change control that is generally utilised during the preliminary planning and design stage of a project. (Many companies will elect to move straight to a change control system in a design stage of a complex project. This has the advantage of formality, more accurate records and documentation as well as a strong traceability and accountability feature). Commissioning An engineering term that covers all aspects of bringing a system or subsystem to a position where it is regarded as being ready for use in pharmaceutical manufacture. Commissioning involves all the basis requirements of Installation Qualification (IQ) and Operational Qualification (OQ).
GLOSSARY
Definitions of terms relating to qualification and validation which are not given in the glossary of the current EC Guide to GMP, but which are used in this Annex, are given below. Change Control A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status. The intent is to determine the need for action that would ensure and document that the system is maintained in a validated state. Change Management A less formal approach to change control that is generally utilised during the preliminary planning and design stage of a project. (Many companies will elect to move straight to a change control system in a design stage of a complex project. This has the advantage of formality, more accurate records and documentation as well as a strong traceability and accountability feature). Commissioning An engineering term that covers all aspects of bringing a system or subsystem to a position where it is regarded as being ready for use in pharmaceutical manufacture. Commissioning involves all the basis requirements of Installation Qualification (IQ) and Operational Qualification (OQ).
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Concurrent Validation Validation carried out during routine production of products intended for sale. Critical Variable Study A study that serves to measure variables (parameters) critical to the satisfactory operation of a piece of equipment or plant and to assure their operation within monitored and controlled limits. Examples of variables would be pressure, temperature, flow rates, time etc. Design qualification (DQ) The documented verification of the user requirements for an equipment and its ancillary systems. Installation Qualification (IQ) The performance and documentation of tests to ensure that equipment (such as machines, measuring equipment) used in a manufacturing process, are appropriately selected, correctly installed and work in accordance with established specifications. Limit of Detection The lowest amount of analyte in a sample which can be detected but not quantitated as an exact value. The Limit of Detection is mostly a parameter of limit tests. Limit of Quantitation The lowest amount of analyte in a sample which can be quantitatively determined with defined precision and accuracy under the stated experimental conditions. Minor changes Changes having no direct impact on final or in-process product quality. Operational Qualification (OQ) Documented verification that the system or sub-system performs as intended throughout all anticipated operating ranges.
Concurrent Validation Validation carried out during routine production of products intended for sale. Critical Variable Study A study that serves to measure variables (parameters) critical to the satisfactory operation of a piece of equipment or plant and to assure their operation within monitored and controlled limits. Examples of variables would be pressure, temperature, flow rates, time etc. Design qualification (DQ) The documented verification of the user requirements for an equipment and its ancillary systems. Installation Qualification (IQ) The performance and documentation of tests to ensure that equipment (such as machines, measuring equipment) used in a manufacturing process, are appropriately selected, correctly installed and work in accordance with established specifications. Limit of Detection The lowest amount of analyte in a sample which can be detected but not quantitated as an exact value. The Limit of Detection is mostly a parameter of limit tests. Limit of Quantitation The lowest amount of analyte in a sample which can be quantitatively determined with defined precision and accuracy under the stated experimental conditions. Minor changes Changes having no direct impact on final or in-process product quality. Operational Qualification (OQ) Documented verification that the system or sub-system performs as intended throughout all anticipated operating ranges.
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Process Validation Documented verification that the integrated system functions as intended, in its normal operating environment. (The term Performance Qualification may be used also). Note: Processes may be proven also by documented verification through appropriate testing that the finished product produced by a specified process meets all release requirements. This may be called Product Qualification. Piping & Instrument Diagrams (P&IDs) Engineering schematic drawings that provide details of the interrelationship of equipment, services, material flows, plant controls and alarms. The P&ID also provide the reference for each tag or label used for identification. Pre-Determined Acceptance Criteria The criteria assigned, before undertaking testing, to allow evaluation of test results to demonstrate compliance with a test phase of delivery requirement. Plant Functional Specifications Specifications that document functions, standards and permitted tolerances of systems (plant) or system components (equipment) and which define the operating capabilities of the equipment. Process Capability Study A process capability study is a statistical method that compares process information (e.g. X and s) to the upper and lower specification limits. Process Capability Index (CpK) A process capability index CpK represents the true measure of process capability _ _ CpK = X - LSL or USL - X 3s 3s where LSL = Lower specification limit USL = Upper specification limit _ X = Mean s = Standard deviation
Process Validation Documented verification that the integrated system functions as intended, in its normal operating environment. (The term Performance Qualification may be used also). Note: Processes may be proven also by documented verification through appropriate testing that the finished product produced by a specified process meets all release requirements. This may be called Product Qualification. Piping & Instrument Diagrams (P&IDs) Engineering schematic drawings that provide details of the interrelationship of equipment, services, material flows, plant controls and alarms. The P&ID also provide the reference for each tag or label used for identification. Pre-Determined Acceptance Criteria The criteria assigned, before undertaking testing, to allow evaluation of test results to demonstrate compliance with a test phase of delivery requirement. Plant Functional Specifications Specifications that document functions, standards and permitted tolerances of systems (plant) or system components (equipment) and which define the operating capabilities of the equipment. Process Capability Study A process capability study is a statistical method that compares process information (e.g. X and s) to the upper and lower specification limits. Process Capability Index (CpK) A process capability index CpK represents the true measure of process capability _ _ CpK = X - LSL or USL - X 3s 3s where LSL = Lower specification limit USL = Upper specification limit _ X = Mean s = Standard deviation
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Prospective Validation Establishing documented evidence that a process, procedure, system, equipment or mechanism used in manufacture does what it purports to do based on a pre-planned validation protocol. Qualification Identification of equipment attributes related to the performance of a particular function or functions and allocation of certain limits or restrictions to those attributes. Retrospective Validation Validation of a process for a product which has been marketed based upon accumulated manufacturing, testing and control batch data. Re-Validation A repeat of the process validation to provide an assurance that changes in the process/equipment introduced in accordance with change control procedures do not adversely affect process characteristics and product quality. Sensitivity Capacity of the test procedure to record small variations in concentration of a component, with a defined degree of precision. Simulated Product A material that closely approximates the physical and, where practical, the chemical characteristics (e.g. viscosity, particle size, pH etc.) of the product under validation. In many cases, these characteristics may be satisfied by a placebo product batch. Validation Master Plan A document providing information on the companys validation work programme. It should define details of and timescales for the validation work to be performed. Responsibilities relating to the plan should be stated.
Prospective Validation Establishing documented evidence that a process, procedure, system, equipment or mechanism used in manufacture does what it purports to do based on a pre-planned validation protocol. Qualification Identification of equipment attributes related to the performance of a particular function or functions and allocation of certain limits or restrictions to those attributes. Retrospective Validation Validation of a process for a product which has been marketed based upon accumulated manufacturing, testing and control batch data. Re-Validation A repeat of the process validation to provide an assurance that changes in the process/equipment introduced in accordance with change control procedures do not adversely affect process characteristics and product quality. Sensitivity Capacity of the test procedure to record small variations in concentration of a component, with a defined degree of precision. Simulated Product A material that closely approximates the physical and, where practical, the chemical characteristics (e.g. viscosity, particle size, pH etc.) of the product under validation. In many cases, these characteristics may be satisfied by a placebo product batch. Validation Master Plan A document providing information on the companys validation work programme. It should define details of and timescales for the validation work to be performed. Responsibilities relating to the plan should be stated.
Validation Protocol A written plan stating how validation will be conducted, including test parameters, product characteristics, production equipment and decision points on what constitutes acceptable test results. Validation Report Document reporting the validation activities, the validation data and the conclusions drawn. Worst Case A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.
Validation Protocol A written plan stating how validation will be conducted, including test parameters, product characteristics, production equipment and decision points on what constitutes acceptable test results. Validation Report Document reporting the validation activities, the validation data and the conclusions drawn. Worst Case A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.
canadian guide for validation
canadian guide for validation
cleaning validation guidelines

Supersedes Date issued: 2000-05-01 Date of implementation: 2000-05-01 *Revision were made to this document 2002-02-14 to reflect changes to the Health Products and Food Branch organizational structure. There were no other changes made to the content of the document.
cleaning validation guidelines

Supersedes Date issued: 2000-05-01 Date of implementation: 2000-05-01 *Revision were made to this document 2002-02-14 to reflect changes to the Health Products and Food Branch organizational structure. There were no other changes made to the content of the document.
1.0 Scope This document on Cleaning Validation is intended to address special considerations and issues pertaining to validation of cleaning procedures for equipment used in the manufacture of pharmaceutical products, radiopharmaceuticals, and biological drugs. The document is also intended to establish inspection consistency and uniformity with respect to equipment cleaning procedures. Principles incorporated in international guidance have been taken into account in the preparation of this document. The document is intended to cover validation of equipment cleaning for the removal of contaminants associated with previous products, residues of cleaning agents as well as the control of potential microbial contaminants. 2.0 Introduction This document provides some guidance on issues and topics related to cleaning validation. This topic reflects an area in pharmaceutical, biological and radiopharmaceutical manufacturing that is noted as being important by both the Inspectorate and the pharmaceutical industry. This guideline has been prepared to provide guidance to inspectors, evaluators and industry in reviewing the issues covered. Utilization of this information should facilitate compliance with Division 2 Part C of the Regulations to the Food and Drugs Act. It is not intended that the recommendations made in these guidelines become requirements under all circumstances. Information provided in the document for limits to be applied in defined circumstances as well as the number of batches to be utilized for cleaning validation studies is for guidance purposes only. Inspectors, evaluators and industry may consider other limits if proposed and documented in accordance with appropriate scientific justification. 3.0 Principles 3.1 The objective of the cleaning validation is to verify the effectiveness of the cleaning procedure for removal of product residues, degradation products, preservatives, excipients and/or cleaning agents so that the
1.0 Scope This document on Cleaning Validation is intended to address special considerations and issues pertaining to validation of cleaning procedures for equipment used in the manufacture of pharmaceutical products, radiopharmaceuticals, and biological drugs. The document is also intended to establish inspection consistency and uniformity with respect to equipment cleaning procedures. Principles incorporated in international guidance have been taken into account in the preparation of this document. The document is intended to cover validation of equipment cleaning for the removal of contaminants associated with previous products, residues of cleaning agents as well as the control of potential microbial contaminants. 2.0 Introduction This document provides some guidance on issues and topics related to cleaning validation. This topic reflects an area in pharmaceutical, biological and radiopharmaceutical manufacturing that is noted as being important by both the Inspectorate and the pharmaceutical industry. This guideline has been prepared to provide guidance to inspectors, evaluators and industry in reviewing the issues covered. Utilization of this information should facilitate compliance with Division 2 Part C of the Regulations to the Food and Drugs Act. It is not intended that the recommendations made in these guidelines become requirements under all circumstances. Information provided in the document for limits to be applied in defined circumstances as well as the number of batches to be utilized for cleaning validation studies is for guidance purposes only. Inspectors, evaluators and industry may consider other limits if proposed and documented in accordance with appropriate scientific justification. 3.0 Principles 3.1 The objective of the cleaning validation is to verify the effectiveness of the cleaning procedure for removal of product residues, degradation products, preservatives, excipients and/or cleaning agents so that the
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analytical monitoring may be reduced to a minimum in the routine phase. In addition one needs to ensure there is no risk associated with crosscontamination of active ingredients. 3.2 Cleaning procedures must strictly follow carefully established and validated methods. 3.3 Appropriate cleaning procedures must be developed for all productcontact equipment used in the production process. Consideration should also be given to non-contact parts into which product may migrate, e.g., seals, flanges, mixing shaft, fans of ovens, heating elements etc. 3.4 Relevant process equipment cleaning validation methods are required for biological drugs because of their inherent characteristics (proteins are sticky by nature), parenteral product purity requirements, the complexity of equipment and the broad spectrum of materials which need to be cleaned. 3.5 Cleaning procedures for products and processes which are very similar do not need to be individually validated. This could be dependent on what is common, equipment and surface area, or an environment involving all product-contact equipment. It is considered acceptable to select a representative range of similar products and processes. The physical similarities of the products, the formulation, the manner and quantity of use by the consumer, the nature of other product previously manufactured, the size of batch in comparison to previously manufactured product are critical issues that justify a validation program. A single validation study under consideration of the worst case can then be carried out which takes account of the relevant criteria. For biological drugs, including vaccines, bracketing may be considered acceptable for similar products and/or equipment provided appropriate justification, based on sound, scientific rationale is given. Some examples are cleaning of fermenters of the same design but with different vessel capacity used for the same type of recombinant proteins expressed in the same rodent cell line and cultivated in closely related growth media; a multiantigen vaccine used to represent the individual antigen or other combinations of them when validating the same or similar equipment that is used at stages of formulation (adsorption) and/or holding. Validation of cleaning of fermenters should be done upon individual pathogen basis.
analytical monitoring may be reduced to a minimum in the routine phase. In addition one needs to ensure there is no risk associated with crosscontamination of active ingredients. 3.2 Cleaning procedures must strictly follow carefully established and validated methods. 3.3 Appropriate cleaning procedures must be developed for all productcontact equipment used in the production process. Consideration should also be given to non-contact parts into which product may migrate, e.g., seals, flanges, mixing shaft, fans of ovens, heating elements etc. 3.4 Relevant process equipment cleaning validation methods are required for biological drugs because of their inherent characteristics (proteins are sticky by nature), parenteral product purity requirements, the complexity of equipment and the broad spectrum of materials which need to be cleaned. 3.5 Cleaning procedures for products and processes which are very similar do not need to be individually validated. This could be dependent on what is common, equipment and surface area, or an environment involving all product-contact equipment. It is considered acceptable to select a representative range of similar products and processes. The physical similarities of the products, the formulation, the manner and quantity of use by the consumer, the nature of other product previously manufactured, the size of batch in comparison to previously manufactured product are critical issues that justify a validation program. A single validation study under consideration of the worst case can then be carried out which takes account of the relevant criteria. For biological drugs, including vaccines, bracketing may be considered acceptable for similar products and/or equipment provided appropriate justification, based on sound, scientific rationale is given. Some examples are cleaning of fermenters of the same design but with different vessel capacity used for the same type of recombinant proteins expressed in the same rodent cell line and cultivated in closely related growth media; a multiantigen vaccine used to represent the individual antigen or other combinations of them when validating the same or similar equipment that is used at stages of formulation (adsorption) and/or holding. Validation of cleaning of fermenters should be done upon individual pathogen basis.
HPFBI: cleaning validation guidelines (2002)
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4.0 Validation of cleaning processes 4.1 As a general concept, until the validation of the cleaning procedure has been completed, the product contact equipment should be dedicated. 4.2 In a multi-product facility, the effort of validating the cleaning of a specific piece of equipment which has been exposed to a product and the cost of permanently dedicating the equipment to a single product should be considered. 4.3 Equipment cleaning validation may be performed concurrently with actual production steps during process development and clinical manufacturing. Validation programs should be continued through full scale commercial production. 4.4 It is usually not considered acceptable to test-until-clean. This concept involves cleaning, sampling and testing with repetition of this sequence until an acceptable residue limit is attained. For the system or equipment with a validated cleaning procedure, this practice of resampling should not be utilized. 4.5 Products which simulate the physicochemical properties of the substance to be removed may be considered for use instead of the substances themselves, when such substances are either toxic or hazardous. 4.6 Raw materials sourced from different suppliers may have different physical properties and impurity profiles. When applicable such differences should be considered when designing cleaning procedures, as the materials may behave differently. 4.7 All pertinent parameters should be checked to ensure the process as it will ultimately be run is validated. Therefore, if critical temperatures are needed to effect cleaning, then these should be verified. Any chemical agents added should be verified for type as well as quantity. Volumes of wash and rinse fluids, and velocity measurements for cleaning fluids should be measured as appropriate. 4.8 If automated procedures are utilized (Clean-In-Place: CIP), consideration should be given to monitoring the critical control points and the parameters with appropriate sensors and alarm points to ensure the process is highly controlled.
4.0 Validation of cleaning processes 4.1 As a general concept, until the validation of the cleaning procedure has been completed, the product contact equipment should be dedicated. 4.2 In a multi-product facility, the effort of validating the cleaning of a specific piece of equipment which has been exposed to a product and the cost of permanently dedicating the equipment to a single product should be considered. 4.3 Equipment cleaning validation may be performed concurrently with actual production steps during process development and clinical manufacturing. Validation programs should be continued through full scale commercial production. 4.4 It is usually not considered acceptable to test-until-clean. This concept involves cleaning, sampling and testing with repetition of this sequence until an acceptable residue limit is attained. For the system or equipment with a validated cleaning procedure, this practice of resampling should not be utilized. 4.5 Products which simulate the physicochemical properties of the substance to be removed may be considered for use instead of the substances themselves, when such substances are either toxic or hazardous. 4.6 Raw materials sourced from different suppliers may have different physical properties and impurity profiles. When applicable such differences should be considered when designing cleaning procedures, as the materials may behave differently. 4.7 All pertinent parameters should be checked to ensure the process as it will ultimately be run is validated. Therefore, if critical temperatures are needed to effect cleaning, then these should be verified. Any chemical agents added should be verified for type as well as quantity. Volumes of wash and rinse fluids, and velocity measurements for cleaning fluids should be measured as appropriate. 4.8 If automated procedures are utilized (Clean-In-Place: CIP), consideration should be given to monitoring the critical control points and the parameters with appropriate sensors and alarm points to ensure the process is highly controlled.
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4.9 Validation of cleaning processes should be based on a worst-case scenario including: (i) challenge of the cleaning process to show that the challenge soil can be recovered in sufficient quantity or demonstrate log removal to ensure that the cleaning process is indeed removing the soil to the required level, and (ii) the use of reduced cleaning parameters such as overloading of contaminants, over drying of equipment surfaces, minimal concentration of cleaning agents and/or minimum contact time of detergents. 4.10 At least three (3) consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. 5.0 Equipment and Personnel 5.1 All processing equipment should be specifically designed to facilitate cleanability and permit visual inspection and whenever possible, the equipment should be made of smooth surfaces of non-reactive materials. 5.2 Critical areas i.e. those hardest to clean should be identified, particularly in large systems that employ semi-automatic or fully automatic CIP systems. 5.3 Dedicated product-contact equipment should be used for products which are difficult to remove (e.g. tarry or gummy residues in the bulk manufacturing), for equipment which is difficult to clean (e.g. bags for fluid bed dryers), or for products with a high safety risk (e.g. biologicals or products of high potency which may be difficult to detect below an acceptable limit). 5.4 In a bulk process, particularly for very potent chemicals such as some steroids, the issue of by-products needs to be considered if equipment is not dedicated. 5.5 It is difficult to validate a manual cleaning procedure, i.e. an inherently variable/cleaning procedure. Therefore, operators carrying out manual cleaning procedures should be adequately trained, monitored, and periodically assessed.
4.9 Validation of cleaning processes should be based on a worst-case scenario including: (i) challenge of the cleaning process to show that the challenge soil can be recovered in sufficient quantity or demonstrate log removal to ensure that the cleaning process is indeed removing the soil to the required level, and (ii) the use of reduced cleaning parameters such as overloading of contaminants, over drying of equipment surfaces, minimal concentration of cleaning agents and/or minimum contact time of detergents. 4.10 At least three (3) consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. 5.0 Equipment and Personnel 5.1 All processing equipment should be specifically designed to facilitate cleanability and permit visual inspection and whenever possible, the equipment should be made of smooth surfaces of non-reactive materials. 5.2 Critical areas i.e. those hardest to clean should be identified, particularly in large systems that employ semi-automatic or fully automatic CIP systems. 5.3 Dedicated product-contact equipment should be used for products which are difficult to remove (e.g. tarry or gummy residues in the bulk manufacturing), for equipment which is difficult to clean (e.g. bags for fluid bed dryers), or for products with a high safety risk (e.g. biologicals or products of high potency which may be difficult to detect below an acceptable limit). 5.4 In a bulk process, particularly for very potent chemicals such as some steroids, the issue of by-products needs to be considered if equipment is not dedicated. 5.5 It is difficult to validate a manual cleaning procedure, i.e. an inherently variable/cleaning procedure. Therefore, operators carrying out manual cleaning procedures should be adequately trained, monitored, and periodically assessed.
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6.0 Microbiological considerations 6.1 Whether or not CIP systems are used for cleaning of processing equipment, microbiological aspects of equipment cleaning should be considered. This consists largely of preventive measures rather than removal of contamination once it has occurred. 6.2 There should be some documented evidence that routine cleaning and storage of equipment do not allow microbial proliferation. For example, equipment should be dried before storage, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations. Time-frames for the storage of unclean equipment, prior to commencement of cleaning, as well as time frames and conditions for the storage of cleaned equipment should be established. 6.3 The control of the bio-burden through adequate cleaning and storage of equipment is important to ensure that subsequent sterilization or sanitization procedures achieve the necessary assurance of sterility. This is also particularly important from the standpoint of the control of pyrogens in sterile processing since equipment sterilization processes may not be adequate to achieve significant inactivation or removal of pyrogens. 7.0 Documentation 7.1 Detailed cleaning procedure(s) are to be documented in SOPs 7.2 A cleaning validation protocol should describe the procedure used to validate the cleaning process. It should include in addition to other information: description of the equipment used; interval between the end of production and the beginning of the cleaning procedures; cleaning procedures to be used for each product, each manufacturing system or each piece of equipment; sampling procedures with rationales; analytical methods including limit of detection and limit of quantitation; acceptance criteria with rationales and conditions for revalidation. 7.3 Depending upon the complexity of the system and cleaning processes, the amount of documentation necessary for executing various cleaning steps or procedures may vary. 7.4 When more complex cleaning procedures are required, it is important to document the critical cleaning steps. In this regard, specific documentation on the equipment itself which includes information about who cleaned it,
6.0 Microbiological considerations 6.1 Whether or not CIP systems are used for cleaning of processing equipment, microbiological aspects of equipment cleaning should be considered. This consists largely of preventive measures rather than removal of contamination once it has occurred. 6.2 There should be some documented evidence that routine cleaning and storage of equipment do not allow microbial proliferation. For example, equipment should be dried before storage, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations. Time-frames for the storage of unclean equipment, prior to commencement of cleaning, as well as time frames and conditions for the storage of cleaned equipment should be established. 6.3 The control of the bio-burden through adequate cleaning and storage of equipment is important to ensure that subsequent sterilization or sanitization procedures achieve the necessary assurance of sterility. This is also particularly important from the standpoint of the control of pyrogens in sterile processing since equipment sterilization processes may not be adequate to achieve significant inactivation or removal of pyrogens. 7.0 Documentation 7.1 Detailed cleaning procedure(s) are to be documented in SOPs 7.2 A cleaning validation protocol should describe the procedure used to validate the cleaning process. It should include in addition to other information: description of the equipment used; interval between the end of production and the beginning of the cleaning procedures; cleaning procedures to be used for each product, each manufacturing system or each piece of equipment; sampling procedures with rationales; analytical methods including limit of detection and limit of quantitation; acceptance criteria with rationales and conditions for revalidation. 7.3 Depending upon the complexity of the system and cleaning processes, the amount of documentation necessary for executing various cleaning steps or procedures may vary. 7.4 When more complex cleaning procedures are required, it is important to document the critical cleaning steps. In this regard, specific documentation on the equipment itself which includes information about who cleaned it,
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when the cleaning was carried out, the product which was previously processed on the equipment being cleaned should be available. However, for relatively simple cleaning operations, the mere documentation that the overall cleaning process was performed might be sufficient. 7.5 Other factors such as history of cleaning, residue levels found after cleaning, and variability of test results may also dictate the amount of documentation required. For example, when variable residue levels are detected following cleaning, particularly for a process that is believed to be acceptable, one must establish the effectiveness of the process and of the operator performance. Appropriate evaluations must be made and when operator performance is deemed a problem, more extensive documentation (guidance) and training may be required. 8.0 Analytical methods
when the cleaning was carried out, the product which was previously processed on the equipment being cleaned should be available. However, for relatively simple cleaning operations, the mere documentation that the overall cleaning process was performed might be sufficient. 7.5 Other factors such as history of cleaning, residue levels found after cleaning, and variability of test results may also dictate the amount of documentation required. For example, when variable residue levels are detected following cleaning, particularly for a process that is believed to be acceptable, one must establish the effectiveness of the process and of the operator performance. Appropriate evaluations must be made and when operator performance is deemed a problem, more extensive documentation (guidance) and training may be required. 8.0 Analytical methods
8.1 The analytical methods used to detect residuals or contaminants should be specific for the substance or the class of substances to be assayed (e.g., product residue, detergent residue and/or endotoxin) and be validated before the cleaning validation study is carried out. 8.2 The specificity and sensitivity of the analytical methods should be determined. If levels of contamination or residual are not detected, it does not mean that there is no residual contaminant present after cleaning,. It only means that the levels of contaminant greater than the sensitivity or detection limit of the analytical method are not present in the sample. 8.3 In the case of biological drugs, the use of product-specific assay(s) such as immunoassay(s) to monitor the presence of biological carry-over may not be adequate, a negative test may be the result of denaturation of protein epitope(s). Product-specific assay(s) can be used in addition to total organic carbon (TOC) for the detection of protein residue. 8.4 The analytical method and the percent recovery of contaminants should be challenged in combination with the sampling method(s) used (see below). This is to show that contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery. This is necessary before any conclusions can be made based on the sample results. A negative test may also be the result of poor sampling technique.
8.1 The analytical methods used to detect residuals or contaminants should be specific for the substance or the class of substances to be assayed (e.g., product residue, detergent residue and/or endotoxin) and be validated before the cleaning validation study is carried out. 8.2 The specificity and sensitivity of the analytical methods should be determined. If levels of contamination or residual are not detected, it does not mean that there is no residual contaminant present after cleaning,. It only means that the levels of contaminant greater than the sensitivity or detection limit of the analytical method are not present in the sample. 8.3 In the case of biological drugs, the use of product-specific assay(s) such as immunoassay(s) to monitor the presence of biological carry-over may not be adequate, a negative test may be the result of denaturation of protein epitope(s). Product-specific assay(s) can be used in addition to total organic carbon (TOC) for the detection of protein residue. 8.4 The analytical method and the percent recovery of contaminants should be challenged in combination with the sampling method(s) used (see below). This is to show that contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery. This is necessary before any conclusions can be made based on the sample results. A negative test may also be the result of poor sampling technique.
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9.0 Sampling, rinsing, rinse samples and detergents 9.0 Sampling, rinsing, rinse samples and detergents 9.1 There are two general types of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods is generally the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling. 9.2 Direct Surface Sampling (i) Areas hardest to clean and which are reasonably accessible can be evaluated by direct sampling method, leading to establishing a level of contamination or residue per given surface area. Additionally, residues that are dried out or are insoluble can be sampled by physical removal. (ii) The suitability of the material to be used for sampling and of the sampling medium should be determined. The ability to recover a sample accurately may be affected by the choice of sampling material. It is important to assure that the sampling medium and solvent (used for extraction from the medium) are satisfactory and can be readily used. 9.3 Rinse Samples (i) Rinse samples allow sampling of a large surface area and of inaccessible systems or ones that cannot be routinely disassembled. However consideration should be given to the fact that the residue or contaminant may be insoluble or may be physically occluded in the equipment. (ii) A direct measurement of the residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process. 9.4 Indirect testing such as conductivity testing may be of some value for routine monitoring once a cleaning process has been validated. This could be applicable to reactors or centrifuge and piping between such large equipment can be sampled only using rinse solution samples. 9.5 If the placebo method is used to validate the cleaning process then it should be used in conjunction with rinse and/or swab samples. It is difficult to provide assurance that the contaminate will be uniformly dispersed throughout the system or that it would be worn off the equipment surface uniformly. Additionally, if the contaminant or residue is of large enough particle size, it may not be uniformly dispersed in the placebo. Finally, the 9.1 There are two general types of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods is generally the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling. 9.2 Direct Surface Sampling (i) Areas hardest to clean and which are reasonably accessible can be evaluated by direct sampling method, leading to establishing a level of contamination or residue per given surface area. Additionally, residues that are dried out or are insoluble can be sampled by physical removal. (ii) The suitability of the material to be used for sampling and of the sampling medium should be determined. The ability to recover a sample accurately may be affected by the choice of sampling material. It is important to assure that the sampling medium and solvent (used for extraction from the medium) are satisfactory and can be readily used. 9.3 Rinse Samples (i) Rinse samples allow sampling of a large surface area and of inaccessible systems or ones that cannot be routinely disassembled. However consideration should be given to the fact that the residue or contaminant may be insoluble or may be physically occluded in the equipment. (ii) A direct measurement of the residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process. 9.4 Indirect testing such as conductivity testing may be of some value for routine monitoring once a cleaning process has been validated. This could be applicable to reactors or centrifuge and piping between such large equipment can be sampled only using rinse solution samples. 9.5 If the placebo method is used to validate the cleaning process then it should be used in conjunction with rinse and/or swab samples. It is difficult to provide assurance that the contaminate will be uniformly dispersed throughout the system or that it would be worn off the equipment surface uniformly. Additionally, if the contaminant or residue is of large enough particle size, it may not be uniformly dispersed in the placebo. Finally, the
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analytical power of the assay may be greatly reduced by dilution of the contaminant. 9.6 It is important to use visual inspection in addition to analytical methodology to ensure the process is acceptable. 9.7 When detergents are used in the cleaning process, their composition should be known to the user and their removal should be demonstrated. 9.8 Detergents should be easily removable, being used to facilitate the cleaning during the cleaning process. Acceptable limits should be defined for detergent residues after cleaning. The possibility of detergent breakdown should also be considered when validating cleaning procedures. 9.9 Water for injection should be used in the last rinse for product-contact equipment to be utilized in the fabrication of sterile products. 9.10 Purified water is considered acceptable for product-contact equipment used in the fabrication of non-sterile products. NOTE: Because of the presence of varying levels of organic and inorganic residues as well as of chlorine, tap water should not be used in the last rinse of any cleaning procedure for productcontact equipment. 10.0 Establishment of limits 10.1 The fabricators rationale for selecting limits for product residues should be logical and based on the materials involved and their therapeutic dose. The limits should be practical, achievable, and verifiable. 10.2 In establishing product residual limits, it may not be adequate to focus only on the main reactant since by-products/chemical variations (active decomposition material) may be more difficult to remove. In addition to chemical testing, Thin Layer chromatography screening may be needed in certain circumstances. 10.3 The approach for setting limits can be (1) product specific cleaning validation for all products; (2) grouping into product families and choosing a worst case product; (3) grouping into groups of risk (e.g., very soluble products, similar potency, highly toxic products or difficult to detect);
analytical power of the assay may be greatly reduced by dilution of the contaminant. 9.6 It is important to use visual inspection in addition to analytical methodology to ensure the process is acceptable. 9.7 When detergents are used in the cleaning process, their composition should be known to the user and their removal should be demonstrated. 9.8 Detergents should be easily removable, being used to facilitate the cleaning during the cleaning process. Acceptable limits should be defined for detergent residues after cleaning. The possibility of detergent breakdown should also be considered when validating cleaning procedures. 9.9 Water for injection should be used in the last rinse for product-contact equipment to be utilized in the fabrication of sterile products. 9.10 Purified water is considered acceptable for product-contact equipment used in the fabrication of non-sterile products. NOTE: Because of the presence of varying levels of organic and inorganic residues as well as of chlorine, tap water should not be used in the last rinse of any cleaning procedure for productcontact equipment. 10.0 Establishment of limits 10.1 The fabricators rationale for selecting limits for product residues should be logical and based on the materials involved and their therapeutic dose. The limits should be practical, achievable, and verifiable. 10.2 In establishing product residual limits, it may not be adequate to focus only on the main reactant since by-products/chemical variations (active decomposition material) may be more difficult to remove. In addition to chemical testing, Thin Layer chromatography screening may be needed in certain circumstances. 10.3 The approach for setting limits can be (1) product specific cleaning validation for all products; (2) grouping into product families and choosing a worst case product; (3) grouping into groups of risk (e.g., very soluble products, similar potency, highly toxic products or difficult to detect);
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(4) setting limits on not allowing more then a certain fraction of carryover; (5) different safety factors for different dosage forms. 10.4 Carry-over of product residues should meet defined criteria for example the most stringent of the following criteria (i, ii, iii): (i) NMT 0.1% of the normal therapeutic dose of any product to appear in the maximum daily dose of the following product; (ii) NMT 10 ppm of any product to appear in another product; (iii) No quantity of residue to be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible. (iv) For certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limits should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products. NOTE: Some limits that have been mentioned by industry representatives in the literature or in presentations include analytical detection levels such as 10 ppm, biological activity levels such as 1/1000 of the normal therapeutic dose, and organoleptic levels such as no visible residue. Environmental Protection Agency and toxicologists suggest that an acceptable level of a toxic material may be that which is no more than 1/ 1000 of a toxic dose or 1/100 - 1/1000 of an amount which is not known to show any harmful biological effect in the most sensitive animal system known, e.g., no effect. 11.0 Conclusion The cleaning validation programme should be based on detailed cleaning procedures, a good training programme, a validation protocol, validated chemical and microbiological methods, a change control programme, a final report and any auditing required to ensure compliance.
(4) setting limits on not allowing more then a certain fraction of carryover; (5) different safety factors for different dosage forms. 10.4 Carry-over of product residues should meet defined criteria for example the most stringent of the following criteria (i, ii, iii): (i) NMT 0.1% of the normal therapeutic dose of any product to appear in the maximum daily dose of the following product; (ii) NMT 10 ppm of any product to appear in another product; (iii) No quantity of residue to be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible. (iv) For certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limits should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products. NOTE: Some limits that have been mentioned by industry representatives in the literature or in presentations include analytical detection levels such as 10 ppm, biological activity levels such as 1/1000 of the normal therapeutic dose, and organoleptic levels such as no visible residue. Environmental Protection Agency and toxicologists suggest that an acceptable level of a toxic material may be that which is no more than 1/ 1000 of a toxic dose or 1/100 - 1/1000 of an amount which is not known to show any harmful biological effect in the most sensitive animal system known, e.g., no effect. 11.0 Conclusion The cleaning validation programme should be based on detailed cleaning procedures, a good training programme, a validation protocol, validated chemical and microbiological methods, a change control programme, a final report and any auditing required to ensure compliance.
12.0 References 1. FDA, Guide to Inspections of Validation of Cleaning Processes, 1993. 2. Pharmaceutical Inspection Convention Draft Document, Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation and Cleaning Validation, 1998.
12.0 References 1. FDA, Guide to Inspections of Validation of Cleaning Processes, 1993. 2. Pharmaceutical Inspection Convention Draft Document, Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation and Cleaning Validation, 1998.
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cleaning validation guidance: WHO TRS 937 (2006)
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Appendix 3
CLEANING VALIDATION
1. Principle 2. Scope 3. General 4. Cleaning validation protocols and reports 4.1 Cleaning validation protocols 4.2 Cleaning validation reports 5. Personnel 6. Equipment 7. Detergents 8. Microbiology 9. Sampling 9.1 General 9.2 Direct surface sampling (direct method) 9.3 Rinse samples (indirect method) 9.4 Batch placebo method 10. Analytical methods 11. Establishing acceptable limits
Appendix 3
CLEANING VALIDATION
1. Principle 2. Scope 3. General 4. Cleaning validation protocols and reports 4.1 Cleaning validation protocols 4.2 Cleaning validation reports 5. Personnel 6. Equipment 7. Detergents 8. Microbiology 9. Sampling 9.1 General 9.2 Direct surface sampling (direct method) 9.3 Rinse samples (indirect method) 9.4 Batch placebo method 10. Analytical methods 11. Establishing acceptable limits
1 Principle
1.1 The objectives of good manufacturing practices (GMP) include the prevention of possible contamination and cross-contamination of pharmaceutical starting materials and products. 1.2 Pharmaceutical products can be contaminated by a variety of substances such as contaminants associated with microbes, previous products (both active pharmaceutical ingredients (API) and excipient residues), residues of cleaning agents, airborne materials, such as dust and particulate matter, lubricants and ancillary material, such as disinfectants, and decomposition residues from:
1 Principle
1.1 The objectives of good manufacturing practices (GMP) include the prevention of possible contamination and cross-contamination of pharmaceutical starting materials and products. 1.2 Pharmaceutical products can be contaminated by a variety of substances such as contaminants associated with microbes, previous products (both active pharmaceutical ingredients (API) and excipient residues), residues of cleaning agents, airborne materials, such as dust and particulate matter, lubricants and ancillary material, such as disinfectants, and decomposition residues from:
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product residue breakdown occasioned by, e.g. the use of strong acids and alkalis during the cleaning process; and breakdown products of the detergents, acids and alkalis that may be used as part of the cleaning process. 1.3 Adequate cleaning procedures play an important role in preventing contamination and cross-contamination. Validation of cleaning methods provides documented evidence that an approved cleaning procedure will provide clean equipment, suitable for its intended use. 1.4 The objective of cleaning validation is to prove that the equipment is consistently cleaned of product, detergent and microbial residues to an acceptable level, to prevent possible contamination and crosscontamination. 1.5 Cleaning validation is not necessarily required for non-critical cleaning such as that which takes place between batches of the same product (or different lots of the same intermediate in a bulk process), or of floors, walls, the outside of vessels, and following some intermediate steps. 1.6 Cleaning validation should be considered important in multiproduct facilities and should be performed among others, for equipment, sanitization procedures and garment laundering.
product residue breakdown occasioned by, e.g. the use of strong acids and alkalis during the cleaning process; and breakdown products of the detergents, acids and alkalis that may be used as part of the cleaning process. 1.3 Adequate cleaning procedures play an important role in preventing contamination and cross-contamination. Validation of cleaning methods provides documented evidence that an approved cleaning procedure will provide clean equipment, suitable for its intended use. 1.4 The objective of cleaning validation is to prove that the equipment is consistently cleaned of product, detergent and microbial residues to an acceptable level, to prevent possible contamination and crosscontamination. 1.5 Cleaning validation is not necessarily required for non-critical cleaning such as that which takes place between batches of the same product (or different lots of the same intermediate in a bulk process), or of floors, walls, the outside of vessels, and following some intermediate steps. 1.6 Cleaning validation should be considered important in multiproduct facilities and should be performed among others, for equipment, sanitization procedures and garment laundering.
2. Scope
2.1 These guidelines describe the general aspects of cleaning validation, excluding specialized cleaning or inactivation that may be required, e.g. for removal of viral or mycoplasmal contaminants in the biological manufacturing industry. 2.2 Normally cleaning validation would be applicable for critical cleaning such as cleaning between manufacturing of one product and another, of surfaces that come into contact with products, drug products and API.
2. Scope
2.1 These guidelines describe the general aspects of cleaning validation, excluding specialized cleaning or inactivation that may be required, e.g. for removal of viral or mycoplasmal contaminants in the biological manufacturing industry. 2.2 Normally cleaning validation would be applicable for critical cleaning such as cleaning between manufacturing of one product and another, of surfaces that come into contact with products, drug products and API.
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3. General
3.1 There should be written SOPs detailing the cleaning process for equipment and apparatus. The cleaning procedures should be validated. 3.2 The manufacturer should have a cleaning policy and an appropriate procedure for cleaning validation, covering: surfaces that come into contact with the product; cleaning after product changeover (when one pharmaceutical formulation is being changed for another, completely different formulation); between batches in campaigns (when the same formula is being manufactured over a period of time, and on different days); bracketing products for cleaning validation. (This often arises where products contain substances with similar properties (such as solubility) or the same substance in different strengths. An acceptable strategy is to first manufacture the more dilute form (not necessarily the lowest dose) and then the most concentrated form. There are sometimes families of products which differ slightly as to actives or excipients.); and periodic evaluation and revalidation of the number of batches manufactured between cleaning validations. 3.3. At least three consecutive applications of the cleaning procedure should be performed and shown to be successful to prove that the method is validated.
3. General
3.1 There should be written SOPs detailing the cleaning process for equipment and apparatus. The cleaning procedures should be validated. 3.2 The manufacturer should have a cleaning policy and an appropriate procedure for cleaning validation, covering: surfaces that come into contact with the product; cleaning after product changeover (when one pharmaceutical formulation is being changed for another, completely different formulation); between batches in campaigns (when the same formula is being manufactured over a period of time, and on different days); bracketing products for cleaning validation. (This often arises where products contain substances with similar properties (such as solubility) or the same substance in different strengths. An acceptable strategy is to first manufacture the more dilute form (not necessarily the lowest dose) and then the most concentrated form. There are sometimes families of products which differ slightly as to actives or excipients.); and periodic evaluation and revalidation of the number of batches manufactured between cleaning validations. 3.3. At least three consecutive applications of the cleaning procedure should be performed and shown to be successful to prove that the method is validated.
4. Cleaning validation protocols and reports

4.1 Cleaning validation protocols 4.1.1 Cleaning validation should be described in cleaning validation protocols, which should be formally approved, e.g. by the quality control or quality assurance unit. 4.1.2 In preparing the cleaning validation protocol, the following should be considered: disassembly of system;
4. Cleaning validation protocols and reports

4.1 Cleaning validation protocols 4.1.1 Cleaning validation should be described in cleaning validation protocols, which should be formally approved, e.g. by the quality control or quality assurance unit. 4.1.2 In preparing the cleaning validation protocol, the following should be considered: disassembly of system;
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precleaning; cleaning agent, concentration, solution volume, water quality; time and temperature; flow rate, pressure and rinsing; complexity and design of the equipment; training of operators; and size of the system. 4.1.3 The cleaning validation protocol should include: the objectives of the validation process; the people responsible for performing/approving the validation study; the description of the equipment to be used, including a list of the equipment, make, model, serial number or other unique code; the interval between the end of production and the commencement of the cleaning procedure (interval may be part of the validation challenge study itself) the maximum period that equipment may be left dirty before being cleaned as well as the establishment of the time that should elapse after cleaning and before use; the levels of microorganisms (bioburden); the cleaning procedures (documented in an existing SOP, including definition of any automated process) to be used for each product, each manufacturing system or each piece of equipment; all the equipment used for routine monitoring, e.g. conductivity meters, pH meters and total organic carbon analysers; the number of cleaning cycles to be performed consecutively; the sampling procedures to be used (direct sampling, rinse sampling, inprocess monitoring and sampling locations) and the rationale for their use; the data on recovery studies (efficiency of the recovery of the sampling technique should be established); the analytical methods (specificity and sensitivity) including the limit of detection and the limit of quantification; the acceptance criteria (with rationale for setting the specific limits) including a margin for error and for sampling efficiency;
precleaning; cleaning agent, concentration, solution volume, water quality; time and temperature; flow rate, pressure and rinsing; complexity and design of the equipment; training of operators; and size of the system. 4.1.3 The cleaning validation protocol should include: the objectives of the validation process; the people responsible for performing/approving the validation study; the description of the equipment to be used, including a list of the equipment, make, model, serial number or other unique code; the interval between the end of production and the commencement of the cleaning procedure (interval may be part of the validation challenge study itself) the maximum period that equipment may be left dirty before being cleaned as well as the establishment of the time that should elapse after cleaning and before use; the levels of microorganisms (bioburden); the cleaning procedures (documented in an existing SOP, including definition of any automated process) to be used for each product, each manufacturing system or each piece of equipment; all the equipment used for routine monitoring, e.g. conductivity meters, pH meters and total organic carbon analysers; the number of cleaning cycles to be performed consecutively; the sampling procedures to be used (direct sampling, rinse sampling, inprocess monitoring and sampling locations) and the rationale for their use; the data on recovery studies (efficiency of the recovery of the sampling technique should be established); the analytical methods (specificity and sensitivity) including the limit of detection and the limit of quantification; the acceptance criteria (with rationale for setting the specific limits) including a margin for error and for sampling efficiency;
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the choice of the cleaning agent should be documented and approved by the quality unit and should be scientifically justified on the basis of, e.g. the solubility of the materials to be removed; the design and construction of the equipment and surface materials to be cleaned; the safety of the cleaning agent; the ease of removal and detection; the product attributes; the minimum temperature and volume of cleaning agent and rinse solution; and the manufacturers recommendations; revalidation requirements. 4.1.4 Cleaning procedures for products and processes which are very similar do not need to be individually validated. A validation study of the worst case may be considered acceptable. There should be a justified validation programme for this approach referred to as bracketing, addressing critical issues relating to the selected product, equipment or process. 4.1.5 Where bracketing of products is done, consideration should be given to type of products and equipment. 4.1.6 Bracketing by product should be done only when the products concerned are similar in nature or property and will be processed using the same equipment. Identical cleaning procedures should then be used for these products. 4.1.7 When a representative product is chosen, this should be the one that is most difficult to clean. 4.1.8 Bracketing by equipment should be done only when it is similar equipment, or the same equipment in different sizes (e.g. 300-l, 500-l and 1000-l tanks). An alternative approach may be to validate the smallest and the largest sizes separately.
the choice of the cleaning agent should be documented and approved by the quality unit and should be scientifically justified on the basis of, e.g. the solubility of the materials to be removed; the design and construction of the equipment and surface materials to be cleaned; the safety of the cleaning agent; the ease of removal and detection; the product attributes; the minimum temperature and volume of cleaning agent and rinse solution; and the manufacturers recommendations; revalidation requirements. 4.1.4 Cleaning procedures for products and processes which are very similar do not need to be individually validated. A validation study of the worst case may be considered acceptable. There should be a justified validation programme for this approach referred to as bracketing, addressing critical issues relating to the selected product, equipment or process. 4.1.5 Where bracketing of products is done, consideration should be given to type of products and equipment. 4.1.6 Bracketing by product should be done only when the products concerned are similar in nature or property and will be processed using the same equipment. Identical cleaning procedures should then be used for these products. 4.1.7 When a representative product is chosen, this should be the one that is most difficult to clean. 4.1.8 Bracketing by equipment should be done only when it is similar equipment, or the same equipment in different sizes (e.g. 300-l, 500-l and 1000-l tanks). An alternative approach may be to validate the smallest and the largest sizes separately.
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4.2 Cleaning validation reports 4.2.1 The relevant cleaning records (signed by the operator, checked by production and reviewed by quality assurance) and source data (original results) should be kept. The results of the cleaning validation should be presented in cleaning validation reports stating the outcome and conclusion.
4.2 Cleaning validation reports 4.2.1 The relevant cleaning records (signed by the operator, checked by production and reviewed by quality assurance) and source data (original results) should be kept. The results of the cleaning validation should be presented in cleaning validation reports stating the outcome and conclusion.
5. Personnel
5.1 Personnel or operators who perform cleaning routinely should be trained and should be effectively supervised.
5. Personnel
5.1 Personnel or operators who perform cleaning routinely should be trained and should be effectively supervised.
6. Equipment
6.1 Normally only procedures for the cleaning of surfaces of the equipment that come into contact with the product need to be validated. Consideration should be given to non-contact parts of the equipment into which product or any process material may migrate. Critical areas should be identified (independently from method of cleaning), particularly in large systems employing semi-automatic or fully automatic clean-in-place systems. 6.2 Dedicated equipment should be used for products which are difficult to clean, equipment which is difficult to clean, or for products with a high safety risk where it is not possible to achieve the required cleaning acceptance limits using a validated cleaning procedure. 6.3 Ideally, there should be one process for cleaning a piece of equipment or system. This will depend on the products being produced, whether the cleaning occurs between batches of the same product (as in a large campaign) or whether the cleaning occurs between batches of different products. 6.4 The design of equipment may influence the effectiveness of the cleaning process. Consideration should therefore be given to the design of the equipment when preparing the cleaning validation protocol, e.g. Vblenders, transfer pumps or filling lines.
6. Equipment
6.1 Normally only procedures for the cleaning of surfaces of the equipment that come into contact with the product need to be validated. Consideration should be given to non-contact parts of the equipment into which product or any process material may migrate. Critical areas should be identified (independently from method of cleaning), particularly in large systems employing semi-automatic or fully automatic clean-in-place systems. 6.2 Dedicated equipment should be used for products which are difficult to clean, equipment which is difficult to clean, or for products with a high safety risk where it is not possible to achieve the required cleaning acceptance limits using a validated cleaning procedure. 6.3 Ideally, there should be one process for cleaning a piece of equipment or system. This will depend on the products being produced, whether the cleaning occurs between batches of the same product (as in a large campaign) or whether the cleaning occurs between batches of different products. 6.4 The design of equipment may influence the effectiveness of the cleaning process. Consideration should therefore be given to the design of the equipment when preparing the cleaning validation protocol, e.g. Vblenders, transfer pumps or filling lines.
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7. Detergents
7.1 Detergents should facilitate the cleaning process and be easily removable. Detergents that have persistent residues such as cationic detergents which adhere very strongly to glass and are difficult to remove, should be avoided where possible. 7.2 The composition of the detergent should be known to the manufacturer and its removal during rinsing, demonstrated. 7.3 Acceptable limits for detergent residues after cleaning should be defined. The possibility of detergent breakdown should also be considered when validating cleaning procedures. 7.4 Detergents should be released by quality control and, where possible, should meet local food standards or regulations.
7. Detergents
7.1 Detergents should facilitate the cleaning process and be easily removable. Detergents that have persistent residues such as cationic detergents which adhere very strongly to glass and are difficult to remove, should be avoided where possible. 7.2 The composition of the detergent should be known to the manufacturer and its removal during rinsing, demonstrated. 7.3 Acceptable limits for detergent residues after cleaning should be defined. The possibility of detergent breakdown should also be considered when validating cleaning procedures. 7.4 Detergents should be released by quality control and, where possible, should meet local food standards or regulations.
8. Microbiology
8.1 The need to include measures to prevent microbial growth and remove contamination where it has occurred should be considered. 8.2 There should be documented evidence to indicate that routine cleaning and storage of equipment does not allow microbial proliferation. 8.3 The period and conditions for storage of unclean equipment before cleaning, and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. 8.4 Equipment should be stored in a dry condition after cleaning. Stagnant water should not be allowed to remain in equipment after cleaning. 8.5 Control of the bioburden through adequate cleaning and appropriate storage of equipment is important to ensure that subsequent sterilization or sanitization procedures achieve the necessary assurance of sterility, and the control of pyrogens in sterile processing. Equipment sterilization processes may not be adequate to achieve significant inactivation or removal of pyrogens.
8. Microbiology
8.1 The need to include measures to prevent microbial growth and remove contamination where it has occurred should be considered. 8.2 There should be documented evidence to indicate that routine cleaning and storage of equipment does not allow microbial proliferation. 8.3 The period and conditions for storage of unclean equipment before cleaning, and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. 8.4 Equipment should be stored in a dry condition after cleaning. Stagnant water should not be allowed to remain in equipment after cleaning. 8.5 Control of the bioburden through adequate cleaning and appropriate storage of equipment is important to ensure that subsequent sterilization or sanitization procedures achieve the necessary assurance of sterility, and the control of pyrogens in sterile processing. Equipment sterilization processes may not be adequate to achieve significant inactivation or removal of pyrogens.
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9. Sampling
9.1 General 9.1.1 Equipment should normally be cleaned as soon as possible after use. This may be especially important for operations with topical products, suspensions and bulk drug or where the drying of residues will directly affect the efficiency of a cleaning procedure. 9.1.2 Two methods of sampling are considered to be acceptable. These are direct surface sampling and rinse samples. A combination of the two methods is generally the most desirable. 9.1.3 The practice of resampling should not be used before or during cleaning and operations and is acceptable only in rare cases. Constant retesting and resampling can show that the cleaning process is not validated because these retests actually document the presence of unacceptable residue and contaminants resulting from an ineffective cleaning process. 9.2 Direct surface sampling (direct method) Note: This method of sampling is the most commonly used and involves taking an inert material (e.g. cotton wool) on the end of a probe (referred to as a swab) and rubbing it methodically across a surface. The type of sampling material used and its potential impact on the test data is important as the sampling material may interfere with the test. (For example, the adhesive used in swabs has been found to interfere with the analysis of samples.) 9.2.1 Factors that should be considered include the supplier of the swab, area swabbed, number of swabs used, whether they are wet or dry swabs, swab handling and swabbing technique. 9.2.2 The location from which the sample is taken should take into consideration the composition of the equipment (e.g. glass or steel) and the location (e.g. blades, tank walls or fittings). Worst case locations should be considered. The protocol should identify the sampling locations.
9. Sampling
9.1 General 9.1.1 Equipment should normally be cleaned as soon as possible after use. This may be especially important for operations with topical products, suspensions and bulk drug or where the drying of residues will directly affect the efficiency of a cleaning procedure. 9.1.2 Two methods of sampling are considered to be acceptable. These are direct surface sampling and rinse samples. A combination of the two methods is generally the most desirable. 9.1.3 The practice of resampling should not be used before or during cleaning and operations and is acceptable only in rare cases. Constant retesting and resampling can show that the cleaning process is not validated because these retests actually document the presence of unacceptable residue and contaminants resulting from an ineffective cleaning process. 9.2 Direct surface sampling (direct method) Note: This method of sampling is the most commonly used and involves taking an inert material (e.g. cotton wool) on the end of a probe (referred to as a swab) and rubbing it methodically across a surface. The type of sampling material used and its potential impact on the test data is important as the sampling material may interfere with the test. (For example, the adhesive used in swabs has been found to interfere with the analysis of samples.) 9.2.1 Factors that should be considered include the supplier of the swab, area swabbed, number of swabs used, whether they are wet or dry swabs, swab handling and swabbing technique. 9.2.2 The location from which the sample is taken should take into consideration the composition of the equipment (e.g. glass or steel) and the location (e.g. blades, tank walls or fittings). Worst case locations should be considered. The protocol should identify the sampling locations.
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9.2.3 Critical areas, i.e. those hardest to clean, should be identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place systems. 9.2.4 The sampling medium and solvent used should be appropriate to the task. 9.3 Rinse samples (indirect method) Note: This method allows sampling of a large surface, of areas that are inaccessible or that cannot be routinely disassembled and provides an overall picture. Rinse samples may give sufficient evidence of adequate cleaning where accessibility of equipment parts can preclude direct surface sampling, and may be useful for checking for residues of cleaning agents, e.g. detergents. 9.3.1 Rinse samples should be used in combination with other sampling methods such as surface sampling. 9.3.2. There should be evidence that samples are accurately recovered. For example, a recovery of > 80% is considered good, > 50% reasonable and < 50% questionable. 9.4 Batch placebo method Note: This method relies on the manufacture of a placebo batch which is then checked for carry-over of the previous product. It is an expensive and laborious process. It is difficult to provide assurance that the contaminants will be dislodged from the equipment surface uniformly. Additionally, if the particles of the contaminant or residue are large enough, they may not be uniformly dispersed in the placebo batch. 9.4.1 The batch placebo method should be used in conjunction with rinse and/or surface sampling method(s). 9.4.2 Samples should be taken throughout the process of manufacture. Traces of the preceding products should be sought in these samples. (Note that the sensitivity of the assay may be greatly reduced by dilution of the contaminant.)
9.2.3 Critical areas, i.e. those hardest to clean, should be identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place systems. 9.2.4 The sampling medium and solvent used should be appropriate to the task. 9.3 Rinse samples (indirect method) Note: This method allows sampling of a large surface, of areas that are inaccessible or that cannot be routinely disassembled and provides an overall picture. Rinse samples may give sufficient evidence of adequate cleaning where accessibility of equipment parts can preclude direct surface sampling, and may be useful for checking for residues of cleaning agents, e.g. detergents. 9.3.1 Rinse samples should be used in combination with other sampling methods such as surface sampling. 9.3.2. There should be evidence that samples are accurately recovered. For example, a recovery of > 80% is considered good, > 50% reasonable and < 50% questionable. 9.4 Batch placebo method Note: This method relies on the manufacture of a placebo batch which is then checked for carry-over of the previous product. It is an expensive and laborious process. It is difficult to provide assurance that the contaminants will be dislodged from the equipment surface uniformly. Additionally, if the particles of the contaminant or residue are large enough, they may not be uniformly dispersed in the placebo batch. 9.4.1 The batch placebo method should be used in conjunction with rinse and/or surface sampling method(s). 9.4.2 Samples should be taken throughout the process of manufacture. Traces of the preceding products should be sought in these samples. (Note that the sensitivity of the assay may be greatly reduced by dilution of the contaminant.)
10. Analytical methods

10.1 The analytical methods should be validated before the cleaning validation is performed. 10.2 The methods chosen should detect residuals or contaminants specific for the substance(s) being assayed at an appropriate level of cleanliness (sensitivity). 10.3 Validation of the analytical method should include as appropriate: precision, linearity and selectivity (the latter if specific analytes are targeted); limit of detection (LOD); limit of quantitation (LOQ); recovery, by spiking with the analyte; and reproducibility. 10.4 The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminants. 10.5 Suitable methods that are sensitive and specific should be used where possible and may include chromatographic methods (e.g. high pressure liquid chromotography (HPLC), gas chromotography (GC), and high pressure thin-layer chromatography (HPTLC)). Other methods may include (alone or in combination) measurement of total organic carbon (TOC), pH, or conductivity; ultraviolet (UV) spectroscopy; and enzymelinked immunosorbent assay (ELISA).
10. Analytical methods

10.1 The analytical methods should be validated before the cleaning validation is performed. 10.2 The methods chosen should detect residuals or contaminants specific for the substance(s) being assayed at an appropriate level of cleanliness (sensitivity). 10.3 Validation of the analytical method should include as appropriate: precision, linearity and selectivity (the latter if specific analytes are targeted); limit of detection (LOD); limit of quantitation (LOQ); recovery, by spiking with the analyte; and reproducibility. 10.4 The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminants. 10.5 Suitable methods that are sensitive and specific should be used where possible and may include chromatographic methods (e.g. high pressure liquid chromotography (HPLC), gas chromotography (GC), and high pressure thin-layer chromatography (HPTLC)). Other methods may include (alone or in combination) measurement of total organic carbon (TOC), pH, or conductivity; ultraviolet (UV) spectroscopy; and enzymelinked immunosorbent assay (ELISA).
11. Establishing acceptable limits

Note: uniform distribution of contaminants is not guaranteed. 11.1 The acceptance criteria established for contaminant levels in the sample should be practical, achievable and verifiable. The rationale for the residue limits established should be logical, and based on the knowledge of the materials involved.
11. Establishing acceptable limits

Note: uniform distribution of contaminants is not guaranteed. 11.1 The acceptance criteria established for contaminant levels in the sample should be practical, achievable and verifiable. The rationale for the residue limits established should be logical, and based on the knowledge of the materials involved.
11.2 Each situation should be assessed individually. The manner in which limits are established should be carefully considered. In establishing residual limits it may not be adequate to focus only on the principal reactant, because other chemical variations may be more difficult to remove. 11.3 Where necessary, screening using thin-layer chromatography should be performed in addition to chemical analyses. 11.4 There should be no residue from the previous product, from reaction by-products and degradants, or from the cleaning process itself (e.g. detergents or solvents). 11.5 The limit-setting approach can: be product-specific; group products into families and choose a worst case product; group products into groups according to risk, e.g. very soluble products, products with similar potency, highly toxic, or difficult to detect products; use different safety factors for different dosage forms based on physiological response (this method is essential for potent materials). 11.6 Limits may be expressed as a concentration in a subsequent product (ppm), limit per surface area (mcg/cm2), or in rinse water as ppm. 11.7 The sensitivity of the analytical methods should be defined to enable reasonable limits to be set. 11.8 The rationale for selecting limits for carry-over of product residues should meet defined criteria. 11.9 The three most commonly used criteria are: visually clean. (No residue should be visible on equipment after cleaning.) Spiking studies should determine the concentration at which most active ingredients are visible. This criterion may not be suitable for high-potency, low-dosage drugs; no more than 10 ppm of one product will appear in another product (basis for heavy metals in starting materials); and no more than 0.1% of the normal therapeutic dose of one product will appear in the maximum daily dose of a subsequent product.
11.2 Each situation should be assessed individually. The manner in which limits are established should be carefully considered. In establishing residual limits it may not be adequate to focus only on the principal reactant, because other chemical variations may be more difficult to remove. 11.3 Where necessary, screening using thin-layer chromatography should be performed in addition to chemical analyses. 11.4 There should be no residue from the previous product, from reaction by-products and degradants, or from the cleaning process itself (e.g. detergents or solvents). 11.5 The limit-setting approach can: be product-specific; group products into families and choose a worst case product; group products into groups according to risk, e.g. very soluble products, products with similar potency, highly toxic, or difficult to detect products; use different safety factors for different dosage forms based on physiological response (this method is essential for potent materials). 11.6 Limits may be expressed as a concentration in a subsequent product (ppm), limit per surface area (mcg/cm2), or in rinse water as ppm. 11.7 The sensitivity of the analytical methods should be defined to enable reasonable limits to be set. 11.8 The rationale for selecting limits for carry-over of product residues should meet defined criteria. 11.9 The three most commonly used criteria are: visually clean. (No residue should be visible on equipment after cleaning.) Spiking studies should determine the concentration at which most active ingredients are visible. This criterion may not be suitable for high-potency, low-dosage drugs; no more than 10 ppm of one product will appear in another product (basis for heavy metals in starting materials); and no more than 0.1% of the normal therapeutic dose of one product will appear in the maximum daily dose of a subsequent product.
11.10 The most stringent of three options should be used. 11.11 Certain allergenic ingredients (e.g. penicillins and cephalosporins) and highly potent material (e.g. anovulent steroids, potent steroids and cytotoxics) should be undetectable by the best available analytical methods. (In practice this may mean that dedicated manufacturing facilities should be used for the manufacturing and processing of such products.)
11.10 The most stringent of three options should be used. 11.11 Certain allergenic ingredients (e.g. penicillins and cephalosporins) and highly potent material (e.g. anovulent steroids, potent steroids and cytotoxics) should be undetectable by the best available analytical methods. (In practice this may mean that dedicated manufacturing facilities should be used for the manufacturing and processing of such products.)
cleaning validation in active pharmaceutical ingredient manufacturing plants

APIC - 1999
cleaning validation in active pharmaceutical ingredient manufacturing plants

APIC - 1999
1. FOREWORD
This Guideline has been produced by the Active Pharmaceutical Ingredients Committee (APIC) Working group. Different organizations will be influenced by their companies and the markets that they serve in the approaches that they take and the policies that they have with respect to the subject. It is also valuable to bear in mind that this is an area that is changing rapidly and what was considered as being acceptable 2-5 years ago is now not adequate. Therefore, companies should be aware of the need to continuously update themselves on current regulatory requirements.
1. FOREWORD
This Guideline has been produced by the Active Pharmaceutical Ingredients Committee (APIC) Working group. Different organizations will be influenced by their companies and the markets that they serve in the approaches that they take and the policies that they have with respect to the subject. It is also valuable to bear in mind that this is an area that is changing rapidly and what was considered as being acceptable 2-5 years ago is now not adequate. Therefore, companies should be aware of the need to continuously update themselves on current regulatory requirements.
2. OBJECTIVE
The intention of this document has been to define a comprehensive approach to the Validation of Cleaning procedures in Active Pharmaceutical Ingredient manufacturing facilities. Cleaning Validation in the context of Active Pharmaceutical Ingredient manufacture may be defined as: The process of providing documented evidence that the cleaning methods employed within a facility consistently controls potential carryover of product (including intermediates and impurities), cleaning agents and extraneous material into subsequent product to a level which is below predetermined levels. It is necessary to Validate Cleaning procedures for the following reasons: a. It is a customer requirement - it ensures the safety and purity of the product. b. It is a regulatory requirement in Active Pharmaceutical Ingredient product manufacture. c. It also assures from an internal control and compliance point of view the quality of the process.
2. OBJECTIVE
The intention of this document has been to define a comprehensive approach to the Validation of Cleaning procedures in Active Pharmaceutical Ingredient manufacturing facilities. Cleaning Validation in the context of Active Pharmaceutical Ingredient manufacture may be defined as: The process of providing documented evidence that the cleaning methods employed within a facility consistently controls potential carryover of product (including intermediates and impurities), cleaning agents and extraneous material into subsequent product to a level which is below predetermined levels. It is necessary to Validate Cleaning procedures for the following reasons: a. It is a customer requirement - it ensures the safety and purity of the product. b. It is a regulatory requirement in Active Pharmaceutical Ingredient product manufacture. c. It also assures from an internal control and compliance point of view the quality of the process.
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3. SCOPE
This Document will serve to: 1. Define the basic concepts and terms associated with Cleaning Validation in the Active Pharmaceutical Ingredient industry. 2. Serve as a guide from which Masterplans, Protocols and Reports may be compiled. Note: General validation principles and a glossary of terms also relevant to cleaning validation are detailed in the CEFIC / EFPIA Guide entitled Good Manufacturing Practices for Active Pharmaceutical Ingredient Manufacturers. It applies to sterile APIs only up to the point where the API is rendered sterile.
3. SCOPE
This Document will serve to: 1. Define the basic concepts and terms associated with Cleaning Validation in the Active Pharmaceutical Ingredient industry. 2. Serve as a guide from which Masterplans, Protocols and Reports may be compiled. Note: General validation principles and a glossary of terms also relevant to cleaning validation are detailed in the CEFIC / EFPIA Guide entitled Good Manufacturing Practices for Active Pharmaceutical Ingredient Manufacturers. It applies to sterile APIs only up to the point where the API is rendered sterile.
4. POTENTIAL RESIDUES
The Active Pharmaceutical Ingredient Industry involves (in general) the manufacture of Active Pharmaceutical Ingredients by both chemical and physical means through a series of multiple step processes. Plants or individual pieces of equipment, including ancillary equipment, may be used in multi-product manufacture or dedicated to individual products. The result of inadequate cleaning procedures is that any of a number of contaminants may be present in the next batch manufactured on the equipment such as: 1. Precursors to the Active Pharmaceutical Ingredient 2. By-products and/or degradation products of the Active Pharmaceutical Ingredient 3. The previous product 4. Solvents and other materials employed during the manufacturing process. 5. Micro-organisms This is particularly the case where microbial growth may be sustained by the product. 6. Cleaning agents themselves and lubricants
4. POTENTIAL RESIDUES
The Active Pharmaceutical Ingredient Industry involves (in general) the manufacture of Active Pharmaceutical Ingredients by both chemical and physical means through a series of multiple step processes. Plants or individual pieces of equipment, including ancillary equipment, may be used in multi-product manufacture or dedicated to individual products. The result of inadequate cleaning procedures is that any of a number of contaminants may be present in the next batch manufactured on the equipment such as: 1. Precursors to the Active Pharmaceutical Ingredient 2. By-products and/or degradation products of the Active Pharmaceutical Ingredient 3. The previous product 4. Solvents and other materials employed during the manufacturing process. 5. Micro-organisms This is particularly the case where microbial growth may be sustained by the product. 6. Cleaning agents themselves and lubricants
validation of cleaning methods: apic policy and implementation guide
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5. CURRENT REGULATORY GUIDANCE

Refer to the reference section of this document for details of current Regulatory Guidance.
5. CURRENT REGULATORY GUIDANCE

Refer to the reference section of this document for details of current Regulatory Guidance.
6. CLEANING VALIDATION POLICY

The main focus of this document will be to describe equipment and ancillary equipment / process Cleaning Validation in an Active Pharmaceutical Ingredient manufacturing plant. However, it is appropriate to start by giving a brief introduction as to how the concept of Cleaning Validation should be approached in a facility. It is advisable for Active Pharmaceutical Ingredient manufacturing facilities to hold an official Cleaning Validation Policy. Specific department responsibilities should be outlined in this and it should be approved by senior management. This policy should serve to provide a general guideline and direction for company personnel, regulatory authorities and customers as to how the company deals with areas associated with Cleaning Validation. The policy should incorporate the following types of statements: Definition of terms employed during validation i.e. rinse vs. flush vs. wash etc. A statement specifying what company policy is on validation of cleaning procedures related to equipment (including ancillary) and processes. Company policy re dedication of equipment in certain cases (if products are deemed too dangerous and / or highly active to manufacture on multi-product equipment). Analytical validation policy. The policy should also state the rational for the methods by which acceptance criteria is determined. Revalidation policy.
6. CLEANING VALIDATION POLICY

The main focus of this document will be to describe equipment and ancillary equipment / process Cleaning Validation in an Active Pharmaceutical Ingredient manufacturing plant. However, it is appropriate to start by giving a brief introduction as to how the concept of Cleaning Validation should be approached in a facility. It is advisable for Active Pharmaceutical Ingredient manufacturing facilities to hold an official Cleaning Validation Policy. Specific department responsibilities should be outlined in this and it should be approved by senior management. This policy should serve to provide a general guideline and direction for company personnel, regulatory authorities and customers as to how the company deals with areas associated with Cleaning Validation. The policy should incorporate the following types of statements: Definition of terms employed during validation i.e. rinse vs. flush vs. wash etc. A statement specifying what company policy is on validation of cleaning procedures related to equipment (including ancillary) and processes. Company policy re dedication of equipment in certain cases (if products are deemed too dangerous and / or highly active to manufacture on multi-product equipment). Analytical validation policy. The policy should also state the rational for the methods by which acceptance criteria is determined. Revalidation policy.
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7. LEVELS OF CLEANING
The degree or level of cleaning and validation required for processes in Active Pharmaceutical Ingredient manufacturing depends largely on: The equipment usage (i.e. dedicated equipment or not) The stage of manufacture (early, intermediate or final step) The nature of the potential contaminants (toxicity, solubility etc.)
7. LEVELS OF CLEANING
The degree or level of cleaning and validation required for processes in Active Pharmaceutical Ingredient manufacturing depends largely on: The equipment usage (i.e. dedicated equipment or not) The stage of manufacture (early, intermediate or final step) The nature of the potential contaminants (toxicity, solubility etc.)
Each of the above three bullets must be evaluated based on the next product, not only toxicology etc. The rational for this statement is given below: In general, the higher the potential for finished Active Pharmaceutical Ingredient contamination the greater the requirement to validate cleaning methods to ensure product safety. Active Pharmaceutical Ingredient manufacturers may have different levels of cleaning requirements in facilities based on the stage of the process being cleaned and the subsequent product to be manufactured. Table 1 illustrates an example of how a company may decide on the level of cleaning between lots. It is the responsibility of the manufacturer to demonstrate that the level of cleaning and validation performed is adequate based on each individual situation and on a justifiable scientific rational. Cleaning should be carried out as soon as practical after the end of processing and should leave the plant in a suitable condition for next use.
Table 1: levels of cleaning
Each of the above three bullets must be evaluated based on the next product, not only toxicology etc. The rational for this statement is given below: In general, the higher the potential for finished Active Pharmaceutical Ingredient contamination the greater the requirement to validate cleaning methods to ensure product safety. Active Pharmaceutical Ingredient manufacturers may have different levels of cleaning requirements in facilities based on the stage of the process being cleaned and the subsequent product to be manufactured. Table 1 illustrates an example of how a company may decide on the level of cleaning between lots. It is the responsibility of the manufacturer to demonstrate that the level of cleaning and validation performed is adequate based on each individual situation and on a justifiable scientific rational. Cleaning should be carried out as soon as practical after the end of processing and should leave the plant in a suitable condition for next use.
Table 1: levels of cleaning
LEVEL LEVEL 2
USED WHEN i.e. Product changeover of equipment used in final step Intermediates of one batch to final step of another
CLEANING VALIDATION REQUIRED yes essential
LEVEL LEVEL 2
USED WHEN i.e. Product changeover of equipment used in final step Intermediates of one batch to final step of another
CLEANING VALIDATION REQUIRED yes essential
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LEVEL 1
i.e. Intermediates or final Step of one product to intermediate of another Early Step to intermediates in a product sequence i.e. in-campaign, batch to batch changeover
progression between level 0 and 2 depending on process and nature of contaminant based on scientific rational
LEVEL 1
i.e. Intermediates or final Step of one product to intermediate of another Early Step to intermediates in a product sequence i.e. in-campaign, batch to batch changeover
progression between level 0 and 2 depending on process and nature of contaminant based on scientific rational
LEVEL 0
no validation required
LEVEL 0
no validation required
NB: ALL PROCESSES MUST BE EVALUATED INDIVIDUALLY
NB: ALL PROCESSES MUST BE EVALUATED INDIVIDUALLY
8. ELEMENTS OF CLEANING VALIDATION

A brief outline of the various elements of a basic cleaning validation study is given below (see also Figure 1). This is followed by a more detailed view of the individual elements in this section. I. Establishment of acceptance criteria II. Cleaning procedure Identification of the equipment characterization of the products (Previous: activity/toxicity, solubility, subsequent: dosage, lot size) determination and characterization of the cleaning agents III. Analytical method and its validation IV . Sampling Procedure and necessary validation of same V . Validation protocol VI. Validation report
8. ELEMENTS OF CLEANING VALIDATION

A brief outline of the various elements of a basic cleaning validation study is given below (see also Figure 1). This is followed by a more detailed view of the individual elements in this section. I. Establishment of acceptance criteria II. Cleaning procedure Identification of the equipment characterization of the products (Previous: activity/toxicity, solubility, subsequent: dosage, lot size) determination and characterization of the cleaning agents III. Analytical method and its validation IV . Sampling Procedure and necessary validation of same V . Validation protocol VI. Validation report
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Figure 1: Cleaning Validation Process DETERMINE THE MOST APPROPRIATE CLEANING PROCEDURE FOR THE EQUIPMENT 1 Generate acceptance criteria data for the contaminant. 2 The cleaning method will be determined by the process, the equipment the cleaning agents and the cleaning techniques available. 3 All aspects of the cleaning procedure should be clearly defined in SOPs be they manual / CIP or COP EVALUATE EQUIPMENT SURFACES AND DETERMINE 1 Worst case locations to sample (swab sampling) 2 Volume and type of rinse solvent to be employed (rinse sampling) 3 Equipment surface area (necessary to calculate carryover into subsequent batches)
Figure 1: Cleaning Validation Process DETERMINE THE MOST APPROPRIATE CLEANING PROCEDURE FOR THE EQUIPMENT 1 Generate acceptance criteria data for the contaminant. 2 The cleaning method will be determined by the process, the equipment the cleaning agents and the cleaning techniques available. 3 All aspects of the cleaning procedure should be clearly defined in SOPs be they manual / CIP or COP EVALUATE EQUIPMENT SURFACES AND DETERMINE 1 Worst case locations to sample (swab sampling) 2 Volume and type of rinse solvent to be employed (rinse sampling) 3 Equipment surface area (necessary to calculate carryover into subsequent batches)
STAGE 1
STAGE 1
DEVELOP AND VALIDATE THE SAMPLING AND CHOSEN ANALYTICAL METHODS FOR THE COMPOUND(S) BEING CLEANED 1 Swab 2 Rinse (determine % recovery, limit of detection, limit of quantitation, accuracy of method, reproducibility, stability over time ...etc.)
DEVELOP AND VALIDATE THE SAMPLING AND CHOSEN ANALYTICAL METHODS FOR THE COMPOUND(S) BEING CLEANED 1 Swab 2 Rinse (determine % recovery, limit of detection, limit of quantitation, accuracy of method, reproducibility, stability over time ...etc.)
STAGE 2
DEVELOP A CLEANING VALIDATION PROTOCOL FOR THE PRODUCT AND THE EQUIPMENT BEING CLEANED That should encompass for example: 1 Introduction 2 Scope 3 Equipment 4 Cleaning procedure 5 Sampling procedures 6 Analytical testing procedure 7 Acceptance/Cleaning limits. 8 Acceptance criteria for the validation.
STAGE 2
DEVELOP A CLEANING VALIDATION PROTOCOL FOR THE PRODUCT AND THE EQUIPMENT BEING CLEANED That should encompass for example: 1 Introduction 2 Scope 3 Equipment 4 Cleaning procedure 5 Sampling procedures 6 Analytical testing procedure 7 Acceptance/Cleaning limits. 8 Acceptance criteria for the validation.
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Figure 1: Cleaning Validation Process (contd) INTERIM REPORT: GENERATE INTERIM CLEANING VALIDATION REPORTS ON A CLEAN BY CLEAN BASIS DETAILING THE ACCEPTABILITY OF THE CLEANING PROCEDURE FOR THE EQUIPMENT AND THE PRODUCT. This is only required where there is a long period of time between manufacture of the validation runs (see stage 4 for reporting requirements).
Figure 1: Cleaning Validation Process (contd) INTERIM REPORT: GENERATE INTERIM CLEANING VALIDATION REPORTS ON A CLEAN BY CLEAN BASIS DETAILING THE ACCEPTABILITY OF THE CLEANING PROCEDURE FOR THE EQUIPMENT AND THE PRODUCT. This is only required where there is a long period of time between manufacture of the validation runs (see stage 4 for reporting requirements).
STAGE 3
STAGE 3
STAGE 4
GENERATEACLEANING VALIDATION REPORT DETAILING THEACCEPTABILITY OFTHE CLEANING PROCEDURE FOR THE EQUIPMENTAND THE PRODUCT The report should give a full detailed background and introduction to the cleaning Validation study and should evaluate all data generated with respect to the acceptance criteria employed for the study. The report should also indicate the requirement if any for revalidation (period of time /change control etc.)
STAGE 4
GENERATEACLEANING VALIDATION REPORT DETAILING THEACCEPTABILITY OFTHE CLEANING PROCEDURE FOR THE EQUIPMENTAND THE PRODUCT The report should give a full detailed background and introduction to the cleaning Validation study and should evaluate all data generated with respect to the acceptance criteria employed for the study. The report should also indicate the requirement if any for revalidation (period of time /change control etc.)
8.1 Establishment of acceptance criteria The Cleaning Validation should demonstrate that the procedure consistently removes residues of the substance previously manufactured down to levels that are acceptable and that the cleaning procedure itself does not contribute unacceptable levels of residual materials to the equipment. The limits set should be practical, achievable and justifiable.
8.1 Establishment of acceptance criteria The Cleaning Validation should demonstrate that the procedure consistently removes residues of the substance previously manufactured down to levels that are acceptable and that the cleaning procedure itself does not contribute unacceptable levels of residual materials to the equipment. The limits set should be practical, achievable and justifiable.
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In Active Pharmaceutical Ingredient manufacture there may be partial reactants and unwanted by-products which may not have been chemically identified. Therefore, it may be necessary to focus on by-products as well as the principle reactant. Companies should decide on which residue(s) to quantify based on sound scientific rational. 8.1.1 Chemical determination It is generally the residual Active Pharmaceutical Ingredient or intermediate, which is of greatest concern rather than reaction side products or residual impurities. There are a number of options available when determining acceptance criteria. Where either toxicological or therapeutic data if available then calculation A or B is preferable. If data is not available for either of these calculations or if the result is more stringent calculation C should be used. A. Limiting the level based on toxicity data. An Acceptable Daily Intake (ADI) is calculated with suitable safety factors applied and this is converted to the maximum allowable carryover to the API. B. Pharmacological Dose Method: The philosophy is to reduce the levels of residual product in each piece of equipment, such that no greater than 1/1000 of the normal therapeutic dose will be present per typical dose of the next product to be run in the equipment. The validation protocol should include a calculation, which ties this philosophy to the acceptance criteria for the samples to be tested. C. Limiting the level of product which could appear in the following products. Limits from 10ppm up to 0.1% (based on the ICH impurity document which indicates that up to 0.1% of an individual unknown or 0.5% total unknowns material may be present in the product being tested) Note FDA Statement on 0.1% impurities FDA statement: P. Alcock, in Human Drug cGMP Notes, P. Motise, June 98: ...we have found that some firms have incorrectly applied as their
In Active Pharmaceutical Ingredient manufacture there may be partial reactants and unwanted by-products which may not have been chemically identified. Therefore, it may be necessary to focus on by-products as well as the principle reactant. Companies should decide on which residue(s) to quantify based on sound scientific rational. 8.1.1 Chemical determination It is generally the residual Active Pharmaceutical Ingredient or intermediate, which is of greatest concern rather than reaction side products or residual impurities. There are a number of options available when determining acceptance criteria. Where either toxicological or therapeutic data if available then calculation A or B is preferable. If data is not available for either of these calculations or if the result is more stringent calculation C should be used. A. Limiting the level based on toxicity data. An Acceptable Daily Intake (ADI) is calculated with suitable safety factors applied and this is converted to the maximum allowable carryover to the API. B. Pharmacological Dose Method: The philosophy is to reduce the levels of residual product in each piece of equipment, such that no greater than 1/1000 of the normal therapeutic dose will be present per typical dose of the next product to be run in the equipment. The validation protocol should include a calculation, which ties this philosophy to the acceptance criteria for the samples to be tested. C. Limiting the level of product which could appear in the following products. Limits from 10ppm up to 0.1% (based on the ICH impurity document which indicates that up to 0.1% of an individual unknown or 0.5% total unknowns material may be present in the product being tested) Note FDA Statement on 0.1% impurities FDA statement: P. Alcock, in Human Drug cGMP Notes, P. Motise, June 98: ...we have found that some firms have incorrectly applied as their
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acceptance limit the 0.1% impurity identification threshold as discussed in both the ICH impurity guideline and the U.S.P. General Notices. This application of the 0.1% impurity threshold is inappropriate because the limit is intended for qualifying impurities that are associated with the manufacturing process of related compound and not extraneous impurities caused by cross contamination. .. ) may be used depending on the stage of the process. It is also necessary to evaluate the ability of the cleaning procedure to remove any cleaning agents introduced. The acceptance criteria for the residual-cleaning agents should reflect the absence of these materials, within the range of the capabilities of the assay and sampling methods. The individual company must decide on the Acceptance Criteria which are justifiable for their particular situation. 8.1.2 Physical determination There should be provision during routine cleaning for a visual examination of the equipment, verifying that it is free of visible residues. The validation protocol should include this requirement as an acceptance criteria. During validation, special attention should be given to areas that are hard to clean (e.g. agitator shafts, thermowells, discharge valves etc.) and areas that would be difficult to verify on a routine basis. 8.1.3 Microbiological determination Appropriate studies should be performed (e.g. swabs and/or rinse sampling) where the possibility of microbial contamination of subsequent product is deemed possible and presents a product quality risk. 8.2 Cleaning procedures Written cleaning procedures for each piece of equipment and process1 (If one cleaning procedure has been shown to be adequate for a number of products, then it is only necessary to have one cleaning SOP for those products for each piece of equipment.) must be prepared. It is vital that the equipment design is evaluated in detail in conjunction with the product residues to be removed, the available cleaning agents and cleaning techniques when determining the optimum cleaning procedure for the equipment.
acceptance limit the 0.1% impurity identification threshold as discussed in both the ICH impurity guideline and the U.S.P. General Notices. This application of the 0.1% impurity threshold is inappropriate because the limit is intended for qualifying impurities that are associated with the manufacturing process of related compound and not extraneous impurities caused by cross contamination. .. ) may be used depending on the stage of the process. It is also necessary to evaluate the ability of the cleaning procedure to remove any cleaning agents introduced. The acceptance criteria for the residual-cleaning agents should reflect the absence of these materials, within the range of the capabilities of the assay and sampling methods. The individual company must decide on the Acceptance Criteria which are justifiable for their particular situation. 8.1.2 Physical determination There should be provision during routine cleaning for a visual examination of the equipment, verifying that it is free of visible residues. The validation protocol should include this requirement as an acceptance criteria. During validation, special attention should be given to areas that are hard to clean (e.g. agitator shafts, thermowells, discharge valves etc.) and areas that would be difficult to verify on a routine basis. 8.1.3 Microbiological determination Appropriate studies should be performed (e.g. swabs and/or rinse sampling) where the possibility of microbial contamination of subsequent product is deemed possible and presents a product quality risk. 8.2 Cleaning procedures Written cleaning procedures for each piece of equipment and process1 (If one cleaning procedure has been shown to be adequate for a number of products, then it is only necessary to have one cleaning SOP for those products for each piece of equipment.) must be prepared. It is vital that the equipment design is evaluated in detail in conjunction with the product residues to be removed, the available cleaning agents and cleaning techniques when determining the optimum cleaning procedure for the equipment.
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Cleaning procedures should be sufficiently detailed to remove the possibility of any inconsistencies during the cleaning process. A. Equipment parameters to be evaluated Identification of the equipment to be cleaned Difficult to clean areas Property of materials Ease of disassembly Fixed or not Etc. B. Residues to be cleaned Cleaning limits Solubilitys of the residues Length of campaigns Etc. C. Cleaning agent parameters to be evaluated Preferably materials that are normally used in the process Detergents available (as a general guide, minimize use of detergents unless absolutely required) Solubility properties Environmental considerations. Health and safety considerations Etc. D. Cleaning techniques to be evaluated Manual cleaning CIP (Clean-in place) COP (clean-out-of-place) Semi automatic Automatic Time considerations Number of cleaning cycles Etc.
Cleaning procedures should be sufficiently detailed to remove the possibility of any inconsistencies during the cleaning process. A. Equipment parameters to be evaluated Identification of the equipment to be cleaned Difficult to clean areas Property of materials Ease of disassembly Fixed or not Etc. B. Residues to be cleaned Cleaning limits Solubilitys of the residues Length of campaigns Etc. C. Cleaning agent parameters to be evaluated Preferably materials that are normally used in the process Detergents available (as a general guide, minimize use of detergents unless absolutely required) Solubility properties Environmental considerations. Health and safety considerations Etc. D. Cleaning techniques to be evaluated Manual cleaning CIP (Clean-in place) COP (clean-out-of-place) Semi automatic Automatic Time considerations Number of cleaning cycles Etc.
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E. Other requirements Procedures must be determined to be operator independent i.e. rugged and reproducible, during the validation studies. The Cleaning documentation should include the following items in order to ensure that it can be followed reproducibly and maintained subsequent to Validation. Detailed definition of levels of cleaning to be performed. Detailed description of cleaning methods. The necessity to inspect and verify equipment cleanliness prior to manufacture of next batch should be stated in the SOP and recorded on the batch record. The SOP should detail where verification of cycle parameters (if automated) and checklists (for complex manual procedures) is necessary. Where microbial contamination may be an issue, consideration should be given to the integrity of the vessel prior to manufacture.
E. Other requirements Procedures must be determined to be operator independent i.e. rugged and reproducible, during the validation studies. The Cleaning documentation should include the following items in order to ensure that it can be followed reproducibly and maintained subsequent to Validation. Detailed definition of levels of cleaning to be performed. Detailed description of cleaning methods. The necessity to inspect and verify equipment cleanliness prior to manufacture of next batch should be stated in the SOP and recorded on the batch record. The SOP should detail where verification of cycle parameters (if automated) and checklists (for complex manual procedures) is necessary. Where microbial contamination may be an issue, consideration should be given to the integrity of the vessel prior to manufacture.
Written cleaning procedures may also include additional items not specified above, these would include, as an example, the steps needed to protect the equipment from contamination after cleaning. 8.3 Sampling In developing the sampling plan for a validation study, it makes scientific sense to incorporate an understanding of the acceptance criteria and the limitations of the sampling method relative to the surface to be sampled. The two methods of sampling generally employed are swab and / or rinse sampling. (If neither or these methods is shown be a scientifically sound method for testing in a specific instance then an alternative is to consider testing the next product.) The selection of either of these techniques must be consistent with sound scientific judgment and must support the objective of the study, which is to demonstrate that the amount of residual material in the equipment has been reduced to acceptable levels.
Written cleaning procedures may also include additional items not specified above, these would include, as an example, the steps needed to protect the equipment from contamination after cleaning. 8.3 Sampling In developing the sampling plan for a validation study, it makes scientific sense to incorporate an understanding of the acceptance criteria and the limitations of the sampling method relative to the surface to be sampled. The two methods of sampling generally employed are swab and / or rinse sampling. (If neither or these methods is shown be a scientifically sound method for testing in a specific instance then an alternative is to consider testing the next product.) The selection of either of these techniques must be consistent with sound scientific judgment and must support the objective of the study, which is to demonstrate that the amount of residual material in the equipment has been reduced to acceptable levels.
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Each method is described in brief below. 1. SWAB: Swab sampling does not cover the entire equipment surface area therefore sites must be chosen with care. It is important that, as a minimum, the swab sites represent worst case locations on the equipment and that the result is then extrapolated to account for the total product contact surface area. This calculation makes it possible to make a worst case determination of potential carryover into subsequent product. Due to the nature of this method which employs physical forces as well as chemical forces it may be necessary to perform sampling technique evaluation. Swabbing efficiency (% recovery) for the swabbing method must be determined. It is necessary to ensure that extractables of the swab do not interfere with the sampling method. Using this technique it is possible to sample insoluble residues due to the physical action associated it.
Each method is described in brief below. 1. SWAB: Swab sampling does not cover the entire equipment surface area therefore sites must be chosen with care. It is important that, as a minimum, the swab sites represent worst case locations on the equipment and that the result is then extrapolated to account for the total product contact surface area. This calculation makes it possible to make a worst case determination of potential carryover into subsequent product. Due to the nature of this method which employs physical forces as well as chemical forces it may be necessary to perform sampling technique evaluation. Swabbing efficiency (% recovery) for the swabbing method must be determined. It is necessary to ensure that extractables of the swab do not interfere with the sampling method. Using this technique it is possible to sample insoluble residues due to the physical action associated it.
2. RINSE: The solvent rinse occurs after cleaning has been completed This method is not as direct as swabbing but will cover the entire surface area (and parts inaccessible to swabs) It is important to ensure chosen solvent has appropriate recovery for residues being quantified This method allows much greater ease of sampling than swabbing A reduced no of samples are required to generate a carryover figure. (Other sampling methods which may be employed in addition to swab / rinse sampling during a validation may include: placebo sampling, testing subsequent batches for residues, use of coupons (test pieces), etc. )
2. RINSE: The solvent rinse occurs after cleaning has been completed This method is not as direct as swabbing but will cover the entire surface area (and parts inaccessible to swabs) It is important to ensure chosen solvent has appropriate recovery for residues being quantified This method allows much greater ease of sampling than swabbing A reduced no of samples are required to generate a carryover figure. (Other sampling methods which may be employed in addition to swab / rinse sampling during a validation may include: placebo sampling, testing subsequent batches for residues, use of coupons (test pieces), etc. )
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8.4 Analytical methods In order for the analytical testing of the cleaning validation samples (swabs or rinses) to yield meaningful results, the analytical methods used should be validated. This should be documented. The basic requirements are: The ability to detect the target substance(s) at levels consistent with the acceptance criteria The ability to detect the target substance(s) in the presence of other materials that may also be present in the sample (selectivity)
8.4 Analytical methods In order for the analytical testing of the cleaning validation samples (swabs or rinses) to yield meaningful results, the analytical methods used should be validated. This should be documented. The basic requirements are: The ability to detect the target substance(s) at levels consistent with the acceptance criteria The ability to detect the target substance(s) in the presence of other materials that may also be present in the sample (selectivity)
(Companies might want to consider the following: Where more than one impurity is suspected (which is probably the normal case in API manufacturing) a method could be proposed that is not necessarily specific for each of the impurities but detects them all together. Then additionally the assumption must be made, that the worst case (e.g. most active) impurity represents the whole residue. This is secure approach for the patients and could be accepted by the authorities. It is also an practicable approach for the industry because such methods are for example dry residue determination for non volatile impurities or TOC determination for water rinses, which are very simple methods. ) The analytical method should include a calculation to convert the amount of residue detected in the sample to 100% if the recovery data generated indicates a recovery outside of an allowed range. Stability of samples over time if the time interval between removal and testing of samples potentially effects sample integrity.
(Companies might want to consider the following: Where more than one impurity is suspected (which is probably the normal case in API manufacturing) a method could be proposed that is not necessarily specific for each of the impurities but detects them all together. Then additionally the assumption must be made, that the worst case (e.g. most active) impurity represents the whole residue. This is secure approach for the patients and could be accepted by the authorities. It is also an practicable approach for the industry because such methods are for example dry residue determination for non volatile impurities or TOC determination for water rinses, which are very simple methods. ) The analytical method should include a calculation to convert the amount of residue detected in the sample to 100% if the recovery data generated indicates a recovery outside of an allowed range. Stability of samples over time if the time interval between removal and testing of samples potentially effects sample integrity.
8.5 Validation protocols A Validation Protocol is necessary to define the specific items and activities that will constitute a cleaning validation study. It is advisable for companies to have drawn up a Master Validation plan indicating the overall Cleaning Validation strategy for either the product range / equipment type / entire site.
8.5 Validation protocols A Validation Protocol is necessary to define the specific items and activities that will constitute a cleaning validation study. It is advisable for companies to have drawn up a Master Validation plan indicating the overall Cleaning Validation strategy for either the product range / equipment type / entire site.
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The protocol must be prepared prior to the initiation of the study and must either include or reference the documentation required to provide the following information: The objective of the study: What cleaning process is to be validated (indicating the product to be removed and the equipment from which it is to be removed)? If this study is to be employed to demonstrate the acceptability of the cleaning procedure for a group of products the rational for doing so should also be detailed here. The cleaning procedure(s) to be validated should be identified i.e. cleaning agents, soakage times, equipment parameters, number of cleaning cycles etc. Scope of the study: The company must evaluate the process and determine which residues are to be tested for and which are not to be based on sound scientific rational. What residues (including cleaning agents) are to be tested for, why those residues (if more residues may be present than are being tested for all residues should be under control see comments at 8.4). How many times should the study be run before a report is compiled and recommendations made. Listing of the process parameters to be verified This is particularly necessary when automated or semi-automated cleaning techniques are to be employed. Sampling and inspection procedure to be used. The types of sampling methods to be used, where the samples are to be removed from and how many samples are to be taken. Any particular requirements should also be stated i.e. for sterile sampling / sampling light sensitive products. An equipment sampling diagram should be referenced.
The protocol must be prepared prior to the initiation of the study and must either include or reference the documentation required to provide the following information: The objective of the study: What cleaning process is to be validated (indicating the product to be removed and the equipment from which it is to be removed)? If this study is to be employed to demonstrate the acceptability of the cleaning procedure for a group of products the rational for doing so should also be detailed here. The cleaning procedure(s) to be validated should be identified i.e. cleaning agents, soakage times, equipment parameters, number of cleaning cycles etc. Scope of the study: The company must evaluate the process and determine which residues are to be tested for and which are not to be based on sound scientific rational. What residues (including cleaning agents) are to be tested for, why those residues (if more residues may be present than are being tested for all residues should be under control see comments at 8.4). How many times should the study be run before a report is compiled and recommendations made. Listing of the process parameters to be verified This is particularly necessary when automated or semi-automated cleaning techniques are to be employed. Sampling and inspection procedure to be used. The types of sampling methods to be used, where the samples are to be removed from and how many samples are to be taken. Any particular requirements should also be stated i.e. for sterile sampling / sampling light sensitive products. An equipment sampling diagram should be referenced.
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Personnel responsibilities during the study Test methods to be used (should be referenced): See Section 8.4. Acceptance criteria Physical: see section 8.1.2 Chemical: see section 8.1.1 (The rational for this criterion should be given along with a calculation step.) Change control: See section 10. Approval of protocol before the study. 8.6 Validation reports A validation report is necessary to present the results and conclusions and secure approval of the study. The report should include the following: Summary of or reference to the procedures used to clean, sample and test Physical and analytical test results or references for same, as well as any pertinent observations Conclusions regarding the acceptability of the results, and the status of the procedure(s) being validated Any recommendations based on the results or relevant information obtained during the study including revalidation practices if applicable. Approval of conclusions Review any deviations for the protocol that occurred. In cases where it is unlikely that further batches of the product will be manufactured for a period of time it is advisable to generate interim reports on a batch by batch basis until such time as the cleaning validation study has been completed. (Typically, in Active Pharmaceutical Ingredient Pharmaceutical manufacture, verification is deemed appropriate during development of the cleaning methods. Where products are manufactured infrequently, verification may be
Personnel responsibilities during the study Test methods to be used (should be referenced): See Section 8.4. Acceptance criteria Physical: see section 8.1.2 Chemical: see section 8.1.1 (The rational for this criterion should be given along with a calculation step.) Change control: See section 10. Approval of protocol before the study. 8.6 Validation reports A validation report is necessary to present the results and conclusions and secure approval of the study. The report should include the following: Summary of or reference to the procedures used to clean, sample and test Physical and analytical test results or references for same, as well as any pertinent observations Conclusions regarding the acceptability of the results, and the status of the procedure(s) being validated Any recommendations based on the results or relevant information obtained during the study including revalidation practices if applicable. Approval of conclusions Review any deviations for the protocol that occurred. In cases where it is unlikely that further batches of the product will be manufactured for a period of time it is advisable to generate interim reports on a batch by batch basis until such time as the cleaning validation study has been completed. (Typically, in Active Pharmaceutical Ingredient Pharmaceutical manufacture, verification is deemed appropriate during development of the cleaning methods. Where products are manufactured infrequently, verification may be
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applied over a period of time until all measuring data has been collected for the Validation Report.) The report should conclude an appropriate level of verification subsequent to validation.
applied over a period of time until all measuring data has been collected for the Validation Report.) The report should conclude an appropriate level of verification subsequent to validation.
9. MINIMUM REQUIREMENTS
If company policy is not to validate all equipment cleaning procedures for all products then as a minimum requirement the validation policy should encompass conditions which represent the most appropriate challenges (worst case) to the procedure. These would include, as an example, such things as: Removal of products which contain the products with the greatest biological activity. Removal of products containing the products/intermediates/ byproducts with the least solubility.
9. MINIMUM REQUIREMENTS
If company policy is not to validate all equipment cleaning procedures for all products then as a minimum requirement the validation policy should encompass conditions which represent the most appropriate challenges (worst case) to the procedure. These would include, as an example, such things as: Removal of products which contain the products with the greatest biological activity. Removal of products containing the products/intermediates/ byproducts with the least solubility.
These represent studies that are minimally required as part of a validation, the results from which could be used to support lesser challenges to the procedure. It is often termed product grouping. The maximum idle time before cleaning.
These represent studies that are minimally required as part of a validation, the results from which could be used to support lesser challenges to the procedure. It is often termed product grouping. The maximum idle time before cleaning.
A validation program generally encompasses three consecutive successful replicates to establish that the procedure is reproducibly effective although companies should evaluate each situation individually. Where equipment of similar size, design and construction is cleaned by the same procedure, studies need not be conducted on each unit, as long as a total of three successful replicates are done on similar pieces of equipment (equipment grouping). Concurrent Validation may be appropriate when product is manufactured infrequently.
A validation program generally encompasses three consecutive successful replicates to establish that the procedure is reproducibly effective although companies should evaluate each situation individually. Where equipment of similar size, design and construction is cleaned by the same procedure, studies need not be conducted on each unit, as long as a total of three successful replicates are done on similar pieces of equipment (equipment grouping). Concurrent Validation may be appropriate when product is manufactured infrequently.
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10. CHANGE CONTROL

Validated cleaning procedures should be included in the change control program. This will ensure that any proposed changes are evaluated fully for their impact on the validated state of the procedure. Where deemed necessary, the proposed revised procedure may need to be validated prior to routine implementation. Cf. Change control chapter in the CEFIC / EFPIA Guide entitled Good Manufacturing Practices for Active Ingredient Manufacturers In the absence of an intentional change to a procedure, it is reasonable to assume that properly trained operators or a properly qualified automated system will be able to execute the procedure reproducibly and obtain the desired outcome - reduction of residue to acceptable levels. There may exist special circumstances that would suggest that this assumption be verified via testing. This may be addressed by periodic reviews or reevaluations.
10. CHANGE CONTROL

Validated cleaning procedures should be included in the change control program. This will ensure that any proposed changes are evaluated fully for their impact on the validated state of the procedure. Where deemed necessary, the proposed revised procedure may need to be validated prior to routine implementation. Cf. Change control chapter in the CEFIC / EFPIA Guide entitled Good Manufacturing Practices for Active Ingredient Manufacturers In the absence of an intentional change to a procedure, it is reasonable to assume that properly trained operators or a properly qualified automated system will be able to execute the procedure reproducibly and obtain the desired outcome - reduction of residue to acceptable levels. There may exist special circumstances that would suggest that this assumption be verified via testing. This may be addressed by periodic reviews or reevaluations.
11. SUMMARY
A validation policy should be written for a plant including cleaning validation. Any cleaning validation program should contain the following elements: 1. Assess equipment and products (previous, following) 2. Assess impact of this process on routine processes. If covered under bracketing then no further validation is required. 3. Determine an appropriate cleaning agent and method 4. Determine acceptance criteria for the residue(s) (including cleaning agents). 5. Determine degree of evaluation required to validate the procedure. 6. Decide what residue(s) (including cleaning agents), are to be tested for based on solubilities, toxicities etc. and document rational behind decision. 7. Develop sampling and analytical methods for recovery and detection of residues (swab/rinse, HPLC/dry residue etc.)
11. SUMMARY
A validation policy should be written for a plant including cleaning validation. Any cleaning validation program should contain the following elements: 1. Assess equipment and products (previous, following) 2. Assess impact of this process on routine processes. If covered under bracketing then no further validation is required. 3. Determine an appropriate cleaning agent and method 4. Determine acceptance criteria for the residue(s) (including cleaning agents). 5. Determine degree of evaluation required to validate the procedure. 6. Decide what residue(s) (including cleaning agents), are to be tested for based on solubilities, toxicities etc. and document rational behind decision. 7. Develop sampling and analytical methods for recovery and detection of residues (swab/rinse, HPLC/dry residue etc.)
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8. Acceptance Criteria for the Validation 9. Compile and approve Validation protocol 10. Perform Validation Studies in accordance with protocol 11. Compile and approve a Validation report documenting studies, conclusions and recommendations. 12. Revalidation policy
8. Acceptance Criteria for the Validation 9. Compile and approve Validation protocol 10. Perform Validation Studies in accordance with protocol 11. Compile and approve a Validation report documenting studies, conclusions and recommendations. 12. Revalidation policy
12. REFERENCES
ICH: ICH Good Manufacturing Practice Guideline for Active Pharmaceutical Ingredients. (July 23 1999) PIC : Principles of Qualification and Validation in Pharmaceutical Manufacture - Recommendations on Cleaning Validation. (ref. Document PR 1/ 99 March 1999) FDA: Guide to inspections of validation of cleaning processes (July 1993) Biotechnology inspection guide (1991) Foreign inspection guide (1992) Guide to inspection of bulk pharmaceutical chemicals Guide to inspections of topical drug products Manufacture, processing or holding of active pharmaceutical ingredients, draft document, FDA, March 1998. CEFIC / EFPIA: Good Manufacturing Practices for Active Ingredient Manufacturers August 1996. PHRMA : Draft PhRMA BPC Cleaning Validation Guideline. (November 1996 Edition) OTHER PUBLICATIONS S.W. Harder, The validation of cleaning processes, pharmaceutical technology. (1984)
12. REFERENCES
ICH: ICH Good Manufacturing Practice Guideline for Active Pharmaceutical Ingredients. (July 23 1999) PIC : Principles of Qualification and Validation in Pharmaceutical Manufacture - Recommendations on Cleaning Validation. (ref. Document PR 1/ 99 March 1999) FDA: Guide to inspections of validation of cleaning processes (July 1993) Biotechnology inspection guide (1991) Foreign inspection guide (1992) Guide to inspection of bulk pharmaceutical chemicals Guide to inspections of topical drug products Manufacture, processing or holding of active pharmaceutical ingredients, draft document, FDA, March 1998. CEFIC / EFPIA: Good Manufacturing Practices for Active Ingredient Manufacturers August 1996. PHRMA : Draft PhRMA BPC Cleaning Validation Guideline. (November 1996 Edition) OTHER PUBLICATIONS S.W. Harder, The validation of cleaning processes, pharmaceutical technology. (1984)
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James Agalloco, Points to consider in the validation of equipment cleaning procedures, Journal of parenteral science and technology. (October 1992) Fourman Mullen, Determining cleaning validation acceptance limits for pharmaceutical manufacturing operations, pharmaceutical technology. (April 1993) Mc Cormick, Cullen, Cleaning validation, pharmaceutical process validation, second edition. (1992) Mc Arthur, Vasilevsky, Cleaning validation for biological products: case study, pharmaceutical engineering. (November / December 1995) Zeller, Cleaning Validation and residue limits: a contribution to current discussions, pharmaceutical technology Europe. (November 1993)
James Agalloco, Points to consider in the validation of equipment cleaning procedures, Journal of parenteral science and technology. (October 1992) Fourman Mullen, Determining cleaning validation acceptance limits for pharmaceutical manufacturing operations, pharmaceutical technology. (April 1993) Mc Cormick, Cullen, Cleaning validation, pharmaceutical process validation, second edition. (1992) Mc Arthur, Vasilevsky, Cleaning validation for biological products: case study, pharmaceutical engineering. (November / December 1995) Zeller, Cleaning Validation and residue limits: a contribution to current discussions, pharmaceutical technology Europe. (November 1993)
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guidance on aspects of cleaning validation in active pharmaceutical ingredient plants

APIC
guidance on aspects of cleaning validation in active pharmaceutical ingredient plants

APIC
1.0 FOREWORD
This document has been prepared by the cleaning validation task force within the active pharmaceutical ingredient committee (APIC) of CEFIC. In recent years the subject of cleaning validation in active pharmaceutical ingredient manufacturing plants has received a large amount of attention from regulators, companies and customers alike. It is important that the requirements for the finished manufacturing companies are not transferred back in the process to active pharmaceutical ingredient manufacturers without consideration for the different processes that take place at this stage. The document reflects the outcome of discussions between APIC member companies on how cleaning validation requirements could be fulfilled and implemented as part of routine operations. It should be read in conjunction with the APIC document entitled Cleaning Validation in Active Pharmaceutical Ingredient Manufacturing Plants.
1.0 FOREWORD
This document has been prepared by the cleaning validation task force within the active pharmaceutical ingredient committee (APIC) of CEFIC. In recent years the subject of cleaning validation in active pharmaceutical ingredient manufacturing plants has received a large amount of attention from regulators, companies and customers alike. It is important that the requirements for the finished manufacturing companies are not transferred back in the process to active pharmaceutical ingredient manufacturers without consideration for the different processes that take place at this stage. The document reflects the outcome of discussions between APIC member companies on how cleaning validation requirements could be fulfilled and implemented as part of routine operations. It should be read in conjunction with the APIC document entitled Cleaning Validation in Active Pharmaceutical Ingredient Manufacturing Plants.
2.0 OBJECTIVE
This document has been prepared only to assist companies in the formulation of cleaning validation programmes and should not be considered a technical standard but a starting point for internal discussions. The document includes examples on how member companies have dealt with specific areas and issues that arise when performing cleaning validation.
2.0 OBJECTIVE
This document has been prepared only to assist companies in the formulation of cleaning validation programmes and should not be considered a technical standard but a starting point for internal discussions. The document includes examples on how member companies have dealt with specific areas and issues that arise when performing cleaning validation.
3.0 SCOPE
Five specific areas are addressed in this Guidance document, namely: o Acceptance Criteria
3.0 SCOPE
Five specific areas are addressed in this Guidance document, namely: o Acceptance Criteria
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o o o o
Levels of Cleaning Bracketing and Worst Case Rating Determination of the amount of residue Cleaning Validation Protocol
o o o o
Levels of Cleaning Bracketing and Worst Case Rating Determination of the amount of residue Cleaning Validation Protocol
Finally the most frequently asked questions are answered.
Finally the most frequently asked questions are answered.
4.0 ACCEPTANCE CRITERIA

4.1 Introduction Companies must demonstrate during validation that the cleaning procedure routinely employed for a piece of equipment limits potential carryover to an acceptable level. That limit established must be calculated based on sound scientific rational. This section provides practical guidance as to how that acceptance criteria can be calculated. It is important that companies evaluate all cases individually. There may be specific instances where the product mix in the equipment require further consideration. 4.2 Methods of Calculating Acceptance Criteria 4.2.1 Based on Therapeutic Daily Dose The principle for the requirement is that the standard Therapeutic Daily Dose (TDD) of the following substance (contaminated. substance, in this case called next) may be contaminated by no more than a certain proportion (usually 1/1000 part) of the TDD of the substance investigated in the cleaning validation (contaminating substance, in this case called previous). This method only applies when the therapeutic daily dose is known. It is generally used for final product changeover API Process A to API Process B
4.0 ACCEPTANCE CRITERIA

4.1 Introduction Companies must demonstrate during validation that the cleaning procedure routinely employed for a piece of equipment limits potential carryover to an acceptable level. That limit established must be calculated based on sound scientific rational. This section provides practical guidance as to how that acceptance criteria can be calculated. It is important that companies evaluate all cases individually. There may be specific instances where the product mix in the equipment require further consideration. 4.2 Methods of Calculating Acceptance Criteria 4.2.1 Based on Therapeutic Daily Dose The principle for the requirement is that the standard Therapeutic Daily Dose (TDD) of the following substance (contaminated. substance, in this case called next) may be contaminated by no more than a certain proportion (usually 1/1000 part) of the TDD of the substance investigated in the cleaning validation (contaminating substance, in this case called previous). This method only applies when the therapeutic daily dose is known. It is generally used for final product changeover API Process A to API Process B
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PROCEDURE Establish the limit for Maximum Allowable Carryover (MACO) according to the following equation. TDDprevious x MBS MACO = SF x TDDnext
PROCEDURE Establish the limit for Maximum Allowable Carryover (MACO) according to the following equation. TDDprevious x MBS MACO = SF x TDDnext
MACO Maximum Allowable Carryover: acceptable transferred amount from the investigated product (previous) TDDprevious Standard therapeutic dose of the investigated product (in the same dosage form as TDDnext) TDDnext Standard therapeutic dose of the daily dose for the next product MBS Minimum batch size for the next product(s) (where MACO can end up) SF Safety factor (normally 1000 is used in calculations based on TDD) EXAMPLE 1: Product A will be cleaned out. The product has a standard daily dose of 10 mg and the batch size is 200 kg. The next product B has standard a daily dose of 250 mg and the batch size is 50 kg. Both A and B are administrated orally and SF is set to 1000. Calculate the MACO for A in B! MACO 10 (mg) x 50 000 000 (mg) = = 2 000 (mg) 1000 x 250 (mg)
MACO Maximum Allowable Carryover: acceptable transferred amount from the investigated product (previous) TDDprevious Standard therapeutic dose of the investigated product (in the same dosage form as TDDnext) TDDnext Standard therapeutic dose of the daily dose for the next product MBS Minimum batch size for the next product(s) (where MACO can end up) SF Safety factor (normally 1000 is used in calculations based on TDD) EXAMPLE 1: Product A will be cleaned out. The product has a standard daily dose of 10 mg and the batch size is 200 kg. The next product B has standard a daily dose of 250 mg and the batch size is 50 kg. Both A and B are administrated orally and SF is set to 1000. Calculate the MACO for A in B! MACO 10 (mg) x 50 000 000 (mg) = = 2 000 (mg) 1000 x 250 (mg)
Result: MACO is 2 g (2000 mg)
Result: MACO is 2 g (2000 mg)
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EXAMPLE 2: Now product B in example 1 will be cleaned out. The following product is product A in example 1. Calculate the MACO for B in A! 250 (mg) x 200 000 000 (mg) MACO = -------------------------------------- = 5 000 000 (mg) 1000 x 10 (mg) Result: MACO is 5 kg (5 000 000 mg) In API manufacture it is possible to obtain a very high MACO figure. In example 2, the figure obtained is clearly unacceptable. Although there would be no effects expected, the equipment would be obviously dirty and a general GMP limit should be chosen (see 4.2.3 - how to select limits). Instead of calculating each potential product change situation, the worst case scenario can be chosen. Then a case with most active API (lowest TDD) is chosen to end up in the following API with the smallest ratio of batch size divided with TDD (MBS/TDD ratio). This could be done if the safety factor is the same for all products (otherwise the lowest MBS/ (TDDxSF) ratio should be chosen). 4.2.2 Based on Toxicological Data In cases in which a therapeutic dose is not known (e.g. for intermediates and detergents), toxicity data may be used for calculating MACO. PROCEDURE Calculate the so called NOEL number (No Observable Effect Level) according to the following equation and use the result for the establishment of MACO. (See [3] - for reference.) LD50 (g/kg) x 70 (kg a person) NOEL = 2000
EXAMPLE 2: Now product B in example 1 will be cleaned out. The following product is product A in example 1. Calculate the MACO for B in A! 250 (mg) x 200 000 000 (mg) MACO = -------------------------------------- = 5 000 000 (mg) 1000 x 10 (mg) Result: MACO is 5 kg (5 000 000 mg) In API manufacture it is possible to obtain a very high MACO figure. In example 2, the figure obtained is clearly unacceptable. Although there would be no effects expected, the equipment would be obviously dirty and a general GMP limit should be chosen (see 4.2.3 - how to select limits). Instead of calculating each potential product change situation, the worst case scenario can be chosen. Then a case with most active API (lowest TDD) is chosen to end up in the following API with the smallest ratio of batch size divided with TDD (MBS/TDD ratio). This could be done if the safety factor is the same for all products (otherwise the lowest MBS/ (TDDxSF) ratio should be chosen). 4.2.2 Based on Toxicological Data In cases in which a therapeutic dose is not known (e.g. for intermediates and detergents), toxicity data may be used for calculating MACO. PROCEDURE Calculate the so called NOEL number (No Observable Effect Level) according to the following equation and use the result for the establishment of MACO. (See [3] - for reference.) LD50 (g/kg) x 70 (kg a person) NOEL = 2000
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From the NOEL number a MACO can then be calculated according to: NOEL x MBS MACO = SF x TDDnext MACO Maximum Allowable Carryover: acceptable transferred amount from the investigated product (previous) NOEL No Observed Effect Level LD50 Lethal Dose 50 in g/kg animal. The identification of the animal (mouse, rat etc.) and the way of entry (IV, oral etc.) is important. 70 kg 70 kg is the weight of an average adult 2000 2000 is an empirical constant TDDnext Largest normal daily dose for the next product MBS Minimum batch size for the next product(s) (where MACO can end up) SF Safety factor The safety factor (SF) varies depending on the route of administration. Generally a factor of 200 is employed when manufacturing APIs to be administered in oral dosage forms. SF can vary depending on substance/ dosage form according to (suppose tox values from oral administration) as for example as presented on the next page. Safety factors: Topicals 10 - 100 Oral products 100 - 1000 Parenterals 1000 - 10 000 Remarks: APIs in development may require higher safety factors due to lack of knowledge. To calculate MACO values from tox data is frequently done when therapeutic dosage data is not available or not relevant. It is generally employed if the previous product is an intermediate and the following product an API. 4.2.3 General Limit If the calculation methods based on therapeutic doses or toxicological data (see 4.2.1 or 4.2.2) result in unacceptably high or irrelevant carryover figures, or toxicological data for intermediates are not known, the approach of a
From the NOEL number a MACO can then be calculated according to: NOEL x MBS MACO = SF x TDDnext MACO Maximum Allowable Carryover: acceptable transferred amount from the investigated product (previous) NOEL No Observed Effect Level LD50 Lethal Dose 50 in g/kg animal. The identification of the animal (mouse, rat etc.) and the way of entry (IV, oral etc.) is important. 70 kg 70 kg is the weight of an average adult 2000 2000 is an empirical constant TDDnext Largest normal daily dose for the next product MBS Minimum batch size for the next product(s) (where MACO can end up) SF Safety factor The safety factor (SF) varies depending on the route of administration. Generally a factor of 200 is employed when manufacturing APIs to be administered in oral dosage forms. SF can vary depending on substance/ dosage form according to (suppose tox values from oral administration) as for example as presented on the next page. Safety factors: Topicals 10 - 100 Oral products 100 - 1000 Parenterals 1000 - 10 000 Remarks: APIs in development may require higher safety factors due to lack of knowledge. To calculate MACO values from tox data is frequently done when therapeutic dosage data is not available or not relevant. It is generally employed if the previous product is an intermediate and the following product an API. 4.2.3 General Limit If the calculation methods based on therapeutic doses or toxicological data (see 4.2.1 or 4.2.2) result in unacceptably high or irrelevant carryover figures, or toxicological data for intermediates are not known, the approach of a
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general limit may be suitable. Companies may chose to have such an upper limit as a policy. The general limit is often set as an upper limit for the maximum concentration (MAXCONC) of a contaminating substance in a subsequent batch. The concentration (CONC) of the investigated substance which can be accepted in the next batch, according to dose related calculations, is: MACO CONC = MBS MACO Maximum Allowable Carryover: acceptable transferred amount from the investigated product (previous). Calculated from therapeutic doses and/or tox data. MACOppm Maximum Allowable Carryover: acceptable transferred amount from the investigated product (previous). Calculated from general ppm limit. CONC Concentration (kg/kg or ppm) of previous substance in the next batch. Based on MACO calculated from therapeutic doses and/or tox data. MAXCONC General limit for maximum allowed concentration (kg/kg or ppm) of previous substance in the next batch. MBS Minimum batch size for the next product(s) (where MACO can end up) A general upper limit for the maximum concentration of a contaminating substance in a subsequent batch (MAXCONC) is often set to 5-100 ppm depending on the nature of products produced from the individual company (e.g. toxicity, pharmacological activity, 10 ppm in APIs is very frequent). Note - If you decide to employ the concept of levels of cleaning (ref. section 5), then different safety factors (ppm limits) may be used for different levels. Especially if the product cleaned out is within the same synthetic chain and covered by the specification of the API, much higher (qualified) levels are acceptable.
general limit may be suitable. Companies may chose to have such an upper limit as a policy. The general limit is often set as an upper limit for the maximum concentration (MAXCONC) of a contaminating substance in a subsequent batch. The concentration (CONC) of the investigated substance which can be accepted in the next batch, according to dose related calculations, is: MACO CONC = MBS MACO Maximum Allowable Carryover: acceptable transferred amount from the investigated product (previous). Calculated from therapeutic doses and/or tox data. MACOppm Maximum Allowable Carryover: acceptable transferred amount from the investigated product (previous). Calculated from general ppm limit. CONC Concentration (kg/kg or ppm) of previous substance in the next batch. Based on MACO calculated from therapeutic doses and/or tox data. MAXCONC General limit for maximum allowed concentration (kg/kg or ppm) of previous substance in the next batch. MBS Minimum batch size for the next product(s) (where MACO can end up) A general upper limit for the maximum concentration of a contaminating substance in a subsequent batch (MAXCONC) is often set to 5-100 ppm depending on the nature of products produced from the individual company (e.g. toxicity, pharmacological activity, 10 ppm in APIs is very frequent). Note - If you decide to employ the concept of levels of cleaning (ref. section 5), then different safety factors (ppm limits) may be used for different levels. Especially if the product cleaned out is within the same synthetic chain and covered by the specification of the API, much higher (qualified) levels are acceptable.
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If the calculated concentration (CONC) of the previous product (based on MACO calculated from therapeutic doses/tox data) exceeds the general upper limit (MAXCONC), then MAXCONC level will be the limit. PROCEDURE Establish MACOppm, based on a general limit, using the following equations. MACOppm = MAXCONC x MBS E.g. for a general limit of 100 ppm: MACO = 0.01% of the minimum batch size (MBS), and for a general limit of 10 ppm: MACO = 0.001% of the minimum batch size (MBS). Remarks: The ICH impurity document (Q 3) indicates that up to 0.1% of an individual unknown or 0.5% total unknowns may be present in the product being tested. Example 3: A product B will be cleaned out. The product has a standard daily dose of 250 mg and the batch size is 50 kg. The next product A has a standard daily dose of 10 mg and the batch size is 200 kg. The general limit of the company is 10 ppm. Calculate the MACOppm for B in A! MACOppm = 0.00001 (mg/mg) x 200 000 000 (mg) = 2000 (mg) Result: MACOppm is 2 g (2 000 mg) In the worst case a maximum of 2 g of B may appear in API A. This is more reasonable than the limit 5 kg calculated in example 2. 4.2.4 Swab Limits If homogeneous distribution is assumed on all surfaces, a recommended value can be set for the content in a swab. This can be used as basic information for preparation of a method of analysis and detection limit. PROCEDURE Establish the target value for swab limit for the whole equipment train, using the following equation:
If the calculated concentration (CONC) of the previous product (based on MACO calculated from therapeutic doses/tox data) exceeds the general upper limit (MAXCONC), then MAXCONC level will be the limit. PROCEDURE Establish MACOppm, based on a general limit, using the following equations. MACOppm = MAXCONC x MBS E.g. for a general limit of 100 ppm: MACO = 0.01% of the minimum batch size (MBS), and for a general limit of 10 ppm: MACO = 0.001% of the minimum batch size (MBS). Remarks: The ICH impurity document (Q 3) indicates that up to 0.1% of an individual unknown or 0.5% total unknowns may be present in the product being tested. Example 3: A product B will be cleaned out. The product has a standard daily dose of 250 mg and the batch size is 50 kg. The next product A has a standard daily dose of 10 mg and the batch size is 200 kg. The general limit of the company is 10 ppm. Calculate the MACOppm for B in A! MACOppm = 0.00001 (mg/mg) x 200 000 000 (mg) = 2000 (mg) Result: MACOppm is 2 g (2 000 mg) In the worst case a maximum of 2 g of B may appear in API A. This is more reasonable than the limit 5 kg calculated in example 2. 4.2.4 Swab Limits If homogeneous distribution is assumed on all surfaces, a recommended value can be set for the content in a swab. This can be used as basic information for preparation of a method of analysis and detection limit. PROCEDURE Establish the target value for swab limit for the whole equipment train, using the following equation:
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MACO [g] Target value [g/dm ] = Total surface [dm2]

2
MACO [g] Target value [g/dm ] = Total surface [dm2]

2
Also other methods with different swab limits for different surfaces in a piece of equipment and/or equipment train can be used. Using this approach, the total amount found on the equipment train has to be below the MACO (see 4.2.4.2 - how to evaluate this). 4.2.4.1 Setting Acceptance Criteria for Swab Limits For each item tested, normally two acceptance criteria (AC) are set. AC1. The acceptance criterion .no visible residue. shall always be applied. AC2. The most stringent of the following swab limits are normally used for swab tests: Swab limit based on therapeutic dose or tox calculations (see 4.2.1 and 4.2.2) Swab limit based on a general ppm limit (see 4.2.3)
Also other methods with different swab limits for different surfaces in a piece of equipment and/or equipment train can be used. Using this approach, the total amount found on the equipment train has to be below the MACO (see 4.2.4.2 - how to evaluate this). 4.2.4.1 Setting Acceptance Criteria for Swab Limits For each item tested, normally two acceptance criteria (AC) are set. AC1. The acceptance criterion .no visible residue. shall always be applied. AC2. The most stringent of the following swab limits are normally used for swab tests: Swab limit based on therapeutic dose or tox calculations (see 4.2.1 and 4.2.2) Swab limit based on a general ppm limit (see 4.2.3)
AC3. The MACO must not be exceeded for the total equipment train (see 4.2.4.2). Usually either AC2 or AC3 is used (swab limits are calculated from MACO). However, both can be used and then different swab limits can be set for different types of equipment. Some swab limits can be higher than the target value, if others to compensate are lower. This as long as the total calculated amount is below the MACO (see 4.2.4.2). In determining acceptance limits, all possible cases of following products in the relevant equipment shall be taken into account. It is proposed that a matrix be set up in which the limits for all cases are calculated. Either acceptance criteria for each product in the equipment can be prepared or the worst case of all product combinations may be selected. EXAMPLE 4: Several substances are produced in the same equipment train (Dryer X), as presented in the following table. Any of the other six substances can be
AC3. The MACO must not be exceeded for the total equipment train (see 4.2.4.2). Usually either AC2 or AC3 is used (swab limits are calculated from MACO). However, both can be used and then different swab limits can be set for different types of equipment. Some swab limits can be higher than the target value, if others to compensate are lower. This as long as the total calculated amount is below the MACO (see 4.2.4.2). In determining acceptance limits, all possible cases of following products in the relevant equipment shall be taken into account. It is proposed that a matrix be set up in which the limits for all cases are calculated. Either acceptance criteria for each product in the equipment can be prepared or the worst case of all product combinations may be selected. EXAMPLE 4: Several substances are produced in the same equipment train (Dryer X), as presented in the following table. Any of the other six substances can be
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produced after Substance C. Substance C can be administered both in oral and parental dosage form. The company policy is based on three requirements: 1. No product shall contain more than 10 ppm of a contaminating substance from a previous batch. 2. No patient shall be exposed to more than 1/1000 of the therapeutic dose (TDD for the same dosage form) of another API. 3. If the TDD is not known for the same dosage form, then no patient shall be exposed to more than 1/10000 of the NOEL for another API (with not known TDD for the same dosage form). Calculate the MACO value and swab limit for Substance C! In this case the same swab limit shall apply to all surfaces.
Data table
produced after Substance C. Substance C can be administered both in oral and parental dosage form. The company policy is based on three requirements: 1. No product shall contain more than 10 ppm of a contaminating substance from a previous batch. 2. No patient shall be exposed to more than 1/1000 of the therapeutic dose (TDD for the same dosage form) of another API. 3. If the TDD is not known for the same dosage form, then no patient shall be exposed to more than 1/10000 of the NOEL for another API (with not known TDD for the same dosage form). Calculate the MACO value and swab limit for Substance C! In this case the same swab limit shall apply to all surfaces.
Data table
Area: 1500 dm2 Dryer X Substance A Substance B Substance C Substance D Substance E Substance F Substance G
MBS kg 200 50 200 120 200 1000 50
TDD Safety factor NOEL mg (SF) mg Oral Par Inhal Oral Par Oral Par Inhal 10 250 40 40 375 120 40 400 400 35 1000 1000 1000 1000 10000 10000 1000 1000 10000 2500 1000 1000 1000 8000 1000 11000 1000
Area: 1500 dm2 Dryer X Substance A Substance B Substance C Substance D Substance E Substance F Substance G
MBS kg 200 50 200 120 200 1000 50
TDD Safety factor NOEL mg (SF) mg Oral Par Inhal Oral Par Oral Par Inhal 10 250 40 40 375 120 40 400 400 35 1000 1000 1000 1000 10000 10000 1000 1000 10000 2500 1000 1000 1000 8000 1000 11000 1000
15
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Calculation of upper general limit (10 ppm): The next batches may contain maximum 10 ppm of Substance C. The upper general limit for Substance C is calculated (from equation in 4.2.3) from the lowest MBS of the possible substance of next batches.; in this case 50 kg valid for Substance B and G: MACOppm = 10 x 10-6 (kg/kg) x 50 (kg) = 5 x 10-4 (kg) = 500 (mg)
Calculation of upper general limit (10 ppm): The next batches may contain maximum 10 ppm of Substance C. The upper general limit for Substance C is calculated (from equation in 4.2.3) from the lowest MBS of the possible substance of next batches.; in this case 50 kg valid for Substance B and G: MACOppm = 10 x 10-6 (kg/kg) x 50 (kg) = 5 x 10-4 (kg) = 500 (mg)
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This corresponds to a swab limit equal to a target value (from equation in 4.2.4): MACO 500 000 [g] Target value [g/dm2] = = = 333 [g/dm2] Total surface 1500 [dm2] So the general upper MACO is 500 mg - corresponding to a swab limit of 333 [g/dm2]. This has to be compared to the limits calculated based on doses / NOELs. Matrix calculations of swab limit according to requirement based on therapeutic dose/NOEL: For each possible next product, the MACO is calculated according to the equation in 4.2.1 - (when TDD is known) or according to the equation in 4.2.2 - (NOEL is used when TDD is not known). The corresponding concentration in ppm is calculated in accordance with the equation in 4.2.3. Then a target value for swabs is calculated according to 4.2.4. The safety factor for Substance C is 1000 both for oral and parental use, and will be constant in all calculations. The TDDprevious is 40 mg for all the oral calculations and 120 mg for all the parental calculations. For the next substance, batch size and TDDnext/NOEL have to be collected from the data table for each substance in each dosage form. The results are inserted in the following table (two valid figures in the results). The worst cases for MACO and swab limits are indicated with bold. The total worst case comparing oral and parental calculations are indicated with bold on the last line of the table. Substance
Oral Substance B 8000 Substance E 1000 Substance F 3600 Worst case 1000
This corresponds to a swab limit equal to a target value (from equation in 4.2.4): MACO 500 000 [g] Target value [g/dm2] = = = 333 [g/dm2] Total surface 1500 [dm2] So the general upper MACO is 500 mg - corresponding to a swab limit of 333 [g/dm2]. This has to be compared to the limits calculated based on doses / NOELs. Matrix calculations of swab limit according to requirement based on therapeutic dose/NOEL: For each possible next product, the MACO is calculated according to the equation in 4.2.1 - (when TDD is known) or according to the equation in 4.2.2 - (NOEL is used when TDD is not known). The corresponding concentration in ppm is calculated in accordance with the equation in 4.2.3. Then a target value for swabs is calculated according to 4.2.4. The safety factor for Substance C is 1000 both for oral and parental use, and will be constant in all calculations. The TDDprevious is 40 mg for all the oral calculations and 120 mg for all the parental calculations. For the next substance, batch size and TDDnext/NOEL have to be collected from the data table for each substance in each dosage form. The results are inserted in the following table (two valid figures in the results). The worst cases for MACO and swab limits are indicated with bold. The total worst case comparing oral and parental calculations are indicated with bold on the last line of the table. Substance
Oral Substance B 8000 Substance E 1000 Substance F 3600 Worst case 1000
MACO [mg]
Par 2400 60000 300000 2400 -
CONC [ppm]
4000 320 160 5 4 48 300 300 -
Target value for swabs [g/dm2]

Par 1600 240000 40000 200000 110000 1600 Inhal* 530000 43000 5300 80000 670 2400 89000 670
MACO [mg]
Par 2400 60000 300000 2400 -
CONC [ppm]
4000 320 160 5 4 48 300 300 -
Target value for swabs [g/dm2]

Par 1600 240000 40000 200000 110000 1600 Inhal* 530000 43000 5300 80000 670 2400 89000 670
Inhal*Oral Par Inhal Oral
Inhal*Oral Par Inhal Oral
Substance A 800000 64000 Substance D 120000 360000
Substance A 800000 64000 Substance D 120000 360000
1000 3000 -
1000 3000 -
Substance G 130000 170000
2700 3400 -
Substance G 130000 170000
2700 3400 -
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* The symbol .-. indicates that these values are missing, because no product is administrated by inhalation. The lowest swab limit occurs, according to dose calculations (670 g/ dm2), when Substance E is manufactured after the Substance C. This also results in the lowest MACO (1000 mg = 1 g). As evident from the table, the corresponding CONC is 5 ppm. This value is below the general limit because the MBS for Substance E (200 kg) is larger than the MBS for the worst case (50 kg). A comparison, of MACO and swab limit, for values based on the general 10 ppm limit and values based on TDD/NOEL calculations, is presented in the following table. Value of MACO Target value swabs 10 ppm limit 500 mg 330 g/dm2 TDD/NOEL based limit 1000 mg 670 g/dm2 Most stringent case 500 mg 330 g/dm2
* The symbol .-. indicates that these values are missing, because no product is administrated by inhalation. The lowest swab limit occurs, according to dose calculations (670 g/ dm2), when Substance E is manufactured after the Substance C. This also results in the lowest MACO (1000 mg = 1 g). As evident from the table, the corresponding CONC is 5 ppm. This value is below the general limit because the MBS for Substance E (200 kg) is larger than the MBS for the worst case (50 kg). A comparison, of MACO and swab limit, for values based on the general 10 ppm limit and values based on TDD/NOEL calculations, is presented in the following table. Value of MACO Target value swabs 10 ppm limit 500 mg 330 g/dm2 TDD/NOEL based limit 1000 mg 670 g/dm2 Most stringent case 500 mg 330 g/dm2
As evident from the comparison, the most stringent requirements result from the calculations based on the 10 ppm limit. Result: The swab limit for Substance C in Dryer X will be 330 g/dm2 and the MACO will be 500 mg. Note that in example 4, the limits for Substance C were calculated. To determine the limits for the other substances, a matrix must be set up for each substance. Then for each substance, MACO and target values are calculated. For each Substance a similar comparison against the limit calculated from MAXCONC should be done and the most stringent limits to be selected. 4.2.4.2 Evaluation of results When all surfaces have been sampled and the samples have been analysed, then the results are compared to the acceptance criteria. Below the case when a MACO is set as an acceptance criteria is used. In this case the total amount shall be calculated, and this implies that some results can be above the target limit, if of course others are below.
As evident from the comparison, the most stringent requirements result from the calculations based on the 10 ppm limit. Result: The swab limit for Substance C in Dryer X will be 330 g/dm2 and the MACO will be 500 mg. Note that in example 4, the limits for Substance C were calculated. To determine the limits for the other substances, a matrix must be set up for each substance. Then for each substance, MACO and target values are calculated. For each Substance a similar comparison against the limit calculated from MAXCONC should be done and the most stringent limits to be selected. 4.2.4.2 Evaluation of results When all surfaces have been sampled and the samples have been analysed, then the results are compared to the acceptance criteria. Below the case when a MACO is set as an acceptance criteria is used. In this case the total amount shall be calculated, and this implies that some results can be above the target limit, if of course others are below.
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PROCEDURE Establish the possible Carry Over (CO) from the swab results, using the following equation: CO [g] = ( Ai [dm2] x mi [g/dm2] )
PROCEDURE Establish the possible Carry Over (CO) from the swab results, using the following equation: CO [g] = ( Ai [dm2] x mi [g/dm2] )
CO True (measured) total quantity of substance (possible carryover) on the cleaned surface in contact with the product, calculated from results of swab tests. Ai Area for the tested piece of equipment # i. mi Quantity, in g/dm2, for each swab per area of swabbed surface (normally 1 dm2) EXAMPLE 5: A company has carried out a cleaning validation study according to an approved protocol. The results of the swabs are presented in the following table. The individual swab results have been calculated as well as the CO.
Swab # Swab position Swab result non compensated (mg/dm2) Swab 1 Swab 2 Swab 3 Swab 4 Swab 5 Swab 5 Inlet valve Outlet valve Dryer roof Dryer centre left Dryer centre right Total area 0.30 0.40 0.20 Swab result compensated for 95% recovery (mg/dm2) 0.32 0.42 0.21 0.21 0.25* 0.21 1500 0.36 Area of Amount on part part of of dryer (g) dryer (dm2) 2 2 249 250 997 0.0006 0.0008 0.052 0.053 0.25* (calculated from worst case) 0.20 -
CO True (measured) total quantity of substance (possible carryover) on the cleaned surface in contact with the product, calculated from results of swab tests. Ai Area for the tested piece of equipment # i. mi Quantity, in g/dm2, for each swab per area of swabbed surface (normally 1 dm2) EXAMPLE 5: A company has carried out a cleaning validation study according to an approved protocol. The results of the swabs are presented in the following table. The individual swab results have been calculated as well as the CO.
Swab # Swab position Swab result non compensated (mg/dm2) Swab 1 Swab 2 Swab 3 Swab 4 Swab 5 Inlet valve Outlet valve Dryer roof Dryer centre left Dryer centre right Total area 0.30 0.40 0.20 Swab result compensated for 95% recovery (mg/dm2) 0.32 0.42 0.21 0.21 0.25* 0.21 1500 0.36 Area of Amount on part part of of dryer (g) dryer (dm2) 2 2 249 250 997 0.0006 0.0008 0.052 0.053 0.25* (calculated from worst case) 0.20 -
Dryer bottom 0.20 0.24*
Dryer bottom 0.20 0.24*
Swab 5
* When several swabs are taken on the same surface, the worst case result is used to calculate the CO.
* When several swabs are taken on the same surface, the worst case result is used to calculate the CO.
Now it is time to evaluate the results. Do that for case a) and b) below!
Now it is time to evaluate the results. Do that for case a) and b) below!
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a) If the acceptance criterion is a swab limit of 0.33 mg/dm2: are the results acceptable? b) If the acceptance criterion is a MACO of 0.50 g: are the results acceptable? Answer a): The results are not acceptable. The swab of the outlet valve is not approved. This must be treated as a deviation, and action must be taken. The current cleaning procedure is not qualified for the outlet valve (however, for the other areas). Answer b): The results are acceptable since the total amount is lower than the MACO. As evident from the different results in a) and b), companies may find it easier to evaluate against the MACO. However, it is advisable to have a policy for swab limit as well. Especially because analytical methods are validated within a certain range for swab results. Another reason is that some pieces could be very contaminated, and it is not good practice to clean certain pieces very thoroughly in order to let other be dirty. One example of policy, to set limits for both MACO and swabs, is to have the following acceptance criteria: AC 3: The MACO must not be exceeded for the total equipment train (see 4.2.4.2). AC 2: The most stringent of the following swab limits: Swab limit based on therapeutic dose (see 4.2.1) or NOEL (see 4.2.2). Swab limit based on a general ppm limit (see 4.2.3) AC 2.1 For all areas except for valves: the calculated swab limit. AC 2.2 For valves: 10 times the calculated swab limit if AC 3 can still be fulfilled. As mentioned before, AC 2.2 implies that in order to have a higher swab limit on valves or other pieces of equipment, the swab results for other areas have to be lower than the target value, in order for the CO to be below the MACO. 4.2.5 Rinse Limits The residue amount in the equipment can be assumed to be equal to the amount of residue in the last wash /boil) or rinse solvent portion. The
a) If the acceptance criterion is a swab limit of 0.33 mg/dm2: are the results acceptable? b) If the acceptance criterion is a MACO of 0.50 g: are the results acceptable? Answer a): The results are not acceptable. The swab of the outlet valve is not approved. This must be treated as a deviation, and action must be taken. The current cleaning procedure is not qualified for the outlet valve (however, for the other areas). Answer b): The results are acceptable since the total amount is lower than the MACO. As evident from the different results in a) and b), companies may find it easier to evaluate against the MACO. However, it is advisable to have a policy for swab limit as well. Especially because analytical methods are validated within a certain range for swab results. Another reason is that some pieces could be very contaminated, and it is not good practice to clean certain pieces very thoroughly in order to let other be dirty. One example of policy, to set limits for both MACO and swabs, is to have the following acceptance criteria: AC 3: The MACO must not be exceeded for the total equipment train (see 4.2.4.2). AC 2: The most stringent of the following swab limits: Swab limit based on therapeutic dose (see 4.2.1) or NOEL (see 4.2.2). Swab limit based on a general ppm limit (see 4.2.3) AC 2.1 For all areas except for valves: the calculated swab limit. AC 2.2 For valves: 10 times the calculated swab limit if AC 3 can still be fulfilled. As mentioned before, AC 2.2 implies that in order to have a higher swab limit on valves or other pieces of equipment, the swab results for other areas have to be lower than the target value, in order for the CO to be below the MACO. 4.2.5 Rinse Limits The residue amount in the equipment can be assumed to be equal to the amount of residue in the last wash /boil) or rinse solvent portion. The
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assumption is based on the worst case consideration, that a further washing or rinsing run (or any reaction) would not wash more than the same amount of residue out of the equipment as the analysed solvent portion did. The MACO is usually calculated on each individual product change over scenario according to the procedures outlined in chapter 4.2.1 . 4.2.3 and individual acceptance criteria are established using the following equation: MACO [mg] Target value [mg/l] = Volume of rinse or boil [l] For quantitation a solvent sample (e.g. 1 l) is taken, the residue in the sample is determined by a suitable analytical method and the residue in the whole equipment is calculated according to the following equation: M = V * (C - CB)
assumption is based on the worst case consideration, that a further washing or rinsing run (or any reaction) would not wash more than the same amount of residue out of the equipment as the analysed solvent portion did. The MACO is usually calculated on each individual product change over scenario according to the procedures outlined in chapter 4.2.1 . 4.2.3 and individual acceptance criteria are established using the following equation: MACO [mg] Target value [mg/l] = Volume of rinse or boil [l] For quantitation a solvent sample (e.g. 1 l) is taken, the residue in the sample is determined by a suitable analytical method and the residue in the whole equipment is calculated according to the following equation: M = V * (C - CB)
M Amount of residue in the cleaned equipment in mg. V Volume of the last rinse or wash solvent portion in l. C Concentration of impurities in the sample in mg/l. CB Blank of the cleaning or rinsing solvent in mg/l. If several samples are taken during one run, one and the same blank can be used for all samples provided the same solvent lot was used for the whole run. Requirement: M < Target value.
M Amount of residue in the cleaned equipment in mg. V Volume of the last rinse or wash solvent portion in l. C Concentration of impurities in the sample in mg/l. CB Blank of the cleaning or rinsing solvent in mg/l. If several samples are taken during one run, one and the same blank can be used for all samples provided the same solvent lot was used for the whole run. Requirement: M < Target value.
5.0 LEVELS OF CLEANING

5.1 Introduction The manufacturing process of an Active Pharmaceutical Ingredient (API) typically consists of various chemical reaction and purification steps followed by physical changes. In general early steps undergo further processing and purification and so potential carryover of the previous product would be removed. The amount or as we will call it here, level of cleaning required in order to ensure that the API is free from unacceptable levels of contamination by previous substances varies depending on the step being cleaned and the next substance being manufactured in the same piece of equipment (train).
5.0 LEVELS OF CLEANING

5.1 Introduction The manufacturing process of an Active Pharmaceutical Ingredient (API) typically consists of various chemical reaction and purification steps followed by physical changes. In general early steps undergo further processing and purification and so potential carryover of the previous product would be removed. The amount or as we will call it here, level of cleaning required in order to ensure that the API is free from unacceptable levels of contamination by previous substances varies depending on the step being cleaned and the next substance being manufactured in the same piece of equipment (train).
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APIs and related intermediates are often produced in multi-purpose equipment with frequent product changes which results in a high amount of cleaning. During the course of this chapter the reader will be introduced to the concept of using different levels of cleaning, thereby giving the opportunity to minimize the amount of cleaning and cleaning validation required without effecting the safety of the API. 5.2 Procedure The CEFIC . APIC Guide to Cleaning Validation recommends three levels of cleaning that may be implemented. This approach is outlined in the table below, however it should be mentioned that additional levels might be necessary depending on the nature of the process and requirements of individual companies. Level 2 Thoroughness of cleaning Carry over of the previous product is critical. Cleaning required until predetermined stringent carry over limits are met. Carry over of the previous product is less critical. Cleaning should reduce the potential carry over to a less stringent limit as required for level 2. Only gross cleaning if carry over of the previous product is not critical. Cleaning Validation Essential.
APIs and related intermediates are often produced in multi-purpose equipment with frequent product changes which results in a high amount of cleaning. During the course of this chapter the reader will be introduced to the concept of using different levels of cleaning, thereby giving the opportunity to minimize the amount of cleaning and cleaning validation required without effecting the safety of the API. 5.2 Procedure The CEFIC . APIC Guide to Cleaning Validation recommends three levels of cleaning that may be implemented. This approach is outlined in the table below, however it should be mentioned that additional levels might be necessary depending on the nature of the process and requirements of individual companies. Level 2 Thoroughness of cleaning Carry over of the previous product is critical. Cleaning required until predetermined stringent carry over limits are met. Carry over of the previous product is less critical. Cleaning should reduce the potential carry over to a less stringent limit as required for level 2. Only gross cleaning if carry over of the previous product is not critical. Cleaning Validation Essential.
Increase from not required to necessary (lower acceptable carry over limits). Not required.
Increase from not required to necessary (lower acceptable carry over limits). Not required.
A general approach how these levels could be established for typical product changeover situations in a multi-purpose API-plant is outlined in figure 1.
A general approach how these levels could be established for typical product changeover situations in a multi-purpose API-plant is outlined in figure 1.
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Figure 1: Typical Product Changeover Scenarios
Figure 1: Typical Product Changeover Scenarios
API - Process A 0 or 1 Intermediate A - 3 0 Intermediate A - 2 0 Intermediate A - 1 1 or 2 0 Crude API A 0 2 1
API - Process B
API - Process A 0 or 1 Intermediate A - 3 0 Intermediate A - 2 0 0
API - Process B
>
Intermediate B - 3 0 or 1 0 Intermediate B - 2 0 Intermediate B - 1 1 or 2 0
>
Intermediate B - 3 0 or 1 0 Intermediate B - 2 0 0
>
>
>
1 or 2
Intermediate A - 1 0 Crude API A 0
Intermediate B - 1 1 or 2 0
>
Crude API B 0
>
Crude API B 0 2
>
Final API A (purification) 0 Physical Operations
>
2
Final API B (purification) 0 Physical Operations
>
Final API A (purification) 0 Physical Operations
>
2
Final API B (purification) 0 Physical Operations
>
>
>
The levels established as shown in figure 1 are based on the approach that in general the thoroughness of cleaning will increase and the acceptable carry over of the previous product will decrease from early steps in the route of synthesis to the final API due the fact that early steps undergo further processing and/or purification and so the potential carry over will be reduced by further processing. Principally two different product changeover scenarios exist which have a big impact on the cleaning level required: 1. Previous and following product do belong to the same synthetic chain (product changeover within process A or within process B
The levels established as shown in figure 1 are based on the approach that in general the thoroughness of cleaning will increase and the acceptable carry over of the previous product will decrease from early steps in the route of synthesis to the final API due the fact that early steps undergo further processing and/or purification and so the potential carry over will be reduced by further processing. Principally two different product changeover scenarios exist which have a big impact on the cleaning level required: 1. Previous and following product do belong to the same synthetic chain (product changeover within process A or within process B
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2. Previous and following product do not belong to the same synthetic chain (A-x- to B-x; x = 0; 1; 2; 3 including crude and final API A and B) If the product changeover is within the same synthetic chain (1) there are two different situations possible: Previous and following product is identical (in campaign cleaning) In this instance level 0 may be applied with no cleaning validation required. However potential degradants, accumulation of side products and microbiological growth should be considered. If applicable idle time (maximum period of time until complete and thorough cleaning of the equipment has to be done) for cleaning should be established. In some instances e.g. at the physical steps no equipment cleaning at all may be performed between batch to batch changeover (dryer, blender, micronizer). Complete cleaning is done after finishing the campaign or after an idle time if established. Cleaning between different steps of the same synthetic chain. There are two different situations possible: 1. The following product is the next step in the synthetic chain. There is a very low risk to effect the quality of the final API, because the previous product is the starting material of the following process and the analytical methods applied for the following product are usually suitable to detect the previous product which is covered and limited by the impurity profile. For this situation level 0 also applies. 2. The following product is not the next step of the synthetic chain. In general there is a higher potential for contamination of the API if the following product in a sequence is close to the final API - step. So progression of levels from early steps to later steps in the synthetic chain is expected as outlined in figure 1. In the example of product changeover A-2 to Final API A level 2 may be chosen if A-2 is not specified in the specification of API A or A-2 is a toxic compound. If it is specified or harmless, level 1 may be acceptable.
2. Previous and following product do not belong to the same synthetic chain (A-x- to B-x; x = 0; 1; 2; 3 including crude and final API A and B) If the product changeover is within the same synthetic chain (1) there are two different situations possible: Previous and following product is identical (in campaign cleaning) In this instance level 0 may be applied with no cleaning validation required. However potential degradants, accumulation of side products and microbiological growth should be considered. If applicable idle time (maximum period of time until complete and thorough cleaning of the equipment has to be done) for cleaning should be established. In some instances e.g. at the physical steps no equipment cleaning at all may be performed between batch to batch changeover (dryer, blender, micronizer). Complete cleaning is done after finishing the campaign or after an idle time if established. Cleaning between different steps of the same synthetic chain. There are two different situations possible: 1. The following product is the next step in the synthetic chain. There is a very low risk to effect the quality of the final API, because the previous product is the starting material of the following process and the analytical methods applied for the following product are usually suitable to detect the previous product which is covered and limited by the impurity profile. For this situation level 0 also applies. 2. The following product is not the next step of the synthetic chain. In general there is a higher potential for contamination of the API if the following product in a sequence is close to the final API - step. So progression of levels from early steps to later steps in the synthetic chain is expected as outlined in figure 1. In the example of product changeover A-2 to Final API A level 2 may be chosen if A-2 is not specified in the specification of API A or A-2 is a toxic compound. If it is specified or harmless, level 1 may be acceptable.
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If the product changeover is not within the same synthetic chain (2) the level of cleaning required depends of the stage of manufacture. If the following product is an early stage in the API - chain, in general lower levels are required than if it is an intermediate or final stage. The progression of levels is outlined in figure 1, however an individual risk assessment for each potential product changeover scenario has to be performed to decide which level is applicable. This risk assessment should address the following topics: Toxicological / pharmacological activity of the previous product, its side products or degradants Maximum daily dose of the following product Microbiological growth Batch size of the following product Solubility, experience, difficult to remove previous product
If the product changeover is not within the same synthetic chain (2) the level of cleaning required depends of the stage of manufacture. If the following product is an early stage in the API - chain, in general lower levels are required than if it is an intermediate or final stage. The progression of levels is outlined in figure 1, however an individual risk assessment for each potential product changeover scenario has to be performed to decide which level is applicable. This risk assessment should address the following topics: Toxicological / pharmacological activity of the previous product, its side products or degradants Maximum daily dose of the following product Microbiological growth Batch size of the following product Solubility, experience, difficult to remove previous product
Instead of the investigation of each individual cleaning situation similar situations could be grouped and classified using bracketing concepts (ref. section 6).
Instead of the investigation of each individual cleaning situation similar situations could be grouped and classified using bracketing concepts (ref. section 6).
6.0 BRACKETING AND WORST CASE RATING

6.1 Introduction The cleaning processes of multiple product use equipment in API facilities are subject to requirements for cleaning validation. The validation effort could be huge. In order to minimize the amount of validation required, a worst case approach for the validation can be used. 1. By means of a bracketing procedure the substances are grouped. 2. A worst case rating procedure is used to select the worst case in each group. 3. Validation of the worst case situation takes place. However, it is of utmost importance that a documented scientific rational for the chosen worst cases exists. It is recommended that at formal worst case rating project is carried out, including studies to support the worst case rating. When finalized, the
6.0 BRACKETING AND WORST CASE RATING

6.1 Introduction The cleaning processes of multiple product use equipment in API facilities are subject to requirements for cleaning validation. The validation effort could be huge. In order to minimize the amount of validation required, a worst case approach for the validation can be used. 1. By means of a bracketing procedure the substances are grouped. 2. A worst case rating procedure is used to select the worst case in each group. 3. Validation of the worst case situation takes place. However, it is of utmost importance that a documented scientific rational for the chosen worst cases exists. It is recommended that at formal worst case rating project is carried out, including studies to support the worst case rating. When finalized, the
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results of the worst case rating shall give the priority of the validation efforts of the program. This chapter gives an overview of the suggested work to be carried out, the acceptance criteria and the methodology for evaluation of the data. It should be emphasized that this is only an example to give guidance. The equipment, the substances produced and the procedures in place may vary; and this results in other solutions than those given in this example. The worst case rating priority will then support a conclusion that the cleaning procedures are effective for all drug substances within the bracket, including those not individually tested. 6.2 Bracketing Procedure The objective of a bracketing project, is for the company to demonstrate that it has a scientific rationale for its worst case rating of the substances in the cleaning validation program. The first thing to do is to make groups and sub groups - which we will term bracketing from which worst cases will later be selected based on the results from the rating. The bracketing procedure should be included in a company policy, or an SOP or an equivalent document on cleaning validation. A multi purpose facility, Clean Company, is presented as an example we will follow. a) Equipment Train The Clean Company is a multipurpose site for synthesis and isolation of organic substances (see figure 1). It is divided into six equipment trains separated from each other and intended for different use (earlier API steps, final API purification, drying etc.). In TrainA 9 substances can be produced, in TrainB 9 substances can be produced, in TrainC 8 substances can be produced, in TrainD 8 substances can be produced, in TrainE 10 substances can be produced, and in TrainF 11 substances can be produced. With no bracketing and worst case rating, cleaning validation studies would be required for each of the 55 substances. The first grouping criteria is that the substances in a group are produced in identical equipment trains. The ideal with regard to cleaning validation (as will be discussed in 6.3) each train could be considered as a group. Then 6 worst cases would ideally be identified. In reality, the number of worst
results of the worst case rating shall give the priority of the validation efforts of the program. This chapter gives an overview of the suggested work to be carried out, the acceptance criteria and the methodology for evaluation of the data. It should be emphasized that this is only an example to give guidance. The equipment, the substances produced and the procedures in place may vary; and this results in other solutions than those given in this example. The worst case rating priority will then support a conclusion that the cleaning procedures are effective for all drug substances within the bracket, including those not individually tested. 6.2 Bracketing Procedure The objective of a bracketing project, is for the company to demonstrate that it has a scientific rationale for its worst case rating of the substances in the cleaning validation program. The first thing to do is to make groups and sub groups - which we will term bracketing from which worst cases will later be selected based on the results from the rating. The bracketing procedure should be included in a company policy, or an SOP or an equivalent document on cleaning validation. A multi purpose facility, Clean Company, is presented as an example we will follow. a) Equipment Train The Clean Company is a multipurpose site for synthesis and isolation of organic substances (see figure 1). It is divided into six equipment trains separated from each other and intended for different use (earlier API steps, final API purification, drying etc.). In TrainA 9 substances can be produced, in TrainB 9 substances can be produced, in TrainC 8 substances can be produced, in TrainD 8 substances can be produced, in TrainE 10 substances can be produced, and in TrainF 11 substances can be produced. With no bracketing and worst case rating, cleaning validation studies would be required for each of the 55 substances. The first grouping criteria is that the substances in a group are produced in identical equipment trains. The ideal with regard to cleaning validation (as will be discussed in 6.3) each train could be considered as a group. Then 6 worst cases would ideally be identified. In reality, the number of worst
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cases identified will often be something between these two extremes (more than 6, but less than 55). CleanCompany Train A X X X Train D X X X X x Worst x case x x x x x x x x x x Worst case x x Train B x x
Worst x case
cases identified will often be something between these two extremes (more than 6, but less than 55). CleanCompany
Train C x x x x Worst case x x x x x x x x
Train A X X X Train D x x x x X X X X x Worst x case x x x x x x x x x x Worst case x x
Train B x x
Worst x case
Train C x x x x Worst case x x x x x x x x
x x x
x x x
Train E x x x x x x x x x Worst x case x x
Train F x Worst case x x x x x x x
Train E x x x x x x x x xWorst x case x x
Train F x Worst case x x x x x x x x x x x
Figure 1 CleanCompanys ideal example (1 train considered as 1 group) gives 6 worst cases.
Figure 1 CleanCompanys ideal example (1 train considered as 1 group) gives 6 worst cases.
In this example the main classes in this bracketing are based on the different Trains. The following equipment classes are maintained: o Train A o Train B o Train C b) Substances If the company has two or more trains used for the same purpose (such as earlier API steps, final API purification, drying etc) a choice of which products to be produced in each of the trains used for the same purpose is done. The combination of substances (starting materials, intermediates or APIs) in a train can be chosen based on one or more of the following strategies, or combinations of them: o Train E o Train F o Train D
In this example the main classes in this bracketing are based on the different Trains. The following equipment classes are maintained: o Train A o Train B o Train C b) Substances If the company has two or more trains used for the same purpose (such as earlier API steps, final API purification, drying etc) a choice of which products to be produced in each of the trains used for the same purpose is done. The combination of substances (starting materials, intermediates or APIs) in a train can be chosen based on one or more of the following strategies, or combinations of them: o Train E o Train F o Train D
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o Produce in the same train substances with the same cleaning procedure. o Produce in the same train substances with very low therapeutic doses as well as low daily doses and/or low batch sizes (and the opposite). o Produce in the same train substances with very low therapeutic doses (and the opposite). o Produce in the same train non toxic substances. o Produce in the same train substances with high solubility (and the opposite). Also a choice of maximum flexibility can be used, but this could result in low limits for residues (for example if the substance to be cleaned out has a very low therapeutic dose, and the following substance has a small batch size and/or a very high daily dose) and thus longer cleaning times. Advantages and disadvantages with several cleaning procedures, compared to one cleaning procedure, will be discussed in section 6.3. More explanations on effects of different strategies will be evident from section 6.4. 6.3 Cleaning Procedures For one train, in which several substances are being produced, several cleaning procedures often exist. In order to be able to defend the bracketing into groups, the second criterion is that the same cleaning procedure (method) shall be used for the substances within a group. Cleaning procedures (before change of products) can for example be considered to be the same if: 1. Same or equivalent issued cleaning batch records/cleaning SOPs. 2. Same solvent, solubility or similar properties. For API, the cleaning procedures have often been developed for maximum efficiency with regard to less time required to clean out a specific substance. In many cases specific cleaning procedures exists for each product. Advantages and disadvantages with several cleaning procedures, compared to one cleaning procedure, are presented in the following table. The same cleaning procedure for all substances (chosen to clean out the most difficult substance)
o Produce in the same train substances with the same cleaning procedure. o Produce in the same train substances with very low therapeutic doses as well as low daily doses and/or low batch sizes (and the opposite). o Produce in the same train substances with very low therapeutic doses (and the opposite). o Produce in the same train non toxic substances. o Produce in the same train substances with high solubility (and the opposite). Also a choice of maximum flexibility can be used, but this could result in low limits for residues (for example if the substance to be cleaned out has a very low therapeutic dose, and the following substance has a small batch size and/or a very high daily dose) and thus longer cleaning times. Advantages and disadvantages with several cleaning procedures, compared to one cleaning procedure, will be discussed in section 6.3. More explanations on effects of different strategies will be evident from section 6.4. 6.3 Cleaning Procedures For one train, in which several substances are being produced, several cleaning procedures often exist. In order to be able to defend the bracketing into groups, the second criterion is that the same cleaning procedure (method) shall be used for the substances within a group. Cleaning procedures (before change of products) can for example be considered to be the same if: 1. Same or equivalent issued cleaning batch records/cleaning SOPs. 2. Same solvent, solubility or similar properties. For API, the cleaning procedures have often been developed for maximum efficiency with regard to less time required to clean out a specific substance. In many cases specific cleaning procedures exists for each product. Advantages and disadvantages with several cleaning procedures, compared to one cleaning procedure, are presented in the following table. The same cleaning procedure for all substances (chosen to clean out the most difficult substance)
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+ Minimum number of cleaning validation studies (perhaps only one)
- Not optimal cleaning procedures for each substance - longer clean out times on average as well as higher consumption of solvents. - Normally a low limit for residues valid for all substances. Optimised cleaning procedures for each substance + Minimum clean out time on average. - Maximum number of cleaning validation studies (as many as there are cleaning procedures) In the example the CleanCompany has evaluated the cleaning procedures. The cleaning procedures have been examined and categorised into different classes. Substances in the same class are cleaned in the same way, using the same solvents and usually exhibit some chemical similarity with each other (e. g. salts, chemical structure etc.). In this example, totally, four cleaning procedure classes are included:
+ Minimum number of cleaning validation studies (perhaps only one)
- Not optimal cleaning procedures for each substance - longer clean out times on average as well as higher consumption of solvents. - Normally a low limit for residues valid for all substances. Optimised cleaning procedures for each substance + Minimum clean out time on average. - Maximum number of cleaning validation studies (as many as there are cleaning procedures) In the example the CleanCompany has evaluated the cleaning procedures. The cleaning procedures have been examined and categorised into different classes. Substances in the same class are cleaned in the same way, using the same solvents and usually exhibit some chemical similarity with each other (e. g. salts, chemical structure etc.). In this example, totally, four cleaning procedure classes are included:
o o o o
Class I water soluble substances. Class II substance - typeB. Class III acetone soluble substances. Class IV separate class for special substances.
o o o o
Class I water soluble substances. Class II substance - typeB. Class III acetone soluble substances. Class IV separate class for special substances.
6.4 Investigations and Worst Case Rating (WCR) A worst case rating study, will prioritise existing drug substances, in a cleaning validation program, based on information on applicable criteria chosen by the company. Clean company chose the following criteria which are relevant to the molecule preparation in their facility (companies should evaluate individual situations): Hardest to clean: experience from production Solubility in used solvent Highest toxicity Lowest therapeutic dose Lowest limit (based on therapeutic doses / tox data, batch sizes, surface areas etc.) f) Other scientific rationales a) b) c) d) e)
6.4 Investigations and Worst Case Rating (WCR) A worst case rating study, will prioritise existing drug substances, in a cleaning validation program, based on information on applicable criteria chosen by the company. Clean company chose the following criteria which are relevant to the molecule preparation in their facility (companies should evaluate individual situations): Hardest to clean: experience from production Solubility in used solvent Highest toxicity Lowest therapeutic dose Lowest limit (based on therapeutic doses / tox data, batch sizes, surface areas etc.) f) Other scientific rationales a) b) c) d) e)
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In order to present documented evidence supporting the scientific rating for each criterion, investigations should be carried out and formal reports should be written. For each criterion groups of rating with corresponding descriptive terms should be presented. When available, the descriptive terms can be chosen from the scientific literature on the subject (i. e. for solubility and toxicity). For other cases the rating is based on scientific investigations carried out by the company and collecting experience regarding details on the cleaning processes (i. e. experience from production). The descriptive terms for swab limits (based on therapeutic doses/tox data, batch sizes, surface areas etc.) could be chosen based on the possibility to normally detect the actual level by visual inspection. Clean Company chose to execute the WCR according to a formal protocol, in which the rating system was identified and the rating documented. In a report the results including the WCR were summarised, as well as conclusions. a) Hardest to Clean out - Experience from Production One criterion which can be used is, experience from production with regard to how difficult a substance is to clean out. The study is recommended to be in the form of interviews with operators and supervisors. A standardised sheet with questions could be used in which the answers are noted. Hardto-clean substances are identified and the difficulty of cleaning could be rated according to the three categories suggested below. The opinions of the personnel are subjective, and therefore there are no scientifically rationales. Category: 1 = Easy b) Solubility A solubility-rating should be carried out based on the solubilities of the substances in the solvents used for cleaning. Suggested rating numbers, with explanations, are presented in the table below. The descriptive terms are given in [1] - page 53 - USP 24 under Reference Tables (Description and Solubility, 2254) 2 = Medium 3 = Difficult
In order to present documented evidence supporting the scientific rating for each criterion, investigations should be carried out and formal reports should be written. For each criterion groups of rating with corresponding descriptive terms should be presented. When available, the descriptive terms can be chosen from the scientific literature on the subject (i. e. for solubility and toxicity). For other cases the rating is based on scientific investigations carried out by the company and collecting experience regarding details on the cleaning processes (i. e. experience from production). The descriptive terms for swab limits (based on therapeutic doses/tox data, batch sizes, surface areas etc.) could be chosen based on the possibility to normally detect the actual level by visual inspection. Clean Company chose to execute the WCR according to a formal protocol, in which the rating system was identified and the rating documented. In a report the results including the WCR were summarised, as well as conclusions. a) Hardest to Clean out - Experience from Production One criterion which can be used is, experience from production with regard to how difficult a substance is to clean out. The study is recommended to be in the form of interviews with operators and supervisors. A standardised sheet with questions could be used in which the answers are noted. Hardto-clean substances are identified and the difficulty of cleaning could be rated according to the three categories suggested below. The opinions of the personnel are subjective, and therefore there are no scientifically rationales. Category: 1 = Easy b) Solubility A solubility-rating should be carried out based on the solubilities of the substances in the solvents used for cleaning. Suggested rating numbers, with explanations, are presented in the table below. The descriptive terms are given in [1] - page 53 - USP 24 under Reference Tables (Description and Solubility, 2254) 2 = Medium 3 = Difficult
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Group
Included descriptive terms part of solute by weight
Approximate quantities of solvent by volume for 1 less than 1 part from 1 to 10 parts from 10 to 30 parts from 30 to 100 parts from 100 to 1 000 parts from 1 000 to 10 000 parts more than 10 000 parts -
Group
Included descriptive terms part of solute by weight
Approximate quantities of solvent by volume for 1 less than 1 part from 1 to 10 parts from 10 to 30 parts from 30 to 100 parts from 100 to 1 000 parts from 1 000 to 10 000 parts more than 10 000 parts -
1 2 3
Very soluble Freely soluble Soluble Sparingly soluble Slightly soluble Very slightly soluble Practically insoluble Insoluble
1 2 3
Very soluble Freely soluble Soluble Sparingly soluble Slightly soluble Very slightly soluble Practically insoluble Insoluble
c) Toxicity An evaluation including classification of non-toxic and toxic substances as well as a rating according to the toxicities should be carried out. Possible rating numbers, with explanations, are presented in the table below. The descriptive terms are given in [2] - page 53 - Casarett, Doull,s; Toxicology - The Basic Science of Poisons; Ed.2; 1980.
Group 1 2 3 4 5 Included descriptive terms Practically nontoxic Slightly toxic Moderately toxic Very toxic Extremely toxic Supertoxic Probable oral lethal dose for humans (mg/kg) > 15 000 5 000 - 15 000 500 - 5 000 50 - 500 5 - 50 <5
c) Toxicity An evaluation including classification of non-toxic and toxic substances as well as a rating according to the toxicities should be carried out. Possible rating numbers, with explanations, are presented in the table below. The descriptive terms are given in [2] - page 53 - Casarett, Doull,s; Toxicology - The Basic Science of Poisons; Ed.2; 1980.
Group 1 2 3 4 5 Included descriptive terms Practically nontoxic Slightly toxic Moderately toxic Very toxic Extremely toxic Supertoxic Probable oral lethal dose for humans (mg/kg) > 15 000 5 000 - 15 000 500 - 5 000 50 - 500 5 - 50 <5
d) Therapeutic Doses An investigation of therapeutic doses is typically based on oral and parenteral data. In the cases where the therapeutic doses are not available, corresponding values based on the toxicity could be used (recalculated according to company procedure). An example of rating numbers, with explanations, are presented in the table below.
d) Therapeutic Doses An investigation of therapeutic doses is typically based on oral and parenteral data. In the cases where the therapeutic doses are not available, corresponding values based on the toxicity could be used (recalculated according to company procedure). An example of rating numbers, with explanations, are presented in the table below.
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Group 1 2 3 4 5 e) Limits
Included dose intervals (smallest therapeutic dose) >1000 mg 100-1000 mg 10-99 mg 1-9 mg <1 mg
Group 1 2 3 4 5 e) Limits
Included dose intervals (smallest therapeutic dose) >1000 mg 100-1000 mg 10-99 mg 1-9 mg <1 mg
Acceptance limits swabs for the substances should be calculated according to company procedures. From the acceptable amount (MACO) and the area in product contact, the swab limit can be calculated (see also 4.2.4): Limit = MACO Area in product contact
Acceptance limits swabs for the substances should be calculated according to company procedures. From the acceptable amount (MACO) and the area in product contact, the swab limit can be calculated (see also 4.2.4): Limit = MACO Area in product contact
As evident from the description of how to calculate swab limits, the product combination and the area of the product contact surfaces have to be known. During this study, an evaluation of the combinations of substances in the different equipment classes could be carried out. If for example only one substance has a very low swab limit, it could be recommended to produce it in another train. Low swab limits usually results in very ambitious cleaning processes, and very low detection limits of the analytical methods. Rating Group 1 2 3 4 5 Descriptive terms High limit Moderately high limit Moderately low limit Low limit Very low limit Rationale Most probably detectable on equipment by visual evaluation Probably detectable on equipment by visual evaluation Possibly detectable on equipment by visual evaluation Probably not detectable on equipment by visual evaluation Impossibly detectable on equipment by visual evaluation
As evident from the description of how to calculate swab limits, the product combination and the area of the product contact surfaces have to be known. During this study, an evaluation of the combinations of substances in the different equipment classes could be carried out. If for example only one substance has a very low swab limit, it could be recommended to produce it in another train. Low swab limits usually results in very ambitious cleaning processes, and very low detection limits of the analytical methods. Rating Group 1 2 3 4 5 Descriptive terms High limit Moderately high limit Moderately low limit Low limit Very low limit Rationale Most probably detectable on equipment by visual evaluation Probably detectable on equipment by visual evaluation Possibly detectable on equipment by visual evaluation Probably not detectable on equipment by visual evaluation Impossibly detectable on equipment by visual evaluation
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f) Other Scientific Rationales Other scientific criteria than those suggested in section 6.4 a)-e) can be used. 6.5 Worst Case Rating The substances are scientifically matrixed by equipment class (train/ equipment) and cleaning class (procedure). Each existing combination of the classes is considered as a group. When this bracketing has been carried out, the Worst Case Rating (WCR) can start. For at least one worst case in each group, cleaning validation studies shall be carried out. The rating procedure for CleanCompany presented as an example could be used. a) Rating Procedure During a worst case rating, the results of the investigations are summarised for each substance in each equipment class. If the evaluation of the cleaning procedures indicates that some of the substances have unique cleaning procedures, then each of those substances will be considered as a group (with one group member which is the worst case). If all the substances in a cleaning class (train/equipment) will be tested, then individual swab limits may be used for each substance. In case of groups, where only some worst cases are tested, the strategy described below shall be followed. The following methodology shall normally be applied when a priority based on a worst case shall be used. Choice of common, general residual limit Evaluate if the lowest calculated limit is reasonable to apply on all substances. If that is the case, this swab limit shall be valid as a common general limit for the specific equipment. If the lowest limit is found to be too low as common limit for all substances, then the second lowest limit is evaluated and so on. Criteria for the validation of the cleaning processes 1. For the substances with common, general swab limit, it is required that the substance with the lowest solubility shall be tested for each cleaning method. If more than one substance fulfils this criterion,
f) Other Scientific Rationales Other scientific criteria than those suggested in section 6.4 a)-e) can be used. 6.5 Worst Case Rating The substances are scientifically matrixed by equipment class (train/ equipment) and cleaning class (procedure). Each existing combination of the classes is considered as a group. When this bracketing has been carried out, the Worst Case Rating (WCR) can start. For at least one worst case in each group, cleaning validation studies shall be carried out. The rating procedure for CleanCompany presented as an example could be used. a) Rating Procedure During a worst case rating, the results of the investigations are summarised for each substance in each equipment class. If the evaluation of the cleaning procedures indicates that some of the substances have unique cleaning procedures, then each of those substances will be considered as a group (with one group member which is the worst case). If all the substances in a cleaning class (train/equipment) will be tested, then individual swab limits may be used for each substance. In case of groups, where only some worst cases are tested, the strategy described below shall be followed. The following methodology shall normally be applied when a priority based on a worst case shall be used. Choice of common, general residual limit Evaluate if the lowest calculated limit is reasonable to apply on all substances. If that is the case, this swab limit shall be valid as a common general limit for the specific equipment. If the lowest limit is found to be too low as common limit for all substances, then the second lowest limit is evaluated and so on. Criteria for the validation of the cleaning processes 1. For the substances with common, general swab limit, it is required that the substance with the lowest solubility shall be tested for each cleaning method. If more than one substance fulfils this criterion,
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then the substance shall be chosen which, based on experience is most difficult to clean. 2. Any substance which does not fall within this bracket must be validated individually. b) Evaluation of Rating The worst case rating can be executed according to an issued protocol in which the methods and procedures for the rating will be identified. The applicable investigations presented in section 6.4 a)-f) would then be used (and could be enclosed to the protocol or a report, to support the rationales for the rating). A matrix system, for each equipment class (such as a dryer), can be set up as evident from the following table where Train A of CleanCompany has been chosen. In this case a formal rating matrix has been filled in for Train A. Altogether four cleaning classes were identified for the substances produced in TrainA. All the categories are introduced as columns in a matrix.
Substance Cleaning a): Hardest b): c): d):Ther. e): Swab f):Other Method to clean* Solubility Toxicity dose limit Class III IV III III II II III I I 2.3 2.2 2.1 1.9 2.8 2.5 2.2 1.6 1.8 1 1 1 1 2 2 1 2 1 4 2 3 3 2 2 2 3 2 3 4 2 3 3 3 3 3 3 4 4 4 4 4 3 4 4 4 NA NA NA NA NA NA NA NA NA
then the substance shall be chosen which, based on experience is most difficult to clean. 2. Any substance which does not fall within this bracket must be validated individually. b) Evaluation of Rating The worst case rating can be executed according to an issued protocol in which the methods and procedures for the rating will be identified. The applicable investigations presented in section 6.4 a)-f) would then be used (and could be enclosed to the protocol or a report, to support the rationales for the rating). A matrix system, for each equipment class (such as a dryer), can be set up as evident from the following table where Train A of CleanCompany has been chosen. In this case a formal rating matrix has been filled in for Train A. Altogether four cleaning classes were identified for the substances produced in TrainA. All the categories are introduced as columns in a matrix.
Substance Cleaning a): Hardest b): c): d):Ther. e): Swab f):Other Method to clean* Solubility Toxicity dose limit Class III IV III III II II III I I 2.3 2.2 2.1 1.9 2.8 2.5 2.2 1.6 1.8 1 1 1 1 2 2 1 2 1 4 2 3 3 2 2 2 3 2 3 4 2 3 3 3 3 3 3 4 4 4 4 4 3 4 4 4 NA NA NA NA NA NA NA NA NA
Esubstance Fsubstance Csubstance Lsubstance Osubstance Msubstance Psubtance Rsubstance Tsubstance
Esubstance Fsubstance Csubstance Lsubstance Osubstance Msubstance Psubtance Rsubstance Tsubstance
* Each figure is the mean value for different questions answered by operators and supervisors. The lowest limit is 22 g/dm2 (Fsubstance), but the general limit was set to 40 g/dm2 since all the other substances have a limit above 42 g/dm2. Therefore, Fsubstance will be tested according to criterion no 2 (section 6.5a).
* Each figure is the mean value for different questions answered by operators and supervisors. The lowest limit is 22 g/dm2 (Fsubstance), but the general limit was set to 40 g/dm2 since all the other substances have a limit above 42 g/dm2. Therefore, Fsubstance will be tested according to criterion no 2 (section 6.5a).
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Substances with the lowest solubility in used solvents in each class will be tested (according to criterion no 1). In this case three substances will be tested at a limit of 40 g/dm2. The results from the rating is presented in the following figure. Criterion for Class Substance Swab limit validation 1. General limit NA Fsubstance 22 g/dm2 limit 40 g/dm2 40 g/dm2 40 g/dm2 NA Comments Tested due to lower limit than general
Substances with the lowest solubility in used solvents in each class will be tested (according to criterion no 1). In this case three substances will be tested at a limit of 40 g/dm2. The results from the rating is presented in the following figure. Criterion for Class Substance Swab limit validation 1. General limit NA Fsubstance 22 g/dm2 limit 40 g/dm2 40 g/dm2 40 g/dm2 NA Comments Tested due to lower limit than general
2. Worst Case in each class
Fsubstance only product, tested at low limit In case a substance of top priority is not produced regularly, the substance with the second highest priority will be tested in order to show that the cleaning procedure is sufficient for all the other substances in that class. The substance of top priority will then be tested at the first possible occasion. The WCR example for all the Trains within CleanCompany resulted in 20 worst cases to test. This is considerably less than 55 which would be the case without the rating. But it is more than 6 which should be the ideal case, and this is due to many cleaning classed identified instead of the ideal case with one class for each equipment train. However, the choice was to partly use cleaning methods effective for each product class. The WCR could typically result in a report including a priority, based on the rating, for the substances in the cleaning validation program. It is recommended that the applicable background investigations shall be completed, approved and enclosed to the protocol or the report. c) Re-rating Change control should be applied to the WCR. If the conditions for the rating are changed, then a re-rating procedure should be carried out. The following table gives examples where a formal re-rating procedure may be required:
I: II: III: IV:
Rsubstance Qsubstance Esubstance NA
2. Worst Case in each class
Fsubstance only product, tested at low limit In case a substance of top priority is not produced regularly, the substance with the second highest priority will be tested in order to show that the cleaning procedure is sufficient for all the other substances in that class. The substance of top priority will then be tested at the first possible occasion. The WCR example for all the Trains within CleanCompany resulted in 20 worst cases to test. This is considerably less than 55 which would be the case without the rating. But it is more than 6 which should be the ideal case, and this is due to many cleaning classed identified instead of the ideal case with one class for each equipment train. However, the choice was to partly use cleaning methods effective for each product class. The WCR could typically result in a report including a priority, based on the rating, for the substances in the cleaning validation program. It is recommended that the applicable background investigations shall be completed, approved and enclosed to the protocol or the report. c) Re-rating Change control should be applied to the WCR. If the conditions for the rating are changed, then a re-rating procedure should be carried out. The following table gives examples where a formal re-rating procedure may be required:
I: II: III: IV:
Rsubstance Qsubstance Esubstance NA
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o o o o
Changed cleaning method Changed process Changed / additional new product Changed / new equipment
o o o o
Changed cleaning method Changed process Changed / additional new product Changed / new equipment
After re-rating, it is recommended to issue an official controlled document including a worst case listing or table, with the same type of result presented for the involved substances/ equipment/methods, as for the original rating.
After re-rating, it is recommended to issue an official controlled document including a worst case listing or table, with the same type of result presented for the involved substances/ equipment/methods, as for the original rating.
7.0 DETERMINATION OF THE AMOUNT OF RESIDUE

7.1 Introduction This section provides a practical guidance how the amount of residue in cleaned equipment can be determined based on requirements from regulatory authorities [1] , actual requirements on analytical validation [2] and experience. The section covers specific requirements on analytical and sampling methods validation for cleaning validation purposes. Further examples of sampling methods are given and a short recommendation on use of analytical methods. Several formulas for residue quantitation are proposed. Whereas the acceptance limit (Mper) is a calculated figure (See section Acceptance Limits) and represents the specification for the equipment cleanliness, the amount of residue (M) in the equipment is the target value of the system (The system is defined by: the equipment, the cleaning the sampling and the analytical methods and by the product to be cleaned out of the equipment. ) and must be determined by suitable methods. Principally the determination proceeds in two steps. These are the sampling and the quantitation of the contaminant in the sample. Because the decision on acceptable cleanliness of the equipment bears potential risk for the product quality, it must be made based on correct and scientifically sound values for M (and Mper, see section Acceptance Limits). Therefore the method for determination of M must be suitably validated [1]. For suitable validation at least the specificity, sensitivity and recovery should be determined.
7.0 DETERMINATION OF THE AMOUNT OF RESIDUE

7.1 Introduction This section provides a practical guidance how the amount of residue in cleaned equipment can be determined based on requirements from regulatory authorities [1] , actual requirements on analytical validation [2] and experience. The section covers specific requirements on analytical and sampling methods validation for cleaning validation purposes. Further examples of sampling methods are given and a short recommendation on use of analytical methods. Several formulas for residue quantitation are proposed. Whereas the acceptance limit (Mper) is a calculated figure (See section Acceptance Limits) and represents the specification for the equipment cleanliness, the amount of residue (M) in the equipment is the target value of the system (The system is defined by: the equipment, the cleaning the sampling and the analytical methods and by the product to be cleaned out of the equipment. ) and must be determined by suitable methods. Principally the determination proceeds in two steps. These are the sampling and the quantitation of the contaminant in the sample. Because the decision on acceptable cleanliness of the equipment bears potential risk for the product quality, it must be made based on correct and scientifically sound values for M (and Mper, see section Acceptance Limits). Therefore the method for determination of M must be suitably validated [1]. For suitable validation at least the specificity, sensitivity and recovery should be determined.
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For validation, a surface similar to the equipment surface can be spiked with the expected contaminant, subsequently the contaminant can be recovered and analyzed by the methods to be validated. If possible both the sampling and the analytical method should be validated together (as a chain) at least for recovery and sensitivity (Limit of Quantitation - LOQ, or Limit of Detection - LOD). 7.2 Validation Requirements General The requirements for analytical methods validation are defined in [2]. According to [2] . page 53 - there are four types of analytical methods with principally different validation requirements (Table 1). This list should be considered typical for the analytical procedures cited but occasional exceptions should be dealt with on a case-by-case basis. It should be noted that robustness is not listed in the table but should be considered at an appropriate stage in the development of the analytical procedure. In practice, it is usually possible to design the experimental work such that the appropriate validation characteristics can be considered simultaneously to provide a sound, overall knowledge of the capabilities of the analytical procedure, for instance: specificity, linearity, range, accuracy and precision. The validation of an analytical method should occur in compliance with pre-established acceptance criteria. The criteria can be documented in a written general policy or in a Validation Plan. However there should be one Validation Report per method validated, summarizing the specific results.
For validation, a surface similar to the equipment surface can be spiked with the expected contaminant, subsequently the contaminant can be recovered and analyzed by the methods to be validated. If possible both the sampling and the analytical method should be validated together (as a chain) at least for recovery and sensitivity (Limit of Quantitation - LOQ, or Limit of Detection - LOD). 7.2 Validation Requirements General The requirements for analytical methods validation are defined in [2]. According to [2] . page 53 - there are four types of analytical methods with principally different validation requirements (Table 1). This list should be considered typical for the analytical procedures cited but occasional exceptions should be dealt with on a case-by-case basis. It should be noted that robustness is not listed in the table but should be considered at an appropriate stage in the development of the analytical procedure. In practice, it is usually possible to design the experimental work such that the appropriate validation characteristics can be considered simultaneously to provide a sound, overall knowledge of the capabilities of the analytical procedure, for instance: specificity, linearity, range, accuracy and precision. The validation of an analytical method should occur in compliance with pre-established acceptance criteria. The criteria can be documented in a written general policy or in a Validation Plan. However there should be one Validation Report per method validated, summarizing the specific results.
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Table 1: Requirements List
Table 1: Requirements List
Type of Analytical Procedure Characteristic Accuracy Precision Repeatability Intermediate Precision Specificity2) Detection Limit Quantitation Limit Linearity Range
Identification
Testing for Impurities Assay Quantitative Limit + + +1) + -3) + + + + + + + +1) + + +
Type of Analytical Procedure Characteristic Accuracy Precision Repeatability Intermediate Precision Specificity2) Detection Limit Quantitation Limit Linearity Range
Identification
Testing for Impurities Assay Quantitative Limit + + +1) + -3) + + + + + + + +1) + + +
+ -
+ -
- Signifies that this characteristic is not normally evaluated. + Signifies that this characteristic is normally evaluated. 1) In cases where reproducibility has been performed, intermediate precision is not needed. 2) Lack of specificity of one analytical procedure could be compensated by other supporting analytical procedure(s). 3) May be needed in some cases. It is usual to employ the requirements for Testing for Impurities when validating cleaning validation analytical methods. The requirements for Quantitative Testing for Impurities can apply for example in cases, where a method should be suitable for several possible acceptance limits ( E.g. the measured amount of residue M must be compared with acceptance limits between 5 and 750 g/Equipment. This is possible when the method will be used for several change overs.) and therefore quantitation of the residue over a certain range may be necessary. The requirements for Limit Testing for Impurities can apply for example in cases, where the method should be suitable for one specific acceptance limit ( E.g. the measured M must be compared with Mper = 105 g/Equipment). In the following some aspects of analytical methods validation specific to cleaning validation are emphasized. For further details refer to [2]. According
- Signifies that this characteristic is not normally evaluated. + Signifies that this characteristic is normally evaluated. 1) In cases where reproducibility has been performed, intermediate precision is not needed. 2) Lack of specificity of one analytical procedure could be compensated by other supporting analytical procedure(s). 3) May be needed in some cases. It is usual to employ the requirements for Testing for Impurities when validating cleaning validation analytical methods. The requirements for Quantitative Testing for Impurities can apply for example in cases, where a method should be suitable for several possible acceptance limits ( E.g. the measured amount of residue M must be compared with acceptance limits between 5 and 750 g/Equipment. This is possible when the method will be used for several change overs.) and therefore quantitation of the residue over a certain range may be necessary. The requirements for Limit Testing for Impurities can apply for example in cases, where the method should be suitable for one specific acceptance limit ( E.g. the measured M must be compared with Mper = 105 g/Equipment). In the following some aspects of analytical methods validation specific to cleaning validation are emphasized. For further details refer to [2]. According
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to [2] - specificity is a basic requirement for all types of analytical methods. In case of cleaning validation it may occur, that not all potential impurities are clearly specified. It is important to note that in such a situation a specific method may not always detect all impurities. Studies should be performed to characterize the unknown impurities, develop and validate suitable analytical methods. However this can be an unacceptably time consuming task. In this case a method which detects all potential impurities together can be suitable even, when it is not specific for each of the impurities. For example in a case, where it is sure that only non volatile impurities occur, the dry residue determination could be a suitable method (which is specific for the sum of non volatile impurities), provided the validation requirements according to Table 1 are satisfied (e.g. sensitivity). Then for the acceptance of the equipment for the following production it must be assumed that the whole dry residue consists of the worst case impurity (most toxic, most active etc.). In some cases a combination of several methods can achieve the necessary specificity. After completion of a cleaning validation study an unspecific method (e.g. dry residue) may be used for the routine checks after cleaning of an equipment by the validated cleaning procedure. The precondition for this practice is, that during the validation study it was shown that the unspecific method is suitable for the intended purpose. If possible, the sensitivity of impurity detection for cleaning validation should be determined for the sampling and analytical methods together. This can be achieved for example by spiking of a surface equivalent (material, polish grade) to the equipment surface with different known amounts of the impurity. Subsequently the impurity is recovered and analyzed by the same sampling and analytical methods, which will be used for the cleaning validation study. The overall results of this procedure are then compared to criteria for detection or quantitation limits as defined in [2]. The limits may subsequently be validated by the analysis of samples known to be near at the limits. The measured values below LOQ should be reported as = LOQ (worst case approach). For example if LOQ is 10 mg/l, the measured blank 7 mg/
to [2] - specificity is a basic requirement for all types of analytical methods. In case of cleaning validation it may occur, that not all potential impurities are clearly specified. It is important to note that in such a situation a specific method may not always detect all impurities. Studies should be performed to characterize the unknown impurities, develop and validate suitable analytical methods. However this can be an unacceptably time consuming task. In this case a method which detects all potential impurities together can be suitable even, when it is not specific for each of the impurities. For example in a case, where it is sure that only non volatile impurities occur, the dry residue determination could be a suitable method (which is specific for the sum of non volatile impurities), provided the validation requirements according to Table 1 are satisfied (e.g. sensitivity). Then for the acceptance of the equipment for the following production it must be assumed that the whole dry residue consists of the worst case impurity (most toxic, most active etc.). In some cases a combination of several methods can achieve the necessary specificity. After completion of a cleaning validation study an unspecific method (e.g. dry residue) may be used for the routine checks after cleaning of an equipment by the validated cleaning procedure. The precondition for this practice is, that during the validation study it was shown that the unspecific method is suitable for the intended purpose. If possible, the sensitivity of impurity detection for cleaning validation should be determined for the sampling and analytical methods together. This can be achieved for example by spiking of a surface equivalent (material, polish grade) to the equipment surface with different known amounts of the impurity. Subsequently the impurity is recovered and analyzed by the same sampling and analytical methods, which will be used for the cleaning validation study. The overall results of this procedure are then compared to criteria for detection or quantitation limits as defined in [2]. The limits may subsequently be validated by the analysis of samples known to be near at the limits. The measured values below LOQ should be reported as = LOQ (worst case approach). For example if LOQ is 10 mg/l, the measured blank 7 mg/
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l and the measured residue amount 3 mg/l, the calculation should be: M = 10 - 10 = 0 mg/l (and not M = 3 - 7 = - 4 mg/l). Because the resulting 0 mg/l again are below LOQ, the reported value for this sample should be = LOQ = 10 mg/l. So for further calculations e.g. of the residue amount in the equipment 10 mg/l should be used (and not - 4 mg/l nor 0 mg/l). Usually it can be assumed that for quantitative impurity determination the LOQ should approximately be 0.5 of the specification (i.e. for cleaning validation 0.5 of the acceptance limit = Mper) or lower. LOQ should never be higher than the specification (Mper). In the following sections three methods of LOQ/LOD determination are outlined. Based on Visual Evaluation Visual evaluation may be used for non-instrumental methods but may also be used with instrumental methods. Frequently this approach is used for TLC. Based on Signal-to-Noise Approach This approach can only be applied to analytical procedures, which exhibit baseline noise (e.g. GC, HPLC). A signal-to-noise ratio (S/N) between 3 or 2:1 is generally considered acceptable for estimation the detection limit (LOD) and a typical ratio for acceptable quantitation limit is 10:1 (LOQ). The value for S/N can be calculated according to Equation 1 and Figure 1:
l and the measured residue amount 3 mg/l, the calculation should be: M = 10 - 10 = 0 mg/l (and not M = 3 - 7 = - 4 mg/l). Because the resulting 0 mg/l again are below LOQ, the reported value for this sample should be = LOQ = 10 mg/l. So for further calculations e.g. of the residue amount in the equipment 10 mg/l should be used (and not - 4 mg/l nor 0 mg/l). Usually it can be assumed that for quantitative impurity determination the LOQ should approximately be 0.5 of the specification (i.e. for cleaning validation 0.5 of the acceptance limit = Mper) or lower. LOQ should never be higher than the specification (Mper). In the following sections three methods of LOQ/LOD determination are outlined. Based on Visual Evaluation Visual evaluation may be used for non-instrumental methods but may also be used with instrumental methods. Frequently this approach is used for TLC. Based on Signal-to-Noise Approach This approach can only be applied to analytical procedures, which exhibit baseline noise (e.g. GC, HPLC). A signal-to-noise ratio (S/N) between 3 or 2:1 is generally considered acceptable for estimation the detection limit (LOD) and a typical ratio for acceptable quantitation limit is 10:1 (LOQ). The value for S/N can be calculated according to Equation 1 and Figure 1:
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Equation 1: S/N = (2 * H)/hn H High of the peak from the mean baseline.. hn The maximum deviation of the baseline within the range of 5 to 20 fold width of peak at half height. Based on the Standard Deviation of the Response and the Slope The detection limit may be expressed by Equation 2, the quantitation limit by Equation 3. Equation 2: LOD = (3.3 * s)/S Equation 3: LOQ = (10 * s)/S s The standard deviation of the response. S The slope of the calibration curve. Where the s values may be obtained for example by analyzing an appropriate number of blank samples and calculating the standard deviation of these responses. Alternatively a specific calibration curve can be studied using samples containing an analyte in the range of LOD or LOQ respectively. The residual standard deviation of a regression line or the standard deviation of yintercepts of regression lines may be used as the standard deviation s. If possible, the recovery of impurity detection for cleaning validation should be determined for the sampling and analytical methods together This can be achieved for example by spiking of a surface equivalent (material, polish grade) to the equipment surface to be cleaned with different known amounts of the impurity. Subsequently the impurity is recovered and analyzed by the same sampling and analytical methods which will be used for the cleaning validation study. The overall measured results of this procedure are then compared to the actual amounts applied to the surface. The recovery usually is determined during the accuracy determination and should be reported as % of the known applied amount of the impurity. As example for quantitative impurity determination recoveries of = 90 % are usually regarded acceptable. Therefore for cleaning validation recoveries of = 90 % do not need to be taken into account for the calculation of the true
Equation 1: S/N = (2 * H)/hn H High of the peak from the mean baseline.. hn The maximum deviation of the baseline within the range of 5 to 20 fold width of peak at half height. Based on the Standard Deviation of the Response and the Slope The detection limit may be expressed by Equation 2, the quantitation limit by Equation 3. Equation 2: LOD = (3.3 * s)/S Equation 3: LOQ = (10 * s)/S s The standard deviation of the response. S The slope of the calibration curve. Where the s values may be obtained for example by analyzing an appropriate number of blank samples and calculating the standard deviation of these responses. Alternatively a specific calibration curve can be studied using samples containing an analyte in the range of LOD or LOQ respectively. The residual standard deviation of a regression line or the standard deviation of yintercepts of regression lines may be used as the standard deviation s. If possible, the recovery of impurity detection for cleaning validation should be determined for the sampling and analytical methods together This can be achieved for example by spiking of a surface equivalent (material, polish grade) to the equipment surface to be cleaned with different known amounts of the impurity. Subsequently the impurity is recovered and analyzed by the same sampling and analytical methods which will be used for the cleaning validation study. The overall measured results of this procedure are then compared to the actual amounts applied to the surface. The recovery usually is determined during the accuracy determination and should be reported as % of the known applied amount of the impurity. As example for quantitative impurity determination recoveries of = 90 % are usually regarded acceptable. Therefore for cleaning validation recoveries of = 90 % do not need to be taken into account for the calculation of the true
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value for M. Recoveries of < 90 % must be included in the calculation for M (Equation 4) and recoveries of < 50 % should be omitted. Equation 4: M = Mres * 1/R M True value for the amount of residue remaining in the equipment after cleaning. Mres The measured amount of residue (sampling and then analytical measurement). R Recovery in % divided by 100 (for 75 %: 75/100 = 0.75). In Table 2 the requirements for the validation of Quantitative Testing for Impurities according to [2] - which were not addressed in the previous sections are summarized. Additionally Acceptance Criteria are proposed. The proposed Acceptance Criteria are examples only. Different Acceptance Criteria may be established based on sound scientific rationale. It is important to note, that the summarized requirements should be used for validation of Quantitative Testing for Impurities during cleaning validation studies. According to section 0 validation of Quantitative Testing for Impurities will be usually applied when it is foreseen to use the analytical method for several specifications of the residue amount in the equipment (= Acceptance Limit, = Mper). The lowest foreseen Acceptance Limit is referred as MperMin, the highest as MperMax inTable 2. For one specific Acceptance Limit normally Limit Testing for Impurities and corresponding validation of the analytical method is sufficient. If exceptionally for one specific Acceptance Limit the validation of Quantitative Testing for Impurities will be used, then MperMin = MperMax = Mper. For the experimental work as described in Table 2, the samples can be spiked with appropriate levels of the impurities (when standards are available) or exceptionally compared with another well-characterized procedure (standards not available) to obtain the true values of the analyte concentrations.
value for M. Recoveries of < 90 % must be included in the calculation for M (Equation 4) and recoveries of < 50 % should be omitted. Equation 4: M = Mres * 1/R M True value for the amount of residue remaining in the equipment after cleaning. Mres The measured amount of residue (sampling and then analytical measurement). R Recovery in % divided by 100 (for 75 %: 75/100 = 0.75). In Table 2 the requirements for the validation of Quantitative Testing for Impurities according to [2] - which were not addressed in the previous sections are summarized. Additionally Acceptance Criteria are proposed. The proposed Acceptance Criteria are examples only. Different Acceptance Criteria may be established based on sound scientific rationale. It is important to note, that the summarized requirements should be used for validation of Quantitative Testing for Impurities during cleaning validation studies. According to section 0 validation of Quantitative Testing for Impurities will be usually applied when it is foreseen to use the analytical method for several specifications of the residue amount in the equipment (= Acceptance Limit, = Mper). The lowest foreseen Acceptance Limit is referred as MperMin, the highest as MperMax inTable 2. For one specific Acceptance Limit normally Limit Testing for Impurities and corresponding validation of the analytical method is sufficient. If exceptionally for one specific Acceptance Limit the validation of Quantitative Testing for Impurities will be used, then MperMin = MperMax = Mper. For the experimental work as described in Table 2, the samples can be spiked with appropriate levels of the impurities (when standards are available) or exceptionally compared with another well-characterized procedure (standards not available) to obtain the true values of the analyte concentrations.
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Table 2: Validation Requirements
Table 2: Validation Requirements
Experiments
Possible Acceptance Criteria
Experiments
Possible Acceptance Criteria
Accuracy: Perform a minimum of 9 determinations over a minimum of 3 concentration levels covering the specific range (e.g. 3 concentrations/3 replicates each of the total analytical procedure). Determine analyte with respect to the total amount of residue in the sample (e.g. weight/weight). Report: o Accuracy as percent recovery or 90.00 - 110.00 % o Difference between the mean and the accepted true value. 10.00 % (P = 95 %) o Confidence intervals. Precision: Investigate using homogenous, authentic samples or (if not possible) using artificially prepared samples. Perform a minimum of 9 determinations covering the specified range for the procedure (e.g. 3 concentrations/3 replicates each) or a minimum of 6 determinations at 100 % of the test concentration. Repeatability (intra-assay precision): Establish precision under the same operating conditions over a short interval of time. Report: o Standard deviation see Srel (interdependent with Srel) o Overall relative standard deviation 10.00 % over the whole range of the method o Relative standard deviation within one 20.00 % concentration level o Confidence interval Intermediate Precision (may include robustness, ruggedness): Establish precision on different days, for different analysts, on different equipment and after variation of method parameters (= robustness, e.g. stability of solutions, variations of pH, of mobile phase composition, of
Accuracy: Perform a minimum of 9 determinations over a minimum of 3 concentration levels covering the specific range (e.g. 3 concentrations/3 replicates each of the total analytical procedure). Determine analyte with respect to the total amount of residue in the sample (e.g. weight/weight). Report: o Accuracy as percent recovery or 90.00 - 110.00 % o Difference between the mean and the accepted true value. 10.00 % (P = 95 %) o Confidence intervals. Precision: Investigate using homogenous, authentic samples or (if not possible) using artificially prepared samples. Perform a minimum of 9 determinations covering the specified range for the procedure (e.g. 3 concentrations/3 replicates each) or a minimum of 6 determinations at 100 % of the test concentration. Repeatability (intra-assay precision): Establish precision under the same operating conditions over a short interval of time. Report: o Standard deviation see Srel (interdependent with Srel) o Overall relative standard deviation 10.00 % over the whole range of the method o Relative standard deviation within one 20.00 % concentration level o Confidence interval Intermediate Precision (may include robustness, ruggedness): Establish precision on different days, for different analysts, on different equipment and after variation of method parameters (= robustness, e.g. stability of solutions, variations of pH, of mobile phase composition, of
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flow rate, of temperature, of columns etc.). It is not necessary to study these effects individually. Experimental design (matrix) may be applied. Report: o Standard deviation (interdependent see Srel with relative standard deviation) o Relative standard deviation 3 * Srel from repeatability or 10 % whichever is greater o Confidence interval Specificity: Demonstrate the discrimination of the analyte in the presence of the other impurities: o Test samples containing the analyte Specify acceptable and other impurities. Obtain positive deviation and correct results for the analyte. o Test samples without the analyte. Negative results o For chromatographic procedures use Specify acceptable representative chromatograms to resolution of peaks document specificity. Label individual components appropriately. Linearity: Measure a minimum of 5 concentrations across the range of the procedure (dilute standard stock solution or prepare synthetic mixtures). Plot the signals as function of concentration. Evaluate the plot: o Visually Linear o Statistically (e.g. regression line by the method of least squares) o correlation coefficient 0.99000 o y-intercept Confidence band (P = 95 %) contains 0 o slope of the regression line o residual sum of squares
flow rate, of temperature, of columns etc.). It is not necessary to study these effects individually. Experimental design (matrix) may be applied. Report: o Standard deviation (interdependent see Srel with relative standard deviation) o Relative standard deviation 3 * Srel from repeatability or 10 % whichever is greater o Confidence interval Specificity: Demonstrate the discrimination of the analyte in the presence of the other impurities: o Test samples containing the analyte Specify acceptable and other impurities. Obtain positive deviation and correct results for the analyte. o Test samples without the analyte. Negative results o For chromatographic procedures use Specify acceptable representative chromatograms to resolution of peaks document specificity. Label individual components appropriately. Linearity: Measure a minimum of 5 concentrations across the range of the procedure (dilute standard stock solution or prepare synthetic mixtures). Plot the signals as function of concentration. Evaluate the plot: o Visually Linear o Statistically (e.g. regression line by the method of least squares) o correlation coefficient 0.99000 o y-intercept Confidence band (P = 95 %) contains 0 o slope of the regression line o residual sum of squares
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Range: Confirm that the analytical procedure provides an acceptable degree of linearity, accuracy and precision within or at the extremes of the specified range. Minimum specified ranges: o From the reporting level to 120 % of From LOQ or 80 % of MperMax. The reporting level for MperMin to 120 % of cleaning validation reasonably will MperMax be the LOQ. However, the reporting level must be below MperMin and should be below or at 80% of MperMin.
Range: Confirm that the analytical procedure provides an acceptable degree of linearity, accuracy and precision within or at the extremes of the specified range. Minimum specified ranges: o From the reporting level to 120 % of From LOQ or 80 % of MperMax. The reporting level for MperMin to 120 % of cleaning validation reasonably will MperMax be the LOQ. However, the reporting level must be below MperMin and should be below or at 80% of MperMin.
7.3 Sampling Methods In the following some examples for sampling methods are presented. Depending on case-by-case considerations the most suitable method must be chosen. For all methods the sampling points must be fixed in a manner that the true contamination of the equipment will be reflected. Rinse, Wash Solvent Sampling Usually the API equipment will be cleaned by several washing cycles (runs). Sometimes rinsing cycles/runs (e.g. to rinse out the washing solvent) may follow the washing cycles. This section outlines the quantitation of the amount of residue remaining in the equipment after cleaning based on the amount of residue in the last run of the routinely used cleaning procedure. Final rinse / final boil sampling The residue amount in the equipment can be assumed to be equal to the amount of residue in the last wash or rinse solvent portion. The assumption is based on the worst case consideration, that a further washing or rinsing run (or any reaction) would not wash more than the same amount of residue out of the equipment as the analyzed solvent portion did. The advantage of this sampling method is, that the whole equipment will be reached by the solvent, even difficult to reach locations which can not be disassembled (e.g. sealings, slots, condensers, piping). Therefore if appropriately designed this method will probably give the best picture of the amount of residue in the equipment.
7.3 Sampling Methods In the following some examples for sampling methods are presented. Depending on case-by-case considerations the most suitable method must be chosen. For all methods the sampling points must be fixed in a manner that the true contamination of the equipment will be reflected. Rinse, Wash Solvent Sampling Usually the API equipment will be cleaned by several washing cycles (runs). Sometimes rinsing cycles/runs (e.g. to rinse out the washing solvent) may follow the washing cycles. This section outlines the quantitation of the amount of residue remaining in the equipment after cleaning based on the amount of residue in the last run of the routinely used cleaning procedure. Final rinse / final boil sampling The residue amount in the equipment can be assumed to be equal to the amount of residue in the last wash or rinse solvent portion. The assumption is based on the worst case consideration, that a further washing or rinsing run (or any reaction) would not wash more than the same amount of residue out of the equipment as the analyzed solvent portion did. The advantage of this sampling method is, that the whole equipment will be reached by the solvent, even difficult to reach locations which can not be disassembled (e.g. sealings, slots, condensers, piping). Therefore if appropriately designed this method will probably give the best picture of the amount of residue in the equipment.
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For quantitation a solvent sample (e.g. 1 l) is taken, the residue in the sample is determined by a suitable analytical method and the residue in the whole equipment is calculated according to Equation 5. Equation 5: M = V * (C - CB) M V C CB Amount of residue in the cleaned equipment in mg. Volume of the last rinse or wash solvent portion in l. Concentration of impurities in the sample in mg/l. Blank of the cleaning or rinsing solvent in mg/l. If several samples are taken during one run, one and the same blank can be used for all samples provided the same solvent lot was used for the whole run.
For quantitation a solvent sample (e.g. 1 l) is taken, the residue in the sample is determined by a suitable analytical method and the residue in the whole equipment is calculated according to Equation 5. Equation 5: M = V * (C - CB) M V C CB Amount of residue in the cleaned equipment in mg. Volume of the last rinse or wash solvent portion in l. Concentration of impurities in the sample in mg/l. Blank of the cleaning or rinsing solvent in mg/l. If several samples are taken during one run, one and the same blank can be used for all samples provided the same solvent lot was used for the whole run.
Swab sampling During swab sampling usually a small area of the cleaned equipment is swabbed with a pre-defined material and method (swab material, solvent, technique). Subsequently the swab is extracted and the extract examined by a suitable analytical method. Then the quantified residue of the samples is extrapolated to the whole equipment (see Equation 6). It is important: o That the validation of the swab sampling is performed on the same surface (material, polish grade, area in dm2) and with the same materials as the routine sampling of the equipment. o To choose the swabbing material such that its extractable materials do not interfere with the expected residue. o To choose the sampling points such that they represent the worst case spots of the equipment. The disadvantage of this sampling method for the often complex API equipment is, that difficult to reach areas (e.g. sealings, slots, condensers, piping) may not be accessible by swabbing. Nevertheless these areas may be the critical areas for the determination of the amount of residue in the equipment.
Swab sampling During swab sampling usually a small area of the cleaned equipment is swabbed with a pre-defined material and method (swab material, solvent, technique). Subsequently the swab is extracted and the extract examined by a suitable analytical method. Then the quantified residue of the samples is extrapolated to the whole equipment (see Equation 6). It is important: o That the validation of the swab sampling is performed on the same surface (material, polish grade, area in dm2) and with the same materials as the routine sampling of the equipment. o To choose the swabbing material such that its extractable materials do not interfere with the expected residue. o To choose the sampling points such that they represent the worst case spots of the equipment. The disadvantage of this sampling method for the often complex API equipment is, that difficult to reach areas (e.g. sealings, slots, condensers, piping) may not be accessible by swabbing. Nevertheless these areas may be the critical areas for the determination of the amount of residue in the equipment.
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Equation 6:
M = (1 / WF) * (Ftot * (Mi / Fi) / N) = (1 / WF) * (Ftot * ((Ci - CBi) / Fi) / N
Equation 6:
M = (1 / WF) * (Ftot * (Mi / Fi) / N) = (1 / WF) * (Ftot * ((Ci - CBi) / Fi) / N
M WF Ftot Mi Ci CBi
Fi N i
Amount of residue in the cleaned equipment in mg. Recovery rate for the whole chain swab/analytical method (e.g. 0.8 for 80%). The entire inner surface of the equipment in dm2. Amount of residue (e.g. previous product) in the sample i in mg. Gross amount of residue in the sample i in mg. Blank of the sample i in mg. To establish the blank, a swab (or several swabs) can be treated in the similar way as a sampling swab except swabbing of the contaminated surface. Usually one and the same blank can be used for all N sampling swabs. Area swabbed by the swab i in dm2. Number of swab samples. Sample identifier (current number from 1 to N).
M WF Ftot Mi Ci CBi
Fi N i
Amount of residue in the cleaned equipment in mg. Recovery rate for the whole chain swab/analytical method (e.g. 0.8 for 80%). The entire inner surface of the equipment in dm2. Amount of residue (e.g. previous product) in the sample i in mg. Gross amount of residue in the sample i in mg. Blank of the sample i in mg. To establish the blank, a swab (or several swabs) can be treated in the similar way as a sampling swab except swabbing of the contaminated surface. Usually one and the same blank can be used for all N sampling swabs. Area swabbed by the swab i in dm2. Number of swab samples. Sample identifier (current number from 1 to N).
Exceptionally the first production batch (placebo batch) of the following product (or another placebo product) may be sampled and analyzed for impurities (for preceding product). As analytical methods usually chromatographic methods will be used (e.g. HPLC, GC, TLC). Stamps In this exceptionally used sampling method, .coins. (stamps) will be placed on appropriate sampling points in the equipment during the manufacturing of the previous product and during cleaning . After cleaning the contamination of the coins will be analyzed. The overall equipment contamination will be calculated by extrapolation of the coin.s contamination to the whole equipment. For quantitation the coins may be first swabbed and the samples further analysed. 7.4 Analytical Methods A sample isolated by any of the sampling methods (section 7.3) must further be analysed by a suitable analytical method (e.g. HPLC, GC, TLC, dry
Exceptionally the first production batch (placebo batch) of the following product (or another placebo product) may be sampled and analyzed for impurities (for preceding product). As analytical methods usually chromatographic methods will be used (e.g. HPLC, GC, TLC). Stamps In this exceptionally used sampling method, .coins. (stamps) will be placed on appropriate sampling points in the equipment during the manufacturing of the previous product and during cleaning . After cleaning the contamination of the coins will be analyzed. The overall equipment contamination will be calculated by extrapolation of the coin.s contamination to the whole equipment. For quantitation the coins may be first swabbed and the samples further analysed. 7.4 Analytical Methods A sample isolated by any of the sampling methods (section 7.3) must further be analysed by a suitable analytical method (e.g. HPLC, GC, TLC, dry
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residue, TOC, UV, titration, conductivity, pH). The suitability of the method can be documented by appropriate validation as delineated in section 7.2. A combination of analytical methods can be used if appropriate. For example evaporation of the solvent of the samples and analysis of the dry residue by another method (e.g. HPLC) can enhance the sensitivity of the final analytical method by factor 106. Or the use of several methods (e.g. titration, HPLC) can provide the required specificity.
residue, TOC, UV, titration, conductivity, pH). The suitability of the method can be documented by appropriate validation as delineated in section 7.2. A combination of analytical methods can be used if appropriate. For example evaporation of the solvent of the samples and analysis of the dry residue by another method (e.g. HPLC) can enhance the sensitivity of the final analytical method by factor 106. Or the use of several methods (e.g. titration, HPLC) can provide the required specificity.
8.0 CLEANING VALIDATION PROTOCOL

PREPARED BY (DEPT.): ___________DATE:______ REVIEWED BY (DEPT.) : __________DATE:______ APPROVED BY (DEPT.) : __________DATE:______ APPROVED BY (DEPT.) : __________DATE:______ APPROVED BY (DEPT.) : __________DATE:______ TITLE: PROTOCOL NO: _______________________________________
8.0 CLEANING VALIDATION PROTOCOL

PREPARED BY (DEPT.): ___________DATE:______ REVIEWED BY (DEPT.) : __________DATE:______ APPROVED BY (DEPT.) : __________DATE:______ APPROVED BY (DEPT.) : __________DATE:______ APPROVED BY (DEPT.) : __________DATE:______ TITLE: PROTOCOL NO: _______________________________________
PROTOCOL ISSUE DATE:_________________________________ CLEANING SOP REFERENCE AND ISSUE NO.:______________ TABLE OF CONTENTS 8.1 Background 8.2 Purpose 8.3 Scope 8.4 Responsibility 8.5 Sampling procedure 8.6 Testing procedure 8.7 Acceptance criteria 8.8 Deviations
PROTOCOL ISSUE DATE:_________________________________ CLEANING SOP REFERENCE AND ISSUE NO.:______________ TABLE OF CONTENTS 8.1 Background 8.2 Purpose 8.3 Scope 8.4 Responsibility 8.5 Sampling procedure 8.6 Testing procedure 8.7 Acceptance criteria 8.8 Deviations
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8.1 Background Equipment X is routinely cleaned after product Y (or group of products*) according to procedure XXX...... *If group of products describe rational for chosing this grouping strategy. Describe: Equipment. Cleaning method. Cleaning agents.
8.1 Background Equipment X is routinely cleaned after product Y (or group of products*) according to procedure XXX...... *If group of products describe rational for chosing this grouping strategy. Describe: Equipment. Cleaning method. Cleaning agents.
8.2 Purpose The purpose of this study is to demonstrate that remaining product residues previous in a piece of equipment are always within the established acceptance criteria if the equipment is cleaned by a defined cleaning method. 8.3 Scope A visual test and a chemical evaluation of the equipment will be performed after a clean to demonstrate that product residue(s) (active ingredient, intermediates and / or excipients) and cleaning agent residues (exclude solvents used in process) have been removed to levels within the acceptance criteria. The equipment cleanliness will be proven by testing and evaluation of samples in accordance with this protocol from Z* consecutive cleans. (*Z: Generally three consecutive cleans are acceptable, however, companies must determine the number adequate for their operation.) In order for the cleaning procedure to be deemed valid all data generated during the study must be within the acceptance criteria detailed in section 8.7 (page 44) of this protocol. A report will be written assessing the data generated and thus determining the validity of the cleaning process. The equipment must not be used to process another product until clearance indicating that the equipment is adequately clean has been received from the validation department in accordance with process transfer SOP AAA (or detail what ever system is in-place to ensure that equipment is not used).
8.2 Purpose The purpose of this study is to demonstrate that remaining product residues previous in a piece of equipment are always within the established acceptance criteria if the equipment is cleaned by a defined cleaning method. 8.3 Scope A visual test and a chemical evaluation of the equipment will be performed after a clean to demonstrate that product residue(s) (active ingredient, intermediates and / or excipients) and cleaning agent residues (exclude solvents used in process) have been removed to levels within the acceptance criteria. The equipment cleanliness will be proven by testing and evaluation of samples in accordance with this protocol from Z* consecutive cleans. (*Z: Generally three consecutive cleans are acceptable, however, companies must determine the number adequate for their operation.) In order for the cleaning procedure to be deemed valid all data generated during the study must be within the acceptance criteria detailed in section 8.7 (page 44) of this protocol. A report will be written assessing the data generated and thus determining the validity of the cleaning process. The equipment must not be used to process another product until clearance indicating that the equipment is adequately clean has been received from the validation department in accordance with process transfer SOP AAA (or detail what ever system is in-place to ensure that equipment is not used).
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8.4 Responsibility The responsibility for completion of this study lies as follows (for example): Scheduling: Manufacturing, QA, QC and Engineering. Cleaning of equipment: Manufacturing Removal of samples: QA Testing of samples: QC Review of data and approval of study: Validation / Manufacturing / QC 8.5 Sampling Procedure Remove swab and rinse samples from the equipment as detailed in section 7.3 of this guidance document. SWAB SAMPLES: See attached equipment sampling diagram (It is important to show clearly where the sampling locations are). Swab samples should be removed according to swabbing procedure SOP BBB (or if there is no SOP in place describe in the text the validated sampling technique for the QA sampler). The swab sampling locations are as follows: Product residue samples: list of sample locations and no of swabs to be removed. Cleaning agent samples: list of sample locations and no of swabs to be removed. Samples should be removed from the locations on the equipment deemed to be worst case i.e. most difficult to clean locations and therefore where product is most likely to reside if cleaning has not been adequate. It is pertinent that these locations have been determined scientifically and can be rationalised if necessary. RINSE SAMPLES: Rinse samples should be removed according to procedure SOP CCC (or if there is no SOP in place describe the validated sampling technique for the QA sampler). The volume of liquid used to rinse the equipment should be detailed. (volume must be shown to be sufficient to cover all product contact surfaces of the
8.4 Responsibility The responsibility for completion of this study lies as follows (for example): Scheduling: Manufacturing, QA, QC and Engineering. Cleaning of equipment: Manufacturing Removal of samples: QA Testing of samples: QC Review of data and approval of study: Validation / Manufacturing / QC 8.5 Sampling Procedure Remove swab and rinse samples from the equipment as detailed in section 7.3 of this guidance document. SWAB SAMPLES: See attached equipment sampling diagram (It is important to show clearly where the sampling locations are). Swab samples should be removed according to swabbing procedure SOP BBB (or if there is no SOP in place describe in the text the validated sampling technique for the QA sampler). The swab sampling locations are as follows: Product residue samples: list of sample locations and no of swabs to be removed. Cleaning agent samples: list of sample locations and no of swabs to be removed. Samples should be removed from the locations on the equipment deemed to be worst case i.e. most difficult to clean locations and therefore where product is most likely to reside if cleaning has not been adequate. It is pertinent that these locations have been determined scientifically and can be rationalised if necessary. RINSE SAMPLES: Rinse samples should be removed according to procedure SOP CCC (or if there is no SOP in place describe the validated sampling technique for the QA sampler). The volume of liquid used to rinse the equipment should be detailed. (volume must be shown to be sufficient to cover all product contact surfaces of the
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equipment). The volumes of the rinse samples should also be stipulated in the protocol. All sampling details (swab and rinse) should be referenced in Table 1. Samples should then be sent to the QC department for analysis. Any relevant sample transfer conditions should be noted. 8.6 Testing procedure Rinse samples should be tested for: - Product residues in accordance with analytical protocol - Cleaning agent residues in accordance with analytical protocol Swab samples should be tested for: - Product residues in accordance with analytical protocol - Cleaning agent residues in accordance with analytical protocol Note the limits of quantitation and detection as well as the % recovery for the tests being performed. The analytical protocol should include a calculation to convert the amount of residue detected in the sample to 100% (i.e. if the analytical validation results indicate that only 50% of spiked active / cleaning agent is recovered using the swabbing / rinse method of choice, the amount of active cleaning agent recovered per sample should be multiplied by 2 to bring result to 100%). All data generated should be attached to this study and returned to the Validation department where calculations and adherence to acceptance criteria is determined. 8.7 Acceptance criteria o The Visual cleanliness of the equipment must be checked and verified after cleaning according to the procedure xxx: Equipment is visually clean: Signed (manu): ____ Date: _______ Verified (QA?): _____ Date: _______
equipment). The volumes of the rinse samples should also be stipulated in the protocol. All sampling details (swab and rinse) should be referenced in Table 1. Samples should then be sent to the QC department for analysis. Any relevant sample transfer conditions should be noted. 8.6 Testing procedure Rinse samples should be tested for: - Product residues in accordance with analytical protocol - Cleaning agent residues in accordance with analytical protocol Swab samples should be tested for: - Product residues in accordance with analytical protocol - Cleaning agent residues in accordance with analytical protocol Note the limits of quantitation and detection as well as the % recovery for the tests being performed. The analytical protocol should include a calculation to convert the amount of residue detected in the sample to 100% (i.e. if the analytical validation results indicate that only 50% of spiked active / cleaning agent is recovered using the swabbing / rinse method of choice, the amount of active cleaning agent recovered per sample should be multiplied by 2 to bring result to 100%). All data generated should be attached to this study and returned to the Validation department where calculations and adherence to acceptance criteria is determined. 8.7 Acceptance criteria o The Visual cleanliness of the equipment must be checked and verified after cleaning according to the procedure xxx: Equipment is visually clean: Signed (manu): ____ Date: _______ Verified (QA?): _____ Date: _______
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o The swab / rinse sample acceptance criteria for product and cleaning agent residues should be detailed along with a rational for the figures quoted. (Unlike product residues, it is expected that no (or for ultra sensitive analytical test methods - very low), detergent levels remain after cleaning. Detergents are not part of the manufacturing process and are only added to facilitate cleaning. Thus they should be easily removed. Otherwise a different detergent should be selected.) Reference: Please see chapter 5 of this guidance document for examples of calculating acceptance criteria. In addition a sample calculation detailing how the residual levels of active ingredient / cleaning agent for the entire equipment are computed should be given. POINTS TO CONSIDER: Surface area calculations should be performed, verified and kept on file for all equipment evaluated (photos may be incorporated into the protocol to ensure samples are taken from the correct position). Worst case sample residue values can be used to determine the worst case level of contamination on the equipment. (Alternatively, determine what the worst case swab level and use that as the limit.) When the worst case result recorded is less than the limit of quantitation but greater than the limit of detection for the test method, the value denoting the limit of quantitation should be used to perform the calculations. When the worst case result recorded is less than the limit of detection for the test being performed the value denoting the limit of detection should be used to perform the calculations.
o The swab / rinse sample acceptance criteria for product and cleaning agent residues should be detailed along with a rational for the figures quoted. (Unlike product residues, it is expected that no (or for ultra sensitive analytical test methods - very low), detergent levels remain after cleaning. Detergents are not part of the manufacturing process and are only added to facilitate cleaning. Thus they should be easily removed. Otherwise a different detergent should be selected.) Reference: Please see chapter 5 of this guidance document for examples of calculating acceptance criteria. In addition a sample calculation detailing how the residual levels of active ingredient / cleaning agent for the entire equipment are computed should be given. POINTS TO CONSIDER: Surface area calculations should be performed, verified and kept on file for all equipment evaluated (photos may be incorporated into the protocol to ensure samples are taken from the correct position). Worst case sample residue values can be used to determine the worst case level of contamination on the equipment. (Alternatively, determine what the worst case swab level and use that as the limit.) When the worst case result recorded is less than the limit of quantitation but greater than the limit of detection for the test method, the value denoting the limit of quantitation should be used to perform the calculations. When the worst case result recorded is less than the limit of detection for the test being performed the value denoting the limit of detection should be used to perform the calculations.
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TABLE 1: SAMPLE REFERENCE TABLE
TABLE 1: SAMPLE REFERENCE TABLE
sample swab sample swab sample swab sample swab sample swab sample swab sample swab sample swab sample swab sample swab sample sample rinse sample 1 rinse sample 1
to be tested for Active Cleaning agent Active Cleaning agent Active Cleaning agent Active Cleaning agent Active Cleaning agent test for Active Cleaning agent
area swabbed
total surface area (cm2) xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx
sample ref.
signed / date
sample swab sample swab sample swab sample swab sample swab sample swab sample swab sample swab sample swab sample swab sample
to be tested for Active Cleaning agent Active Cleaning agent Active Cleaning agent Active Cleaning agent Active Cleaning agent test for Active Cleaning agent
area swabbed
total surface area (cm2) xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx
sample ref.
signed / date
sample volume
total volume of rinse
sample ref.
signed / date
sample rinse sample 1 rinse sample 1
sample volume
total volume of rinse
sample ref.
signed / date
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8.8 Deviations from protocol Please indicate whether or not Planned/ Unplanned* deviations occurred during the completion of this Validation Protocol and give details of same. ____________________________________________________________________ ____________________________________________________________________ ____________________________________________________________________ ____________________________________________________________________ ____________________________________________________________________ ____________________________________________________________________ Signed: __________________ Verified: _________________ (*please delete as appropriate, If no deviations please delete both)
8.8 Deviations from protocol Please indicate whether or not Planned/ Unplanned* deviations occurred during the completion of this Validation Protocol and give details of same. ____________________________________________________________________ ____________________________________________________________________ ____________________________________________________________________ ____________________________________________________________________ ____________________________________________________________________ ____________________________________________________________________ Signed: __________________ Verified: _________________ (*please delete as appropriate, If no deviations please delete both)
9.0 VALIDATION QUESTIONS

Remarks: References given in this question and answer section refer to the Cleaning Validation Guideline of CEFIC APIC, published on September 6, 1999. (See [1] page 53 - for reference.) Question 1: When should a company validate/ revalidate cleaning procedures? When is validation not required? Advice: Ref. Section 7.0 and 10.0 Companies must look at each situation individually and determine the need for validation. Section 7.0 provides a basic template, which may be used as a starting point in this evaluation. The necessity to revalidate cleaning procedures should be determined under change control parameters - See Section 10.0. If routine verification procedures are used, these should be monitored to ensure that the procedure is in control. Companies may consider a periodic revalidation of cleaning methods, which are subject to variation (i.e. manual procedures etc.), as an additional precaution.
9.0 VALIDATION QUESTIONS

Remarks: References given in this question and answer section refer to the Cleaning Validation Guideline of CEFIC APIC, published on September 6, 1999. (See [1] page 53 - for reference.) Question 1: When should a company validate/ revalidate cleaning procedures? When is validation not required? Advice: Ref. Section 7.0 and 10.0 Companies must look at each situation individually and determine the need for validation. Section 7.0 provides a basic template, which may be used as a starting point in this evaluation. The necessity to revalidate cleaning procedures should be determined under change control parameters - See Section 10.0. If routine verification procedures are used, these should be monitored to ensure that the procedure is in control. Companies may consider a periodic revalidation of cleaning methods, which are subject to variation (i.e. manual procedures etc.), as an additional precaution.
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Question 2: When is it appropriate to use Prospective, Concurrent or Retrospective Validation Advice: Ref. Section 9.0 Retrospective Validation of cleaning is not condoned by regulatory Authorities. Prospective Validation is the ideal method of validation. In situations where very few runs are manufactured in any given period and/or a business decision has been taken to release the next material manufactured after cleaning based on a high level of testing of the equipment (i.e. Validation level,) concurrent release of material may take place. Question 3: What level of testing is needed after cleaning validation? Advice: Ref. Section 8.6 The answer to this question depends on individual situations. Typically, companies perform visual inspection and remove rinse samples as required. A practical approach for monitoring the effectiveness of cleaning after completion of cleaning validation in an effective, scientific sound and inexpensive way is given below: 1.) Visual inspection of the cleaned equipment. Only after this check is considered satisfactory, proceed with the next step. 2.) Take a rinse and/or swab sample (one litre of rinsing liquid is usually required) 3.) Determine the dry residue by evaporating about 500 ml to dryness in a small flask using a rotary evaporator. This unspecific test covers also inorganic salts, known or unknown organic products and will detect the total residues. (this test might be omitted for the drying equipment, in this instance we have a pure API or intermediate and typically no potential for side products, degradation, etc.) 4.) If the result meets the specification, proceed to specific (chromatographic) technique. Start with a TLC-limit test (inexpensive and fast to validate, broad detection range UV and specific derivatisation
Question 2: When is it appropriate to use Prospective, Concurrent or Retrospective Validation Advice: Ref. Section 9.0 Retrospective Validation of cleaning is not condoned by regulatory Authorities. Prospective Validation is the ideal method of validation. In situations where very few runs are manufactured in any given period and/or a business decision has been taken to release the next material manufactured after cleaning based on a high level of testing of the equipment (i.e. Validation level,) concurrent release of material may take place. Question 3: What level of testing is needed after cleaning validation? Advice: Ref. Section 8.6 The answer to this question depends on individual situations. Typically, companies perform visual inspection and remove rinse samples as required. A practical approach for monitoring the effectiveness of cleaning after completion of cleaning validation in an effective, scientific sound and inexpensive way is given below: 1.) Visual inspection of the cleaned equipment. Only after this check is considered satisfactory, proceed with the next step. 2.) Take a rinse and/or swab sample (one litre of rinsing liquid is usually required) 3.) Determine the dry residue by evaporating about 500 ml to dryness in a small flask using a rotary evaporator. This unspecific test covers also inorganic salts, known or unknown organic products and will detect the total residues. (this test might be omitted for the drying equipment, in this instance we have a pure API or intermediate and typically no potential for side products, degradation, etc.) 4.) If the result meets the specification, proceed to specific (chromatographic) technique. Start with a TLC-limit test (inexpensive and fast to validate, broad detection range UV and specific derivatisation
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if these techniques are combined, the method is very specific for the different impurities potentially present in the sample. Apply 2 samples: the last washing liquid (to see all potential residues), the rinsing liquid (to look for the residue) and two standards: one of the suspected residual product at a concentration that is the limit accepted, and a 1:2 dilution of the standard. If the main spot in the rinsing liquid has lower intensity than the standard, the equipment is clean. The second standard is for confirmation of detection. 5.) If TLC is not the appropriate technique, revert to HPLC or GC. Question 4: What critical parameters need to be looked at during cleaning validation? Advice: Ref. Section 8.2 for details It is vital that the equipment design is evaluated in detail in conjunction with the product residues to be removed, the available cleaning agents and the cleaning techniques. Also the ruggedness and reproducibility of the cleaning method should be covered. Question 5: What number of cleans should be run in order to validate a cleaning procedure? Advice: Ref. Section 9.0 A validation program generally encompasses three consecutive successful replicates. However, companies should evaluate each situation individually. Question 6: Is it acceptable for a validated cleaning procedure to be continued until the analytical results demonstrate it is clean? Advice: Regulatory authorities do not condone this practice. Question 7: Is it necessary for companies to validate a maximum time allowed for a piece of equipment to be dirty before cleaning? Advice: Companies should have SOPs in place, which require cleaning to be performed immediately after production has stopped. This scenario should be validated.
if these techniques are combined, the method is very specific for the different impurities potentially present in the sample. Apply 2 samples: the last washing liquid (to see all potential residues), the rinsing liquid (to look for the residue) and two standards: one of the suspected residual product at a concentration that is the limit accepted, and a 1:2 dilution of the standard. If the main spot in the rinsing liquid has lower intensity than the standard, the equipment is clean. The second standard is for confirmation of detection. 5.) If TLC is not the appropriate technique, revert to HPLC or GC. Question 4: What critical parameters need to be looked at during cleaning validation? Advice: Ref. Section 8.2 for details It is vital that the equipment design is evaluated in detail in conjunction with the product residues to be removed, the available cleaning agents and the cleaning techniques. Also the ruggedness and reproducibility of the cleaning method should be covered. Question 5: What number of cleans should be run in order to validate a cleaning procedure? Advice: Ref. Section 9.0 A validation program generally encompasses three consecutive successful replicates. However, companies should evaluate each situation individually. Question 6: Is it acceptable for a validated cleaning procedure to be continued until the analytical results demonstrate it is clean? Advice: Regulatory authorities do not condone this practice. Question 7: Is it necessary for companies to validate a maximum time allowed for a piece of equipment to be dirty before cleaning? Advice: Companies should have SOPs in place, which require cleaning to be performed immediately after production has stopped. This scenario should be validated.
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However, if for some reason immediate cleaning is not always possible, companies should consider the effect of time on the material deposited on the equipment. It may be possible to Group or Bracket products, and validate a worst case scenario. Question 8: Is it necessary for companies to validate a maximum time allowed for a piece of equipment to be left clean before re-use? Advice: Companies should have SOPs in place to ensure that pieces of equipment are adequately protected from any contamination after cleaning has taken place i.e. ensure that the equipment is adequately covered, closed from dust etc. If the company feels that there is any risk of contamination during idle time after cleaning, validation should be considered. Question 9: Is it necessary to establish time limits for cleaning if equipment is not used frequently? Advice: Please see previous advice to question 8. Question 10: What is the maximum time allowed after cleaning with water as last rinse? Advice: Equipment should not be left with water in it after cleaning. The last step of the cleaning procedure involve drying with solvent or flushing with Nitrogen, thus ensuring that there is no opportunity for microbial growth. Question 11: Is it possible that a deterioration of equipment may take place over time, thus invalidating the original validation results Advice: Materials used to manufacture equipment for the pharmaceutical/ chemical industry is of a very high standard. However, equipment materials used should be evaluated to ensure their durability over time as part of the preventative maintenance programme. The possibility of surface roughness and any possible effects that it may have on cleaning should be considered. Companies employing verification methods after validation should monitor analytical data generated as part of this process.
However, if for some reason immediate cleaning is not always possible, companies should consider the effect of time on the material deposited on the equipment. It may be possible to Group or Bracket products, and validate a worst case scenario. Question 8: Is it necessary for companies to validate a maximum time allowed for a piece of equipment to be left clean before re-use? Advice: Companies should have SOPs in place to ensure that pieces of equipment are adequately protected from any contamination after cleaning has taken place i.e. ensure that the equipment is adequately covered, closed from dust etc. If the company feels that there is any risk of contamination during idle time after cleaning, validation should be considered. Question 9: Is it necessary to establish time limits for cleaning if equipment is not used frequently? Advice: Please see previous advice to question 8. Question 10: What is the maximum time allowed after cleaning with water as last rinse? Advice: Equipment should not be left with water in it after cleaning. The last step of the cleaning procedure involve drying with solvent or flushing with Nitrogen, thus ensuring that there is no opportunity for microbial growth. Question 11: Is it possible that a deterioration of equipment may take place over time, thus invalidating the original validation results Advice: Materials used to manufacture equipment for the pharmaceutical/ chemical industry is of a very high standard. However, equipment materials used should be evaluated to ensure their durability over time as part of the preventative maintenance programme. The possibility of surface roughness and any possible effects that it may have on cleaning should be considered. Companies employing verification methods after validation should monitor analytical data generated as part of this process.
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Question 12: If a company has validated a worst case scenario (grouping or bracketing regime), should they also need to validate a less worst case? Advice: When grouping products and determining worst case situation scenario for validation, companies should determine whether or not the worst case being validated is one, which is appropriate for routine manufacture. For operational reasons it may be beneficial to validate a .less. stringent cleaning procedure for some products. Question 13: In a case of a dedicated plant with no degradants, is there a need to validate? Advice: Ref. Section 7.0 Companies should consider each situation individually and validate where there is a potential for contamination. In the above situation, there may not be a need. However, consideration should be given to the number of runs being performed prior to full cleaning. Question 14: Should cleaning validation be part of a development programme? Advice: While it is not a requirement of ICH that cleaning validation be performed during development phase the following should be considered: If the equipment being cleaned after the development product in question is used to manufacture commercial product, it is essential to verify the appropriate cleanliness of the equipment prior to re-use. Development of the Cleaning procedure for the product should take place at development phase for validation when the product becomes commercially available. Question 15: Is it necessary to include microbiological testing / aspects in the cleaning validation programme? Advice: Ref. Section 8.1 Yes, if the following product needs to have a low microbiological load, also depending on the cleaning agent used, if there is any risk for
Question 12: If a company has validated a worst case scenario (grouping or bracketing regime), should they also need to validate a less worst case? Advice: When grouping products and determining worst case situation scenario for validation, companies should determine whether or not the worst case being validated is one, which is appropriate for routine manufacture. For operational reasons it may be beneficial to validate a .less. stringent cleaning procedure for some products. Question 13: In a case of a dedicated plant with no degradants, is there a need to validate? Advice: Ref. Section 7.0 Companies should consider each situation individually and validate where there is a potential for contamination. In the above situation, there may not be a need. However, consideration should be given to the number of runs being performed prior to full cleaning. Question 14: Should cleaning validation be part of a development programme? Advice: While it is not a requirement of ICH that cleaning validation be performed during development phase the following should be considered: If the equipment being cleaned after the development product in question is used to manufacture commercial product, it is essential to verify the appropriate cleanliness of the equipment prior to re-use. Development of the Cleaning procedure for the product should take place at development phase for validation when the product becomes commercially available. Question 15: Is it necessary to include microbiological testing / aspects in the cleaning validation programme? Advice: Ref. Section 8.1 Yes, if the following product needs to have a low microbiological load, also depending on the cleaning agent used, if there is any risk for
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microbiological contamination of the subsequent product (e.g. if water is used for final cleaning). Question 16: Which analytical methods should be used in cleaning validation studies (is only HPLC - testing acceptable?) and to which extend should these methods be validated? Advice: Ref. Section 7.0 of this Guidance on Aspects Document Any analytical method suitable for its intended use could be used. In general limit tests are performed in cleaning validation studies which result in less stringent validation requirements. (as outlined in ICH-Q2A and Q2B). However, if a company decides to validate analytical methods, suitable for the determination of the residue over a certain range (e.g. decaycurve, to prove the success of cleaning during proceeding of a defined cleaning procedure consisting of individual cleaning steps) also less stringent validation requirements for e.g. linearity and accuracy could be established compared with figures typically required in the validation of API release testing methods. Question 17: Do we have to wait for swap and rinse samples to be approved prior using the equipment for production? Advice: During cleaning validation studies it is recommended to wait for completion of all planned tests prior to release equipment for further use (to be able to perform an investigation if tests fail). In routine operations (after validation has been completed) the release of equipment pending testing results (verification, monitoring status of the tests) could be done. Responsibilities and circumstances for using equipment pending release should be defined within the company.
microbiological contamination of the subsequent product (e.g. if water is used for final cleaning). Question 16: Which analytical methods should be used in cleaning validation studies (is only HPLC - testing acceptable?) and to which extend should these methods be validated? Advice: Ref. Section 7.0 of this Guidance on Aspects Document Any analytical method suitable for its intended use could be used. In general limit tests are performed in cleaning validation studies which result in less stringent validation requirements. (as outlined in ICH-Q2A and Q2B). However, if a company decides to validate analytical methods, suitable for the determination of the residue over a certain range (e.g. decaycurve, to prove the success of cleaning during proceeding of a defined cleaning procedure consisting of individual cleaning steps) also less stringent validation requirements for e.g. linearity and accuracy could be established compared with figures typically required in the validation of API release testing methods. Question 17: Do we have to wait for swap and rinse samples to be approved prior using the equipment for production? Advice: During cleaning validation studies it is recommended to wait for completion of all planned tests prior to release equipment for further use (to be able to perform an investigation if tests fail). In routine operations (after validation has been completed) the release of equipment pending testing results (verification, monitoring status of the tests) could be done. Responsibilities and circumstances for using equipment pending release should be defined within the company.
10.0 REFERENCES
Bracketing and Worst Case Rating 1. USP 24, The United States Pharmacopoeia, United States Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, MD 20852.
10.0 REFERENCES
Bracketing and Worst Case Rating 1. USP 24, The United States Pharmacopoeia, United States Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, MD 20852.
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2. Casarett and Doull; .Toxicology - The Basic Science of Poisons.; Macmillan Publishing Co, Inc. New York, Ed.2; 1980. 3. William E. Hall, Ph.D., Hall & Associates, Validation of Cleaning Processes for Bulk Pharmaceutical Chemical Processes, Journal of Validation Technology. Determination of the Amount of Residue 1. PIC PH I/96, in .Pharm. Ind. 58, Nr. 4 (1996); Draft API GMP Guide, PIC, Geneva September .97; Guide to Inspections Validation of Cleaning Processes, FDA, 93; Draft Guidance for Industry Manufacturing, Processing, or Holding API, FDA, April 98. 2. Validation of Analytical Procedures: Q2A, Definitions and Terminology, ICH, October 1994; Q2B, Methodology, ICH, November 1996. Validation Questions 1. Cleaning Validation in Active Pharmaceutical Ingredient Manufacturing Plants, CEFIC-APIC, September 6, 1999.
2. Casarett and Doull; .Toxicology - The Basic Science of Poisons.; Macmillan Publishing Co, Inc. New York, Ed.2; 1980. 3. William E. Hall, Ph.D., Hall & Associates, Validation of Cleaning Processes for Bulk Pharmaceutical Chemical Processes, Journal of Validation Technology. Determination of the Amount of Residue 1. PIC PH I/96, in .Pharm. Ind. 58, Nr. 4 (1996); Draft API GMP Guide, PIC, Geneva September .97; Guide to Inspections Validation of Cleaning Processes, FDA, 93; Draft Guidance for Industry Manufacturing, Processing, or Holding API, FDA, April 98. 2. Validation of Analytical Procedures: Q2A, Definitions and Terminology, ICH, October 1994; Q2B, Methodology, ICH, November 1996. Validation Questions 1. Cleaning Validation in Active Pharmaceutical Ingredient Manufacturing Plants, CEFIC-APIC, September 6, 1999.
11.0 GLOSSARY
Ai Area for the tested piece of equipment # i. CO True (measured) total quantity of substance (possible carryover) on the cleaned surface in contact with the product, calculated from results of swab tests. CONC Concentration (kg/kg or ppm) of previous substance in the next batch. Based on MACO calculated from therapeutic doses and/or tox data. LD50 Lethal Dose 50 in g/kg animal. The identification of the animal (mouse rat etc.) and the way of entry (IV, oral etc.) is important. LOD Limit of detection. LOQ Limit of quantification. mi Quantity (in weight/area) for each swab per area of swabbed surface (normally 1 dm2).
11.0 GLOSSARY
Ai Area for the tested piece of equipment # i. CO True (measured) total quantity of substance (possible carryover) on the cleaned surface in contact with the product, calculated from results of swab tests. CONC Concentration (kg/kg or ppm) of previous substance in the next batch. Based on MACO calculated from therapeutic doses and/or tox data. LD50 Lethal Dose 50 in g/kg animal. The identification of the animal (mouse rat etc.) and the way of entry (IV, oral etc.) is important. LOD Limit of detection. LOQ Limit of quantification. mi Quantity (in weight/area) for each swab per area of swabbed surface (normally 1 dm2).
MACO Maximum Allowable Carryover: acceptable transferred amount from the investigated product (previous). MACOppm Maximum Allowable Carryover: acceptable transferred amount from the investigated product (previous). Calculated from general ppm limit. MAXCONC General limit for maximum allowed concentration (kg/kg or ppm) of previous substance in the next batch. MBS Minimum batch size for the next product(s) (where MACO can end up). NOEL No Observed Effect Level. Rinsing cycle Sometimes rinsing cycles/runs may follow the washing cycles. The rinsing cycles may be part of the routine cleaning procedure (e.g. to rinse out the washing solvent) or may be used for sampling purposes (e.g. rinsing with water after washing with detergents). Rinsing cycles that are not part of the routine cleaning procedure may be used for enhanced sampling during the cleaning validation exercise. SF Safety factor. Srel Relative standard deviation, coefficient of variation. TDDnext Standard therapeutic dose of the daily dose for the next product. TDDprevious Standard therapeutic dose of the investigated product (in the same dosage form as TDDnext). Washing cycle Usually the API equipment will be washed through with several portions of solvent one after the other by the same repeated process. One cleaning process repetition with one of these portions is termed washing cycle (run).
MACO Maximum Allowable Carryover: acceptable transferred amount from the investigated product (previous). MACOppm Maximum Allowable Carryover: acceptable transferred amount from the investigated product (previous). Calculated from general ppm limit. MAXCONC General limit for maximum allowed concentration (kg/kg or ppm) of previous substance in the next batch. MBS Minimum batch size for the next product(s) (where MACO can end up). NOEL No Observed Effect Level. Rinsing cycle Sometimes rinsing cycles/runs may follow the washing cycles. The rinsing cycles may be part of the routine cleaning procedure (e.g. to rinse out the washing solvent) or may be used for sampling purposes (e.g. rinsing with water after washing with detergents). Rinsing cycles that are not part of the routine cleaning procedure may be used for enhanced sampling during the cleaning validation exercise. SF Safety factor. Srel Relative standard deviation, coefficient of variation. TDDnext Standard therapeutic dose of the daily dose for the next product. TDDprevious Standard therapeutic dose of the investigated product (in the same dosage form as TDDnext). Washing cycle Usually the API equipment will be washed through with several portions of solvent one after the other by the same repeated process. One cleaning process repetition with one of these portions is termed washing cycle (run).
GUIDANCE FOR INDUSTRY
GUIDANCE FOR INDUSTRY
Analytical Procedures and Methods Validation

Chemistry, Manufacturing, and Controls Documentation

Chemistry, Manufacturing, and Controls Documentation
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) August 2000
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) August 2000

This draft guidance1, when finalized, will represent the Food and Drug Administrations current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes, regulations, or both.

This draft guidance1, when finalized, will represent the Food and Drug Administrations current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes, regulations, or both.
I. INTRODUCTION
This guidance provides recommendations to applicants on submitting analytical procedures2, validation data, and samples to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products3. This guidance is intended to assist applicants in assembling information, submitting samples, and presenting data to support analytical methodologies. The recommendations apply to drug substances and drug products covered in new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), product license applications (PLAs), and supplements to these applications4. The principles also apply to drug substances and drug products covered in Type II drug master files (DMFs). If a different approach is chosen, the applicant is encouraged to discuss the matter in advance with the center with product jurisdiction to prevent the expenditure of resources on preparing a submission that may later be determined to be unacceptable.
1
I. INTRODUCTION
This guidance provides recommendations to applicants on submitting analytical procedures2, validation data, and samples to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products3. This guidance is intended to assist applicants in assembling information, submitting samples, and presenting data to support analytical methodologies. The recommendations apply to drug substances and drug products covered in new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), product license applications (PLAs), and supplements to these applications4. The principles also apply to drug substances and drug products covered in Type II drug master files (DMFs). If a different approach is chosen, the applicant is encouraged to discuss the matter in advance with the center with product jurisdiction to prevent the expenditure of resources on preparing a submission that may later be determined to be unacceptable.
1
This guidance has been prepared by the Analytical Methods Technical Committee of the Chemistry, Manufacturing, and Controls Coordinating Committee (CMC CC) in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration (FDA).
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This guidance has been prepared by the Analytical Methods Technical Committee of the Chemistry, Manufacturing, and Controls Coordinating Committee (CMC CC) in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration (FDA).
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Analytical procedure is interchangeable with method or test procedure .
Analytical procedure is interchangeable with method or test procedure .
The terms drug substance and drug product, as used in this guidance, refer to human drugs and biologics.
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The terms drug substance and drug product, as used in this guidance, refer to human drugs and biologics.
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Sponsors preparing investigational new drug applications (INDs) should also consider the recommendations in this guidance. However, the amount and depth of the information that should be submitted to support an IND depends in large part on the phase of the investigation and the specific testing proposed in humans (see section V).
Sponsors preparing investigational new drug applications (INDs) should also consider the recommendations in this guidance. However, the amount and depth of the information that should be submitted to support an IND depends in large part on the phase of the investigation and the specific testing proposed in humans (see section V).
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The principles of methods validation described in this guidance apply to all types of analytical procedures. However, the specific recommendations in this guidance may not be applicable to certain unique analytical procedures for products such as biological, biotechnological, botanical, or radiopharmaceutical drugs. For example, many bioassays are based on animal challenge models, immunogenicity assessments, or other immunoassays that have unique features that should be considered when submitting analytical procedure and methods validation information. Furthermore, specific recommendations for biological and immunochemical tests that may be necessary for characterization and quality control of many drug substances and drug products are beyond the scope of this guidance document. Although this guidance does not specifically address the submission of analytical procedures and validation data for raw materials, intermediates, excipients, container closure components, and other materials used in the production of drug substances and drug products, validated analytical procedures should be used to analyze these materials. For questions on appropriate validation approaches for analytical procedures or submission of information not addressed in this guidance, applicants should consult with the appropriate chemistry review staff at FDA. This guidance, when finalized, will replace the FDA guidance for industry on Submitting Samples and Analytical Data for Methods Validation (February 1987).
The principles of methods validation described in this guidance apply to all types of analytical procedures. However, the specific recommendations in this guidance may not be applicable to certain unique analytical procedures for products such as biological, biotechnological, botanical, or radiopharmaceutical drugs. For example, many bioassays are based on animal challenge models, immunogenicity assessments, or other immunoassays that have unique features that should be considered when submitting analytical procedure and methods validation information. Furthermore, specific recommendations for biological and immunochemical tests that may be necessary for characterization and quality control of many drug substances and drug products are beyond the scope of this guidance document. Although this guidance does not specifically address the submission of analytical procedures and validation data for raw materials, intermediates, excipients, container closure components, and other materials used in the production of drug substances and drug products, validated analytical procedures should be used to analyze these materials. For questions on appropriate validation approaches for analytical procedures or submission of information not addressed in this guidance, applicants should consult with the appropriate chemistry review staff at FDA. This guidance, when finalized, will replace the FDA guidance for industry on Submitting Samples and Analytical Data for Methods Validation (February 1987).
II. BACKGROUND
Each NDA and ANDA must include the analytical procedures necessary to ensure the identity, strength, quality, purity, and potency of the drug substance and drug product, including bioavailability of the drug product (21 CFR 314.50(d)(1) and 314.94(a)(9)(i)). Data must be available to establish that the analytical procedures used in testing meet proper standards of accuracy and reliability (21 CFR 211.165(e) and 211.194(a)(2)). Methods validation is the process of demonstrating that analytical procedures are suitable for their intended use. The methods validation process for analytical procedures begins with the planned and systematic collection by the applicant of the validation data to support the analytical procedures. The review chemist evaluates the analytical procedures and validation data submitted in the NDA or ANDA. On request from FDA, an
II. BACKGROUND
Each NDA and ANDA must include the analytical procedures necessary to ensure the identity, strength, quality, purity, and potency of the drug substance and drug product, including bioavailability of the drug product (21 CFR 314.50(d)(1) and 314.94(a)(9)(i)). Data must be available to establish that the analytical procedures used in testing meet proper standards of accuracy and reliability (21 CFR 211.165(e) and 211.194(a)(2)). Methods validation is the process of demonstrating that analytical procedures are suitable for their intended use. The methods validation process for analytical procedures begins with the planned and systematic collection by the applicant of the validation data to support the analytical procedures. The review chemist evaluates the analytical procedures and validation data submitted in the NDA or ANDA. On request from FDA, an
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NDA or ANDA applicant must submit samples of drug product, drug substance, noncompendial reference standards, and blanks so that the applicants drug substance and drug product analytical procedures can be evaluated by FDA laboratories (21 CFR 314.50(e) and 314.94(a)(10)). The FDA laboratory analysis demonstrates that the analytical procedures are reproducible by laboratory testing. The review chemists and laboratory analysts determine the suitability of the analytical procedures for regulatory purposes. FDA investigators inspect the analytical laboratory testing sites to ensure that the analytical procedures used for release and stability testing comply with current good manufacturing practices (CGMPs) (21 CFR part 211) or good laboratory practices (GLPs) (21 CFR part 58), as appropriate. Each BLA and PLA must include a full description of the manufacturing methods, including analytical procedures, that demonstrate that the manufactured product meets prescribed standards of safety, purity, and potency (21 CFR 601.2(a) and 601.2(c)(1)(iv)). Data must be available to establish that the analytical procedures used in testing meet proper standards of accuracy and reliability (21 CFR 211.194(a)(2)). For BLAs, PLAs, and their supplements, the analytical procedures and their validation are submitted as part of the license application or supplement and are evaluated by the review committee. Representative samples of the product must be submitted and summaries of results of tests performed on the lots represented by the submitted sample must be provided (21 CFR 601.2(a) and 601.2(c)(1)(vi)). The review committee chair may request analytical testing by CBER laboratory analysts to evaluate the applicant=s analytical procedures and verify the test results. All analytical procedures are of equal importance from a validation perspective. In general, validated analytical procedures should be used, irrespective of whether they are for in-process, release, acceptance, or stability testing. Each quantitative analytical procedure should be designed to minimize assay variation. Analytical procedures and validation data are submitted in the sections of the application on analytical procedures and controls. Recommendations on information to be submitted are included in sections III through IX and XI of this guidance. Information on submission of the methods validation package to the NDA or ANDA and samples to the FDA laboratories is provided in section X.
NDA or ANDA applicant must submit samples of drug product, drug substance, noncompendial reference standards, and blanks so that the applicants drug substance and drug product analytical procedures can be evaluated by FDA laboratories (21 CFR 314.50(e) and 314.94(a)(10)). The FDA laboratory analysis demonstrates that the analytical procedures are reproducible by laboratory testing. The review chemists and laboratory analysts determine the suitability of the analytical procedures for regulatory purposes. FDA investigators inspect the analytical laboratory testing sites to ensure that the analytical procedures used for release and stability testing comply with current good manufacturing practices (CGMPs) (21 CFR part 211) or good laboratory practices (GLPs) (21 CFR part 58), as appropriate. Each BLA and PLA must include a full description of the manufacturing methods, including analytical procedures, that demonstrate that the manufactured product meets prescribed standards of safety, purity, and potency (21 CFR 601.2(a) and 601.2(c)(1)(iv)). Data must be available to establish that the analytical procedures used in testing meet proper standards of accuracy and reliability (21 CFR 211.194(a)(2)). For BLAs, PLAs, and their supplements, the analytical procedures and their validation are submitted as part of the license application or supplement and are evaluated by the review committee. Representative samples of the product must be submitted and summaries of results of tests performed on the lots represented by the submitted sample must be provided (21 CFR 601.2(a) and 601.2(c)(1)(vi)). The review committee chair may request analytical testing by CBER laboratory analysts to evaluate the applicant=s analytical procedures and verify the test results. All analytical procedures are of equal importance from a validation perspective. In general, validated analytical procedures should be used, irrespective of whether they are for in-process, release, acceptance, or stability testing. Each quantitative analytical procedure should be designed to minimize assay variation. Analytical procedures and validation data are submitted in the sections of the application on analytical procedures and controls. Recommendations on information to be submitted are included in sections III through IX and XI of this guidance. Information on submission of the methods validation package to the NDA or ANDA and samples to the FDA laboratories is provided in section X.
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III. TYPES OF ANALYTICAL PROCEDURES

A. Regulatory Analytical Procedure A regulatory analytical procedure is the analytical procedure used to evaluate a defined characteristic of the drug substance or drug product. The analytical procedures in the U.S. Pharmacopeia/National Formulary (USP/NF) are those legally recognized under section 501(b) of the Food, Drug, and Cosmetic Act (the Act) as the regulatory analytical procedures for compendial items. For purposes of determining compliance with the Act, the regulatory analytical procedure is used. B. Alternative Analytical Procedure An alternative analytical procedure is an analytical procedure proposed by the applicant for use instead of the regulatory analytical procedure. A validated alternative analytical procedure should be submitted only if it is shown to perform equal to or better than the regulatory analytical procedure. If an alternative analytical procedure is submitted, the applicant should provide a rationale for its inclusion and identify its use (e.g., release, stability testing), validation data, and comparative data to the regulatory analytical procedure. C. Stability-Indicating Assay A stability-indicating assay is a validated quantitative analytical procedure that can detect he changes with time in the pertinent properties of the drug substance and drug product. A stability-indicating assay accurately measures the active ingredients, without interference from degradation products, process impurities, excipients, or other potential impurities. If an applicant submits a non-stability-indicating analytical procedure for release testing, then an analytical procedure capable of qualitatively and quantitatively monitoring the impurities, including degradation products, should complement it. Assay analytical procedures for stability studies should be stability-indicating, unless scientifically justified.
III. TYPES OF ANALYTICAL PROCEDURES

A. Regulatory Analytical Procedure A regulatory analytical procedure is the analytical procedure used to evaluate a defined characteristic of the drug substance or drug product. The analytical procedures in the U.S. Pharmacopeia/National Formulary (USP/NF) are those legally recognized under section 501(b) of the Food, Drug, and Cosmetic Act (the Act) as the regulatory analytical procedures for compendial items. For purposes of determining compliance with the Act, the regulatory analytical procedure is used. B. Alternative Analytical Procedure An alternative analytical procedure is an analytical procedure proposed by the applicant for use instead of the regulatory analytical procedure. A validated alternative analytical procedure should be submitted only if it is shown to perform equal to or better than the regulatory analytical procedure. If an alternative analytical procedure is submitted, the applicant should provide a rationale for its inclusion and identify its use (e.g., release, stability testing), validation data, and comparative data to the regulatory analytical procedure. C. Stability-Indicating Assay A stability-indicating assay is a validated quantitative analytical procedure that can detect he changes with time in the pertinent properties of the drug substance and drug product. A stability-indicating assay accurately measures the active ingredients, without interference from degradation products, process impurities, excipients, or other potential impurities. If an applicant submits a non-stability-indicating analytical procedure for release testing, then an analytical procedure capable of qualitatively and quantitatively monitoring the impurities, including degradation products, should complement it. Assay analytical procedures for stability studies should be stability-indicating, unless scientifically justified.
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IV. REFERENCE STANDARDS

A. Types of Standards A reference standard (i.e., primary standard) may be obtained from the USP/NF or other official sources (e.g., CBER, 21 CFR 610.20). If there are questions on whether a source of a standard would be considered by FDA to be an official source, applicants should contact the appropriate chemistry review staff. When there is no official source, a reference standard should be of the highest possible purity and be fully characterized. A working standard (i.e., in-house or secondary standard) is a standard that is qualified against and used instead of the reference standard. B. Certificate of Analysis A certificate of analysis (COA) for reference standards from non-official sources should be submitted in the section of the application on analytical procedures and controls. For standards from official sources, the user should ensure the suitability of the reference standard. The standard should be stored correctly and used within the established use interval. C. Characterization of a Reference Standard Reference standards from USP/NF and other official sources do not require further characterization. A reference standard that is not obtained from an official source should be of the highest purity that can be obtained by reasonable effort, and it should be thoroughly characterized to ensure its identity, strength, quality, purity, and potency. The qualitative and quantitative analytical procedures used to characterize a reference standard are expected to be different from, and more extensive than, those used to control the identity, strength, quality, purity, and potency of the drug substance or the drug product. Analytical procedures used to characterize a reference standard should not rely solely on comparison testing to a previously designated reference standard. Generally, this characterization information should include: O A brief description of the manufacture of the reference standard, if the manufacturing process differs from that of the drug substance. Any
IV. REFERENCE STANDARDS

A. Types of Standards A reference standard (i.e., primary standard) may be obtained from the USP/NF or other official sources (e.g., CBER, 21 CFR 610.20). If there are questions on whether a source of a standard would be considered by FDA to be an official source, applicants should contact the appropriate chemistry review staff. When there is no official source, a reference standard should be of the highest possible purity and be fully characterized. A working standard (i.e., in-house or secondary standard) is a standard that is qualified against and used instead of the reference standard. B. Certificate of Analysis A certificate of analysis (COA) for reference standards from non-official sources should be submitted in the section of the application on analytical procedures and controls. For standards from official sources, the user should ensure the suitability of the reference standard. The standard should be stored correctly and used within the established use interval. C. Characterization of a Reference Standard Reference standards from USP/NF and other official sources do not require further characterization. A reference standard that is not obtained from an official source should be of the highest purity that can be obtained by reasonable effort, and it should be thoroughly characterized to ensure its identity, strength, quality, purity, and potency. The qualitative and quantitative analytical procedures used to characterize a reference standard are expected to be different from, and more extensive than, those used to control the identity, strength, quality, purity, and potency of the drug substance or the drug product. Analytical procedures used to characterize a reference standard should not rely solely on comparison testing to a previously designated reference standard. Generally, this characterization information should include: O A brief description of the manufacture of the reference standard, if the manufacturing process differs from that of the drug substance. Any
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additional purification procedures used in the preparation of the reference standard should be described. O Legible reproductions of the relevant spectra, chromatograms, thin-layer chromatogram (TLC) photographs or reproductions, and other appropriate instrumental recordings. O Data establishing purity. The data should be obtained by using appropriate tests, such as TLC, gas chromatography (GC), high-pressure liquid chromatography (HPLC), phase solubility analysis, appropriate thermometric analytical procedures, and others as necessary. O Appropriate chemical attribute information, such as structural formula, empirical formula, and molecular weight. Information to substantiate the proof of structure should include appropriate analytical tests, such as elemental analysis, infrared spectrophotometry (IR), ultraviolet spectrophotometry (UV), nuclear magnetic resonance spectroscopy (NMR), and mass spectrometry (MS), as well as applicable functional group analysis. Detailed interpretation of the test data in support of the claimed structure should be provided. O A physical description of the material, including its color and physical form. O Appropriate physical constants such as melting range, boiling range, refractive index, dissociation constants (pK values), and optical rotation. O A detailed description of the analytical procedures used to characterize the reference standard. For biotechnological/biological product reference standards, the recommendations on characterization information above may apply and should be considered. However, additional and/or different tests would be important to assess physicochemical characteristics, structural characteristics, biological activity, and/or immunochemical activity. Physicochemical determinations may include isoform, electrophoretic, and liquid chromatographic patterns, as well as spectroscopic profiles. Structural characterization may include a determination of amino acid sequence, amino acid composition, peptide map, and carbohydrate structure.
additional purification procedures used in the preparation of the reference standard should be described. O Legible reproductions of the relevant spectra, chromatograms, thin-layer chromatogram (TLC) photographs or reproductions, and other appropriate instrumental recordings. O Data establishing purity. The data should be obtained by using appropriate tests, such as TLC, gas chromatography (GC), high-pressure liquid chromatography (HPLC), phase solubility analysis, appropriate thermometric analytical procedures, and others as necessary. O Appropriate chemical attribute information, such as structural formula, empirical formula, and molecular weight. Information to substantiate the proof of structure should include appropriate analytical tests, such as elemental analysis, infrared spectrophotometry (IR), ultraviolet spectrophotometry (UV), nuclear magnetic resonance spectroscopy (NMR), and mass spectrometry (MS), as well as applicable functional group analysis. Detailed interpretation of the test data in support of the claimed structure should be provided. O A physical description of the material, including its color and physical form. O Appropriate physical constants such as melting range, boiling range, refractive index, dissociation constants (pK values), and optical rotation. O A detailed description of the analytical procedures used to characterize the reference standard. For biotechnological/biological product reference standards, the recommendations on characterization information above may apply and should be considered. However, additional and/or different tests would be important to assess physicochemical characteristics, structural characteristics, biological activity, and/or immunochemical activity. Physicochemical determinations may include isoform, electrophoretic, and liquid chromatographic patterns, as well as spectroscopic profiles. Structural characterization may include a determination of amino acid sequence, amino acid composition, peptide map, and carbohydrate structure.
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Biological and/or immunochemical activity should be assessed using the same analytical procedures used to determine product potency. These can include animal-based, cell culture based, biochemical, or ligand/receptorbinding assays. While these tests may be needed for complete characterization of certain reference standards, specific recommendations for validation of biological and immunochemical tests are not contained in this guidance document.
Biological and/or immunochemical activity should be assessed using the same analytical procedures used to determine product potency. These can include animal-based, cell culture based, biochemical, or ligand/receptorbinding assays. While these tests may be needed for complete characterization of certain reference standards, specific recommendations for validation of biological and immunochemical tests are not contained in this guidance document.
V. METHODS VALIDATION FOR INDS

For an investigational new drug, sufficient information is required in each phase of an investigation to ensure proper identification, quality, purity, strength, and/or potency. The amount of information on analytical procedures and methods validation necessary will vary with the phase of the investigation (21 CFR 312.23(a)(7)). For general guidance on analytical procedures and methods validation information to be submitted for phase 1 studies, sponsors should refer to the FDA guidance for industry on Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products (November 1995). General guidance regarding analytical procedures and methods validation information to be submitted for phase 2 or phase 3 studies will be provided in the FDA guidance for industry INDs for Phase 2 and 3 Studies of Drugs, Including Specified Therapeutic BiotechnologyDerived Products, Chemistry, Manufacturing, and Controls Content and Format, when finalized (draft guidance published April 1999). All analytical procedures should be fully developed and validation completed when the NDA, ANDA, BLA, or PLA is submitted.
V. METHODS VALIDATION FOR INDS

For an investigational new drug, sufficient information is required in each phase of an investigation to ensure proper identification, quality, purity, strength, and/or potency. The amount of information on analytical procedures and methods validation necessary will vary with the phase of the investigation (21 CFR 312.23(a)(7)). For general guidance on analytical procedures and methods validation information to be submitted for phase 1 studies, sponsors should refer to the FDA guidance for industry on Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products (November 1995). General guidance regarding analytical procedures and methods validation information to be submitted for phase 2 or phase 3 studies will be provided in the FDA guidance for industry INDs for Phase 2 and 3 Studies of Drugs, Including Specified Therapeutic BiotechnologyDerived Products, Chemistry, Manufacturing, and Controls Content and Format, when finalized (draft guidance published April 1999). All analytical procedures should be fully developed and validation completed when the NDA, ANDA, BLA, or PLA is submitted.
VI. CONTENT AND FORMAT OF ANALYTICAL PROCEDURES FOR NDAS, ANDAS, BLAS, AND PLAS
Any analytical procedure submitted in an NDA, ANDA, BLA, or PLA should be described in sufficient detail to allow a competent analyst to reproduce the necessary conditions and obtain results comparable to the applicants. Aspects of the analytical procedure that require special attention should be described. If the analytical procedure used is in the current revision of
VI. CONTENT AND FORMAT OF ANALYTICAL PROCEDURES FOR NDAS, ANDAS, BLAS, AND PLAS
Any analytical procedure submitted in an NDA, ANDA, BLA, or PLA should be described in sufficient detail to allow a competent analyst to reproduce the necessary conditions and obtain results comparable to the applicants. Aspects of the analytical procedure that require special attention should be described. If the analytical procedure used is in the current revision of
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the USP/NF or other FDA recognized standard references (e.g., AOAC International Book Of Methods) and the referenced analytical procedure is not modified, a statement indicating the analytical procedure and reference may be provided rather than a description of the method (21 CFR 211.194). A description of analytical procedures from any other published sources should be provided, because the referenced sources may not be readily accessible to the reviewer. The following is a list of information that should typically be included in a description of an analytical procedure. A. Principle A statement of the principle of the analytical procedure should be included. For example, separation is based on isocratic reversed phase HPLC with detection by UV. B. Sampling The number of samples (e.g., vials, tablets) selected, how they are used (i.e., as individual or composite samples), and the number of replicate analyses per sample should be described. C. Equipment and Equipment Parameters A listing of all equipment (e.g., instrument type, detector, column type, dimensions) should be included, as well as a list of equipment parameters (e.g., flow rate, temperatures, run time, wavelength settings). A drawing representing the experimental configuration (e.g., illustrating positions for a spray pattern analytical procedure) should be provided, when appropriate. D. Reagents A list of reagents and their grades (e.g., USP/NF, American Chemical Society (ACS) Analytical Reagent) should be included. If in-house or modified commercial reagents are used, directions for their preparation should be included. Unstable or potentially hazardous reagents should be identified, and storage conditions, directions for safe use, and usable shelf life for these reagents should be specified.
the USP/NF or other FDA recognized standard references (e.g., AOAC International Book Of Methods) and the referenced analytical procedure is not modified, a statement indicating the analytical procedure and reference may be provided rather than a description of the method (21 CFR 211.194). A description of analytical procedures from any other published sources should be provided, because the referenced sources may not be readily accessible to the reviewer. The following is a list of information that should typically be included in a description of an analytical procedure. A. Principle A statement of the principle of the analytical procedure should be included. For example, separation is based on isocratic reversed phase HPLC with detection by UV. B. Sampling The number of samples (e.g., vials, tablets) selected, how they are used (i.e., as individual or composite samples), and the number of replicate analyses per sample should be described. C. Equipment and Equipment Parameters A listing of all equipment (e.g., instrument type, detector, column type, dimensions) should be included, as well as a list of equipment parameters (e.g., flow rate, temperatures, run time, wavelength settings). A drawing representing the experimental configuration (e.g., illustrating positions for a spray pattern analytical procedure) should be provided, when appropriate. D. Reagents A list of reagents and their grades (e.g., USP/NF, American Chemical Society (ACS) Analytical Reagent) should be included. If in-house or modified commercial reagents are used, directions for their preparation should be included. Unstable or potentially hazardous reagents should be identified, and storage conditions, directions for safe use, and usable shelf life for these reagents should be specified.
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E. System Suitability Testing System suitability test parameters and acceptance criteria are based on the concept that the equipment, electronics, analytical operations, and samples to be analyzed constitute an integrated system. System suitability testing ensures that the system is working properly at the time of analysis. Appropriate system suitability criteria should be defined and included in the analytical procedure. All chromatographic analytical procedures should include system suitability testing and criteria. Parameters typically used in system suitability evaluations are defined and discussed in the CDER reviewer guidance on Validation of Chromatographic Methods (November 1994). System suitability testing is recommended as a component of any analytical procedure, not just those that involve chromatographic techniques. Regardless of the type of analytical procedure, testing should be used to confirm that the system will function correctly independent of the environmental conditions. For example, titration analytical procedures should always include the evaluation of a blank (commonly referred to as a blank titration). F. Preparation of Standards Procedures for the preparation of all standard solutions (e.g., stock, working standard solutions, internal standards) should be included. G. Preparation of Samples Sample preparation for individual tests should be clearly described. Specific details should be provided for unusual sample preparations (e.g., solidphase extraction, derivatization). H. Procedure A step-by-step description of the procedure should be provided. The description should include, where appropriate, equilibration times, injection sampling sequence, and system suitability or start-up parameters. Unusual hazards should be identified.
E. System Suitability Testing System suitability test parameters and acceptance criteria are based on the concept that the equipment, electronics, analytical operations, and samples to be analyzed constitute an integrated system. System suitability testing ensures that the system is working properly at the time of analysis. Appropriate system suitability criteria should be defined and included in the analytical procedure. All chromatographic analytical procedures should include system suitability testing and criteria. Parameters typically used in system suitability evaluations are defined and discussed in the CDER reviewer guidance on Validation of Chromatographic Methods (November 1994). System suitability testing is recommended as a component of any analytical procedure, not just those that involve chromatographic techniques. Regardless of the type of analytical procedure, testing should be used to confirm that the system will function correctly independent of the environmental conditions. For example, titration analytical procedures should always include the evaluation of a blank (commonly referred to as a blank titration). F. Preparation of Standards Procedures for the preparation of all standard solutions (e.g., stock, working standard solutions, internal standards) should be included. G. Preparation of Samples Sample preparation for individual tests should be clearly described. Specific details should be provided for unusual sample preparations (e.g., solidphase extraction, derivatization). H. Procedure A step-by-step description of the procedure should be provided. The description should include, where appropriate, equilibration times, injection sampling sequence, and system suitability or start-up parameters. Unusual hazards should be identified.
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I. Calculations Representative calculations, with a tabulation defining all symbols and numerical factors, and specific instructions for the calculation of degradation products and impurities should be included. Any mathematical transformations or formulas used in data analysis should be described in detail. These may include logarithmic transformations used to obtain a linear relationship from exponential data, or the use of multiple order regression analyses. J. Reporting of Results 1. General The format used to report results (e.g., percent label claim, weight/weight, weight/volume, parts per million (ppm)) including the specific number of significant igures to be reported should be provided. 2. Impurities Analytical Procedures The name and location/identifier (e.g., retention time (RT), relative retention time (RRT)) of impurities and the type of impurity (e.g., process, degradant, excipient degradant) should be included in the analytical procedures for impurities in the drug substance and drug product. The detection limit (DL) or quantitation limit (QL) should be stated, as appropriate. The DL or QL can be set using the drug substances detection response. Reporting of organic impurities should cover (1) specified identified impurities by name, (2) specified unidentified impurities by location/identifier, (3) any unspecified impurities, and (4) total impurities. The total organic impurities for the drug product or drug substance is the sum of all impurities equal to or greater than their individual QL. See recommendations regarding appropriate QLs in FDA impurities guidances (see references). Inorganic impurities and residual solvents should also be addressed. For the drug product, drug substance process impurities may be excluded from reporting if an acceptable rationale is provided in the sections on analytical procedures and controls. Drug product impurities from the drug product manufacturing process, packaging, and labeling should be addressed.
I. Calculations Representative calculations, with a tabulation defining all symbols and numerical factors, and specific instructions for the calculation of degradation products and impurities should be included. Any mathematical transformations or formulas used in data analysis should be described in detail. These may include logarithmic transformations used to obtain a linear relationship from exponential data, or the use of multiple order regression analyses. J. Reporting of Results 1. General The format used to report results (e.g., percent label claim, weight/weight, weight/volume, parts per million (ppm)) including the specific number of significant igures to be reported should be provided. 2. Impurities Analytical Procedures The name and location/identifier (e.g., retention time (RT), relative retention time (RRT)) of impurities and the type of impurity (e.g., process, degradant, excipient degradant) should be included in the analytical procedures for impurities in the drug substance and drug product. The detection limit (DL) or quantitation limit (QL) should be stated, as appropriate. The DL or QL can be set using the drug substances detection response. Reporting of organic impurities should cover (1) specified identified impurities by name, (2) specified unidentified impurities by location/identifier, (3) any unspecified impurities, and (4) total impurities. The total organic impurities for the drug product or drug substance is the sum of all impurities equal to or greater than their individual QL. See recommendations regarding appropriate QLs in FDA impurities guidances (see references). Inorganic impurities and residual solvents should also be addressed. For the drug product, drug substance process impurities may be excluded from reporting if an acceptable rationale is provided in the sections on analytical procedures and controls. Drug product impurities from the drug product manufacturing process, packaging, and labeling should be addressed.
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The above reporting information may not be strictly applicable to all products (e.g., biological, biotechnological, botanical, radiopharmaceutical drugs), but any significant process and product-related impurities should be determined and reported.
The above reporting information may not be strictly applicable to all products (e.g., biological, biotechnological, botanical, radiopharmaceutical drugs), but any significant process and product-related impurities should be determined and reported.
VII. METHODS VALIDATION FOR NDAS, ANDAS, BLAS, AND PLAS

A. Noncompendial Analytical Procedures In an NDA, ANDA, BLA, or PLA, data must be submitted to establish that the analytical procedures used in testing meet proper standards of accuracy and reliability (21 CFR 211.194(a)(2)). Methods validation is the process of demonstrating that analytical procedures are suitable for their intended use. At the time of submission, the NDA, ANDA, BLA, or PLA should contain methods validation information to support the adequacy of the analytical procedures. The International Conference on Harmonisation (ICH) guidance Q2A Text on Validation of Analytical Procedures (March 1995) and Q2B Validation of Analytical Procedures: Methodology (November 1996) provide recommendations on validation of analytical procedures. Analytical procedures outside the scope of the ICH guidances should still be validated. 1. Validation Characteristics Applicants should submit information on the validation characteristics of their proposed analytical procedures (see ICH Q2A and ICH Q2B). Although not all of the validation characteristics are needed for all types of tests (see section VII.A.3), typical validation characteristics are: O Accuracy O Precision (repeatability and intermediate precision) O Specificity O Detection limit O Quantitation limit O Linearity O Range O Robustness
VII. METHODS VALIDATION FOR NDAS, ANDAS, BLAS, AND PLAS

A. Noncompendial Analytical Procedures In an NDA, ANDA, BLA, or PLA, data must be submitted to establish that the analytical procedures used in testing meet proper standards of accuracy and reliability (21 CFR 211.194(a)(2)). Methods validation is the process of demonstrating that analytical procedures are suitable for their intended use. At the time of submission, the NDA, ANDA, BLA, or PLA should contain methods validation information to support the adequacy of the analytical procedures. The International Conference on Harmonisation (ICH) guidance Q2A Text on Validation of Analytical Procedures (March 1995) and Q2B Validation of Analytical Procedures: Methodology (November 1996) provide recommendations on validation of analytical procedures. Analytical procedures outside the scope of the ICH guidances should still be validated. 1. Validation Characteristics Applicants should submit information on the validation characteristics of their proposed analytical procedures (see ICH Q2A and ICH Q2B). Although not all of the validation characteristics are needed for all types of tests (see section VII.A.3), typical validation characteristics are: O Accuracy O Precision (repeatability and intermediate precision) O Specificity O Detection limit O Quantitation limit O Linearity O Range O Robustness
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2. Other Methods Validation Information Methods validation information should also include: O Data to demonstrate the stability of all analytical sample preparations through the time required to complete the analysis. O Legible reproductions of representative instrument output or recordings (e.g., chromatograms) and raw data output (e.g., integrated areas), as appropriate. Instrument output for placebo, standard, and sample should also be provided (see section VII.A.2.c). O Representative calculations using submitted raw data, to show how the impurities in drug substance are calculated. O Information from stress studies (see section VII.A.2.b). O Impurities labeled with their names and location identifiers (e.g., RRT for chromatographic data) for the impurity analytical procedure. O For drug substances: o A discussion of the possible formation and control of polymorphic and enantiomeric substances. o Identification and characterization of each organic impurity, as appropriate. This information may not be needed for all products (e.g., botanicals). Other impurities (e.g., inorganics, residual solvents) should be addressed and quantitated. Recommendations on submitting information on impurities is provided in various FDA guidances such as the ICH guidance Q3A Impurities in New Drug Substances (January 1996). o A list of known impurities, with structure if available, including process impurities, degradants, and possible isomers. O For drug products: o A degradation pathway for the drug substance in the dosage form, where possible. o Data demonstrating recovery from the sample matrix as illustrated by the accuracy studies. o Data demonstrating that neither the freshly prepared nor the degraded placebo interferes with the quantitation of the active ingredient.
2. Other Methods Validation Information Methods validation information should also include: O Data to demonstrate the stability of all analytical sample preparations through the time required to complete the analysis. O Legible reproductions of representative instrument output or recordings (e.g., chromatograms) and raw data output (e.g., integrated areas), as appropriate. Instrument output for placebo, standard, and sample should also be provided (see section VII.A.2.c). O Representative calculations using submitted raw data, to show how the impurities in drug substance are calculated. O Information from stress studies (see section VII.A.2.b). O Impurities labeled with their names and location identifiers (e.g., RRT for chromatographic data) for the impurity analytical procedure. O For drug substances: o A discussion of the possible formation and control of polymorphic and enantiomeric substances. o Identification and characterization of each organic impurity, as appropriate. This information may not be needed for all products (e.g., botanicals). Other impurities (e.g., inorganics, residual solvents) should be addressed and quantitated. Recommendations on submitting information on impurities is provided in various FDA guidances such as the ICH guidance Q3A Impurities in New Drug Substances (January 1996). o A list of known impurities, with structure if available, including process impurities, degradants, and possible isomers. O For drug products: o A degradation pathway for the drug substance in the dosage form, where possible. o Data demonstrating recovery from the sample matrix as illustrated by the accuracy studies. o Data demonstrating that neither the freshly prepared nor the degraded placebo interferes with the quantitation of the active ingredient.
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ICH Q2A and Q2B address almost all of the validation parameters. Areas that should be provided in more detail are described below. a. Robustness Robustness, a measure of the analytical procedures capability to remain unaffected by small but deliberate variations, is described in ICH Q2A and Q2B. Such testing should be performed during development of the analytical procedure and the data discussed and/or submitted. In cases where an effect is observed, representative instrument output (e.g., chromatograms) should be submitted. b. Stress Studies Degradation information obtained from stress studies (e.g., products of acid and base hydrolysis, thermal degradation, photolysis, oxidation) for the drug substance and for the active ingredient in the drug product should be provided to demonstrate the specificity of the assay and analytical procedures for impurities. The stress studies should demonstrate that impurities and degradants from the active ingredient and drug product excipients do not interfere with the quantitation of the active ingredient. Stress studies are described in various FDA guidances relating to the stability of drug products (see references). The design of the stress studies and the results should be submitted to the stability section of the application. Representative instrument output (e.g., chromatograms) and/or other appropriate data (e.g., degradation information obtained from stress studies) should be submitted in the sections on analytical procedures and controls. c. Instrument Output/Raw Data i. Organic Impurities Representative data should be submitted to support an assessment of the organic impurities. Representative data for residual solvents are generally not needed. Instrument output and the raw numerical values (e.g., peak area) with appropriate identification and labeling (e.g., RT for chromatographic peaks, chemical shift (d) and coupling constant (J) for NMR) should be provided. The impurity profile should be assessed at the quantitation limit and the instrument output provided. Additional information should be
ICH Q2A and Q2B address almost all of the validation parameters. Areas that should be provided in more detail are described below. a. Robustness Robustness, a measure of the analytical procedures capability to remain unaffected by small but deliberate variations, is described in ICH Q2A and Q2B. Such testing should be performed during development of the analytical procedure and the data discussed and/or submitted. In cases where an effect is observed, representative instrument output (e.g., chromatograms) should be submitted. b. Stress Studies Degradation information obtained from stress studies (e.g., products of acid and base hydrolysis, thermal degradation, photolysis, oxidation) for the drug substance and for the active ingredient in the drug product should be provided to demonstrate the specificity of the assay and analytical procedures for impurities. The stress studies should demonstrate that impurities and degradants from the active ingredient and drug product excipients do not interfere with the quantitation of the active ingredient. Stress studies are described in various FDA guidances relating to the stability of drug products (see references). The design of the stress studies and the results should be submitted to the stability section of the application. Representative instrument output (e.g., chromatograms) and/or other appropriate data (e.g., degradation information obtained from stress studies) should be submitted in the sections on analytical procedures and controls. c. Instrument Output/Raw Data i. Organic Impurities Representative data should be submitted to support an assessment of the organic impurities. Representative data for residual solvents are generally not needed. Instrument output and the raw numerical values (e.g., peak area) with appropriate identification and labeling (e.g., RT for chromatographic peaks, chemical shift (d) and coupling constant (J) for NMR) should be provided. The impurity profile should be assessed at the quantitation limit and the instrument output provided. Additional information should be
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provided to confirm that the impurity profile is adequately characterized. For example, a representative chromatogram using detection at a low wavelength, such as 205 nm, and double the proposed total run time could be submitted to support the specificity of the analytical procedure. For quantitation purposes, the response factor of the drug substance may be used for impurities without a reference standard. In cases where the response factors are not close, this practice may still be acceptable, provided a correction factor is applied or the impurities are, in fact, being overestimated. Acceptance criteria and analytical procedures used to estimate identified or unidentified impurities often are based on analytical assumptions (e.g., equivalent detector response). Assumptions should be discussed and justified. ii. Drug Substance Data should be submitted showing the separation and detection of impurities using spiked or stress samples. Complete impurity profiles as graphic output (e.g., chromatograms) and raw data (e.g, integrated peak areas) of representative batches should be submitted in the sections on analytical procedures and controls for the drug substance. For ANDAs and related submissions, appropriate information for the batches used in the biobatch or submission batch should be provided. All responses (e.g., peaks) should be labeled. The analytical procedure used should be capable of differentiating changes, if any, between past and present batches. The quantitation limit and the type of organic impurity (e.g., degradant, process impurity) should be stated. The analytical procedure number, batch number, manufacturing date and site, and date of analysis should be provided. iii. Drug Product Information such as instrument output (e.g., chromatograms) and raw data (e.g., integrated peak areas) from representative batches under long-term and accelerated stability conditions, and stressed samples should be submitted in the sections on analytical procedures and controls of the drug product. For ANDAs and related submissions, appropriate information for the biobatch or submission batch should be provided. References to the raw data (e.g., chromatograms) should be included in the stability section
provided to confirm that the impurity profile is adequately characterized. For example, a representative chromatogram using detection at a low wavelength, such as 205 nm, and double the proposed total run time could be submitted to support the specificity of the analytical procedure. For quantitation purposes, the response factor of the drug substance may be used for impurities without a reference standard. In cases where the response factors are not close, this practice may still be acceptable, provided a correction factor is applied or the impurities are, in fact, being overestimated. Acceptance criteria and analytical procedures used to estimate identified or unidentified impurities often are based on analytical assumptions (e.g., equivalent detector response). Assumptions should be discussed and justified. ii. Drug Substance Data should be submitted showing the separation and detection of impurities using spiked or stress samples. Complete impurity profiles as graphic output (e.g., chromatograms) and raw data (e.g, integrated peak areas) of representative batches should be submitted in the sections on analytical procedures and controls for the drug substance. For ANDAs and related submissions, appropriate information for the batches used in the biobatch or submission batch should be provided. All responses (e.g., peaks) should be labeled. The analytical procedure used should be capable of differentiating changes, if any, between past and present batches. The quantitation limit and the type of organic impurity (e.g., degradant, process impurity) should be stated. The analytical procedure number, batch number, manufacturing date and site, and date of analysis should be provided. iii. Drug Product Information such as instrument output (e.g., chromatograms) and raw data (e.g., integrated peak areas) from representative batches under long-term and accelerated stability conditions, and stressed samples should be submitted in the sections on analytical procedures and controls of the drug product. For ANDAs and related submissions, appropriate information for the biobatch or submission batch should be provided. References to the raw data (e.g., chromatograms) should be included in the stability section
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of the application. At a minimum, the submission should include instrument output and raw data for release testing and at the latest available time point for the same batch. All responses (e.g., peaks) should be labeled and identified. In addition, the analytical procedure number, batch number of the drug product, manufacturing date, date of analysis, source and batch number of drug substance, manufacturing site, and container/closure information should be provided. The analytical procedures used should be capable of differentiating changes, if any, between past and present batches. The quantitation limit and the type (e.g., degradant, leachables from packaging) should be reported. Multiple methodologies can be used. If process impurities from the drug substance and excipients with their related impurities are not reported in the impurities analytical procedure, the potential locations/identifier (e.g., RT, RRT) of these compounds should be described and listed in the analytical procedure. 3. Recommended Validation Characteristics for Types of Tests Table 1 is a summary of the validation characteristics that should be addressed during validation of different types of analytical procedures. The same methodology can be used for several purposes. The validation information should support the intended purpose of the test. For example, if Raman spectroscopy is the methodology selected to quantitate polymorphic forms as impurities, or chiral HPLC for enantiomeric impurities, the recommended validation characteristics in Table 1 under quantitative testing for impurities would apply. However, if Raman spectroscopy or chiral HPLC are used for the purpose of identification or as specific tests, the recommended validation characteristics listed for those types of tests would apply.
of the application. At a minimum, the submission should include instrument output and raw data for release testing and at the latest available time point for the same batch. All responses (e.g., peaks) should be labeled and identified. In addition, the analytical procedure number, batch number of the drug product, manufacturing date, date of analysis, source and batch number of drug substance, manufacturing site, and container/closure information should be provided. The analytical procedures used should be capable of differentiating changes, if any, between past and present batches. The quantitation limit and the type (e.g., degradant, leachables from packaging) should be reported. Multiple methodologies can be used. If process impurities from the drug substance and excipients with their related impurities are not reported in the impurities analytical procedure, the potential locations/identifier (e.g., RT, RRT) of these compounds should be described and listed in the analytical procedure. 3. Recommended Validation Characteristics for Types of Tests Table 1 is a summary of the validation characteristics that should be addressed during validation of different types of analytical procedures. The same methodology can be used for several purposes. The validation information should support the intended purpose of the test. For example, if Raman spectroscopy is the methodology selected to quantitate polymorphic forms as impurities, or chiral HPLC for enantiomeric impurities, the recommended validation characteristics in Table 1 under quantitative testing for impurities would apply. However, if Raman spectroscopy or chiral HPLC are used for the purpose of identification or as specific tests, the recommended validation characteristics listed for those types of tests would apply.
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Table 1. Recommended Validation Characteristics of the Various Types of Tests.

Type of Tests / Identification Testing for Impurities Assay Specific Characteristics Dissolution Tests (Measurement Only), Content/ Potency Quantitative Accuracy + + +1 + -3 + + + + Limit + + -3 + + +1 +5 + + + +4 +4 +4 +4 +4
Table 1. Recommended Validation Characteristics of the Various Types of Tests.

Type of Tests / Identification Testing for Impurities Assay Specific Characteristics Dissolution Tests (Measurement Only), Content/ Potency Quantitative Accuracy + + +1 + -3 + + + + Limit + + -3 + + +1 +5 + + + +4 +4 +4 +4 +4
Precision-Repeatability Precision-Intermediate Precision Specificity Detection Limit Quantitation Limit Linearity Range Robustness +2 -
Precision-Repeatability Precision-Intermediate Precision Specificity Detection Limit Quantitation Limit Linearity Range Robustness +2 -
NOTE: - Signifies that this characteristic is not normally evaluated. + Signifies that this characteristic is normally evaluated. 1 In cases where reproducibility has been performed, intermediate precision is not needed. 2 Lack of specificity for an analytical procedure may be compensated for by the addition of a second analytical procedure. 3 May be needed in some cases. 4 May not be needed in some cases. 5 Lack of specificity for an assay for release may be compensated for by impurities testing.
NOTE: - Signifies that this characteristic is not normally evaluated. + Signifies that this characteristic is normally evaluated. 1 In cases where reproducibility has been performed, intermediate precision is not needed. 2 Lack of specificity for an analytical procedure may be compensated for by the addition of a second analytical procedure. 3 May be needed in some cases. 4 May not be needed in some cases. 5 Lack of specificity for an assay for release may be compensated for by impurities testing.
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a. Identification Identification analytical procedures may include tests such as IR, differential scanning calorimetry (DSC), X-ray diffraction (XRD), UV, and HPLC retention time. A specific identification test should be included for the active ingredient whenever possible. In cases where a nonspecific identification analytical procedure is proposed for the active ingredient, two independent analytical procedures are generally sufficient, if justified. For other identification tests (e.g., a chiral HPLC retention time as confirmation for the presence of an enantiomer, chloride test for a counterion) a single test is acceptable. This concept of the number of identification tests is applicable to both the drug substance and drug product. b. Impurities The validation characteristics under quantitative testing for impurities, as described in Table 1, apply, regardless of which methodology is used to quantitate impurities. If the same analytical procedure is proposed as a limit test, validation characteristics under limit testing for impurities will apply. c. Assay Assay includes the content of the active ingredient, preservative (if used), and measurement of content in dissolution and content uniformity samples. d. Specific Tests Specific tests to control the drug substance, excipient, or drug product can include tests such as particle size analysis, droplet distribution, spray pattern, dissolution (excludes measurement), optical rotation, and methodologies such as DSC, XRD, and Raman spectroscopy. The validation characteristics may differ for the various analytical procedures. For example, accuracy, repeatability, intermediate precision and robustness should be evaluated for molecular size distribution gel permeation chromatography (GPC). B. Compendial Analytical Procedures The suitability of a compendial analytical procedure must be verified under actual conditions of use (21 CFR 211.194(a)(2)). Information to demonstrate that USP/NF analytical procedures are suitable for the drug product or drug substance should be included in the submission. Information on the
a. Identification Identification analytical procedures may include tests such as IR, differential scanning calorimetry (DSC), X-ray diffraction (XRD), UV, and HPLC retention time. A specific identification test should be included for the active ingredient whenever possible. In cases where a nonspecific identification analytical procedure is proposed for the active ingredient, two independent analytical procedures are generally sufficient, if justified. For other identification tests (e.g., a chiral HPLC retention time as confirmation for the presence of an enantiomer, chloride test for a counterion) a single test is acceptable. This concept of the number of identification tests is applicable to both the drug substance and drug product. b. Impurities The validation characteristics under quantitative testing for impurities, as described in Table 1, apply, regardless of which methodology is used to quantitate impurities. If the same analytical procedure is proposed as a limit test, validation characteristics under limit testing for impurities will apply. c. Assay Assay includes the content of the active ingredient, preservative (if used), and measurement of content in dissolution and content uniformity samples. d. Specific Tests Specific tests to control the drug substance, excipient, or drug product can include tests such as particle size analysis, droplet distribution, spray pattern, dissolution (excludes measurement), optical rotation, and methodologies such as DSC, XRD, and Raman spectroscopy. The validation characteristics may differ for the various analytical procedures. For example, accuracy, repeatability, intermediate precision and robustness should be evaluated for molecular size distribution gel permeation chromatography (GPC). B. Compendial Analytical Procedures The suitability of a compendial analytical procedure must be verified under actual conditions of use (21 CFR 211.194(a)(2)). Information to demonstrate that USP/NF analytical procedures are suitable for the drug product or drug substance should be included in the submission. Information on the
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specificity, intermediate precision, and stability of the sample solution should be included. Compendial assay analytical procedures may not be stabilityindicating, and this should be considered when developing the specification (see section III.C). For compendial items, additional analytical procedures, such as impurities or osmolality, may be requested to support the quality of the drug product or drug substance. These additional analytical procedures should be validated (see section VII.A).
specificity, intermediate precision, and stability of the sample solution should be included. Compendial assay analytical procedures may not be stabilityindicating, and this should be considered when developing the specification (see section III.C). For compendial items, additional analytical procedures, such as impurities or osmolality, may be requested to support the quality of the drug product or drug substance. These additional analytical procedures should be validated (see section VII.A).
VIII. STATISTICAL ANALYSIS

A. General Methods validation includes an assessment of the adequacy of the analytical procedure. Statistical analysis (e.g., linear regression analysis, relative standard deviation) of methods validation data is often used to demonstrate the validity of the method. The statistical procedures for the analysis of the validation data should be determined prior to the start of any validation study. The procedure followed, including the amount of data to collect and the criteria used in determining the acceptability of the analytical procedure, should be specified. The raw methods validation data and statistical procedures used to analyze the raw data should be provided and discussed in the sections on analytical procedures and controls. All statistical procedures used in the analysis of the data should be based on sound principles and be suitable for evaluating the dataset. B. Comparative Studies Comparative studies are performed to evaluate intermediate precision (e.g., different equipment, analysts, days). Comparative studies are also used to evaluate between laboratory variability (i.e., reproducibility) when an analytical procedure is used in more than one laboratory or to compare and evaluate the precision and accuracy of two analytical procedures (e.g., regulatory analytical procedure and an alternative analytical procedure). When comparative studies are performed, homogeneous samples from the same batch should be used, if feasible. Comparative results should be statistically analyzed and discussed and any bias explained.
VIII. STATISTICAL ANALYSIS

A. General Methods validation includes an assessment of the adequacy of the analytical procedure. Statistical analysis (e.g., linear regression analysis, relative standard deviation) of methods validation data is often used to demonstrate the validity of the method. The statistical procedures for the analysis of the validation data should be determined prior to the start of any validation study. The procedure followed, including the amount of data to collect and the criteria used in determining the acceptability of the analytical procedure, should be specified. The raw methods validation data and statistical procedures used to analyze the raw data should be provided and discussed in the sections on analytical procedures and controls. All statistical procedures used in the analysis of the data should be based on sound principles and be suitable for evaluating the dataset. B. Comparative Studies Comparative studies are performed to evaluate intermediate precision (e.g., different equipment, analysts, days). Comparative studies are also used to evaluate between laboratory variability (i.e., reproducibility) when an analytical procedure is used in more than one laboratory or to compare and evaluate the precision and accuracy of two analytical procedures (e.g., regulatory analytical procedure and an alternative analytical procedure). When comparative studies are performed, homogeneous samples from the same batch should be used, if feasible. Comparative results should be statistically analyzed and discussed and any bias explained.
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C. Statistics For information on statistical techniques used in making comparisons, as well as other general information on the interpretation and treatment of analytical data, appropriate literature or texts should be consulted (see references).
C. Statistics For information on statistical techniques used in making comparisons, as well as other general information on the interpretation and treatment of analytical data, appropriate literature or texts should be consulted (see references).
IX. REVALIDATION
When sponsors make changes in the analytical procedure, drug substance (e.g., route of synthesis), or drug product (e.g., composition), the changes may necessitate revalidation of the analytical procedures. Revalidation should be performed to ensure that the analytical procedure maintains its characteristics (e.g., specificity) and to demonstrate that the analytical procedure continues to ensure the identity, strength, quality, purity, and potency of the drug substance and drug product, and the bioavailability of the drug product. The degree of revalidation depends on the nature of the change. When a different regulatory analytical procedure is substituted (e.g., HPLC for titration), the new procedure should be validated (see section VII). If during each use an analytical procedure can meet the established system suitability requirements only with repeated adjustments to the operating conditions stated in the analytical procedure, the analytical procedure should be reevaluated, amended, and revalidated, as appropriate. FDA intends to provide guidance in the future on post-approval changes in analytical procedures.
IX. REVALIDATION
When sponsors make changes in the analytical procedure, drug substance (e.g., route of synthesis), or drug product (e.g., composition), the changes may necessitate revalidation of the analytical procedures. Revalidation should be performed to ensure that the analytical procedure maintains its characteristics (e.g., specificity) and to demonstrate that the analytical procedure continues to ensure the identity, strength, quality, purity, and potency of the drug substance and drug product, and the bioavailability of the drug product. The degree of revalidation depends on the nature of the change. When a different regulatory analytical procedure is substituted (e.g., HPLC for titration), the new procedure should be validated (see section VII). If during each use an analytical procedure can meet the established system suitability requirements only with repeated adjustments to the operating conditions stated in the analytical procedure, the analytical procedure should be reevaluated, amended, and revalidated, as appropriate. FDA intends to provide guidance in the future on post-approval changes in analytical procedures.
X. METHODS VALIDATION PACKAGE: CONTENTS AND PROCESSING

Part of the methods validation process may include FDA laboratory analysis to demonstrate that an analytical procedure is reproducible by laboratory testing. A methods validation package (see X.A) and samples (see X.B) will be needed for this process.
X. METHODS VALIDATION PACKAGE: CONTENTS AND PROCESSING

Part of the methods validation process may include FDA laboratory analysis to demonstrate that an analytical procedure is reproducible by laboratory testing. A methods validation package (see X.A) and samples (see X.B) will be needed for this process.
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A. Methods Validation Package The methods validation package will usually include information copied from pertinent sections of the application. To aid the review chemist, these copies should retain the original pagination of the application sections. For ANDA and NDA products, the archival copy and extra copies of the methods validation packages should be submitted with the application. For ANDAs and related supplemental applications, one archival copy and two extra copies of the methods validation package should be submitted. For NDAs and related supplemental applications, one archival copy and three extra copies should be submitted. For BLAs and PLAs, a separate methods validation package need not be submitted. Information similar to that specified here should be included in the BLA or PLA submission. The methods validation package should include: 1. Tabular List of All Samples to Be Submitted The list should include the lot number, identity (with chemical name and structure where required for clarity), package type and size, date of manufacture, and quantity of the samples. 2. Analytical Procedures A detailed description of each of the analytical procedures listed in the specifications should be submitted. The description should be sufficient to allow the FDA laboratory analysts to perform the analytical procedure (see section VI). 3. Validation Data Appropriate validation data to support the analytical procedures should be submitted. Individual values as well as summary tables should be provided. Representative instrument output and raw data and information regarding stress studies should be included (see section VII). 4. Results The results obtained by the applicant for the submitted samples should be provided. Alternatively, COAs could be submitted. The dates of analysis should be stated.
A. Methods Validation Package The methods validation package will usually include information copied from pertinent sections of the application. To aid the review chemist, these copies should retain the original pagination of the application sections. For ANDA and NDA products, the archival copy and extra copies of the methods validation packages should be submitted with the application. For ANDAs and related supplemental applications, one archival copy and two extra copies of the methods validation package should be submitted. For NDAs and related supplemental applications, one archival copy and three extra copies should be submitted. For BLAs and PLAs, a separate methods validation package need not be submitted. Information similar to that specified here should be included in the BLA or PLA submission. The methods validation package should include: 1. Tabular List of All Samples to Be Submitted The list should include the lot number, identity (with chemical name and structure where required for clarity), package type and size, date of manufacture, and quantity of the samples. 2. Analytical Procedures A detailed description of each of the analytical procedures listed in the specifications should be submitted. The description should be sufficient to allow the FDA laboratory analysts to perform the analytical procedure (see section VI). 3. Validation Data Appropriate validation data to support the analytical procedures should be submitted. Individual values as well as summary tables should be provided. Representative instrument output and raw data and information regarding stress studies should be included (see section VII). 4. Results The results obtained by the applicant for the submitted samples should be provided. Alternatively, COAs could be submitted. The dates of analysis should be stated.
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5. Composition The components and composition of the drug product should be provided. 6. Specifications The specifications for the drug substance and the drug product should be included. 7. Material Safety Data Sheets The applicant should include material safety data sheets (MSDSs) for all samples, standards, and reagents (29 CFR 1910.1200(g)). As appropriate, MSDSs should be provided for other materials used in the analytical procedures listed in the methods validation package. In the case of toxic or hazardous materials, MSDSs should be posted on the outside of the package to facilitate safe handling. B. Selection and Shipment of Samples On request from CDER, an NDA or ANDA applicant must submit samples of drug product, drug substance, noncompendial reference standards, and blanks, so that the suitability of the applicants drug substance and drug product analytical procedures can be evaluated by FDA laboratories (21 CFR 314.50(e) and 314.94(a)(10)). For BLAs and PLAs, representative samples of the product must be submitted, and summaries of the results of tests performed on the lots represented by the submitted sample must be provided (21 CFR 601.2(a) and 601.2(c)(1)(vi)). For CDER products, the number of sets of samples that should be submitted for methods validation will be identified in the instructions forwarded to the applicant by the FDA laboratory. In general, the quantity of samples in each set should be double the amount needed to carry out the testing as performed by the applicant. Along with the drug substance and the drug product samples, the applicant should submit internal standards, non-USP reference standards, samples of impurities, degradation products, and unusual reagents. A set of samples will be shipped to each assigned laboratory. For biological products, CBER should be consulted on the submission of samples and supporting materials.
5. Composition The components and composition of the drug product should be provided. 6. Specifications The specifications for the drug substance and the drug product should be included. 7. Material Safety Data Sheets The applicant should include material safety data sheets (MSDSs) for all samples, standards, and reagents (29 CFR 1910.1200(g)). As appropriate, MSDSs should be provided for other materials used in the analytical procedures listed in the methods validation package. In the case of toxic or hazardous materials, MSDSs should be posted on the outside of the package to facilitate safe handling. B. Selection and Shipment of Samples On request from CDER, an NDA or ANDA applicant must submit samples of drug product, drug substance, noncompendial reference standards, and blanks, so that the suitability of the applicants drug substance and drug product analytical procedures can be evaluated by FDA laboratories (21 CFR 314.50(e) and 314.94(a)(10)). For BLAs and PLAs, representative samples of the product must be submitted, and summaries of the results of tests performed on the lots represented by the submitted sample must be provided (21 CFR 601.2(a) and 601.2(c)(1)(vi)). For CDER products, the number of sets of samples that should be submitted for methods validation will be identified in the instructions forwarded to the applicant by the FDA laboratory. In general, the quantity of samples in each set should be double the amount needed to carry out the testing as performed by the applicant. Along with the drug substance and the drug product samples, the applicant should submit internal standards, non-USP reference standards, samples of impurities, degradation products, and unusual reagents. A set of samples will be shipped to each assigned laboratory. For biological products, CBER should be consulted on the submission of samples and supporting materials.
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Unless specified differently by the reviewer, samples from any batch, preferably samples from an aged batch, may be selected for NDAs and NDA supplemental applications. The submitted drug product samples should be from a batch made with the proposed market formulation. For ANDAs and appropriate supplements, a sample of the finished product from a batch being used to support approval of the submission should be used. If a sample is selected from a batch not described in the application, an amendment containing a copy of the batch record and certificate of analysis should be provided to the ANDA. For supplements that do not require submission and review of an exhibit batch record and associated data, any commercial batch may be submitted. For biological products, samples from several consecutively manufactured batches should be submitted. The drug product should be supplied in its original packaging. Bulk substances (e.g., drug substances, impurities, excipients) should be stored in opaque nonreactive containers. To prevent breakage during shipping, the samples should be adequately packaged in a sturdy container. Samples shipped from outside the United States should contain the appropriate customs forms to reduce delay in delivery. If special storage precautions (e.g., freezing, use of an inert gas blanket) are required to protect sample integrity, arrangements should be made in advance with the validating laboratory for scheduled direct delivery. If a sample is toxic or potentially hazardous, the container should be prominently labeled with an appropriate warning and precautionary handling instructions. C. Responsibilities of the Various Parties 1. Applicant In the sections of the application on analytical procedures and controls, the applicant should provide a name, address, telephone number, and facsimile number so that samples can be requested. If this information is not provided, the contact person and address listed in the NDA, ANDA, BLA, or PLA submission will be used. The methods validation packages should be compiled and submitted with the NDA or ANDA submission. For BLAs and PLAs, a separate methods validation package need not be submitted.
Unless specified differently by the reviewer, samples from any batch, preferably samples from an aged batch, may be selected for NDAs and NDA supplemental applications. The submitted drug product samples should be from a batch made with the proposed market formulation. For ANDAs and appropriate supplements, a sample of the finished product from a batch being used to support approval of the submission should be used. If a sample is selected from a batch not described in the application, an amendment containing a copy of the batch record and certificate of analysis should be provided to the ANDA. For supplements that do not require submission and review of an exhibit batch record and associated data, any commercial batch may be submitted. For biological products, samples from several consecutively manufactured batches should be submitted. The drug product should be supplied in its original packaging. Bulk substances (e.g., drug substances, impurities, excipients) should be stored in opaque nonreactive containers. To prevent breakage during shipping, the samples should be adequately packaged in a sturdy container. Samples shipped from outside the United States should contain the appropriate customs forms to reduce delay in delivery. If special storage precautions (e.g., freezing, use of an inert gas blanket) are required to protect sample integrity, arrangements should be made in advance with the validating laboratory for scheduled direct delivery. If a sample is toxic or potentially hazardous, the container should be prominently labeled with an appropriate warning and precautionary handling instructions. C. Responsibilities of the Various Parties 1. Applicant In the sections of the application on analytical procedures and controls, the applicant should provide a name, address, telephone number, and facsimile number so that samples can be requested. If this information is not provided, the contact person and address listed in the NDA, ANDA, BLA, or PLA submission will be used. The methods validation packages should be compiled and submitted with the NDA or ANDA submission. For BLAs and PLAs, a separate methods validation package need not be submitted.
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When an FDA laboratory contacts the applicant for samples, the applicant should provide FDA laboratories with the samples within 10 working days. With the exception of sample delivery arrangements, all communications concerning validation at the FDA laboratories should be made through or with the knowledge of the review chemist for CDER applications, or the BLA/PLA committee chair for CBER applications. 2. Review Chemist The review chemist will review the application to determine that the analytical procedures are adequate to ensure the identity, strength, quality, purity, and potency of the drug substance and/or drug product. Any changes in the methods resulting from the review of the application may require resubmission of the methods validation package. The review chemist, in coordination with the appropriate FDA laboratories, will decide which analytical procedures are to be validated. Comments from the FDA laboratories, if any, will be forwarded by the review chemist to the applicant on completion of the studies by the laboratories. 3. FDA Laboratory An FDA laboratory will contact applicants with instructions on the submission of samples and the addresses to which samples should be mailed. The laboratory will test the samples according to the submitted analytical procedures to determine whether the analytical procedures are acceptable for quality control and suitable for regulatory purposes. Results and comments will be forwarded to the review chemist on completion of the studies. 4. Investigator The investigator inspects the analytical laboratory testing sites where the release and stability testing are performed to ensure that the analytical procedures are performed in compliance with CGMP/GLP.
When an FDA laboratory contacts the applicant for samples, the applicant should provide FDA laboratories with the samples within 10 working days. With the exception of sample delivery arrangements, all communications concerning validation at the FDA laboratories should be made through or with the knowledge of the review chemist for CDER applications, or the BLA/PLA committee chair for CBER applications. 2. Review Chemist The review chemist will review the application to determine that the analytical procedures are adequate to ensure the identity, strength, quality, purity, and potency of the drug substance and/or drug product. Any changes in the methods resulting from the review of the application may require resubmission of the methods validation package. The review chemist, in coordination with the appropriate FDA laboratories, will decide which analytical procedures are to be validated. Comments from the FDA laboratories, if any, will be forwarded by the review chemist to the applicant on completion of the studies by the laboratories. 3. FDA Laboratory An FDA laboratory will contact applicants with instructions on the submission of samples and the addresses to which samples should be mailed. The laboratory will test the samples according to the submitted analytical procedures to determine whether the analytical procedures are acceptable for quality control and suitable for regulatory purposes. Results and comments will be forwarded to the review chemist on completion of the studies. 4. Investigator The investigator inspects the analytical laboratory testing sites where the release and stability testing are performed to ensure that the analytical procedures are performed in compliance with CGMP/GLP.
XI. METHODOLOGY
Sections II through IX provide general information on the submission of analytical procedures and methods validation information, including
XI. METHODOLOGY
Sections II through IX provide general information on the submission of analytical procedures and methods validation information, including
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validation characteristics. Additional information on certain methodologies is provided below. A. High-Pressure Liquid Chromatography (HPLC) The widespread use of HPLC analytical procedures and the multitude of commercial sources of columns and packings frequently have created problems in assessing comparability. Many of the following points may also apply to other chromatographic analytical procedures. 1. Column The following characteristics are useful for defining a particular column and, if known, should be included in the analytical procedure description. If method development has indicated that columns from only one commercial source are suitable, this information should be included as part of the analytical procedure. If more than one column is suitable, a listing of columns found to be equivalent should be included. a. Column Parameters O O O O O Material: glass, stainless steel, plastic Dimensions: length, inner diameter Frit size Filter type Precolumn and/or guard column type, if used
validation characteristics. Additional information on certain methodologies is provided below. A. High-Pressure Liquid Chromatography (HPLC) The widespread use of HPLC analytical procedures and the multitude of commercial sources of columns and packings frequently have created problems in assessing comparability. Many of the following points may also apply to other chromatographic analytical procedures. 1. Column The following characteristics are useful for defining a particular column and, if known, should be included in the analytical procedure description. If method development has indicated that columns from only one commercial source are suitable, this information should be included as part of the analytical procedure. If more than one column is suitable, a listing of columns found to be equivalent should be included. a. Column Parameters O O O O O Material: glass, stainless steel, plastic Dimensions: length, inner diameter Frit size Filter type Precolumn and/or guard column type, if used
b. Packing Material O Particle type: size, shape, pore diameter O Surface modification (e.g., bonded surface type, surface coverage, percent carbon, additional silylation) O Recommended pH range for column use 2. System Suitability Testing Each analytical procedure submitted should include an appropriate number of system suitability tests defining the critical characteristics of that system.
b. Packing Material O Particle type: size, shape, pore diameter O Surface modification (e.g., bonded surface type, surface coverage, percent carbon, additional silylation) O Recommended pH range for column use 2. System Suitability Testing Each analytical procedure submitted should include an appropriate number of system suitability tests defining the critical characteristics of that system.
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Criteria for all system suitability testing should be provided. The system suitability tests listed below are defined in CDER=s reviewer guidance on Validation of Chromatographic Methods (November 1994). O O O O O O Tailing factor Relative retention Resolution Relative standard deviation (RSD) Capacity factor Number of theoretical plates
Criteria for all system suitability testing should be provided. The system suitability tests listed below are defined in CDER=s reviewer guidance on Validation of Chromatographic Methods (November 1994). O O O O O O Tailing factor Relative retention Resolution Relative standard deviation (RSD) Capacity factor Number of theoretical plates
The RSD is normally performed at the beginning of the run. However, for assays with lengthy run times or as otherwise justified by the applicant, the reported average may be taken from injections at the beginning and end of the run, or at the beginning, middle, and end of the run. If an internal standard is used, the minimum acceptable resolution between the internal standard and one or more active ingredients should be specified. If the analytical procedure is used to control the level of impurities, the minimum resolution between the active ingredient and the closest eluting impurity, or the two peaks eluting closest to each other, should be given. 3. Operating Parameters The sequence of injection of blanks, system suitability standards, other standards, and samples should be defined. Flow rates, temperatures, and gradients should be described. Complete details should be provided for the preparation of the mobile phase, including the order of addition of the reagents and the methods of degassing and filtration. The effect of adjustments in mobile phase composition on retention times should be included in the analytical procedure. The rationale for the use of precolumns and/or guard columns should be provided and justified. Any special requirements, such as the use of inert tubing or injection valves, should be specified. B. Gas Chromatography (GC) At a minimum, the following parameters should be included in the description of a GC procedure. Additional parameters should be specified if required by
The RSD is normally performed at the beginning of the run. However, for assays with lengthy run times or as otherwise justified by the applicant, the reported average may be taken from injections at the beginning and end of the run, or at the beginning, middle, and end of the run. If an internal standard is used, the minimum acceptable resolution between the internal standard and one or more active ingredients should be specified. If the analytical procedure is used to control the level of impurities, the minimum resolution between the active ingredient and the closest eluting impurity, or the two peaks eluting closest to each other, should be given. 3. Operating Parameters The sequence of injection of blanks, system suitability standards, other standards, and samples should be defined. Flow rates, temperatures, and gradients should be described. Complete details should be provided for the preparation of the mobile phase, including the order of addition of the reagents and the methods of degassing and filtration. The effect of adjustments in mobile phase composition on retention times should be included in the analytical procedure. The rationale for the use of precolumns and/or guard columns should be provided and justified. Any special requirements, such as the use of inert tubing or injection valves, should be specified. B. Gas Chromatography (GC) At a minimum, the following parameters should be included in the description of a GC procedure. Additional parameters should be specified if required by
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the analytical procedure. If method development has indicated that columns from only one commercial source are suitable, this information should be included as part of the analytical procedure. If more than one column is suitable, a listing of columns found to be equivalent should be included. 1. Column O O O O Column dimensions: length, internal diameter, external diameter Stationary phase Column material (e.g., silica, glass, stainless steel) Column conditioning procedure
the analytical procedure. If method development has indicated that columns from only one commercial source are suitable, this information should be included as part of the analytical procedure. If more than one column is suitable, a listing of columns found to be equivalent should be included. 1. Column O O O O Column dimensions: length, internal diameter, external diameter Stationary phase Column material (e.g., silica, glass, stainless steel) Column conditioning procedure
2. Operating Parameters O Gases: purity, flow rate, pressure O Temperatures: column, injector, detector (including temperature program, if used) O Injection (e.g., split, splitless, on-column) O Detector O Typical retention time and total run time 3. System Suitability Testing Appropriate system suitability criteria should be defined and included in all analytical procedures. If an internal standard is used, the minimum acceptable resolution between the internal standard and one or more active ingredient should be specified. If the analytical procedure is used to control the level of impurities, the minimum resolution between the active ingredient and the closest eluting impurity, or the two peaks eluting closest to each other, should be given. The RSD is normally performed at the beginning of the run. However, for assays with lengthy run times or as otherwise justified by the applicant, the reported average may be taken from injections at the beginning and end of the run, or beginning, middle, and end of the run.
2. Operating Parameters O Gases: purity, flow rate, pressure O Temperatures: column, injector, detector (including temperature program, if used) O Injection (e.g., split, splitless, on-column) O Detector O Typical retention time and total run time 3. System Suitability Testing Appropriate system suitability criteria should be defined and included in all analytical procedures. If an internal standard is used, the minimum acceptable resolution between the internal standard and one or more active ingredient should be specified. If the analytical procedure is used to control the level of impurities, the minimum resolution between the active ingredient and the closest eluting impurity, or the two peaks eluting closest to each other, should be given. The RSD is normally performed at the beginning of the run. However, for assays with lengthy run times or as otherwise justified by the applicant, the reported average may be taken from injections at the beginning and end of the run, or beginning, middle, and end of the run.
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C. Spectrophotometry, Spectroscopy, Spectrometry and Related Physical Methodologies These analytical procedures include, but are not limited to, IR spectrophotometry, near IR spectrophotometry (NIR), UV/visible spectrophotometry (UV/Vis), atomic emission and atomic absorption, NMR, Raman spectroscopy, MS, and XRD. Spectrometric analytical procedures may not be stability-indicating. The bias of the analytical procedure should be evaluated by comparing it with a chromatographic procedure, where appropriate. When manually operated equipment is used, the description of the analytical procedure should include an acceptance criterion for the amount of time that may elapse between sampling and reading. Appropriate system suitability and/or calibration testing is recommended. Validation criteria should include specificity (demonstrating no interference of placebo), linearity, repeatability, intermediate precision, and robustness. D. Capillary Electrophoresis (CE) At a minimum, the parameters listed below should be specified for a capillary electrophoretic analytical procedure. Additional parameters may be included as required by the procedure. If method development has indicated that capillaries from only one commercial source are suitable, this information should be included as part of the analytical procedure. If more than one capillary is suitable, a listing of capillaries found to be equivalent should be included. 1. Capillary O Capillary dimensions: length, length to detector, internal diameter, external diameter O Capillary material O Capillary internal coating (if any) 2. Operating Parameters O Capillary preparation procedure: procedure to be followed before the first use, before the first run of the day, before each run (e.g., flush with 100 millimolar sodium hydroxide, flush with running buffer)
C. Spectrophotometry, Spectroscopy, Spectrometry and Related Physical Methodologies These analytical procedures include, but are not limited to, IR spectrophotometry, near IR spectrophotometry (NIR), UV/visible spectrophotometry (UV/Vis), atomic emission and atomic absorption, NMR, Raman spectroscopy, MS, and XRD. Spectrometric analytical procedures may not be stability-indicating. The bias of the analytical procedure should be evaluated by comparing it with a chromatographic procedure, where appropriate. When manually operated equipment is used, the description of the analytical procedure should include an acceptance criterion for the amount of time that may elapse between sampling and reading. Appropriate system suitability and/or calibration testing is recommended. Validation criteria should include specificity (demonstrating no interference of placebo), linearity, repeatability, intermediate precision, and robustness. D. Capillary Electrophoresis (CE) At a minimum, the parameters listed below should be specified for a capillary electrophoretic analytical procedure. Additional parameters may be included as required by the procedure. If method development has indicated that capillaries from only one commercial source are suitable, this information should be included as part of the analytical procedure. If more than one capillary is suitable, a listing of capillaries found to be equivalent should be included. 1. Capillary O Capillary dimensions: length, length to detector, internal diameter, external diameter O Capillary material O Capillary internal coating (if any) 2. Operating Parameters O Capillary preparation procedure: procedure to be followed before the first use, before the first run of the day, before each run (e.g., flush with 100 millimolar sodium hydroxide, flush with running buffer)
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O Running buffer: composition, including a detailed preparation procedure with the order of addition of the components O Injection: mode (e.g., electrokinetic, hydrodynamic), parameters (e.g., voltage, pressure, time) O Detector O Typical migration time and total run time O Model of CE equipment used O Voltage (if constant voltage) O Current (if constant current) O Polarity (e.g., polarity of electrode by detector) 3. System Suitability Testing Each analytical procedure should include the appropriate system suitability tests defining the critical characteristics of that system. Other parameters may be included at the discretion of the applicant. If an internal standard is used, the minimum acceptable resolution between the internal standard and one or more active ingredient should be specified. If the analytical procedure is used to control the level of impurities, the minimum resolution between the active ingredient and the closest eluting impurity, or the two peaks eluting closest to each other, should be given. E. Optical Rotation Optical rotation is used for the measurement of stereochemical purity. Visual polarimeters rely a monochromatic source, which traditionally was sodium D, but has expanded to virtually any wavelength. If measurements are to be made at a wavelength other than sodium D, an explanation for selecting the wavelength should be given, along with a comparison of the specific rotation at sodium D and the wavelength to be used. Circular dichroism (CD) spectra may suffice for this purpose. In addition to the provisions of USP <781>, procedures for measurement of specific rotation should include the solvent, concentration, and, for aqueous solutions, the pH to which the solution should be adjusted. The conditions and equipment should be shown to be suitable to confirm the stereochemical identity of a racemate or an enantiomer.
O Running buffer: composition, including a detailed preparation procedure with the order of addition of the components O Injection: mode (e.g., electrokinetic, hydrodynamic), parameters (e.g., voltage, pressure, time) O Detector O Typical migration time and total run time O Model of CE equipment used O Voltage (if constant voltage) O Current (if constant current) O Polarity (e.g., polarity of electrode by detector) 3. System Suitability Testing Each analytical procedure should include the appropriate system suitability tests defining the critical characteristics of that system. Other parameters may be included at the discretion of the applicant. If an internal standard is used, the minimum acceptable resolution between the internal standard and one or more active ingredient should be specified. If the analytical procedure is used to control the level of impurities, the minimum resolution between the active ingredient and the closest eluting impurity, or the two peaks eluting closest to each other, should be given. E. Optical Rotation Optical rotation is used for the measurement of stereochemical purity. Visual polarimeters rely a monochromatic source, which traditionally was sodium D, but has expanded to virtually any wavelength. If measurements are to be made at a wavelength other than sodium D, an explanation for selecting the wavelength should be given, along with a comparison of the specific rotation at sodium D and the wavelength to be used. Circular dichroism (CD) spectra may suffice for this purpose. In addition to the provisions of USP <781>, procedures for measurement of specific rotation should include the solvent, concentration, and, for aqueous solutions, the pH to which the solution should be adjusted. The conditions and equipment should be shown to be suitable to confirm the stereochemical identity of a racemate or an enantiomer.
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The enantiomeric purity can be expressed as enantiomeric excess (e.e.), using the following formula as an example: e.e. = 100% * {{M} - [m]}/{[M] + [m]} where [M] and [m] are the concentrations of the major and minor enantiomers, respectively. This yields values of zero for a racemate and 100 percent for a pure enantiomer. An intermediate concentration gives intermediate values; for example, 97:3 would give an e.e. 94 percent. Appropriate system suitability and/or calibration testing is recommended. Validation criteria should include specificity, and intermediate precision. F. Methodologies Relating to Particle Size Analysis Particle size analysis is an important element for quality control and regulatory evaluation of certain drug substances and drug products. The normal concepts of validation may differ for particle size methodologies as compared to other analytical methodologies such as HPLC. However, a standard mixture may be used for calibration. Particle size evaluation can include characteristics of size, morphology, surface, and population of particles. The following parameters are useful for describing particle size analysis for characterization of drug substances and drug products. 1. Particle Size Methods Types of particle size methods include, but are not limited to: a. Nonfractionation methods that evaluate an entire population of particles O O O O Microscopy (optical, electron) Light scattering (dynamic, photon correlation, laser diffraction) Electrozone sensing Photozone sensing
The enantiomeric purity can be expressed as enantiomeric excess (e.e.), using the following formula as an example: e.e. = 100% * {{M} - [m]}/{[M] + [m]} where [M] and [m] are the concentrations of the major and minor enantiomers, respectively. This yields values of zero for a racemate and 100 percent for a pure enantiomer. An intermediate concentration gives intermediate values; for example, 97:3 would give an e.e. 94 percent. Appropriate system suitability and/or calibration testing is recommended. Validation criteria should include specificity, and intermediate precision. F. Methodologies Relating to Particle Size Analysis Particle size analysis is an important element for quality control and regulatory evaluation of certain drug substances and drug products. The normal concepts of validation may differ for particle size methodologies as compared to other analytical methodologies such as HPLC. However, a standard mixture may be used for calibration. Particle size evaluation can include characteristics of size, morphology, surface, and population of particles. The following parameters are useful for describing particle size analysis for characterization of drug substances and drug products. 1. Particle Size Methods Types of particle size methods include, but are not limited to: a. Nonfractionation methods that evaluate an entire population of particles O O O O Microscopy (optical, electron) Light scattering (dynamic, photon correlation, laser diffraction) Electrozone sensing Photozone sensing
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b. Fractionation methods that use physical techniques to separate particles on the basis of size O O O O Sieving Cascade impactor Sedimentation Size exclusion chromatography
b. Fractionation methods that use physical techniques to separate particles on the basis of size O O O O Sieving Cascade impactor Sedimentation Size exclusion chromatography
2. Calibration and Validation Characteristics To ensure proper instrument operation, the system should be calibrated according to the manufacturers and/or the laboratorys specification, as appropriate. The methods validation usually involves evaluation of intermediate precision and robustness. Assurance should be provided that the data generated are reproducible and control the products quality. See additional information in sections V and VII. G. Dissolution The equipment used for dissolution is covered by USP <711> or USP <724>. The dissolution procedure description and validation should include the following. 1. Dissolution Medium A brief discussion of the reasons for selecting the medium. 2. Procedure A dissolution test consists of a dissolution procedure and method of analysis (automated on-line analysis or manual sampling followed by HPLC analysis). The written procedure should cover the following items: O Apparatus O Preparation of standard O Preparation of sample O Method of analysis (e.g., UV, HPLC) O Sampling procedure (e.g., intervals, filtration, handling of samples, dilutions)
2. Calibration and Validation Characteristics To ensure proper instrument operation, the system should be calibrated according to the manufacturers and/or the laboratorys specification, as appropriate. The methods validation usually involves evaluation of intermediate precision and robustness. Assurance should be provided that the data generated are reproducible and control the products quality. See additional information in sections V and VII. G. Dissolution The equipment used for dissolution is covered by USP <711> or USP <724>. The dissolution procedure description and validation should include the following. 1. Dissolution Medium A brief discussion of the reasons for selecting the medium. 2. Procedure A dissolution test consists of a dissolution procedure and method of analysis (automated on-line analysis or manual sampling followed by HPLC analysis). The written procedure should cover the following items: O Apparatus O Preparation of standard O Preparation of sample O Method of analysis (e.g., UV, HPLC) O Sampling procedure (e.g., intervals, filtration, handling of samples, dilutions)
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O Calculations O Acceptance criteria Regardless of the method of analysis, system suitability criteria should be described. Blank and standard solution spectra or chromatograms should be included. 3. Validation Characteristics Both the dissolution procedure and the method of analysis should be validated. The time needed for the completion of the sample analysis should be stated in the procedure. Data should be submitted to support the stability of the dissolution sample during the procedure. If filters are used on-line or during sample preparation, appropriate recovery studies should be performed and documented and any bias should be addressed. H. Other Instrumentation 1. Noncommercial Instrumentation FDA encourages the development and use of the most appropriate instrumentation. However, the use of rare or exotic systems not only places an undue burden on the regulatory laboratory, but also may delay the validation process. When noncommercial instrumentation is used, the instrumentation should be capable of being constructed from commercially available components at a reasonable cost, if possible. For unique methodologies or instrumentation requiring contract fabrication, the applicants cooperation with the FDA laboratories in helping facilitate duplication of the analytical procedure is important. In addition to design and equipment specifications, complete performance assessment procedures should be provided. Such systems may be found suitable for regulatory use. 2. Automated Analytical Procedures The use of automated analytical procedures, although desirable for control testing, may lead to delay in regulatory methods validation because FDA laboratories have to assemble and validate the system before running
O Calculations O Acceptance criteria Regardless of the method of analysis, system suitability criteria should be described. Blank and standard solution spectra or chromatograms should be included. 3. Validation Characteristics Both the dissolution procedure and the method of analysis should be validated. The time needed for the completion of the sample analysis should be stated in the procedure. Data should be submitted to support the stability of the dissolution sample during the procedure. If filters are used on-line or during sample preparation, appropriate recovery studies should be performed and documented and any bias should be addressed. H. Other Instrumentation 1. Noncommercial Instrumentation FDA encourages the development and use of the most appropriate instrumentation. However, the use of rare or exotic systems not only places an undue burden on the regulatory laboratory, but also may delay the validation process. When noncommercial instrumentation is used, the instrumentation should be capable of being constructed from commercially available components at a reasonable cost, if possible. For unique methodologies or instrumentation requiring contract fabrication, the applicants cooperation with the FDA laboratories in helping facilitate duplication of the analytical procedure is important. In addition to design and equipment specifications, complete performance assessment procedures should be provided. Such systems may be found suitable for regulatory use. 2. Automated Analytical Procedures The use of automated analytical procedures, although desirable for control testing, may lead to delay in regulatory methods validation because FDA laboratories have to assemble and validate the system before running
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samples. To avoid this delay, applicants should demonstrate the equivalence of a manual procedure to the automated procedure based on the same principle whenever possible.
samples. To avoid this delay, applicants should demonstrate the equivalence of a manual procedure to the automated procedure based on the same principle whenever possible.
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ATTACHMENT A
NDA, ANDA, BLA, AND PLA SUBMISSION CONTENTS
The information relating to analytical procedures and methods validation that should be submitted in NDAs, ANDAs, BLAs, and PLAs is identified below with a cross-reference to the section of this guidance that provides recommendations and/or discussion on the topics. Information that should be included in the analytical procedures and controls sections O Reference standard information Section IV o Analytical procedures Section III, VI o Validation data Section VII o Stress studies Section VII.A.2.c o Instrument output/raw data for impurities Section VII.A.2.b o Statistical analysis Section VIII o Revalidation, as needed Section IX Information that should be included in the methods validation package5 o Contents of the MV Package Section XI o Representative instrument output/data for stress studies Section VII.A.2.c O Representative instrument output and raw data for initial and oldest sample of a batch Section VII.A.2.b Information that should be included in the stability section O Stress study designs and results Section VII.A.2.b O Reference (volume and page number of submission) to instrument output and raw data submitted to the section dedicated to analytical procedures and controls Section VII.A 2.c
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ATTACHMENT A
NDA, ANDA, BLA, AND PLA SUBMISSION CONTENTS
The information relating to analytical procedures and methods validation that should be submitted in NDAs, ANDAs, BLAs, and PLAs is identified below with a cross-reference to the section of this guidance that provides recommendations and/or discussion on the topics. Information that should be included in the analytical procedures and controls sections O Reference standard information Section IV o Analytical procedures Section III, VI o Validation data Section VII o Stress studies Section VII.A.2.c o Instrument output/raw data for impurities Section VII.A.2.b o Statistical analysis Section VIII o Revalidation, as needed Section IX Information that should be included in the methods validation package5 o Contents of the MV Package Section XI o Representative instrument output/data for stress studies Section VII.A.2.c O Representative instrument output and raw data for initial and oldest sample of a batch Section VII.A.2.b Information that should be included in the stability section O Stress study designs and results Section VII.A.2.b O Reference (volume and page number of submission) to instrument output and raw data submitted to the section dedicated to analytical procedures and controls Section VII.A 2.c
5
For BLAs and PLAs, a separate methods validation package need not be submitted. Information similar to what is listed here should be included in the BLA or PLA submission.
For BLAs and PLAs, a separate methods validation package need not be submitted. Information similar to what is listed here should be included in the BLA or PLA submission.
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ATTACHMENT B
METHODS VALIDATION PROBLEMS AND DELAY
Listed below are examples of common problems that can delay successful validation. O Failure to provide a sample of a critical impurity, degradation product, internal standard, or novel reagent O Failure to submit well-characterized reference standards for noncompendial drugs O Failure to provide sufficient detail or use of unacceptable analytical procedures. For example: o Use of arbitrary arithmetic corrections o Failure to provide system suitability tests o Differing content uniformity and assay analytical procedures without showing equivalence factors for defining corrections as required by the current USP chapter <905> - Uniformity of Dosage Units O Failure to submit complete or legible data. For example: o Failure to label instrument output to indicate sample identity o Failure to label the axes O Inappropriate shipping procedures. For example: o Failure to properly label samples o Failure to package samples in accordance with product storage conditions o Inadequate shipping forms (e.g., missing customs form for samples from outside the United States) O Failure to describe proper storage conditions on shipping containers
ATTACHMENT B
METHODS VALIDATION PROBLEMS AND DELAY
Listed below are examples of common problems that can delay successful validation. O Failure to provide a sample of a critical impurity, degradation product, internal standard, or novel reagent O Failure to submit well-characterized reference standards for noncompendial drugs O Failure to provide sufficient detail or use of unacceptable analytical procedures. For example: o Use of arbitrary arithmetic corrections o Failure to provide system suitability tests o Differing content uniformity and assay analytical procedures without showing equivalence factors for defining corrections as required by the current USP chapter <905> - Uniformity of Dosage Units O Failure to submit complete or legible data. For example: o Failure to label instrument output to indicate sample identity o Failure to label the axes O Inappropriate shipping procedures. For example: o Failure to properly label samples o Failure to package samples in accordance with product storage conditions o Inadequate shipping forms (e.g., missing customs form for samples from outside the United States) O Failure to describe proper storage conditions on shipping containers
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REFERENCES
FDA DOCUMENTS6
Guidance for Industry: ANDAs: Impurities in Drug Products (Draft, December 1998). Guidance for Industry: ANDAs: Impurities in Drug Substances (February 2000). Guidance for Industry: CMC Content and Format of INDs for Phase 2 and 3 Studies of Drugs, Including Specified Therapeutic BiotechnologyDerived Products (Draft, December 1997). Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including WellCharacterized, Therapeutic, Biotechnology derived Products (February 1995). Guidance for Industry: Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production (Draft, September 1998). Guidance for Industry: Stability Testing of Drug Substances and Drug Products (Draft, June1998). Guidance for Industry: Submission of Chemistry, Manufacturing, and Controls Information for Synthetic Peptide Substances (November 1994). Guidance for Industry: Submitting Documentation for the Stability of Human Drugs and Biologics (February 1987). Reviewer Guidance: Validation of Chromatographic Methods (November 1994). FDA CDER MAPP 5221.1 Requesting Methods Validation for ANDAs (November 1998).
REFERENCES
FDA DOCUMENTS6
Guidance for Industry: ANDAs: Impurities in Drug Products (Draft, December 1998). Guidance for Industry: ANDAs: Impurities in Drug Substances (February 2000). Guidance for Industry: CMC Content and Format of INDs for Phase 2 and 3 Studies of Drugs, Including Specified Therapeutic BiotechnologyDerived Products (Draft, December 1997). Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including WellCharacterized, Therapeutic, Biotechnology derived Products (February 1995). Guidance for Industry: Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production (Draft, September 1998). Guidance for Industry: Stability Testing of Drug Substances and Drug Products (Draft, June1998). Guidance for Industry: Submission of Chemistry, Manufacturing, and Controls Information for Synthetic Peptide Substances (November 1994). Guidance for Industry: Submitting Documentation for the Stability of Human Drugs and Biologics (February 1987). Reviewer Guidance: Validation of Chromatographic Methods (November 1994). FDA CDER MAPP 5221.1 Requesting Methods Validation for ANDAs (November 1998).
6 Draft guidances have been included for completeness only. As draft documents, they are not intended to be implemented until published in final form.
Draft guidances have been included for completeness only. As draft documents, they are not intended to be implemented until published in final form.
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INTERNATIONAL CONFERENCE ON HARMONIZATION GUIDANCES

ICH Q1A: Stability Testing of New Drug Substances and Products (November 1994) ICH Q1B: Photostability Testing of New Drug Substances and Products (November 1996) ICH Q1C: Stability Testing for New Dosage Forms (May 1997) ICH Q2A: Text on Validation of Analytical Procedures (March 1995) ICH Q2B: Validation of Analytical Procedures: Methodology (May 1997) ICH Q3A: Impurities in New Drug Substances (January 1996) ICH Q3B: Impurities in New Drug Products (May 1997) ICH Q3C: Impurities: Residual Solvents (December 1997) ICH Q5C: Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products (July 1996) ICH Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (Draft (Step 2) November 1997) ICH Q6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (March 1999)
INTERNATIONAL CONFERENCE ON HARMONIZATION GUIDANCES

ICH Q1A: Stability Testing of New Drug Substances and Products (November 1994) ICH Q1B: Photostability Testing of New Drug Substances and Products (November 1996) ICH Q1C: Stability Testing for New Dosage Forms (May 1997) ICH Q2A: Text on Validation of Analytical Procedures (March 1995) ICH Q2B: Validation of Analytical Procedures: Methodology (May 1997) ICH Q3A: Impurities in New Drug Substances (January 1996) ICH Q3B: Impurities in New Drug Products (May 1997) ICH Q3C: Impurities: Residual Solvents (December 1997) ICH Q5C: Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products (July 1996) ICH Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (Draft (Step 2) November 1997) ICH Q6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (March 1999)
U.S. PHARMACOPEIA/NATIONAL FORMULARY

Chapter <621> Chromatography; US Pharmacopeia 23, United States Pharmacopeial Convention, Inc., Rockville MD: 1994 Chapter <781> Optical Rotation, US Pharmacopea 23, United States Pharmacopeial Convention, Inc., Rockville, MD: 1994 Chapter <1225> Validation of Compendial Methods; US Pharmacopeia 23, United States Pharmacopeial Convention, Inc., Rockville MD: 1994 Interpretation and Treatment of Analytical Data; USP Pharmacopeial Forum, United States Pharmacopeial Convention, Inc., Rockville MD: 1994, Volume 24, Number 5, pp. 7051 - 7056
U.S. PHARMACOPEIA/NATIONAL FORMULARY

Chapter <621> Chromatography; US Pharmacopeia 23, United States Pharmacopeial Convention, Inc., Rockville MD: 1994 Chapter <781> Optical Rotation, US Pharmacopea 23, United States Pharmacopeial Convention, Inc., Rockville, MD: 1994 Chapter <1225> Validation of Compendial Methods; US Pharmacopeia 23, United States Pharmacopeial Convention, Inc., Rockville MD: 1994 Interpretation and Treatment of Analytical Data; USP Pharmacopeial Forum, United States Pharmacopeial Convention, Inc., Rockville MD: 1994, Volume 24, Number 5, pp. 7051 - 7056
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Miller, J.C., J.N. Miller, and E. Horwood, Statistics for Analytical Chemistry, 3rd edition, Prentice Hall, 1993. Saunders, B.D., and R.G. Trapp, Basic and Clinical Biostatistics, 2nd edition, Appleton and Lange, 1994.
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Miller, J.C., J.N. Miller, and E. Horwood, Statistics for Analytical Chemistry, 3rd edition, Prentice Hall, 1993. Saunders, B.D., and R.G. Trapp, Basic and Clinical Biostatistics, 2nd edition, Appleton and Lange, 1994.
GLOSSARY
Acceptance Criteria: Numerical limits, ranges, or other suitable measures for acceptance of the results of analytical procedures. Active moiety: The molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance (21 CFR 314.108(a)). The active moiety is the entire molecule or ion, not the active site. Detection Limit: The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample that can be detected, but not necessarily quantitated as an exact value. Drug Product: A finished dosage form, for example, a tablet, capsule, or solution that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients (21 CFR 314.3(b)). Drug Substance/Active Ingredient: An active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body. The active ingredient does not include intermediates used in the synthesis of such ingredient. The term includes those components that may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect (21 CFR 210.3(b)(7) and 314.3(b)).
GLOSSARY
Acceptance Criteria: Numerical limits, ranges, or other suitable measures for acceptance of the results of analytical procedures. Active moiety: The molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance (21 CFR 314.108(a)). The active moiety is the entire molecule or ion, not the active site. Detection Limit: The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample that can be detected, but not necessarily quantitated as an exact value. Drug Product: A finished dosage form, for example, a tablet, capsule, or solution that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients (21 CFR 314.3(b)). Drug Substance/Active Ingredient: An active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body. The active ingredient does not include intermediates used in the synthesis of such ingredient. The term includes those components that may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect (21 CFR 210.3(b)(7) and 314.3(b)).
Placebo (or Blank): A dosage form that is identical to the drug product except that the drug substance is absent or replaced by an inert ingredient or a mixture of the drug product excipients quantitatively equivalent to those found in the drug product dosage form. Quantitation Limit: The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample that can be quantitatively determined with suitable precision and accuracy. The quantitation limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and/or degradation products. Reagent: For analytical procedures, any substance used in a reaction for the purpose of detecting, measuring, examining, or analyzing other substances. Specification: The quality standards (i.e., tests, analytical procedures, and acceptance criteria) provided in an approved application to confirm the quality of the drug substances, drug products, intermediates, raw materials, reagents, and other components including container closure systems, and in-process materials. Spiking: The addition of a small known amount of a known compound to a standard, sample, or placebo, typically for the purpose of confirming the performance of an analytical procedure or the calibration of an instrument. Stability-Indicating Assay: A validated quantitative analytical procedure that can detect the changes with time in the pertinent properties (e.g., active ingredient, preservative level) of the drug substance and drug product. A stability-indicating assay accurately measures the active ingredients without interference from degradation products, process impurities, excipients, or other potential impurities. Working Standard: A standard that is qualified against and used instead of the reference standard (also known as in-house or secondary standard).
Placebo (or Blank): A dosage form that is identical to the drug product except that the drug substance is absent or replaced by an inert ingredient or a mixture of the drug product excipients quantitatively equivalent to those found in the drug product dosage form. Quantitation Limit: The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample that can be quantitatively determined with suitable precision and accuracy. The quantitation limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and/or degradation products. Reagent: For analytical procedures, any substance used in a reaction for the purpose of detecting, measuring, examining, or analyzing other substances. Specification: The quality standards (i.e., tests, analytical procedures, and acceptance criteria) provided in an approved application to confirm the quality of the drug substances, drug products, intermediates, raw materials, reagents, and other components including container closure systems, and in-process materials. Spiking: The addition of a small known amount of a known compound to a standard, sample, or placebo, typically for the purpose of confirming the performance of an analytical procedure or the calibration of an instrument. Stability-Indicating Assay: A validated quantitative analytical procedure that can detect the changes with time in the pertinent properties (e.g., active ingredient, preservative level) of the drug substance and drug product. A stability-indicating assay accurately measures the active ingredients without interference from degradation products, process impurities, excipients, or other potential impurities. Working Standard: A standard that is qualified against and used instead of the reference standard (also known as in-house or secondary standard).
Appendix 4
ANALYTICAL METHOD VALIDATION
1. 2. 3. 4. 5. 6. Principle General Pharmacopoeial methods Non-pharmacopoeial methods Method validation Characteristics of analytical procedures
Appendix 4
ANALYTICAL METHOD VALIDATION
1. 2. 3. 4. 5. 6. Principle General Pharmacopoeial methods Non-pharmacopoeial methods Method validation Characteristics of analytical procedures
1. Principle
1.1 This appendix presents some information on the characteristics that should be considered during validation of analytical methods. Approaches other than those specified in this appendix may be followed and may be acceptable. Manufacturers should choose the validation protocol and procedures most suitable for testing of their product. 1.2 The manufacturer should demonstrate (through validation) that the analytical procedure is suitable for its intended purpose. 1.3 Analytical methods, whether or not they indicate stability, should be validated. 1.4 The analytical method should be validated by research and development before being transferred to the quality control unit when appropriate.
1. Principle
1.1 This appendix presents some information on the characteristics that should be considered during validation of analytical methods. Approaches other than those specified in this appendix may be followed and may be acceptable. Manufacturers should choose the validation protocol and procedures most suitable for testing of their product. 1.2 The manufacturer should demonstrate (through validation) that the analytical procedure is suitable for its intended purpose. 1.3 Analytical methods, whether or not they indicate stability, should be validated. 1.4 The analytical method should be validated by research and development before being transferred to the quality control unit when appropriate.
2. General
2.1 There should be specifications for both, materials and products. The tests to be performed should be described in the documentation on standard test methods. 2.2 Specifications and standard test methods in pharmacopoeias (pharmacopoeial methods), or suitably developed specifications or test
2. General
2.1 There should be specifications for both, materials and products. The tests to be performed should be described in the documentation on standard test methods. 2.2 Specifications and standard test methods in pharmacopoeias (pharmacopoeial methods), or suitably developed specifications or test
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methods (non-pharmacopoeial methods) as approved by the national drug regulatory authority may be used. 2.3 Well-characterized reference materials, with documented purity, should be used in the validation study. 2.4 The most common analytical procedures include identification tests, assay of drug substances and pharmaceutical products, quantitative tests for content of impurities and limit tests for impurities. Other analytical procedures include dissolution testing and determination of particle size. 2.5 The results of analytical procedures should be reliable, accurate and reproducible. The characteristics that should be considered during validation of analytical methods are discussed in paragraph 6. 2.6 Verification or revalidation should be performed when relevant, for example, when there are changes in the process for synthesis of the drug substance; changes in the composition of the finished product; changes in the analytical procedure; when analytical methods are transferred from one laboratory to another; or when major pieces of equipment instruments change. 2.7 The verification or degree of revalidation depend on the nature of the change(s). 2.8 There should be evidence that the analysts, who are responsible for certain tests, are appropriately qualified to perform those analyses (analyst proficiency).
methods (non-pharmacopoeial methods) as approved by the national drug regulatory authority may be used. 2.3 Well-characterized reference materials, with documented purity, should be used in the validation study. 2.4 The most common analytical procedures include identification tests, assay of drug substances and pharmaceutical products, quantitative tests for content of impurities and limit tests for impurities. Other analytical procedures include dissolution testing and determination of particle size. 2.5 The results of analytical procedures should be reliable, accurate and reproducible. The characteristics that should be considered during validation of analytical methods are discussed in paragraph 6. 2.6 Verification or revalidation should be performed when relevant, for example, when there are changes in the process for synthesis of the drug substance; changes in the composition of the finished product; changes in the analytical procedure; when analytical methods are transferred from one laboratory to another; or when major pieces of equipment instruments change. 2.7 The verification or degree of revalidation depend on the nature of the change(s). 2.8 There should be evidence that the analysts, who are responsible for certain tests, are appropriately qualified to perform those analyses (analyst proficiency).
3. Pharmacopoeial methods
3.1 When pharmacopoeial methods are used, evidence should be available to prove that such methods are suitable for routine use in the laboratory (verification). 3.2 Pharmacopoeial methods used for determination of content or impurities in pharmaceutical products should also have been demonstrated to be specific with respect to the substance under consideration (no placebo interference).
3. Pharmacopoeial methods
3.1 When pharmacopoeial methods are used, evidence should be available to prove that such methods are suitable for routine use in the laboratory (verification). 3.2 Pharmacopoeial methods used for determination of content or impurities in pharmaceutical products should also have been demonstrated to be specific with respect to the substance under consideration (no placebo interference).
analytical method validation guidance: WHO TRS 937 (2006)
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4. Non-pharmacopoeial methods
4.1 Non-pharmacopoeial methods should be appropriately validated.
4. Non-pharmacopoeial methods
4.1 Non-pharmacopoeial methods should be appropriately validated.
5. Method validation
5.1 Validation should be performed in accordance with the validation protocol. The protocol should include procedures and acceptance criteria for all characteristics. The results should be documented in the validation report. 5.2 Justification should be provided when non-pharmacopoeial methods are used if pharmacopoeial methods are available. Justification should include data such as comparisons with the pharmacopoeial or other methods. 5.3 Standard test methods should be described in detail and should provide sufficient information to allow properly trained analysts to perform the analysis in a reliable manner. As a minimum, the description should include the chromatographic conditions (in the case of chromatographic tests), reagents needed, reference standards, the formulae for the calculation of results and system suitability tests.
5. Method validation
5.1 Validation should be performed in accordance with the validation protocol. The protocol should include procedures and acceptance criteria for all characteristics. The results should be documented in the validation report. 5.2 Justification should be provided when non-pharmacopoeial methods are used if pharmacopoeial methods are available. Justification should include data such as comparisons with the pharmacopoeial or other methods. 5.3 Standard test methods should be described in detail and should provide sufficient information to allow properly trained analysts to perform the analysis in a reliable manner. As a minimum, the description should include the chromatographic conditions (in the case of chromatographic tests), reagents needed, reference standards, the formulae for the calculation of results and system suitability tests.
6. Characteristics of analytical procedures

6.1 Characteristics that should be considered during validation of analytical methods include: specificity linearity range accuracy precision detection limit quantitation limit robustness.
6. Characteristics of analytical procedures

6.1 Characteristics that should be considered during validation of analytical methods include: specificity linearity range accuracy precision detection limit quantitation limit robustness.
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6.1.1 Accuracy is the degree of agreement of test results with the true value, or the closeness of the results obtained by the procedure to the true value. It is normally established on samples of the material to be examined that have been prepared to quantitative accuracy. Accuracy should be established across the specified range of the analytical procedure. Note: it is acceptable to use a spiked placebo where a known quantity or concentration of a reference material is used. 6.1.2 Precision is the degree of agreement among individual results. The complete procedure should be applied repeatedly to separate, identical samples drawn from the same homogeneous batch of material. It should be measured by the scatter of individual results from the mean (good grouping) and expressed as the relative standard deviation (RSD). 6.1.2.1 Repeatability should be assessed using a minimum of nine determinations covering the specified range for the procedure e.g. three concentrations/three replicates each, or a minimum of six determinations at 100% of the test concentration. 6.1.2.2 Intermediate precision expresses within-laboratory variations (usually on different days, different analysts and different equipment). If reproducibility is assessed, a measure of intermediate precision is not required. 6.1.2.3 Reproducibility expresses precision between laboratories. 6.1.3 Robustness (or ruggedness) is the ability of the procedure to provide analytical results of acceptable accuracy and precision under a variety of conditions. The results from separate samples are influenced by changes in the operational or environmental conditions. Robustness should be considered during the development phase, and should show the reliability of an analysis when deliberate variations are made in method parameters. 6.1.3.1 Factors that can have an effect on robustness when performing chromatographic analysis include: stability of test and standard samples and solutions; reagents (e.g. different suppliers); different columns (e.g. different lots and/or suppliers);
6.1.1 Accuracy is the degree of agreement of test results with the true value, or the closeness of the results obtained by the procedure to the true value. It is normally established on samples of the material to be examined that have been prepared to quantitative accuracy. Accuracy should be established across the specified range of the analytical procedure. Note: it is acceptable to use a spiked placebo where a known quantity or concentration of a reference material is used. 6.1.2 Precision is the degree of agreement among individual results. The complete procedure should be applied repeatedly to separate, identical samples drawn from the same homogeneous batch of material. It should be measured by the scatter of individual results from the mean (good grouping) and expressed as the relative standard deviation (RSD). 6.1.2.1 Repeatability should be assessed using a minimum of nine determinations covering the specified range for the procedure e.g. three concentrations/three replicates each, or a minimum of six determinations at 100% of the test concentration. 6.1.2.2 Intermediate precision expresses within-laboratory variations (usually on different days, different analysts and different equipment). If reproducibility is assessed, a measure of intermediate precision is not required. 6.1.2.3 Reproducibility expresses precision between laboratories. 6.1.3 Robustness (or ruggedness) is the ability of the procedure to provide analytical results of acceptable accuracy and precision under a variety of conditions. The results from separate samples are influenced by changes in the operational or environmental conditions. Robustness should be considered during the development phase, and should show the reliability of an analysis when deliberate variations are made in method parameters. 6.1.3.1 Factors that can have an effect on robustness when performing chromatographic analysis include: stability of test and standard samples and solutions; reagents (e.g. different suppliers); different columns (e.g. different lots and/or suppliers);
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extraction time; variations of pH of a mobile phase; variations in mobile phase composition; temperature; and flow rate. 6.1.4 Linearity indicates the ability to produce results that are directly proportional to the concentration of the analyte in samples. A series of samples should be prepared in which the analyte concentrations span the claimed range of the procedure. If there is a linear relationship, test results should be evaluated by appropriate statistical methods. A minimum of five concentrations should be used. 6.1.5 Range is an expression of the lowest and highest levels of analyte that have been demonstrated to be determinable for the product. The specified range is normally derived from linearity studies. 6.1.6 Specificity (selectivity) is the ability to measure unequivocally the desired analyte in the presence of components such as excipients and impurities that may also be expected to be present. An investigation of specificity should be conducted during the validation of identification tests, the determination of impurities and assay. 6.1.7 Detection limit (limit of detection) is the smallest quantity of an analyte that can be detected, and not necessarily determined, in a quantitative fashion. Approaches may include instrumental or noninstrumental procedures and could include those based on: visual evaluation; signal to noise ratio; standard deviation of the response and the slope; standard deviation of the blank; and calibration curve.
extraction time; variations of pH of a mobile phase; variations in mobile phase composition; temperature; and flow rate. 6.1.4 Linearity indicates the ability to produce results that are directly proportional to the concentration of the analyte in samples. A series of samples should be prepared in which the analyte concentrations span the claimed range of the procedure. If there is a linear relationship, test results should be evaluated by appropriate statistical methods. A minimum of five concentrations should be used. 6.1.5 Range is an expression of the lowest and highest levels of analyte that have been demonstrated to be determinable for the product. The specified range is normally derived from linearity studies. 6.1.6 Specificity (selectivity) is the ability to measure unequivocally the desired analyte in the presence of components such as excipients and impurities that may also be expected to be present. An investigation of specificity should be conducted during the validation of identification tests, the determination of impurities and assay. 6.1.7 Detection limit (limit of detection) is the smallest quantity of an analyte that can be detected, and not necessarily determined, in a quantitative fashion. Approaches may include instrumental or noninstrumental procedures and could include those based on: visual evaluation; signal to noise ratio; standard deviation of the response and the slope; standard deviation of the blank; and calibration curve.
6.1.8 Quantitation limit (limit of quantitation) is the lowest concentration of an analyte in a sample that may be determined with acceptable accuracy and precision. Approaches may include instrumental or non-instrumental procedures and could include those based on: visual evaluation;
6.1.8 Quantitation limit (limit of quantitation) is the lowest concentration of an analyte in a sample that may be determined with acceptable accuracy and precision. Approaches may include instrumental or non-instrumental procedures and could include those based on: visual evaluation;
signal to noise ratio; standard deviation of the response and the slope; standard deviation of the blank; and calibration curve.
signal to noise ratio; standard deviation of the response and the slope; standard deviation of the blank; and calibration curve.
6.2 Characteristics (including tests) that should be considered when using different types of analytical procedures are summarized in Table 1.
Table 1 Characteristics to consider during analytical validation
Type of analytical Identifi cation procedure Testing for impurities Testing for impurities Assay dissolution (measurement only) content/potency
6.2 Characteristics (including tests) that should be considered when using different types of analytical procedures are summarized in Table 1.
Table 1 Characteristics to consider during analytical validation
Type of analytical Identifi cation procedure Testing for impurities Testing for impurities Assay dissolution (measurement only) content/potency
Characteristics
Quantitative tests + + + + + b + + +
Limit tests
Characteristics
Quantitative tests + + + + + b + + +
Limit tests
Accuracy Precision Repeatability Intermediate precisiona Specifi city Detection limit Quantitation limit Linearity Range + a b
+ +
+ + + + + +
Accuracy Precision Repeatability Intermediate precisiona Specifi city Detection limit Quantitation limit Linearity Range + a b
+ +
+ + + + + +
Characteristic is normally not evaluated; Characteristic should normally be evaluated. In cases where a reproducibility study has been performed, intermediate precision is not needed. May be needed in some cases.
Characteristic is normally not evaluated; Characteristic should normally be evaluated. In cases where a reproducibility study has been performed, intermediate precision is not needed. May be needed in some cases.
6.3 System suitability testing System suitability testing is an integral part of many analytical procedures. The tests are based on the concept that the equipment, electronics, analytical operations and samples to be analysed constitute an integral system that can be evaluated as such. System suitability test parameters that need to be established for a particular procedure depend on the type of procedure being evaluated, for instance, a resolution test for an HPLC procedure.
6.3 System suitability testing System suitability testing is an integral part of many analytical procedures. The tests are based on the concept that the equipment, electronics, analytical operations and samples to be analysed constitute an integral system that can be evaluated as such. System suitability test parameters that need to be established for a particular procedure depend on the type of procedure being evaluated, for instance, a resolution test for an HPLC procedure.
validation of analytical methods
validation of analytical methods
validation of analytical methods: review and strategy

DR LUDWIG HUBER, AGILENT TECHNOLOGIES
validation of analytical methods: review and strategy

DR LUDWIG HUBER, AGILENT TECHNOLOGIES
1. ABSTRACT
The process of analytical methods validation should demonstrate that the method is fit for its purpose. The validation should follow a plan that includes the scope of the method, the method performance characteristics and acceptance limits. Parameters usually examined in the validation process are limits of detection and quantitation, accuracy, precision, selectivity/ specificity, linearity, range and ruggedness. A validation report should be generated with all experimental conditions and the complete statistics. When standard methods are used in the laboratory, their scope should be in line with the scope of the laboratories method requirements and the suitability of the entire analytical system in the specific laboratorys environment should be verified for the method.
1. ABSTRACT
The process of analytical methods validation should demonstrate that the method is fit for its purpose. The validation should follow a plan that includes the scope of the method, the method performance characteristics and acceptance limits. Parameters usually examined in the validation process are limits of detection and quantitation, accuracy, precision, selectivity/ specificity, linearity, range and ruggedness. A validation report should be generated with all experimental conditions and the complete statistics. When standard methods are used in the laboratory, their scope should be in line with the scope of the laboratories method requirements and the suitability of the entire analytical system in the specific laboratorys environment should be verified for the method.
2. INTRODUCTION
Method validation is the process to confirm that the analytical procedure employed for a specific test is suitable for its intended use. Methods need to be validated or revalidated before their introduction into routine use whenever the conditions change for which the method has been validated, e.g., instrument with different characteristics whenever the method is changed, and the change is outside the original scope of the method.
2. INTRODUCTION
Method validation is the process to confirm that the analytical procedure employed for a specific test is suitable for its intended use. Methods need to be validated or revalidated before their introduction into routine use whenever the conditions change for which the method has been validated, e.g., instrument with different characteristics whenever the method is changed, and the change is outside the original scope of the method.
Method validation has received considerable attention in literature and from industrial committees and regulatory agencies. The Guidance on the Interpretation of the EN 45000 Series of Standards and ISO/IEC Guide 25
Method validation has received considerable attention in literature and from industrial committees and regulatory agencies. The Guidance on the Interpretation of the EN 45000 Series of Standards and ISO/IEC Guide 25
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includes a chapter on the validation of methods (1) with a list of nine validation parameters. The International Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use (2) has developed a consensus text on the validation of analytical procedures. The document includes definitions for eight validation characteristics. An extension with more detailed methodology is in preparation and nearly completed (3). The United States Environmental Protection Agency (US EPA) prepared a guidance for methods development and validation for the Resource Conservation and Recovery Act (RCRA) (4). The American Association of Official Analytical Chemists (AOAC), the United States Environmental Protection Agency (USP) and other scientific organizations provide methods that are validated through multilaboratory studies. The United States Food and Drug Administration (US FDA) has proposed guidelines on submitting samples and analytical data for methods validation (5-7). The United States Pharmacopoeia (USP) has published specific guidelines for method validation for compound evaluation (8). There are no official guidelines referring to biological fluids. The pharmaceutical industry uses methodology published in the literature (9,10). The most comprehensive document was published as the Conference Report of the Washington Conference on Analytical Methods Validation: Bioavailability, Bioequivalence and Pharmacokinetic Studies held in 1990 (sponsored by the American Association of Pharmaceutical Scientists, the AOAC and the US FDA, among others) (10). The report presents guiding principles for validation of studies in both human and animal subjects that may be referred to in developing future formal guidelines. Representatives of the pharmaceutical and chemical industry have published papers on the validation of analytical methods. Hokanson (11,12 ) applied the life cycle approach, developed for computerized systems, to the validation and revalidation of methods. Green (13) gave a practical guide for analytical method validation with a description of a set of minimum requirements for a method. Renger and his colleagues (14) described the validation of a specific analytical procedure for the analysis of theophylline in a tablet using high performance thin layer chromatography (HPTLC). The validation procedure in that article is based on requirements for European Union multistate registration. Wegscheider (15) has published
includes a chapter on the validation of methods (1) with a list of nine validation parameters. The International Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use (2) has developed a consensus text on the validation of analytical procedures. The document includes definitions for eight validation characteristics. An extension with more detailed methodology is in preparation and nearly completed (3). The United States Environmental Protection Agency (US EPA) prepared a guidance for methods development and validation for the Resource Conservation and Recovery Act (RCRA) (4). The American Association of Official Analytical Chemists (AOAC), the United States Environmental Protection Agency (USP) and other scientific organizations provide methods that are validated through multilaboratory studies. The United States Food and Drug Administration (US FDA) has proposed guidelines on submitting samples and analytical data for methods validation (5-7). The United States Pharmacopoeia (USP) has published specific guidelines for method validation for compound evaluation (8). There are no official guidelines referring to biological fluids. The pharmaceutical industry uses methodology published in the literature (9,10). The most comprehensive document was published as the Conference Report of the Washington Conference on Analytical Methods Validation: Bioavailability, Bioequivalence and Pharmacokinetic Studies held in 1990 (sponsored by the American Association of Pharmaceutical Scientists, the AOAC and the US FDA, among others) (10). The report presents guiding principles for validation of studies in both human and animal subjects that may be referred to in developing future formal guidelines. Representatives of the pharmaceutical and chemical industry have published papers on the validation of analytical methods. Hokanson (11,12 ) applied the life cycle approach, developed for computerized systems, to the validation and revalidation of methods. Green (13) gave a practical guide for analytical method validation with a description of a set of minimum requirements for a method. Renger and his colleagues (14) described the validation of a specific analytical procedure for the analysis of theophylline in a tablet using high performance thin layer chromatography (HPTLC). The validation procedure in that article is based on requirements for European Union multistate registration. Wegscheider (15) has published
validation of analytical methods: theory and practical guide
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procedures for method validation with special focus on calibration, recovery experiments, method comparison and investigation of ruggedness. The association of official analytical chemists (AOAC) (16) has developed a Peer-Verified Methods validation program with detailed guidelines on what parameters should be validated. This article gives a review and a strategy for the validation of analytical methods for both in-house developed as well as standard methods and a recommendation on the documentation that should be produced during and at the end of method validation.
procedures for method validation with special focus on calibration, recovery experiments, method comparison and investigation of ruggedness. The association of official analytical chemists (AOAC) (16) has developed a Peer-Verified Methods validation program with detailed guidelines on what parameters should be validated. This article gives a review and a strategy for the validation of analytical methods for both in-house developed as well as standard methods and a recommendation on the documentation that should be produced during and at the end of method validation.
3. STRATEGY FOR VALIDATION OF METHODS

The validity of a specific method should be demonstrated in laboratory experiments using samples or standards that are similar 1. Develop a validation protocol or operating procedure for the validation 2. Define the application, purpose and scope of the method 3. Define the performance parameters and acceptance criteria 4. Define validation experiments 5. Verify relevant performance characteristics of equipment 6. Qualify materials, e.g. standards and reagents 7. Perform pre-validation experiments 8. Adjust method parameters or/and acceptance criteria if necessary 9. Perform full internal (and external) validation experiments 10. Develop SOPs for executing the method in the routine 11. Define criteria for revalidation 12. Define type and frequency of system suitability tests and/or analytical quality control (AQC) checks for the routine 13. Document validation experiments and results in the validation report
Table 1. Steps in Method Validation
3. STRATEGY FOR VALIDATION OF METHODS

The validity of a specific method should be demonstrated in laboratory experiments using samples or standards that are similar 1. Develop a validation protocol or operating procedure for the validation 2. Define the application, purpose and scope of the method 3. Define the performance parameters and acceptance criteria 4. Define validation experiments 5. Verify relevant performance characteristics of equipment 6. Qualify materials, e.g. standards and reagents 7. Perform pre-validation experiments 8. Adjust method parameters or/and acceptance criteria if necessary 9. Perform full internal (and external) validation experiments 10. Develop SOPs for executing the method in the routine 11. Define criteria for revalidation 12. Define type and frequency of system suitability tests and/or analytical quality control (AQC) checks for the routine 13. Document validation experiments and results in the validation report
Table 1. Steps in Method Validation
to the unknown samples analyzed in the routine. The preparation and execution should follow a validation protocol, preferably written in a step
to the unknown samples analyzed in the routine. The preparation and execution should follow a validation protocol, preferably written in a step
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by step instruction format. Possible steps for a complete method validation are listed in Table 1. First the scope of the method and its validation criteria should be defined. These include: compounds, matrices, type of information: qualitative or quantitative, detection and quantitation limits, linear range, precision and accuracy type of equipment and location
by step instruction format. Possible steps for a complete method validation are listed in Table 1. First the scope of the method and its validation criteria should be defined. These include: compounds, matrices, type of information: qualitative or quantitative, detection and quantitation limits, linear range, precision and accuracy type of equipment and location
The methods performance characteristics should be based on the intended use of the method. For example, if the method will be used for qualitative trace level analysis, there is no need to test and validate the methods linearity over the full dynamic range of the equipment. Initial parameters should be chosen according to the analysts best judgment. Finally, parameters should be agreed between the lab generating the data and the client using the data. The scope of the method should include the different types of equipment and the locations where the method will be run. For example, if the method is to be run on one specific instrument in one specific laboratory, there is no need to use instruments from other vendors or to include other laboratories in the validation experiments. In this way the experiments can be limited to what is really necessary. Before an instrument is used to validate a method, its performance should be verified using generic standards (18,19). Satisfactory results for a method can only be obtained with well-performing equipment. Special attention should be paid to the equipment characteristics that are critical for the method. For example, if detection limit is critical for a specific method, the instruments specification for baseline noise and, for certain detectors also the response to specified compounds, should be verified. Any material used to determine critical validation parameters, such as reagents and reference standards, should be checked for accurate composition and purity.
The methods performance characteristics should be based on the intended use of the method. For example, if the method will be used for qualitative trace level analysis, there is no need to test and validate the methods linearity over the full dynamic range of the equipment. Initial parameters should be chosen according to the analysts best judgment. Finally, parameters should be agreed between the lab generating the data and the client using the data. The scope of the method should include the different types of equipment and the locations where the method will be run. For example, if the method is to be run on one specific instrument in one specific laboratory, there is no need to use instruments from other vendors or to include other laboratories in the validation experiments. In this way the experiments can be limited to what is really necessary. Before an instrument is used to validate a method, its performance should be verified using generic standards (18,19). Satisfactory results for a method can only be obtained with well-performing equipment. Special attention should be paid to the equipment characteristics that are critical for the method. For example, if detection limit is critical for a specific method, the instruments specification for baseline noise and, for certain detectors also the response to specified compounds, should be verified. Any material used to determine critical validation parameters, such as reagents and reference standards, should be checked for accurate composition and purity.
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If there is no or little information on the methods performance characteristics, it is recommended to prove the methods suitability for its intended use in initial experiments. These studies should include the approximate precision, working range and detection limits. If the preliminary validation data appear to be inappropriate, either the method itself, the equipment, the analysis technique or the acceptance limits should be changed. In this way method development and validation is an iterative process. For example, in liquid chromatography selectivity is achieved through selection of mobile phase composition. For quantitative measurements the resolution factor between two peaks should be 2.5 or higher. If this value is not achieved, the mobile phase composition needs further optimization. There are no official guidelines on the sequence of validation experiments and the optimal sequence can depend on the method itself. Based on my experience, for a liquid chromatographic method the following sequence has been proven to be useful: 1. selectivity of standards (optimizing separation and detection of standard mixtures) 2. precision of retention times and peak areas 3. linearity, limit of quantitation, limit of detection, range 4. selectivity with real samples 5. trueness/accuracy, at different concentrations 6. ruggedness (interlaboratory studies) The more time consuming experiments such as accuracy and ruggedness are put towards the end. Some of the parameters as listed under two to five can be measured in combined experiments. For example, when the precision of peak areas is measured over the full concentration range, the data can be used to validate the linearity. During method validation the parameters, acceptance limits and frequency of ongoing system suitability tests or quality control checks should be defined. Criteria should be defined to indicate when the method and system are out of statistical control. The goal is to optimize these experiments such that with a minimum number of control analyses the method and the complete analytical system will provide long-term results that will meet the objectives defined in the scope of the method.
If there is no or little information on the methods performance characteristics, it is recommended to prove the methods suitability for its intended use in initial experiments. These studies should include the approximate precision, working range and detection limits. If the preliminary validation data appear to be inappropriate, either the method itself, the equipment, the analysis technique or the acceptance limits should be changed. In this way method development and validation is an iterative process. For example, in liquid chromatography selectivity is achieved through selection of mobile phase composition. For quantitative measurements the resolution factor between two peaks should be 2.5 or higher. If this value is not achieved, the mobile phase composition needs further optimization. There are no official guidelines on the sequence of validation experiments and the optimal sequence can depend on the method itself. Based on my experience, for a liquid chromatographic method the following sequence has been proven to be useful: 1. selectivity of standards (optimizing separation and detection of standard mixtures) 2. precision of retention times and peak areas 3. linearity, limit of quantitation, limit of detection, range 4. selectivity with real samples 5. trueness/accuracy, at different concentrations 6. ruggedness (interlaboratory studies) The more time consuming experiments such as accuracy and ruggedness are put towards the end. Some of the parameters as listed under two to five can be measured in combined experiments. For example, when the precision of peak areas is measured over the full concentration range, the data can be used to validate the linearity. During method validation the parameters, acceptance limits and frequency of ongoing system suitability tests or quality control checks should be defined. Criteria should be defined to indicate when the method and system are out of statistical control. The goal is to optimize these experiments such that with a minimum number of control analyses the method and the complete analytical system will provide long-term results that will meet the objectives defined in the scope of the method.
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A validation report should be prepared that includes: objective and scope of the method (applicability, type) type of compounds and matrix detailed chemicals, reagents, reference standards and control sample preparations procedures for quality checks of standards and chemicals used safety considerations method parameters critical parameters indicated from robustness testing listing of equipment and its functional and performance requirements, e.g. cell dimensions, baseline noise, column temperature range detailed conditions on how the experiments were conducted, including sample preparation statistical procedures and representative calculations procedures for quality control in the routine (e.g., system suitability tests) representative plots, e.g. chromatograms, spectra and calibration curves method acceptance limit performance data the expected uncertainty of measurement results criteria for revalidation person who developed and initially validated the method summary and conclusions
A validation report should be prepared that includes: objective and scope of the method (applicability, type) type of compounds and matrix detailed chemicals, reagents, reference standards and control sample preparations procedures for quality checks of standards and chemicals used safety considerations method parameters critical parameters indicated from robustness testing listing of equipment and its functional and performance requirements, e.g. cell dimensions, baseline noise, column temperature range detailed conditions on how the experiments were conducted, including sample preparation statistical procedures and representative calculations procedures for quality control in the routine (e.g., system suitability tests) representative plots, e.g. chromatograms, spectra and calibration curves method acceptance limit performance data the expected uncertainty of measurement results criteria for revalidation person who developed and initially validated the method summary and conclusions
4. VALIDATION OF STANDARD METHODS

A laboratory applying a specific method should have documentary evidence that the method has been appropriately validated. The responsibility remains firmly with the user to ensure that the validation documented in the method is sufficiently complete to meet his or her needs. (1) This holds for standard methods, for example, from EPA, ASTM, ISO or USP, as well as for methods developed in-house. If standard methods are used, it should be verified that the scope of the method and validation data, for example, sample matrix, linearity, range and detection limits comply with the laboratorys analyses requirements; otherwise, the validation of the standard
4. VALIDATION OF STANDARD METHODS

A laboratory applying a specific method should have documentary evidence that the method has been appropriately validated. The responsibility remains firmly with the user to ensure that the validation documented in the method is sufficiently complete to meet his or her needs. (1) This holds for standard methods, for example, from EPA, ASTM, ISO or USP, as well as for methods developed in-house. If standard methods are used, it should be verified that the scope of the method and validation data, for example, sample matrix, linearity, range and detection limits comply with the laboratorys analyses requirements; otherwise, the validation of the standard
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method should be repeated using the laboratorys own criteria. The laboratory should demonstrate the validity of the method in the laboratories environment. Full validation of a standard method is recommended where no information on type and results of validation can be found in the standard method documentation.
method should be repeated using the laboratorys own criteria. The laboratory should demonstrate the validity of the method in the laboratories environment. Full validation of a standard method is recommended where no information on type and results of validation can be found in the standard method documentation.
5. REVALIDATION
Operating ranges should be defined for each method based on experience with similar methods, or they should be investigated during method developments. These ranges should be verified during method validation in robustness studies and should be part of the method characteristics. Availability of such operating ranges makes it easier to decide when a method should be revalidated. A revalidation is necessary whenever a method is changed and the new parameter is outside the operating range. If, for example, the operating range of the column temperature has been specified to be between 30 and 40 C, the method should be revalidated if, for whatever reason, the new operating parameter has been selected as 41 C. Revalidation is also required if the sample matrix changes and if the instrument type changes, for example if a brand with significantly different instrument characteristics is used. For example, a revalidation is necessary, if a High-Performance Liquid Chromatographic method has been developed and validated on a pump with a delay volume of 5 ml and the new pump only has 0.5 ml. Part or full revalidation may also be considered if system suitability tests or the results of quality control sample analysis are out of preset acceptance criteria and the source of the error can not be tracked back to instruments or anything else.
5. REVALIDATION
Operating ranges should be defined for each method based on experience with similar methods, or they should be investigated during method developments. These ranges should be verified during method validation in robustness studies and should be part of the method characteristics. Availability of such operating ranges makes it easier to decide when a method should be revalidated. A revalidation is necessary whenever a method is changed and the new parameter is outside the operating range. If, for example, the operating range of the column temperature has been specified to be between 30 and 40 C, the method should be revalidated if, for whatever reason, the new operating parameter has been selected as 41 C. Revalidation is also required if the sample matrix changes and if the instrument type changes, for example if a brand with significantly different instrument characteristics is used. For example, a revalidation is necessary, if a High-Performance Liquid Chromatographic method has been developed and validated on a pump with a delay volume of 5 ml and the new pump only has 0.5 ml. Part or full revalidation may also be considered if system suitability tests or the results of quality control sample analysis are out of preset acceptance criteria and the source of the error can not be tracked back to instruments or anything else.
6. PARAMETERS FOR METHOD VALIDATION

The parameters for method validation have been defined in different working groups of national and international committees and are described in literature. Unfortunately some of the definitions are different between different organizations. An attempt for harmonization was made for pharmaceutical applications through the International Conference on
6. PARAMETERS FOR METHOD VALIDATION

The parameters for method validation have been defined in different working groups of national and international committees and are described in literature. Unfortunately some of the definitions are different between different organizations. An attempt for harmonization was made for pharmaceutical applications through the International Conference on
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Harmonization (2,3) where representatives from the industry and regulatory agencies from USA, Europe and Japan defined parameters, requirements and, to some extent, also methodology for analytical methods validation. The parameters as defined by the ICH and by other organizations and authors are summarized in Table 2 and described in brief in the following paragraphs.
Harmonization (2,3) where representatives from the industry and regulatory agencies from USA, Europe and Japan defined parameters, requirements and, to some extent, also methodology for analytical methods validation. The parameters as defined by the ICH and by other organizations and authors are summarized in Table 2 and described in brief in the following paragraphs.
7. SELECTIVITY/SPECIFITY
The terms selectivity and specificity are often used interchangeably. A detailed discussion of this term as defined by different organizations has been made by Vessmann (17). He particularly pointed out the difference between the specificity as defined by IUPAC/WELAC and ICH. (IUPAC:
7. SELECTIVITY/SPECIFITY
The terms selectivity and specificity are often used interchangeably. A detailed discussion of this term as defined by different organizations has been made by Vessmann (17). He particularly pointed out the difference between the specificity as defined by IUPAC/WELAC and ICH. (IUPAC:
Specificity (*) Selectivity Precision (*) repeatability (*) intermediate precision (*) reproducibility (**) Accuracy (*) Trueness Bias Linearity (*) Range (*) Limit of detection (*) Limit of quantitation (*) Robustness (**) Ruggedness
Table 2. Possible parameters for method validation
Specificity (*) Selectivity Precision (*) repeatability (*) intermediate precision (*) reproducibility (**) Accuracy (*) Trueness Bias Linearity (*) Range (*) Limit of detection (*) Limit of quantitation (*) Robustness (**) Ruggedness
Table 2. Possible parameters for method validation
(*) Included in ICH publications (**) Terminology included in ICH publication but are not part of required parameters
(*) Included in ICH publications (**) Terminology included in ICH publication but are not part of required parameters
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International Union of Pure and Applied Chemistry, WELAC: Western European Laboratory Accreditation Conference). Even inconsistent with ICH, the term specific generally refers to a method that produces a response for a single analyte only while the term selective refers to a method which provides responses for a number of chemical entities that may or may not be distinguished from each other. If the response is distinguished from all other responses, the method is said to be selective. Since there are very few methods that respond to only one analyte, the term selectivity is usually more appropriate. The USP monograph (8) defines selectivity of an analytical method as its ability to measure accurately an analyte in the presence of interference, such as synthetic precursors, excipients, enantiomers and known (or likely) degradation products that may be expected to be present in the sample matrix. Selectivity in liquid chromatography is obtained by choosing optimal columns and setting chromatographic conditions, such as mobile phase composition, column temperature and detector wavelength.
International Union of Pure and Applied Chemistry, WELAC: Western European Laboratory Accreditation Conference). Even inconsistent with ICH, the term specific generally refers to a method that produces a response for a single analyte only while the term selective refers to a method which provides responses for a number of chemical entities that may or may not be distinguished from each other. If the response is distinguished from all other responses, the method is said to be selective. Since there are very few methods that respond to only one analyte, the term selectivity is usually more appropriate. The USP monograph (8) defines selectivity of an analytical method as its ability to measure accurately an analyte in the presence of interference, such as synthetic precursors, excipients, enantiomers and known (or likely) degradation products that may be expected to be present in the sample matrix. Selectivity in liquid chromatography is obtained by choosing optimal columns and setting chromatographic conditions, such as mobile phase composition, column temperature and detector wavelength.
Figure 1. Examples of pure and impure HPLC peaks.
Figure 1. Examples of pure and impure HPLC peaks.
The chromatographic signal does not indicate any impurity in either peak. Spectral evaluation, however, identifies the peak on the left as impure.
The chromatographic signal does not indicate any impurity in either peak. Spectral evaluation, however, identifies the peak on the left as impure.
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It is a difficult task in chromatography to ascertain whether the peaks within a sample chromatogram are pure or consist of more than one compound. While in the past chromatographic parameters such as mobile phase composition or the column have been modified, more recently the application of spectroscopic detectors coupled on-line to the chromatograph have been suggested (3,5). UV/Visible diode-array detectors and massspectrometers acquire spectra on-line throughout the entire chromatogram. The spectra acquired during the elution of a peak are normalized and overlaid for graphical presentation. If the normalized spectra are different, the peak consists of at least two compounds. The principles of diode-array detection in HPLC and their application and limitations to peak purity are described in the literature (20-22). Examples of pure and impure HPLC peaks are shown in Figure 1. While the chromatographic signal indicates no impurities in either peak, the spectral evaluation identifies the peak on the left as impure. The level of impurities that can be detected with this method depends on the spectral difference, on the detectors performance and on the software algorithm. Under ideal conditions, peak impurities of 0.05 to 0.1% can be detected.
It is a difficult task in chromatography to ascertain whether the peaks within a sample chromatogram are pure or consist of more than one compound. While in the past chromatographic parameters such as mobile phase composition or the column have been modified, more recently the application of spectroscopic detectors coupled on-line to the chromatograph have been suggested (3,5). UV/Visible diode-array detectors and massspectrometers acquire spectra on-line throughout the entire chromatogram. The spectra acquired during the elution of a peak are normalized and overlaid for graphical presentation. If the normalized spectra are different, the peak consists of at least two compounds. The principles of diode-array detection in HPLC and their application and limitations to peak purity are described in the literature (20-22). Examples of pure and impure HPLC peaks are shown in Figure 1. While the chromatographic signal indicates no impurities in either peak, the spectral evaluation identifies the peak on the left as impure. The level of impurities that can be detected with this method depends on the spectral difference, on the detectors performance and on the software algorithm. Under ideal conditions, peak impurities of 0.05 to 0.1% can be detected.
8. PRECISION AND REPRODUCIBILITY

The precision of a method is the extent to which the individual test results of multiple injections of a series of standards agree. The measured standard deviation can be subdivided into three categories: repeatability, intermediate precision and reproducibility (2,3). Repeatability is obtained when the analysis is carried out in one laboratory by one operator using one piece of equipment over a relatively short timespan. At least 5 or 6 determinations of three different matrices at two or three different concentrations should be done and the relative standard deviation calculated. The acceptance criteria for precision depend very much on the type of analysis. While for compound analysis in pharmaceutical quality control precision of better than 1 % RSD is easily achieved, for biological samples the precision is more like 15% at the concentration limits and 10% at other concentration levels. For environmental and food samples, the precision is very much
8. PRECISION AND REPRODUCIBILITY

The precision of a method is the extent to which the individual test results of multiple injections of a series of standards agree. The measured standard deviation can be subdivided into three categories: repeatability, intermediate precision and reproducibility (2,3). Repeatability is obtained when the analysis is carried out in one laboratory by one operator using one piece of equipment over a relatively short timespan. At least 5 or 6 determinations of three different matrices at two or three different concentrations should be done and the relative standard deviation calculated. The acceptance criteria for precision depend very much on the type of analysis. While for compound analysis in pharmaceutical quality control precision of better than 1 % RSD is easily achieved, for biological samples the precision is more like 15% at the concentration limits and 10% at other concentration levels. For environmental and food samples, the precision is very much
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dependent on the sample matrix, the concentration of the analyte and on the analysis technique. It can vary between 2% and more than 20%. The AOAC manual for the Peer Verified Methods program (16) includes a table with estimated precision data as a function of analyte concentration. Analyte % 100 10 1 0.1 0.01 0.001 0.0001 0.00001 0.000001 0.0000001 Analyte ratio 1 10-1 10-2 10-3 10-4 10-5 10-6 10-7 10-8 10-9
(Ref. 16)
dependent on the sample matrix, the concentration of the analyte and on the analysis technique. It can vary between 2% and more than 20%. The AOAC manual for the Peer Verified Methods program (16) includes a table with estimated precision data as a function of analyte concentration. Analyte % 100 10 1 0.1 0.01 0.001 0.0001 0.00001 0.000001 0.0000001 Analyte ratio 1 10-1 10-2 10-3 10-4 10-5 10-6 10-7 10-8 10-9
(Ref. 16)
Unit 100% 10% 1% 0.1 % 100 ppm 10 ppm 1 ppm 100 ppb 10 ppb 1 ppb
RSD (%) 1.3 2.8 2.7 3.7 5.3 7.3 11 15 21 30
Unit 100% 10% 1% 0.1 % 100 ppm 10 ppm 1 ppm 100 ppb 10 ppb 1 ppb
RSD (%) 1.3 2.8 2.7 3.7 5.3 7.3 11 15 21 30
Table 3. Analyte concentration versus precision within or between days
Table 3. Analyte concentration versus precision within or between days
Intermediate precision is a term that has been defined by ICH (2) as the long-term variability of the measurement process and is determined by comparing the results of a method run within a single laboratory over a number of weeks. A methods intermediate precision may reflect discrepancies in results obtained by different operators, from different instruments, with standards and reagents from different suppliers, with columns from different batches or a combination of these. The objective of intermediate precision validation is to verify that in the same laboratory the method will provide the same results once the development phase is over. Reproducibility as defined by ICH (2,3) represents the precision obtained between laboratories. The objective is to verify that the method will provide
Intermediate precision is a term that has been defined by ICH (2) as the long-term variability of the measurement process and is determined by comparing the results of a method run within a single laboratory over a number of weeks. A methods intermediate precision may reflect discrepancies in results obtained by different operators, from different instruments, with standards and reagents from different suppliers, with columns from different batches or a combination of these. The objective of intermediate precision validation is to verify that in the same laboratory the method will provide the same results once the development phase is over. Reproducibility as defined by ICH (2,3) represents the precision obtained between laboratories. The objective is to verify that the method will provide
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the same results in different laboratories. The reproducibility of an analytical method is determined by analyzing aliquots from homogeneous lots in different laboratories with different analysts and by using operational and environmental conditions that may differ from but are still within the specified parameters of the method (interlaboratory tests). Validation of reproducibility is important if the method will used in different laboratories. Differences in room temperature and humidity Operators with different experience and thoroughness Equipment with different characteristics, e.g. delay volume of an HPLC system Variations in material and instrument conditions, e.g. in HPLC , mobile phases composition, pH, flow rate of mobile phase Equipment and consumables of different ages Columns from different suppliers or different batches Solvents, reagents and other material with different quality
Table 4. Typical variations affecting a methods reproducibility
the same results in different laboratories. The reproducibility of an analytical method is determined by analyzing aliquots from homogeneous lots in different laboratories with different analysts and by using operational and environmental conditions that may differ from but are still within the specified parameters of the method (interlaboratory tests). Validation of reproducibility is important if the method will used in different laboratories. Differences in room temperature and humidity Operators with different experience and thoroughness Equipment with different characteristics, e.g. delay volume of an HPLC system Variations in material and instrument conditions, e.g. in HPLC , mobile phases composition, pH, flow rate of mobile phase Equipment and consumables of different ages Columns from different suppliers or different batches Solvents, reagents and other material with different quality
Table 4. Typical variations affecting a methods reproducibility
9. ACCURACY AND RECOVERY

The accuracy of an analytical method is the extent to which test results generated by the method and the true value agree. The true value for accuracy assessment can be obtained in several ways. One alternative is to compare results of the method with results from an established reference method. This approach assumes that the uncertainty of the reference method is known. Secondly, accuracy can be assessed by analyzing a sample with known concentrations, for example, a certified reference material, and comparing the measured value with the true value as supplied with the material. If such certified reference material is not available, blank sample matrix of interest can be spiked with a known concentration by weight or volume. After extraction of the analyte from the matrix and injection into the analytical instrument, its recovery can be determined by comparing the response of the extract with the response of the reference material dissolved in a pure solvent. Because this accuracy assessment measures the effectiveness of sample preparation, care should be taken to mimic the actual sample preparation as closely as possible.
9. ACCURACY AND RECOVERY

The accuracy of an analytical method is the extent to which test results generated by the method and the true value agree. The true value for accuracy assessment can be obtained in several ways. One alternative is to compare results of the method with results from an established reference method. This approach assumes that the uncertainty of the reference method is known. Secondly, accuracy can be assessed by analyzing a sample with known concentrations, for example, a certified reference material, and comparing the measured value with the true value as supplied with the material. If such certified reference material is not available, blank sample matrix of interest can be spiked with a known concentration by weight or volume. After extraction of the analyte from the matrix and injection into the analytical instrument, its recovery can be determined by comparing the response of the extract with the response of the reference material dissolved in a pure solvent. Because this accuracy assessment measures the effectiveness of sample preparation, care should be taken to mimic the actual sample preparation as closely as possible.
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The concentration should cover the range of concern and should particularly include one concentration close to the quantitation limit. The expected recovery depends on the sample matrix, the sample processing procedure and on the analyte concentration. The AOAC manual for the Peer Verified Methods program (16) includes a table with estimated recovery data as a function analyte concentration. Active Ingredient (%) 100 >=10 >=1 >=0.1 0.01 0.001 0.0001 0.00001 0.000001 0.0000001 Analyte ratio 1 10-1 10-2 10-3 10-4 10-5 10-6 10-7 10-8 10-9 (Ref 16) Unit 100% 10% 1% 0.1 % 100 ppm 10 ppm 1 ppm 100 ppb 10 ppb 1 ppb Mean recovery (%) 98-102 98-102 97-103 95-105 90-107 80-110 80-110 80-110 60-115 40-120
The concentration should cover the range of concern and should particularly include one concentration close to the quantitation limit. The expected recovery depends on the sample matrix, the sample processing procedure and on the analyte concentration. The AOAC manual for the Peer Verified Methods program (16) includes a table with estimated recovery data as a function analyte concentration. Active Ingredient (%) 100 >=10 >=1 >=0.1 0.01 0.001 0.0001 0.00001 0.000001 0.0000001 Analyte ratio 1 10-1 10-2 10-3 10-4 10-5 10-6 10-7 10-8 10-9 (Ref 16) Unit 100% 10% 1% 0.1 % 100 ppm 10 ppm 1 ppm 100 ppb 10 ppb 1 ppb Mean recovery (%) 98-102 98-102 97-103 95-105 90-107 80-110 80-110 80-110 60-115 40-120
Table 4. Analyte recovery at different concentrations
Table 4. Analyte recovery at different concentrations
10. LINEARITY AND CALIBRATION CURVE

The linearity of an analytical method is its ability to elicit test results that are directly, or by means of well-defined mathematical transformations, proportional to the concentration of analytes in samples within a given range. Linearity is determined by a series of three to six injections of five or more standards whose concentrations span 80-120 percent of the expected concentration range. The response should be directly or by means of a well defined mathematical calculation proportional to the concentrations of the analytes. A linear regression equation applied to the results should have an intercept not significantly different from zero. If a significant nonzero intercept is obtained, it should be demonstrated that there is no effect on the accuracy of the method.
10. LINEARITY AND CALIBRATION CURVE

The linearity of an analytical method is its ability to elicit test results that are directly, or by means of well-defined mathematical transformations, proportional to the concentration of analytes in samples within a given range. Linearity is determined by a series of three to six injections of five or more standards whose concentrations span 80-120 percent of the expected concentration range. The response should be directly or by means of a well defined mathematical calculation proportional to the concentrations of the analytes. A linear regression equation applied to the results should have an intercept not significantly different from zero. If a significant nonzero intercept is obtained, it should be demonstrated that there is no effect on the accuracy of the method.
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Frequently the linearity is evaluated graphically in addition or alternatively to mathematical evaluation. The evaluation is made by visual inspection of a plot of signal height or peak area as a function of analyte concentration. Because deviations from linearity are sometimes difficult to detect two additional graphical procedures can be used. The first one is to plot the deviations from the regression line versus the concentration or versus the logarithm of the concentration, if the concentration range covers several decades. For linear ranges the deviations should be equally distributed between positive and negative values.
Frequently the linearity is evaluated graphically in addition or alternatively to mathematical evaluation. The evaluation is made by visual inspection of a plot of signal height or peak area as a function of analyte concentration. Because deviations from linearity are sometimes difficult to detect two additional graphical procedures can be used. The first one is to plot the deviations from the regression line versus the concentration or versus the logarithm of the concentration, if the concentration range covers several decades. For linear ranges the deviations should be equally distributed between positive and negative values.
Figure 2. Graphical presentations of linearity
Figure 2. Graphical presentations of linearity
Rc = Line of constant response
Rc = Line of constant response
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An other approach is to divide signal data by their respective concentrations yielding the relative responses. A graph is plotted with the relative responses on the Y-axis and the corresponding concentrations on the X-axis on a log scale. The obtained line should be horizontal over the full linear range. At higher concentrations, there will typically be a negative deviation from linearity. Parallel horizontal lines are drawn in the graph corresponding to, for example, 95 percent and 105 percent of the horizontal line. The method is linear up to the point where the plotted relative response line intersects the 95 percent line. Figure 2 shows a comparison of the 2 graphical evaluations on the example of caffeine using High-Performance Liquid Chromatography. Plot of caffeine sample using HPLC. Plotting the sensitivity (response/ amount) gives clear indication of the linear range. Plotting the amount on a logarithmic scale has a significant advantage for wide linear ranges.
An other approach is to divide signal data by their respective concentrations yielding the relative responses. A graph is plotted with the relative responses on the Y-axis and the corresponding concentrations on the X-axis on a log scale. The obtained line should be horizontal over the full linear range. At higher concentrations, there will typically be a negative deviation from linearity. Parallel horizontal lines are drawn in the graph corresponding to, for example, 95 percent and 105 percent of the horizontal line. The method is linear up to the point where the plotted relative response line intersects the 95 percent line. Figure 2 shows a comparison of the 2 graphical evaluations on the example of caffeine using High-Performance Liquid Chromatography. Plot of caffeine sample using HPLC. Plotting the sensitivity (response/ amount) gives clear indication of the linear range. Plotting the amount on a logarithmic scale has a significant advantage for wide linear ranges.
11. RANGE
The range of an analytical method is the interval between the upper and lower levels (including these levels) that have been demonstrated to be determined with precision, accuracy and linearity using the method as written. The range is normally expressed in the same units as the test results (e.g. percentage, parts per million) obtained by the analytical method.
11. RANGE
The range of an analytical method is the interval between the upper and lower levels (including these levels) that have been demonstrated to be determined with precision, accuracy and linearity using the method as written. The range is normally expressed in the same units as the test results (e.g. percentage, parts per million) obtained by the analytical method.
12. LIMIT OF DETECTION AND QUANTITATION

The limit of detection is the point at which a measured value is larger than the uncertainty associated with it. It is the lowest concentration of analyte in a sample that can be detected but not necessarily quantified. In chromatography the detection limit is the injected amount that results in a peak with a height at least twice or three times as high as the baseline noise level. The limit of quantitation is the minimum injected amount that gives precise measurements , in chromatography typically requiring peak heights 10 to 20 times higher than baseline noise. If the required precision of the method at the limit of quantitation has been specified, the EURACHEM (1) approach can be used. A number of samples with decreasing amounts of the analyte are injected six times. The calculated RSD% of the precision is plotted
12. LIMIT OF DETECTION AND QUANTITATION

The limit of detection is the point at which a measured value is larger than the uncertainty associated with it. It is the lowest concentration of analyte in a sample that can be detected but not necessarily quantified. In chromatography the detection limit is the injected amount that results in a peak with a height at least twice or three times as high as the baseline noise level. The limit of quantitation is the minimum injected amount that gives precise measurements , in chromatography typically requiring peak heights 10 to 20 times higher than baseline noise. If the required precision of the method at the limit of quantitation has been specified, the EURACHEM (1) approach can be used. A number of samples with decreasing amounts of the analyte are injected six times. The calculated RSD% of the precision is plotted
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Figure 3. Limit of quantitation with the EURACHEM method
Figure 3. Limit of quantitation with the EURACHEM method
against the analyte amount. The amount that orresponds to the previously defined required precision is equal to the limit of quantitation.
against the analyte amount. The amount that orresponds to the previously defined required precision is equal to the limit of quantitation.
13. ROBUSTNESS
Robustness tests examine the effect operational parameters have on the analysis results. For the determination of a methods robustness a number of chromatographic parameters, for example, flow rate, column temperature, injection volume, detection wavelength or mobile phase composition are varied within a realistic range and the quantitative influence of the variables is determined. If the influence of the parameter is within a previously specified tolerance, the parameter is said to be within the methods robustness range. Obtaining data on these effects will allow to judge whether a method needs to be revalidated when one or more of parameters are changed, for example to compensate for column performance over time. In the ICH document (3) it is recommended to consider the evaluation a methods robustness during the development phase, but it is not required to be included as part of a registration application.
13. ROBUSTNESS
Robustness tests examine the effect operational parameters have on the analysis results. For the determination of a methods robustness a number of chromatographic parameters, for example, flow rate, column temperature, injection volume, detection wavelength or mobile phase composition are varied within a realistic range and the quantitative influence of the variables is determined. If the influence of the parameter is within a previously specified tolerance, the parameter is said to be within the methods robustness range. Obtaining data on these effects will allow to judge whether a method needs to be revalidated when one or more of parameters are changed, for example to compensate for column performance over time. In the ICH document (3) it is recommended to consider the evaluation a methods robustness during the development phase, but it is not required to be included as part of a registration application.
14. REFERENCES
1. EURACHEM Guidance Document No. 1/WELAC Guidance Document No. WGD 2: Accreditation for chemical laboratories: Guidance on the
14. REFERENCES
1. EURACHEM Guidance Document No. 1/WELAC Guidance Document No. WGD 2: Accreditation for chemical laboratories: Guidance on the
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interpretation of the EN 45000 series of standards and ISO/IEC Guide 25,1993. Available from the EURACHEM Secretariat, PO Box 46, Teddington, Middlesex, TW11 ONH, UK, 2. International Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use, Validation of analytical procedures, ICH-Q2A, Geneva 1995. 3. International Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use, Validation of analytical procedures: Methodology, ICH-Q2B, Geneva 1996. 4. US EPA, Guidance for methods development and methods validation for the Resource Conservation and Recovery Act (RCRA) Program, Washington, 1995 5. US FDA Technical Review Guide: Validation of Chromatographic Methods, Center for Drug Evaluation and Research (CDER), Rockville, MD, 1993 6. US FDA, General principles of validation, Rockville, MD, Center for Drug Evaluation and Research (CDER), May 1987. 7. US FDA, Guidelines for submitting samples and analytical data for method validation, Rockville, MD, Center for Drugs and Biologics Department of Health and Human Services , Feb. 1987 8. General Chapter <1225>, Validation of compendial methods, United States Pharmacopeia XXIII, National Formulary, XVIII, Rockville, MD, The United States Pharmacopeial Convention, Inc, 1995, 17101612 9. Szepesi, M. Gazdag and K. Mihalyfi, Selection of HPLC methods in pharmaceutical analysis -III method validation, J.Chromatogr. 464, 265-278 10. P. Shah et al., Analytical methods validation: Bioavailability, bioequivalence and pharmacokinetic studies, Eur. J. Drug Metabolism and Pharmacokinetics, 16(4), 249-255, 1989 (1991) 11. Hokanson, A life cycle approach to the validation of analytical methods during pharmaceutical product development, part I: The initial validation process, Pharm.Tech., Sept. 1994, 118-130
interpretation of the EN 45000 series of standards and ISO/IEC Guide 25,1993. Available from the EURACHEM Secretariat, PO Box 46, Teddington, Middlesex, TW11 ONH, UK, 2. International Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use, Validation of analytical procedures, ICH-Q2A, Geneva 1995. 3. International Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use, Validation of analytical procedures: Methodology, ICH-Q2B, Geneva 1996. 4. US EPA, Guidance for methods development and methods validation for the Resource Conservation and Recovery Act (RCRA) Program, Washington, 1995 5. US FDA Technical Review Guide: Validation of Chromatographic Methods, Center for Drug Evaluation and Research (CDER), Rockville, MD, 1993 6. US FDA, General principles of validation, Rockville, MD, Center for Drug Evaluation and Research (CDER), May 1987. 7. US FDA, Guidelines for submitting samples and analytical data for method validation, Rockville, MD, Center for Drugs and Biologics Department of Health and Human Services , Feb. 1987 8. General Chapter <1225>, Validation of compendial methods, United States Pharmacopeia XXIII, National Formulary, XVIII, Rockville, MD, The United States Pharmacopeial Convention, Inc, 1995, 17101612 9. Szepesi, M. Gazdag and K. Mihalyfi, Selection of HPLC methods in pharmaceutical analysis -III method validation, J.Chromatogr. 464, 265-278 10. P. Shah et al., Analytical methods validation: Bioavailability, bioequivalence and pharmacokinetic studies, Eur. J. Drug Metabolism and Pharmacokinetics, 16(4), 249-255, 1989 (1991) 11. Hokanson, A life cycle approach to the validation of analytical methods during pharmaceutical product development, part I: The initial validation process, Pharm.Tech., Sept. 1994, 118-130
12. G.C. Hokanson, A life cycle approach to the validation of analytical methods during pharmaceutical product development, part II: Changes and the need for additional validation, Pharm.Tech., Oct. 1994, 92-100. 13. J.M.Green, A practical guide to analytical method validation, Anal.Chem. News & Features, May 1, 1996, 305A/309A 14. B. Renger, H.Jehle, M.Fischer and w. Funk, Validation of analytical procedures in pharmaceutical analytical chemistry: HPTLC assay of theophylline in an effervescent tablet, J.Planar Chrom., 8, July/Aug 1995, 269-278 15. Wegscheider, Validation of analytical methods, in Accreditation and quality assurance in analytical chemistry, edited by H. Guenzler, Springer Verlag, Berlin 1996 16. AOAC Peer Verified methods Program, Manual on policies and procedures, Arlington, VA, Nov 1993 17. J.Vessman, Selectivity or specificity ? Validation of analytical methods from the perspective of an analytical chemist in the pharmaceutical industry, J.Pharm&Biomed Analysis, 14 (1996) 867/869 18. Huber, L. Validation of computerized analytical systems, Part 3: Installation and operational qualification; LC-GC Magazine 1996, 14(9), 806-812 19. L. Huber, Validation of Computerized Analytical Systems, Interpharm, Buffalo Grove, IL, 1995 20. Huber, Applications of diode-array detection in HPLC, Waldbronn, Germany, Agilent Technologies, 1989, publ. number 12-5953-2330 21. D. Marr, P. Horvath, B. J. Clark, A. F. Fell, Assessment of peak homogeneity in HPLC by computer-aided photodiode-array detection, Anal. Proceed., 23, 254-257, 1986 22. Huber and S. George, Diode-array detection in highperformance liquid chromatography, New York, Marcel Dekker, ISBN 0-8247-4, 1993
12. G.C. Hokanson, A life cycle approach to the validation of analytical methods during pharmaceutical product development, part II: Changes and the need for additional validation, Pharm.Tech., Oct. 1994, 92-100. 13. J.M.Green, A practical guide to analytical method validation, Anal.Chem. News & Features, May 1, 1996, 305A/309A 14. B. Renger, H.Jehle, M.Fischer and w. Funk, Validation of analytical procedures in pharmaceutical analytical chemistry: HPTLC assay of theophylline in an effervescent tablet, J.Planar Chrom., 8, July/Aug 1995, 269-278 15. Wegscheider, Validation of analytical methods, in Accreditation and quality assurance in analytical chemistry, edited by H. Guenzler, Springer Verlag, Berlin 1996 16. AOAC Peer Verified methods Program, Manual on policies and procedures, Arlington, VA, Nov 1993 17. J.Vessman, Selectivity or specificity ? Validation of analytical methods from the perspective of an analytical chemist in the pharmaceutical industry, J.Pharm&Biomed Analysis, 14 (1996) 867/869 18. Huber, L. Validation of computerized analytical systems, Part 3: Installation and operational qualification; LC-GC Magazine 1996, 14(9), 806-812 19. L. Huber, Validation of Computerized Analytical Systems, Interpharm, Buffalo Grove, IL, 1995 20. Huber, Applications of diode-array detection in HPLC, Waldbronn, Germany, Agilent Technologies, 1989, publ. number 12-5953-2330 21. D. Marr, P. Horvath, B. J. Clark, A. F. Fell, Assessment of peak homogeneity in HPLC by computer-aided photodiode-array detection, Anal. Proceed., 23, 254-257, 1986 22. Huber and S. George, Diode-array detection in highperformance liquid chromatography, New York, Marcel Dekker, ISBN 0-8247-4, 1993
a practical guide to analytical method validation

J MARK GREEN
a practical guide to analytical method validation

J MARK GREEN
Doing a thorough method validation can be tedious, but the consequences of not doing it right are wasted time, money, and resources The ability to provide timely, accurate, and reliable data is central to the role of analytical chemists and is especially true in the discovery, development, and manufacture of pharmaceuticals. Analytical data are used to screen potential drug candidates, aid in the development of drug syntheses, support formulation studies, monitor the stability of bulk pharmaceuticals and formulated products, and test final products for release. The quality of analytical data is a key factor in the success of a drug development program. The process of method development and validation has a direct impact on the quality of these data. Although a thorough validation cannot rule out all potential problems, the process of method development and validation should address the most common ones. Examples of typical problems that can be minimized or avoided are synthesis impurities that coelute with the analyte peak in an HPLC assay; a particular type of column that no longer produces the separation needed because the supplier of the column has changed the manufacturing
Doing a thorough method validation can be tedious, but the consequences of not doing it right are wasted time, money, and resources The ability to provide timely, accurate, and reliable data is central to the role of analytical chemists and is especially true in the discovery, development, and manufacture of pharmaceuticals. Analytical data are used to screen potential drug candidates, aid in the development of drug syntheses, support formulation studies, monitor the stability of bulk pharmaceuticals and formulated products, and test final products for release. The quality of analytical data is a key factor in the success of a drug development program. The process of method development and validation has a direct impact on the quality of these data. Although a thorough validation cannot rule out all potential problems, the process of method development and validation should address the most common ones. Examples of typical problems that can be minimized or avoided are synthesis impurities that coelute with the analyte peak in an HPLC assay; a particular type of column that no longer produces the separation needed because the supplier of the column has changed the manufacturing
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process; an assay method that is transferred to a second laboratory where they are unable to achieve the same detection limit; and a quality assurance audit of a validation report that finds no documentation on how the method was performed during the validation. Problems increase as additional people, laboratories, and equipment are used to perform the method. When the method is used in the developers laboratory, a small adjustment can usually be made to make the method work, but the flexibility to change it is lost once the method is transferred to other laboratories or used for official product testing. This is especially true in the pharmaceutical industry, where methods are submitted to regulatory agencies and changes may require formal approval before they can be implemented for official testing. The best way to minimize method problems is to perform adequate validation experiments during development. What is method validation? Method validation is the process of proving that an analytical method is acceptable for its intended purpose. For pharmaceutical methods, guidelines from the United States Pharmacopeia (USP) (1), International Conference on Harmonisation (ICH) (2), and the Food and Drug Administration (FDA) (3, 4) provide a framework for performing such validations. In general, methods for regulatory submission must include studies on specificity, linearity, accuracy, precision, range, detection limit, quantitation limit, and robustness. Although there is general agreement about what type of studies should be done, there is great diversity in how they are performed (5). The literature contains diverse approaches to performing validations ( 6 - 10 ). This Report presents an approach to performing validation studies that encompasses much of the current literature and provides practical guidance. This approach should be viewed with the understanding that validation requirements are continually changing and vary widely, depending on the type of drug being tested, the stage of drug development, and the regulatory group that will review the drug application. For our purposes, we will discuss validation studies as they apply to chromatographic methods, although the same principles apply to other analytical techniques. In the early stages of drug development, it is usually not necessary to perform all of the various validation studies. Many researchers focus on specificity, linearity, accuracy, and precision studies for drugs in the
process; an assay method that is transferred to a second laboratory where they are unable to achieve the same detection limit; and a quality assurance audit of a validation report that finds no documentation on how the method was performed during the validation. Problems increase as additional people, laboratories, and equipment are used to perform the method. When the method is used in the developers laboratory, a small adjustment can usually be made to make the method work, but the flexibility to change it is lost once the method is transferred to other laboratories or used for official product testing. This is especially true in the pharmaceutical industry, where methods are submitted to regulatory agencies and changes may require formal approval before they can be implemented for official testing. The best way to minimize method problems is to perform adequate validation experiments during development. What is method validation? Method validation is the process of proving that an analytical method is acceptable for its intended purpose. For pharmaceutical methods, guidelines from the United States Pharmacopeia (USP) (1), International Conference on Harmonisation (ICH) (2), and the Food and Drug Administration (FDA) (3, 4) provide a framework for performing such validations. In general, methods for regulatory submission must include studies on specificity, linearity, accuracy, precision, range, detection limit, quantitation limit, and robustness. Although there is general agreement about what type of studies should be done, there is great diversity in how they are performed (5). The literature contains diverse approaches to performing validations ( 6 - 10 ). This Report presents an approach to performing validation studies that encompasses much of the current literature and provides practical guidance. This approach should be viewed with the understanding that validation requirements are continually changing and vary widely, depending on the type of drug being tested, the stage of drug development, and the regulatory group that will review the drug application. For our purposes, we will discuss validation studies as they apply to chromatographic methods, although the same principles apply to other analytical techniques. In the early stages of drug development, it is usually not necessary to perform all of the various validation studies. Many researchers focus on specificity, linearity, accuracy, and precision studies for drugs in the
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preclinical through Phase II (preliminary efficacy) stages. The remaining studies are performed when the drug reaches the Phase III (efficacy) stage of development and has a higher probability of becoming a marketed product. The process of validating a method cannot be separated from the actual development of the method conditions, because the developer will not know whether the method conditions are acceptable until validation studies are performed. The development and validation of a new analytical method may therefore be an iterative process. Results of validation studies may indicate that a change in the procedure is necessary, which may then require revalidation. During each validation study, key method parameters are determined and then used for all subsequent validation steps. To minimize repetitious studies and ensure that the validation data are generated under conditions equivalent to the final procedure, we recommend the following sequence of studies. Establish minimum criteria The first step in the method development and validation cycle should be to set minimum requirements, which are essentially acceptance specifications for the method. A complete list of criteria should be agreed on by the developer and the end users before the method is developed so that expectations are clear. For example, is it critical that method precision (RSD) be 2%? Does the method need to be accurate to within 2% of the target concentration? Is it acceptable to have only one supplier of the HPLC column used in the analysis? During the actual studies and in the final validation report, these criteria will allow clear judgment about the acceptability of the analytical method. Examples of minimum criteria are provided throughout this article that indicate practical ways to evaluate the acceptability of data from each validation study. The statistics generated for making comparisons are similar to what analysts will generate later in the routine use of the method and therefore can serve as a tool for evaluating later questionable data. More rigorous statistical evaluation techniques are available and should be used in some instances, but these may not allow as direct a comparison for method troubleshooting during routine use.
preclinical through Phase II (preliminary efficacy) stages. The remaining studies are performed when the drug reaches the Phase III (efficacy) stage of development and has a higher probability of becoming a marketed product. The process of validating a method cannot be separated from the actual development of the method conditions, because the developer will not know whether the method conditions are acceptable until validation studies are performed. The development and validation of a new analytical method may therefore be an iterative process. Results of validation studies may indicate that a change in the procedure is necessary, which may then require revalidation. During each validation study, key method parameters are determined and then used for all subsequent validation steps. To minimize repetitious studies and ensure that the validation data are generated under conditions equivalent to the final procedure, we recommend the following sequence of studies. Establish minimum criteria The first step in the method development and validation cycle should be to set minimum requirements, which are essentially acceptance specifications for the method. A complete list of criteria should be agreed on by the developer and the end users before the method is developed so that expectations are clear. For example, is it critical that method precision (RSD) be 2%? Does the method need to be accurate to within 2% of the target concentration? Is it acceptable to have only one supplier of the HPLC column used in the analysis? During the actual studies and in the final validation report, these criteria will allow clear judgment about the acceptability of the analytical method. Examples of minimum criteria are provided throughout this article that indicate practical ways to evaluate the acceptability of data from each validation study. The statistics generated for making comparisons are similar to what analysts will generate later in the routine use of the method and therefore can serve as a tool for evaluating later questionable data. More rigorous statistical evaluation techniques are available and should be used in some instances, but these may not allow as direct a comparison for method troubleshooting during routine use.
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Demonstrate specificity For chromatographic methods, developing a separation involves demonstrating specificity, which is the ability of the method to accurately measure the analyte response in the presence of all potential sample components. The response of the analyte in test mixtures containing the analyte and all potential sample components (placebo formulation, synthesis intermediates, excipients, degradation products, process impurities, etc.) is compared with the response of a solution containing only the analyte. Other potential sample components are generated by exposing the analyte to stress conditions sufficient to degrade it to 80 - 90% purity. For bulk pharmaceuticals, stress conditions such as heat (50 oC), light (600 FC), acid (0.1 N HCl), base (0.1 N NaOH), and oxidant (3% H2O2) are typical. For formulated products, heat, light, and humidity (RH = 85%) are often used. The resulting mixtures are then analyzed, and the analyte peak is evaluated for peak purity and resolution from the nearest eluting peak. If an alternate chromatographic column is to be allowed in the final method procedure, it should be identified during these studies. Once acceptable resolution is obtained for the analyte and potential sample components, the chromatographic parameters, such as column type, mobile-phase composition, flow rate, and detection mode, are considered set. An example of specificity criteria for an assay method is that the analyte peak will have baseline chromatographic resolution of at least 1.5 from all other sample components. If this cannot be achieved, the unresolved components at their maximum expected levels will not affect the final assay result by more than 0.5%. An example of specificity criteria for an impurity method is that all impurity peaks that are 0.1% by area will have baseline chromatographic resolution from the main component peak(s) and, where practical, will have resolution from all other impurities. Demonstrate linearity A linearity study verifies that the sample solutions are in a concentration range where analyte response is linearly proportional to concentration. For assay methods, this study is generally performed by preparing standard solutions at five concentration levels, from 50% to 150% of the target analyte concentration. Five levels are required to allow detection of curvature in
Demonstrate specificity For chromatographic methods, developing a separation involves demonstrating specificity, which is the ability of the method to accurately measure the analyte response in the presence of all potential sample components. The response of the analyte in test mixtures containing the analyte and all potential sample components (placebo formulation, synthesis intermediates, excipients, degradation products, process impurities, etc.) is compared with the response of a solution containing only the analyte. Other potential sample components are generated by exposing the analyte to stress conditions sufficient to degrade it to 80 - 90% purity. For bulk pharmaceuticals, stress conditions such as heat (50 oC), light (600 FC), acid (0.1 N HCl), base (0.1 N NaOH), and oxidant (3% H2O2) are typical. For formulated products, heat, light, and humidity (RH = 85%) are often used. The resulting mixtures are then analyzed, and the analyte peak is evaluated for peak purity and resolution from the nearest eluting peak. If an alternate chromatographic column is to be allowed in the final method procedure, it should be identified during these studies. Once acceptable resolution is obtained for the analyte and potential sample components, the chromatographic parameters, such as column type, mobile-phase composition, flow rate, and detection mode, are considered set. An example of specificity criteria for an assay method is that the analyte peak will have baseline chromatographic resolution of at least 1.5 from all other sample components. If this cannot be achieved, the unresolved components at their maximum expected levels will not affect the final assay result by more than 0.5%. An example of specificity criteria for an impurity method is that all impurity peaks that are 0.1% by area will have baseline chromatographic resolution from the main component peak(s) and, where practical, will have resolution from all other impurities. Demonstrate linearity A linearity study verifies that the sample solutions are in a concentration range where analyte response is linearly proportional to concentration. For assay methods, this study is generally performed by preparing standard solutions at five concentration levels, from 50% to 150% of the target analyte concentration. Five levels are required to allow detection of curvature in
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the plotted data. The standards are evaluated using the chromatographic conditions determined during the specificity studies. Standards should be prepared and analyzed a minimum of three times. The 50% to 150% range for this study is wider than what is required by the FDA guidelines. In the final method procedure, a tighter range of three standards is generally used, such as 80%, 100%, and 120% of target; and in some instances, a single standard concentration is used. Validating over a wider range provides confidence that the routine standard levels are well removed from nonlinear response concentrations, that the method covers a wide enough range to incorporate the limits of content uniformity testing, and that it allows quantitation of crude samples in support of process development. For impurity methods, linearity is determined by preparing standard solutions at five concentration levels over a range such as 0.05 wt% - 2.5 wt%. Acceptability of linearity data is often judged by examining the correlation coefficient and y-intercept of the linear regression line for the response versus concentration plot. A correlation coefficient of r > 0.999 is generally considered as evidence of acceptable fit of the data to the regression line. The y-intercept should be less than a few percent of the response obtained for the analyte at the target level. Although these are very practical ways of evaluating linearity data, they are not true measures of linearity (11, 12). These parameters, by themselves, can be misleading and should not be used without a visual examination of the response versus concentration plot. An example of how the use of correlation coefficients can be misleading can be seen in data from an HPLC method for quantitation of mannitol. This method uses an internal standard, so the data are recorded as peak area ratios (mannitol area/internal standard area). Figure 1 is a plot of mannitol peak area ratio versus mannitol concentration for standards analyzed by the method. Although the correlation coefficient of the linear regression is > 0.999 (top), the plot indicates small deviations from linearity at low and high concentrations. An Figure 1. Peak area ratio (circles) and response factor (squares) versus concentration foris mannitol. alternate way of evaluating the data to plot Response Factor versus Concentration (also shown 1). (Top) Concentration range in is Figure 5 - 80 mg/mL. For peak area ration line, y = 0.09775 + 0.080569x and correlatin coefficient = 0.99952. If an equivalent response was obtained at each concentration, the data (Bottom) Concentration range is 12 - 28 mg/mL. For peak area ratio line, points would form a straight line with a zero slope. The response factors y = 0.027 + 0.08625x and correlation coefficiant = 0.99965.
the plotted data. The standards are evaluated using the chromatographic conditions determined during the specificity studies. Standards should be prepared and analyzed a minimum of three times. The 50% to 150% range for this study is wider than what is required by the FDA guidelines. In the final method procedure, a tighter range of three standards is generally used, such as 80%, 100%, and 120% of target; and in some instances, a single standard concentration is used. Validating over a wider range provides confidence that the routine standard levels are well removed from nonlinear response concentrations, that the method covers a wide enough range to incorporate the limits of content uniformity testing, and that it allows quantitation of crude samples in support of process development. For impurity methods, linearity is determined by preparing standard solutions at five concentration levels over a range such as 0.05 wt% - 2.5 wt%. Acceptability of linearity data is often judged by examining the correlation coefficient and y-intercept of the linear regression line for the response versus concentration plot. A correlation coefficient of r > 0.999 is generally considered as evidence of acceptable fit of the data to the regression line. The y-intercept should be less than a few percent of the response obtained for the analyte at the target level. Although these are very practical ways of evaluating linearity data, they are not true measures of linearity (11, 12). These parameters, by themselves, can be misleading and should not be used without a visual examination of the response versus concentration plot. An example of how the use of correlation coefficients can be misleading can be seen in data from an HPLC method for quantitation of mannitol. This method uses an internal standard, so the data are recorded as peak area ratios (mannitol area/internal standard area). Figure 1 is a plot of mannitol peak area ratio versus mannitol concentration for standards analyzed by the method. Although the correlation coefficient of the linear regression is > 0.999 (top), the plot indicates small deviations from linearity at low and high concentrations. An Figure 1. Peak area ratio (circles) and response factor (squares) versus concentration foris mannitol. alternate way of evaluating the data to plot Response Factor versus Concentration (also shown 1). (Top) Concentration range in is Figure 5 - 80 mg/mL. For peak area ration line, y = 0.09775 + 0.080569x and correlatin coefficient = 0.99952. If an equivalent response was obtained at each concentration, the data (Bottom) Concentration range is 12 - 28 mg/mL. For peak area ratio line, points would form a straight line with a zero slope. The response factors y = 0.027 + 0.08625x and correlation coefficiant = 0.99965.
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plotted in Figure 1(top) vary greatly over the range and fall only within 15% of the target concentration. A second set of mannitol data, over a narrower range of concentrations, is shown in Figure 1(bottom). The response factors for all concentrations in this range are within 1.5% of the target concentration response. The near-zero slope of the response factor plot indicates that a linear response is obtained over this concentration range. At the completion of linearity studies, the appropriate concentration range for the standards and the injection volume should be set for all subsequent studies. An example of a linearity criteria for an assay method is that the correlation coefficient for each of three curves (five concentration levels each) will be 0.99 for the range 80% N 120% of the target concentration. The yintercept will be 2% of the target concentration response. An alternate criteria is that a plot of response factor versus concentration will show all values within 2.5% of the target-level response factor for concentrations between 80% and 120% of the target concentration. For an impurity method, the correlation coefficient for each of three curves (five concentration levels each) will be 0.98 for the range 0% - 1 2.5% of the main component concentration. The y-intercept will be 10% of the response produced for a 2.5 wt% impurity. An alternate criteria is that a plot of response factor versus concentration will show all values within 5% of the mean response factor for concentrations 0.5 wt% and within 10% of the mean response factor for concentrations 0.5 wt%. Demonstrate accuracy The accuracy of a method is the closeness of the measured value to the true value for the sample. Accuracy is usually determined in one of four ways. First, accuracy can be assessed by analyzing a sample of known concentration and comparing the measured value to the true value. National Institute of Standards and Technology (NIST) reference standards are often used; however, such a well-characterized sample is usually not available for new drug-related analytes. The second approach is to compare test results from the new method with results from an existing alternate method that is known to be accurate. Again, for pharmaceutical studies, such an alternate method is usually not available. The third and fourth approaches are based on the recovery of known amounts of analyte spiked into sample matrix.
plotted in Figure 1(top) vary greatly over the range and fall only within 15% of the target concentration. A second set of mannitol data, over a narrower range of concentrations, is shown in Figure 1(bottom). The response factors for all concentrations in this range are within 1.5% of the target concentration response. The near-zero slope of the response factor plot indicates that a linear response is obtained over this concentration range. At the completion of linearity studies, the appropriate concentration range for the standards and the injection volume should be set for all subsequent studies. An example of a linearity criteria for an assay method is that the correlation coefficient for each of three curves (five concentration levels each) will be 0.99 for the range 80% N 120% of the target concentration. The yintercept will be 2% of the target concentration response. An alternate criteria is that a plot of response factor versus concentration will show all values within 2.5% of the target-level response factor for concentrations between 80% and 120% of the target concentration. For an impurity method, the correlation coefficient for each of three curves (five concentration levels each) will be 0.98 for the range 0% - 1 2.5% of the main component concentration. The y-intercept will be 10% of the response produced for a 2.5 wt% impurity. An alternate criteria is that a plot of response factor versus concentration will show all values within 5% of the mean response factor for concentrations 0.5 wt% and within 10% of the mean response factor for concentrations 0.5 wt%. Demonstrate accuracy The accuracy of a method is the closeness of the measured value to the true value for the sample. Accuracy is usually determined in one of four ways. First, accuracy can be assessed by analyzing a sample of known concentration and comparing the measured value to the true value. National Institute of Standards and Technology (NIST) reference standards are often used; however, such a well-characterized sample is usually not available for new drug-related analytes. The second approach is to compare test results from the new method with results from an existing alternate method that is known to be accurate. Again, for pharmaceutical studies, such an alternate method is usually not available. The third and fourth approaches are based on the recovery of known amounts of analyte spiked into sample matrix.
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The third approach, which is the most widely used recovery study, is performed by spiking analyte in blank matrices. For assay methods, spiked samples are prepared in triplicate at three levels over a range of 50% - 150% of the target concentration. If potential impurities have been isolated, they should be added to the matrix to mimic impure samples. For impurity methods, spiked samples are prepared in triplicate at three levels over a range that covers the expected impurity content of the sample, such as 0.1% - 2.5 wt%. The analyte levels in the spiked samples should be determined using the same quantitation procedure as will be used in the final method procedure (i.e., same number and levels of standards, same number of sample and standard injections, etc.). The percent recovery should then be calculated. The fourth approach is the technique of standard additions, which can also be used to determine recovery of spiked analyte. This approach is used if it is not possible to prepare a blank sample matrix without the presence of the analyte. This can occur, for example, with lyophilized material, in which the speciation in the lyophilized material is significantly different when the analyte is absent. An example of an accuracy criteria for an assay method is that the mean recovery will be 100 2% at each concentration over the range of 80% 120% of the target concentration. For an impurity method, the mean recovery will be within 0.1% absolute of the theoretical concentration or 10% relative, whichever is greater, for impurities in the range of 0.1% - 2.5 wt%. Determine the range The range of an analytical method is the concentration interval over which acceptable accuracy, linearity, and precision are obtained. In practice, the range is determined using data from the linearity and accuracy studies. Assuming that acceptable linearity and accuracy (recovery) results were obtained as described earlier, the only remaining factor to be evaluated is precision. This precision data should be available from the triplicate analyses of spiked samples in the accuracy study. Figure 2 illustrates how precision may change as a function of analyte level. The %RSD values for ethanol quantitation by GC increased significantly as the concentration decreased from 1000 ppm to 10 ppm. Higher variability is expected as the analyte levels approach the detection limit for the method.
The third approach, which is the most widely used recovery study, is performed by spiking analyte in blank matrices. For assay methods, spiked samples are prepared in triplicate at three levels over a range of 50% - 150% of the target concentration. If potential impurities have been isolated, they should be added to the matrix to mimic impure samples. For impurity methods, spiked samples are prepared in triplicate at three levels over a range that covers the expected impurity content of the sample, such as 0.1% - 2.5 wt%. The analyte levels in the spiked samples should be determined using the same quantitation procedure as will be used in the final method procedure (i.e., same number and levels of standards, same number of sample and standard injections, etc.). The percent recovery should then be calculated. The fourth approach is the technique of standard additions, which can also be used to determine recovery of spiked analyte. This approach is used if it is not possible to prepare a blank sample matrix without the presence of the analyte. This can occur, for example, with lyophilized material, in which the speciation in the lyophilized material is significantly different when the analyte is absent. An example of an accuracy criteria for an assay method is that the mean recovery will be 100 2% at each concentration over the range of 80% 120% of the target concentration. For an impurity method, the mean recovery will be within 0.1% absolute of the theoretical concentration or 10% relative, whichever is greater, for impurities in the range of 0.1% - 2.5 wt%. Determine the range The range of an analytical method is the concentration interval over which acceptable accuracy, linearity, and precision are obtained. In practice, the range is determined using data from the linearity and accuracy studies. Assuming that acceptable linearity and accuracy (recovery) results were obtained as described earlier, the only remaining factor to be evaluated is precision. This precision data should be available from the triplicate analyses of spiked samples in the accuracy study. Figure 2 illustrates how precision may change as a function of analyte level. The %RSD values for ethanol quantitation by GC increased significantly as the concentration decreased from 1000 ppm to 10 ppm. Higher variability is expected as the analyte levels approach the detection limit for the method.
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Figure 2. %RSD versus concentration for a GC headspace analysis of ethanol.
Figure 2. %RSD versus concentration for a GC headspace analysis of ethanol.
The developer must judge at what concentration the imprecision becomes too great for the intended use of the method. An example of range criteria for an assay method is that the acceptable range will be defined as the concentration interval over which linearity and accuracy are obtained per previously discussed criteria and that yields a precision of 3% RSD. For an impurity method, the acceptable range will be defined as the concentration interval over which linearity and accuracy are obtained per the above criteria, and that, in addition, yields a precision of 10% RSD. Determine precision, Round 1 The precision of an analytical method is the amount of scatter in the results obtained from multiple analyses of a homogeneous sample. To be meaningful, the precision study must be performed using the exact sample and standard preparation procedures that will be used in the final method.
The developer must judge at what concentration the imprecision becomes too great for the intended use of the method. An example of range criteria for an assay method is that the acceptable range will be defined as the concentration interval over which linearity and accuracy are obtained per previously discussed criteria and that yields a precision of 3% RSD. For an impurity method, the acceptable range will be defined as the concentration interval over which linearity and accuracy are obtained per the above criteria, and that, in addition, yields a precision of 10% RSD. Determine precision, Round 1 The precision of an analytical method is the amount of scatter in the results obtained from multiple analyses of a homogeneous sample. To be meaningful, the precision study must be performed using the exact sample and standard preparation procedures that will be used in the final method.
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The first type of precision study is instrument precision or injection repeatability (3). A minimum of 10 injections of one sample solution is made to test the performance of the chromatographic instrument. The second type is repeatability or intra-assay precision (2). Intra-assay precision data are obtained by repeatedly analyzing, in one laboratory on one day, aliquots of a homogeneous sample, each of which has been independently prepared according to the method procedure. From these precision studies, the sample preparation procedure, the number of replicate samples to be prepared, and the number of injections required for each sample in the final method procedure will be set. Two additional types of precision studies are described later in Round 2. An example of precision criteria for an assay method is that the instrument precision (RSD) will be 1% and the intra-assay precision will be 2%. For an impurity method, at the limit of quantitation, the instrument precision will be 5% and the intra-assay precision will be 10%. Widen the scope Once these validation studies are complete, the method developers should be confident in the ability of the method to provide good quantitation in their own laboratories. This result may be sufficient for many methods, especially in the early phases of drug development. The remaining studies should provide greater assurance that the method will work well in other laboratories, where different operators, instruments, and reagents are involved and where it will be used over much longer periods of time. This is a good time to begin accumulating data for two or more system suitability criteria, which are required prior to routine use of the method to ensure that it is performing appropriately. Typically, the process involves making five injections of a standard solution and evaluating several chromatographic parameters (1) such as resolution, area % reproducibility, number of theoretical plates, and tailing factor. Establish the detection limit The detection limit of a method is the lowest analyte concentration that produces a response detectable above the noise level of the system, typically, three times the noise level. The detection limit needs to be determined only for impurity methods in which chromatographic peaks near the detection
The first type of precision study is instrument precision or injection repeatability (3). A minimum of 10 injections of one sample solution is made to test the performance of the chromatographic instrument. The second type is repeatability or intra-assay precision (2). Intra-assay precision data are obtained by repeatedly analyzing, in one laboratory on one day, aliquots of a homogeneous sample, each of which has been independently prepared according to the method procedure. From these precision studies, the sample preparation procedure, the number of replicate samples to be prepared, and the number of injections required for each sample in the final method procedure will be set. Two additional types of precision studies are described later in Round 2. An example of precision criteria for an assay method is that the instrument precision (RSD) will be 1% and the intra-assay precision will be 2%. For an impurity method, at the limit of quantitation, the instrument precision will be 5% and the intra-assay precision will be 10%. Widen the scope Once these validation studies are complete, the method developers should be confident in the ability of the method to provide good quantitation in their own laboratories. This result may be sufficient for many methods, especially in the early phases of drug development. The remaining studies should provide greater assurance that the method will work well in other laboratories, where different operators, instruments, and reagents are involved and where it will be used over much longer periods of time. This is a good time to begin accumulating data for two or more system suitability criteria, which are required prior to routine use of the method to ensure that it is performing appropriately. Typically, the process involves making five injections of a standard solution and evaluating several chromatographic parameters (1) such as resolution, area % reproducibility, number of theoretical plates, and tailing factor. Establish the detection limit The detection limit of a method is the lowest analyte concentration that produces a response detectable above the noise level of the system, typically, three times the noise level. The detection limit needs to be determined only for impurity methods in which chromatographic peaks near the detection
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limit will be observed. The detection limit should be estimated early in the method development-validation process and should be repeated using the specific wording of the final procedure if any changes have been made. It is important to test the method detection limit on different instruments, such as those used in the different laboratories to which the method will be transferred. An example of a detection limit criteria is that, at the 0.05% level, an impurity will have S/N 3. Establish the quantitation limit The quantitation limit is the lowest level of analyte that can be accurately and precisely measured. This limit is required only for impurity methods and is determined by reducing the analyte concentration until a level is reached where the precision of the method is unacceptable. If not determined experimentally, the quantitation limit is often calculated as the analyte concentration that gives S/N 10. An example of quantitation limit criteria is that the limit will be defined as the lowest concentration level for which an RSD 20% is obtained when an intra-assay precision study is performed. Establish stability During the earlier validation studies, the method developer gained some information on the stability of reagents, mobile phases, standards, and sample solutions. For routine testing in which many samples are prepared and analyzed each day, it is often essential that solutions be stable enough to allow for delays such as instrument breakdowns or overnight analyses using autosamplers. At this point, the limits of stability should be tested. Samples and standards should be tested over at least a 48-h period, and quantitation of components should be determined by comparison to freshly prepared standards. If the solutions are not stable over 48 h, storage conditions or additives should be identified that can improve stability. An example of stability criteria for assay methods is that sample and standard solutions and the mobile phase will be stable for 48 h under defined storage conditions. Acceptable stability is 2% change in standard or sample response, relative to freshly prepared standards. The mobile phase is considered to have acceptable stability if aged mobile phase produces equivalent chromatography (capacity factors, resolution, or tailing factor) and assay results are within 2% of the value obtained with fresh mobile phase.
limit will be observed. The detection limit should be estimated early in the method development-validation process and should be repeated using the specific wording of the final procedure if any changes have been made. It is important to test the method detection limit on different instruments, such as those used in the different laboratories to which the method will be transferred. An example of a detection limit criteria is that, at the 0.05% level, an impurity will have S/N 3. Establish the quantitation limit The quantitation limit is the lowest level of analyte that can be accurately and precisely measured. This limit is required only for impurity methods and is determined by reducing the analyte concentration until a level is reached where the precision of the method is unacceptable. If not determined experimentally, the quantitation limit is often calculated as the analyte concentration that gives S/N 10. An example of quantitation limit criteria is that the limit will be defined as the lowest concentration level for which an RSD 20% is obtained when an intra-assay precision study is performed. Establish stability During the earlier validation studies, the method developer gained some information on the stability of reagents, mobile phases, standards, and sample solutions. For routine testing in which many samples are prepared and analyzed each day, it is often essential that solutions be stable enough to allow for delays such as instrument breakdowns or overnight analyses using autosamplers. At this point, the limits of stability should be tested. Samples and standards should be tested over at least a 48-h period, and quantitation of components should be determined by comparison to freshly prepared standards. If the solutions are not stable over 48 h, storage conditions or additives should be identified that can improve stability. An example of stability criteria for assay methods is that sample and standard solutions and the mobile phase will be stable for 48 h under defined storage conditions. Acceptable stability is 2% change in standard or sample response, relative to freshly prepared standards. The mobile phase is considered to have acceptable stability if aged mobile phase produces equivalent chromatography (capacity factors, resolution, or tailing factor) and assay results are within 2% of the value obtained with fresh mobile phase.
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For impurity methods, the sample and standard solutions and mobile phase will be stable for 48 h under defined storage conditions. Acceptable stability is 20% change in standard or sample response at the limit of quantitation, relative to freshly prepared standards. The mobile phase is considered to have acceptable stability if aged mobile phase produces equivalent chromatography and if impurity results at the limit of quantitation are within 20% of the values obtained with fresh mobile phase. Establish precision, Round 2 The remaining precision studies comprise much of what historically has been called ruggedness. Intermediate precision (2) is the precision obtained when the assay is performed by multiple analysts, using multiple instruments, on multiple days, in one laboratory. Different sources of reagents and multiple lots of columns should also be included in this study. Intermediate precision results are used to identify which of the above factors contribute significant variability to the final result. The last type of precision study is reproducibility (2), which is determined by testing homogeneous samples in multiple laboratories, often as part of interlaboratory crossover studies. The evaluation of reproducibility results often focuses more on measuring bias in results than on determining differences in precision alone. Statistical equivalence is often used as a measure of acceptable interlaboratory results. An alternative, more practical approach is the use of analytical equivalence in which a range of acceptable results is chosen prior to the study and used to judge the acceptability of the results obtained from the different laboratories. An example of reproducibility criteria for an assay method could be that the assay results obtained in multiple laboratories will be statistically equivalent or the mean results will be within 2% of the value obtained by the primary testing lab. For an impurity method, results obtained in multiple laboratories will be statistically equivalent or the mean results will be within 10% (relative) of the value obtained by the primary testing lab for impurities 1wt%, within 25% for impurities from 0.1% - 1.0wt%, and within 50% for impurities 0.1wt%. Is it robust? The robustness of a method is its ability to remain unaffected by small changes in parameters such as percent organic content and pH of the
For impurity methods, the sample and standard solutions and mobile phase will be stable for 48 h under defined storage conditions. Acceptable stability is 20% change in standard or sample response at the limit of quantitation, relative to freshly prepared standards. The mobile phase is considered to have acceptable stability if aged mobile phase produces equivalent chromatography and if impurity results at the limit of quantitation are within 20% of the values obtained with fresh mobile phase. Establish precision, Round 2 The remaining precision studies comprise much of what historically has been called ruggedness. Intermediate precision (2) is the precision obtained when the assay is performed by multiple analysts, using multiple instruments, on multiple days, in one laboratory. Different sources of reagents and multiple lots of columns should also be included in this study. Intermediate precision results are used to identify which of the above factors contribute significant variability to the final result. The last type of precision study is reproducibility (2), which is determined by testing homogeneous samples in multiple laboratories, often as part of interlaboratory crossover studies. The evaluation of reproducibility results often focuses more on measuring bias in results than on determining differences in precision alone. Statistical equivalence is often used as a measure of acceptable interlaboratory results. An alternative, more practical approach is the use of analytical equivalence in which a range of acceptable results is chosen prior to the study and used to judge the acceptability of the results obtained from the different laboratories. An example of reproducibility criteria for an assay method could be that the assay results obtained in multiple laboratories will be statistically equivalent or the mean results will be within 2% of the value obtained by the primary testing lab. For an impurity method, results obtained in multiple laboratories will be statistically equivalent or the mean results will be within 10% (relative) of the value obtained by the primary testing lab for impurities 1wt%, within 25% for impurities from 0.1% - 1.0wt%, and within 50% for impurities 0.1wt%. Is it robust? The robustness of a method is its ability to remain unaffected by small changes in parameters such as percent organic content and pH of the
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mobile phase, buffer concentration, temperature, and injection volume. These method parameters may be evaluated one factor at a time or simultaneously as part of a factorial experiment (13). Obtaining data on the effects of these parameters may allow a range of acceptable values to be included in the final method procedure. For example, if column performance changes over time, adjusting the mobile-phase strength to compensate for changes in the column may be allowed if such data are included in the validation. An example of robustness criteria is that the effects of the following changes in chromatographic conditions will be determined: methanol content in mobile phase adjusted by 2%, mobile-phase pH adjusted by 0.1 pH units, and column temperature adjusted by 5 oC. If these changes are within the limits that produce acceptable chromatography, they will be incorporated in the method procedure. Doing it right the first time Performing a thorough method validation can be a tedious process, but the quality of data generated with the method is directly linked to the quality of this process. Time constraints often do not allow for sufficient method validations. Many researchers have experienced the consequences of invalid methods and realized that the amount of time and resources required to solve problems discovered later exceeds what would have been expended initially if the validation studies had been performed properly. We hope that we have provided a guide to help you wend your way efficiently through the method validation maze and eliminate many of the problems common to inadequately validated analytical methods. I wish to thank Bruce Burgess, Joseph Glajch, and the DuPont Merck radiopharmaceuticals methods quality team for their contributions in formulating many of the concepts presented in this paper.
mobile phase, buffer concentration, temperature, and injection volume. These method parameters may be evaluated one factor at a time or simultaneously as part of a factorial experiment (13). Obtaining data on the effects of these parameters may allow a range of acceptable values to be included in the final method procedure. For example, if column performance changes over time, adjusting the mobile-phase strength to compensate for changes in the column may be allowed if such data are included in the validation. An example of robustness criteria is that the effects of the following changes in chromatographic conditions will be determined: methanol content in mobile phase adjusted by 2%, mobile-phase pH adjusted by 0.1 pH units, and column temperature adjusted by 5 oC. If these changes are within the limits that produce acceptable chromatography, they will be incorporated in the method procedure. Doing it right the first time Performing a thorough method validation can be a tedious process, but the quality of data generated with the method is directly linked to the quality of this process. Time constraints often do not allow for sufficient method validations. Many researchers have experienced the consequences of invalid methods and realized that the amount of time and resources required to solve problems discovered later exceeds what would have been expended initially if the validation studies had been performed properly. We hope that we have provided a guide to help you wend your way efficiently through the method validation maze and eliminate many of the problems common to inadequately validated analytical methods. I wish to thank Bruce Burgess, Joseph Glajch, and the DuPont Merck radiopharmaceuticals methods quality team for their contributions in formulating many of the concepts presented in this paper.
REFERENCES
(1) U.S. Pharmacopeia 23, pp. 1982-84, United States Pharmacopeial Convention, Inc., 1994.
REFERENCES
(1) U.S. Pharmacopeia 23, pp. 1982-84, United States Pharmacopeial Convention, Inc., 1994.
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(2) International Conference on Harmonisation, Draft Guideline on Validation of Analytical Procedures: Definitions and Terminology, Federal Register, Volume 60, pp. 11260, March 1, 1995. (3) Reviewer Guidance, Validation of Chromatographic Methods, Center for Drug Evaluation and Research, Food and Drug Administration, 1994. (4) Guideline for Submitting Samples and Analytical Data for Methods Validation, Food and Drug Administration, 1987. (5) Clarke, G. S. J. Pharm. Biomed. Anal. 1994, 12, 643. (6) Inman, E. L.; Frischman, J. K.; Jimenez, P. J.; Winkel, G. D.; Persinger, M. L.; Rutherford, B. S. J. Chromatogr. Sci. 1987, 25, 252. (7) Wilson, T. D. J. Pharm. Biomed. Anal. 1990, 8, 389. (8) Adamovics, J. A., Chromatographic Analysis of Pharmaceuticals, M. Dekker, New York, 1990. (9) Hokanson, G. C. Pharm. Technol. 1994, 18, 118. (10) Carr. G. P.; Wahlich, J. C. J. Pharm. Biomed. Anal. 1990, 8, 613. (11) Cassidy, R.; Janoski, M. LC-GC 1992, 10, 692. (12) Dorschel, C. A.; Ekmanis, J. L.; Oberholtzer, J. E.; Warren, F. V.; Bidlingmeyer, B. A. Anal. Chem. 1989, 61, 951 A. (13) Virlichie, J. L.; Ayache, A. S.T.P. Pharma Pratiques 1995, 5, 37.
(2) International Conference on Harmonisation, Draft Guideline on Validation of Analytical Procedures: Definitions and Terminology, Federal Register, Volume 60, pp. 11260, March 1, 1995. (3) Reviewer Guidance, Validation of Chromatographic Methods, Center for Drug Evaluation and Research, Food and Drug Administration, 1994. (4) Guideline for Submitting Samples and Analytical Data for Methods Validation, Food and Drug Administration, 1987. (5) Clarke, G. S. J. Pharm. Biomed. Anal. 1994, 12, 643. (6) Inman, E. L.; Frischman, J. K.; Jimenez, P. J.; Winkel, G. D.; Persinger, M. L.; Rutherford, B. S. J. Chromatogr. Sci. 1987, 25, 252. (7) Wilson, T. D. J. Pharm. Biomed. Anal. 1990, 8, 389. (8) Adamovics, J. A., Chromatographic Analysis of Pharmaceuticals, M. Dekker, New York, 1990. (9) Hokanson, G. C. Pharm. Technol. 1994, 18, 118. (10) Carr. G. P.; Wahlich, J. C. J. Pharm. Biomed. Anal. 1990, 8, 613. (11) Cassidy, R.; Janoski, M. LC-GC 1992, 10, 692. (12) Dorschel, C. A.; Ekmanis, J. L.; Oberholtzer, J. E.; Warren, F. V.; Bidlingmeyer, B. A. Anal. Chem. 1989, 61, 951 A. (13) Virlichie, J. L.; Ayache, A. S.T.P. Pharma Pratiques 1995, 5, 37.
General Principles of Software Validation

FINAL GUIDANCE FOR INDUSTRY AND FDA STAFF

FINAL GUIDANCE FOR INDUSTRY AND FDA STAFF
Document issued on: January 11, 2002 This document supersedes the draft document, General Principles of Software Validation, Version 1.1, dated June 9, 1997.
U.S. Department Of Health and Human Services Food and Drug Administration Center for Devices and Radiological Health Center for Biologics Evaluation and Research
Document issued on: January 11, 2002 This document supersedes the draft document, General Principles of Software Validation, Version 1.1, dated June 9, 1997.
U.S. Department Of Health and Human Services Food and Drug Administration Center for Devices and Radiological Health Center for Biologics Evaluation and Research
PREFACE
PREFACE
Public Comment
Comments and suggestions may be submitted at any time for Agency consideration to Dockets Management Branch, Division of Management Systems and Policy, Office of Human Resources and Management Services, Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD, 20852. When submitting comments, please refer to the exact title of this guidance document. Comments may not be acted upon by the Agency until the document is next revised or updated. For questions regarding the use or interpretation of this guidance which involve the Center for Devices and Radiological Health (CDRH), contact John F. Murray at (301) 594-4659 or email jfm@cdrh.fda.gov. For questions regarding the use or interpretation of this guidance which involve the Center for Biologics Evaluation and Research (CBER) contact Jerome Davis at (301) 827-6220 or email davis@cber.fda.gov.
Public Comment
Comments and suggestions may be submitted at any time for Agency consideration to Dockets Management Branch, Division of Management Systems and Policy, Office of Human Resources and Management Services, Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD, 20852. When submitting comments, please refer to the exact title of this guidance document. Comments may not be acted upon by the Agency until the document is next revised or updated. For questions regarding the use or interpretation of this guidance which involve the Center for Devices and Radiological Health (CDRH), contact John F. Murray at (301) 594-4659 or email jfm@cdrh.fda.gov. For questions regarding the use or interpretation of this guidance which involve the Center for Biologics Evaluation and Research (CBER) contact Jerome Davis at (301) 827-6220 or email davis@cber.fda.gov.
Additional Copies
CDRH Additional copies are available from the Internet at: http://www.fda.gov/cdrh/comp/guidance/938.pdf or via CDRH Facts-OnDemand. In order to receive this document via your fax machine, call the CDRH Facts-On-Demand system at 800-899-0381 or 301-827-0111 from a touch-tone telephone. Press 1 to enter the system. At the second voice prompt, press 1 to order a document. Enter the document number 938 followed by the pound sign (#). Follow the remaining voice prompts to complete your request.
Additional Copies
CDRH Additional copies are available from the Internet at: http://www.fda.gov/cdrh/comp/guidance/938.pdf or via CDRH Facts-OnDemand. In order to receive this document via your fax machine, call the CDRH Facts-On-Demand system at 800-899-0381 or 301-827-0111 from a touch-tone telephone. Press 1 to enter the system. At the second voice prompt, press 1 to order a document. Enter the document number 938 followed by the pound sign (#). Follow the remaining voice prompts to complete your request.
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CBER Additional copies are available from the Internet at: http://www.fda.gov/cber/guidelines.htm, by writing to CBER, Office of Communication, Training, and Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Rockville, Maryland 20852-1448, or by telephone request at 1-800-835-5709 or 301-827-1800.
CBER Additional copies are available from the Internet at: http://www.fda.gov/cber/guidelines.htm, by writing to CBER, Office of Communication, Training, and Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Rockville, Maryland 20852-1448, or by telephone request at 1-800-835-5709 or 301-827-1800.
USFDA general principles of software validation (2002)
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TABLE OF CONTENTS
SECTION 1. PURPOSE SECTION 2. SCOPE 2.1. Applicability 2.2. Audience 2.3. THE LEAST BURDENSOME APPROACH 2.4. Regulatory Requirements for Software Validation 2.4. Quality System Regulation vs Pre-Market Submissions SECTION 3. CONTEXT FOR SOFTWARE VALIDATION 3.1. Definitions and Terminology 3.1.1 Requirements and Specifications 3.1.2 Verification and Validation 3.1.3 IQ/OQ/PQ 3.2. Software Development as Part of System Design 3.3. Software is Different from Hardware 3.4. Benefits of Software Validation 3.5 Design Review SECTION 4. PRINCIPLES OF SOFTWARE VALIDATION 4.1. Requirements 4.2. Defect Prevention 4.3. Time and Effort 4.4. Software Life Cycle 4.5. Plans 4.6. Procedures 4.7. Software Validation After a Change 4.8. Validation Coverage 4.9. Independence of Review 4.10. Flexibility and Responsibility SECTION 5. ACTIVITIES AND TASKS 5.1. Software Life Cycle Activities 5.2. Typical Tasks Supporting Validation
TABLE OF CONTENTS
SECTION 1. PURPOSE SECTION 2. SCOPE 2.1. Applicability 2.2. Audience 2.3. THE LEAST BURDENSOME APPROACH 2.4. Regulatory Requirements for Software Validation 2.4. Quality System Regulation vs Pre-Market Submissions SECTION 3. CONTEXT FOR SOFTWARE VALIDATION 3.1. Definitions and Terminology 3.1.1 Requirements and Specifications 3.1.2 Verification and Validation 3.1.3 IQ/OQ/PQ 3.2. Software Development as Part of System Design 3.3. Software is Different from Hardware 3.4. Benefits of Software Validation 3.5 Design Review SECTION 4. PRINCIPLES OF SOFTWARE VALIDATION 4.1. Requirements 4.2. Defect Prevention 4.3. Time and Effort 4.4. Software Life Cycle 4.5. Plans 4.6. Procedures 4.7. Software Validation After a Change 4.8. Validation Coverage 4.9. Independence of Review 4.10. Flexibility and Responsibility SECTION 5. ACTIVITIES AND TASKS 5.1. Software Life Cycle Activities 5.2. Typical Tasks Supporting Validation
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5.2.1. Quality Planning 5.2.2. Requirements 5.2.3. Design 5.2.4. Construction or Coding 5.2.5. Testing by the Software Developer 5.2.6. User Site Testing 5.2.7. Maintenance and Software Changes SECTION 6. VALIDATION OFAUTOMATED PROCESS EQUIPMENT AND QUALITY SYSTEM SOFTWARE 6.1. How Much Validation Evidence Is Needed? 6.2. Defined User Requirements 6.3. Validation of Off-the-Shelf Software and Automated Equipment APPENDIX A- REFERENCES Food and Drug Administration References Other Government References International and National Consensus Standards Production Process Software References General Software Quality References APPENDIX B - DEVELOPMENT TEAM
5.2.1. Quality Planning 5.2.2. Requirements 5.2.3. Design 5.2.4. Construction or Coding 5.2.5. Testing by the Software Developer 5.2.6. User Site Testing 5.2.7. Maintenance and Software Changes SECTION 6. VALIDATION OFAUTOMATED PROCESS EQUIPMENT AND QUALITY SYSTEM SOFTWARE 6.1. How Much Validation Evidence Is Needed? 6.2. Defined User Requirements 6.3. Validation of Off-the-Shelf Software and Automated Equipment APPENDIX A- REFERENCES Food and Drug Administration References Other Government References International and National Consensus Standards Production Process Software References General Software Quality References APPENDIX B - DEVELOPMENT TEAM
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This document is intended to provide guidance. It represents the Agencys current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind Food and Drug Administration (FDA) or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.

This document is intended to provide guidance. It represents the Agencys current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind Food and Drug Administration (FDA) or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.
SECTION 1. PURPOSE
This guidance outlines general validation principles that the Food and Drug Administration (FDA) considers to be applicable to the validation of medical device software or the validation of software used to design, develop, or manufacture medical devices. This final guidance document, Version 2.0, supersedes the draft document, General Principles of Software Validation, Version 1.1, dated June 9, 1997.
SECTION 1. PURPOSE
This guidance outlines general validation principles that the Food and Drug Administration (FDA) considers to be applicable to the validation of medical device software or the validation of software used to design, develop, or manufacture medical devices. This final guidance document, Version 2.0, supersedes the draft document, General Principles of Software Validation, Version 1.1, dated June 9, 1997.
SECTION 2. SCOPE
This guidance describes how certain provisions of the medical device Quality System regulation apply to software and the agencys current approach to evaluating a software validation system. For example, this document lists elements that are acceptable to the FDA for the validation of software; however, it does not list all of the activities and tasks that must, in all instances, be used to comply with the law. The scope of this guidance is somewhat broader than the scope of validation in the strictest definition of that term. Planning, verification, testing, traceability, configuration management, and many other aspects of good software engineering discussed in this guidance are important activities that together help to support a final conclusion that software is validated. This guidance recommends an integration of software life cycle management and risk management activities. Based on the intended use and the safety risk associated with the software to be developed, the software developer
SECTION 2. SCOPE
This guidance describes how certain provisions of the medical device Quality System regulation apply to software and the agencys current approach to evaluating a software validation system. For example, this document lists elements that are acceptable to the FDA for the validation of software; however, it does not list all of the activities and tasks that must, in all instances, be used to comply with the law. The scope of this guidance is somewhat broader than the scope of validation in the strictest definition of that term. Planning, verification, testing, traceability, configuration management, and many other aspects of good software engineering discussed in this guidance are important activities that together help to support a final conclusion that software is validated. This guidance recommends an integration of software life cycle management and risk management activities. Based on the intended use and the safety risk associated with the software to be developed, the software developer
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should determine the specific approach, the combination of techniques to be used, and the level of effort to be applied. While this guidance does not recommend any specific life cycle model or any specific technique or method, it does recommend that software validation and verification activities be conducted throughout the entire software life cycle. Where the software is developed by someone other than the device manufacturer (e.g., off-the-shelf software) the software developer may not be directly responsible for compliance with FDA regulations. In that case, the party with regulatory responsibility (i.e., the device manufacturer) needs to assess the adequacy of the off-the-shelf software developers activities and determine what additional efforts are needed to establish that the software is validated for the device manufacturers intended use. 2.1. APPLICABILITY This guidance applies to: Software used as a component, part, or accessory of a medical device; Software that is itself a medical device (e.g., blood establishment software); Software used in the production of a device (e.g., programmable logic controllers in manufacturing equipment); and Software used in implementation of the device manufacturers quality system (e.g., software that records and maintains the device history record). This document is based on generally recognized software validation principles and, therefore, can be applied to any software. For FDA purposes, this guidance applies to any software related to a regulated medical device, as defined by Section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act) and by current FDA software and regulatory policy. This document does not specifically identify which software is or is not regulated. 2.2. AUDIENCE This guidance provides useful information and recommendations to the following individuals: Persons subject to the medical device Quality System regulation
should determine the specific approach, the combination of techniques to be used, and the level of effort to be applied. While this guidance does not recommend any specific life cycle model or any specific technique or method, it does recommend that software validation and verification activities be conducted throughout the entire software life cycle. Where the software is developed by someone other than the device manufacturer (e.g., off-the-shelf software) the software developer may not be directly responsible for compliance with FDA regulations. In that case, the party with regulatory responsibility (i.e., the device manufacturer) needs to assess the adequacy of the off-the-shelf software developers activities and determine what additional efforts are needed to establish that the software is validated for the device manufacturers intended use. 2.1. APPLICABILITY This guidance applies to: Software used as a component, part, or accessory of a medical device; Software that is itself a medical device (e.g., blood establishment software); Software used in the production of a device (e.g., programmable logic controllers in manufacturing equipment); and Software used in implementation of the device manufacturers quality system (e.g., software that records and maintains the device history record). This document is based on generally recognized software validation principles and, therefore, can be applied to any software. For FDA purposes, this guidance applies to any software related to a regulated medical device, as defined by Section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act) and by current FDA software and regulatory policy. This document does not specifically identify which software is or is not regulated. 2.2. AUDIENCE This guidance provides useful information and recommendations to the following individuals: Persons subject to the medical device Quality System regulation
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Persons responsible for the design, development, or production of medical device software Persons responsible for the design, development, production, or procurement of automated tools used for the design, development, or manufacture of medical devices or software tools used to implement the quality system itself FDA Investigators FDA Compliance Officers FDA Scientific Reviewers 2.3. THE LEAST BURDENSOME APPROACH We believe we should consider the least burdensome approach in all areas of medical device regulation. This guidance reflects our careful review of the relevant scientific and legal requirements and what we believe is the least burdensome way for you to comply with those requirements. However, if you believe that an alternative approach would be less burdensome, please contact us so we can consider your point of view. You may send your written comments to the contact person listed in the preface to this guidance or to the CDRH Ombudsman. Comprehensive information on CDRHs Ombudsman, including ways to contact him, can be found on the Internet at: http://www.fda.gov/cdrh/resolvingdisputes/ombudsman.html. 2.4. REGULATORY REQUIREMENTS FOR SOFTWARE VALIDATION The FDAs analysis of 3140 medical device recalls conducted between 1992 and 1998 reveals that 242 of them (7.7%) are attributable to software failures. Of those software related recalls, 192 (or 79%) were caused by software defects that were introduced when changes were made to the software after its initial production and distribution. Software validation and other related good software engineering practices discussed in this guidance are a principal means of avoiding such defects and resultant recalls. Software validation is a requirement of the Quality System regulation, which was published in the Federal Register on October 7, 1996 and took effect on June 1, 1997. (See Title 21 Code of Federal Regulations (CFR) Part 820, and 61 Federal Register (FR) 52602, respectively.) Validation requirements apply
Persons responsible for the design, development, or production of medical device software Persons responsible for the design, development, production, or procurement of automated tools used for the design, development, or manufacture of medical devices or software tools used to implement the quality system itself FDA Investigators FDA Compliance Officers FDA Scientific Reviewers 2.3. THE LEAST BURDENSOME APPROACH We believe we should consider the least burdensome approach in all areas of medical device regulation. This guidance reflects our careful review of the relevant scientific and legal requirements and what we believe is the least burdensome way for you to comply with those requirements. However, if you believe that an alternative approach would be less burdensome, please contact us so we can consider your point of view. You may send your written comments to the contact person listed in the preface to this guidance or to the CDRH Ombudsman. Comprehensive information on CDRHs Ombudsman, including ways to contact him, can be found on the Internet at: http://www.fda.gov/cdrh/resolvingdisputes/ombudsman.html. 2.4. REGULATORY REQUIREMENTS FOR SOFTWARE VALIDATION The FDAs analysis of 3140 medical device recalls conducted between 1992 and 1998 reveals that 242 of them (7.7%) are attributable to software failures. Of those software related recalls, 192 (or 79%) were caused by software defects that were introduced when changes were made to the software after its initial production and distribution. Software validation and other related good software engineering practices discussed in this guidance are a principal means of avoiding such defects and resultant recalls. Software validation is a requirement of the Quality System regulation, which was published in the Federal Register on October 7, 1996 and took effect on June 1, 1997. (See Title 21 Code of Federal Regulations (CFR) Part 820, and 61 Federal Register (FR) 52602, respectively.) Validation requirements apply
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to software used as components in medical devices, to software that is itself a medical device, and to software used in production of the device or in implementation of the device manufacturers quality system. Unless specifically exempted in a classification regulation, any medical device software product developed after June 1, 1997, regardless of its device class, is subject to applicable design control provisions. (See of 21 CFR 820.30.) This requirement includes the completion of current development projects, all new development projects, and all changes made to existing medical device software. Specific requirements for validation of device software are found in 21 CFR 820.30(g). Other design controls, such as planning, input, verification, and reviews, are required for medical device software. (See 21 CFR 820.30.) The corresponding documented results from these activities can provide additional support for a conclusion that medical device software is validated. Any software used to automate any part of the device production process or any part of the quality system must be validated for its intended use, as required by 21 CFR 820.70(i). This requirement applies to any software used to automate device design, testing, component acceptance, manufacturing, labeling, packaging, distribution, complaint handling, or to automate any other aspect of the quality system. In addition, computer systems used to create, modify, and maintain electronic records and to manage electronic signatures are also subject to the validation requirements. (See 21 CFR 11.10(a).) Such computer systems must be validated to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records. Software for the above applications may be developed in-house or under contract. However, software is frequently purchased off-the-shelf for a particular intended use. All production and/or quality system software, even if purchased off-the-shelf, should have documented requirements that fully define its intended use, and information against which testing results and other evidence can be compared, to show that the software is validated for its intended use. The use of off-the-shelf software in automated medical devices and in automated manufacturing and quality system operations is increasing. Offthe-shelf software may have many capabilities, only a few of which are
to software used as components in medical devices, to software that is itself a medical device, and to software used in production of the device or in implementation of the device manufacturers quality system. Unless specifically exempted in a classification regulation, any medical device software product developed after June 1, 1997, regardless of its device class, is subject to applicable design control provisions. (See of 21 CFR 820.30.) This requirement includes the completion of current development projects, all new development projects, and all changes made to existing medical device software. Specific requirements for validation of device software are found in 21 CFR 820.30(g). Other design controls, such as planning, input, verification, and reviews, are required for medical device software. (See 21 CFR 820.30.) The corresponding documented results from these activities can provide additional support for a conclusion that medical device software is validated. Any software used to automate any part of the device production process or any part of the quality system must be validated for its intended use, as required by 21 CFR 820.70(i). This requirement applies to any software used to automate device design, testing, component acceptance, manufacturing, labeling, packaging, distribution, complaint handling, or to automate any other aspect of the quality system. In addition, computer systems used to create, modify, and maintain electronic records and to manage electronic signatures are also subject to the validation requirements. (See 21 CFR 11.10(a).) Such computer systems must be validated to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records. Software for the above applications may be developed in-house or under contract. However, software is frequently purchased off-the-shelf for a particular intended use. All production and/or quality system software, even if purchased off-the-shelf, should have documented requirements that fully define its intended use, and information against which testing results and other evidence can be compared, to show that the software is validated for its intended use. The use of off-the-shelf software in automated medical devices and in automated manufacturing and quality system operations is increasing. Offthe-shelf software may have many capabilities, only a few of which are
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needed by the device manufacturer. Device manufacturers are responsible for the adequacy of the software used in their devices, and used to produce devices. When device manufacturers purchase off-the-shelf software, they must ensure that it will perform as intended in their chosen application. For off-the-shelf software used in manufacturing or in the quality system, additional guidance is included in Section 6.3 of this document. For device software, additional useful information may be found in FDAs Guidance for Industry, FDA Reviewers, and Compliance on Off-The-Shelf Software Use in Medical Devices. 2.4. QUALITY SYSTEM REGULATION VS PRE-MARKET SUBMISSIONS This document addresses Quality System regulation issues that involve the implementation of software validation. It provides guidance for the management and control of the software validation process. The management and control of the software validation process should not be confused with any other validation requirements, such as process validation for an automated manufacturing process. Device manufacturers may use the same procedures and records for compliance with quality system and design control requirements, as well as for pre-market submissions to FDA. This document does not cover any specific safety or efficacy issues related to software validation. Design issues and documentation requirements for pre-market submissions of regulated software are not addressed by this document. Specific issues related to safety and efficacy, and the documentation required in pre-market submissions, should be addressed to the Office of Device Evaluation (ODE), Center for Devices and Radiological Health (CDRH) or to the Office of Blood Research and Review, Center for Biologics Evaluation and Research (CBER). See the references in Appendix A for applicable FDA guidance documents for pre-market submissions.
needed by the device manufacturer. Device manufacturers are responsible for the adequacy of the software used in their devices, and used to produce devices. When device manufacturers purchase off-the-shelf software, they must ensure that it will perform as intended in their chosen application. For off-the-shelf software used in manufacturing or in the quality system, additional guidance is included in Section 6.3 of this document. For device software, additional useful information may be found in FDAs Guidance for Industry, FDA Reviewers, and Compliance on Off-The-Shelf Software Use in Medical Devices. 2.4. QUALITY SYSTEM REGULATION VS PRE-MARKET SUBMISSIONS This document addresses Quality System regulation issues that involve the implementation of software validation. It provides guidance for the management and control of the software validation process. The management and control of the software validation process should not be confused with any other validation requirements, such as process validation for an automated manufacturing process. Device manufacturers may use the same procedures and records for compliance with quality system and design control requirements, as well as for pre-market submissions to FDA. This document does not cover any specific safety or efficacy issues related to software validation. Design issues and documentation requirements for pre-market submissions of regulated software are not addressed by this document. Specific issues related to safety and efficacy, and the documentation required in pre-market submissions, should be addressed to the Office of Device Evaluation (ODE), Center for Devices and Radiological Health (CDRH) or to the Office of Blood Research and Review, Center for Biologics Evaluation and Research (CBER). See the references in Appendix A for applicable FDA guidance documents for pre-market submissions.
SECTION 3. CONTEXT FOR SOFTWARE VALIDATION

Many people have asked for specific guidance on what FDA expects them to do to ensure compliance with the Quality System regulation with regard to software validation. Information on software validation presented in this document is not new. Validation of software, using the principles and tasks
SECTION 3. CONTEXT FOR SOFTWARE VALIDATION

Many people have asked for specific guidance on what FDA expects them to do to ensure compliance with the Quality System regulation with regard to software validation. Information on software validation presented in this document is not new. Validation of software, using the principles and tasks
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listed in Sections 4 and 5, has been conducted in many segments of the software industry for well over 20 years. Due to the great variety of medical devices, processes, and manufacturing facilities, it is not possible to state in one document all of the specific validation elements that are applicable. However, a general application of several broad concepts can be used successfully as guidance for software validation. These broad concepts provide an acceptable framework for building a comprehensive approach to software validation. Additional specific information is available from many of the references listed in Appendix A. 3.1. DEFINITIONS AND TERMINOLOGY Unless defined in the Quality System regulation, or otherwise specified below, all other terms used in this guidance are as defined in the current edition of the FDA Glossary of Computerized System and Software Development Terminology. The medical device Quality System regulation (21 CFR 820.3(k)) defines establish to mean define, document, and implement. Where it appears in this guidance, the words establish and established should be interpreted to have this same meaning. Some definitions found in the medical device Quality System regulation can be confusing when compared to commonly used terminology in the software industry. Examples are requirements, specification, verification, and validation. 3.1.1 Requirements and Specifications While the Quality System regulation states that design input requirements must be documented, and that specified requirements must be verified, the regulation does not further clarify the distinction between the terms requirement and specification. A requirement can be any need or expectation for a system or for its software. Requirements reflect the stated or implied needs of the customer, and may be market-based, contractual, or statutory, as well as an organizations internal requirements. There can be many different kinds of requirements (e.g., design, functional, implementation, interface, performance, or physical requirements). Software
listed in Sections 4 and 5, has been conducted in many segments of the software industry for well over 20 years. Due to the great variety of medical devices, processes, and manufacturing facilities, it is not possible to state in one document all of the specific validation elements that are applicable. However, a general application of several broad concepts can be used successfully as guidance for software validation. These broad concepts provide an acceptable framework for building a comprehensive approach to software validation. Additional specific information is available from many of the references listed in Appendix A. 3.1. DEFINITIONS AND TERMINOLOGY Unless defined in the Quality System regulation, or otherwise specified below, all other terms used in this guidance are as defined in the current edition of the FDA Glossary of Computerized System and Software Development Terminology. The medical device Quality System regulation (21 CFR 820.3(k)) defines establish to mean define, document, and implement. Where it appears in this guidance, the words establish and established should be interpreted to have this same meaning. Some definitions found in the medical device Quality System regulation can be confusing when compared to commonly used terminology in the software industry. Examples are requirements, specification, verification, and validation. 3.1.1 Requirements and Specifications While the Quality System regulation states that design input requirements must be documented, and that specified requirements must be verified, the regulation does not further clarify the distinction between the terms requirement and specification. A requirement can be any need or expectation for a system or for its software. Requirements reflect the stated or implied needs of the customer, and may be market-based, contractual, or statutory, as well as an organizations internal requirements. There can be many different kinds of requirements (e.g., design, functional, implementation, interface, performance, or physical requirements). Software
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requirements are typically derived from the system requirements for those aspects of system functionality that have been allocated to software. Software requirements are typically stated in functional terms and are defined, refined, and updated as a development project progresses. Success in accurately and completely documenting software requirements is a crucial factor in successful validation of the resulting software. A specification is defined as a document that states requirements. (See 21 CFR 820.3(y).) It may refer to or include drawings, patterns, or other relevant documents and usually indicates the means and the criteria whereby conformity with the requirement can be checked. There are many different kinds of written specifications, e.g., system requirements specification, software requirements specification, software design specification, software test specification, software integration specification, etc. All of these documents establish specified requirements and are design outputs for which various forms of verification are necessary. 3.1.2 Verification and Validation The Quality System regulation is harmonized with ISO 8402:1994, which treats verification and validation as separate and distinct terms. On the other hand, many software engineering journal articles and textbooks use the terms verification and validation interchangeably, or in some cases refer to software verification, validation, and testing (VV&T) as if it is a single concept, with no distinction among the three terms. Software verification provides objective evidence that the design outputs of a particular phase of the software development life cycle meet all of the specified requirements for that phase. Software verification looks for consistency, completeness, and correctness of the software and its supporting documentation, as it is being developed, and provides support for a subsequent conclusion that software is validated. Software testing is one of many verification activities intended to confirm that software development output meets its input requirements. Other verification activities include various static and dynamic analyses, code and document inspections, walkthroughs, and other techniques. Software validation is a part of the design validation for a finished device, but is not separately defined in the Quality System regulation. For purposes of this guidance, FDA considers software validation to be confirmation
requirements are typically derived from the system requirements for those aspects of system functionality that have been allocated to software. Software requirements are typically stated in functional terms and are defined, refined, and updated as a development project progresses. Success in accurately and completely documenting software requirements is a crucial factor in successful validation of the resulting software. A specification is defined as a document that states requirements. (See 21 CFR 820.3(y).) It may refer to or include drawings, patterns, or other relevant documents and usually indicates the means and the criteria whereby conformity with the requirement can be checked. There are many different kinds of written specifications, e.g., system requirements specification, software requirements specification, software design specification, software test specification, software integration specification, etc. All of these documents establish specified requirements and are design outputs for which various forms of verification are necessary. 3.1.2 Verification and Validation The Quality System regulation is harmonized with ISO 8402:1994, which treats verification and validation as separate and distinct terms. On the other hand, many software engineering journal articles and textbooks use the terms verification and validation interchangeably, or in some cases refer to software verification, validation, and testing (VV&T) as if it is a single concept, with no distinction among the three terms. Software verification provides objective evidence that the design outputs of a particular phase of the software development life cycle meet all of the specified requirements for that phase. Software verification looks for consistency, completeness, and correctness of the software and its supporting documentation, as it is being developed, and provides support for a subsequent conclusion that software is validated. Software testing is one of many verification activities intended to confirm that software development output meets its input requirements. Other verification activities include various static and dynamic analyses, code and document inspections, walkthroughs, and other techniques. Software validation is a part of the design validation for a finished device, but is not separately defined in the Quality System regulation. For purposes of this guidance, FDA considers software validation to be confirmation
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by examination and provision of objective evidence that software specifications conform to user needs and intended uses, and that the particular requirements implemented through software can be consistently fulfilled. In practice, software validation activities may occur both during, as well as at the end of the software development life cycle to ensure that all requirements have been fulfilled. Since software is usually part of a larger hardware system, the validation of software typically includes evidence that all software requirements have been implemented correctly and completely and are traceable to system requirements. A conclusion that software is validated is highly dependent upon comprehensive software testing, inspections, analyses, and other verification tasks performed at each stage of the software development life cycle. Testing of device software functionality in a simulated use environment, and user site testing are typically included as components of an overall design validation program for a software automated device. Software verification and validation are difficult because a developer cannot test forever, and it is hard to know how much evidence is enough. In large measure, software validation is a matter of developing a level of confidence that the device meets all requirements and user expectations for the software automated functions and features of the device. Measures such as defects found in specifications documents, estimates of defects remaining, testing coverage, and other techniques are all used to develop an acceptable level of confidence before shipping the product. The level of confidence, and therefore the level of software validation, verification, and testing effort needed, will vary depending upon the safety risk (hazard) posed by the automated functions of the device. Additional guidance regarding safety risk management for software may be found in Section 4 of FDAs Guidance for the Content of Pre-market Submissions for Software Contained in Medical Devices, and in the international standards ISO/IEC 14971-1 and IEC 60601-1-4 referenced in Appendix A. 3.1.3 IQ/OQ/PQ For many years, both FDA and regulated industry have attempted to understand and define software validation within the context of process validation terminology. For example, industry documents and other FDA validation guidance sometimes describe user site software validation in terms of installation qualification (IQ), operational qualification (OQ) and
by examination and provision of objective evidence that software specifications conform to user needs and intended uses, and that the particular requirements implemented through software can be consistently fulfilled. In practice, software validation activities may occur both during, as well as at the end of the software development life cycle to ensure that all requirements have been fulfilled. Since software is usually part of a larger hardware system, the validation of software typically includes evidence that all software requirements have been implemented correctly and completely and are traceable to system requirements. A conclusion that software is validated is highly dependent upon comprehensive software testing, inspections, analyses, and other verification tasks performed at each stage of the software development life cycle. Testing of device software functionality in a simulated use environment, and user site testing are typically included as components of an overall design validation program for a software automated device. Software verification and validation are difficult because a developer cannot test forever, and it is hard to know how much evidence is enough. In large measure, software validation is a matter of developing a level of confidence that the device meets all requirements and user expectations for the software automated functions and features of the device. Measures such as defects found in specifications documents, estimates of defects remaining, testing coverage, and other techniques are all used to develop an acceptable level of confidence before shipping the product. The level of confidence, and therefore the level of software validation, verification, and testing effort needed, will vary depending upon the safety risk (hazard) posed by the automated functions of the device. Additional guidance regarding safety risk management for software may be found in Section 4 of FDAs Guidance for the Content of Pre-market Submissions for Software Contained in Medical Devices, and in the international standards ISO/IEC 14971-1 and IEC 60601-1-4 referenced in Appendix A. 3.1.3 IQ/OQ/PQ For many years, both FDA and regulated industry have attempted to understand and define software validation within the context of process validation terminology. For example, industry documents and other FDA validation guidance sometimes describe user site software validation in terms of installation qualification (IQ), operational qualification (OQ) and
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performance qualification (PQ). Definitions of these terms and additional information regarding IQ/OQ/PQ may be found in FDAs Guideline on General Principles of Process Validation, dated May 11, 1987, and in FDAs Glossary of Computerized System and Software Development Terminology, dated August 1995. While IQ/OQ/PQ terminology has served its purpose well and is one of many legitimate ways to organize software validation tasks at the user site, this terminology may not be well understood among many software professionals, and it is not used elsewhere in this document. However, both FDA personnel and device manufacturers need to be aware of these differences in terminology as they ask for and provide information regarding software validation. 3.2. SOFTWARE DEVELOPMENT AS PART OF SYSTEM DESIGN The decision to implement system functionality using software is one that is typically made during system design. Software requirements are typically derived from the overall system requirements and design for those aspects in the system that are to be implemented using software. There are user needs and intended uses for a finished device, but users typically do not specify whether those requirements are to be met by hardware, software, or some combination of both. Therefore, software validation must be considered within the context of the overall design validation for the system. A documented requirements specification represents the users needs and intended uses from which the product is developed. A primary goal of software validation is to then demonstrate that all completed software products comply with all documented software and system requirements. The correctness and completeness of both the system requirements and the software requirements should be addressed as part of the design validation process for the device. Software validation includes confirmation of conformance to all software specifications and confirmation that all software requirements are traceable to the system specifications. Confirmation is an important part of the overall design validation to ensure that all aspects of the medical device conform to user needs and intended uses.
performance qualification (PQ). Definitions of these terms and additional information regarding IQ/OQ/PQ may be found in FDAs Guideline on General Principles of Process Validation, dated May 11, 1987, and in FDAs Glossary of Computerized System and Software Development Terminology, dated August 1995. While IQ/OQ/PQ terminology has served its purpose well and is one of many legitimate ways to organize software validation tasks at the user site, this terminology may not be well understood among many software professionals, and it is not used elsewhere in this document. However, both FDA personnel and device manufacturers need to be aware of these differences in terminology as they ask for and provide information regarding software validation. 3.2. SOFTWARE DEVELOPMENT AS PART OF SYSTEM DESIGN The decision to implement system functionality using software is one that is typically made during system design. Software requirements are typically derived from the overall system requirements and design for those aspects in the system that are to be implemented using software. There are user needs and intended uses for a finished device, but users typically do not specify whether those requirements are to be met by hardware, software, or some combination of both. Therefore, software validation must be considered within the context of the overall design validation for the system. A documented requirements specification represents the users needs and intended uses from which the product is developed. A primary goal of software validation is to then demonstrate that all completed software products comply with all documented software and system requirements. The correctness and completeness of both the system requirements and the software requirements should be addressed as part of the design validation process for the device. Software validation includes confirmation of conformance to all software specifications and confirmation that all software requirements are traceable to the system specifications. Confirmation is an important part of the overall design validation to ensure that all aspects of the medical device conform to user needs and intended uses.
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3.3. SOFTWARE IS DIFFERENT FROM HARDWARE While software shares many of the same engineering tasks as hardware, it has some very important differences. For example: The vast majority of software problems are traceable to errors made during the design and development process. While the quality of a hardware product is highly dependent on design, development and manufacture, the quality of a software product is dependent primarily on design and development with a minimum concern for software manufacture. Software manufacturing consists of reproduction that can be easily verified. It is not difficult to manufacture thousands of program copies that function exactly the same as the original; the difficulty comes in getting the original program to meet all specifications. One of the most significant features of software is branching, i.e., the ability to execute alternative series of commands, based on differing inputs. This feature is a major contributing factor for another characteristic of software - its complexity. Even short programs can be very complex and difficult to fully understand. Typically, testing alone cannot fully verify that software is complete and correct. In addition to testing, other verification techniques and a structured and documented development process should be combined to ensure a comprehensive validation approach. Unlike hardware, software is not a physical entity and does not wear out. In fact, software may improve with age, as latent defects are discovered and removed. However, as software is constantly updated and changed, such improvements are sometimes countered by new defects introduced into the software during the change. Unlike some hardware failures, software failures occur without advanced warning. The softwares branching that allows it to follow differing paths during execution, may hide some latent defects until long after a software product has been introduced into the marketplace. Another related characteristic of software is the speed and ease with which it can be changed. This factor can cause both software and nonsoftware professionals to believe that software problems can be corrected easily. Combined with a lack of understanding of software, it can lead managers to believe that tightly controlled engineering is not needed as
3.3. SOFTWARE IS DIFFERENT FROM HARDWARE While software shares many of the same engineering tasks as hardware, it has some very important differences. For example: The vast majority of software problems are traceable to errors made during the design and development process. While the quality of a hardware product is highly dependent on design, development and manufacture, the quality of a software product is dependent primarily on design and development with a minimum concern for software manufacture. Software manufacturing consists of reproduction that can be easily verified. It is not difficult to manufacture thousands of program copies that function exactly the same as the original; the difficulty comes in getting the original program to meet all specifications. One of the most significant features of software is branching, i.e., the ability to execute alternative series of commands, based on differing inputs. This feature is a major contributing factor for another characteristic of software - its complexity. Even short programs can be very complex and difficult to fully understand. Typically, testing alone cannot fully verify that software is complete and correct. In addition to testing, other verification techniques and a structured and documented development process should be combined to ensure a comprehensive validation approach. Unlike hardware, software is not a physical entity and does not wear out. In fact, software may improve with age, as latent defects are discovered and removed. However, as software is constantly updated and changed, such improvements are sometimes countered by new defects introduced into the software during the change. Unlike some hardware failures, software failures occur without advanced warning. The softwares branching that allows it to follow differing paths during execution, may hide some latent defects until long after a software product has been introduced into the marketplace. Another related characteristic of software is the speed and ease with which it can be changed. This factor can cause both software and nonsoftware professionals to believe that software problems can be corrected easily. Combined with a lack of understanding of software, it can lead managers to believe that tightly controlled engineering is not needed as
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much for software as it is for hardware. In fact, the opposite is true. Because of its complexity, the development process for software should be even more tightly controlled than for hardware, in order to prevent problems that cannot be easily detected later in the development process. Seemingly insignificant changes in software code can create unexpected and very significant problems elsewhere in the software program. The software development process should be sufficiently well planned, controlled, and documented to detect and correct unexpected results from software changes. Given the high demand for software professionals and the highly mobile workforce, the software personnel who make maintenance changes to software may not have been involved in the original software development. Therefore, accurate and thorough documentation is essential. Historically, software components have not been as frequently standardized and interchangeable as hardware components. However, medical device software developers are beginning to use component-based development tools and techniques. Object-oriented methodologies and the use of off-the-shelf software components hold promise for faster and less expensive software development. However, component-based approaches require very careful attention during integration. Prior to integration, time is needed to fully define and develop reusable software code and to fully understand the behavior of off-the-shelf components. For these and other reasons, software engineering needs an even greater level of managerial scrutiny and control than does hardware engineering. 3.4. BENEFITS OF SOFTWARE VALIDATION Software validation is a critical tool used to assure the quality of device software and software automated operations. Software validation can increase the usability and reliability of the device, resulting in decreased failure rates, fewer recalls and corrective actions, less risk to patients and users, and reduced liability to device manufacturers. Software validation can also reduce long term costs by making it easier and less costly to reliably modify software and revalidate software changes. Software maintenance can represent a very large percentage of the total cost of software over its entire life cycle. An established comprehensive software
much for software as it is for hardware. In fact, the opposite is true. Because of its complexity, the development process for software should be even more tightly controlled than for hardware, in order to prevent problems that cannot be easily detected later in the development process. Seemingly insignificant changes in software code can create unexpected and very significant problems elsewhere in the software program. The software development process should be sufficiently well planned, controlled, and documented to detect and correct unexpected results from software changes. Given the high demand for software professionals and the highly mobile workforce, the software personnel who make maintenance changes to software may not have been involved in the original software development. Therefore, accurate and thorough documentation is essential. Historically, software components have not been as frequently standardized and interchangeable as hardware components. However, medical device software developers are beginning to use component-based development tools and techniques. Object-oriented methodologies and the use of off-the-shelf software components hold promise for faster and less expensive software development. However, component-based approaches require very careful attention during integration. Prior to integration, time is needed to fully define and develop reusable software code and to fully understand the behavior of off-the-shelf components. For these and other reasons, software engineering needs an even greater level of managerial scrutiny and control than does hardware engineering. 3.4. BENEFITS OF SOFTWARE VALIDATION Software validation is a critical tool used to assure the quality of device software and software automated operations. Software validation can increase the usability and reliability of the device, resulting in decreased failure rates, fewer recalls and corrective actions, less risk to patients and users, and reduced liability to device manufacturers. Software validation can also reduce long term costs by making it easier and less costly to reliably modify software and revalidate software changes. Software maintenance can represent a very large percentage of the total cost of software over its entire life cycle. An established comprehensive software
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validation process helps to reduce the long-term cost of software by reducing the cost of validation for each subsequent release of the software. 3.5 DESIGN REVIEW Design reviews are documented, comprehensive, and systematic examinations of a design to evaluate the adequacy of the design requirements, to evaluate the capability of the design to meet these requirements, and to identify problems. While there may be many informal technical reviews that occur within the development team during a software project, a formal design review is more structured and includes participation from others outside the development team. Formal design reviews may reference or include results from other formal and informal reviews. Design reviews may be conducted separately for the software, after the software is integrated with the hardware into the system, or both. Design reviews should include examination of development plans, requirements specifications, design specifications, testing plans and procedures, all other documents and activities associated with the project, verification results from each stage of the defined life cycle, and validation results for the overall device. Design review is a primary tool for managing and evaluating development projects. For example, formal design reviews allow management to confirm that all goals defined in the software validation plan have been achieved. The Quality System regulation requires that at least one formal design review be conducted during the device design process. However, it is recommended that multiple design reviews be conducted (e.g., at the end of each software life cycle activity, in preparation for proceeding to the next activity). Formal design review is especially important at or near the end of the requirements activity, before major resources have been committed to specific design solutions. Problems found at this point can be resolved more easily, save time and money, and reduce the likelihood of missing a critical issue. Answers to some key questions should be documented during formal design reviews. These include: Have the appropriate tasks and expected results, outputs, or products been established for each software life cycle activity?
validation process helps to reduce the long-term cost of software by reducing the cost of validation for each subsequent release of the software. 3.5 DESIGN REVIEW Design reviews are documented, comprehensive, and systematic examinations of a design to evaluate the adequacy of the design requirements, to evaluate the capability of the design to meet these requirements, and to identify problems. While there may be many informal technical reviews that occur within the development team during a software project, a formal design review is more structured and includes participation from others outside the development team. Formal design reviews may reference or include results from other formal and informal reviews. Design reviews may be conducted separately for the software, after the software is integrated with the hardware into the system, or both. Design reviews should include examination of development plans, requirements specifications, design specifications, testing plans and procedures, all other documents and activities associated with the project, verification results from each stage of the defined life cycle, and validation results for the overall device. Design review is a primary tool for managing and evaluating development projects. For example, formal design reviews allow management to confirm that all goals defined in the software validation plan have been achieved. The Quality System regulation requires that at least one formal design review be conducted during the device design process. However, it is recommended that multiple design reviews be conducted (e.g., at the end of each software life cycle activity, in preparation for proceeding to the next activity). Formal design review is especially important at or near the end of the requirements activity, before major resources have been committed to specific design solutions. Problems found at this point can be resolved more easily, save time and money, and reduce the likelihood of missing a critical issue. Answers to some key questions should be documented during formal design reviews. These include: Have the appropriate tasks and expected results, outputs, or products been established for each software life cycle activity?
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Do the tasks and expected results, outputs, or products of each software life cycle activity: - Comply with the requirements of other software life cycle activities in terms of correctness, completeness, consistency, and accuracy? - Satisfy the standards, practices, and conventions of that activity? - Establish a proper basis for initiating tasks for the next software life cycle activity?
Do the tasks and expected results, outputs, or products of each software life cycle activity: - Comply with the requirements of other software life cycle activities in terms of correctness, completeness, consistency, and accuracy? - Satisfy the standards, practices, and conventions of that activity? - Establish a proper basis for initiating tasks for the next software life cycle activity?
SECTION 4. PRINCIPLES OF SOFTWARE VALIDATION

This section lists the general principles that should be considered for the validation of software. 4.1. REQUIREMENTS A documented software requirements specification provides a baseline for both validation and verification. The software validation process cannot be completed without an established software requirements specification (Ref: 21 CFR 820.3(z) and (aa) and 820.30(f) and (g)). 4.2. DEFECT PREVENTION Software quality assurance needs to focus on preventing the introduction of defects into the software development process and not on trying to test quality into the software code after it is written. Software testing is very limited in its ability to surface all latent defects in software code. For example, the complexity of most software prevents it from being exhaustively tested. Software testing is a necessary activity. However, in most cases software testing by itself is not sufficient to establish confidence that the software is fit for its intended use. In order to establish that confidence, software developers should use a mixture of methods and techniques to prevent software errors and to detect software errors that do occur. The best mix of methods depends on many factors including the development environment, application, size of project, language, and risk. 4.3. TIME AND EFFORT To build a case that the software is validated requires time and effort. Preparation for software validation should begin early, i.e., during design
SECTION 4. PRINCIPLES OF SOFTWARE VALIDATION

This section lists the general principles that should be considered for the validation of software. 4.1. REQUIREMENTS A documented software requirements specification provides a baseline for both validation and verification. The software validation process cannot be completed without an established software requirements specification (Ref: 21 CFR 820.3(z) and (aa) and 820.30(f) and (g)). 4.2. DEFECT PREVENTION Software quality assurance needs to focus on preventing the introduction of defects into the software development process and not on trying to test quality into the software code after it is written. Software testing is very limited in its ability to surface all latent defects in software code. For example, the complexity of most software prevents it from being exhaustively tested. Software testing is a necessary activity. However, in most cases software testing by itself is not sufficient to establish confidence that the software is fit for its intended use. In order to establish that confidence, software developers should use a mixture of methods and techniques to prevent software errors and to detect software errors that do occur. The best mix of methods depends on many factors including the development environment, application, size of project, language, and risk. 4.3. TIME AND EFFORT To build a case that the software is validated requires time and effort. Preparation for software validation should begin early, i.e., during design
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and development planning and design input. The final conclusion that the software is validated should be based on evidence collected from planned efforts conducted throughout the software lifecycle. 4.4. SOFTWARE LIFE CYCLE Software validation takes place within the environment of an established software life cycle. The software life cycle contains software engineering tasks and documentation necessary to support the software validation effort. In addition, the software life cycle contains specific verification and validation tasks that are appropriate for the intended use of the software. This guidance does not recommend any particular life cycle models - only that they should be selected and used for a software development project. 4.5. PLANS The software validation process is defined and controlled through the use of a plan. The software validation plan defines what is to be accomplished through the software validation effort. Software validation plans are a significant quality system tool. Software validation plans specify areas such as scope, approach, resources, schedules and the types and extent of activities, tasks, and work items. 4.6. PROCEDURES The software validation process is executed through the use of procedures. These procedures establish how to conduct the software validation effort. The procedures should identify the specific actions or sequence of actions that must be taken to complete individual validation activities, tasks, and work items. 4.7. SOFTWARE VALIDATION AFTER A CHANGE Due to the complexity of software, a seemingly small local change may have a significant global system impact. When any change (even a small change) is made to the software, the validation status of the software needs to be reestablished. Whenever software is changed, a validation analysis should be conducted not just for validation of the individual change, but also to determine the extent and impact of that change on the entire software system. Based on this analysis, the software developer should then conduct
and development planning and design input. The final conclusion that the software is validated should be based on evidence collected from planned efforts conducted throughout the software lifecycle. 4.4. SOFTWARE LIFE CYCLE Software validation takes place within the environment of an established software life cycle. The software life cycle contains software engineering tasks and documentation necessary to support the software validation effort. In addition, the software life cycle contains specific verification and validation tasks that are appropriate for the intended use of the software. This guidance does not recommend any particular life cycle models - only that they should be selected and used for a software development project. 4.5. PLANS The software validation process is defined and controlled through the use of a plan. The software validation plan defines what is to be accomplished through the software validation effort. Software validation plans are a significant quality system tool. Software validation plans specify areas such as scope, approach, resources, schedules and the types and extent of activities, tasks, and work items. 4.6. PROCEDURES The software validation process is executed through the use of procedures. These procedures establish how to conduct the software validation effort. The procedures should identify the specific actions or sequence of actions that must be taken to complete individual validation activities, tasks, and work items. 4.7. SOFTWARE VALIDATION AFTER A CHANGE Due to the complexity of software, a seemingly small local change may have a significant global system impact. When any change (even a small change) is made to the software, the validation status of the software needs to be reestablished. Whenever software is changed, a validation analysis should be conducted not just for validation of the individual change, but also to determine the extent and impact of that change on the entire software system. Based on this analysis, the software developer should then conduct
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an appropriate level of software regression testing to show that unchanged but vulnerable portions of the system have not been adversely affected. Design controls and appropriate regression testing provide the confidence that the software is validated after a software change. 4.8. VALIDATION COVERAGE Validation coverage should be based on the softwares complexity and safety risk - not on firm size or resource constraints. The selection of validation activities, tasks, and work items should be commensurate with the complexity of the software design and the risk associated with the use of the software for the specified intended use. For lower risk devices, only baseline validation activities may be conducted. As the risk increases additional validation activities should be added to cover the additional risk. Validation documentation should be sufficient to demonstrate that all software validation plans and procedures have been completed successfully. 4.9. INDEPENDENCE OF REVIEW Validation activities should be conducted using the basic quality assurance precept of independence of review. Self-validation is extremely difficult. When possible, an independent evaluation is always better, especially for higher risk applications. Some firms contract out for a third-party independent verification and validation, but this solution may not always be feasible. Another approach is to assign internal staff members that are not involved in a particular design or its implementation, but who have sufficient knowledge to evaluate the project and conduct the verification and validation activities. Smaller firms may need to be creative in how tasks are organized and assigned in order to maintain internal independence of review. 4.10. FLEXIBILITY AND RESPONSIBILITY Specific implementation of these software validation principles may be quite different from one application to another. The device manufacturer has flexibility in choosing how to apply these validation principles, but retains ultimate responsibility for demonstrating that the software has been validated.
an appropriate level of software regression testing to show that unchanged but vulnerable portions of the system have not been adversely affected. Design controls and appropriate regression testing provide the confidence that the software is validated after a software change. 4.8. VALIDATION COVERAGE Validation coverage should be based on the softwares complexity and safety risk - not on firm size or resource constraints. The selection of validation activities, tasks, and work items should be commensurate with the complexity of the software design and the risk associated with the use of the software for the specified intended use. For lower risk devices, only baseline validation activities may be conducted. As the risk increases additional validation activities should be added to cover the additional risk. Validation documentation should be sufficient to demonstrate that all software validation plans and procedures have been completed successfully. 4.9. INDEPENDENCE OF REVIEW Validation activities should be conducted using the basic quality assurance precept of independence of review. Self-validation is extremely difficult. When possible, an independent evaluation is always better, especially for higher risk applications. Some firms contract out for a third-party independent verification and validation, but this solution may not always be feasible. Another approach is to assign internal staff members that are not involved in a particular design or its implementation, but who have sufficient knowledge to evaluate the project and conduct the verification and validation activities. Smaller firms may need to be creative in how tasks are organized and assigned in order to maintain internal independence of review. 4.10. FLEXIBILITY AND RESPONSIBILITY Specific implementation of these software validation principles may be quite different from one application to another. The device manufacturer has flexibility in choosing how to apply these validation principles, but retains ultimate responsibility for demonstrating that the software has been validated.
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Software is designed, developed, validated, and regulated in a wide spectrum of environments, and for a wide variety of devices with varying levels of risk. FDA regulated medical device applications include software that: Is a component, part, or accessory of a medical device; Is itself a medical device; or Is used in manufacturing, design and development, or other parts of the quality system. In each environment, software components from many sources may be used to create the application (e.g., in-house developed software, off-theshelf software, contract software, shareware). In addition, software components come in many different forms (e.g., application software, operating systems, compilers, debuggers, configuration management tools, and many more). The validation of software in these environments can be a complex undertaking; therefore, it is appropriate that all of these software validation principles be considered when designing the software validation process. The resultant software validation process should be commensurate with the safety risk associated with the system, device, or process. Software validation activities and tasks may be dispersed, occurring at different locations and being conducted by different organizations. However, regardless of the distribution of tasks, contractual relations, source of components, or the development environment, the device manufacturer or specification developer retains ultimate responsibility for ensuring that the software is validated.
Software is designed, developed, validated, and regulated in a wide spectrum of environments, and for a wide variety of devices with varying levels of risk. FDA regulated medical device applications include software that: Is a component, part, or accessory of a medical device; Is itself a medical device; or Is used in manufacturing, design and development, or other parts of the quality system. In each environment, software components from many sources may be used to create the application (e.g., in-house developed software, off-theshelf software, contract software, shareware). In addition, software components come in many different forms (e.g., application software, operating systems, compilers, debuggers, configuration management tools, and many more). The validation of software in these environments can be a complex undertaking; therefore, it is appropriate that all of these software validation principles be considered when designing the software validation process. The resultant software validation process should be commensurate with the safety risk associated with the system, device, or process. Software validation activities and tasks may be dispersed, occurring at different locations and being conducted by different organizations. However, regardless of the distribution of tasks, contractual relations, source of components, or the development environment, the device manufacturer or specification developer retains ultimate responsibility for ensuring that the software is validated.
SECTION 5. ACTIVITIES AND TASKS

Software validation is accomplished through a series of activities and tasks that are planned and executed at various stages of the software development life cycle. These tasks may be one time occurrences or may be iterated many times, depending on the life cycle model used and the scope of changes made as the software project progresses. 5.1. SOFTWARE LIFE CYCLE ACTIVITIES This guidance does not recommend the use of any specific software life cycle model. Software developers should establish a software life cycle
SECTION 5. ACTIVITIES AND TASKS

Software validation is accomplished through a series of activities and tasks that are planned and executed at various stages of the software development life cycle. These tasks may be one time occurrences or may be iterated many times, depending on the life cycle model used and the scope of changes made as the software project progresses. 5.1. SOFTWARE LIFE CYCLE ACTIVITIES This guidance does not recommend the use of any specific software life cycle model. Software developers should establish a software life cycle
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model that is appropriate for their product and organization. The software life cycle model that is selected should cover the software from its birth to its retirement. Activities in a typical software life cycle model include the following: Quality Planning System Requirements Definition Detailed Software Requirements Specification Software Design Specification Construction or Coding Testing Installation Operation and Support Maintenance Retirement
model that is appropriate for their product and organization. The software life cycle model that is selected should cover the software from its birth to its retirement. Activities in a typical software life cycle model include the following: Quality Planning System Requirements Definition Detailed Software Requirements Specification Software Design Specification Construction or Coding Testing Installation Operation and Support Maintenance Retirement
Verification, testing, and other tasks that support software validation occur during each of these activities. A life cycle model organizes these software development activities in various ways and provides a framework for monitoring and controlling the software development project. Several software life cycle models (e.g., waterfall, spiral, rapid prototyping, incremental development, etc.) are defined in FDAs Glossary of Computerized System and Software Development Terminology, dated August 1995. These and many other life cycle models are described in various references listed in Appendix A. 5.2. TYPICAL TASKS SUPPORTING VALIDATION For each of the software life cycle activities, there are certain typical tasks that support a conclusion that the software is validated. However, the specific tasks to be performed, their order of performance, and the iteration and timing of their performance will be dictated by the specific software life cycle model that is selected and the safety risk associated with the software application. For very low risk applications, certain tasks may not be needed at all. However, the software developer should at least consider each of these tasks and should define and document which tasks are or are not appropriate for their specific application. The following discussion is generic
Verification, testing, and other tasks that support software validation occur during each of these activities. A life cycle model organizes these software development activities in various ways and provides a framework for monitoring and controlling the software development project. Several software life cycle models (e.g., waterfall, spiral, rapid prototyping, incremental development, etc.) are defined in FDAs Glossary of Computerized System and Software Development Terminology, dated August 1995. These and many other life cycle models are described in various references listed in Appendix A. 5.2. TYPICAL TASKS SUPPORTING VALIDATION For each of the software life cycle activities, there are certain typical tasks that support a conclusion that the software is validated. However, the specific tasks to be performed, their order of performance, and the iteration and timing of their performance will be dictated by the specific software life cycle model that is selected and the safety risk associated with the software application. For very low risk applications, certain tasks may not be needed at all. However, the software developer should at least consider each of these tasks and should define and document which tasks are or are not appropriate for their specific application. The following discussion is generic
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and is not intended to prescribe any particular software life cycle model or any particular order in which tasks are to be performed. 5.2.1. Quality Planning Design and development planning should culminate in a plan that identifies necessary tasks, procedures for anomaly reporting and resolution, necessary resources, and management review requirements, including formal design reviews. A software life cycle model and associated activities should be identified, as well as those tasks necessary for each software life cycle activity. The plan should include: The specific tasks for each life cycle activity; Enumeration of important quality factors (e.g., reliability, maintainability, and usability); Methods and procedures for each task; Task acceptance criteria; Criteria for defining and documenting outputs in terms that will allow evaluation of their conformance to input requirements; Inputs for each task; Outputs from each task; Roles, resources, and responsibilities for each task; Risks and assumptions; and Documentation of user needs.
and is not intended to prescribe any particular software life cycle model or any particular order in which tasks are to be performed. 5.2.1. Quality Planning Design and development planning should culminate in a plan that identifies necessary tasks, procedures for anomaly reporting and resolution, necessary resources, and management review requirements, including formal design reviews. A software life cycle model and associated activities should be identified, as well as those tasks necessary for each software life cycle activity. The plan should include: The specific tasks for each life cycle activity; Enumeration of important quality factors (e.g., reliability, maintainability, and usability); Methods and procedures for each task; Task acceptance criteria; Criteria for defining and documenting outputs in terms that will allow evaluation of their conformance to input requirements; Inputs for each task; Outputs from each task; Roles, resources, and responsibilities for each task; Risks and assumptions; and Documentation of user needs.
Management must identify and provide the appropriate software development environment and resources. (See 21 CFR 820.20(b)(1) and (2).) Typically, each task requires personnel as well as physical resources. The plan should identify the personnel, the facility and equipment resources for each task, and the role that risk (hazard) management will play. A configuration management plan should be developed that will guide and control multiple parallel development activities and ensure proper communications and documentation. Controls are necessary to ensure positive and correct correspondence among all approved versions of the specifications documents, source code, object code, and test suites that comprise a software system. The controls also should ensure accurate identification of, and access to, the currently approved versions.
Management must identify and provide the appropriate software development environment and resources. (See 21 CFR 820.20(b)(1) and (2).) Typically, each task requires personnel as well as physical resources. The plan should identify the personnel, the facility and equipment resources for each task, and the role that risk (hazard) management will play. A configuration management plan should be developed that will guide and control multiple parallel development activities and ensure proper communications and documentation. Controls are necessary to ensure positive and correct correspondence among all approved versions of the specifications documents, source code, object code, and test suites that comprise a software system. The controls also should ensure accurate identification of, and access to, the currently approved versions.
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Procedures should be created for reporting and resolving software anomalies found through validation or other activities. Management should identify the reports and specify the contents, format, and responsible organizational elements for each report. Procedures also are necessary for the review and approval of software development results, including the responsible organizational elements for such reviews and approvals. Typical Tasks - Quality Planning Risk (Hazard) Management Plan Configuration Management Plan Software Quality Assurance Plan o - Software Verification and Validation Plan Verification and Validation Tasks, and Acceptance Criteria Schedule and Resource Allocation (for software verification and validation activities) Reporting Requirements o - Formal Design Review Requirements o - Other Technical Review Requirements Problem Reporting and Resolution Procedures Other Support Activities
Procedures should be created for reporting and resolving software anomalies found through validation or other activities. Management should identify the reports and specify the contents, format, and responsible organizational elements for each report. Procedures also are necessary for the review and approval of software development results, including the responsible organizational elements for such reviews and approvals. Typical Tasks - Quality Planning Risk (Hazard) Management Plan Configuration Management Plan Software Quality Assurance Plan o - Software Verification and Validation Plan Verification and Validation Tasks, and Acceptance Criteria Schedule and Resource Allocation (for software verification and validation activities) Reporting Requirements o - Formal Design Review Requirements o - Other Technical Review Requirements Problem Reporting and Resolution Procedures Other Support Activities
5.2.2. Requirements Requirements development includes the identification, analysis, and documentation of information about the device and its intended use. Areas of special importance include allocation of system functions to hardware/ software, operating conditions, user characteristics, potential hazards, and anticipated tasks. In addition, the requirements should state clearly the intended use of the software. The software requirements specification document should contain a written definition of the software functions. It is not possible to validate software without predetermined and documented software requirements. Typical software requirements specify the following: All software system inputs;
5.2.2. Requirements Requirements development includes the identification, analysis, and documentation of information about the device and its intended use. Areas of special importance include allocation of system functions to hardware/ software, operating conditions, user characteristics, potential hazards, and anticipated tasks. In addition, the requirements should state clearly the intended use of the software. The software requirements specification document should contain a written definition of the software functions. It is not possible to validate software without predetermined and documented software requirements. Typical software requirements specify the following: All software system inputs;
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All software system outputs; All functions that the software system will perform; All performance requirements that the software will meet, (e.g., data throughput, reliability, and timing); The definition of all external and user interfaces, as well as any internal software-to-system interfaces; How users will interact with the system; What constitutes an error and how errors should be handled; Required response times; The intended operating environment for the software, if this is a design constraint (e.g., hardware platform, operating system); All ranges, limits, defaults, and specific values that the software will accept; and All safety related requirements, specifications, features, or functions that will be implemented in software.
All software system outputs; All functions that the software system will perform; All performance requirements that the software will meet, (e.g., data throughput, reliability, and timing); The definition of all external and user interfaces, as well as any internal software-to-system interfaces; How users will interact with the system; What constitutes an error and how errors should be handled; Required response times; The intended operating environment for the software, if this is a design constraint (e.g., hardware platform, operating system); All ranges, limits, defaults, and specific values that the software will accept; and All safety related requirements, specifications, features, or functions that will be implemented in software.
Software safety requirements are derived from a technical risk management process that is closely integrated with the system requirements development process. Software requirement specifications should identify clearly the potential hazards that can result from a software failure in the system as well as any safety requirements to be implemented in software. The consequences of software failure should be evaluated, along with means of mitigating such failures (e.g., hardware mitigation, defensive programming, etc.). From this analysis, it should be possible to identify the most appropriate measures necessary to prevent harm. The Quality System regulation requires a mechanism for addressing incomplete, ambiguous, or conflicting requirements. (See 21 CFR 820.30(c).) Each requirement (e.g., hardware, software, user, operator interface, and safety) identified in the software requirements specification should be evaluated for accuracy, completeness, consistency, testability, correctness, and clarity. For example, software requirements should be evaluated to verify that: There are no internal inconsistencies among requirements; All of the performance requirements for the system have been spelled out;
Software safety requirements are derived from a technical risk management process that is closely integrated with the system requirements development process. Software requirement specifications should identify clearly the potential hazards that can result from a software failure in the system as well as any safety requirements to be implemented in software. The consequences of software failure should be evaluated, along with means of mitigating such failures (e.g., hardware mitigation, defensive programming, etc.). From this analysis, it should be possible to identify the most appropriate measures necessary to prevent harm. The Quality System regulation requires a mechanism for addressing incomplete, ambiguous, or conflicting requirements. (See 21 CFR 820.30(c).) Each requirement (e.g., hardware, software, user, operator interface, and safety) identified in the software requirements specification should be evaluated for accuracy, completeness, consistency, testability, correctness, and clarity. For example, software requirements should be evaluated to verify that: There are no internal inconsistencies among requirements; All of the performance requirements for the system have been spelled out;
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Fault tolerance, safety, and security requirements are complete and correct; Allocation of software functions is accurate and complete; Software requirements are appropriate for the system hazards; and All requirements are expressed in terms that are measurable or objectively verifiable.
Fault tolerance, safety, and security requirements are complete and correct; Allocation of software functions is accurate and complete; Software requirements are appropriate for the system hazards; and All requirements are expressed in terms that are measurable or objectively verifiable.
A software requirements traceability analysis should be conducted to trace software requirements to (and from) system requirements and to risk analysis results. In addition to any other analyses and documentation used to verify software requirements, a formal design review is recommended to confirm that requirements are fully specified and appropriate before extensive software design efforts begin. Requirements can be approved and released incrementally, but care should be taken that interactions and interfaces among software (and hardware) requirements are properly reviewed, analyzed, and controlled. Typical Tasks - Requirements Preliminary Risk Analysis Traceability Analysis o - Software Requirements to System Requirements (and vice versa) o - Software Requirements to Risk Analysis Description of User Characteristics Listing of Characteristics and Limitations of Primary and Secondary Memory Software Requirements Evaluation Software User Interface Requirements Analysis System Test Plan Generation Acceptance Test Plan Generation Ambiguity Review or Analysis
A software requirements traceability analysis should be conducted to trace software requirements to (and from) system requirements and to risk analysis results. In addition to any other analyses and documentation used to verify software requirements, a formal design review is recommended to confirm that requirements are fully specified and appropriate before extensive software design efforts begin. Requirements can be approved and released incrementally, but care should be taken that interactions and interfaces among software (and hardware) requirements are properly reviewed, analyzed, and controlled. Typical Tasks - Requirements Preliminary Risk Analysis Traceability Analysis o - Software Requirements to System Requirements (and vice versa) o - Software Requirements to Risk Analysis Description of User Characteristics Listing of Characteristics and Limitations of Primary and Secondary Memory Software Requirements Evaluation Software User Interface Requirements Analysis System Test Plan Generation Acceptance Test Plan Generation Ambiguity Review or Analysis
5.2.3. Design In the design process, the software requirements specification is translated into a logical and physical representation of the software to be implemented. The software design specification is a description of what the software
5.2.3. Design In the design process, the software requirements specification is translated into a logical and physical representation of the software to be implemented. The software design specification is a description of what the software
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should do and how it should do it. Due to complexity of the project or to enable persons with varying levels of technical responsibilities to clearly understand design information, the design specification may contain both a high level summary of the design and detailed design information. The completed software design specification constrains the programmer/coder to stay within the intent of the agreed upon requirements and design. A complete software design specification will relieve the programmer from the need to make ad hoc design decisions. The software design needs to address human factors. Use error caused by designs that are either overly complex or contrary to users intuitive expectations for operation is one of the most persistent and critical problems encountered by FDA. Frequently, the design of the software is a factor in such use errors. Human factors engineering should be woven into the entire design and development process, including the device design requirements, analyses, and tests. Device safety and usability issues should be considered when developing flowcharts, state diagrams, prototyping tools, and test plans. Also, task and function analyses, risk analyses, prototype tests and reviews, and full usability tests should be performed. Participants from the user population should be included when applying these methodologies. The software design specification should include: Software requirements specification, including predetermined criteria for acceptance of the software; Software risk analysis; Development procedures and coding guidelines (or other programming procedures); Systems documentation (e.g., a narrative or a context diagram) that describes the systems context in which the program is intended to function, including the relationship of hardware, software, and the physical environment; Hardware to be used; Parameters to be measured or recorded; Logical structure (including control logic) and logical processing steps (e.g., algorithms); Data structures and data flow diagrams;
should do and how it should do it. Due to complexity of the project or to enable persons with varying levels of technical responsibilities to clearly understand design information, the design specification may contain both a high level summary of the design and detailed design information. The completed software design specification constrains the programmer/coder to stay within the intent of the agreed upon requirements and design. A complete software design specification will relieve the programmer from the need to make ad hoc design decisions. The software design needs to address human factors. Use error caused by designs that are either overly complex or contrary to users intuitive expectations for operation is one of the most persistent and critical problems encountered by FDA. Frequently, the design of the software is a factor in such use errors. Human factors engineering should be woven into the entire design and development process, including the device design requirements, analyses, and tests. Device safety and usability issues should be considered when developing flowcharts, state diagrams, prototyping tools, and test plans. Also, task and function analyses, risk analyses, prototype tests and reviews, and full usability tests should be performed. Participants from the user population should be included when applying these methodologies. The software design specification should include: Software requirements specification, including predetermined criteria for acceptance of the software; Software risk analysis; Development procedures and coding guidelines (or other programming procedures); Systems documentation (e.g., a narrative or a context diagram) that describes the systems context in which the program is intended to function, including the relationship of hardware, software, and the physical environment; Hardware to be used; Parameters to be measured or recorded; Logical structure (including control logic) and logical processing steps (e.g., algorithms); Data structures and data flow diagrams;
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Definitions of variables (control and data) and description of where they are used; Error, alarm, and warning messages; Supporting software (e.g., operating systems, drivers, other application software); Communication links (links among internal modules of the software, links with the supporting software, links with the hardware, and links with the user); Security measures (both physical and logical security); and Any additional constraints not identified in the above elements.
Definitions of variables (control and data) and description of where they are used; Error, alarm, and warning messages; Supporting software (e.g., operating systems, drivers, other application software); Communication links (links among internal modules of the software, links with the supporting software, links with the hardware, and links with the user); Security measures (both physical and logical security); and Any additional constraints not identified in the above elements.
The first four of the elements noted above usually are separate pre-existing documents that are included by reference in the software design specification. Software requirements specification was discussed in the preceding section, as was software risk analysis. Written development procedures serve as a guide to the organization, and written programming procedures serve as a guide to individual programmers. As software cannot be validated without knowledge of the context in which it is intended to function, systems documentation is referenced. If some of the above elements are not included in the software, it may be helpful to future reviewers and maintainers of the software if that is clearly stated (e.g., There are no error messages in this program). The activities that occur during software design have several purposes. Software design evaluations are conducted to determine if the design is complete, correct, consistent, unambiguous, feasible, and maintainable. Appropriate consideration of software architecture (e.g., modular structure) during design can reduce the magnitude of future validation efforts when software changes are needed. Software design evaluations may include analyses of control flow, data flow, complexity, timing, sizing, memory allocation, criticality analysis, and many other aspects of the design. A traceability analysis should be conducted to verify that the software design implements all of the software requirements. As a technique for identifying where requirements are not sufficient, the traceability analysis should also verify that all aspects of the design are traceable to software requirements. An analysis of communication links should be conducted to evaluate the proposed design with respect to hardware, user, and related software requirements. The software risk analysis should be re-examined to determine
The first four of the elements noted above usually are separate pre-existing documents that are included by reference in the software design specification. Software requirements specification was discussed in the preceding section, as was software risk analysis. Written development procedures serve as a guide to the organization, and written programming procedures serve as a guide to individual programmers. As software cannot be validated without knowledge of the context in which it is intended to function, systems documentation is referenced. If some of the above elements are not included in the software, it may be helpful to future reviewers and maintainers of the software if that is clearly stated (e.g., There are no error messages in this program). The activities that occur during software design have several purposes. Software design evaluations are conducted to determine if the design is complete, correct, consistent, unambiguous, feasible, and maintainable. Appropriate consideration of software architecture (e.g., modular structure) during design can reduce the magnitude of future validation efforts when software changes are needed. Software design evaluations may include analyses of control flow, data flow, complexity, timing, sizing, memory allocation, criticality analysis, and many other aspects of the design. A traceability analysis should be conducted to verify that the software design implements all of the software requirements. As a technique for identifying where requirements are not sufficient, the traceability analysis should also verify that all aspects of the design are traceable to software requirements. An analysis of communication links should be conducted to evaluate the proposed design with respect to hardware, user, and related software requirements. The software risk analysis should be re-examined to determine
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whether any additional hazards have been identified and whether any new hazards have been introduced by the design. At the end of the software design activity, a Formal Design Review should be conducted to verify that the design is correct, consistent, complete, accurate, and testable, before moving to implement the design. Portions of the design can be approved and released incrementally for implementation; but care should be taken that interactions and communication links among various elements are properly reviewed, analyzed, and controlled. Most software development models will be iterative. This is likely to result in several versions of both the software requirement specification and the software design specification. All approved versions should be archived and controlled in accordance with established configuration management procedures. Typical Tasks - Design Updated Software Risk Analysis Traceability Analysis - Design Specification to Software Requirements (and vice versa) Software Design Evaluation Design Communication Link Analysis Module Test Plan Generation Integration Test Plan Generation Test Design Generation (module, integration, system, and acceptance)
whether any additional hazards have been identified and whether any new hazards have been introduced by the design. At the end of the software design activity, a Formal Design Review should be conducted to verify that the design is correct, consistent, complete, accurate, and testable, before moving to implement the design. Portions of the design can be approved and released incrementally for implementation; but care should be taken that interactions and communication links among various elements are properly reviewed, analyzed, and controlled. Most software development models will be iterative. This is likely to result in several versions of both the software requirement specification and the software design specification. All approved versions should be archived and controlled in accordance with established configuration management procedures. Typical Tasks - Design Updated Software Risk Analysis Traceability Analysis - Design Specification to Software Requirements (and vice versa) Software Design Evaluation Design Communication Link Analysis Module Test Plan Generation Integration Test Plan Generation Test Design Generation (module, integration, system, and acceptance)
5.2.4. Construction or Coding Software may be constructed either by coding (i.e., programming) or by assembling together previously coded software components (e.g., from code libraries, off-the-shelf software, etc.) for use in a new application. Coding is the software activity where the detailed design specification is implemented as source code. Coding is the lowest level of abstraction for the software development process. It is the last stage in decomposition of the software requirements where module specifications are translated into a programming language.
5.2.4. Construction or Coding Software may be constructed either by coding (i.e., programming) or by assembling together previously coded software components (e.g., from code libraries, off-the-shelf software, etc.) for use in a new application. Coding is the software activity where the detailed design specification is implemented as source code. Coding is the lowest level of abstraction for the software development process. It is the last stage in decomposition of the software requirements where module specifications are translated into a programming language.
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Coding usually involves the use of a high-level programming language, but may also entail the use of assembly language (or microcode) for time-critical operations. The source code may be either compiled or interpreted for use on a target hardware platform. Decisions on the selection of programming languages and software build tools (assemblers, linkers, and compilers) should include consideration of the impact on subsequent quality evaluation tasks (e.g., availability of debugging and testing tools for the chosen language). Some compilers offer optional levels and commands for error checking to assist in debugging the code. Different levels of error checking may be used throughout the coding process, and warnings or other messages from the compiler may or may not be recorded. However, at the end of the coding and debugging process, the most rigorous level of error checking is normally used to document what compilation errors still remain in the software. If the most rigorous level of error checking is not used for final translation of the source code, then justification for use of the less rigorous translation error checking should be documented. Also, for the final compilation, there should be documentation of the compilation process and its outcome, including any warnings or other messages from the compiler and their resolution, or justification for the decision to leave issues unresolved. Firms frequently adopt specific coding guidelines that establish quality policies and procedures related to the software coding process. Source code should be evaluated to verify its compliance with specified coding guidelines. Such guidelines should include coding conventions regarding clarity, style, complexity management, and commenting. Code comments should provide useful and descriptive information for a module, including expected inputs and outputs, variables referenced, expected data types, and operations to be performed. Source code should also be evaluated to verify its compliance with the corresponding detailed design specification. Modules ready for integration and test should have documentation of compliance with coding guidelines and any other applicable quality policies and procedures. Source code evaluations are often implemented as code inspections and code walkthroughs. Such static analyses provide a very effective means to detect errors before execution of the code. They allow for examination of each error in isolation and can also help in focusing later dynamic testing of the software. Firms may use manual (desk) checking with appropriate
Coding usually involves the use of a high-level programming language, but may also entail the use of assembly language (or microcode) for time-critical operations. The source code may be either compiled or interpreted for use on a target hardware platform. Decisions on the selection of programming languages and software build tools (assemblers, linkers, and compilers) should include consideration of the impact on subsequent quality evaluation tasks (e.g., availability of debugging and testing tools for the chosen language). Some compilers offer optional levels and commands for error checking to assist in debugging the code. Different levels of error checking may be used throughout the coding process, and warnings or other messages from the compiler may or may not be recorded. However, at the end of the coding and debugging process, the most rigorous level of error checking is normally used to document what compilation errors still remain in the software. If the most rigorous level of error checking is not used for final translation of the source code, then justification for use of the less rigorous translation error checking should be documented. Also, for the final compilation, there should be documentation of the compilation process and its outcome, including any warnings or other messages from the compiler and their resolution, or justification for the decision to leave issues unresolved. Firms frequently adopt specific coding guidelines that establish quality policies and procedures related to the software coding process. Source code should be evaluated to verify its compliance with specified coding guidelines. Such guidelines should include coding conventions regarding clarity, style, complexity management, and commenting. Code comments should provide useful and descriptive information for a module, including expected inputs and outputs, variables referenced, expected data types, and operations to be performed. Source code should also be evaluated to verify its compliance with the corresponding detailed design specification. Modules ready for integration and test should have documentation of compliance with coding guidelines and any other applicable quality policies and procedures. Source code evaluations are often implemented as code inspections and code walkthroughs. Such static analyses provide a very effective means to detect errors before execution of the code. They allow for examination of each error in isolation and can also help in focusing later dynamic testing of the software. Firms may use manual (desk) checking with appropriate
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controls to ensure consistency and independence. Source code evaluations should be extended to verification of internal linkages between modules and layers (horizontal and vertical interfaces), and compliance with their design specifications. Documentation of the procedures used and the results of source code evaluations should be maintained as part of design verification. A source code traceability analysis is an important tool to verify that all code is linked to established specifications and established test procedures. A source code traceability analysis should be conducted and documented to verify that: Each element of the software design specification has been implemented in code; Modules and functions implemented in code can be traced back to an element in the software design specification and to the risk analysis; Tests for modules and functions can be traced back to an element in the software design specification and to the risk analysis; and Tests for modules and functions can be traced to source code for the same modules and functions.
controls to ensure consistency and independence. Source code evaluations should be extended to verification of internal linkages between modules and layers (horizontal and vertical interfaces), and compliance with their design specifications. Documentation of the procedures used and the results of source code evaluations should be maintained as part of design verification. A source code traceability analysis is an important tool to verify that all code is linked to established specifications and established test procedures. A source code traceability analysis should be conducted and documented to verify that: Each element of the software design specification has been implemented in code; Modules and functions implemented in code can be traced back to an element in the software design specification and to the risk analysis; Tests for modules and functions can be traced back to an element in the software design specification and to the risk analysis; and Tests for modules and functions can be traced to source code for the same modules and functions.
Typical Tasks - Construction or Coding Traceability Analyses o - Source Code to Design Specification (and vice versa) o - Test Cases to Source Code and to Design Specification Source Code and Source Code Documentation Evaluation Source Code Interface Analysis Test Procedure and Test Case Generation (module, integration, system, and acceptance)
Typical Tasks - Construction or Coding Traceability Analyses o - Source Code to Design Specification (and vice versa) o - Test Cases to Source Code and to Design Specification Source Code and Source Code Documentation Evaluation Source Code Interface Analysis Test Procedure and Test Case Generation (module, integration, system, and acceptance)
5.2.5. Testing by the Software Developer Software testing entails running software products under known conditions with defined inputs and documented outcomes that can be compared to their predefined expectations. It is a time consuming, difficult, and imperfect activity. As such, it requires early planning in order to be effective and efficient.
5.2.5. Testing by the Software Developer Software testing entails running software products under known conditions with defined inputs and documented outcomes that can be compared to their predefined expectations. It is a time consuming, difficult, and imperfect activity. As such, it requires early planning in order to be effective and efficient.
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Test plans and test cases should be created as early in the software development process as feasible. They should identify the schedules, environments, resources (personnel, tools, etc.), methodologies, cases (inputs, procedures, outputs, expected results), documentation, and reporting criteria. The magnitude of effort to be applied throughout the testing process can be linked to complexity, criticality, reliability, and/or safety issues (e.g., requiring functions or modules that produce critical outcomes to be challenged with intensive testing of their fault tolerance features). Descriptions of categories of software and software testing effort appear in the literature, for example: NIST Special Publication 500-235, Structured Testing: A Testing Methodology Using the Cyclomatic Complexity Metric; NUREG/CR-6293, Verification and Validation Guidelines for High Integrity Systems; and IEEE Computer Society Press, Handbook of Software Reliability Engineering.
Test plans and test cases should be created as early in the software development process as feasible. They should identify the schedules, environments, resources (personnel, tools, etc.), methodologies, cases (inputs, procedures, outputs, expected results), documentation, and reporting criteria. The magnitude of effort to be applied throughout the testing process can be linked to complexity, criticality, reliability, and/or safety issues (e.g., requiring functions or modules that produce critical outcomes to be challenged with intensive testing of their fault tolerance features). Descriptions of categories of software and software testing effort appear in the literature, for example: NIST Special Publication 500-235, Structured Testing: A Testing Methodology Using the Cyclomatic Complexity Metric; NUREG/CR-6293, Verification and Validation Guidelines for High Integrity Systems; and IEEE Computer Society Press, Handbook of Software Reliability Engineering.
Software test plans should identify the particular tasks to be conducted at each stage of development and include justification of the level of effort represented by their corresponding completion criteria. Software testing has limitations that must be recognized and considered when planning the testing of a particular software product. Except for the simplest of programs, software cannot be exhaustively tested. Generally it is not feasible to test a software product with all possible inputs, nor is it possible to test all possible data processing paths that can occur during program execution. There is no one type of testing or testing methodology that can ensure a particular software product has been thoroughly tested. Testing of all program functionality does not mean all of the program has been tested. Testing of all of a programs code does not mean all necessary functionality is present in the program. Testing of all program functionality and all program code does not mean the program is 100% correct! Software testing that finds no errors should not be interpreted to mean that errors do not exist in the software product; it may mean the testing was superficial. An essential element of a software test case is the expected result. It is the key detail that permits objective evaluation of the actual test result. This necessary testing information is obtained from the corresponding, predefined definition or specification. A software specification document
Software test plans should identify the particular tasks to be conducted at each stage of development and include justification of the level of effort represented by their corresponding completion criteria. Software testing has limitations that must be recognized and considered when planning the testing of a particular software product. Except for the simplest of programs, software cannot be exhaustively tested. Generally it is not feasible to test a software product with all possible inputs, nor is it possible to test all possible data processing paths that can occur during program execution. There is no one type of testing or testing methodology that can ensure a particular software product has been thoroughly tested. Testing of all program functionality does not mean all of the program has been tested. Testing of all of a programs code does not mean all necessary functionality is present in the program. Testing of all program functionality and all program code does not mean the program is 100% correct! Software testing that finds no errors should not be interpreted to mean that errors do not exist in the software product; it may mean the testing was superficial. An essential element of a software test case is the expected result. It is the key detail that permits objective evaluation of the actual test result. This necessary testing information is obtained from the corresponding, predefined definition or specification. A software specification document
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must identify what, when, how, why, etc., is to be achieved with an engineering (i.e., measurable or objectively verifiable) level of detail in order for it to be confirmed through testing. The real effort of effective software testing lies in the definition of what is to be tested rather than in the performance of the test. A software testing process should be based on principles that foster effective examinations of a software product. Applicable software testing tenets include: The expected test outcome is predefined; A good test case has a high probability of exposing an error; A successful test is one that finds an error; There is independence from coding; Both application (user) and software (programming) expertise are employed; Testers use different tools from coders; Examining only the usual case is insufficient; Test documentation permits its reuse and an independent confirmation of the pass/fail status of a test outcome during subsequent review.
must identify what, when, how, why, etc., is to be achieved with an engineering (i.e., measurable or objectively verifiable) level of detail in order for it to be confirmed through testing. The real effort of effective software testing lies in the definition of what is to be tested rather than in the performance of the test. A software testing process should be based on principles that foster effective examinations of a software product. Applicable software testing tenets include: The expected test outcome is predefined; A good test case has a high probability of exposing an error; A successful test is one that finds an error; There is independence from coding; Both application (user) and software (programming) expertise are employed; Testers use different tools from coders; Examining only the usual case is insufficient; Test documentation permits its reuse and an independent confirmation of the pass/fail status of a test outcome during subsequent review.
Once the prerequisite tasks (e.g., code inspection) have been successfully completed, software testing begins. It starts with unit level testing and concludes with system level testing. There may be a distinct integration level of testing. A software product should be challenged with test cases based on its internal structure and with test cases based on its external specification. These tests should provide a thorough and rigorous examination of the software products compliance with its functional, performance, and interface definitions and requirements. Code-based testing is also known as structural testing or white-box testing. It identifies test cases based on knowledge obtained from the source code, detailed design specification, and other development documents. These test cases challenge the control decisions made by the program; and the programs data structures including configuration tables. Structural testing can identify dead code that is never executed when the program
Once the prerequisite tasks (e.g., code inspection) have been successfully completed, software testing begins. It starts with unit level testing and concludes with system level testing. There may be a distinct integration level of testing. A software product should be challenged with test cases based on its internal structure and with test cases based on its external specification. These tests should provide a thorough and rigorous examination of the software products compliance with its functional, performance, and interface definitions and requirements. Code-based testing is also known as structural testing or white-box testing. It identifies test cases based on knowledge obtained from the source code, detailed design specification, and other development documents. These test cases challenge the control decisions made by the program; and the programs data structures including configuration tables. Structural testing can identify dead code that is never executed when the program
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is run. Structural testing is accomplished primarily with unit (module) level testing, but can be extended to other levels of software testing. The level of structural testing can be evaluated using metrics that are designed to show what percentage of the software structure has been evaluated during structural testing. These metrics are typically referred to as coverage and are a measure of completeness with respect to test selection criteria. The amount of structural coverage should be commensurate with the level of risk posed by the software. Use of the term coverage usually means 100% coverage. For example, if a testing program has achieved statement coverage, it means that 100% of the statements in the software have been executed at least once. Common structural coverage metrics include: Statement Coverage - This criteria requires sufficient test cases for each program statement to be executed at least once; however, its achievement is insufficient to provide confidence in a software products behavior. Decision (Branch) Coverage - This criteria requires sufficient test cases for each program decision or branch to be executed so that each possible outcome occurs at least once. It is considered to be a minimum level of coverage for most software products, but decision coverage alone is insufficient for high-integrity applications. Condition Coverage - This criteria requires sufficient test cases for each condition in a program decision to take on all possible outcomes at least once. It differs from branch coverage only when multiple conditions must be evaluated to reach a decision. Multi-Condition Coverage - This criteria requires sufficient test cases to exercise all possible combinations of conditions in a program decision. Loop Coverage - This criteria requires sufficient test cases for all program loops to be executed for zero, one, two, and many iterations covering initialization, typical running and termination (boundary) conditions. Path Coverage - This criteria requires sufficient test cases for each feasible path, basis path, etc., from start to exit of a defined program segment, to be executed at least once. Because of the very large number of possible paths through a software program, path coverage is generally not achievable. The amount of path coverage is normally established based on the risk or criticality of the software under test.
is run. Structural testing is accomplished primarily with unit (module) level testing, but can be extended to other levels of software testing. The level of structural testing can be evaluated using metrics that are designed to show what percentage of the software structure has been evaluated during structural testing. These metrics are typically referred to as coverage and are a measure of completeness with respect to test selection criteria. The amount of structural coverage should be commensurate with the level of risk posed by the software. Use of the term coverage usually means 100% coverage. For example, if a testing program has achieved statement coverage, it means that 100% of the statements in the software have been executed at least once. Common structural coverage metrics include: Statement Coverage - This criteria requires sufficient test cases for each program statement to be executed at least once; however, its achievement is insufficient to provide confidence in a software products behavior. Decision (Branch) Coverage - This criteria requires sufficient test cases for each program decision or branch to be executed so that each possible outcome occurs at least once. It is considered to be a minimum level of coverage for most software products, but decision coverage alone is insufficient for high-integrity applications. Condition Coverage - This criteria requires sufficient test cases for each condition in a program decision to take on all possible outcomes at least once. It differs from branch coverage only when multiple conditions must be evaluated to reach a decision. Multi-Condition Coverage - This criteria requires sufficient test cases to exercise all possible combinations of conditions in a program decision. Loop Coverage - This criteria requires sufficient test cases for all program loops to be executed for zero, one, two, and many iterations covering initialization, typical running and termination (boundary) conditions. Path Coverage - This criteria requires sufficient test cases for each feasible path, basis path, etc., from start to exit of a defined program segment, to be executed at least once. Because of the very large number of possible paths through a software program, path coverage is generally not achievable. The amount of path coverage is normally established based on the risk or criticality of the software under test.
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Data Flow Coverage - This criteria requires sufficient test cases for each feasible data flow to be executed at least once. A number of data flow testing strategies are available. Definition-based or specification-based testing is also known as functional testing or black-box testing. It identifies test cases based on the definition of what the software product (whether it be a unit (module) or a complete program) is intended to do. These test cases challenge the intended use or functionality of a program, and the programs internal and external interfaces. Functional testing can be applied at all levels of software testing, from unit to system level testing. The following types of functional software testing involve generally increasing levels of effort: Normal Case - Testing with usual inputs is necessary. However, testing a software product only with expected, valid inputs does not thoroughly test that software product. By itself, normal case testing cannot provide sufficient confidence in the dependability of the software product. Output Forcing - Choosing test inputs to ensure that selected (or all) software outputs are generated by testing. Robustness - Software testing should demonstrate that a software product behaves correctly when given unexpected, invalid inputs. Methods for identifying a sufficient set of such test cases include Equivalence Class Partitioning, Boundary Value Analysis, and Special Case Identification (Error Guessing). While important and necessary, these techniques do not ensure that all of the most appropriate challenges to a software product have been identified for testing. Combinations of Inputs - The functional testing methods identified above all emphasize individual or single test inputs. Most software products operate with multiple inputs under their conditions of use. Thorough software product testing should consider the combinations of inputs a software unit or system may encounter during operation. Error guessing can be extended to identify combinations of inputs, but it is an ad hoc technique. Cause-effect graphing is one functional software testing technique that systematically identifies combinations of inputs to a software product for inclusion in test cases.
Data Flow Coverage - This criteria requires sufficient test cases for each feasible data flow to be executed at least once. A number of data flow testing strategies are available. Definition-based or specification-based testing is also known as functional testing or black-box testing. It identifies test cases based on the definition of what the software product (whether it be a unit (module) or a complete program) is intended to do. These test cases challenge the intended use or functionality of a program, and the programs internal and external interfaces. Functional testing can be applied at all levels of software testing, from unit to system level testing. The following types of functional software testing involve generally increasing levels of effort: Normal Case - Testing with usual inputs is necessary. However, testing a software product only with expected, valid inputs does not thoroughly test that software product. By itself, normal case testing cannot provide sufficient confidence in the dependability of the software product. Output Forcing - Choosing test inputs to ensure that selected (or all) software outputs are generated by testing. Robustness - Software testing should demonstrate that a software product behaves correctly when given unexpected, invalid inputs. Methods for identifying a sufficient set of such test cases include Equivalence Class Partitioning, Boundary Value Analysis, and Special Case Identification (Error Guessing). While important and necessary, these techniques do not ensure that all of the most appropriate challenges to a software product have been identified for testing. Combinations of Inputs - The functional testing methods identified above all emphasize individual or single test inputs. Most software products operate with multiple inputs under their conditions of use. Thorough software product testing should consider the combinations of inputs a software unit or system may encounter during operation. Error guessing can be extended to identify combinations of inputs, but it is an ad hoc technique. Cause-effect graphing is one functional software testing technique that systematically identifies combinations of inputs to a software product for inclusion in test cases.
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Functional and structural software test case identification techniques provide specific inputs for testing, rather than random test inputs. One weakness of these techniques is the difficulty in linking structural and functional test completion criteria to a software products reliability. Advanced software testing methods, such as statistical testing, can be employed to provide further assurance that a software product is dependable. Statistical testing uses randomly generated test data from defined distributions based on an operational profile (e.g., expected use, hazardous use, or malicious use of the software product). Large amounts of test data are generated and can be targeted to cover particular areas or concerns, providing an increased possibility of identifying individual and multiple rare operating conditions that were not anticipated by either the software products designers or its testers. Statistical testing also provides high structural coverage. It does require a stable software product. Thus, structural and functional testing are prerequisites for statistical testing of a software product. Another aspect of software testing is the testing of software changes. Changes occur frequently during software development. These changes are the result of 1) debugging that finds an error and it is corrected, 2) new or changed requirements (requirements creep), and 3) modified designs as more effective or efficient implementations are found. Once a software product has been baselined (approved), any change to that product should have its own mini life cycle, including testing. Testing of a changed software product requires additional effort. Not only should it demonstrate that the change was implemented correctly, testing should also demonstrate that the change did not adversely impact other parts of the software product. Regression analysis and testing are employed to provide assurance that a change has not created problems elsewhere in the software product. Regression analysis is the determination of the impact of a change based on review of the relevant documentation (e.g., software requirements specification, software design specification, source code, test plans, test cases, test scripts, etc.) in order to identify the necessary regression tests to be run. Regression testing is the rerunning of test cases that a program has previously executed correctly and comparing the current result to the previous result in order to detect unintended effects of a software change. Regression analysis and regression testing should also be employed when using integration methods to build a software product to ensure that newly integrated modules do not adversely impact the operation of previously integrated modules.
Functional and structural software test case identification techniques provide specific inputs for testing, rather than random test inputs. One weakness of these techniques is the difficulty in linking structural and functional test completion criteria to a software products reliability. Advanced software testing methods, such as statistical testing, can be employed to provide further assurance that a software product is dependable. Statistical testing uses randomly generated test data from defined distributions based on an operational profile (e.g., expected use, hazardous use, or malicious use of the software product). Large amounts of test data are generated and can be targeted to cover particular areas or concerns, providing an increased possibility of identifying individual and multiple rare operating conditions that were not anticipated by either the software products designers or its testers. Statistical testing also provides high structural coverage. It does require a stable software product. Thus, structural and functional testing are prerequisites for statistical testing of a software product. Another aspect of software testing is the testing of software changes. Changes occur frequently during software development. These changes are the result of 1) debugging that finds an error and it is corrected, 2) new or changed requirements (requirements creep), and 3) modified designs as more effective or efficient implementations are found. Once a software product has been baselined (approved), any change to that product should have its own mini life cycle, including testing. Testing of a changed software product requires additional effort. Not only should it demonstrate that the change was implemented correctly, testing should also demonstrate that the change did not adversely impact other parts of the software product. Regression analysis and testing are employed to provide assurance that a change has not created problems elsewhere in the software product. Regression analysis is the determination of the impact of a change based on review of the relevant documentation (e.g., software requirements specification, software design specification, source code, test plans, test cases, test scripts, etc.) in order to identify the necessary regression tests to be run. Regression testing is the rerunning of test cases that a program has previously executed correctly and comparing the current result to the previous result in order to detect unintended effects of a software change. Regression analysis and regression testing should also be employed when using integration methods to build a software product to ensure that newly integrated modules do not adversely impact the operation of previously integrated modules.
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In order to provide a thorough and rigorous examination of a software product, development testing is typically organized into levels. As an example, a software products testing can be organized into unit, integration, and system levels of testing. 1) Unit (module or component) level testing focuses on the early examination of sub-program functionality and ensures that functionality not visible at the system level is examined by testing. Unit testing ensures that quality software units are furnished for integration into the finished software product. 2) Integration level testing focuses on the transfer of data and control across a programs internal and external interfaces. External interfaces are those with other software (including operating system software), system hardware, and the users and can be described as communications links. 3) System level testing demonstrates that all specified functionality exists and that the software product is trustworthy. This testing verifies the asbuilt programs functionality and performance with respect to the requirements for the software product as exhibited on the specified operating platform(s). System level software testing addresses functional concerns and the following elements of a devices software that are related to the intended use(s): Performance issues (e.g., response times, reliability measurements); Responses to stress conditions, e.g., behavior under maximum load, continuous use; Operation of internal and external security features; Effectiveness of recovery procedures, including disaster recovery; Usability; Compatibility with other software products; Behavior in each of the defined hardware configurations; and Accuracy of documentation. Control measures (e.g., a traceability analysis) should be used to ensure that the intended coverage is achieved. System level testing also exhibits the software products behavior in the intended operating environment. The location of such testing is dependent upon the software developers ability to produce the target operating
In order to provide a thorough and rigorous examination of a software product, development testing is typically organized into levels. As an example, a software products testing can be organized into unit, integration, and system levels of testing. 1) Unit (module or component) level testing focuses on the early examination of sub-program functionality and ensures that functionality not visible at the system level is examined by testing. Unit testing ensures that quality software units are furnished for integration into the finished software product. 2) Integration level testing focuses on the transfer of data and control across a programs internal and external interfaces. External interfaces are those with other software (including operating system software), system hardware, and the users and can be described as communications links. 3) System level testing demonstrates that all specified functionality exists and that the software product is trustworthy. This testing verifies the asbuilt programs functionality and performance with respect to the requirements for the software product as exhibited on the specified operating platform(s). System level software testing addresses functional concerns and the following elements of a devices software that are related to the intended use(s): Performance issues (e.g., response times, reliability measurements); Responses to stress conditions, e.g., behavior under maximum load, continuous use; Operation of internal and external security features; Effectiveness of recovery procedures, including disaster recovery; Usability; Compatibility with other software products; Behavior in each of the defined hardware configurations; and Accuracy of documentation. Control measures (e.g., a traceability analysis) should be used to ensure that the intended coverage is achieved. System level testing also exhibits the software products behavior in the intended operating environment. The location of such testing is dependent upon the software developers ability to produce the target operating
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environment(s). Depending upon the circumstances, simulation and/or testing at (potential) customer locations may be utilized. Test plans should identify the controls needed to ensure that the intended coverage is achieved and that proper documentation is prepared when planned system level testing is conducted at sites not directly controlled by the software developer. Also, for a software product that is a medical device or a component of a medical device that is to be used on humans prior to FDA clearance, testing involving human subjects may require an Investigational Device Exemption (IDE) or Institutional Review Board (IRB) approval. Test procedures, test data, and test results should be documented in a manner permitting objective pass/fail decisions to be reached. They should also be suitable for review and objective decision making subsequent to running the test, and they should be suitable for use in any subsequent regression testing. Errors detected during testing should be logged, classified, reviewed, and resolved prior to release of the software. Software error data that is collected and analyzed during a development life cycle may be used to determine the suitability of the software product for release for commercial distribution. Test reports should comply with the requirements of the corresponding test plans. Software products that perform useful functions in medical devices or their production are often complex. Software testing tools are frequently used to ensure consistency, thoroughness, and efficiency in the testing of such software products and to fulfill the requirements of the planned testing activities. These tools may include supporting software built in-house to facilitate unit (module) testing and subsequent integration testing (e.g., drivers and stubs) as well as commercial software testing tools. Such tools should have a degree of quality no less than the software product they are used to develop. Appropriate documentation providing evidence of the validation of these software tools for their intended use should be maintained (see section 6 of this guidance). Typical Tasks - Testing by the Software Developer Test Planning Structural Test Case Identification Functional Test Case Identification
environment(s). Depending upon the circumstances, simulation and/or testing at (potential) customer locations may be utilized. Test plans should identify the controls needed to ensure that the intended coverage is achieved and that proper documentation is prepared when planned system level testing is conducted at sites not directly controlled by the software developer. Also, for a software product that is a medical device or a component of a medical device that is to be used on humans prior to FDA clearance, testing involving human subjects may require an Investigational Device Exemption (IDE) or Institutional Review Board (IRB) approval. Test procedures, test data, and test results should be documented in a manner permitting objective pass/fail decisions to be reached. They should also be suitable for review and objective decision making subsequent to running the test, and they should be suitable for use in any subsequent regression testing. Errors detected during testing should be logged, classified, reviewed, and resolved prior to release of the software. Software error data that is collected and analyzed during a development life cycle may be used to determine the suitability of the software product for release for commercial distribution. Test reports should comply with the requirements of the corresponding test plans. Software products that perform useful functions in medical devices or their production are often complex. Software testing tools are frequently used to ensure consistency, thoroughness, and efficiency in the testing of such software products and to fulfill the requirements of the planned testing activities. These tools may include supporting software built in-house to facilitate unit (module) testing and subsequent integration testing (e.g., drivers and stubs) as well as commercial software testing tools. Such tools should have a degree of quality no less than the software product they are used to develop. Appropriate documentation providing evidence of the validation of these software tools for their intended use should be maintained (see section 6 of this guidance). Typical Tasks - Testing by the Software Developer Test Planning Structural Test Case Identification Functional Test Case Identification
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Traceability Analysis - Testing o - Unit (Module) Tests to Detailed Design o - Integration Tests to High Level Design o - System Tests to Software Requirements Unit (Module) Test Execution Integration Test Execution Functional Test Execution System Test Execution Acceptance Test Execution Test Results Evaluation Error Evaluation/Resolution Final Test Report
Traceability Analysis - Testing o - Unit (Module) Tests to Detailed Design o - Integration Tests to High Level Design o - System Tests to Software Requirements Unit (Module) Test Execution Integration Test Execution Functional Test Execution System Test Execution Acceptance Test Execution Test Results Evaluation Error Evaluation/Resolution Final Test Report
5.2.6. User Site Testing Testing at the user site is an essential part of software validation. The Quality System regulation requires installation and inspection procedures (including testing where appropriate) as well as documentation of inspection and testing to demonstrate proper installation. (See 21 CFR 820.170.) Likewise, manufacturing equipment must meet specified requirements, and automated systems must be validated for their intended use. (See 21 CFR 820.70(g) and 21 CFR 820.70(i) respectively.) Terminology regarding user site testing can be confusing. Terms such as beta test, site validation, user acceptance test, installation verification, and installation testing have all been used to describe user site testing. For purposes of this guidance, the term user site testing encompasses all of these and any other testing that takes place outside of the developers controlled environment. This testing should take place at a users site with the actual hardware and software that will be part of the installed system configuration. The testing is accomplished through either actual or simulated use of the software being tested within the context in which it is intended to function. Guidance contained here is general in nature and is applicable to any user site testing. However, in some areas (e.g., blood establishment systems) there may be specific site validation issues that need to be considered in
5.2.6. User Site Testing Testing at the user site is an essential part of software validation. The Quality System regulation requires installation and inspection procedures (including testing where appropriate) as well as documentation of inspection and testing to demonstrate proper installation. (See 21 CFR 820.170.) Likewise, manufacturing equipment must meet specified requirements, and automated systems must be validated for their intended use. (See 21 CFR 820.70(g) and 21 CFR 820.70(i) respectively.) Terminology regarding user site testing can be confusing. Terms such as beta test, site validation, user acceptance test, installation verification, and installation testing have all been used to describe user site testing. For purposes of this guidance, the term user site testing encompasses all of these and any other testing that takes place outside of the developers controlled environment. This testing should take place at a users site with the actual hardware and software that will be part of the installed system configuration. The testing is accomplished through either actual or simulated use of the software being tested within the context in which it is intended to function. Guidance contained here is general in nature and is applicable to any user site testing. However, in some areas (e.g., blood establishment systems) there may be specific site validation issues that need to be considered in
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the planning of user site testing. Test planners should check with the FDA Center(s) with the corresponding product jurisdiction to determine whether there are any additional regulatory requirements for user site testing. User site testing should follow a pre-defined written plan with a formal summary of testing and a record of formal acceptance. Documented evidence of all testing procedures, test input data, and test results should be retained. There should be evidence that hardware and software are installed and configured as specified. Measures should ensure that all system components are exercised during the testing and that the versions of these components are those specified. The testing plan should specify testing throughout the full range of operating conditions and should specify continuation for a sufficient time to allow the system to encounter a wide spectrum of conditions and events in an effort to detect any latent faults that are not apparent during more normal activities. Some of the evaluations that have been performed earlier by the software developer at the developers site should be repeated at the site of actual use. These may include tests for a high volume of data, heavy loads or stresses, security, fault testing (avoidance, detection, tolerance, and recovery), error messages, and implementation of safety requirements. The developer may be able to furnish the user with some of the test data sets to be used for this purpose. In addition to an evaluation of the systems ability to properly perform its intended functions, there should be an evaluation of the ability of the users of the system to understand and correctly interface with it. Operators should be able to perform the intended functions and respond in an appropriate and timely manner to all alarms, warnings, and error messages. During user site testing, records should be maintained of both proper system performance and any system failures that are encountered. The revision of the system to compensate for faults detected during this user site testing should follow the same procedures and controls as for any other software change. The developers of the software may or may not be involved in the user site testing. If the developers are involved, they may seamlessly carry over to the users site the last portions of design-level systems testing. If the
the planning of user site testing. Test planners should check with the FDA Center(s) with the corresponding product jurisdiction to determine whether there are any additional regulatory requirements for user site testing. User site testing should follow a pre-defined written plan with a formal summary of testing and a record of formal acceptance. Documented evidence of all testing procedures, test input data, and test results should be retained. There should be evidence that hardware and software are installed and configured as specified. Measures should ensure that all system components are exercised during the testing and that the versions of these components are those specified. The testing plan should specify testing throughout the full range of operating conditions and should specify continuation for a sufficient time to allow the system to encounter a wide spectrum of conditions and events in an effort to detect any latent faults that are not apparent during more normal activities. Some of the evaluations that have been performed earlier by the software developer at the developers site should be repeated at the site of actual use. These may include tests for a high volume of data, heavy loads or stresses, security, fault testing (avoidance, detection, tolerance, and recovery), error messages, and implementation of safety requirements. The developer may be able to furnish the user with some of the test data sets to be used for this purpose. In addition to an evaluation of the systems ability to properly perform its intended functions, there should be an evaluation of the ability of the users of the system to understand and correctly interface with it. Operators should be able to perform the intended functions and respond in an appropriate and timely manner to all alarms, warnings, and error messages. During user site testing, records should be maintained of both proper system performance and any system failures that are encountered. The revision of the system to compensate for faults detected during this user site testing should follow the same procedures and controls as for any other software change. The developers of the software may or may not be involved in the user site testing. If the developers are involved, they may seamlessly carry over to the users site the last portions of design-level systems testing. If the
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developers are not involved, it is all the more important that the user have persons who understand the importance of careful test planning, the definition of expected test results, and the recording of all test outputs. Typical Tasks - User Site Testing Acceptance Test Execution Test Results Evaluation Error Evaluation/Resolution Final Test Report
developers are not involved, it is all the more important that the user have persons who understand the importance of careful test planning, the definition of expected test results, and the recording of all test outputs. Typical Tasks - User Site Testing Acceptance Test Execution Test Results Evaluation Error Evaluation/Resolution Final Test Report
5.2.7. Maintenance and Software Changes As applied to software, the term maintenance does not mean the same as when applied to hardware. The operational maintenance of hardware and software are different because their failure/error mechanisms are different. Hardware maintenance typically includes preventive hardware maintenance actions, component replacement, and corrective changes. Software maintenance includes corrective, perfective, and adaptive maintenance but does not include preventive maintenance actions or software component replacement. Changes made to correct errors and faults in the software are corrective maintenance. Changes made to the software to improve the performance, maintainability, or other attributes of the software system are perfective maintenance. Software changes to make the software system usable in a changed environment are adaptive maintenance. When changes are made to a software system, either during initial development or during post release maintenance, sufficient regression analysis and testing should be conducted to demonstrate that portions of the software not involved in the change were not adversely impacted. This is in addition to testing that evaluates the correctness of the implemented change(s). The specific validation effort necessary for each software change is determined by the type of change, the development products affected, and the impact of those products on the operation of the software. Careful and complete documentation of the design structure and interrelationships of various modules, interfaces, etc., can limit the validation effort needed when
5.2.7. Maintenance and Software Changes As applied to software, the term maintenance does not mean the same as when applied to hardware. The operational maintenance of hardware and software are different because their failure/error mechanisms are different. Hardware maintenance typically includes preventive hardware maintenance actions, component replacement, and corrective changes. Software maintenance includes corrective, perfective, and adaptive maintenance but does not include preventive maintenance actions or software component replacement. Changes made to correct errors and faults in the software are corrective maintenance. Changes made to the software to improve the performance, maintainability, or other attributes of the software system are perfective maintenance. Software changes to make the software system usable in a changed environment are adaptive maintenance. When changes are made to a software system, either during initial development or during post release maintenance, sufficient regression analysis and testing should be conducted to demonstrate that portions of the software not involved in the change were not adversely impacted. This is in addition to testing that evaluates the correctness of the implemented change(s). The specific validation effort necessary for each software change is determined by the type of change, the development products affected, and the impact of those products on the operation of the software. Careful and complete documentation of the design structure and interrelationships of various modules, interfaces, etc., can limit the validation effort needed when
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a change is made. The level of effort needed to fully validate a change is also dependent upon the degree to which validation of the original software was documented and archived. For example, test documentation, test cases, and results of previous verification and validation testing need to be archived if they are to be available for performing subsequent regression testing. Failure to archive this information for later use can significantly increase the level of effort and expense of revalidating the software after a change is made. In addition to software verification and validation tasks that are part of the standard software development process, the following additional maintenance tasks should be addressed: Software Validation Plan Revision - For software that was previously validated, the existing software validation plan should be revised to support the validation of the revised software. If no previous software validation plan exists, such a plan should be established to support the validation of the revised software. Anomaly Evaluation - Software organizations frequently maintain documentation, such as software problem reports that describe software anomalies discovered and the specific corrective action taken to fix each anomaly. Too often, however, mistakes are repeated because software developers do not take the next step to determine the root causes of problems and make the process and procedural changes needed to avoid recurrence of the problem. Software anomalies should be evaluated in terms of their severity and their effects on system operation and safety, but they should also be treated as symptoms of process deficiencies in the quality system. A root cause analysis of anomalies can identify specific quality system deficiencies. Where trends are identified (e.g., recurrence of similar software anomalies), appropriate corrective and preventive actions must be implemented and documented to avoid further recurrence of similar quality problems. (See 21 CFR 820.100.) Problem Identification and Resolution Tracking - All problems discovered during maintenance of the software should be documented. The resolution of each problem should be tracked to ensure it is fixed, for historical reference, and for trending. Proposed Change Assessment - All proposed modifications, enhancements, or additions should be assessed to determine the effect
a change is made. The level of effort needed to fully validate a change is also dependent upon the degree to which validation of the original software was documented and archived. For example, test documentation, test cases, and results of previous verification and validation testing need to be archived if they are to be available for performing subsequent regression testing. Failure to archive this information for later use can significantly increase the level of effort and expense of revalidating the software after a change is made. In addition to software verification and validation tasks that are part of the standard software development process, the following additional maintenance tasks should be addressed: Software Validation Plan Revision - For software that was previously validated, the existing software validation plan should be revised to support the validation of the revised software. If no previous software validation plan exists, such a plan should be established to support the validation of the revised software. Anomaly Evaluation - Software organizations frequently maintain documentation, such as software problem reports that describe software anomalies discovered and the specific corrective action taken to fix each anomaly. Too often, however, mistakes are repeated because software developers do not take the next step to determine the root causes of problems and make the process and procedural changes needed to avoid recurrence of the problem. Software anomalies should be evaluated in terms of their severity and their effects on system operation and safety, but they should also be treated as symptoms of process deficiencies in the quality system. A root cause analysis of anomalies can identify specific quality system deficiencies. Where trends are identified (e.g., recurrence of similar software anomalies), appropriate corrective and preventive actions must be implemented and documented to avoid further recurrence of similar quality problems. (See 21 CFR 820.100.) Problem Identification and Resolution Tracking - All problems discovered during maintenance of the software should be documented. The resolution of each problem should be tracked to ensure it is fixed, for historical reference, and for trending. Proposed Change Assessment - All proposed modifications, enhancements, or additions should be assessed to determine the effect
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each change would have on the system. This information should determine the extent to which verification and/or validation tasks need to be iterated. Task Iteration - For approved software changes, all necessary verification and validation tasks should be performed to ensure that planned changes are implemented correctly, all documentation is complete and up to date, and no unacceptable changes have occurred in software performance. Documentation Updating - Documentation should be carefully reviewed to determine which documents have been impacted by a change. All approved documents (e.g., specifications, test procedures, user manuals, etc.) that have been affected should be updated in accordance with configuration management procedures. Specifications should be updated before any maintenance and software changes are made.
each change would have on the system. This information should determine the extent to which verification and/or validation tasks need to be iterated. Task Iteration - For approved software changes, all necessary verification and validation tasks should be performed to ensure that planned changes are implemented correctly, all documentation is complete and up to date, and no unacceptable changes have occurred in software performance. Documentation Updating - Documentation should be carefully reviewed to determine which documents have been impacted by a change. All approved documents (e.g., specifications, test procedures, user manuals, etc.) that have been affected should be updated in accordance with configuration management procedures. Specifications should be updated before any maintenance and software changes are made.
SECTION 6. VALIDATION OF AUTOMATED PROCESS EQUIPMENT AND QUALITY SYSTEM SOFTWARE

The Quality System regulation requires that when computers or automated data processing systems are used as part of production or the quality system, the [device] manufacturer shall validate computer software for its intended use according to an established protocol. (See 21 CFR 820.70(i)). This has been a regulatory requirement of FDAs medical device Good Manufacturing Practice (GMP) regulations since 1978. In addition to the above validation requirement, computer systems that implement part of a device manufacturers production processes or quality system (or that are used to create and maintain records required by any other FDA regulation) are subject to the Electronic Records; Electronic Signatures regulation. (See 21 CFR Part 11.) This regulation establishes additional security, data integrity, and validation requirements when records are created or maintained electronically. These additional Part 11 requirements should be carefully considered and included in system requirements and software requirements for any automated record keeping systems. System validation and software validation should demonstrate that all Part 11 requirements have been met. Computers and automated equipment are used extensively throughout all aspects of medical device design, laboratory testing and analysis, product
SECTION 6. VALIDATION OF AUTOMATED PROCESS EQUIPMENT AND QUALITY SYSTEM SOFTWARE

The Quality System regulation requires that when computers or automated data processing systems are used as part of production or the quality system, the [device] manufacturer shall validate computer software for its intended use according to an established protocol. (See 21 CFR 820.70(i)). This has been a regulatory requirement of FDAs medical device Good Manufacturing Practice (GMP) regulations since 1978. In addition to the above validation requirement, computer systems that implement part of a device manufacturers production processes or quality system (or that are used to create and maintain records required by any other FDA regulation) are subject to the Electronic Records; Electronic Signatures regulation. (See 21 CFR Part 11.) This regulation establishes additional security, data integrity, and validation requirements when records are created or maintained electronically. These additional Part 11 requirements should be carefully considered and included in system requirements and software requirements for any automated record keeping systems. System validation and software validation should demonstrate that all Part 11 requirements have been met. Computers and automated equipment are used extensively throughout all aspects of medical device design, laboratory testing and analysis, product
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inspection and acceptance, production and process control, environmental controls, packaging, labeling, traceability, document control, complaint management, and many other aspects of the quality system. Increasingly, automated plant floor operations can involve extensive use of embedded systems in: programmable logic controllers; digital function controllers; statistical process control; supervisory control and data acquisition; robotics; human-machine interfaces; input/output devices; and computer operating systems.
inspection and acceptance, production and process control, environmental controls, packaging, labeling, traceability, document control, complaint management, and many other aspects of the quality system. Increasingly, automated plant floor operations can involve extensive use of embedded systems in: programmable logic controllers; digital function controllers; statistical process control; supervisory control and data acquisition; robotics; human-machine interfaces; input/output devices; and computer operating systems.
Software tools are frequently used to design, build, and test the software that goes into an automated medical device. Many other commercial software applications, such as word processors, spreadsheets, databases, and flowcharting software are used to implement the quality system. All of these applications are subject to the requirement for software validation, but the validation approach used for each application can vary widely. Whether production or quality system software is developed in-house by the device manufacturer, developed by a contractor, or purchased off-theshelf, it should be developed using the basic principles outlined elsewhere in this guidance. The device manufacturer has latitude and flexibility in defining how validation of that software will be accomplished, but validation should be a key consideration in deciding how and by whom the software will be developed or from whom it will be purchased. The software developer defines a life cycle model. Validation is typically supported by: verifications of the outputs from each stage of that software development life cycle; and checking for proper operation of the finished software in the device manufacturers intended use environment.
Software tools are frequently used to design, build, and test the software that goes into an automated medical device. Many other commercial software applications, such as word processors, spreadsheets, databases, and flowcharting software are used to implement the quality system. All of these applications are subject to the requirement for software validation, but the validation approach used for each application can vary widely. Whether production or quality system software is developed in-house by the device manufacturer, developed by a contractor, or purchased off-theshelf, it should be developed using the basic principles outlined elsewhere in this guidance. The device manufacturer has latitude and flexibility in defining how validation of that software will be accomplished, but validation should be a key consideration in deciding how and by whom the software will be developed or from whom it will be purchased. The software developer defines a life cycle model. Validation is typically supported by: verifications of the outputs from each stage of that software development life cycle; and checking for proper operation of the finished software in the device manufacturers intended use environment.
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6.1. HOW MUCH VALIDATION EVIDENCE IS NEEDED? The level of validation effort should be commensurate with the risk posed by the automated operation. In addition to risk other factors, such as the complexity of the process software and the degree to which the device manufacturer is dependent upon that automated process to produce a safe and effective device, determine the nature and extent of testing needed as part of the validation effort. Documented requirements and risk analysis of the automated process help to define the scope of the evidence needed to show that the software is validated for its intended use. For example, an automated milling machine may require very little testing if the device manufacturer can show that the output of the operation is subsequently fully verified against the specification before release. On the other hand, extensive testing may be needed for: a plant-wide electronic record and electronic signature system; an automated controller for a sterilization cycle; or automated test equipment used for inspection and acceptance of finished circuit boards in a life-sustaining / life-supporting device.
6.1. HOW MUCH VALIDATION EVIDENCE IS NEEDED? The level of validation effort should be commensurate with the risk posed by the automated operation. In addition to risk other factors, such as the complexity of the process software and the degree to which the device manufacturer is dependent upon that automated process to produce a safe and effective device, determine the nature and extent of testing needed as part of the validation effort. Documented requirements and risk analysis of the automated process help to define the scope of the evidence needed to show that the software is validated for its intended use. For example, an automated milling machine may require very little testing if the device manufacturer can show that the output of the operation is subsequently fully verified against the specification before release. On the other hand, extensive testing may be needed for: a plant-wide electronic record and electronic signature system; an automated controller for a sterilization cycle; or automated test equipment used for inspection and acceptance of finished circuit boards in a life-sustaining / life-supporting device.
Numerous commercial software applications may be used as part of the quality system (e.g., a spreadsheet or statistical package used for quality system calculations, a graphics package used for trend analysis, or a commercial database used for recording device history records or for complaint management). The extent of validation evidence needed for such software depends on the device manufacturers documented intended use of that software. For example, a device manufacturer who chooses not to use all the vendor-supplied capabilities of the software only needs to validate those functions that will be used and for which the device manufacturer is dependent upon the software results as part of production or the quality system. However, high risk applications should not be running in the same operating environment with non-validated software functions, even if those software functions are not used. Risk mitigation techniques such as memory partitioning or other approaches to resource protection may need to be considered when high risk applications and lower risk applications are to be used in the same operating environment. When software is upgraded or any changes are made to the software, the device manufacturer should consider how those changes may impact the used portions of the software and must reconfirm the validation of those portions of the software that are used. (See 21 CFR 820.70(i).)
Numerous commercial software applications may be used as part of the quality system (e.g., a spreadsheet or statistical package used for quality system calculations, a graphics package used for trend analysis, or a commercial database used for recording device history records or for complaint management). The extent of validation evidence needed for such software depends on the device manufacturers documented intended use of that software. For example, a device manufacturer who chooses not to use all the vendor-supplied capabilities of the software only needs to validate those functions that will be used and for which the device manufacturer is dependent upon the software results as part of production or the quality system. However, high risk applications should not be running in the same operating environment with non-validated software functions, even if those software functions are not used. Risk mitigation techniques such as memory partitioning or other approaches to resource protection may need to be considered when high risk applications and lower risk applications are to be used in the same operating environment. When software is upgraded or any changes are made to the software, the device manufacturer should consider how those changes may impact the used portions of the software and must reconfirm the validation of those portions of the software that are used. (See 21 CFR 820.70(i).)
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6.2. DEFINED USER REQUIREMENTS A very important key to software validation is a documented user requirements specification that defines: the intended use of the software or automated equipment; and the extent to which the device manufacturer is dependent upon that software or equipment for production of a quality medical device.
6.2. DEFINED USER REQUIREMENTS A very important key to software validation is a documented user requirements specification that defines: the intended use of the software or automated equipment; and the extent to which the device manufacturer is dependent upon that software or equipment for production of a quality medical device.
The device manufacturer (user) needs to define the expected operating environment including any required hardware and software configurations, software versions, utilities, etc. The user also needs to: document requirements for system performance, quality, error handling, startup, shutdown, security, etc.; identify any safety related functions or features, such as sensors, alarms, interlocks, logical processing steps, or command sequences; and define objective criteria for determining acceptable performance.
The device manufacturer (user) needs to define the expected operating environment including any required hardware and software configurations, software versions, utilities, etc. The user also needs to: document requirements for system performance, quality, error handling, startup, shutdown, security, etc.; identify any safety related functions or features, such as sensors, alarms, interlocks, logical processing steps, or command sequences; and define objective criteria for determining acceptable performance.
The validation must be conducted in accordance with a documented protocol, and the validation results must also be documented. (See 21 CFR 820.70(i).) Test cases should be documented that will exercise the system to challenge its performance against the pre-determined criteria, especially for its most critical parameters. Test cases should address error and alarm conditions, startup, shutdown, all applicable user functions and operator controls, potential operator errors, maximum and minimum ranges of allowed values, and stress conditions applicable to the intended use of the equipment. The test cases should be executed and the results should be recorded and evaluated to determine whether the results support a conclusion that the software is validated for its intended use. A device manufacturer may conduct a validation using their own personnel or may depend on a third party such as the equipment/software vendor or a consultant. In any case, the device manufacturer retains the ultimate responsibility for ensuring that the production and quality system software: is validated according to a written procedure for the particular intended use; and will perform as intended in the chosen application.
The validation must be conducted in accordance with a documented protocol, and the validation results must also be documented. (See 21 CFR 820.70(i).) Test cases should be documented that will exercise the system to challenge its performance against the pre-determined criteria, especially for its most critical parameters. Test cases should address error and alarm conditions, startup, shutdown, all applicable user functions and operator controls, potential operator errors, maximum and minimum ranges of allowed values, and stress conditions applicable to the intended use of the equipment. The test cases should be executed and the results should be recorded and evaluated to determine whether the results support a conclusion that the software is validated for its intended use. A device manufacturer may conduct a validation using their own personnel or may depend on a third party such as the equipment/software vendor or a consultant. In any case, the device manufacturer retains the ultimate responsibility for ensuring that the production and quality system software: is validated according to a written procedure for the particular intended use; and will perform as intended in the chosen application.
The device manufacturer should have documentation including:
The device manufacturer should have documentation including:
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defined user requirements; validation protocol used; acceptance criteria; test cases and results; and a validation summary
defined user requirements; validation protocol used; acceptance criteria; test cases and results; and a validation summary
that objectively confirms that the software is validated for its intended use. 6.3. VALIDATION OF OFF-THE-SHELF SOFTWARE AND AUTOMATED EQUIPMENT Most of the automated equipment and systems used by device manufacturers are supplied by third-party vendors and are purchased offthe-shelf (OTS). The device manufacturer is responsible for ensuring that the product development methodologies used by the OTS software developer are appropriate and sufficient for the device manufacturers intended use of that OTS software. For OTS software and equipment, the device manufacturer may or may not have access to the vendors software validation documentation. If the vendor can provide information about their system requirements, software requirements, validation process, and the results of their validation, the medical device manufacturer can use that information as a beginning point for their required validation documentation. The vendors life cycle documentation, such as testing protocols and results, source code, design specification, and requirements specification, can be useful in establishing that the software has been validated. However, such documentation is frequently not available from commercial equipment vendors, or the vendor may refuse to share their proprietary information. Where possible and depending upon the device risk involved, the device manufacturer should consider auditing the vendors design and development methodologies used in the construction of the OTS software and should assess the development and validation documentation generated for the OTS software. Such audits can be conducted by the device manufacturer or by a qualified third party. The audit should demonstrate that the vendors procedures for and results of the verification and validation activities performed the OTS software are appropriate and sufficient for the safety and effectiveness requirements of the medical device to be produced using that software.
that objectively confirms that the software is validated for its intended use. 6.3. VALIDATION OF OFF-THE-SHELF SOFTWARE AND AUTOMATED EQUIPMENT Most of the automated equipment and systems used by device manufacturers are supplied by third-party vendors and are purchased offthe-shelf (OTS). The device manufacturer is responsible for ensuring that the product development methodologies used by the OTS software developer are appropriate and sufficient for the device manufacturers intended use of that OTS software. For OTS software and equipment, the device manufacturer may or may not have access to the vendors software validation documentation. If the vendor can provide information about their system requirements, software requirements, validation process, and the results of their validation, the medical device manufacturer can use that information as a beginning point for their required validation documentation. The vendors life cycle documentation, such as testing protocols and results, source code, design specification, and requirements specification, can be useful in establishing that the software has been validated. However, such documentation is frequently not available from commercial equipment vendors, or the vendor may refuse to share their proprietary information. Where possible and depending upon the device risk involved, the device manufacturer should consider auditing the vendors design and development methodologies used in the construction of the OTS software and should assess the development and validation documentation generated for the OTS software. Such audits can be conducted by the device manufacturer or by a qualified third party. The audit should demonstrate that the vendors procedures for and results of the verification and validation activities performed the OTS software are appropriate and sufficient for the safety and effectiveness requirements of the medical device to be produced using that software.
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Some vendors who are not accustomed to operating in a regulated environment may not have a documented life cycle process that can support the device manufacturers validation requirement. Other vendors may not permit an audit. Where necessary validation information is not available from the vendor, the device manufacturer will need to perform sufficient system level black box testing to establish that the software meets their user needs and intended uses. For many applications black box testing alone is not sufficient. Depending upon the risk of the device produced, the role of the OTS software in the process, the ability to audit the vendor, and the sufficiency of vendor-supplied information, the use of OTS software or equipment may or may not be appropriate, especially if there are suitable alternatives available. The device manufacturer should also consider the implications (if any) for continued maintenance and support of the OTS software should the vendor terminate their support. For some off-the-shelf software development tools, such as software compilers, linkers, editors, and operating systems, exhaustive black-box testing by the device manufacturer may be impractical. Without such testing - a key element of the validation effort - it may not be possible to validate these software tools. However, their proper operation may be satisfactorily inferred by other means. For example, compilers are frequently certified by independent third-party testing, and commercial software products may have bug lists, system requirements and other operational information available from the vendor that can be compared to the device manufacturers intended use to help focus the black-box testing effort. Off-the-shelf operating systems need not be validated as a separate program. However, system-level validation testing of the application software should address all the operating system services used, including maximum loading conditions, file operations, handling of system error conditions, and memory constraints that may be applicable to the intended use of the application program. For more detailed information, see the production and process software references in Appendix A.
Some vendors who are not accustomed to operating in a regulated environment may not have a documented life cycle process that can support the device manufacturers validation requirement. Other vendors may not permit an audit. Where necessary validation information is not available from the vendor, the device manufacturer will need to perform sufficient system level black box testing to establish that the software meets their user needs and intended uses. For many applications black box testing alone is not sufficient. Depending upon the risk of the device produced, the role of the OTS software in the process, the ability to audit the vendor, and the sufficiency of vendor-supplied information, the use of OTS software or equipment may or may not be appropriate, especially if there are suitable alternatives available. The device manufacturer should also consider the implications (if any) for continued maintenance and support of the OTS software should the vendor terminate their support. For some off-the-shelf software development tools, such as software compilers, linkers, editors, and operating systems, exhaustive black-box testing by the device manufacturer may be impractical. Without such testing - a key element of the validation effort - it may not be possible to validate these software tools. However, their proper operation may be satisfactorily inferred by other means. For example, compilers are frequently certified by independent third-party testing, and commercial software products may have bug lists, system requirements and other operational information available from the vendor that can be compared to the device manufacturers intended use to help focus the black-box testing effort. Off-the-shelf operating systems need not be validated as a separate program. However, system-level validation testing of the application software should address all the operating system services used, including maximum loading conditions, file operations, handling of system error conditions, and memory constraints that may be applicable to the intended use of the application program. For more detailed information, see the production and process software references in Appendix A.
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APPENDIX A - REFERENCES
Food and Drug Administration References Design Control Guidance for Medical Device Manufacturers, Center for Devices and Radiological Health, Food and Drug Administration, March 1997. Do It by Design, An Introduction to Human Factors in Medical Devices, Center for Devices and Radiological Health, Food and Drug Administration, March 1997. Electronic Records; Electronic Signatures Final Rule, 62 Federal Register 13430 (March 20, 1997). Glossary of Computerized System and Software Development Terminology, Division of Field Investigations, Office of Regional Operations, Office of Regulatory Affairs, Food and Drug Administration, August 1995. Guidance for the Content of Pre-market Submissions for Software Contained in Medical Devices, Office of Device Evaluation, Center for Devices and Radiological Health, Food and Drug Administration, May 1998. Guidance for Industry, FDA Reviewers and Compliance on Off-the-Shelf Software Use in Medical Devices, Office of Device Evaluation, Center for Devices and Radiological Health, Food and Drug Administration, September 1999. Guideline on General Principles of Process Validation, Center for Drugs and Biologics, & Center For Devices and Radiological Health, Food and Drug Administration, May 1987. Medical Devices; Current Good Manufacturing Practice (CGMP) Final Rule; Quality System Regulation, 61 Federal Register 52602 (October 7, 1996). Reviewer Guidance for a Pre-Market Notification Submission for Blood Establishment Computer Software, Center for Biologics Evaluation and Research, Food and Drug Administration, January 1997
APPENDIX A - REFERENCES
Food and Drug Administration References Design Control Guidance for Medical Device Manufacturers, Center for Devices and Radiological Health, Food and Drug Administration, March 1997. Do It by Design, An Introduction to Human Factors in Medical Devices, Center for Devices and Radiological Health, Food and Drug Administration, March 1997. Electronic Records; Electronic Signatures Final Rule, 62 Federal Register 13430 (March 20, 1997). Glossary of Computerized System and Software Development Terminology, Division of Field Investigations, Office of Regional Operations, Office of Regulatory Affairs, Food and Drug Administration, August 1995. Guidance for the Content of Pre-market Submissions for Software Contained in Medical Devices, Office of Device Evaluation, Center for Devices and Radiological Health, Food and Drug Administration, May 1998. Guidance for Industry, FDA Reviewers and Compliance on Off-the-Shelf Software Use in Medical Devices, Office of Device Evaluation, Center for Devices and Radiological Health, Food and Drug Administration, September 1999. Guideline on General Principles of Process Validation, Center for Drugs and Biologics, & Center For Devices and Radiological Health, Food and Drug Administration, May 1987. Medical Devices; Current Good Manufacturing Practice (CGMP) Final Rule; Quality System Regulation, 61 Federal Register 52602 (October 7, 1996). Reviewer Guidance for a Pre-Market Notification Submission for Blood Establishment Computer Software, Center for Biologics Evaluation and Research, Food and Drug Administration, January 1997
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AS 3563.1-1991, Software Quality Management System, Part 1: Requirements. Published by Standards Australia [Standards Association of Australia], 1 The Crescent, Homebush, NSW 2140. AS 3563.2-1991, Software Quality Management System, Part 2: Implementation Guide. Published by Standards Australia [Standards Association of Australia], 1 The Crescent, Homebush, NSW 2140. IEC 60601-1-4:1996, Medical electrical equipment, Part 1: General requirements for safety, 4. Collateral Standard: Programmable electrical medical systems. International Electrotechnical Commission, 1996. IEC 61506:1997, Industrial process measurement and control Documentation of application software. International Electrotechnical Commission, 1997. IEC 61508:1998, Functional safety of electrical/electronic/programmable electronic safety-related systems. International Electrotechnical Commission, 1998. IEEE Std 1012-1986, Software Verification and Validation Plans, Institute for Electrical and Electronics Engineers, 1986. IEEE Standards Collection, Software Engineering, Institute of Electrical and Electronics Engineers, Inc., 1994. ISBN 1-55937-442-X. ISO 8402:1994, Quality management and quality assurance - Vocabulary. International Organization for Standardization, 1994. ISO 9000-3:1997, Quality management and quality assurance standards Part 3: Guidelines for the application of ISO 9001:1994 to the development, supply, installation and maintenance of computer software. International Organization for Standardization, 1997. ISO 9001:1994, Quality systems - Model for quality assurance in design, development, production, installation, and servicing. International Organization for Standardization, 1994. ISO 13485:1996, Quality systems - Medical devices - Particular requirements for the application of ISO 9001. International Organization for Standardization, 1996. ISO/IEC 12119:1994, Information technology - Software packages - Quality requirements and testing, Joint Technical Committee ISO/IEC JTC 1,
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International Organization for Standardization and International Electrotechnical Commission, 1994. ISO/IEC 12207:1995, Information technology - Software life cycle processes, Joint Technical Committee ISO/IEC JTC 1, Subcommittee SC 7, International Organization for Standardization and International Electrotechnical Commission, 1995. ISO/IEC 14598:1999, Information technology - Software product evaluation, Joint Technical Committee ISO/IEC JTC 1, Subcommittee SC 7, International Organization for Standardization and International Electrotechnical Commission, 1999. ISO 14971-1:1998, Medical Devices - Risk Management - Part 1: Application of Risk Analysis. International Organization for Standardization, 1998. Software Considerations in Airborne Systems and Equipment Certification. Special Committee 167 of RTCA. RTCA Inc., Washington, D.C. Tel: 202-833-9339. Document No. RTCA/DO-178B, December 1992. Production Process Software References The Application of the Principles of GLP to Computerized Systems, Environmental Monograph #116, Organization for Economic Cooperation and Development (OECD), 1995. George J. Grigonis, Jr., Edward J. Subak, Jr., and Michael Wyrick, Validation Key Practices for Computer Systems Used in Regulated Operations, Pharmaceutical Technology, June 1997. Guide to Inspection of Computerized Systems in Drug Processing, Reference Materials and Training Aids for Investigators, Division of Drug Quality Compliance, Associate Director for Compliance, Office of Drugs, National Center for Drugs and Biologics, & Division of Field Investigations, Associate Director for Field Support, Executive Director of Regional Operations, Food and Drug Administration, February 1983. Daniel P. Olivier, Validating Process Software, FDA Investigator Course: Medical Device Process Validation, Food and Drug Administration. GAMP Guide For Validation of Automated Systems in Pharmaceutical Manufacture,Version V3.0, Good Automated Manufacturing Practice
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(GAMP) Forum, March 1998: Volume 1, Part 1: User Guide Part 2: Supplier GuideVolume 2: Best Practice for User and Suppliers. Technical Report No. 18, Validation of Computer-Related Systems. PDA Committee on Validation of Computer-Related Systems. PDA Journal of Pharmaceutical Science and Technology, Volume 49, Number 1, JanuaryFebruary 1995 Supplement. Validation Compliance Annual 1995, International Validation Forum, Inc. General Software Quality References Boris Beizer, Black Box Testing, Techniques for Functional Testing of Software and Systems, John Wiley & Sons, 1995. ISBN 0-471-12094-4. Boris Beizer, Software System Testing and Quality Assurance, International Thomson Computer Press, 1996. ISBN 1-85032-821-8. Boris Beizer, Software Testing Techniques, Second Edition, Van Nostrand Reinhold, 1990. ISBN 0-442-20672-0. Richard Bender, Writing Testable Requirements, Version 1.0, Bender & Associates, Inc., Larkspur, CA 94777, 1996. Frederick P. Brooks, Jr., The Mythical Man-Month, Essays on Software Engineering, Addison-Wesley Longman, Anniversary Edition, 1995. ISBN 0-201-83595-9. Silvana Castano, et.al., Database Security, ACM Press, Addison-Wesley Publishing Company, 1995. ISBN 0-201-59375-0. Computerized Data Systems for Nonclinical Safety Assessment, Current Concepts and Quality Assurance, Drug Information Association, Maple Glen, PA, September 1988. M. S. Deutsch, Software Verification and Validation, Realistic Project Approaches, Prentice Hall, 1982. Robert H. Dunn and Richard S. Ullman, TQM for Computer Software, Second Edition, McGraw-Hill, Inc., 1994. ISBN 0-07-018314-7. Elfriede Dustin, Jeff Rashka, and John Paul, Automated Software Testing Introduction, Management and Performance, Addison Wesley Longman, Inc., 1999. ISBN 0-201-43287-0.
(GAMP) Forum, March 1998: Volume 1, Part 1: User Guide Part 2: Supplier GuideVolume 2: Best Practice for User and Suppliers. Technical Report No. 18, Validation of Computer-Related Systems. PDA Committee on Validation of Computer-Related Systems. PDA Journal of Pharmaceutical Science and Technology, Volume 49, Number 1, JanuaryFebruary 1995 Supplement. Validation Compliance Annual 1995, International Validation Forum, Inc. General Software Quality References Boris Beizer, Black Box Testing, Techniques for Functional Testing of Software and Systems, John Wiley & Sons, 1995. ISBN 0-471-12094-4. Boris Beizer, Software System Testing and Quality Assurance, International Thomson Computer Press, 1996. ISBN 1-85032-821-8. Boris Beizer, Software Testing Techniques, Second Edition, Van Nostrand Reinhold, 1990. ISBN 0-442-20672-0. Richard Bender, Writing Testable Requirements, Version 1.0, Bender & Associates, Inc., Larkspur, CA 94777, 1996. Frederick P. Brooks, Jr., The Mythical Man-Month, Essays on Software Engineering, Addison-Wesley Longman, Anniversary Edition, 1995. ISBN 0-201-83595-9. Silvana Castano, et.al., Database Security, ACM Press, Addison-Wesley Publishing Company, 1995. ISBN 0-201-59375-0. Computerized Data Systems for Nonclinical Safety Assessment, Current Concepts and Quality Assurance, Drug Information Association, Maple Glen, PA, September 1988. M. S. Deutsch, Software Verification and Validation, Realistic Project Approaches, Prentice Hall, 1982. Robert H. Dunn and Richard S. Ullman, TQM for Computer Software, Second Edition, McGraw-Hill, Inc., 1994. ISBN 0-07-018314-7. Elfriede Dustin, Jeff Rashka, and John Paul, Automated Software Testing Introduction, Management and Performance, Addison Wesley Longman, Inc., 1999. ISBN 0-201-43287-0.
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Robert G. Ebenau and Susan H. Strauss, Software Inspection Process, McGraw-Hill, 1994. ISBN 0-07-062166-7. Richard E. Fairley, Software Engineering Concepts, McGraw-Hill Publishing Company, 1985. ISBN 0-07-019902-7. Michael A. Friedman and Jeffrey M. Voas, Software Assessment - Reliability, Safety, Testability, Wiley-Interscience, John Wiley & Sons Inc., 1995. ISBN 0-471-01009-X. Tom Gilb, Dorothy Graham, Software Inspection , Addison-Wesley Publishing Company, 1993. ISBN 0-201-63181-4. Robert B. Grady, Practical Software Metrics for Project Management and Process Improvement, PTR Prentice-Hall Inc., 1992. ISBN 0-13-720384-5. Les Hatton, Safer C: Developing Software for High-integrity and Safetycritical Systems, McGraw-Hill Book Company, 1994. ISBN 0-07-707640-0. Janis V. Halvorsen, A Software Requirements Specification Document Model for the Medical Device Industry, Proceedings IEEE SOUTHEASTCON 93, Banking on Technology, April 4th -7th, 1993, Charlotte, North Carolina. Debra S. Herrmann, Software Safety and Reliability: Techniques, Approaches and Standards of Key Industrial Sectors, IEEE Computer Society, 1999. ISBN 0-7695-0299-7. Bill Hetzel, The Complete Guide to Software Testing, Second Edition, A Wiley-QED Publication, John Wiley & Sons, Inc., 1988. ISBN 0-471-565679. Watts S. Humphrey, A Discipline for Software Engineering. AddisonWesley Longman, 1995. ISBN 0-201-54610-8. Watts S. Humphrey, Managing the Software Process, Addison-Wesley Publishing Company, 1989. ISBN 0-201-18095-2. Capers Jones, Software Quality, Analysis and Guidelines for Success, International Thomson Computer Press, 1997. ISBN 1-85032-867-6. J.M. Juran, Frank M. Gryna, Quality Planning and Analysis, Third Edition, , McGraw-Hill, 1993. ISBN 0-07-033183-9. Stephen H. Kan, Metrics and Models in Software Quality Engineering, Addison-Wesley Publishing Company, 1995. ISBN 0-201-63339-6.
Robert G. Ebenau and Susan H. Strauss, Software Inspection Process, McGraw-Hill, 1994. ISBN 0-07-062166-7. Richard E. Fairley, Software Engineering Concepts, McGraw-Hill Publishing Company, 1985. ISBN 0-07-019902-7. Michael A. Friedman and Jeffrey M. Voas, Software Assessment - Reliability, Safety, Testability, Wiley-Interscience, John Wiley & Sons Inc., 1995. ISBN 0-471-01009-X. Tom Gilb, Dorothy Graham, Software Inspection , Addison-Wesley Publishing Company, 1993. ISBN 0-201-63181-4. Robert B. Grady, Practical Software Metrics for Project Management and Process Improvement, PTR Prentice-Hall Inc., 1992. ISBN 0-13-720384-5. Les Hatton, Safer C: Developing Software for High-integrity and Safetycritical Systems, McGraw-Hill Book Company, 1994. ISBN 0-07-707640-0. Janis V. Halvorsen, A Software Requirements Specification Document Model for the Medical Device Industry, Proceedings IEEE SOUTHEASTCON 93, Banking on Technology, April 4th -7th, 1993, Charlotte, North Carolina. Debra S. Herrmann, Software Safety and Reliability: Techniques, Approaches and Standards of Key Industrial Sectors, IEEE Computer Society, 1999. ISBN 0-7695-0299-7. Bill Hetzel, The Complete Guide to Software Testing, Second Edition, A Wiley-QED Publication, John Wiley & Sons, Inc., 1988. ISBN 0-471-565679. Watts S. Humphrey, A Discipline for Software Engineering. AddisonWesley Longman, 1995. ISBN 0-201-54610-8. Watts S. Humphrey, Managing the Software Process, Addison-Wesley Publishing Company, 1989. ISBN 0-201-18095-2. Capers Jones, Software Quality, Analysis and Guidelines for Success, International Thomson Computer Press, 1997. ISBN 1-85032-867-6. J.M. Juran, Frank M. Gryna, Quality Planning and Analysis, Third Edition, , McGraw-Hill, 1993. ISBN 0-07-033183-9. Stephen H. Kan, Metrics and Models in Software Quality Engineering, Addison-Wesley Publishing Company, 1995. ISBN 0-201-63339-6.
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Cem Kaner, Jack Falk, Hung Quoc Nguyen, Testing Computer Software, Second Edition, Vsn Nostrand Reinhold, 1993. ISBN 0-442-01361-2. Craig Kaplan, Ralph Clark, Victor Tang, Secrets of Software Quality, 40 Innovations from IBM, McGraw-Hill, 1995. ISBN 0-07-911795-3. Edward Kit, Software Testing in the Real World, Addison-Wesley Longman, 1995. ISBN 0-201-87756-2. Alan Kusinitz, Software Validation, Current Issues in Medical Device Quality Systems, Association for the Advancement of Medical Instrumentation, 1997. ISBN 1-57020-075-0. Nancy G. Leveson, Safeware, System Safety and Computers, AddisonWesley Publishing Company, 1995. ISBN 0-201-11972-2. Michael R. Lyu, Editor, Handbook of Software Reliability Engineering, IEEE Computer Society Press, McGraw-Hill, 1996. ISBN 0-07-039400-8. Steven R. Mallory, Software Development and Quality Assurance for the Healthcare Manufacturing Industries, Interpharm Press,Inc., 1994. ISBN 0-935184-58-9. Brian Marick, The Craft of Software Testing, Prentice Hall PTR, 1995. ISBN 0-13-177411-5. Steve McConnell, Rapid Development, Microsoft Press, 1996. ISBN 1-55615900-5. Glenford J. Myers, The Art of Software Testing, John Wiley & Sons, 1979. ISBN 0-471-04328-1. Peter G. Neumann, Computer Related Risks, ACM Press/Addison-Wesley Publishing Co., 1995. ISBN 0-201-55805-X. Daniel Olivier, Conducting Software Audits, Auditing Software for Conformance to FDA Requirements, Computer Application Specialists, San Diego, CA, 1994. William Perry, Effective Methods for Software Testing, John Wiley & Sons, Inc. 1995. ISBN 0-471-06097-6. William E. Perry, Randall W. Rice, Surviving the Top Ten Challenges of Software Testing, Dorset House Publishing, 1997. ISBN 0-932633-38-2.
Cem Kaner, Jack Falk, Hung Quoc Nguyen, Testing Computer Software, Second Edition, Vsn Nostrand Reinhold, 1993. ISBN 0-442-01361-2. Craig Kaplan, Ralph Clark, Victor Tang, Secrets of Software Quality, 40 Innovations from IBM, McGraw-Hill, 1995. ISBN 0-07-911795-3. Edward Kit, Software Testing in the Real World, Addison-Wesley Longman, 1995. ISBN 0-201-87756-2. Alan Kusinitz, Software Validation, Current Issues in Medical Device Quality Systems, Association for the Advancement of Medical Instrumentation, 1997. ISBN 1-57020-075-0. Nancy G. Leveson, Safeware, System Safety and Computers, AddisonWesley Publishing Company, 1995. ISBN 0-201-11972-2. Michael R. Lyu, Editor, Handbook of Software Reliability Engineering, IEEE Computer Society Press, McGraw-Hill, 1996. ISBN 0-07-039400-8. Steven R. Mallory, Software Development and Quality Assurance for the Healthcare Manufacturing Industries, Interpharm Press,Inc., 1994. ISBN 0-935184-58-9. Brian Marick, The Craft of Software Testing, Prentice Hall PTR, 1995. ISBN 0-13-177411-5. Steve McConnell, Rapid Development, Microsoft Press, 1996. ISBN 1-55615900-5. Glenford J. Myers, The Art of Software Testing, John Wiley & Sons, 1979. ISBN 0-471-04328-1. Peter G. Neumann, Computer Related Risks, ACM Press/Addison-Wesley Publishing Co., 1995. ISBN 0-201-55805-X. Daniel Olivier, Conducting Software Audits, Auditing Software for Conformance to FDA Requirements, Computer Application Specialists, San Diego, CA, 1994. William Perry, Effective Methods for Software Testing, John Wiley & Sons, Inc. 1995. ISBN 0-471-06097-6. William E. Perry, Randall W. Rice, Surviving the Top Ten Challenges of Software Testing, Dorset House Publishing, 1997. ISBN 0-932633-38-2.
Roger S. Pressman, Software Engineering, A Practitioners Approach, Third Edition, McGraw-Hill Inc., 1992. ISBN 0-07-050814-3. Roger S. Pressman, A Managers Guide to Software Engineering, McGrawHill Inc., 1993 ISBN 0-07-050820-8. A. P. Sage, J. D. Palmer, Software Systems Engineering, John Wiley & Sons, 1990. Joc Sanders, Eugene Curran, Software Quality, Addison-Wesley Publishing Co., 1994. ISBN 0-201-63198-9. Ken Shumate, Marilyn Keller, Software Specification and Design, A Disciplined Approach for Real-Time Systems, John Wiley & Sons, 1992. ISBN 0-471-53296-7. Dennis D. Smith, Designing Maintainable Software, Springer-Verlag, 1999. ISBN 0-387-98783-5. Ian Sommerville, Software Engineering, Third Edition, Addison Wesley Publishing Co., 1989. ISBN 0-201-17568-1. Karl E. Wiegers, Creating a Software Engineering Culture, Dorset House Publishing, 1996. ISBN 0-932633-33-1. Karl E. Wiegers, Software Inspection, Improving Quality with Software Inspections, Software Development, April 1995, pages 55-64. Karl E. Wiegers, Software Requirements, Microsoft Press, 1999. ISBN 07356-0631-5.
Roger S. Pressman, Software Engineering, A Practitioners Approach, Third Edition, McGraw-Hill Inc., 1992. ISBN 0-07-050814-3. Roger S. Pressman, A Managers Guide to Software Engineering, McGrawHill Inc., 1993 ISBN 0-07-050820-8. A. P. Sage, J. D. Palmer, Software Systems Engineering, John Wiley & Sons, 1990. Joc Sanders, Eugene Curran, Software Quality, Addison-Wesley Publishing Co., 1994. ISBN 0-201-63198-9. Ken Shumate, Marilyn Keller, Software Specification and Design, A Disciplined Approach for Real-Time Systems, John Wiley & Sons, 1992. ISBN 0-471-53296-7. Dennis D. Smith, Designing Maintainable Software, Springer-Verlag, 1999. ISBN 0-387-98783-5. Ian Sommerville, Software Engineering, Third Edition, Addison Wesley Publishing Co., 1989. ISBN 0-201-17568-1. Karl E. Wiegers, Creating a Software Engineering Culture, Dorset House Publishing, 1996. ISBN 0-932633-33-1. Karl E. Wiegers, Software Inspection, Improving Quality with Software Inspections, Software Development, April 1995, pages 55-64. Karl E. Wiegers, Software Requirements, Microsoft Press, 1999. ISBN 07356-0631-5.
APPENDIX B - DEVELOPMENT TEAM

Center for Devices and Radiological Health Office of ComplianceStewart CrumplerOffice of Device EvaluationJames Cheng, Donna-Bea TillmanOffice of Health and Industry Programs Bryan Benesch, Dick SawyerOffice of Science and TechnologyJohn MurrayOffice of Surveillance and BiometricsHoward PressCenter for Drug Evaluation and ResearchOffice of Medical PolicyCharles SnipesCenter for Biologics Evaluation and ResearchOffice of Compliance and Biologics QualityAlice GodziemskiOffice of Regulatory AffairsOffice of Regional OperationsDavid Bergeson, Joan Loreng
APPENDIX B - DEVELOPMENT TEAM

Center for Devices and Radiological Health Office of ComplianceStewart CrumplerOffice of Device EvaluationJames Cheng, Donna-Bea TillmanOffice of Health and Industry Programs Bryan Benesch, Dick SawyerOffice of Science and TechnologyJohn MurrayOffice of Surveillance and BiometricsHoward PressCenter for Drug Evaluation and ResearchOffice of Medical PolicyCharles SnipesCenter for Biologics Evaluation and ResearchOffice of Compliance and Biologics QualityAlice GodziemskiOffice of Regulatory AffairsOffice of Regional OperationsDavid Bergeson, Joan Loreng
VOLUME 4
VOLUME 4

1998 EDITION

1998 EDITION
ANNEX 11: COMPUTERISED SYSTEMS

PRINCIPLE
The introduction of computerised systems into systems of manufacturing, including storage, distribution and quality control does not alter the need to observe the relevant principles given elsewhere in the Guide. Where a computerised system replaces a manual operation, there should be no resultant decrease in product quality or quality assurance. Consideration should be given to the risk of losing aspects of the previous system which could result from reducing the involvement of operators.
ANNEX 11: COMPUTERISED SYSTEMS

PRINCIPLE
The introduction of computerised systems into systems of manufacturing, including storage, distribution and quality control does not alter the need to observe the relevant principles given elsewhere in the Guide. Where a computerised system replaces a manual operation, there should be no resultant decrease in product quality or quality assurance. Consideration should be given to the risk of losing aspects of the previous system which could result from reducing the involvement of operators.
PERSONNEL
1. It is essential that there is the closest co-operation between key personnel and those involved with computer systems. Persons in responsible positions should have the appropriate training for the management and use of systems within their field of responsibility which utilises computers. This should include ensuring that appropriate expertise is available and used to provide advice on aspects of design, validation, installation and operation of computerised system.
PERSONNEL
1. It is essential that there is the closest co-operation between key personnel and those involved with computer systems. Persons in responsible positions should have the appropriate training for the management and use of systems within their field of responsibility which utilises computers. This should include ensuring that appropriate expertise is available and used to provide advice on aspects of design, validation, installation and operation of computerised system.
VALIDATION
2. The extent of validation necessary will depend on a number of factors including the use to which the system is to be put, whether the validation is to be prospective or retrospective and whether or not novel elements are incorporated. Validation should be considered as part of the complete life cycle of a computer system. This cycle includes the stages of planning, specification, programming, testing, commissioning, documentation, operation, monitoring and modifying.
VALIDATION
2. The extent of validation necessary will depend on a number of factors including the use to which the system is to be put, whether the validation is to be prospective or retrospective and whether or not novel elements are incorporated. Validation should be considered as part of the complete life cycle of a computer system. This cycle includes the stages of planning, specification, programming, testing, commissioning, documentation, operation, monitoring and modifying.
SYSTEM
3. Attention should be paid to the siting of equipment in suitable conditions where extraneous factors cannot interfere with the system.
SYSTEM
3. Attention should be paid to the siting of equipment in suitable conditions where extraneous factors cannot interfere with the system.
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4. A written detailed description of the system should be produced (including diagrams as appropriate) and kept up to date. It should describe the principles, objectives, security measures and scope of the system and the main features of the way in which the computer is used and how it interacts with other systems and procedures. 5. The software is a critical component of a computerised system. The user of such software should take all reasonable steps to ensure that it has been produced in accordance with a system of Quality Assurance. 6. The system should include, where appropriate, built-in checks of the correct entry and processing of data. 7. Before a system using a computer is brought into use, it should be thoroughly tested and confirmed as being capable of achieving the desired results. If a manual system is being replaced, the two should be run in parallel for a time, as a part of this testing and validation. 8. Data should only be entered or amended by persons authorised to do so. Suitable methods of deterring unauthorised entry of data include the use of keys, pass cards, personal codes and restricted access to computer terminals. There should be a defined procedure for the issue, cancellation, and alteration of authorisation to enter and amend data, including the changing of personal passwords. Consideration should be given to systems allowing for recording of attempts to access by unauthorised persons. 9. When critical data are being entered manually (for example the weight and batch number of an ingredient during dispensing), there should be an additional check on the accuracy of the record which is made. This check may be done by a second operator or by validated electronic means. 10. The system should record the identity of operators entering or confirming critical data. Authority to amend entered data should be restricted to nominated persons. Any alteration to an entry of critical data should be authorised and recorded with the reason for the change. Consideration should be given to building into the system the creation of a complete record of all entries and amendments (an audit trail). 11. Alterations to a system or to a computer program should only be made in accordance with a defined procedure which should include provision for validating, checking, approving and implementing the change. Such an
4. A written detailed description of the system should be produced (including diagrams as appropriate) and kept up to date. It should describe the principles, objectives, security measures and scope of the system and the main features of the way in which the computer is used and how it interacts with other systems and procedures. 5. The software is a critical component of a computerised system. The user of such software should take all reasonable steps to ensure that it has been produced in accordance with a system of Quality Assurance. 6. The system should include, where appropriate, built-in checks of the correct entry and processing of data. 7. Before a system using a computer is brought into use, it should be thoroughly tested and confirmed as being capable of achieving the desired results. If a manual system is being replaced, the two should be run in parallel for a time, as a part of this testing and validation. 8. Data should only be entered or amended by persons authorised to do so. Suitable methods of deterring unauthorised entry of data include the use of keys, pass cards, personal codes and restricted access to computer terminals. There should be a defined procedure for the issue, cancellation, and alteration of authorisation to enter and amend data, including the changing of personal passwords. Consideration should be given to systems allowing for recording of attempts to access by unauthorised persons. 9. When critical data are being entered manually (for example the weight and batch number of an ingredient during dispensing), there should be an additional check on the accuracy of the record which is made. This check may be done by a second operator or by validated electronic means. 10. The system should record the identity of operators entering or confirming critical data. Authority to amend entered data should be restricted to nominated persons. Any alteration to an entry of critical data should be authorised and recorded with the reason for the change. Consideration should be given to building into the system the creation of a complete record of all entries and amendments (an audit trail). 11. Alterations to a system or to a computer program should only be made in accordance with a defined procedure which should include provision for validating, checking, approving and implementing the change. Such an
EUGGMP Annexure 11: computerised systems and proposed changes
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alteration should only be implemented with the agreement of the person responsible for the part of the system concerned, and the alteration should be recorded. Every significant modification should be validated. 12. For quality auditing purposes, it should be possible to obtain clear printed copies of electronically stored data. 13. Data should be secured by physical or electronic means against wilful or accidental damage, in accordance with item 4.9 of the Guide. Stored data should be checked for accessibility, durability and accuracy. If changes are proposed to the computer equipment or its programs, the above mentioned checks should be performed at a frequency appropriate to the storage medium being used. 14. Data should be protected by backing-up at regular intervals. Back-up data should be stored as long as necessary at a separate and secure location. 15. There should be available adequate alternative arrangements for systems which need to be operated in the event of a breakdown. The time required to bring the alternative arrangements into use should be related to the possible urgency of the need to use them. For example, information required to effect a recall must be available at short notice. 16. The procedures to be followed if the system fails or breaks down should be defined and validated. Any failures and remedial action taken should be recorded. 17. A procedure should be established to record and analyse errors and to enable corrective action to be taken. 18. When outside agencies are used to provide a computer service, there should be a formal agreement including a clear statement of the responsibilities of that outside agency (see Chapter 7). 19. When the release of batches for sale or supply is carried out using a computerised system, the system should allow for only a Qualified Person to release the batches and it should clearly identify and record the person releasing the batches.
alteration should only be implemented with the agreement of the person responsible for the part of the system concerned, and the alteration should be recorded. Every significant modification should be validated. 12. For quality auditing purposes, it should be possible to obtain clear printed copies of electronically stored data. 13. Data should be secured by physical or electronic means against wilful or accidental damage, in accordance with item 4.9 of the Guide. Stored data should be checked for accessibility, durability and accuracy. If changes are proposed to the computer equipment or its programs, the above mentioned checks should be performed at a frequency appropriate to the storage medium being used. 14. Data should be protected by backing-up at regular intervals. Back-up data should be stored as long as necessary at a separate and secure location. 15. There should be available adequate alternative arrangements for systems which need to be operated in the event of a breakdown. The time required to bring the alternative arrangements into use should be related to the possible urgency of the need to use them. For example, information required to effect a recall must be available at short notice. 16. The procedures to be followed if the system fails or breaks down should be defined and validated. Any failures and remedial action taken should be recorded. 17. A procedure should be established to record and analyse errors and to enable corrective action to be taken. 18. When outside agencies are used to provide a computer service, there should be a formal agreement including a clear statement of the responsibilities of that outside agency (see Chapter 7). 19. When the release of batches for sale or supply is carried out using a computerised system, the system should allow for only a Qualified Person to release the batches and it should clearly identify and record the person releasing the batches.
CONCEPT PAPER FOR THE REVISION OF ANNEX 11 OF THE GMP GUIDE ON COMPUTERISED SYSTEMS AND CONSEQUENTIAL AMENDMENT OF CHAPTER 4 OF THE GMP GUIDE
London, 20 December 2006 Doc. Ref. EMEA/INS/GMP/518577/2006
CONCEPT PAPER FOR THE REVISION OF ANNEX 11 OF THE GMP GUIDE ON COMPUTERISED SYSTEMS AND CONSEQUENTIAL AMENDMENT OF CHAPTER 4 OF THE GMP GUIDE
London, 20 December 2006 Doc. Ref. EMEA/INS/GMP/518577/2006
1. INTRODUCTION
The current EC GMP Annex 11 has its origins in national guidelines dating from the early 1980s and over the subsequent years computerised systems and applications have evolved to such an extent that whilst the main principles of the guidance are still valid, the scope and content of the present annex are considered by experts in the area of computerised systems as no longer adequate to meet the needs of either the pharmaceutical industry or inspectors. Chapter 4 of the EC GMP guide concerning documentation is written primarily in the context of traditional paper based media, whereas businesses worldwide increasingly use electronic documentation systems for the archiving and control of documents.
1. INTRODUCTION
The current EC GMP Annex 11 has its origins in national guidelines dating from the early 1980s and over the subsequent years computerised systems and applications have evolved to such an extent that whilst the main principles of the guidance are still valid, the scope and content of the present annex are considered by experts in the area of computerised systems as no longer adequate to meet the needs of either the pharmaceutical industry or inspectors. Chapter 4 of the EC GMP guide concerning documentation is written primarily in the context of traditional paper based media, whereas businesses worldwide increasingly use electronic documentation systems for the archiving and control of documents.
2. PROBLEM STATEMENT
As a result of changes in the working environment, inspectors in the area of computerised systems find it increasingly difficult to relate serious weaknesses in company procedures and processes for the management and use of computerised systems to the current GMP guidance for documentation and computerised systems.
2. PROBLEM STATEMENT
As a result of changes in the working environment, inspectors in the area of computerised systems find it increasingly difficult to relate serious weaknesses in company procedures and processes for the management and use of computerised systems to the current GMP guidance for documentation and computerised systems.
3. DISCUSSION
Today the pharmaceutical industry uses computerised systems and proprietary software for a vast array of local and global networked systems from R&D modelling, PAT, submissions, data collection and processing, automation, electronic documentation to laboratory, manufacturing, logistics and enterprise management applications as well as management of the companys quality system itself. In response to these changes GMP guidelines globally have undergone or are undergoing revision. The present chapter 4 of the GMP Guide only covers a limited range of documents, rather than the entire supply chain and product life cycle, from research and development through clinical trials, production and quality control to marketing.
3. DISCUSSION
Today the pharmaceutical industry uses computerised systems and proprietary software for a vast array of local and global networked systems from R&D modelling, PAT, submissions, data collection and processing, automation, electronic documentation to laboratory, manufacturing, logistics and enterprise management applications as well as management of the companys quality system itself. In response to these changes GMP guidelines globally have undergone or are undergoing revision. The present chapter 4 of the GMP Guide only covers a limited range of documents, rather than the entire supply chain and product life cycle, from research and development through clinical trials, production and quality control to marketing.
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4. RECOMMENDATION
It is proposed that the Ad Hoc GMP Inspection Services Group establishes a drafting group to actively work on a revision of Annex 11 (and consequential changes to Chapter 4) for consultation and adoption. It is perceived that the most significant changes will be necessary for Annex 11, and it is proposed that changes to Chapter 4 be restricted to consequential amendments and should concentrate on better describing the controls appropriate for electronic documentation making general references to more detailed guidance on computerised documentation and records in the Annex. For chapter 4 the following areas might be considered during revision: Consider whether the principles of this chapter need to be extended and updated to cover all types of documentation and to ensure that the principles of good documentation practices are applied throughout the spectrum of regulated activities for a products life-cycle, from investigational materials through submissions, to medicinal product manufacturing, testing, release, distribution and ultimately discontinuation of a product. Consider whether principles for the control of the document management system (electronic or otherwise) for the control and traceability of documents need to be included? Consider new and/or revised sections as needed e.g. the relationship of quality records with real time monitoring and control (e.g. PAT) may need additional guidance or clarification. Consider whether the principles and standards in ISO 17799 (Information Security Management) and PIO11-1 (Good Practices for Computerised Systems in Regulated GxP Environments - PIC/S) need to be introduced. For Annex 11 the drafting group may wish to consider (amongst others) the following: How to capitalise on the output from the PIC/S Expert Circle on Computerised Systems, which has been considering these matters recently and has already made draft proposals for revision. What opportunities exist to emphasise and clarify requirements for risk assessment, electronic records and PAT? Whether to include links to Chapter 4 for documentation systems?
4. RECOMMENDATION
It is proposed that the Ad Hoc GMP Inspection Services Group establishes a drafting group to actively work on a revision of Annex 11 (and consequential changes to Chapter 4) for consultation and adoption. It is perceived that the most significant changes will be necessary for Annex 11, and it is proposed that changes to Chapter 4 be restricted to consequential amendments and should concentrate on better describing the controls appropriate for electronic documentation making general references to more detailed guidance on computerised documentation and records in the Annex. For chapter 4 the following areas might be considered during revision: Consider whether the principles of this chapter need to be extended and updated to cover all types of documentation and to ensure that the principles of good documentation practices are applied throughout the spectrum of regulated activities for a products life-cycle, from investigational materials through submissions, to medicinal product manufacturing, testing, release, distribution and ultimately discontinuation of a product. Consider whether principles for the control of the document management system (electronic or otherwise) for the control and traceability of documents need to be included? Consider new and/or revised sections as needed e.g. the relationship of quality records with real time monitoring and control (e.g. PAT) may need additional guidance or clarification. Consider whether the principles and standards in ISO 17799 (Information Security Management) and PIO11-1 (Good Practices for Computerised Systems in Regulated GxP Environments - PIC/S) need to be introduced. For Annex 11 the drafting group may wish to consider (amongst others) the following: How to capitalise on the output from the PIC/S Expert Circle on Computerised Systems, which has been considering these matters recently and has already made draft proposals for revision. What opportunities exist to emphasise and clarify requirements for risk assessment, electronic records and PAT? Whether to include links to Chapter 4 for documentation systems?
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Whether to use the revision as an opportunity to remove perceived confusion in the validation section and whether extensive revision and updating is needed in line with mature internationally agreed concepts and standards for best practice that now exist. Consider update of all paragraphs where deemed necessary to emphasise the principles of Quality Risk Management as described in ICH Q9. Consider whether new paragraphs are needed on identity and electronic signature requirements in line with current, mature, good practice recommendations and relevant EU directives? As is normal for revisions of the GMP guide the new guidance will apply to medicinal products already authorised and on the market.
Whether to use the revision as an opportunity to remove perceived confusion in the validation section and whether extensive revision and updating is needed in line with mature internationally agreed concepts and standards for best practice that now exist. Consider update of all paragraphs where deemed necessary to emphasise the principles of Quality Risk Management as described in ICH Q9. Consider whether new paragraphs are needed on identity and electronic signature requirements in line with current, mature, good practice recommendations and relevant EU directives? As is normal for revisions of the GMP guide the new guidance will apply to medicinal products already authorised and on the market.
5. PROPOSED TIMETABLE
Formation of drafting group - January 2007 First discussions in the drafting group: February April 2007 and provision of work plan to Ad Hoc GMP Inspection Services Group for ratification. Projected date for first discussion of drafts at Ad Hoc GMP Inspection Services meeting September 2007. Projected date for submission to Commission to release for public consultation December 2007 Projected date for submission of finalised draft to the Commission for adoption December 2008. A decision on whether an implementation period longer than 6 months following publication will be made based on the comments received during the public consultation.
5. PROPOSED TIMETABLE
Formation of drafting group - January 2007 First discussions in the drafting group: February April 2007 and provision of work plan to Ad Hoc GMP Inspection Services Group for ratification. Projected date for first discussion of drafts at Ad Hoc GMP Inspection Services meeting September 2007. Projected date for submission to Commission to release for public consultation December 2007 Projected date for submission of finalised draft to the Commission for adoption December 2008. A decision on whether an implementation period longer than 6 months following publication will be made based on the comments received during the public consultation.
6. RESOURCE REQUIREMENTS FOR PREPARATION

A rapporteur will be appointed and a drafting group consisting of 3-5 experts drawn from the National Competent Authorities of the EEA will be established. Work already done by PIC/S will be taken into account. The drafting group will work mainly by written correspondence but if necessary,
6. RESOURCE REQUIREMENTS FOR PREPARATION

A rapporteur will be appointed and a drafting group consisting of 3-5 experts drawn from the National Competent Authorities of the EEA will be established. Work already done by PIC/S will be taken into account. The drafting group will work mainly by written correspondence but if necessary,
and at the request of the rapporteur, one meeting of the drafting group may be arranged. Any such meeting will coincide with a meeting of Ad Hoc GMP Inspection Services should this prove to be optimal use of resources.
and at the request of the rapporteur, one meeting of the drafting group may be arranged. Any such meeting will coincide with a meeting of Ad Hoc GMP Inspection Services should this prove to be optimal use of resources.
7. IMPACT ASSESSMENT
The implementation of this new guidance as currently envisaged is not intended to introduce any requirement for new equipment. The guidance is intended to facilitate the introduction of new automated systems and by clarifying expectations where existing systems are used in the GMP controlled arena. By utilising experience and output from PIC/S duplication of effort will be reduced. The impact assessment performed at the time of drafting this concept paper will be reviewed upon publication of the final guidance.
7. IMPACT ASSESSMENT
The implementation of this new guidance as currently envisaged is not intended to introduce any requirement for new equipment. The guidance is intended to facilitate the introduction of new automated systems and by clarifying expectations where existing systems are used in the GMP controlled arena. By utilising experience and output from PIC/S duplication of effort will be reduced. The impact assessment performed at the time of drafting this concept paper will be reviewed upon publication of the final guidance.
8. REFERENCES
Eudralex Volume 4 Medicinal Products for Human and Veterinary Use: Good Manufacturing Practice - Chapter 4 Documentation and Annex 11 Computerised Systems. European Commission. Directive 2000/31/EC of the European Parliament and of the Council of 8 June 2000 on certain legal aspects of information society services, in particular electronic commerce, in the Internal Market. OJ L 178, 17/07/2000 P. 0001 0016 Directive 1999/93/EC of the European Parliament and of the Council on a Community framework for electronic signatures. OJ L 13, 19/01/2000 P. 0012 0020 ISO 17799. Information technology - Security techniques - Code of practice for information security management. International Standards Organisation. 2005. PI 011-2. Good Practices for Computerised Systems in Regulated GxP environments. Pharmaceutical Inspection Cooperation Scheme. 2004.
8. REFERENCES
Eudralex Volume 4 Medicinal Products for Human and Veterinary Use: Good Manufacturing Practice - Chapter 4 Documentation and Annex 11 Computerised Systems. European Commission. Directive 2000/31/EC of the European Parliament and of the Council of 8 June 2000 on certain legal aspects of information society services, in particular electronic commerce, in the Internal Market. OJ L 178, 17/07/2000 P. 0001 0016 Directive 1999/93/EC of the European Parliament and of the Council on a Community framework for electronic signatures. OJ L 13, 19/01/2000 P. 0012 0020 ISO 17799. Information technology - Security techniques - Code of practice for information security management. International Standards Organisation. 2005. PI 011-2. Good Practices for Computerised Systems in Regulated GxP environments. Pharmaceutical Inspection Cooperation Scheme. 2004.
Appendix 5
VALIDATION OF COMPUTERIZED SYSTEMS
1. General 2. System specification 3. Functional specification 4. Security 5. Back-ups 6. Validation 7. Validation of hardware and software 7.1 Hardware 7.2 Software
Appendix 5
VALIDATION OF COMPUTERIZED SYSTEMS
1. General 2. System specification 3. Functional specification 4. Security 5. Back-ups 6. Validation 7. Validation of hardware and software 7.1 Hardware 7.2 Software
1. General
1.1 Computer systems should be validated at the level appropriate for their use and application. This is of importance in production as well as in quality control. 1.2 The use of a computer system includes different stages. These are planning, specification, programming, testing, commissioning, document operation, monitoring and modifying. 1.3 The purpose of validation of a computer system is to ensure an acceptable degree of evidence (documented, raw data), confidence (dependability and thorough, rigorous achievement of predetermined specifications), intended use, accuracy, consistency and reliability. 1.4 Both the system specifications and functional specifications should be validated. 1.5 Periodic (or continuous) evaluation should be performed after the initial validation. 1.6 There should be written procedures for performance monitoring, change control, programme and data security, calibration and maintenance, personnel training, emergency recovery and periodic re-evaluation.
1. General
1.1 Computer systems should be validated at the level appropriate for their use and application. This is of importance in production as well as in quality control. 1.2 The use of a computer system includes different stages. These are planning, specification, programming, testing, commissioning, document operation, monitoring and modifying. 1.3 The purpose of validation of a computer system is to ensure an acceptable degree of evidence (documented, raw data), confidence (dependability and thorough, rigorous achievement of predetermined specifications), intended use, accuracy, consistency and reliability. 1.4 Both the system specifications and functional specifications should be validated. 1.5 Periodic (or continuous) evaluation should be performed after the initial validation. 1.6 There should be written procedures for performance monitoring, change control, programme and data security, calibration and maintenance, personnel training, emergency recovery and periodic re-evaluation.
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1.7 Aspects of computerized operations that should be considered during validation include: networks manual back-ups input/output checks process documentation monitoring alarms shutdown recovery.
1.7 Aspects of computerized operations that should be considered during validation include: networks manual back-ups input/output checks process documentation monitoring alarms shutdown recovery.
2. System specification
2.1 There should be a control document or system specification. The control document should state the objectives of a proposed computer system, the data to be entered and stored, the flow of data, how it interacts with other systems and procedures, the information to be produced, the limits of any variable and the operating programme and test programme. (Examples of each document produced by the programme should be included.) 2.2 System elements that need to be considered in computer validation include hardware (equipment), software (procedures) and people (users).
2. System specification
2.1 There should be a control document or system specification. The control document should state the objectives of a proposed computer system, the data to be entered and stored, the flow of data, how it interacts with other systems and procedures, the information to be produced, the limits of any variable and the operating programme and test programme. (Examples of each document produced by the programme should be included.) 2.2 System elements that need to be considered in computer validation include hardware (equipment), software (procedures) and people (users).
3. Functional specification
3.1 A functional or performance specification should provide instructions for testing, operating, and maintaining the system, as well as names of the person(s) responsible for its development and operation. 3.2 The following general aspects should be kept in mind when using computer systems: location power supply temperature, and magnetic disturbances.
3. Functional specification
3.1 A functional or performance specification should provide instructions for testing, operating, and maintaining the system, as well as names of the person(s) responsible for its development and operation. 3.2 The following general aspects should be kept in mind when using computer systems: location power supply temperature, and magnetic disturbances.
validation of computer systems: WHO TRS 937 (2006)
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Fluctuations in the electrical supply can influence computer systems and power supply failure can result in loss of memory. 3.3 The following general good manufacturing practice (GMP) requirements are applicable to computer systems. Verification and revalidation. After a suitable period of running a new system it should be independently reviewed and compared with the system specification and functional specification. Change control. Alterations should only be made in accordance with a defined procedure which should include provision for checking, approving and implementing the change. Checks. Data should be checked periodically to confirm that they have been accurately and reliably transferred.
Fluctuations in the electrical supply can influence computer systems and power supply failure can result in loss of memory. 3.3 The following general good manufacturing practice (GMP) requirements are applicable to computer systems. Verification and revalidation. After a suitable period of running a new system it should be independently reviewed and compared with the system specification and functional specification. Change control. Alterations should only be made in accordance with a defined procedure which should include provision for checking, approving and implementing the change. Checks. Data should be checked periodically to confirm that they have been accurately and reliably transferred.
4. Security
4.1 This is of importance in production as well as in quality control. 4.2 Data should be entered or amended only by persons authorized to do so. Suitable security systems should be in place to prevent unauthorized entry or manipulation of data. The activity of entering data, changing or amending incorrect entries and creating back-ups should all be done in accordance with written, approved standard operating procedures (SOPs). 4.3 The security procedures should be in writing. Security should also extend to devices used to store programmes, such as tapes, disks and magnetic strip cards. Access to these devices should be controlled. 4.4 Traceability is of particular importance and it should be able to identify the persons who made entries/changes, released material, or performed other critical steps in manufacture or control. 4.5 The entry of critical data into a computer by an authorized person (e.g. entry of a master processing formula) requires an independent verification and release for use by a second authorized person.
4. Security
4.1 This is of importance in production as well as in quality control. 4.2 Data should be entered or amended only by persons authorized to do so. Suitable security systems should be in place to prevent unauthorized entry or manipulation of data. The activity of entering data, changing or amending incorrect entries and creating back-ups should all be done in accordance with written, approved standard operating procedures (SOPs). 4.3 The security procedures should be in writing. Security should also extend to devices used to store programmes, such as tapes, disks and magnetic strip cards. Access to these devices should be controlled. 4.4 Traceability is of particular importance and it should be able to identify the persons who made entries/changes, released material, or performed other critical steps in manufacture or control. 4.5 The entry of critical data into a computer by an authorized person (e.g. entry of a master processing formula) requires an independent verification and release for use by a second authorized person.
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4.6 SOPs should be validated for certain systems or processes, e.g. the procedures to be followed if the system fails or breaks down should be defined and tested. Alternative arrangements should be made by the validation team, and a disaster recovery procedure should be available for the systems that need to be operated in the event of a breakdown.
4.6 SOPs should be validated for certain systems or processes, e.g. the procedures to be followed if the system fails or breaks down should be defined and tested. Alternative arrangements should be made by the validation team, and a disaster recovery procedure should be available for the systems that need to be operated in the event of a breakdown.
5. Back-ups
5.1 Regular back-ups of all files and data should be made and stored in a secure location to prevent intentional or accidental damage.
5. Back-ups
5.1 Regular back-ups of all files and data should be made and stored in a secure location to prevent intentional or accidental damage.
6. Validation
6.1 Planning, which should include the validation policy, project plan and SOPs, is one of the steps in the validation process. 6.2 The computer-related systems and vendors should be defined and the vendor and product should be evaluated. The system should be designed and constructed, taking into consideration the types, testing and quality assurance of the software. 6.3 After installation of the system it should be qualified. The extent of the qualification should depend on the complexity of the system. The system should be evaluated and performance qualification, change control, maintenance and calibration, security, contingency planning, SOPs, training, performance monitoring and periodic re-evaluation should be addressed.
6. Validation
6.1 Planning, which should include the validation policy, project plan and SOPs, is one of the steps in the validation process. 6.2 The computer-related systems and vendors should be defined and the vendor and product should be evaluated. The system should be designed and constructed, taking into consideration the types, testing and quality assurance of the software. 6.3 After installation of the system it should be qualified. The extent of the qualification should depend on the complexity of the system. The system should be evaluated and performance qualification, change control, maintenance and calibration, security, contingency planning, SOPs, training, performance monitoring and periodic re-evaluation should be addressed.
7. Validation of hardware and software

Table 1 indicates aspects of computer systems that should be subjected to validation. 7.1 Hardware 7.1.1 As part of the validation process appropriate tests and challenges to the hardware should be performed.
7. Validation of hardware and software

Table 1 indicates aspects of computer systems that should be subjected to validation. 7.1 Hardware 7.1.1 As part of the validation process appropriate tests and challenges to the hardware should be performed.
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Table 1 Summary of validation requirements for computer systems

Hardware 1. Types 1.1 Input device 1.2 Output device 1.3 Signal converter 1.4 Central processing unit (CPU) 1.5 Distribution system 1.6 Peripheral devices 2. Key aspects 2.1 Location environment distance input devices 2.2 Signal conversion 2.3 I/O operation 2.4 Command overrides 2.5 Maintenance Software 1. Level 1.1 Machine language 1.2 Assembly language 1.3 High-level language 1.4 Application language
Table 1 Summary of validation requirements for computer systems

Hardware 1. Types 1.1 Input device 1.2 Output device 1.3 Signal converter 1.4 Central processing unit (CPU) 1.5 Distribution system 1.6 Peripheral devices 2. Key aspects 2.1 Location environment distance input devices 2.2 Signal conversion 2.3 I/O operation 2.4 Command overrides 2.5 Maintenance Software 1. Level 1.1 Machine language 1.2 Assembly language 1.3 High-level language 1.4 Application language
3. Validation 3.1 Function 3.2 Limits 3.3 Worst case 3.4 Reproducibility/consistency 3.5 Documentation 3.6 Revalidation
2. Software identifi cation 2.1 Language 2.2 Name 2.3 Function 2.4 Input 2.5 Output 2.6 Fixed set point 2.7 Variable set point 2.8 Edits 2.9 Input manipulation 2.10 Programme overrides 3. Key aspects 3.1 Software development 3.2 Software security
3. Validation 3.1 Function 3.2 Limits 3.3 Worst case 3.4 Reproducibility/consistency 3.5 Documentation 3.6 Revalidation
2. Software identifi cation 2.1 Language 2.2 Name 2.3 Function 2.4 Input 2.5 Output 2.6 Fixed set point 2.7 Variable set point 2.8 Edits 2.9 Input manipulation 2.10 Programme overrides 3. Key aspects 3.1 Software development 3.2 Software security
4. Validation 4.1 Function 4.2 Worst case 4.3 Repeats 4.4 Documentation 4.5 Revalidation I/O, Input/output. I/O, Input/output.
4. Validation 4.1 Function 4.2 Worst case 4.3 Repeats 4.4 Documentation 4.5 Revalidation
7.1.2 Static, dust, power-feed voltage fluctuations and electromagnetic interference could influence the system. The extent of validation should depend on the complexity of the system. Hardware is considered to be equipment, and the focus should be on location, maintenance and calibration of hardware, as well as on validation/qualification. 7.1.3 The validation/qualification of the hardware should prove:
7.1.2 Static, dust, power-feed voltage fluctuations and electromagnetic interference could influence the system. The extent of validation should depend on the complexity of the system. Hardware is considered to be equipment, and the focus should be on location, maintenance and calibration of hardware, as well as on validation/qualification. 7.1.3 The validation/qualification of the hardware should prove:
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that the capacity of the hardware matches its assigned function (e.g. foreign language); that it operates within the operational limits (e.g. memory, connector ports, input ports); that it performs acceptably under worst-case conditions (e.g. long hours, temperature extremes); and reproducibility/consistency (e.g. by performing at least three runs under different conditions). 7.1.4 The validation should be done in accordance with written qualification protocols and the results should be recorded in the qualification reports. 7.1.5 Revalidation should be performed when significant changes are made. 7.1.6 Much of the hardware validation may be performed by the computer vendor. However, the ultimate responsibility for the suitability of equipment used remains with the company. 7.1.7 Hardware validation data and protocols should be kept by the company. When validation information is produced by an outside firm, e.g. computer vendor, the records maintained by the company need not include all of the voluminous test data; however, such records should be sufficiently complete (including general results and protocols) to allow the company to assess the adequacy of the validation. A mere certification of suitability from the vendor, for example, will be inadequate. 7.2 Software 7.2.1 Software is the term used to describe the complete set of programmes used by a computer, and which should be listed in a menu. 7.2.2 Records are considered as software; focus is placed on accuracy, security, access, retention of records, review, double checks, documentation and accuracy of reproduction. Identification 7.2.3 The company should identify the following key computer programmes:
that the capacity of the hardware matches its assigned function (e.g. foreign language); that it operates within the operational limits (e.g. memory, connector ports, input ports); that it performs acceptably under worst-case conditions (e.g. long hours, temperature extremes); and reproducibility/consistency (e.g. by performing at least three runs under different conditions). 7.1.4 The validation should be done in accordance with written qualification protocols and the results should be recorded in the qualification reports. 7.1.5 Revalidation should be performed when significant changes are made. 7.1.6 Much of the hardware validation may be performed by the computer vendor. However, the ultimate responsibility for the suitability of equipment used remains with the company. 7.1.7 Hardware validation data and protocols should be kept by the company. When validation information is produced by an outside firm, e.g. computer vendor, the records maintained by the company need not include all of the voluminous test data; however, such records should be sufficiently complete (including general results and protocols) to allow the company to assess the adequacy of the validation. A mere certification of suitability from the vendor, for example, will be inadequate. 7.2 Software 7.2.1 Software is the term used to describe the complete set of programmes used by a computer, and which should be listed in a menu. 7.2.2 Records are considered as software; focus is placed on accuracy, security, access, retention of records, review, double checks, documentation and accuracy of reproduction. Identification 7.2.3 The company should identify the following key computer programmes:
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language, name, function (purpose of the programme), input (determine inputs), output (determine outputs), fixed set point (process variable that cannot be changed by the operator), variable set point (entered by the operator), edits (reject input/output that does not conform to limits and minimize errors, e.g. four- or five-character number entry), input manipulation (and equations) and programme overrides (e.g. to stop a mixer before time). 7.2.4 The personnel who have the ability and/or are authorized to write, alter or have access to programmes should be identified. 7.2.5 Software validation should provide assurance that computer programmes (especially those that control manufacturing and processing) will consistently perform as they are supposed to, within pre-established limits. When planning the validation, the following points should be considered. Function: does the programme match the assigned operational function(e.g. generate batch documentation, different batches of material used in a batch listed)? Worst case: perform validation under different conditions (e.g. speed, data volume, frequency). Repeats: sufficient number of times (replicate data entries). Documentation: protocols and reports. Revalidation: needed when significant changes are made.
language, name, function (purpose of the programme), input (determine inputs), output (determine outputs), fixed set point (process variable that cannot be changed by the operator), variable set point (entered by the operator), edits (reject input/output that does not conform to limits and minimize errors, e.g. four- or five-character number entry), input manipulation (and equations) and programme overrides (e.g. to stop a mixer before time). 7.2.4 The personnel who have the ability and/or are authorized to write, alter or have access to programmes should be identified. 7.2.5 Software validation should provide assurance that computer programmes (especially those that control manufacturing and processing) will consistently perform as they are supposed to, within pre-established limits. When planning the validation, the following points should be considered. Function: does the programme match the assigned operational function(e.g. generate batch documentation, different batches of material used in a batch listed)? Worst case: perform validation under different conditions (e.g. speed, data volume, frequency). Repeats: sufficient number of times (replicate data entries). Documentation: protocols and reports. Revalidation: needed when significant changes are made.
process validation of synthetic chemical processes for the production of active pharmaceutical ingredients (APIs)
BY ROGER W. KOOPS, PH.D.
process validation of synthetic chemical processes for the production of active pharmaceutical ingredients (APIs)
BY ROGER W. KOOPS, PH.D.
Abstract A key component to successful process validation of synthetic chemical processes for the manufacture of Active Pharmaceutical Ingredients (APIs) is developing a comprehensive validation program. This paper describes an approach to establishing such a program starting with a corporate policy through the various components of the validation exercise. A lifecycle approach to the validation concept is critical, and begins with the development program and does not end until the product is retired. Circumstances that are unique to synthetic chemical pathways are presented. The paper describes specific details and examples for establishing validation master plans, validation protocols, and writing the final validation report. Additionally, other topics such as deviations and failures, homogeneity, shipping, and process trending are discussed. The paper describes activities that relate directly to manufacturing and quality assurance components of such a program. However, the paper does not attempt to deal with a corresponding program in analytical methods since this is a subject of its own. Additionally, the paper does not deal with any detailed aspects of equipment cleaning validation for the same reason as described above for analytical methods. Equipment cleaning methods should be developed in situ with chemical process development, and cleaning validation should occur either prior to or concurrent with process validation. Definitions Active Pharmaceutical Ingredient (API): A substance intended for use as an active ingredient in a finished dosage form of a drug. Such a substance is intended to furnish pharmacological activity in either the diagnosis, cure mitigation, treatment, or prevention of a disease.1 Intermediate: A compound that is produced en route to an API. The compound has all or at least a portion of its structure that is incorporated into the structure of the final API. Development Report: A report, or series of reports, that describe in detail the development history of an API or intermediate. The report should include a summary of all laboratory experiments used to support the current process, and include a comprehensive batch history profile with a summary of all process changes.
Abstract A key component to successful process validation of synthetic chemical processes for the manufacture of Active Pharmaceutical Ingredients (APIs) is developing a comprehensive validation program. This paper describes an approach to establishing such a program starting with a corporate policy through the various components of the validation exercise. A lifecycle approach to the validation concept is critical, and begins with the development program and does not end until the product is retired. Circumstances that are unique to synthetic chemical pathways are presented. The paper describes specific details and examples for establishing validation master plans, validation protocols, and writing the final validation report. Additionally, other topics such as deviations and failures, homogeneity, shipping, and process trending are discussed. The paper describes activities that relate directly to manufacturing and quality assurance components of such a program. However, the paper does not attempt to deal with a corresponding program in analytical methods since this is a subject of its own. Additionally, the paper does not deal with any detailed aspects of equipment cleaning validation for the same reason as described above for analytical methods. Equipment cleaning methods should be developed in situ with chemical process development, and cleaning validation should occur either prior to or concurrent with process validation. Definitions Active Pharmaceutical Ingredient (API): A substance intended for use as an active ingredient in a finished dosage form of a drug. Such a substance is intended to furnish pharmacological activity in either the diagnosis, cure mitigation, treatment, or prevention of a disease.1 Intermediate: A compound that is produced en route to an API. The compound has all or at least a portion of its structure that is incorporated into the structure of the final API. Development Report: A report, or series of reports, that describe in detail the development history of an API or intermediate. The report should include a summary of all laboratory experiments used to support the current process, and include a comprehensive batch history profile with a summary of all process changes.
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Policy: A written ideology or philosophy concerning a certain subject, and the basis for which procedures are established. Procedure: A written set of instructions on how to perform a specific task, e.g., Standard Operating Procedures (SOPs). Quality Assurance (QA): An independent unit that reviews documentation and activities for compliance to Current Good Manufacturing Practice (cGMP). Quality Control (QC): An independent unit that performs laboratory testing on a compound using prescribed methods. Included in this definition are groups that are responsible for developing and validating test methods, performing routine release testing, and maintaining stability programs. Critical Parameter: A processing parameter that has a critical effect on the downstream processing or quality profile of the intended product. If the parameter is not tightly controlled, the downstream process and/or quality profile of the product could be negatively impacted. Introduction Process validation is arguably the most important event that occurs during a products process lifetime. Too many companies view process validation as a tedious event that takes time, money, effort, and is only needed to satisfy the FDA. Although born as a result of regulatory considerations, process validation should be viewed as a scientific event. That is, process validation is a demonstration and verification of the science that went into developing a process, and should be viewed as a significant accomplishment in the science and art of process development. What is process development? It is the documented demonstration that all of the effort that went into developing a process has led to a process that will consistently produce a given product. This means that process validation does not begin with the first batch to be validated, or the protocol, or the master plan. Rather, it begins in the laboratory at the earliest stages of process development, and is a continuous event that follows a process throughout its lifetime. When viewed in this fashion, and developed in a proactive, comprehensive manner, one has established a program that
Policy: A written ideology or philosophy concerning a certain subject, and the basis for which procedures are established. Procedure: A written set of instructions on how to perform a specific task, e.g., Standard Operating Procedures (SOPs). Quality Assurance (QA): An independent unit that reviews documentation and activities for compliance to Current Good Manufacturing Practice (cGMP). Quality Control (QC): An independent unit that performs laboratory testing on a compound using prescribed methods. Included in this definition are groups that are responsible for developing and validating test methods, performing routine release testing, and maintaining stability programs. Critical Parameter: A processing parameter that has a critical effect on the downstream processing or quality profile of the intended product. If the parameter is not tightly controlled, the downstream process and/or quality profile of the product could be negatively impacted. Introduction Process validation is arguably the most important event that occurs during a products process lifetime. Too many companies view process validation as a tedious event that takes time, money, effort, and is only needed to satisfy the FDA. Although born as a result of regulatory considerations, process validation should be viewed as a scientific event. That is, process validation is a demonstration and verification of the science that went into developing a process, and should be viewed as a significant accomplishment in the science and art of process development. What is process development? It is the documented demonstration that all of the effort that went into developing a process has led to a process that will consistently produce a given product. This means that process validation does not begin with the first batch to be validated, or the protocol, or the master plan. Rather, it begins in the laboratory at the earliest stages of process development, and is a continuous event that follows a process throughout its lifetime. When viewed in this fashion, and developed in a proactive, comprehensive manner, one has established a program that
process validation of synthetic chemical processes for APIs
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supports the quality and success of the product. This paper will describe an approach on how to develop this type of program. Does this mean that, if performed correctly, such a program will guarantee problem-free processing for the life of the product? Certainly not. Humans may like to believe that they can master nature, but nature shows us all too often that we are mistaken. Simple or complex chemical processes all have the ability to go their own path, albeit, many times with the helping hand of humans. This paper will also describe approaches to dealing with problems that may be encountered during process validation. The Validation Program A successful validation program is comprised of many components, many of which need to be implemented well in advance of the actual validation exercise itself. Using a sports analogy, the success of the performance (i.e., validation execution) depends upon the effort and efficiency that went into preparing for the event (i.e., preparation and training). Therefore, a successful validation program begins at the very early stages of process development itself, and does not culminate with the validation event, but rather when the process eventually retires. It is a process lifetime event. A validation program is comprised of many components including the written aspects (policies, procedures, protocols, etc.), the personnel (departments, technical experts, consultants, etc.), and activities (qualification, training, etc.). All of these components should be described and coordinated into a functional, comprehensive program. Figure 1 depicts a typical hierarchical approach to such a program through a program pyramid. The view can be expressed that the top levels of the hierarchy govern the program, but the foundation to success is in the science that is put into process development, equipment and facility qualifications, analytical method development, etc. and ultimately in personnel expertise and training. Corporate Validation Policies A comprehensive corporate validation program is assembled beginning at the very top with a well-defined validation policy. The policy should outline the organizations general validation
supports the quality and success of the product. This paper will describe an approach on how to develop this type of program. Does this mean that, if performed correctly, such a program will guarantee problem-free processing for the life of the product? Certainly not. Humans may like to believe that they can master nature, but nature shows us all too often that we are mistaken. Simple or complex chemical processes all have the ability to go their own path, albeit, many times with the helping hand of humans. This paper will also describe approaches to dealing with problems that may be encountered during process validation. The Validation Program A successful validation program is comprised of many components, many of which need to be implemented well in advance of the actual validation exercise itself. Using a sports analogy, the success of the performance (i.e., validation execution) depends upon the effort and efficiency that went into preparing for the event (i.e., preparation and training). Therefore, a successful validation program begins at the very early stages of process development itself, and does not culminate with the validation event, but rather when the process eventually retires. It is a process lifetime event. A validation program is comprised of many components including the written aspects (policies, procedures, protocols, etc.), the personnel (departments, technical experts, consultants, etc.), and activities (qualification, training, etc.). All of these components should be described and coordinated into a functional, comprehensive program. Figure 1 depicts a typical hierarchical approach to such a program through a program pyramid. The view can be expressed that the top levels of the hierarchy govern the program, but the foundation to success is in the science that is put into process development, equipment and facility qualifications, analytical method development, etc. and ultimately in personnel expertise and training. Corporate Validation Policies A comprehensive corporate validation program is assembled beginning at the very top with a well-defined validation policy. The policy should outline the organizations general validation
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Corporate Validation Policy General Validation Procedures Validation Master Plans Validation Protocols/ Reports/ Operational Standard Operating Procedures (SOPs)/ Master Batch Records
Corporate Validation Policy General Validation Procedures Validation Master Plans Validation Protocols/ Reports/ Operational Standard Operating Procedures (SOPs)/ Master Batch Records
Development Reports, Facility and Equipment Qualifications, Analytical Methods Validation, etc Training, Process Development, Documentation, Quality Assurance (QA), etc
Development Reports, Facility and Equipment Qualifications, Analytical Methods Validation, etc Training, Process Development, Documentation, Quality Assurance (QA), etc
Figure 1: The Validation Program Pyramid
Figure 1: The Validation Program Pyramid
expectations over the lifetime of the process. The policy should define the scientific expectations and documentation that begins from the first day of process development. Some examples of these expectations are described in the Table below. An important aspect of such a global policy is that it exposes employees, who may have very special tasks, to the broader validation program. The employees then become better trained and cognizant of their role in the validation program. For example, chemists who may be normally focused on process development will do much better in organizing their data, writing reports, etc. if they understand what purpose their data and conclusions will serve in the end when process validation protocols are assembled and executed. General training in the concepts of process validation should be given to all individuals who are part of the development and manufacturing program. Another important feature of the policy should be the participation of development personnel in the actual validation exercise. Development personnel are generally the most knowledgeable concerning the process, and can ensure that the technology has been appropriately transferred into the commercial manufacturing environment. In addition, the experience of
expectations over the lifetime of the process. The policy should define the scientific expectations and documentation that begins from the first day of process development. Some examples of these expectations are described in the Table below. An important aspect of such a global policy is that it exposes employees, who may have very special tasks, to the broader validation program. The employees then become better trained and cognizant of their role in the validation program. For example, chemists who may be normally focused on process development will do much better in organizing their data, writing reports, etc. if they understand what purpose their data and conclusions will serve in the end when process validation protocols are assembled and executed. General training in the concepts of process validation should be given to all individuals who are part of the development and manufacturing program. Another important feature of the policy should be the participation of development personnel in the actual validation exercise. Development personnel are generally the most knowledgeable concerning the process, and can ensure that the technology has been appropriately transferred into the commercial manufacturing environment. In addition, the experience of
Process/Product Era Early Process Development Development Chemists Lab Scale ( 1 - 100 g) Pre-clinical/Tox Pilot scale Development (large glass or small reactor scale of 1 - 10kg) First clinical batches Development Chemists Engineers Quality Assurance (QA)/ Quality Control (QC)
Responsible Group
Some Expectations
Initial Scale-Up (10 - 100 kg scale) Phase I/II Clinical
Development Chemists Engineers Plant Personnel QA/QC Commercial Scale-Up Development Chemists (100 - 1000 kg scale) Engineers Phase III Clinical Manufacturing Validation QA/QC Validation at Scale Chemists Engineers Manufacturing Validation QA/QC Commercial manufacturing Chemists and Process monitoring Engineers Manufacturing Validation QA/QC Process improvement evaluation Process monitoring and trending Validation Report Updated Development Report Continued Process Validation
Documented experimental results Standardised grades of materials Preliminary identification of critical process chemistries Periodic Development Reports Documented experimental results Master Batch Records/Change Control/etc Process Flow Diagrams Preliminary identification of critical process engineering and chemistries. Periodic Development Reports Scale-Up Summary Report Identify potential contract manufacturers (if applicable) & Technology Transfer Documented experimental results Impurity characterisation and control Initial identification of critical parameters for Final Process/ ScaleUp Summary Report(s) Consistency batches Impurity profile characterised Critical parameters identified and controlled Final Development Report Validation Master Plan Validation Protocol(s) Validation Execution Validation Report
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participation is invaluable to the chemist and will help them during the development phase. Finally, the policy should describe the responsibility of maintaining the product/process during the product lifetime (lifecycle approach). Each organization may have a different infrastructure that is used to accomplish this. The policy should describe the responsibility for monitoring and trending, process improvements, change control, etc. Corporate Procedures Related to Process Evaluation In todays world, it can be said with a high degree of certainty that most API processes are multi-step synthetic pathways that generally may involve at least one complex chemical transformation. A reasonably accepted validation axiom is that the final process step that produces an API (and any purification thereof) needs to be validated. However, a debate can be started as to when to perform process validation when intermediates are involved. Therefore, an approach to an evaluation procedure for intermediates will be suggested. There is no simple answer to the question of when to apply process validation for intermediate steps in a multi-step process. Each process must be independently evaluated. However, this does not mean that a coherent policy or procedure cannot be established that describes how that evaluation process should take place. In fact, putting such a procedure in place only benefits those that are trying to conduct the evaluation. How should the question of when to validate intermediate process steps be approached in a procedure? Even though each process needs to be evaluated independently, there are some common factors and criteria that can be applied when conducting an evaluation. Multi-step synthetic processes can be classified at the simplest level as either being linear or convergent, or a combination of both approaches. In a linear synthesis, a starting material is either built upon, rearranged, or further elaborated through chemical processes to eventually achieve the desired molecular structure. A convergent synthesis, on the other hand, builds pieces of the molecular structure independently, and then assembles the pieces to achieve the desired molecular structure. Many processes incorporate both elements. The first step of the evaluation is to determine what the starting material is, what are isolated and non-isolated intermediates, what is (or are) the ultimate
participation is invaluable to the chemist and will help them during the development phase. Finally, the policy should describe the responsibility of maintaining the product/process during the product lifetime (lifecycle approach). Each organization may have a different infrastructure that is used to accomplish this. The policy should describe the responsibility for monitoring and trending, process improvements, change control, etc. Corporate Procedures Related to Process Evaluation In todays world, it can be said with a high degree of certainty that most API processes are multi-step synthetic pathways that generally may involve at least one complex chemical transformation. A reasonably accepted validation axiom is that the final process step that produces an API (and any purification thereof) needs to be validated. However, a debate can be started as to when to perform process validation when intermediates are involved. Therefore, an approach to an evaluation procedure for intermediates will be suggested. There is no simple answer to the question of when to apply process validation for intermediate steps in a multi-step process. Each process must be independently evaluated. However, this does not mean that a coherent policy or procedure cannot be established that describes how that evaluation process should take place. In fact, putting such a procedure in place only benefits those that are trying to conduct the evaluation. How should the question of when to validate intermediate process steps be approached in a procedure? Even though each process needs to be evaluated independently, there are some common factors and criteria that can be applied when conducting an evaluation. Multi-step synthetic processes can be classified at the simplest level as either being linear or convergent, or a combination of both approaches. In a linear synthesis, a starting material is either built upon, rearranged, or further elaborated through chemical processes to eventually achieve the desired molecular structure. A convergent synthesis, on the other hand, builds pieces of the molecular structure independently, and then assembles the pieces to achieve the desired molecular structure. Many processes incorporate both elements. The first step of the evaluation is to determine what the starting material is, what are isolated and non-isolated intermediates, what is (or are) the ultimate
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intermediate (or final intermediate), and what synthetic scheme will be required to produce a final API. In fact, determining what constitutes a starting material is a debatable issue. This author has generally taken the following approach in evaluating whether a material is a starting material. First, the material should be a readily available item that has a standard grade (or grades) associated with it, and has been well characterized. It may be produced under contract by a vendor, but in that case, it should be produced by a known and established process, and the end product should be, again, capable of achieving a standard grade. Second, the vendor should be qualified (under a vendor qualification program) so to ensure that a material meets consistent quality standards. A rudimentary quality agreement should be established to outline change notification and quality requirements. If a material is manufactured by a contract party and the process was supplied by the innovator, the material is simply a third-party manufactured intermediate. The contractor now becomes an extension of the innovator, and the transferred process must be included in the full validation evaluation. Once a starting material has been established, each intermediate needs to be evaluated in two ways: 1. How it contributes to the final API, particularly in regard to the impurity profile, and 2. The specific process for that intermediate. Although isolated intermediates should be fully evaluated, non-isolated intermediates should also be evaluated, since there may be processes where stricter controls may be required. For example, an intermediate may not be isolated due to structural instability when not in solution. In this case, concentration and/or potency of the intermediate may be a critical attribute that needs to be controlled. During development stages, an emerging impurity profile of the API should emerge. This profile should be split into two separate profiles to include the final purified API and the initial crude API. From the crude API, an impurity fingerprint can be established concerning the process. Questions can be asked such as what intermediate process steps may contribute to the crude profile? What are the boundaries for purification to the final API? What
intermediate (or final intermediate), and what synthetic scheme will be required to produce a final API. In fact, determining what constitutes a starting material is a debatable issue. This author has generally taken the following approach in evaluating whether a material is a starting material. First, the material should be a readily available item that has a standard grade (or grades) associated with it, and has been well characterized. It may be produced under contract by a vendor, but in that case, it should be produced by a known and established process, and the end product should be, again, capable of achieving a standard grade. Second, the vendor should be qualified (under a vendor qualification program) so to ensure that a material meets consistent quality standards. A rudimentary quality agreement should be established to outline change notification and quality requirements. If a material is manufactured by a contract party and the process was supplied by the innovator, the material is simply a third-party manufactured intermediate. The contractor now becomes an extension of the innovator, and the transferred process must be included in the full validation evaluation. Once a starting material has been established, each intermediate needs to be evaluated in two ways: 1. How it contributes to the final API, particularly in regard to the impurity profile, and 2. The specific process for that intermediate. Although isolated intermediates should be fully evaluated, non-isolated intermediates should also be evaluated, since there may be processes where stricter controls may be required. For example, an intermediate may not be isolated due to structural instability when not in solution. In this case, concentration and/or potency of the intermediate may be a critical attribute that needs to be controlled. During development stages, an emerging impurity profile of the API should emerge. This profile should be split into two separate profiles to include the final purified API and the initial crude API. From the crude API, an impurity fingerprint can be established concerning the process. Questions can be asked such as what intermediate process steps may contribute to the crude profile? What are the boundaries for purification to the final API? What
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should be the desired quality attribute of intermediate A in order to achieve the desired end product? This is why it is important to characterize process impurities as early in the development process as possible. From this type of evaluation, each intermediate process step can be evaluated as to its relative importance in the end product. If an intermediate needs to be controlled since it could contribute to an adverse quality profile of the API, process validation should be applied. Another reason to employ process validation is if an intermediate step is particularly difficult to control or is technically difficult. Process validation in these cases would help ensure that the manufacture of the intermediate is consistent and is performed with an appropriate level of attention. An important factor in approaching any process validation evaluation is to avoid considering it only a regulatory requirement to which only a minimal effort should be applied to satisfy the regulatory requirement. Rather, process validation should be viewed as a scientific approach to ensure critical processes have the integrity required to make a quality product. Additionally, process validation makes good business sense in that well-developed and validated processes ultimately save time and money and increase quality, which is accomplished by reducing, although rarely eliminating, costly batch failures, investigations, inappropriate or inefficient processing, constant reprocessing, etc. Finally, there has always been some discussion whether the validation exercise should be designed so as to stress the accepted parameters by operating at the maximum or minimum accepted level, or to aim for the target of each parameter. Some companies have attempted to matrix the parameter limits in an effort to test the extreme limits of process parameters. Which approach is used may depend on the individual process. However, as a general rule, this author has held the view that the development phase is the place to clearly establish the boundaries of the operating ranges, and how each extreme between parameters affects the final outcome of the process. Process validation, by definition, is used to demonstrate consistency and, thus, should target the desired operating parameter. From a manufacturing standpoint, it is advantageous to operate based upon the targeted parameter values for batch consistency.
should be the desired quality attribute of intermediate A in order to achieve the desired end product? This is why it is important to characterize process impurities as early in the development process as possible. From this type of evaluation, each intermediate process step can be evaluated as to its relative importance in the end product. If an intermediate needs to be controlled since it could contribute to an adverse quality profile of the API, process validation should be applied. Another reason to employ process validation is if an intermediate step is particularly difficult to control or is technically difficult. Process validation in these cases would help ensure that the manufacture of the intermediate is consistent and is performed with an appropriate level of attention. An important factor in approaching any process validation evaluation is to avoid considering it only a regulatory requirement to which only a minimal effort should be applied to satisfy the regulatory requirement. Rather, process validation should be viewed as a scientific approach to ensure critical processes have the integrity required to make a quality product. Additionally, process validation makes good business sense in that well-developed and validated processes ultimately save time and money and increase quality, which is accomplished by reducing, although rarely eliminating, costly batch failures, investigations, inappropriate or inefficient processing, constant reprocessing, etc. Finally, there has always been some discussion whether the validation exercise should be designed so as to stress the accepted parameters by operating at the maximum or minimum accepted level, or to aim for the target of each parameter. Some companies have attempted to matrix the parameter limits in an effort to test the extreme limits of process parameters. Which approach is used may depend on the individual process. However, as a general rule, this author has held the view that the development phase is the place to clearly establish the boundaries of the operating ranges, and how each extreme between parameters affects the final outcome of the process. Process validation, by definition, is used to demonstrate consistency and, thus, should target the desired operating parameter. From a manufacturing standpoint, it is advantageous to operate based upon the targeted parameter values for batch consistency.
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The Process Development Report The Process Development Report (PDR) is the starting point for any process validation activity. The PDR should compile reports and data on the process starting from the first laboratory preparation and continuing through pilot scale on to commercial production. Ideally, interim reports should be prepared during the development process, that will make the compilation of the PDR easier to manage. The PDR should be able to tell the story of how a process evolved from the first laboratory scale synthesis to the applicable scaled up version. The PDR should also provide data and references that supports the current process, identify the critical process parameters and how to control them, and describe the expected impurity profile. The PDR should describe the characterization of the major impurities that compose the impurity profile, and the development efforts to minimize or eliminate impurities. Although the PDR is a technical document, the data contained therein supports the validation activity. The PDR should be used as a basis for developing the validation parameters for the product in question. The PDR should summarize the data in a level of detail that is sufficient to describe the development cycle for the process. Any reader should be able to get a thorough understanding of the process history by reading the report. Development reports can be (and frequently are) requested during a regulatory inspection. Although QA may not be required to approve a development report since it is a technical report (although it is highly recommended), QA should audit the development report for complete traceability to the raw data. This is particularly recommended for data that either supports a process step as critical or not. Ideally, this is done prior to approving process validation protocols. The PDR is a living document and should be continuously updated through the product lifecycle. Many firms create a PDR and then ignore it once process validation starts or is completed. Since improvements to a process can be made throughout the lifetime of the process, these improvements may require additional validation work and regulatory filings. These changes and improvements should initiate an update of the PDR. At a minimum, such documentation practices reflect good scientific discipline.
The Process Development Report The Process Development Report (PDR) is the starting point for any process validation activity. The PDR should compile reports and data on the process starting from the first laboratory preparation and continuing through pilot scale on to commercial production. Ideally, interim reports should be prepared during the development process, that will make the compilation of the PDR easier to manage. The PDR should be able to tell the story of how a process evolved from the first laboratory scale synthesis to the applicable scaled up version. The PDR should also provide data and references that supports the current process, identify the critical process parameters and how to control them, and describe the expected impurity profile. The PDR should describe the characterization of the major impurities that compose the impurity profile, and the development efforts to minimize or eliminate impurities. Although the PDR is a technical document, the data contained therein supports the validation activity. The PDR should be used as a basis for developing the validation parameters for the product in question. The PDR should summarize the data in a level of detail that is sufficient to describe the development cycle for the process. Any reader should be able to get a thorough understanding of the process history by reading the report. Development reports can be (and frequently are) requested during a regulatory inspection. Although QA may not be required to approve a development report since it is a technical report (although it is highly recommended), QA should audit the development report for complete traceability to the raw data. This is particularly recommended for data that either supports a process step as critical or not. Ideally, this is done prior to approving process validation protocols. The PDR is a living document and should be continuously updated through the product lifecycle. Many firms create a PDR and then ignore it once process validation starts or is completed. Since improvements to a process can be made throughout the lifetime of the process, these improvements may require additional validation work and regulatory filings. These changes and improvements should initiate an update of the PDR. At a minimum, such documentation practices reflect good scientific discipline.
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Section Scope Responsibilities Process Description
Content Define the number of batches, steps of the process that will require validation, where and when the validation will be performed etc
Define the responsibilities for preparation, execution, testing, review, approval etc for the overall validation exercise. If any contract services are used, describe each responsibiltiy
Provide an overall schematic of the synthetic pathway for the entire process; include structures of isolated and non-isolated intermediates, critical reagents, and solvents etc. If there are significant by-products produced, these should be indicated as well. Validation Rationale Provide a brief summary of the rationale for the steps that will be validated, as well as the steps that were not identified as requiring validation (provide references to the supporting data) Special requirements Describe any special material, facility or equipment requirements that may be needed to complete the validation. Leave the details for the respective validation protocols. Describe any special procedures Protocols Describe all of the validation protocols that will be written for the validation exercise Master Batch Records List all of the master batch records that will be used throughout the process Data List how data is to becollected, where the raw data will be stored, etc Deviations or Investigations Describe how any failure will be investigated and how it will impact the validation effort Final conclusion Describe the process for final evaluation of the validation exercise. A Final Report should be drafted that correlates all of the validation components (necessary in multi-step processes, where more than one step is to be validated).
Content
Define the scope of the protocol. This should relate back to the overall plan that was described in the Validation Master Plan
Define the responsibilities for preparation, execution, testing, review, approval etc for the overall validation exercise. Define this by department and job responsibiltiy. Management level personnel in the technical and quality areas need to give the final approval.
Section Scope Responsibilities Process Description

conditions, transfers, by-products, waste removal, purification, etc. It is generally useful to identify critical process steps on the PFD. Provide a detailed process flow diagram (PFD) for the process that is to be validated. Show all starting materials, reagents, solvents, process
Materials
Provide a bill of materials for all consumable items used during the process (include filters, filter aids, etc). The bill of materials should list the name of the material, any identification code, the quantity required for the process(in weight and molar ratio), and a reference to the specification. It is also useful to identify where in the process a material is to be used (ie. reference the process steps).
Equipment
Each major piece of equipment should be identified by equipment number (eg. reactors, receivers, tanks, filters, dryers, mills, etc). Equipment Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ) reports and protocols should be referenced. Reference any pertinent equipment operating procedures. Reference the equipment cleaning procedure(s) and also the relevant cleaning validation documentation. Describe any special conditions that may be required with the equipment (eg. cryogenics, pressures, special jacketing materials, etc)
Facilities
List any facility requirements that may be necessary for the process. For example, APIs intended for parenteral use should reference appropriate environmental monitoring procedures and reports. If additional environmental monitoring data is to be collected as part of process validation, this should be described. If automated process control systems are being utilised, the IQ/OQ/PQ documentation should be referenced. Reference all facility IQ/OQ/PQ documentation.
Critical Process Parameters In- process tests Sampling Plan
All critical processing parameters and process limits should be listed. References should be provided to the appropriate data or sections of the Development Report that support the parameter and limits. List the controls that will be used for the critical parameters.
List all of the in-process tests. This list should include the process step where the test will be performed, what the test method will be, who will perform the test, and how the results will be reported. If the in-process test is to be used as a go/no-go decision point, this should be indicated.
A sampling plan should be provided that describes when a sample will be pulled during the execution of the process.
The plan should indicate the sampling location, amount of sample to be taken, how it is to be collected (or reference appropriate procedures), how it is to be labeled, how it is to be transported to the testing facility, etc. The acceptance critieria should be listed. This should include all in-process testing, process parameters monitoring, and final test results. This should describe in detail how deviations would be documented and evaluated as to the impact on validation. Pre-established criteria should be listed, so that if a problem arises, a validation exrcise can be aborted, if necessary
Acceptance criteria Deviations and investigations
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The Process Validation Master Plan The process Validation Master Plan (VMP) is the blueprint to all of the process validation activities. The VMP should describe the entire synthetic route to the API, identify which process steps require process validation, identify starting and raw materials and the sources of these materials. If process validation will be performed at any contact manufacturer that is used to provide an intermediate or API, the VMP should describe the relative responsibilities for each organization. Table 2 lists some of the components that should be included in a VMP. The VMP should not be too detailed as the validation protocol itself is really the document that should provide all of the details. The VMP is also a living document, and should be amended or updated as needed if the plan changes, with the appropriately documented change justification. However, good thought and planning should be put into the original VMP since too many changes to a VMP may give an impression of a poorly planned validation or weak validation program. The VMP should be readily available to all personnel who will be critical players in the validation exercise, including contract sites, as applicable. The Process Validation Protocol The process validation protocol will describe, in detail, the how to for the validation exercise. Any procedure should be either described in detail in the protocol or a reference should be provided to an already established procedure for handling the task. The protocol should be used in training all individuals who will be involved in process validation. There are many components to the protocol and the more critical components are described in Table 3. All components of the validation should be described in the protocol. These would include equipment and facility qualification documents, materials and specifications, sampling procedures, analytical testing (both in-process and final), analytical methods, etc. The protocol should be drafted to be as concise and instructive as possible. Where applicable, data should be entered directly into the protocol. If an exercise is particularly complex, a series of protocols may be preferable. Protocols should have places for reviewers initials or signatures.
The Process Validation Master Plan The process Validation Master Plan (VMP) is the blueprint to all of the process validation activities. The VMP should describe the entire synthetic route to the API, identify which process steps require process validation, identify starting and raw materials and the sources of these materials. If process validation will be performed at any contact manufacturer that is used to provide an intermediate or API, the VMP should describe the relative responsibilities for each organization. Table 2 lists some of the components that should be included in a VMP. The VMP should not be too detailed as the validation protocol itself is really the document that should provide all of the details. The VMP is also a living document, and should be amended or updated as needed if the plan changes, with the appropriately documented change justification. However, good thought and planning should be put into the original VMP since too many changes to a VMP may give an impression of a poorly planned validation or weak validation program. The VMP should be readily available to all personnel who will be critical players in the validation exercise, including contract sites, as applicable. The Process Validation Protocol The process validation protocol will describe, in detail, the how to for the validation exercise. Any procedure should be either described in detail in the protocol or a reference should be provided to an already established procedure for handling the task. The protocol should be used in training all individuals who will be involved in process validation. There are many components to the protocol and the more critical components are described in Table 3. All components of the validation should be described in the protocol. These would include equipment and facility qualification documents, materials and specifications, sampling procedures, analytical testing (both in-process and final), analytical methods, etc. The protocol should be drafted to be as concise and instructive as possible. Where applicable, data should be entered directly into the protocol. If an exercise is particularly complex, a series of protocols may be preferable. Protocols should have places for reviewers initials or signatures.
Process Reaction: charge
Table 4: Examples of Process Parameters that may be Critical Examples of potential critical parameters Order of type of addition for materials, reagents, etc Stoichiometry of materials, reagents, etc Concentration of reaction components Preparation of reaction vessels prior to charge (eg. inerting operations, drying, pressure testing etc. Reaction Reaction temperatures, reaction time, pressures, etc Rate of heating or cooling (or in combination with above parameters) Agitation rates Rates of reflux, distillation, or an azeotropic process Reaction medium parameters such as pH, concentration, etc Reaction: work-up Reaction quench temperatures, times, stoichiometry of quenching materials, etc Bi-phasic extraction parameters such as solvent quantities, agitation, temperature, number of extractions, or time of continuous extraction, pH, etc Seeding quantities, time of seeding, etc, crystal growth rates, maturation times, etc Isolation Filtration rate, temperature, etc Centrifuge rates, feed rates, etc Rinse volumes and frequency, etc Drying Time, temperature, tumble rates (for tumble dryers), agitation rates (for filter dryers), etc Homogeneity of drying Drying rates or profiles, drying cycles, gas bleed rates Milling Hammer or blade speeds, and settings for mills Nitrogen pressure, time, etc for air-jet milling Micronising conditions (where applicable) Miscellaneous Filter integrity (for purification, or bioburden in APIs intended for parenteral use)
Yield (absolute and percentage). Note: Some processes may require the determination of in-process yields incaddition to a final yield. For example, a yield obtained after isolation of a wet cake and prior to drying.
Column conditions for large-scale chromatography
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Table 4: Examples of Process Parameters that may be Critical
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Essentially, the protocol resembles a master record in many ways, but it does provide a greater level of descriptive detail regarding the execution of the process, monitoring of the critical steps, sampling instructions, etc. It is not necessary to repeat all of the instructions that are in the master record, however, critical steps and operations that are unique to the exercise should be fully described. Critical Parameters The identification of critical process parameters is the key to a successful process validation exercise, and to maintaining process consistency throughout the process lifetime. The processing parameters need to be evaluated carefully throughout the development process to truly determine the critical parameters (this is where a well-written PDR is most useful). Table 4 provides some examples of parameters that may be determined to be critical in a chemical process. A critical parameter can represent a chemical reaction issue, an engineering issue, or a combination of both. In some cases, process parameters may need to be classified in different categories than either critical or non-critical. API manufacturing can be very complex, and a parameter may be considered critical, but not necessarily lethal to the process. One challenge to any process validation program is to clearly define the various types of critical parameters. The following is an example of how this might be approached: Process Critical Parameter: A process parameter that if not maintained within established limits would lead to a process failure. This would require routine in-process testing to ensure maintenance of the parameter. For example, a reaction is run at 50 2 C, but the product will rapidly decompose starting at 58 C. This temperature is critical, and if not maintained, could lead to a failure. Process Value Parameter: A process parameter that if not maintained within the established limits could impact the normal course of the process (but may not lead to a failure). This type of parameter may require strict monitoring and verification, but may not require routine in-process testing to control the outcome. For example, an ionic aqueous solution is required for extraction of an organic phase. If the ionic strength is insufficient, an emulsion can form, leading to longer settling times or indeterminate phase
Essentially, the protocol resembles a master record in many ways, but it does provide a greater level of descriptive detail regarding the execution of the process, monitoring of the critical steps, sampling instructions, etc. It is not necessary to repeat all of the instructions that are in the master record, however, critical steps and operations that are unique to the exercise should be fully described. Critical Parameters The identification of critical process parameters is the key to a successful process validation exercise, and to maintaining process consistency throughout the process lifetime. The processing parameters need to be evaluated carefully throughout the development process to truly determine the critical parameters (this is where a well-written PDR is most useful). Table 4 provides some examples of parameters that may be determined to be critical in a chemical process. A critical parameter can represent a chemical reaction issue, an engineering issue, or a combination of both. In some cases, process parameters may need to be classified in different categories than either critical or non-critical. API manufacturing can be very complex, and a parameter may be considered critical, but not necessarily lethal to the process. One challenge to any process validation program is to clearly define the various types of critical parameters. The following is an example of how this might be approached: Process Critical Parameter: A process parameter that if not maintained within established limits would lead to a process failure. This would require routine in-process testing to ensure maintenance of the parameter. For example, a reaction is run at 50 2 C, but the product will rapidly decompose starting at 58 C. This temperature is critical, and if not maintained, could lead to a failure. Process Value Parameter: A process parameter that if not maintained within the established limits could impact the normal course of the process (but may not lead to a failure). This type of parameter may require strict monitoring and verification, but may not require routine in-process testing to control the outcome. For example, an ionic aqueous solution is required for extraction of an organic phase. If the ionic strength is insufficient, an emulsion can form, leading to longer settling times or indeterminate phase
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separation. In this case, the length of the process could be affected without having impact on the overall batch. The key to defining critical parameters is in understanding all aspects of a given process, and ensuring that the right level of control is given to the parameters that need it. One common mistake that is made is defining critical parameters only in terms of the chemical process; engineering parameters frequently are overlooked. It is important to reinforce the concept that a chemical process is the intertwining of both chemical and engineering aspects. Some organizations chose to define parameters only if they could affect the impurity profile or the ability of a material to pass specification. However, the ability of a material to meet specification is not the sole indicator that the process is running smoothly or that it is validated. Critical parameters can also affect things such as yield, without affecting the material specifications. Therefore, the validation protocol should establish criteria for yields, and should be consistent with normal process yield experience during development. Abnormal yields, such as too high or too low, should be a red flag that there may be a problem. A high yield, for example, could mean an unexpected contamination with some salts, incomplete or nonuniform drying, or some other serious problem that could impact the quality of the final product. Finally, the degree to which a critical parameter can be monitored is dependent on the choice and sensitivity of the analytical method. Therefore, it is important to reiterate that the analytical method development and validation program has equal importance towards the success of process validation. Equipment and Facility Qualification In general, it is best to have all facility and equipment qualifications completed prior to process validation (certainly all IQ/OQ should be completed). Performance Qualification (PQ) can be performed during process validation, but it is generally advisable to have completed this testing prior to process validation since it would add additional risk to the exercise. However, there may be some instances where it is useful to concurrently perform an equipment or facility PQ during process validation. In those cases, a separate
separation. In this case, the length of the process could be affected without having impact on the overall batch. The key to defining critical parameters is in understanding all aspects of a given process, and ensuring that the right level of control is given to the parameters that need it. One common mistake that is made is defining critical parameters only in terms of the chemical process; engineering parameters frequently are overlooked. It is important to reinforce the concept that a chemical process is the intertwining of both chemical and engineering aspects. Some organizations chose to define parameters only if they could affect the impurity profile or the ability of a material to pass specification. However, the ability of a material to meet specification is not the sole indicator that the process is running smoothly or that it is validated. Critical parameters can also affect things such as yield, without affecting the material specifications. Therefore, the validation protocol should establish criteria for yields, and should be consistent with normal process yield experience during development. Abnormal yields, such as too high or too low, should be a red flag that there may be a problem. A high yield, for example, could mean an unexpected contamination with some salts, incomplete or nonuniform drying, or some other serious problem that could impact the quality of the final product. Finally, the degree to which a critical parameter can be monitored is dependent on the choice and sensitivity of the analytical method. Therefore, it is important to reiterate that the analytical method development and validation program has equal importance towards the success of process validation. Equipment and Facility Qualification In general, it is best to have all facility and equipment qualifications completed prior to process validation (certainly all IQ/OQ should be completed). Performance Qualification (PQ) can be performed during process validation, but it is generally advisable to have completed this testing prior to process validation since it would add additional risk to the exercise. However, there may be some instances where it is useful to concurrently perform an equipment or facility PQ during process validation. In those cases, a separate
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PQ protocol should be drafted and referenced in the process validation protocol. The Process Validation Report The process validation report should summarize the results of the process validation exercise. If a multi-step synthesis is being validated, each process step that has a validation protocol associated with it should have a final report for that step. A final governing validation report should be written that summarizes the entire effort. A report should be written even if a problem was encountered during the execution of the validation and it was unsuccessful. In this case, the report should describe the investigation conclusion, and the anticipated course of action in correcting the problem. The validation report is also a scientific document, and as such, should be concise and technically clear. The results of the validation exercise should be summarized (all raw data should be referenced for complete traceability), preferably in tabular form with the acceptance criteria (as stated in the protocols) tabulated as well. The acceptability of the results versus the predefined acceptance criteria should be indicated by either a passing or failing notation. In cases where a criterion failed, a discussion should be given concerning the failure, and include the cause of the failure, the affect of the failure on the validation, corrective actions, etc. All deviations should be listed, and a brief summary of each given along with an impact assessment. A definitive statement should be made as to whether all of the criteria have been met and the process is considered validated. Failure to provide a definitive conclusion is an error that is seen commonly in validation reports. Table 5 outlines some sections and content of a validation summary report. The report should also identify the process parameters and components that, if changed, would require additional validation (i.e., revalidation). Reference should be made to the current change control procedures that will govern those changes. Process Validation Deviations and Failures Clearly, it is foolhardy to begin process validation without an assurance that the process is under control, and this is related to the process development program in general. However, even the most well developed process will encounter a deviation or problem. How this problem is handled can make the difference between a successful process validation or validation failure. One common theme when reviewing FDA Warning Letters
PQ protocol should be drafted and referenced in the process validation protocol. The Process Validation Report The process validation report should summarize the results of the process validation exercise. If a multi-step synthesis is being validated, each process step that has a validation protocol associated with it should have a final report for that step. A final governing validation report should be written that summarizes the entire effort. A report should be written even if a problem was encountered during the execution of the validation and it was unsuccessful. In this case, the report should describe the investigation conclusion, and the anticipated course of action in correcting the problem. The validation report is also a scientific document, and as such, should be concise and technically clear. The results of the validation exercise should be summarized (all raw data should be referenced for complete traceability), preferably in tabular form with the acceptance criteria (as stated in the protocols) tabulated as well. The acceptability of the results versus the predefined acceptance criteria should be indicated by either a passing or failing notation. In cases where a criterion failed, a discussion should be given concerning the failure, and include the cause of the failure, the affect of the failure on the validation, corrective actions, etc. All deviations should be listed, and a brief summary of each given along with an impact assessment. A definitive statement should be made as to whether all of the criteria have been met and the process is considered validated. Failure to provide a definitive conclusion is an error that is seen commonly in validation reports. Table 5 outlines some sections and content of a validation summary report. The report should also identify the process parameters and components that, if changed, would require additional validation (i.e., revalidation). Reference should be made to the current change control procedures that will govern those changes. Process Validation Deviations and Failures Clearly, it is foolhardy to begin process validation without an assurance that the process is under control, and this is related to the process development program in general. However, even the most well developed process will encounter a deviation or problem. How this problem is handled can make the difference between a successful process validation or validation failure. One common theme when reviewing FDA Warning Letters
Table 5: Components of the Validation Report
Section Introduction Responsibilities Validation Summary Acceptance criteria
Content
Deviations or Investigations
Revalidation criteria Final Conclusion
Data Final Evaluation and Report
Give a brief description of the validation exercise, referencing the Validation Master Plan (VMP), validation protocol and appropriate background information Define the responsibilities for preparation, review and approval of the Final Report Give a brief descriptive summary of the validation exercise and how it was executed List all of the results (data) collected during the validation. Tabulate the results that correspond to the acceptance criteria as defined in the protocol. Make a pass or fail assessment for each criterion. List all deviations that occurred during the validation and give a brief summary of each (attach copies of each deviation report) Summarise the findings of the investigation, describe any remedial or corrective actions taken, and give a final assessment as to the impact of the deviation on the validation This is a good place to itemise the process requirements that, if changed, would require a revalidation A final assessment should be prepared that states the success (or failure) of a validation, based upon meeting the acceptance criteria, impact of any deviation, and demonstration of process consistency throughout the exercise. Reference should be made to the original raw data Describe the process for final evaluation of the validation exercise. A final report should be drafted that pulls together all of the validation components (necessary in multi-step processes Where more than one step is to be validated).
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Table 5: Components of the Validation Report
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concerning process validation is what companies do (or dont do) when validation problems are encountered, even if the problem is major and the answer is clear (e.g., recognizing a validation failure). In many of these cases, it becomes clear that the process was not ready for validation to begin with, and a price is now being exacted for rushing or cutting corners. One common cause of these failures is due to not properly identifying the critical process parameters. Most scientists will agree that it is more cost effective to spend time upfront to properly develop a process, rather than attempting to fix it after problems are encountered. Nevertheless, many companies insist on doing the opposite by attempting to validate a process that is not fully developed or in control. Of course, there are constant budgetary pressures that apply to any development program. However, with proper planning and a good, proactive program, it will provide a better tool to project the appropriate budgetary needs, and develop a good process that will pay for itself in the end by being prepared for validation. Major problems are generally obvious in the outcome. Batch failures that cannot be attributed to operator error or equipment breakdown unrelated to maintenance issues are considered validation failures.1,2 What about problems that are less clear? The key is a thorough and well-documented investigation. In the end, a decision must be made regarding the impact of the deviation or problem on the validation exercise. This is also where a clear set of pre-defined scenarios (in the protocol or VMP) can make the path very clear. For example, if a failure is encountered due to (blank), then do (blank). The advantage of pre-defined scenarios has already been discussed, but this also includes management approval that there are occurrences and conditions which everyone agrees in advance will require a fresh start. The approach to an investigation is the same for any deviation, and goes back to a fundamental approach to scientific inquiry. The following steps should be performed as soon as possible after the problem is discovered: Document clearly what occurred and when it occurred. Interview personnel as soon as possible (before memories can get clouded) and document the interview. Collect any additional data (as is relevant).
concerning process validation is what companies do (or dont do) when validation problems are encountered, even if the problem is major and the answer is clear (e.g., recognizing a validation failure). In many of these cases, it becomes clear that the process was not ready for validation to begin with, and a price is now being exacted for rushing or cutting corners. One common cause of these failures is due to not properly identifying the critical process parameters. Most scientists will agree that it is more cost effective to spend time upfront to properly develop a process, rather than attempting to fix it after problems are encountered. Nevertheless, many companies insist on doing the opposite by attempting to validate a process that is not fully developed or in control. Of course, there are constant budgetary pressures that apply to any development program. However, with proper planning and a good, proactive program, it will provide a better tool to project the appropriate budgetary needs, and develop a good process that will pay for itself in the end by being prepared for validation. Major problems are generally obvious in the outcome. Batch failures that cannot be attributed to operator error or equipment breakdown unrelated to maintenance issues are considered validation failures.1,2 What about problems that are less clear? The key is a thorough and well-documented investigation. In the end, a decision must be made regarding the impact of the deviation or problem on the validation exercise. This is also where a clear set of pre-defined scenarios (in the protocol or VMP) can make the path very clear. For example, if a failure is encountered due to (blank), then do (blank). The advantage of pre-defined scenarios has already been discussed, but this also includes management approval that there are occurrences and conditions which everyone agrees in advance will require a fresh start. The approach to an investigation is the same for any deviation, and goes back to a fundamental approach to scientific inquiry. The following steps should be performed as soon as possible after the problem is discovered: Document clearly what occurred and when it occurred. Interview personnel as soon as possible (before memories can get clouded) and document the interview. Collect any additional data (as is relevant).
Describe a sequence of events of when and what happened, review batch records, and corroborate events through data and records. Document any and all remedial actions that may have been taken. List all possible causes for the event. After investigating, eliminate causes that do not fit the data. Establish a cause or most probable cause based upon the data. List corrective actions that need to be implemented.
Describe a sequence of events of when and what happened, review batch records, and corroborate events through data and records. Document any and all remedial actions that may have been taken. List all possible causes for the event. After investigating, eliminate causes that do not fit the data. Establish a cause or most probable cause based upon the data. List corrective actions that need to be implemented.
Both from a regulatory perspective and a scientific perspective, any problem that was related to the process means that the validation was impacted. If the problem was serious enough to cause a failure, the validation was not successful. Only events that are not process-related could be written off as not negatively affecting the validation (e.g., power failures, natural disasters, human error, etc.). Even if a process validation failed and the cause was not process-related, the validation should be replaced with a fresh run.1 Ideally, an interim summary report can close the event, and the VMP should then be amended to include the additional process validation run(s). In all cases, the QA unit is required to approve the documented investigation, conclusions, remedial and corrective actions, assessments of impact, etc. Process Validation, Third-Party Manufacturing, and the Virtual Company In a contract situation, all process validation responsibilities should be fully described in a quality agreement between the two parties. The contractee, who is typically the owner of the Investigational New Drug (IND), New Drug Application (NDA), or Abbreviated New Drug Application (ANDA), is ultimately responsible for the product supplied from the contractor. This means that you must be a part of reviewing and approving validation documents (protocols, reports, and data). Since the contractee is ultimately responsible for the work of the contractor, the virtual company should prepare a comprehensive validation master plan, even though the validation work will be performed by a contract organization. The VMP should fully describe the roles and responsibilities of each organization in addition to the items previously discussed. Establishing clear-cut policies and expectations is of particular importance when dealing with contract organizations. European firms typically have a different view on validation and qualification than in the U.S. Thus, the concepts of process validation may not be as universally interpreted as
Both from a regulatory perspective and a scientific perspective, any problem that was related to the process means that the validation was impacted. If the problem was serious enough to cause a failure, the validation was not successful. Only events that are not process-related could be written off as not negatively affecting the validation (e.g., power failures, natural disasters, human error, etc.). Even if a process validation failed and the cause was not process-related, the validation should be replaced with a fresh run.1 Ideally, an interim summary report can close the event, and the VMP should then be amended to include the additional process validation run(s). In all cases, the QA unit is required to approve the documented investigation, conclusions, remedial and corrective actions, assessments of impact, etc. Process Validation, Third-Party Manufacturing, and the Virtual Company In a contract situation, all process validation responsibilities should be fully described in a quality agreement between the two parties. The contractee, who is typically the owner of the Investigational New Drug (IND), New Drug Application (NDA), or Abbreviated New Drug Application (ANDA), is ultimately responsible for the product supplied from the contractor. This means that you must be a part of reviewing and approving validation documents (protocols, reports, and data). Since the contractee is ultimately responsible for the work of the contractor, the virtual company should prepare a comprehensive validation master plan, even though the validation work will be performed by a contract organization. The VMP should fully describe the roles and responsibilities of each organization in addition to the items previously discussed. Establishing clear-cut policies and expectations is of particular importance when dealing with contract organizations. European firms typically have a different view on validation and qualification than in the U.S. Thus, the concepts of process validation may not be as universally interpreted as
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your organizations definition. Therefore, it is important to define these expectations early on in the relationship (preferably during the evaluation phase) so that no surprises are discovered when it counts. These expectations are best defined in a good quality agreement.4 For contractors, it is important to recognize the value in providing a detailed quality agreement or a written set of expectations from your customer (not all virtual companies may be experienced enough to bring this to the table). It is incumbent on either side to take the lead in these situations and be preemptive to avoid any potential misunderstanding. Once there is a problem, especially during or after process validation, there will be a tremendous effort required from both organizations to correct the situation. Finally, it is important that the virtual company have a person-in-the-plant policy, especially during process validation. Although you have hired another company to manufacture (perhaps even develop the process) for you, you must share in the knowledge and expertise of the process. Special Topics Homogeneity The homogeneous nature of the final API is a very critical characteristic that must be demonstrated, and this should be done during process validation. Ideally, homogeneity should be demonstrated at that stage of the process where it is expected to be achieved, not necessarily as a final packaged product. The process step where homogeneity testing is frequently employed is the drying step. Typically, three types of dryers are used: 1. Tray dryers 2. Tumble dryers 3. Filter dryers In each case, the validation protocol should include a sampling plan and frequency to test various locations and times of the drying process. These data should demonstrate the product uniformity during the drying process. Sampling and testing may also be desirable on the filtered wet cake prior to any drying activity to demonstrate homogeneity of crystallization or filtration. Testing at this stage can be focused on attributes that are applicable
your organizations definition. Therefore, it is important to define these expectations early on in the relationship (preferably during the evaluation phase) so that no surprises are discovered when it counts. These expectations are best defined in a good quality agreement.4 For contractors, it is important to recognize the value in providing a detailed quality agreement or a written set of expectations from your customer (not all virtual companies may be experienced enough to bring this to the table). It is incumbent on either side to take the lead in these situations and be preemptive to avoid any potential misunderstanding. Once there is a problem, especially during or after process validation, there will be a tremendous effort required from both organizations to correct the situation. Finally, it is important that the virtual company have a person-in-the-plant policy, especially during process validation. Although you have hired another company to manufacture (perhaps even develop the process) for you, you must share in the knowledge and expertise of the process. Special Topics Homogeneity The homogeneous nature of the final API is a very critical characteristic that must be demonstrated, and this should be done during process validation. Ideally, homogeneity should be demonstrated at that stage of the process where it is expected to be achieved, not necessarily as a final packaged product. The process step where homogeneity testing is frequently employed is the drying step. Typically, three types of dryers are used: 1. Tray dryers 2. Tumble dryers 3. Filter dryers In each case, the validation protocol should include a sampling plan and frequency to test various locations and times of the drying process. These data should demonstrate the product uniformity during the drying process. Sampling and testing may also be desirable on the filtered wet cake prior to any drying activity to demonstrate homogeneity of crystallization or filtration. Testing at this stage can be focused on attributes that are applicable
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such as assay, impurity profile, Organic Volatile Impurities (OVI), loss on drying, moisture, etc. Finally, the packaged product should undergo a comprehensive homogeneity sampling and testing regimen. This should include a combination of physical (appearance, particle size, powder flow, etc.) and chemical tests (assay, impurities, heavy metals, OVI, etc.). A sampling plan should be developed that provides a good matrix for demonstrating homogeneity. The plan should take into consideration the size and volume of the final packaged product. If a material is easily compressed, a compression study should be included, and may be included with a shipping study (see section below). Shipping Studies The final packaged API should be subjected to shipping studies. Stability programs are designed to show the stability of a material under storage, but they do not test movement of the product during shipment. A shipping study can be performed at any time once the final packaging and shipping characteristics are identified. However, it is often convenient to include it in the validation exercise. A shipping study should incorporate the use of portable temperature and humidity monitors to show the environmental conditions that the material has been subjected to during the normal course of shipping. Stress tests of the packaging materials may be performed, but should probably be performed on a suitable placebo. Stress testing should address the conditions of shipment that could impact the quality of the material being shipped (e.g., temperature, humidity, permeability of primary and secondary containers, etc.). APIs that have stringent storage requirements (e.g., refrigeration or frozen), should have equally strict acceptance criteria for the shipping study. If a special shipping container is required, or if a consumable coolant (e.g., dry ice) is utilized, the protocol should include all procedures for preparing the shipment, training of personnel, etc. Stability Testing API: Each process validation batch should be placed in a stability program. Ideally, stability data has already been accumulated to establish a retest period for the API. The stability protocol can be either a standard protocol, or drafted with the validation protocol specifically for the validation exercise,
such as assay, impurity profile, Organic Volatile Impurities (OVI), loss on drying, moisture, etc. Finally, the packaged product should undergo a comprehensive homogeneity sampling and testing regimen. This should include a combination of physical (appearance, particle size, powder flow, etc.) and chemical tests (assay, impurities, heavy metals, OVI, etc.). A sampling plan should be developed that provides a good matrix for demonstrating homogeneity. The plan should take into consideration the size and volume of the final packaged product. If a material is easily compressed, a compression study should be included, and may be included with a shipping study (see section below). Shipping Studies The final packaged API should be subjected to shipping studies. Stability programs are designed to show the stability of a material under storage, but they do not test movement of the product during shipment. A shipping study can be performed at any time once the final packaging and shipping characteristics are identified. However, it is often convenient to include it in the validation exercise. A shipping study should incorporate the use of portable temperature and humidity monitors to show the environmental conditions that the material has been subjected to during the normal course of shipping. Stress tests of the packaging materials may be performed, but should probably be performed on a suitable placebo. Stress testing should address the conditions of shipment that could impact the quality of the material being shipped (e.g., temperature, humidity, permeability of primary and secondary containers, etc.). APIs that have stringent storage requirements (e.g., refrigeration or frozen), should have equally strict acceptance criteria for the shipping study. If a special shipping container is required, or if a consumable coolant (e.g., dry ice) is utilized, the protocol should include all procedures for preparing the shipment, training of personnel, etc. Stability Testing API: Each process validation batch should be placed in a stability program. Ideally, stability data has already been accumulated to establish a retest period for the API. The stability protocol can be either a standard protocol, or drafted with the validation protocol specifically for the validation exercise,
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and should include normal and accelerated storage conditions per the International Conference on Harmonization (ICH) guidelines.3 Intermediates: If an intermediate is going to be stored or stockpiled, stability data and retest periods need to be established. Normally, it is a good idea to perform a hold study on intermediates (e.g., one month, two month etc.) in the event of delays in manufacturing, campaigning, etc. The hold study does not necessarily need to be a part of process validation, but should be performed prior to process validation and under a specific protocol. Monitoring and Trending The key to maintaining a process is through monitoring and trending the process. An extensive database should be established that collects process data. Typically, the critical quality attributes and the critical process parameters are monitored; however, a particular process may require additional factors to be monitored. In establishing a starting point for a process monitoring program, a meaningful data baseline needs to be established, and should be from a process that has the parameters of the process well defined. Although it is always beneficial to monitor process parameters during development, a baseline will probably not be initially established until the first validation batches are produced. However, if there were demonstration batches or other batches produced prior to process validation that are equivalent to the validation batches, these could represent a starting point. There may be processes where even early development batches have enough definition to begin this evaluation. However, enough batches need to be produced to provide a sound statistical base for data evaluation. This number probably should be evaluated on a case-by-case basis, and be based on the process and process attributes that are being monitored (since the confidence level is dependent on the number of batches). An Annual Product Review (APR) is a quality requirement, but in fact, this review should be performed routinely by the appropriate technical group. Process trends should be investigated and addressed, as necessary. This activity should also be captured in PDR updates if there is additional process improvement work that is performed. There are several good software packages available that will assist with routine monitoring and data handling.
and should include normal and accelerated storage conditions per the International Conference on Harmonization (ICH) guidelines.3 Intermediates: If an intermediate is going to be stored or stockpiled, stability data and retest periods need to be established. Normally, it is a good idea to perform a hold study on intermediates (e.g., one month, two month etc.) in the event of delays in manufacturing, campaigning, etc. The hold study does not necessarily need to be a part of process validation, but should be performed prior to process validation and under a specific protocol. Monitoring and Trending The key to maintaining a process is through monitoring and trending the process. An extensive database should be established that collects process data. Typically, the critical quality attributes and the critical process parameters are monitored; however, a particular process may require additional factors to be monitored. In establishing a starting point for a process monitoring program, a meaningful data baseline needs to be established, and should be from a process that has the parameters of the process well defined. Although it is always beneficial to monitor process parameters during development, a baseline will probably not be initially established until the first validation batches are produced. However, if there were demonstration batches or other batches produced prior to process validation that are equivalent to the validation batches, these could represent a starting point. There may be processes where even early development batches have enough definition to begin this evaluation. However, enough batches need to be produced to provide a sound statistical base for data evaluation. This number probably should be evaluated on a case-by-case basis, and be based on the process and process attributes that are being monitored (since the confidence level is dependent on the number of batches). An Annual Product Review (APR) is a quality requirement, but in fact, this review should be performed routinely by the appropriate technical group. Process trends should be investigated and addressed, as necessary. This activity should also be captured in PDR updates if there is additional process improvement work that is performed. There are several good software packages available that will assist with routine monitoring and data handling.
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Conclusion Successful process validation programs begin with a thoughtful and comprehensive corporate policy concerning the process validation program. This policy should recognize that process validation begins at the initial stages of development, and does not end until the lifetime of the product is over. It is important that all employees be fully trained and understand their role in the program. Good science, well-documented development programs, proactive procedures and definitions, and well-written protocols will increase the chances of successful process validation. Finally, process validation does not end at the successful completion of the exercise or final report. Process validation is a lifetime event that requires continuous process monitoring, trending, and evaluation. About the Author Roger W. Koops, Ph.D., is currently the Associate Director of Quality at Genelabs Technologies, Inc. and directs the Quality Assurance and Quality Control groups. He has over 11 years of experience in API process development, manufacturing, and quality related areas including process validation, compliance evaluation of API manufacturing, equipment and facilities, third-party manufacturing, and quality systems. Dr. Koops received his Ph.D. degree in Chemistry from the University of California, Riverside, and his undergraduate degree from Western Washington University. References FDA. Guidance For Industry (draft): Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients. 1998. ICH Q7A (draft): Good Manufacturing Guide for Active Pharmaceutical Ingredients. 1998. ICH Q1A(R): Stability Testing for New Drug Substances and Drug Products. 1994, (R): 2000. Bobrowicz, G., The Quality Agreement: Compliance Considerations in Selecting a Contract Manufacturer. BioPharm. Feb., 2001. p 14.
Conclusion Successful process validation programs begin with a thoughtful and comprehensive corporate policy concerning the process validation program. This policy should recognize that process validation begins at the initial stages of development, and does not end until the lifetime of the product is over. It is important that all employees be fully trained and understand their role in the program. Good science, well-documented development programs, proactive procedures and definitions, and well-written protocols will increase the chances of successful process validation. Finally, process validation does not end at the successful completion of the exercise or final report. Process validation is a lifetime event that requires continuous process monitoring, trending, and evaluation. About the Author Roger W. Koops, Ph.D., is currently the Associate Director of Quality at Genelabs Technologies, Inc. and directs the Quality Assurance and Quality Control groups. He has over 11 years of experience in API process development, manufacturing, and quality related areas including process validation, compliance evaluation of API manufacturing, equipment and facilities, third-party manufacturing, and quality systems. Dr. Koops received his Ph.D. degree in Chemistry from the University of California, Riverside, and his undergraduate degree from Western Washington University. References FDA. Guidance For Industry (draft): Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients. 1998. ICH Q7A (draft): Good Manufacturing Guide for Active Pharmaceutical Ingredients. 1998. ICH Q1A(R): Stability Testing for New Drug Substances and Drug Products. 1994, (R): 2000. Bobrowicz, G., The Quality Agreement: Compliance Considerations in Selecting a Contract Manufacturer. BioPharm. Feb., 2001. p 14.
Article Acronym Listing ANDA API APR cGMP ICH IND IQ NDA OQ OVI PDR PFD PQ QA QC SOP VMP : : : : : : : : : : : : : : : : : Abbreviated New Drug Application Active Pharmaceutical Ingredient Annual Product Review Current Good Manufacturing Practice International Conference on Harmonization Investigational New Drug Installation Qualification New Drug Application Operational Qualification Organic Volatile Impurities Process Development Report Process Flow Diagram Performance Qualification Quality Assurance Quality Control Standard Operating Procedure Validation Master Plan
Article Acronym Listing ANDA API APR cGMP ICH IND IQ NDA OQ OVI PDR PFD PQ QA QC SOP VMP : : : : : : : : : : : : : : : : : Abbreviated New Drug Application Active Pharmaceutical Ingredient Annual Product Review Current Good Manufacturing Practice International Conference on Harmonization Investigational New Drug Installation Qualification New Drug Application Operational Qualification Organic Volatile Impurities Process Development Report Process Flow Diagram Performance Qualification Quality Assurance Quality Control Standard Operating Procedure Validation Master Plan
a case study for integrating and streamlining the validation approach to reduce project resources
BY GRAHAM C. WRIGLEY
AND
a case study for integrating and streamlining the validation approach to reduce project resources
BY GRAHAM C. WRIGLEY
AND
JAN L.
DU
PREEZ, PH.D.
JAN L.
DU
PREEZ, PH.D.
Abstract Pharmaceutical companies typically require considerable resources, in terms of time, money, and specialized personnel, to validate a current Good Manufacturing Practice (cGMP) facility. This can be overwhelming to a small company or plant with limited resources. This paper identifies some of the key areas in a facility upgrade project that have been found to result in inefficiencies, project, and facility start-up delays. It seeks to demonstrate that the integration and streamlining of the design, construction, commissioning, and validation phases can accelerate the start-up effort, reduce the validation effort and costs, produce superior documentation, and ensure that product is produced in a cGMP-compliant facility. It will also prove that even though the original focus of validation was to satisfy regulatory expectations, facility validation has in fact become good business and engineering practice that enhances reliability, cost, and quality of the products. Introduction In the past decade, many far-reaching changes have taken place in the application of cGMP regulations relating to the pharmaceutical industry. The words current and good in cGMP themselves create the expectation for the rigor of control of pharmaceutical manufacturing to continuously improve over time, and convey the notion that as soon as a practice becomes recognized as being of value in assuring the quality of drug products, that practice becomes the standard for the industry. Continuous quality improvement thus is ingrained in the cGMP concept. In this environment, the pharmaceutical industry also constantly seeks improved manufacturing efficiencies to attain marketplace strategic advantage with cost of goods and speed to market imperatives, and increasingly more costly capital expenditures are devoted to achieving this competitive advantage. These strategies often include the building of new facilities or modernizing existing facilities. The design, construction, commissioning, and validation of pharmaceutical facilities are significant challenges for project managers, engineering, and quality professionals. Constantly caught in the dilemma of budget and schedule constraints, they have to deliver an end product that complies with all building, environmental, health and safety governing codes, laws, and regulations. The
Abstract Pharmaceutical companies typically require considerable resources, in terms of time, money, and specialized personnel, to validate a current Good Manufacturing Practice (cGMP) facility. This can be overwhelming to a small company or plant with limited resources. This paper identifies some of the key areas in a facility upgrade project that have been found to result in inefficiencies, project, and facility start-up delays. It seeks to demonstrate that the integration and streamlining of the design, construction, commissioning, and validation phases can accelerate the start-up effort, reduce the validation effort and costs, produce superior documentation, and ensure that product is produced in a cGMP-compliant facility. It will also prove that even though the original focus of validation was to satisfy regulatory expectations, facility validation has in fact become good business and engineering practice that enhances reliability, cost, and quality of the products. Introduction In the past decade, many far-reaching changes have taken place in the application of cGMP regulations relating to the pharmaceutical industry. The words current and good in cGMP themselves create the expectation for the rigor of control of pharmaceutical manufacturing to continuously improve over time, and convey the notion that as soon as a practice becomes recognized as being of value in assuring the quality of drug products, that practice becomes the standard for the industry. Continuous quality improvement thus is ingrained in the cGMP concept. In this environment, the pharmaceutical industry also constantly seeks improved manufacturing efficiencies to attain marketplace strategic advantage with cost of goods and speed to market imperatives, and increasingly more costly capital expenditures are devoted to achieving this competitive advantage. These strategies often include the building of new facilities or modernizing existing facilities. The design, construction, commissioning, and validation of pharmaceutical facilities are significant challenges for project managers, engineering, and quality professionals. Constantly caught in the dilemma of budget and schedule constraints, they have to deliver an end product that complies with all building, environmental, health and safety governing codes, laws, and regulations. The
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facility must also comply with one very important criterion; it must be validated to meet cGMP regulations. Historically, the legal requirement for validation of pharmaceutical manufacturing processes originated in the U.S. with the Food and Drug Administration (FDA) promulgating the cGMP regulation in 1979. This precipitated a widespread rush by pharmaceutical manufacturers to install formalized validation programs suited to their individual needs, financial capabilities, and company philosophy. These regulations have been written in such a way as to leave the interpretation to the user. Confusion and misinterpretation by industry on the scope and extent of this requirement has led to ever increasing costs of bringing pharmaceutical facilities in compliance with these cGMPs. The cost of validating a facility is determined by time spent on documentation, development of protocols and Standard Operating Procedures (SOPs), and the time spent on actual fieldwork, data collection, and analysis.(1) These costs have increased over the years reflecting higher standards required by regulatory authorities, and also because industry has adopted inefficient and costly blanket validation compliance strategies. As a result of this, there is a continuing struggle and challenge of meeting regulatory requirements, keeping overhead costs down, and running a profitable business. It is interesting to note that a good rule of thumb is that total validation costs may run from four (4) percent to eight (8) percent of the total project cost for typical pharmaceutical plant expansion projects.(2) For a new or upgraded facility, commissioning and facility validation is the foundation for assuring success in further manufacturing process validation. Before you begin validating a manufacturing process, an acceptable facility, and the utilities and equipment to support manufacturing operations must be in place. Facility qualification (a part of validation that proves and documents that equipment or ancillary systems are properly installed, work correctly, and actually lead to the expected results), and validation (establishing documented evidence that provides a high degree of assurance that the manufacturing processes, including buildings, systems, and equipment consistently produce the desired results according to predetermined specifications and quality attributes) activities will establish and provide documentary evidence that:
facility must also comply with one very important criterion; it must be validated to meet cGMP regulations. Historically, the legal requirement for validation of pharmaceutical manufacturing processes originated in the U.S. with the Food and Drug Administration (FDA) promulgating the cGMP regulation in 1979. This precipitated a widespread rush by pharmaceutical manufacturers to install formalized validation programs suited to their individual needs, financial capabilities, and company philosophy. These regulations have been written in such a way as to leave the interpretation to the user. Confusion and misinterpretation by industry on the scope and extent of this requirement has led to ever increasing costs of bringing pharmaceutical facilities in compliance with these cGMPs. The cost of validating a facility is determined by time spent on documentation, development of protocols and Standard Operating Procedures (SOPs), and the time spent on actual fieldwork, data collection, and analysis.(1) These costs have increased over the years reflecting higher standards required by regulatory authorities, and also because industry has adopted inefficient and costly blanket validation compliance strategies. As a result of this, there is a continuing struggle and challenge of meeting regulatory requirements, keeping overhead costs down, and running a profitable business. It is interesting to note that a good rule of thumb is that total validation costs may run from four (4) percent to eight (8) percent of the total project cost for typical pharmaceutical plant expansion projects.(2) For a new or upgraded facility, commissioning and facility validation is the foundation for assuring success in further manufacturing process validation. Before you begin validating a manufacturing process, an acceptable facility, and the utilities and equipment to support manufacturing operations must be in place. Facility qualification (a part of validation that proves and documents that equipment or ancillary systems are properly installed, work correctly, and actually lead to the expected results), and validation (establishing documented evidence that provides a high degree of assurance that the manufacturing processes, including buildings, systems, and equipment consistently produce the desired results according to predetermined specifications and quality attributes) activities will establish and provide documentary evidence that:
integrating & streamlining the validation approach: a case study
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The premises, supporting utilities, equipment, and processes have been designed in accordance with the requirements of GMP. This constitutes Design Qualification (DQ). The premises, supporting utilities, and equipment have been built and installed in compliance with their design specifications. This constitutes Installation Qualification (IQ). The facilities, supporting utilities, and equipment operate in accordance with their design specifications. This constitutes Operational Qualification (OQ). The facilities, utilities, or equipment that can affect product quality, performs as intended meeting predetermined acceptance criteria. This constitutes Equipment Performance Qualification (EPQ) Once the facility has been validated (IQ + OQ + Performance Qualification [PQ]), then process validation can commence A specific process will consistently produce a product meeting predetermined specifications and quality attributes. This constitutes Process Validation (PV) or Process Performance Qualification (PPQ).(3)
The premises, supporting utilities, equipment, and processes have been designed in accordance with the requirements of GMP. This constitutes Design Qualification (DQ). The premises, supporting utilities, and equipment have been built and installed in compliance with their design specifications. This constitutes Installation Qualification (IQ). The facilities, supporting utilities, and equipment operate in accordance with their design specifications. This constitutes Operational Qualification (OQ). The facilities, utilities, or equipment that can affect product quality, performs as intended meeting predetermined acceptance criteria. This constitutes Equipment Performance Qualification (EPQ) Once the facility has been validated (IQ + OQ + Performance Qualification [PQ]), then process validation can commence A specific process will consistently produce a product meeting predetermined specifications and quality attributes. This constitutes Process Validation (PV) or Process Performance Qualification (PPQ).(3)
These Good Validation Practices (GVPs) thus play a crucial role in delivering operationally effective, safe, and efficient facilities, process air handling systems, utilities, equipment, and also provide the medium by which compliance is achieved, demonstrated, and retained. Facility validation represents the last phase of the design and construction of a pharmaceutical facility, and is beset by the following problems: Plant commissioning is a vital element in the process of delivering new facilities. Often, varying commissioning practices and methodologies result in inefficient implementation and costly delays when project teams under manage the tasks of commissioning, starting up, and turning over facilities. Too often, the validation process reveals a large burden of unfinished commissioning business, resulting in a delay in facility start-up. As mentioned, validation activities form a significant percentage of time and money in most pharmaceutical capital projects, and the cost of validating and maintaining facilities designed to meet cGMP requirements can be overwhelming to small pharmaceutical companies and plants with limited resources.
These Good Validation Practices (GVPs) thus play a crucial role in delivering operationally effective, safe, and efficient facilities, process air handling systems, utilities, equipment, and also provide the medium by which compliance is achieved, demonstrated, and retained. Facility validation represents the last phase of the design and construction of a pharmaceutical facility, and is beset by the following problems: Plant commissioning is a vital element in the process of delivering new facilities. Often, varying commissioning practices and methodologies result in inefficient implementation and costly delays when project teams under manage the tasks of commissioning, starting up, and turning over facilities. Too often, the validation process reveals a large burden of unfinished commissioning business, resulting in a delay in facility start-up. As mentioned, validation activities form a significant percentage of time and money in most pharmaceutical capital projects, and the cost of validating and maintaining facilities designed to meet cGMP requirements can be overwhelming to small pharmaceutical companies and plants with limited resources.
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Currently, the level of wastage and inefficiency in validation is spiraling out of control. For example, the cost of validation to the industry in the United States has been estimated at $50 billion dollars.(4) This is because most organizations lack a clear understanding of the reason for validation, fail to develop procedures to allow them to conduct efficient validation, and rarely allow themselves sufficient time and resource to plan for validation activities. Validation Master Plans (VMPs) are often rushed and poorly constructed. Content and presentation of documentation is frequently inadequate, and the validators themselves are regularly passed over in training and assessment routines. Advancing manufacturing technology also makes new facilities increasingly more complex, and bring higher expectations for output, quality and efficiency. The fear of high financial losses due to shutdowns are forcing many companys to invest in the benefits afforded by effective commissioning and validation programs.
Currently, the level of wastage and inefficiency in validation is spiraling out of control. For example, the cost of validation to the industry in the United States has been estimated at $50 billion dollars.(4) This is because most organizations lack a clear understanding of the reason for validation, fail to develop procedures to allow them to conduct efficient validation, and rarely allow themselves sufficient time and resource to plan for validation activities. Validation Master Plans (VMPs) are often rushed and poorly constructed. Content and presentation of documentation is frequently inadequate, and the validators themselves are regularly passed over in training and assessment routines. Advancing manufacturing technology also makes new facilities increasingly more complex, and bring higher expectations for output, quality and efficiency. The fear of high financial losses due to shutdowns are forcing many companys to invest in the benefits afforded by effective commissioning and validation programs.
Pharmaceutical industry, regulatory authorities, organizations (e.g., the World Health Organization [WHO]; the Pharmaceutical Inspection Cooperation Scheme [PIC/S]; and the European Community [EC]), institutions, and corporations in countries like the United States, Europe, and Japan are attempting to harmonize their regulations and practices relating to cGMP. Nations worldwide, like Australia and South Africa, are gradually adopting these rules, regulations, and practices. As is for the GMPs, there must also be continuous quality improvement over time in the GVP concept, and ways of streamlining the process of validation, with methods that satisfy quality and business needs, and regulatory requirements must be enforced to ensure that Industry remains competitive and compliant in an effective and efficient manner. (5) This article presents the authors experience in validating an upgraded manufacturing facility, and proposes methodologies to improve, integrate, and streamline the facility validation approaches to address the above shortcomings, identify unnecessary validation activities, and implement new approaches to reduce costs and improve efficiency.
Pharmaceutical industry, regulatory authorities, organizations (e.g., the World Health Organization [WHO]; the Pharmaceutical Inspection Cooperation Scheme [PIC/S]; and the European Community [EC]), institutions, and corporations in countries like the United States, Europe, and Japan are attempting to harmonize their regulations and practices relating to cGMP. Nations worldwide, like Australia and South Africa, are gradually adopting these rules, regulations, and practices. As is for the GMPs, there must also be continuous quality improvement over time in the GVP concept, and ways of streamlining the process of validation, with methods that satisfy quality and business needs, and regulatory requirements must be enforced to ensure that Industry remains competitive and compliant in an effective and efficient manner. (5) This article presents the authors experience in validating an upgraded manufacturing facility, and proposes methodologies to improve, integrate, and streamline the facility validation approaches to address the above shortcomings, identify unnecessary validation activities, and implement new approaches to reduce costs and improve efficiency.
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Project Profile and Scope The manufacturing plant in Cape Town (South Africa) was built in 1982. The facility manufactures multiple consumer healthcare and pharmaceutical prescription products in multi-use equipment. Dosage forms manufactured include oral tablets, capsules, solutions, syrups, suspensions, lotions, creams, ointments, and suppositories. Since mid-1999, the site has undergone a phased refurbishment to improve the manufacturing efficiencies (i.e., improved workflow methods, equipment utilization, manufacturing cycle times, and increased batch sizes), and regulatory compliance (cGMP and Environment, Health and Safety [EHS]). At the same time, it has been necessary to continue production to meet the demands of the marketplace during this construction phase. This fast-track project included: In Phase One, a 90 m2 Stability Chamber, 850 m2 office block, 120 m2 Research and Development (R&D) Pilot Laboratory, and 285 m2 Chemical Weighing Facility; and In Phases Two, Three, and Four, a 1075 m2 Oral Solid Dose Manufacturing facility (Granulation/Blending, Compression and Encapsulation sections) and a 120 m2 Heating, Ventilation and Air Conditioning (HVAC) utility room.
Project Profile and Scope The manufacturing plant in Cape Town (South Africa) was built in 1982. The facility manufactures multiple consumer healthcare and pharmaceutical prescription products in multi-use equipment. Dosage forms manufactured include oral tablets, capsules, solutions, syrups, suspensions, lotions, creams, ointments, and suppositories. Since mid-1999, the site has undergone a phased refurbishment to improve the manufacturing efficiencies (i.e., improved workflow methods, equipment utilization, manufacturing cycle times, and increased batch sizes), and regulatory compliance (cGMP and Environment, Health and Safety [EHS]). At the same time, it has been necessary to continue production to meet the demands of the marketplace during this construction phase. This fast-track project included: In Phase One, a 90 m2 Stability Chamber, 850 m2 office block, 120 m2 Research and Development (R&D) Pilot Laboratory, and 285 m2 Chemical Weighing Facility; and In Phases Two, Three, and Four, a 1075 m2 Oral Solid Dose Manufacturing facility (Granulation/Blending, Compression and Encapsulation sections) and a 120 m2 Heating, Ventilation and Air Conditioning (HVAC) utility room.
Major systems installation included fifteen new plant and process HVAC systems, a Building Management System (BMS) for control of the HVACs, new dust collection plant, new chilled water plant, with upgrades to the existing compressed air and steam supply systems. New process drying, blending, and materials handling equipment items were also installed. Part of the scope of this particular project included the transfer of a limited number of manufacturing processes to the above new equipment. As part of the facility validation, the validation of cleaning procedures and systems in the new facility were handled as a separate project with its own VMP, and for simplicitys sake, will not be covered in this article. The facility design was contracted out to an engineering consulting company, who subcontracted the construction work to various contractors. The consulting engineer was responsible for the coordinating and scheduling of construction. His teams of subcontractors were responsible for the construction,
Major systems installation included fifteen new plant and process HVAC systems, a Building Management System (BMS) for control of the HVACs, new dust collection plant, new chilled water plant, with upgrades to the existing compressed air and steam supply systems. New process drying, blending, and materials handling equipment items were also installed. Part of the scope of this particular project included the transfer of a limited number of manufacturing processes to the above new equipment. As part of the facility validation, the validation of cleaning procedures and systems in the new facility were handled as a separate project with its own VMP, and for simplicitys sake, will not be covered in this article. The facility design was contracted out to an engineering consulting company, who subcontracted the construction work to various contractors. The consulting engineer was responsible for the coordinating and scheduling of construction. His teams of subcontractors were responsible for the construction,
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commissioning, and turnover of the facility. Various equipment vendors and agents were employed at certain stages of the project. A multi-disciplinary project team was formed at the projects inception to cover regulatory and technical concerns. A team comprising of in-house representatives from Engineering, Production, Quality Assurance (QA), Validation, Product Development, EHS, and Technical Training functions, was formed at the projects inception under leadership of the Projects Engineer/Manager. These core team members headed up five sub-project teams to address the following key project deliverables: Facility/Equipment design requirements: This teams role was to define the product, process, operations, maintenance, and compliance requirements influencing the conceptual design of the facility (seven part-time team members assigned full-time equivalents at 25%). Validation: This teams role was to ensure that the facility and system qualification requirements are communicated and met (three part-time team members assigned full-time equivalents at 60%). The project validation scope was very extensive, so an additional temporary backfill validation resource was assigned to the validation manager to assist with routine non-project-related validation activities. It must be said that, here in South Africa, there are no local validation consultants for pharmaceutical companies to call on, therefore in-house expertise has always to be developed and used. All project validation deliverables were reviewed and approved by the site validation and QA functions. Equipment and Utility Decommissioning, Relocation, and Commissioning: This teams role was to ensure that the phased relocation, installation, commissioning, and qualification of existing equipment and utilities is executed according to plan, with minimal impact on production schedules (four part-time team members assigned full-time equivalents at 25%). Process Technology/Product Regulatory Compliance: This teams role was to facilitate the process transfer to the new facility, evaluating the regulatory impact of equipment and process changes, coordinating batch size increases, process optimization, and process validation (seven part-time team members assigned full-time equivalents at 50%).
commissioning, and turnover of the facility. Various equipment vendors and agents were employed at certain stages of the project. A multi-disciplinary project team was formed at the projects inception to cover regulatory and technical concerns. A team comprising of in-house representatives from Engineering, Production, Quality Assurance (QA), Validation, Product Development, EHS, and Technical Training functions, was formed at the projects inception under leadership of the Projects Engineer/Manager. These core team members headed up five sub-project teams to address the following key project deliverables: Facility/Equipment design requirements: This teams role was to define the product, process, operations, maintenance, and compliance requirements influencing the conceptual design of the facility (seven part-time team members assigned full-time equivalents at 25%). Validation: This teams role was to ensure that the facility and system qualification requirements are communicated and met (three part-time team members assigned full-time equivalents at 60%). The project validation scope was very extensive, so an additional temporary backfill validation resource was assigned to the validation manager to assist with routine non-project-related validation activities. It must be said that, here in South Africa, there are no local validation consultants for pharmaceutical companies to call on, therefore in-house expertise has always to be developed and used. All project validation deliverables were reviewed and approved by the site validation and QA functions. Equipment and Utility Decommissioning, Relocation, and Commissioning: This teams role was to ensure that the phased relocation, installation, commissioning, and qualification of existing equipment and utilities is executed according to plan, with minimal impact on production schedules (four part-time team members assigned full-time equivalents at 25%). Process Technology/Product Regulatory Compliance: This teams role was to facilitate the process transfer to the new facility, evaluating the regulatory impact of equipment and process changes, coordinating batch size increases, process optimization, and process validation (seven part-time team members assigned full-time equivalents at 50%).
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Current Good Manufacturing Practice: This teams role was to define workflows and garbing policies for the new facility, ensure that sufficient training had been undertaken, and that there was an understanding of the facility and equipment operation (five part-time team members assigned full-time equivalents at 25%). These five team leaders, project manager, and functional management group constituted the project steering committee. The Fundamentals of Facility Validation Facility validation provides the documentation necessary to demonstrate that facilities, utility systems, and process equipment are operationally effective, safe, and efficient. Figure 1 shows an example of a typical validation flowchart for a pharmaceutical plant with the engineering and validation activities paralleled. The fundamental lifecycle approach to validation has been widely accepted internationally. The basic premise involves dividing the system into components or phases. The project validation lifecycle follows a structured method to plan, design, implement, test, and operate a system from its conception to the termination of its use and decommissioning, or it may reenter the cycle with change and revalidation. The important aspect to note in this flowchart is the interaction and interdependency of many of the engineering and validation activities. Such as: DQ confirms the GMP facility design supporting utilities, and equipment. This can be conducted in parallel with development of Factory Acceptance Testing (FAT) and Site Acceptance Test (SAT) methodologies. Pre-Delivery Inspection (PDI) of major system components can contribute to the IQ Factory acceptance operational tests can contribute to the OQ Commissioning activities can overlap with some IQ/OQ activities, and can confirm the User Requirement Specification (URS) for indirect impact systems IQ verifies construction and installation
Current Good Manufacturing Practice: This teams role was to define workflows and garbing policies for the new facility, ensure that sufficient training had been undertaken, and that there was an understanding of the facility and equipment operation (five part-time team members assigned full-time equivalents at 25%). These five team leaders, project manager, and functional management group constituted the project steering committee. The Fundamentals of Facility Validation Facility validation provides the documentation necessary to demonstrate that facilities, utility systems, and process equipment are operationally effective, safe, and efficient. Figure 1 shows an example of a typical validation flowchart for a pharmaceutical plant with the engineering and validation activities paralleled. The fundamental lifecycle approach to validation has been widely accepted internationally. The basic premise involves dividing the system into components or phases. The project validation lifecycle follows a structured method to plan, design, implement, test, and operate a system from its conception to the termination of its use and decommissioning, or it may reenter the cycle with change and revalidation. The important aspect to note in this flowchart is the interaction and interdependency of many of the engineering and validation activities. Such as: DQ confirms the GMP facility design supporting utilities, and equipment. This can be conducted in parallel with development of Factory Acceptance Testing (FAT) and Site Acceptance Test (SAT) methodologies. Pre-Delivery Inspection (PDI) of major system components can contribute to the IQ Factory acceptance operational tests can contribute to the OQ Commissioning activities can overlap with some IQ/OQ activities, and can confirm the User Requirement Specification (URS) for indirect impact systems IQ verifies construction and installation
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Figure 1 shows an example of a typical validation flowchart for a pharmaceutical plant with the engineering and validation activities paralleled.
Figure 1 shows an example of a typical validation flowchart for a pharmaceutical plant with the engineering and validation activities paralleled.
OQ verifies functional design PQ verifies the URS, and will challenge a collection of both direct impact and indirect impact systems working together
OQ verifies functional design PQ verifies the URS, and will challenge a collection of both direct impact and indirect impact systems working together
Using Figure 1 as a basis for further discussion, each phase of a typical validation project is presented and discussed.
Using Figure 1 as a basis for further discussion, each phase of a typical validation project is presented and discussed.
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Requirements Phase A successful project is dependent on clear definition, communication, and understanding of the project scope and objectives, as defined by the end user and other stakeholder requirements. At the outset of the project after the front end conceptual study has been completed, the user must specify his requirements for individual aspects of the facility, equipment, utility, and systems in terms of function, throughput, operability, and applicable local compliance standards to the engineering service provider. This enables the development and assessment of specific engineering options. These requirements are normally formalized in a detailed URS document. Validation Planning For significant validation efforts involving multiple equipment and utility systems, a project VMP should be developed early in the project, as early as the conceptual engineering design phase, to define the overall validation philosophy and methodology to be used throughout the project. This allows the project and validation managers to plan resource and scheduling requirements, and ensures that design engineer specifications and detailed design are suitable for validation. The VMP should be a structured, detailed plan defining all the testing, acceptance criteria, and documentation required to satisfy the regulatory authorities and support the validation process. Based on an impact assessment, the plan also clearly defines the scope and extent of the qualification or validation process by listing the matrix of products, processes, equipment, or systems affected. The VMP also assigns responsibilities for developing and executing validation program activities, and gives a first look at an anticipated testing execution schedule. At the inception of projects, it is necessary, and in fact, essential, that the project team and project sponsor approve the VMP to enable the release of sufficient financial and staffing resources to support the entire project. Formation of a Project Team Establishing a project team that has adequate skills that are appropriate for the size and complexity of the project is key to the project launch. Project
Requirements Phase A successful project is dependent on clear definition, communication, and understanding of the project scope and objectives, as defined by the end user and other stakeholder requirements. At the outset of the project after the front end conceptual study has been completed, the user must specify his requirements for individual aspects of the facility, equipment, utility, and systems in terms of function, throughput, operability, and applicable local compliance standards to the engineering service provider. This enables the development and assessment of specific engineering options. These requirements are normally formalized in a detailed URS document. Validation Planning For significant validation efforts involving multiple equipment and utility systems, a project VMP should be developed early in the project, as early as the conceptual engineering design phase, to define the overall validation philosophy and methodology to be used throughout the project. This allows the project and validation managers to plan resource and scheduling requirements, and ensures that design engineer specifications and detailed design are suitable for validation. The VMP should be a structured, detailed plan defining all the testing, acceptance criteria, and documentation required to satisfy the regulatory authorities and support the validation process. Based on an impact assessment, the plan also clearly defines the scope and extent of the qualification or validation process by listing the matrix of products, processes, equipment, or systems affected. The VMP also assigns responsibilities for developing and executing validation program activities, and gives a first look at an anticipated testing execution schedule. At the inception of projects, it is necessary, and in fact, essential, that the project team and project sponsor approve the VMP to enable the release of sufficient financial and staffing resources to support the entire project. Formation of a Project Team Establishing a project team that has adequate skills that are appropriate for the size and complexity of the project is key to the project launch. Project
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team representation should be based on the project scope, resource requirements, and key stakeholders. To ensure timely and cost-effective project completion, it is essential to have excellent communication, planning, and coordination between project team members. Organizing these teams, establishing roles, responsibilities and expectations, levels of authority, monitoring performance, and taking corrective actions are fundamental project management issues that challenge project leaders. Facility Systems GMP audit, Design Qualification & Impact Assessment Early involvement by the QA function ensures clear understanding of the projects scope, facility, processes, and equipment. Early involvement by QA, by means of a GMP audit, for example, should provide clear communication of regulatory requirements, ensuring that effective procedures and practices are established upfront for incorporation into the project. This GMP audit can be conducted in parallel with the impact assessment, if required. The functional design of the system or equipment must be confirmed as being correct and appropriate for the requirements of the URS. This confirmation is made by detailed comparisons of the functional design with regulatory requirements, company procedures, manufacturer s documentation, and the URS in a formal DQ protocol. Once the DQ is complete, a risk analysis or impact assessment can be conducted. The key to successful project implementation is a well-defined project scope, which enables the validation team to determine the degree of effort and level of resources required, enabling them to focus on its defined responsibilities. It is the function of the facility, equipment, or utility that determines what level of commissioning and qualification are needed. Developing the project commissioning and validation scope is normally accomplished by conducting a risk analysis or impact assessment, whereby the impact of a system on product quality is evaluated, and the critical components within those systems are identified. It will separate systems and equipment into those that have direct or indirect product contact, others which have product quality impact, and finally those that do not affect the product in any way.
team representation should be based on the project scope, resource requirements, and key stakeholders. To ensure timely and cost-effective project completion, it is essential to have excellent communication, planning, and coordination between project team members. Organizing these teams, establishing roles, responsibilities and expectations, levels of authority, monitoring performance, and taking corrective actions are fundamental project management issues that challenge project leaders. Facility Systems GMP audit, Design Qualification & Impact Assessment Early involvement by the QA function ensures clear understanding of the projects scope, facility, processes, and equipment. Early involvement by QA, by means of a GMP audit, for example, should provide clear communication of regulatory requirements, ensuring that effective procedures and practices are established upfront for incorporation into the project. This GMP audit can be conducted in parallel with the impact assessment, if required. The functional design of the system or equipment must be confirmed as being correct and appropriate for the requirements of the URS. This confirmation is made by detailed comparisons of the functional design with regulatory requirements, company procedures, manufacturer s documentation, and the URS in a formal DQ protocol. Once the DQ is complete, a risk analysis or impact assessment can be conducted. The key to successful project implementation is a well-defined project scope, which enables the validation team to determine the degree of effort and level of resources required, enabling them to focus on its defined responsibilities. It is the function of the facility, equipment, or utility that determines what level of commissioning and qualification are needed. Developing the project commissioning and validation scope is normally accomplished by conducting a risk analysis or impact assessment, whereby the impact of a system on product quality is evaluated, and the critical components within those systems are identified. It will separate systems and equipment into those that have direct or indirect product contact, others which have product quality impact, and finally those that do not affect the product in any way.
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So called direct impact systems are expected to have an impact on product quality. Examples of such systems are when they are either in direct physical contact with the drug product; a system that produces data that is used to accept or reject products; or the system is a process control system that may affect product quality. Indirect impact systems are not expected to have an impact on product quality. Examples here include support systems such as heat transfer systems, electric power, and non-process water sources. These are noncritical and need not be qualified. However, the monitoring and control of critical parameters, which these support systems affect, should be validated. Both types of systems will require commissioning. However, the direct impact systems will be subject to supplementary qualification practices to meet the additional regulatory requirements. No impact systems will not have any impact, either directly or indirectly, on product quality. These systems are designed and commissioned following Good Engineering Practice (GEP) only. Decisions relating to the extent of validation using impact analysis based upon GMP significance is a major opportunity for streamlining validation. This assessment should be carried out by those with the appropriate skills and experience necessary to make an informed decision based on a comprehensive understanding of the product, process, and nature of the facility systems and components. Typical stakeholders may include representatives with process, engineering, validation, and QA experience and responsibilities. A typical pharmaceutical company will expect to qualify and validate the following for a new or upgraded manufacturing facility: Facility design, installation, and function Critical process support utilities e.g., HVAC, compressed air, steam, dust extraction, and water purification systems Process equipment design, installation, and operation
So called direct impact systems are expected to have an impact on product quality. Examples of such systems are when they are either in direct physical contact with the drug product; a system that produces data that is used to accept or reject products; or the system is a process control system that may affect product quality. Indirect impact systems are not expected to have an impact on product quality. Examples here include support systems such as heat transfer systems, electric power, and non-process water sources. These are noncritical and need not be qualified. However, the monitoring and control of critical parameters, which these support systems affect, should be validated. Both types of systems will require commissioning. However, the direct impact systems will be subject to supplementary qualification practices to meet the additional regulatory requirements. No impact systems will not have any impact, either directly or indirectly, on product quality. These systems are designed and commissioned following Good Engineering Practice (GEP) only. Decisions relating to the extent of validation using impact analysis based upon GMP significance is a major opportunity for streamlining validation. This assessment should be carried out by those with the appropriate skills and experience necessary to make an informed decision based on a comprehensive understanding of the product, process, and nature of the facility systems and components. Typical stakeholders may include representatives with process, engineering, validation, and QA experience and responsibilities. A typical pharmaceutical company will expect to qualify and validate the following for a new or upgraded manufacturing facility: Facility design, installation, and function Critical process support utilities e.g., HVAC, compressed air, steam, dust extraction, and water purification systems Process equipment design, installation, and operation
Once the facility has been validated, the following would then need to be conducted: Operating staff training Manufacturing process validation
Once the facility has been validated, the following would then need to be conducted: Operating staff training Manufacturing process validation
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Equipment cleaning procedure validation FAT and Pre-Delivery Inspections (PDI)
Equipment cleaning procedure validation FAT and Pre-Delivery Inspections (PDI)
Wherever possible, advantages should be taken of the opportunity to inspect and test systems or major system components before delivery to the site. This allows a quicker and more efficient remedy of any failings, and avoids delays to the project schedule that would result from discovering problems later on-site. FAT at an equipment vendors location prior to shipping equipment to the facility can significantly reduce overall project timelines if performed properly, in that some or all of the FAT documentation may be used to support commissioning and SAT. FAT ensures that specified equipment performs to the manufacturers designs, and that certification is supplied to confirm correct performance. At this stage, all safety and quality critical items should be examined and documented. All of the documentation should be reviewed and anomalies addressed, together with any issues pertaining to calibration and connected utilities. These operational FATs should contribute to the OQ effort. Pre-delivery inspection and testing of major system components before delivery to the site may also contribute to the IQ effort. Commissioning Plant commissioning efforts address the foundation of the manufacturing facility, and is a vital element in the process of delivering new facilities. It ensures that all building and process systems are designed, installed, functionally tested, and capable of operation in conformance with the design intent. Unlike regulated qualification practices, commissioning activities do not need to meet the compliance needs imposed by regulatory authorities. For the pharmaceutical industry, commissioning may be defined as follows: Commissioning is the process of ensuring all building and process systems are designed, installed, functionally tested, and capable of operation in conformance with the design intent. (6) Another definition is that commissioning is a well planned, documented, and managed engineering approach to the start-up and turnover of facilities, systems, and equipment to the end-user that results in a safe and functional environment that meets established design requirements and stakeholder expectations. (7)
Wherever possible, advantages should be taken of the opportunity to inspect and test systems or major system components before delivery to the site. This allows a quicker and more efficient remedy of any failings, and avoids delays to the project schedule that would result from discovering problems later on-site. FAT at an equipment vendors location prior to shipping equipment to the facility can significantly reduce overall project timelines if performed properly, in that some or all of the FAT documentation may be used to support commissioning and SAT. FAT ensures that specified equipment performs to the manufacturers designs, and that certification is supplied to confirm correct performance. At this stage, all safety and quality critical items should be examined and documented. All of the documentation should be reviewed and anomalies addressed, together with any issues pertaining to calibration and connected utilities. These operational FATs should contribute to the OQ effort. Pre-delivery inspection and testing of major system components before delivery to the site may also contribute to the IQ effort. Commissioning Plant commissioning efforts address the foundation of the manufacturing facility, and is a vital element in the process of delivering new facilities. It ensures that all building and process systems are designed, installed, functionally tested, and capable of operation in conformance with the design intent. Unlike regulated qualification practices, commissioning activities do not need to meet the compliance needs imposed by regulatory authorities. For the pharmaceutical industry, commissioning may be defined as follows: Commissioning is the process of ensuring all building and process systems are designed, installed, functionally tested, and capable of operation in conformance with the design intent. (6) Another definition is that commissioning is a well planned, documented, and managed engineering approach to the start-up and turnover of facilities, systems, and equipment to the end-user that results in a safe and functional environment that meets established design requirements and stakeholder expectations. (7)
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Commissioning process steps include system documentation, equipment start-up, control system calibration, testing and balancing, performance testing, and turnover.
Commissioning process steps include system documentation, equipment start-up, control system calibration, testing and balancing, performance testing, and turnover.
Figure 2 depicts the interaction and interdependency between commissioning and validation activities, and shows the field effort required to validate direct impact critical facility systems, as opposed to no impact and non-critical facility systems. Commissioning incorporates a systematic method of testing and documenting of systems and equipment at the conclusion of project construction, but prior to process validation. Commissioning execution typically occurs between physical completion and turnover to either the
Figure 2 depicts the interaction and interdependency between commissioning and validation activities, and shows the field effort required to validate direct impact critical facility systems, as opposed to no impact and non-critical facility systems. Commissioning incorporates a systematic method of testing and documenting of systems and equipment at the conclusion of project construction, but prior to process validation. Commissioning execution typically occurs between physical completion and turnover to either the
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operational user or the validation team, and entails activities, such as system inspection (visual testing), adjustment and regulation, testing (individual system tests), and performance testing (combined system tests). Commissioning also includes various activities designed to prepare equipment for startup and validation, such as installation of filters, alignment of motors, lubrication, and calibration of critical gauges and instruments. The development of SOP, Preventive Maintenance (PM) procedures, and user training may also be conducted early on during the commissioning phase of the project. Training is a neglected element of most commissioning programs, and proper personnel training should become a part of the commissioning or qualification program (normally during OQ). Knowledge transfer and personnel training is a systematic approach designed to help operating, technical, and maintenance personnel develop the skills and knowledge to start-up and sustain new operations at high levels of performance. On completion of the commissioning activities, there is normally a phased project turnover of the system or equipment to the user or validation team, together with the commissioning documentation (for example; drawings, design documents, test procedures, factory test evidence, field test evidence, calibration data, inspection records, and Operation and Maintenance [O&M] manuals). Delays of many months are encountered when facilities do not have an orderly commissioning/turnover process. Installation and Operational Qualification (IQ/OQ) IQ and OQ are regulated activities that are part of final qualification activities before performance qualification or process validation begins. Commissioning and qualification testing are interrelated, and testing performed during commissioning may be used to support qualification activities. IQ protocol execution should tie in closely with the construction schedule so that as sections or systems are completed, they are inspected, and the results documented in the IQ protocol.
operational user or the validation team, and entails activities, such as system inspection (visual testing), adjustment and regulation, testing (individual system tests), and performance testing (combined system tests). Commissioning also includes various activities designed to prepare equipment for startup and validation, such as installation of filters, alignment of motors, lubrication, and calibration of critical gauges and instruments. The development of SOP, Preventive Maintenance (PM) procedures, and user training may also be conducted early on during the commissioning phase of the project. Training is a neglected element of most commissioning programs, and proper personnel training should become a part of the commissioning or qualification program (normally during OQ). Knowledge transfer and personnel training is a systematic approach designed to help operating, technical, and maintenance personnel develop the skills and knowledge to start-up and sustain new operations at high levels of performance. On completion of the commissioning activities, there is normally a phased project turnover of the system or equipment to the user or validation team, together with the commissioning documentation (for example; drawings, design documents, test procedures, factory test evidence, field test evidence, calibration data, inspection records, and Operation and Maintenance [O&M] manuals). Delays of many months are encountered when facilities do not have an orderly commissioning/turnover process. Installation and Operational Qualification (IQ/OQ) IQ and OQ are regulated activities that are part of final qualification activities before performance qualification or process validation begins. Commissioning and qualification testing are interrelated, and testing performed during commissioning may be used to support qualification activities. IQ protocol execution should tie in closely with the construction schedule so that as sections or systems are completed, they are inspected, and the results documented in the IQ protocol.
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Once the results of the IQ execution have been completed, the OQ execution can begin. OQ protocol execution should tie in closely with the commissioning schedule so that as sections, systems, or equipment is completed, they are tested, and the results documented in the OQ protocol. As part of equipment or system IQ/OQ activities, computerrelated functionality may also be validated as part of combined or individual protocols. Qualification protocols are normally required to be written for direct impact systems. These are individual documents describing the system under consideration, documentation deliverables, testing plans, acceptance criteria, and forms for recording the test results that ensure that a system is installed, and operates in accordance with predetermined specifications. IQ and OQ protocols may be combined into one document, or the protocols may be kept as separate individual documents. After protocol execution is complete, approval by the original protocol signatories is required before the PQ can proceed. For this approval review, a summary report may be written at the end of the OQ stage to summarize the IQ/OQ results, and provide data analysis. It also may be written at the completion of PQ. Performance Qualification (PQ) PQ is the final qualification activity before PV begins. Only direct impact systems will be subject to PQ. The PQ integrates procedures, personnel, systems, and materials to verify that the pharmaceutical utility, environment, equipment, or support system produces the required output. This output may be a product contact utility (clean compressed air, water purified etc.), or environment (HVAC system). At this stage of the qualification exercise, the commissioning activities are normally complete, IQ and OQ are complete, all deviations or snag items from IQ/OQ have been resolved, pertinent SOPs have been approved, and training in these areas are complete and documented. OQ and PQ protocols may be combined into one document, or the protocols may be kept as separate individual documents.
Once the results of the IQ execution have been completed, the OQ execution can begin. OQ protocol execution should tie in closely with the commissioning schedule so that as sections, systems, or equipment is completed, they are tested, and the results documented in the OQ protocol. As part of equipment or system IQ/OQ activities, computerrelated functionality may also be validated as part of combined or individual protocols. Qualification protocols are normally required to be written for direct impact systems. These are individual documents describing the system under consideration, documentation deliverables, testing plans, acceptance criteria, and forms for recording the test results that ensure that a system is installed, and operates in accordance with predetermined specifications. IQ and OQ protocols may be combined into one document, or the protocols may be kept as separate individual documents. After protocol execution is complete, approval by the original protocol signatories is required before the PQ can proceed. For this approval review, a summary report may be written at the end of the OQ stage to summarize the IQ/OQ results, and provide data analysis. It also may be written at the completion of PQ. Performance Qualification (PQ) PQ is the final qualification activity before PV begins. Only direct impact systems will be subject to PQ. The PQ integrates procedures, personnel, systems, and materials to verify that the pharmaceutical utility, environment, equipment, or support system produces the required output. This output may be a product contact utility (clean compressed air, water purified etc.), or environment (HVAC system). At this stage of the qualification exercise, the commissioning activities are normally complete, IQ and OQ are complete, all deviations or snag items from IQ/OQ have been resolved, pertinent SOPs have been approved, and training in these areas are complete and documented. OQ and PQ protocols may be combined into one document, or the protocols may be kept as separate individual documents.
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On completion of the construction phase, individual systems and process areas are reviewed to satisfy compliance with the project objectives and regulatory requirements. Related Programs Related programs are undertaken to provide assistance and information in support of the qualification activities, for example, safety, SOPs, training, PM and calibration, and cleaning validation. The activities within these programs can be addressed and managed through the VMP, or through independent plans and programs referenced within the VMP. Commissioning and qualification of facilities, equipment, and utilities are the foundation for process validation. Process validation includes consideration of the suitability of the materials used, and the physical plant, as well as the performance and reliability of equipment and systems. It is normally addressed separately to the facility qualification plan. Plant Release and Start-up Once IQ/OQ/PQ and process validation is complete, planning for the plant start-up can commence. The facility and systems are considered acceptable for use following the review of the validation documentation that concludes the validation has met all the requirements set forth in the approved validation plan, and that all deviations incurred during this validation have been identified, documented, and resolved. Authority to release and use the facility is granted by the QA Unit. Planning for plant start-up includes planning for technology transfer, personnel training, logistics of raw materials, finished product distribution, and technical and business systems. These elements must be in place prior to start-up to ensure seamless operation of the system. When problems are experienced during the commissioning, qualification, and validation process, it is usually due to the lack of start-up planning at the projects scheduling stage. Periodic Review, Change Control and Revalidation To verify compliance with procedures and policies, validated systems should be subjected to ongoing operational audits. Review of a previously validated system is recommended to identify possible trends in the systems
On completion of the construction phase, individual systems and process areas are reviewed to satisfy compliance with the project objectives and regulatory requirements. Related Programs Related programs are undertaken to provide assistance and information in support of the qualification activities, for example, safety, SOPs, training, PM and calibration, and cleaning validation. The activities within these programs can be addressed and managed through the VMP, or through independent plans and programs referenced within the VMP. Commissioning and qualification of facilities, equipment, and utilities are the foundation for process validation. Process validation includes consideration of the suitability of the materials used, and the physical plant, as well as the performance and reliability of equipment and systems. It is normally addressed separately to the facility qualification plan. Plant Release and Start-up Once IQ/OQ/PQ and process validation is complete, planning for the plant start-up can commence. The facility and systems are considered acceptable for use following the review of the validation documentation that concludes the validation has met all the requirements set forth in the approved validation plan, and that all deviations incurred during this validation have been identified, documented, and resolved. Authority to release and use the facility is granted by the QA Unit. Planning for plant start-up includes planning for technology transfer, personnel training, logistics of raw materials, finished product distribution, and technical and business systems. These elements must be in place prior to start-up to ensure seamless operation of the system. When problems are experienced during the commissioning, qualification, and validation process, it is usually due to the lack of start-up planning at the projects scheduling stage. Periodic Review, Change Control and Revalidation To verify compliance with procedures and policies, validated systems should be subjected to ongoing operational audits. Review of a previously validated system is recommended to identify possible trends in the systems
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performance. This periodic review should be conducted according to an SOP, and in accordance with schedules established and documented in QA audit plans. The frequency of audits should be based on system importance relative to regulated operations. Upon completion of the evaluation, a report of the findings should be issued, including all actions recommended, and the corresponding supportive documentation. The result of this periodic review will then determine the need and degree of system revalidation, if necessary. Change control is essential to the successful management of a system, and should be in-place when the system enters into service. After a system is validated and becomes operational, changes will occur during its operational lifetime, that may impact its validation status. If a change is deemed to have a potential effect on the systems validation, appropriate requalifications and/or revalidation measures should be executed, documented, and approved. Change control maintains functionality as the system evolves, and provides an audit trail that helps maintain the system in an operating and validated state Summary of Project Performance and Outcome In general, the plant start-up went according to schedule with strict timeline and budgetary objectives being met, and cGMP compliance was maintained in the plant throughout the construction phases. Phase One was built, commissioned, and validated by May 2000. (stability chambers, December 1999; pilot lab, September 1999; and chemical weighing in May 2000), Phase One was also audited and approved by the local regulatory agency in July 2000, and by corporate quality auditors in October 2000. Phase Two (Granulation) was built, commissioned, and validated by May 2001. Phase Three (Compression) was built, commissioned, and validated by June 2001. Phase Four (Compression and Encapsulation) was built, commissioned, and validated by January, 2002. Corporate quality auditors inspected and approved the upgraded plant in February 2002.
performance. This periodic review should be conducted according to an SOP, and in accordance with schedules established and documented in QA audit plans. The frequency of audits should be based on system importance relative to regulated operations. Upon completion of the evaluation, a report of the findings should be issued, including all actions recommended, and the corresponding supportive documentation. The result of this periodic review will then determine the need and degree of system revalidation, if necessary. Change control is essential to the successful management of a system, and should be in-place when the system enters into service. After a system is validated and becomes operational, changes will occur during its operational lifetime, that may impact its validation status. If a change is deemed to have a potential effect on the systems validation, appropriate requalifications and/or revalidation measures should be executed, documented, and approved. Change control maintains functionality as the system evolves, and provides an audit trail that helps maintain the system in an operating and validated state Summary of Project Performance and Outcome In general, the plant start-up went according to schedule with strict timeline and budgetary objectives being met, and cGMP compliance was maintained in the plant throughout the construction phases. Phase One was built, commissioned, and validated by May 2000. (stability chambers, December 1999; pilot lab, September 1999; and chemical weighing in May 2000), Phase One was also audited and approved by the local regulatory agency in July 2000, and by corporate quality auditors in October 2000. Phase Two (Granulation) was built, commissioned, and validated by May 2001. Phase Three (Compression) was built, commissioned, and validated by June 2001. Phase Four (Compression and Encapsulation) was built, commissioned, and validated by January, 2002. Corporate quality auditors inspected and approved the upgraded plant in February 2002.
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Certain delays were encountered due to several deficiencies and/or changes in facility or HVAC design; for example, in the Phase Two HVAC installation, with consequent delays in the commissioning, validation activities, and start-up of the granulation facility. Various process system delays were also encountered in Phase Two due to control problems with the new Air Handling Units (AHUs) process equipment. Delays were experienced with the commissioning and validation of the Phase Three HVAC system due to chemical de-humidifier and AHU control issues with the resultant delay in start-up of the compression facility. As phases were completed, knowledge, and experience gained from the design, construction, commissioning, and validation of preceding phases was used and incorporated to improve these activities in subsequent phases.
Certain delays were encountered due to several deficiencies and/or changes in facility or HVAC design; for example, in the Phase Two HVAC installation, with consequent delays in the commissioning, validation activities, and start-up of the granulation facility. Various process system delays were also encountered in Phase Two due to control problems with the new Air Handling Units (AHUs) process equipment. Delays were experienced with the commissioning and validation of the Phase Three HVAC system due to chemical de-humidifier and AHU control issues with the resultant delay in start-up of the compression facility. As phases were completed, knowledge, and experience gained from the design, construction, commissioning, and validation of preceding phases was used and incorporated to improve these activities in subsequent phases.
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In this three-year project, the validation team, consisting of three permanent company employees, generally met all key project milestones, while writing and executing approximately fifty-four validation protocols. Figure 3 shows a breakdown of how their time was spent until the end of Phase Two on various validation activities, including the time taken from the pre-approval of the protocol to the approval of the final validation report. Phase Two of the project, as opposed to Phase Three, involved the installation and qualification/re-qualification of many process equipment items. As shown, the time spent on equipment qualification was significant, and this was due mostly to the delay in completion and approval of many protocols, and their final approval due to the late development, sign-off, and training of operating, cleaning, and maintenance SOPs, PM, calibration schedules, and turnover of commissioning documentation and O&M
In this three-year project, the validation team, consisting of three permanent company employees, generally met all key project milestones, while writing and executing approximately fifty-four validation protocols. Figure 3 shows a breakdown of how their time was spent until the end of Phase Two on various validation activities, including the time taken from the pre-approval of the protocol to the approval of the final validation report. Phase Two of the project, as opposed to Phase Three, involved the installation and qualification/re-qualification of many process equipment items. As shown, the time spent on equipment qualification was significant, and this was due mostly to the delay in completion and approval of many protocols, and their final approval due to the late development, sign-off, and training of operating, cleaning, and maintenance SOPs, PM, calibration schedules, and turnover of commissioning documentation and O&M
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manuals. Figure 4 shows a breakdown of how their time was spent until the end of Phase Four on the various qualification activities.
manuals. Figure 4 shows a breakdown of how their time was spent until the end of Phase Four on the various qualification activities.
Figure 5 shows a final breakdown of how their entire time was spent on the various qualification activities. As part of the validation deliverables, more than sixty operating, cleaning and maintenance SOPs were written/revised, and manu-facturing operators and engineering personnel were trained on them. From the middle of Phase Two, certain strategies were introduced to improve the efficiency, and streamline the validation process for the final two project phases.
Figure 5 shows a final breakdown of how their entire time was spent on the various qualification activities. As part of the validation deliverables, more than sixty operating, cleaning and maintenance SOPs were written/revised, and manu-facturing operators and engineering personnel were trained on them. From the middle of Phase Two, certain strategies were introduced to improve the efficiency, and streamline the validation process for the final two project phases.
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For example, working more closely and meeting regularly with the project and engineering functions, the consulting engineer and contractors ensured that the validation and documentation requirements were clearly understood early on in that particular construction phase schedule. Fieldwork was substantially reduced by integrating installation, commissioning, qualification, and engineering activities. Combining activities and minimizing resource requirements also substantially reduced the amount of fieldwork. The use of standardized documentation templates significantly reduced the time taken to write, review, and approve validation protocols and reports. Identifying SOPs, training, calibration, and maintenance requirements early on in the construction phase enabled operating, maintenance, set-up, and calibration issues to be addressed before qualification commenced. Based upon research conducted in the U.S., it has been estimated that as much as 75% of the dollars spent on validation activities are spent on facility and equipment quali-fication.(8) Industry norms estimate the cost of facility validation to generally range anywhere from four percent up to 10% of the total
For example, working more closely and meeting regularly with the project and engineering functions, the consulting engineer and contractors ensured that the validation and documentation requirements were clearly understood early on in that particular construction phase schedule. Fieldwork was substantially reduced by integrating installation, commissioning, qualification, and engineering activities. Combining activities and minimizing resource requirements also substantially reduced the amount of fieldwork. The use of standardized documentation templates significantly reduced the time taken to write, review, and approve validation protocols and reports. Identifying SOPs, training, calibration, and maintenance requirements early on in the construction phase enabled operating, maintenance, set-up, and calibration issues to be addressed before qualification commenced. Based upon research conducted in the U.S., it has been estimated that as much as 75% of the dollars spent on validation activities are spent on facility and equipment quali-fication.(8) Industry norms estimate the cost of facility validation to generally range anywhere from four percent up to 10% of the total
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installed cost of a project. Recent experiences also indicate that the commissioning process costs between two to four percent of the total installed cost.(6) Figure 6 gives a breakdown of the overall costs for this particular project. In summary, all the major validation milestones, i.e., cost, quality, and time schedule, were met for this project. Further integrating and streamlining the validation approach has the potential to provide even more relief for overburdened validation resources, and these aspects will be discussed in this article. The Use of an Integrated and Streamlined Validation Approach What can be done to control the cost and time of validation? As usual, the answer lies in the management of the validation process. In this section, means to achieve total project success, by using an integrated and streamlined approach to optimize commissioning and validation activities on a project, are discussed. Total project success would mean: Reduced project costs Reduced project schedules and better overall schedule management Reduced start-up time needed in the field Less defects Reduced internal resource needs at the end of the project Adherence to all compliance requirements Better overall project quality
installed cost of a project. Recent experiences also indicate that the commissioning process costs between two to four percent of the total installed cost.(6) Figure 6 gives a breakdown of the overall costs for this particular project. In summary, all the major validation milestones, i.e., cost, quality, and time schedule, were met for this project. Further integrating and streamlining the validation approach has the potential to provide even more relief for overburdened validation resources, and these aspects will be discussed in this article. The Use of an Integrated and Streamlined Validation Approach What can be done to control the cost and time of validation? As usual, the answer lies in the management of the validation process. In this section, means to achieve total project success, by using an integrated and streamlined approach to optimize commissioning and validation activities on a project, are discussed. Total project success would mean: Reduced project costs Reduced project schedules and better overall schedule management Reduced start-up time needed in the field Less defects Reduced internal resource needs at the end of the project Adherence to all compliance requirements Better overall project quality
Streamlining existing commissioning and validation activities adheres to the following basic principles: Start the project by evaluating the impact of a system on product quality Focus resources on the qualification of systems with direct impact on product quality according to GMP Provide contractors, vendors, and engineers with the project validation requirements up-front to enable them to plan installations to meet these requirements
Streamlining existing commissioning and validation activities adheres to the following basic principles: Start the project by evaluating the impact of a system on product quality Focus resources on the qualification of systems with direct impact on product quality according to GMP Provide contractors, vendors, and engineers with the project validation requirements up-front to enable them to plan installations to meet these requirements
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Design and commission those systems that have no direct impact on product quality according to GEP Enhance the commissioning, qualification, and validation documentation generation, review, and approval processes Integrate the commissioning and qualification activities to avoid duplication of work Conduct training of employees, contractors, consultants, and other personnel early in the project lifecycle.
Design and commission those systems that have no direct impact on product quality according to GEP Enhance the commissioning, qualification, and validation documentation generation, review, and approval processes Integrate the commissioning and qualification activities to avoid duplication of work Conduct training of employees, contractors, consultants, and other personnel early in the project lifecycle.
The following details some strategies that could be followed to reduce project resource requirements, and improve the efficiencies of the commissioning and validation programs: Structure the Project Team Appropriately and Define their Roles and Responsibilities Pharmaceutical companies typically require considerable resources, in terms of time, money, and personnel, to validate a cGMP facility. This can be an overwhelming task to a small company or plant with limited resources. Therefore, fundamental project management issues, such as the organization of the project team, establishing roles, responsibilities (project ownership) and expectations, monitoring performance, especially the commissioning process, and taking corrective action are constant challenges to the project manager in achieving cost, schedule, and quality advantages. Taking full advantage of this integrated approach, and subsequently controlling cost, requires a multi-disciplinary team, effective planning and communication, management, and enforcement of the validation plan. The project manager must be capable of managing his own time and resources, the time and resources of every member of the project team, while also weighing the needs of the organization against the needs of the project. Project team representation should be based on the project scope, resource requirements, and key stakeholders impacted by the project outcome. Individual team members need to understand the roles, responsibilities, and levels of authority for both the team leader and other team members. They also must appreciate how the team will be managed e.g., meeting frequency, reports, communications, problem resolution, etc. Typical functions and roles that make up a project team include a project sponsor, project manager, engineering and maintenance, procurement, construction, commissioning leader, operations/
The following details some strategies that could be followed to reduce project resource requirements, and improve the efficiencies of the commissioning and validation programs: Structure the Project Team Appropriately and Define their Roles and Responsibilities Pharmaceutical companies typically require considerable resources, in terms of time, money, and personnel, to validate a cGMP facility. This can be an overwhelming task to a small company or plant with limited resources. Therefore, fundamental project management issues, such as the organization of the project team, establishing roles, responsibilities (project ownership) and expectations, monitoring performance, especially the commissioning process, and taking corrective action are constant challenges to the project manager in achieving cost, schedule, and quality advantages. Taking full advantage of this integrated approach, and subsequently controlling cost, requires a multi-disciplinary team, effective planning and communication, management, and enforcement of the validation plan. The project manager must be capable of managing his own time and resources, the time and resources of every member of the project team, while also weighing the needs of the organization against the needs of the project. Project team representation should be based on the project scope, resource requirements, and key stakeholders impacted by the project outcome. Individual team members need to understand the roles, responsibilities, and levels of authority for both the team leader and other team members. They also must appreciate how the team will be managed e.g., meeting frequency, reports, communications, problem resolution, etc. Typical functions and roles that make up a project team include a project sponsor, project manager, engineering and maintenance, procurement, construction, commissioning leader, operations/
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production, validation, QA, Quality Control (QC), R&D, safety, and a technical writer. To streamline the validation process, it is critical to form the validation team at the start of the project. This will ensure that all validation requirements are integrated into the project design specifications. Project qualification milestones and information that needs to be captured and documented are identified to ensure the completion of all validation responsibilities in a timely and effective manner. Ensure that the most technically qualified individuals or groups are empowered to lead, for example, equipment qualification efforts. Individual project team members need to be intimately involved in the project so that they gain a thorough knowledge of the intended use, design, and operational characteristics of the relevant systems. For validation to be fully integrated into the project, it must also be the responsibility of every member of the rest of the project team to ensure that whatever work is done, it is with the validation endpoint in mind. This will help streamline the validation activities where possible, so that validation does not duplicate work carried out by other disciplines, but merely audits and identifies areas that are incomplete or non-conforming, and collects and collates relevant data. Conduct an Impact Analysis Early on in the Project It is imperative that companies new to validation and with limited resources, establish a reasonable approach to their facility validation.(9) An all too common mistake for many in this situation is to overdo it, and start-up companies typically do not have the resources to support this all or nothing approach. Base the level of documentation and validation on the complexity of the system/facility, available resources, and the potential risk/cost.(10) Performing an impact analysis and identifying direct impact or GMP critical systems and processes for validation can focus resources on systems with direct impact on product quality. This assessment should be integrated into the overall project schedule, and be made by those with appropriate skills and experience to make an informed decision. Indirect impact or no impact systems and their components will not be subjected to qualification, but will be designed, installed, and commissioned according to GEP only. Decisions relating to the extent of validation using this impact analysis are a major opportunity for streamlining validation, as long as the rationale for
production, validation, QA, Quality Control (QC), R&D, safety, and a technical writer. To streamline the validation process, it is critical to form the validation team at the start of the project. This will ensure that all validation requirements are integrated into the project design specifications. Project qualification milestones and information that needs to be captured and documented are identified to ensure the completion of all validation responsibilities in a timely and effective manner. Ensure that the most technically qualified individuals or groups are empowered to lead, for example, equipment qualification efforts. Individual project team members need to be intimately involved in the project so that they gain a thorough knowledge of the intended use, design, and operational characteristics of the relevant systems. For validation to be fully integrated into the project, it must also be the responsibility of every member of the rest of the project team to ensure that whatever work is done, it is with the validation endpoint in mind. This will help streamline the validation activities where possible, so that validation does not duplicate work carried out by other disciplines, but merely audits and identifies areas that are incomplete or non-conforming, and collects and collates relevant data. Conduct an Impact Analysis Early on in the Project It is imperative that companies new to validation and with limited resources, establish a reasonable approach to their facility validation.(9) An all too common mistake for many in this situation is to overdo it, and start-up companies typically do not have the resources to support this all or nothing approach. Base the level of documentation and validation on the complexity of the system/facility, available resources, and the potential risk/cost.(10) Performing an impact analysis and identifying direct impact or GMP critical systems and processes for validation can focus resources on systems with direct impact on product quality. This assessment should be integrated into the overall project schedule, and be made by those with appropriate skills and experience to make an informed decision. Indirect impact or no impact systems and their components will not be subjected to qualification, but will be designed, installed, and commissioned according to GEP only. Decisions relating to the extent of validation using this impact analysis are a major opportunity for streamlining validation, as long as the rationale for
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the decisions taken are documented by the appropriate individuals and are approved. (11) Develop a Robust Validation Master Plan (VMP) If validation is to be integrated into the project, it must have the same status as other activities within the project schedule. The development of a robust validation master plan detailing the scope of work and schedule will ensure that validation is integrated into the project with the same status as other activities within the project schedule. The use of a VMP is an efficient way to insure the requirements for validation are understood, and agreed upon, by everyone involved.(12) The process of integration must begin when conceptual design attributes are transformed into layout drawings, equipment data sheets, and process flow diagrams. The VMP should outline the overall validation philosophy and approach to be used throughout the project lifecycle and should include the following: The qualification rationale and strategy (the VMP could also include the commissioning strategy and plans, but this is uncommon) A list describing the facility, equipment, controls, and systems The process for determining direct, indirect, and no impact systems A detailed testing sequence integrated with the overall construction commissioning and start-up schedule, and reconciled with the VMP The documentation requirements for the project, and Key roles and responsibilities throughout the life of the project
the decisions taken are documented by the appropriate individuals and are approved. (11) Develop a Robust Validation Master Plan (VMP) If validation is to be integrated into the project, it must have the same status as other activities within the project schedule. The development of a robust validation master plan detailing the scope of work and schedule will ensure that validation is integrated into the project with the same status as other activities within the project schedule. The use of a VMP is an efficient way to insure the requirements for validation are understood, and agreed upon, by everyone involved.(12) The process of integration must begin when conceptual design attributes are transformed into layout drawings, equipment data sheets, and process flow diagrams. The VMP should outline the overall validation philosophy and approach to be used throughout the project lifecycle and should include the following: The qualification rationale and strategy (the VMP could also include the commissioning strategy and plans, but this is uncommon) A list describing the facility, equipment, controls, and systems The process for determining direct, indirect, and no impact systems A detailed testing sequence integrated with the overall construction commissioning and start-up schedule, and reconciled with the VMP The documentation requirements for the project, and Key roles and responsibilities throughout the life of the project
The VMP is thus the key that governs the testing and documentation required to satisfy the regulatory authorities. This document will become the common thread for all parties, and thus creates integration and a common mission for the project team. The VMP should become a living document that is periodically updated to reflect current design conditions. Integrate Validation Schedules into the Overall Project Schedule The project manager should ensure the development of a commissioning and validation plan as an integral part of the project plan and schedule. Integrating validation into the overall project schedule can save both time and money. Integrated schedules should be developed with input from the
The VMP is thus the key that governs the testing and documentation required to satisfy the regulatory authorities. This document will become the common thread for all parties, and thus creates integration and a common mission for the project team. The VMP should become a living document that is periodically updated to reflect current design conditions. Integrate Validation Schedules into the Overall Project Schedule The project manager should ensure the development of a commissioning and validation plan as an integral part of the project plan and schedule. Integrating validation into the overall project schedule can save both time and money. Integrated schedules should be developed with input from the
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construction and validation project teams, and be maintained and reissued regularly. IQ/OQ may be conducted as part of the physical completion of the facility, thus tying IQ/OQ closely to the construction contractors scope of work that includes commissioning. To avoid the effort and inconvenience of discovering and rectifying basic problems, it is recommended that all systems go through an informal shakedown phase before IQ/OQ commences. This will help ensure a smooth transition between IQ and OQ, and minimize the number of changes during IQ and OQ. Scheduling of PQ is particularly critical as PQ testing is often the most time consuming part of the qualification. Scheduling should take into account any prerequisites that should be achieved prior to PQ execution (such as commissioning of all support systems, availability of SOPs, system interdependencies). The PQ protocol often receives the greatest amount of scrutiny from the approval team. This often results in a lengthier authorization process, and an adequate amount of time should be allowed in the project schedule for this long approval period. Adopt Formal Commissioning Procedures Depending on the intent of the system, commissioning may be a precursor either to equipment qualification, and ultimately to process validation for direct impact systems. Otherwise, it may be the final activity for indirect impact systems prior to routine operations. If commissioning is not adequately performed, adjustments that would have been recorded on commissioning sheets become non-conformance at the IQ/OQ stage. This is not a desirable consequence, and makes the validation longer and less convincing when audited. The benefits of implementing formal commissioning procedures in facility construction projects are: Verifies that full value is obtained for an owners construction dollar by implementing formal inspection procedures to verify that all systems and equipment are provided, installed, and can be operated as specified and intended
construction and validation project teams, and be maintained and reissued regularly. IQ/OQ may be conducted as part of the physical completion of the facility, thus tying IQ/OQ closely to the construction contractors scope of work that includes commissioning. To avoid the effort and inconvenience of discovering and rectifying basic problems, it is recommended that all systems go through an informal shakedown phase before IQ/OQ commences. This will help ensure a smooth transition between IQ and OQ, and minimize the number of changes during IQ and OQ. Scheduling of PQ is particularly critical as PQ testing is often the most time consuming part of the qualification. Scheduling should take into account any prerequisites that should be achieved prior to PQ execution (such as commissioning of all support systems, availability of SOPs, system interdependencies). The PQ protocol often receives the greatest amount of scrutiny from the approval team. This often results in a lengthier authorization process, and an adequate amount of time should be allowed in the project schedule for this long approval period. Adopt Formal Commissioning Procedures Depending on the intent of the system, commissioning may be a precursor either to equipment qualification, and ultimately to process validation for direct impact systems. Otherwise, it may be the final activity for indirect impact systems prior to routine operations. If commissioning is not adequately performed, adjustments that would have been recorded on commissioning sheets become non-conformance at the IQ/OQ stage. This is not a desirable consequence, and makes the validation longer and less convincing when audited. The benefits of implementing formal commissioning procedures in facility construction projects are: Verifies that full value is obtained for an owners construction dollar by implementing formal inspection procedures to verify that all systems and equipment are provided, installed, and can be operated as specified and intended
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Assures system design performance by testing systems and components in all modes of operation, and verifying proper integration with other building systems Maximizes system operating efficiencies by assuring that design and operational intents are fully understood and implemented Minimizes lost use, down-time, and user inconvenience by assuring that each system is brought on-line and tested prior to system turnover. Avoids financial liabilities by reducing exposure to critical system failures. Reduces maintenance costs and improves maintenance response times by initiating formal operator training and awareness sessions, and providing necessary operating and service manuals. Realizes major cost savings if commissioning protocols are properly integrated into an overall validation plan.
Assures system design performance by testing systems and components in all modes of operation, and verifying proper integration with other building systems Maximizes system operating efficiencies by assuring that design and operational intents are fully understood and implemented Minimizes lost use, down-time, and user inconvenience by assuring that each system is brought on-line and tested prior to system turnover. Avoids financial liabilities by reducing exposure to critical system failures. Reduces maintenance costs and improves maintenance response times by initiating formal operator training and awareness sessions, and providing necessary operating and service manuals. Realizes major cost savings if commissioning protocols are properly integrated into an overall validation plan.
Integrate Commissioning with Validation Activities There are advantages of time, money, and quality in integrating many of the functions carried out by skilled resources, such as engineering contractor and validation teams. A great deal of validation work, that traditionally has been carried out separately from the engineering work, can be associated with the engineering and commissioning of a facility, and be integrated into the project sphere. The responsibility for timely and appropriate execution then becomes that of the combined validation and engineering team, so that they become indispensable to each other and reduce the time spent on validating the facility and scaling up to production. The use of a competent expert multi-disciplinary team will ensure that best practice is deployed and duplication of activities is avoided. Excellent documentation of commissioning can be conducive to a successful validation effort if it is in a form consistent with the requirements of cGMP and quality.(13) Integrating activities such as DQ, FAT, SAT, and commissioning into the qualification and validation activities can control validation costs. Instruments and equipment can be verified at the vendors site during FAT and PDI. This reduces delays caused by identifying problems only after equipment is delivered. If these items are not altered or dismantled in any
Integrate Commissioning with Validation Activities There are advantages of time, money, and quality in integrating many of the functions carried out by skilled resources, such as engineering contractor and validation teams. A great deal of validation work, that traditionally has been carried out separately from the engineering work, can be associated with the engineering and commissioning of a facility, and be integrated into the project sphere. The responsibility for timely and appropriate execution then becomes that of the combined validation and engineering team, so that they become indispensable to each other and reduce the time spent on validating the facility and scaling up to production. The use of a competent expert multi-disciplinary team will ensure that best practice is deployed and duplication of activities is avoided. Excellent documentation of commissioning can be conducive to a successful validation effort if it is in a form consistent with the requirements of cGMP and quality.(13) Integrating activities such as DQ, FAT, SAT, and commissioning into the qualification and validation activities can control validation costs. Instruments and equipment can be verified at the vendors site during FAT and PDI. This reduces delays caused by identifying problems only after equipment is delivered. If these items are not altered or dismantled in any
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way for transport, these checks, if properly documented, could be used in support of SAT or qualification activities. For OQ, by identifying the critical operational criteria that require testing prior to the facility, utility, or equipment being used in production, and planning the schedule accordingly, the duration of testing can be shortened. If FAT is executed for equipment i.e., alarms and interlocks testing, some or all of these tests can be performed at the vendors site, or these tests can be performed as part of commissioning, and be used in support of the OQ. Performance testing carried out as part of commissioning can contribute to PQ if performed consistent with qualification practices. Phase where testing conducted Commissioning Validation Phase Phase FAT SAT IQ OQ PQ x x x x x x x x x x x x x
way for transport, these checks, if properly documented, could be used in support of SAT or qualification activities. For OQ, by identifying the critical operational criteria that require testing prior to the facility, utility, or equipment being used in production, and planning the schedule accordingly, the duration of testing can be shortened. If FAT is executed for equipment i.e., alarms and interlocks testing, some or all of these tests can be performed at the vendors site, or these tests can be performed as part of commissioning, and be used in support of the OQ. Performance testing carried out as part of commissioning can contribute to PQ if performed consistent with qualification practices. Phase where testing conducted Commissioning Validation Phase Phase FAT SAT IQ OQ PQ x x x x x x x x x x x x x
FBD Tests / Verifications
FBD Tests / Verifications
Functional Design/Specification verification As-Built and Plant & Instrumentation Diagrams (P&ID) verification Materials of construction verification Welding information verification Critical component verification Control system component verification Instrument calibration verification Alarms and interlocks testing FBD sequence of operation testing FBD recipe handling and recovery tests Control system security access testing FBD operating parameter control testing FBD: Fluid Bed Dryer SAT: Site Acceptance Testing OQ: Operational qualification
x x x x x x x x x
Functional Design/Specification verification As-Built and Plant & Instrumentation Diagrams (P&ID) verification Materials of construction verification Welding information verification Critical component verification Control system component verification Instrument calibration verification Alarms and interlocks testing FBD sequence of operation testing FBD recipe handling and recovery tests Control system security access testing FBD operating parameter control testing FBD: Fluid Bed Dryer SAT: Site Acceptance Testing OQ: Operational qualification
x x x x x x x x x
FAT: Factory Acceptance Testing IQ: Installation qualification PQ: Performance qualification
FAT: Factory Acceptance Testing IQ: Installation qualification PQ: Performance qualification
Figure 7: Example of integrating commissioning and validation testing
Figure 7: Example of integrating commissioning and validation testing
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Thus, if the integrated approach is used and proper inspections, documentation, and certain required field execution work is accomplished by the construction vendors and contractors, then the validation scope can be reduced to that of review, monitoring, and compiling. The integration of commissioning and qualification merges activities, minimizes resource requirements, and streamlines the validation effort by reducing the number of protocols and reports. To illustrate this integrated approach, Figure 7 shows examples of tests and verifications conducted on a new Fluid Bed Dryer (FBD) at various phases of the project. Enhance the Documentation, Documentation Management, and Approval Process The development of validation documentation is an essential part of any successful validation program.(14) In fact, documentation starts the validation process. For validation work to be integrated into the project framework, the paperwork aspects must be kept to what is strictly necessary for validation. Validation must be logical, structured, verifiable, and above all, correctly documented. The biggest problem facing most protocol writers is the lack of information and time. These problems are usually due to poor integration of validation into the project process, validation requirements not being written into the design specifications, protocol requirements not being relayed to a contractor/equipment vendor, late identification of items (e.g., calibration requirements) that should have been incorporated into the design documents, and no cGMP audit being performed on the design documents (design errors being discovered during qualification). So to streamline the validation approach, conduct a documentation gap analysis when the project is in the design phase to define the validation documentation requirements. Then, provide the vendor or contractor with these guidelines to inform them of the documentation requirements in advance. Request that technical information becomes available for the team as detailed design proceeds. This will minimize the validation team having to struggle to obtain the documentation when under pressure during protocol writing/ execution/field work.(11) This enables the team to begin developing the second level task schedules, staffing schedules, validation plans and protocols, sampling plans, test plans, training materials, etc.
Thus, if the integrated approach is used and proper inspections, documentation, and certain required field execution work is accomplished by the construction vendors and contractors, then the validation scope can be reduced to that of review, monitoring, and compiling. The integration of commissioning and qualification merges activities, minimizes resource requirements, and streamlines the validation effort by reducing the number of protocols and reports. To illustrate this integrated approach, Figure 7 shows examples of tests and verifications conducted on a new Fluid Bed Dryer (FBD) at various phases of the project. Enhance the Documentation, Documentation Management, and Approval Process The development of validation documentation is an essential part of any successful validation program.(14) In fact, documentation starts the validation process. For validation work to be integrated into the project framework, the paperwork aspects must be kept to what is strictly necessary for validation. Validation must be logical, structured, verifiable, and above all, correctly documented. The biggest problem facing most protocol writers is the lack of information and time. These problems are usually due to poor integration of validation into the project process, validation requirements not being written into the design specifications, protocol requirements not being relayed to a contractor/equipment vendor, late identification of items (e.g., calibration requirements) that should have been incorporated into the design documents, and no cGMP audit being performed on the design documents (design errors being discovered during qualification). So to streamline the validation approach, conduct a documentation gap analysis when the project is in the design phase to define the validation documentation requirements. Then, provide the vendor or contractor with these guidelines to inform them of the documentation requirements in advance. Request that technical information becomes available for the team as detailed design proceeds. This will minimize the validation team having to struggle to obtain the documentation when under pressure during protocol writing/ execution/field work.(11) This enables the team to begin developing the second level task schedules, staffing schedules, validation plans and protocols, sampling plans, test plans, training materials, etc.
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Approaches to streamline the amount of paperwork required to give sufficient documented evidence of validation could include: Using standardized protocol and report templates wherever possible, so that reviewers become used to protocol formats and contents Structuring executed protocols as reports to obviate the need for writing a separate report. Combining IQ and OQ documents (to IOQ) will result in fewer documents to develop, track, review, and approve. Keep in mind that IQ still must be completed before OQ commences. Include only the critical tests in the protocol, and do not repeat noncritical ones already conducted in FAT or SAT phases. Setting realistic validation protocol acceptance criteria based upon the process demands for reproducibility and product quality. One of the surest ways to create unneeded work, extra cost, and headaches during the validation program is to set unfounded or unrealistic validation acceptance criteria. Recording deviations in the validation protocol and report rather than developing elaborate deviation systems. Ensuring that commissioning documentation for Direct Impact systems are appropriately planned, created, organized, and authorized so that they may become an integral part of the qualification support documentation. Combining engineering and validation information to minimize duplication. If engineering and equipment validation were fully integrated into the engineering documentation with QA review, protocols would not need to contain information that is adequately stated in the engineering documentation and specifications.
Approaches to streamline the amount of paperwork required to give sufficient documented evidence of validation could include: Using standardized protocol and report templates wherever possible, so that reviewers become used to protocol formats and contents Structuring executed protocols as reports to obviate the need for writing a separate report. Combining IQ and OQ documents (to IOQ) will result in fewer documents to develop, track, review, and approve. Keep in mind that IQ still must be completed before OQ commences. Include only the critical tests in the protocol, and do not repeat noncritical ones already conducted in FAT or SAT phases. Setting realistic validation protocol acceptance criteria based upon the process demands for reproducibility and product quality. One of the surest ways to create unneeded work, extra cost, and headaches during the validation program is to set unfounded or unrealistic validation acceptance criteria. Recording deviations in the validation protocol and report rather than developing elaborate deviation systems. Ensuring that commissioning documentation for Direct Impact systems are appropriately planned, created, organized, and authorized so that they may become an integral part of the qualification support documentation. Combining engineering and validation information to minimize duplication. If engineering and equipment validation were fully integrated into the engineering documentation with QA review, protocols would not need to contain information that is adequately stated in the engineering documentation and specifications.
Once qualification protocols are written, they should be approved, and this may be a time consuming process. Several ways to streamline this process include: Minimizing the number of approvals required Clarifying the review process with all parties early in the project Collecting all comments from all parties on one master document Instituting a formalized protocol tracking process
Once qualification protocols are written, they should be approved, and this may be a time consuming process. Several ways to streamline this process include: Minimizing the number of approvals required Clarifying the review process with all parties early in the project Collecting all comments from all parties on one master document Instituting a formalized protocol tracking process
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Minimizing the number of review cycles allowed by the team Implementing a simple review and approval procedure. However, still bear in mind that protocols should be carefully reviewed to minimize deviations and time-consuming explanations of errors in testing or reports. Instituting protocol review meetings for all parties involved Assuring the protocol review and approval process is included in the overall project schedule
Minimizing the number of review cycles allowed by the team Implementing a simple review and approval procedure. However, still bear in mind that protocols should be carefully reviewed to minimize deviations and time-consuming explanations of errors in testing or reports. Instituting protocol review meetings for all parties involved Assuring the protocol review and approval process is included in the overall project schedule
No matter how well you streamline your documentation, there will still be hundreds of documents drawings, specifications, manuals, inspection reports, and testing reports to support the qualification effort, and a document management system needs to be in place. Active Participation of Quality Assurance (QA) Qualification can be greatly enhanced and streamlined by the early involvement of QA to ensure that knowledge, expertise, and input in the areas of GMP, regulatory expectations, and industry trends are incorporated into the project from design concepts forward. This involvement ensures that appropriate quality practices and procedures are adopted early in the project, and ensures those regulatory requirements and expectations are addressed and met. Practical application of regulatory requirements is key in streamlining and efficiently managing qualification activities. QA provides input to the impact analysis, provides feedback, and approves plans and protocols used to conduct qualification activities, results, and conclusions. During the engineering phase of the project, QA may audit the approved equipment and utility system vendors to verify that they have the necessary quality systems in place to ensure quality of their product or service. Part of the integration concept also involves auditing design and construction activities for compliance with cGMPs, verifying documentation, and keeping a close eye on the installation progress throughout the projects construction phase.8 QA should review and approve all commissioning documentation. Appropriate documented change control should exist throughout the life of the project, and through the long-term maintenance of the validation status after the project is completed. The QA unit should be routinely
No matter how well you streamline your documentation, there will still be hundreds of documents drawings, specifications, manuals, inspection reports, and testing reports to support the qualification effort, and a document management system needs to be in place. Active Participation of Quality Assurance (QA) Qualification can be greatly enhanced and streamlined by the early involvement of QA to ensure that knowledge, expertise, and input in the areas of GMP, regulatory expectations, and industry trends are incorporated into the project from design concepts forward. This involvement ensures that appropriate quality practices and procedures are adopted early in the project, and ensures those regulatory requirements and expectations are addressed and met. Practical application of regulatory requirements is key in streamlining and efficiently managing qualification activities. QA provides input to the impact analysis, provides feedback, and approves plans and protocols used to conduct qualification activities, results, and conclusions. During the engineering phase of the project, QA may audit the approved equipment and utility system vendors to verify that they have the necessary quality systems in place to ensure quality of their product or service. Part of the integration concept also involves auditing design and construction activities for compliance with cGMPs, verifying documentation, and keeping a close eye on the installation progress throughout the projects construction phase.8 QA should review and approve all commissioning documentation. Appropriate documented change control should exist throughout the life of the project, and through the long-term maintenance of the validation status after the project is completed. The QA unit should be routinely
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involved in the engineering change management process as changes may alter the impact assessment, change the design concept, or deviate from the original user specification. Greater End User/Stakeholder Participation Direct impact systems demand closer and more comprehensive hands on involvement from the end-user or stakeholder group. Where appropriate, end-users should become involved in vendor audits to evaluate suitable vendors and FAT of systems prior to shipment. The integrated approach to qualification/validation should also change the way in which protocols are executed. Making those who will be operating and maintaining the system a part of the validation procedure is beneficial because of the experience and understanding they gain. Production and engineering should be responsible for ensuring comprehensive testing of mechanical, electrical, and control functionality, and for ensuring that the documentation complies with the companys engineering standards. Validation will then review many of the qualification activities, instead of performing all of the work themselves. This exposure also will be valuable when the need to revalidate arises because of changes or updates to the system. Separate Related Program Verifications from the Validation Protocols Related programs are undertaken to provide assistance and information in support of the qualification activities, for example, safety, SOPs, training, PM, and calibration. Instead of the activities within these programs being addressed and managed through the VMP, they should be handled, where appropriate, through independent plans and programs that are referenced within the VMP. These programs could be handled under the umbrella of a commissioning team represented by engineering, EHS, technical writing, and training. This will mean that these programs will need to be established early on in the project lifecycle. This will streamline the validation approach by segregating the individual qualification protocols. Safe operation is a necessary requirement for all systems. Safety can be managed in a similar way to the qualification program, and the project team can develop a safety plan specific to the project during construction planning to manage safety.
involved in the engineering change management process as changes may alter the impact assessment, change the design concept, or deviate from the original user specification. Greater End User/Stakeholder Participation Direct impact systems demand closer and more comprehensive hands on involvement from the end-user or stakeholder group. Where appropriate, end-users should become involved in vendor audits to evaluate suitable vendors and FAT of systems prior to shipment. The integrated approach to qualification/validation should also change the way in which protocols are executed. Making those who will be operating and maintaining the system a part of the validation procedure is beneficial because of the experience and understanding they gain. Production and engineering should be responsible for ensuring comprehensive testing of mechanical, electrical, and control functionality, and for ensuring that the documentation complies with the companys engineering standards. Validation will then review many of the qualification activities, instead of performing all of the work themselves. This exposure also will be valuable when the need to revalidate arises because of changes or updates to the system. Separate Related Program Verifications from the Validation Protocols Related programs are undertaken to provide assistance and information in support of the qualification activities, for example, safety, SOPs, training, PM, and calibration. Instead of the activities within these programs being addressed and managed through the VMP, they should be handled, where appropriate, through independent plans and programs that are referenced within the VMP. These programs could be handled under the umbrella of a commissioning team represented by engineering, EHS, technical writing, and training. This will mean that these programs will need to be established early on in the project lifecycle. This will streamline the validation approach by segregating the individual qualification protocols. Safe operation is a necessary requirement for all systems. Safety can be managed in a similar way to the qualification program, and the project team can develop a safety plan specific to the project during construction planning to manage safety.
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SOPs are established to ensure that activities are performed consistently every time. They also play an important role in maintaining the validated state of a system. It is recommended that the SOP program be established early on in the project lifecycle. A project team can write SOPs detailing the operation, maintenance, set-up, and calibration of equipment, as well as SOPs for facility and equipment cleaning. These should preferably be written and finalized prior to the PQ phase. Training is listed as a requirement for compliance with cGMPs. Project training, as well as the ongoing training during the lifecycle of the facility, can be administered within a training program. Apart from operational training, relevant regulatory requirements, specifically GMP, Environmental Protection Agency (EPA), and Occupational Safety and Health Administration (OSHA) requirements should also be communicated as part of the training program. The overall PQ process can be streamlined if a proper training program has been put in place before PQ execution. Key factors that should be addressed in training personnel on a new system include; product and personnel workflow, gowning procedures, applicable equipment/system operation and maintenance, cGMP documentation training, environmental monitoring, swabbing and sampling, and change control. Components that have been determined to be critical to product quality will most likely have more frequent calibration and maintenance schedules. In this manner, these programs are key for maintaining a direct impact system in a validated and controlled state. The process of setting up clear and understandable procedures and carrying out a formal criticality assessment will allow preventative maintenance and calibration activities to be managed to concentrate the resource where it is most needed. In this manner, the calibration of critical instruments will be verified in IQ before undergoing any qualification testing, to ensure that the test results in OQ are valid. This verification, along with the calibration certificates and procedures, provide the documented evidence required to demonstrate that a system operates in a controlled state. The integrated and streamlined approach is not a complicated theory or a great technical breakthrough, but merely a logical and practical approach to facility validation. There is agreement within the pharmaceutical industry that the most effective and efficient approach to accomplishing validation
SOPs are established to ensure that activities are performed consistently every time. They also play an important role in maintaining the validated state of a system. It is recommended that the SOP program be established early on in the project lifecycle. A project team can write SOPs detailing the operation, maintenance, set-up, and calibration of equipment, as well as SOPs for facility and equipment cleaning. These should preferably be written and finalized prior to the PQ phase. Training is listed as a requirement for compliance with cGMPs. Project training, as well as the ongoing training during the lifecycle of the facility, can be administered within a training program. Apart from operational training, relevant regulatory requirements, specifically GMP, Environmental Protection Agency (EPA), and Occupational Safety and Health Administration (OSHA) requirements should also be communicated as part of the training program. The overall PQ process can be streamlined if a proper training program has been put in place before PQ execution. Key factors that should be addressed in training personnel on a new system include; product and personnel workflow, gowning procedures, applicable equipment/system operation and maintenance, cGMP documentation training, environmental monitoring, swabbing and sampling, and change control. Components that have been determined to be critical to product quality will most likely have more frequent calibration and maintenance schedules. In this manner, these programs are key for maintaining a direct impact system in a validated and controlled state. The process of setting up clear and understandable procedures and carrying out a formal criticality assessment will allow preventative maintenance and calibration activities to be managed to concentrate the resource where it is most needed. In this manner, the calibration of critical instruments will be verified in IQ before undergoing any qualification testing, to ensure that the test results in OQ are valid. This verification, along with the calibration certificates and procedures, provide the documented evidence required to demonstrate that a system operates in a controlled state. The integrated and streamlined approach is not a complicated theory or a great technical breakthrough, but merely a logical and practical approach to facility validation. There is agreement within the pharmaceutical industry that the most effective and efficient approach to accomplishing validation
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is to incorporate the validation process into the engineering, procurement, construction, commissioning, and start-up activities associated with a project.(10) Figure 8 depicts how commissioning, qualification, and validation can be integrated
is to incorporate the validation process into the engineering, procurement, construction, commissioning, and start-up activities associated with a project.(10) Figure 8 depicts how commissioning, qualification, and validation can be integrated
This integral approach, as opposed to treating validation as an event in the project lifecycle, will reduce overall project cost and schedule duration, and provide real value-added benefits in the start-up of cGMP compliant facilities. Properly executed validation pays for itself, often in non-financial ways. In summary, the adoption of this integrated and streamlined validation approach will provide the following advantages: Strong management support for this cost-effective validation approach
This integral approach, as opposed to treating validation as an event in the project lifecycle, will reduce overall project cost and schedule duration, and provide real value-added benefits in the start-up of cGMP compliant facilities. Properly executed validation pays for itself, often in non-financial ways. In summary, the adoption of this integrated and streamlined validation approach will provide the following advantages: Strong management support for this cost-effective validation approach
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Uniformity of approach to commissioning, and validation issues with direct input from the project team Optimal usage of available personnel, and proper establishment of priorities through central planning, coordination, and monitoring Optimal usage of technical knowledge from all project team members Effective training of operators in new processes and equipment by actively involving them in validation studies Enhancement of the quality awareness of personnel resulting from active involvement in the project Positive contribution by Industry to the development of emerging cGMP industry validation standards, together with the regulator of the South African pharmaceutical industry, the Medicines Control Council.
Uniformity of approach to commissioning, and validation issues with direct input from the project team Optimal usage of available personnel, and proper establishment of priorities through central planning, coordination, and monitoring Optimal usage of technical knowledge from all project team members Effective training of operators in new processes and equipment by actively involving them in validation studies Enhancement of the quality awareness of personnel resulting from active involvement in the project Positive contribution by Industry to the development of emerging cGMP industry validation standards, together with the regulator of the South African pharmaceutical industry, the Medicines Control Council.
Adopting and applying these practical, integrated, and streamlined proposals can substantially reduce total validation costs. In this case study, validation time and costs for the latter phases of the project were reduced by as much as 50%. Conclusion The word validation has a negative connotation in the pharmaceutical industry, and is still understood by some as unrestrained bureaucracy, paperwork, and procedures whose roots and logic are obscure, and that only serve to slow down progress. In a typical fast track project, this perception further reinforces the views in the minds of some project managers and senior management, governed by budgets and timelines, that validation does not provide beneficial contribution to a project. Validation has in fact given the pharmaceutical industry many positive benefits; we have more assurance of safe and quality products, equipment and systems are more reliable, there is improved process understanding, we have more scientific data on which to base justifications and corrective actions, process-related recalls have been reduced over the last decade, and processes are more reproducible. However, the original visions of validation making, for example, scale-ups from development to routine production more efficient, increasing production
Adopting and applying these practical, integrated, and streamlined proposals can substantially reduce total validation costs. In this case study, validation time and costs for the latter phases of the project were reduced by as much as 50%. Conclusion The word validation has a negative connotation in the pharmaceutical industry, and is still understood by some as unrestrained bureaucracy, paperwork, and procedures whose roots and logic are obscure, and that only serve to slow down progress. In a typical fast track project, this perception further reinforces the views in the minds of some project managers and senior management, governed by budgets and timelines, that validation does not provide beneficial contribution to a project. Validation has in fact given the pharmaceutical industry many positive benefits; we have more assurance of safe and quality products, equipment and systems are more reliable, there is improved process understanding, we have more scientific data on which to base justifications and corrective actions, process-related recalls have been reduced over the last decade, and processes are more reproducible. However, the original visions of validation making, for example, scale-ups from development to routine production more efficient, increasing production
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throughput, reducing in-process, and final product testing, reducing the incidence for reworks, retests, and returns, have all not been realized. As facility construction costs continue to escalate, pharmaceutical companies will continually struggle with the challenge of meeting regulatory requirements and running a profitable business. The current in cGMP requires us to always improve, so Industry must continue to search for methods that reduce costs and improve efficiency. As scientists, validation professionals should never allow themselves to become complacent about investigating and employing new approaches and technologies.(9) The rate of change in technology, legislation, and professional practices is now extremely rapid. With the fields of quality assurance and regulatory compliance in a state of constant flux, validation is in a key position to take the lead, refocus, and begin to dispel the negative perceptions and reverse this disturbing trend toward unnecessary or inefficient facility validation activities to provide positive impact to the corporate bottom line.(15) Validation is a function of risk aversion, and the cost of validation is related to the amount of risk that we wish to avert.(12) This article demonstrates that design, engineering, commissioning, and validation activities can be integrated and streamlined to accelerate the start-up effort, reduce the validation effort and costs, produce superior documentation, and ensure that product is produced in a cGMP-compliant facility. It also proves that even though the original focus of validation was to satisfy regulatory expectations, facility validation, has in fact, become good business and engineering practice that enhances reliability, cost, and quality. Validation ultimately results in bottom line cost savings. About the Authors Graham Wrigley is the Validation Manager for the Pfizer Global Manufacturing plant in Cape Town, South Africa. His group supports process development, process optimization, and all validation activities required to support the manufacture of Over-The-Counter (OTC) healthcare and pharmaceutical products. Graham is a registered pharmacist with 21 years of broad-based experience in the healthcare industry (pharmaceutical industry experience in areas of production, technical services, quality assurance, and validation). He holds a Masters Degree in Industrial Pharmacy.
throughput, reducing in-process, and final product testing, reducing the incidence for reworks, retests, and returns, have all not been realized. As facility construction costs continue to escalate, pharmaceutical companies will continually struggle with the challenge of meeting regulatory requirements and running a profitable business. The current in cGMP requires us to always improve, so Industry must continue to search for methods that reduce costs and improve efficiency. As scientists, validation professionals should never allow themselves to become complacent about investigating and employing new approaches and technologies.(9) The rate of change in technology, legislation, and professional practices is now extremely rapid. With the fields of quality assurance and regulatory compliance in a state of constant flux, validation is in a key position to take the lead, refocus, and begin to dispel the negative perceptions and reverse this disturbing trend toward unnecessary or inefficient facility validation activities to provide positive impact to the corporate bottom line.(15) Validation is a function of risk aversion, and the cost of validation is related to the amount of risk that we wish to avert.(12) This article demonstrates that design, engineering, commissioning, and validation activities can be integrated and streamlined to accelerate the start-up effort, reduce the validation effort and costs, produce superior documentation, and ensure that product is produced in a cGMP-compliant facility. It also proves that even though the original focus of validation was to satisfy regulatory expectations, facility validation, has in fact, become good business and engineering practice that enhances reliability, cost, and quality. Validation ultimately results in bottom line cost savings. About the Authors Graham Wrigley is the Validation Manager for the Pfizer Global Manufacturing plant in Cape Town, South Africa. His group supports process development, process optimization, and all validation activities required to support the manufacture of Over-The-Counter (OTC) healthcare and pharmaceutical products. Graham is a registered pharmacist with 21 years of broad-based experience in the healthcare industry (pharmaceutical industry experience in areas of production, technical services, quality assurance, and validation). He holds a Masters Degree in Industrial Pharmacy.
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Jan du Preez, is Head of Method Development and Validation at the Research Institute for Industrial Pharmacy (Potchefstroom University for Christian Higher Education). He has 25 years experience in product development, analytical chemistry, and physical pharmacy research. References 1 Stocker, A.C., Why Does Validation Cost so Much and Take so Long? (and What we Can do About it). Journal of Validation Technology. Vol. 1, No. 1 (January) 1994. p 5. 2 Gloystein, L., Protocol Structure and IQ/OQ Costs. Journal of Validation Technology. Vol. 3, No. 2 (February). 1997. p 140. 3 Pharmaceutical Inspection Co-operation Scheme (PIC/S). Recommendations on Validation. PIC/S Secretariat, August 2001: 2. 4 Powell-Evans, K. Presentation on Streamlining Validation. Institute of Validation, United Kingdom. 1999. 5 James, P., Integrated Validation: A Way of Streamlining Projects to Reduce Project Validation Time and Cost. Journal of Pharmaceutical Engineering. January/February 1998. p. 78. 6 Signore, A.A., Good Commissioning Practices: Strategic Opportunities for Pharmaceutical Manufacturing. Journal of Pharmaceutical Engineering. May/June 1999. 57, 64 - 65. 7 ISPE Baseline Engineering Guide. Commissioning and Qualification. ISPE; Volume 5, First Edition. March 2001: 12, 25. 8 Odum, J.N. The integration of design, construction, and validation: solving a validation challenge. Journal of Biopharm. Vol. 36, No. 38 (November) 1998. p. 40. 9 Flaherty, W.T., Facility Validation: Management Issues. Journal of Validation Technology. Vol. 2, No. 3 (March) 1996. Pp. 247-248. 10 Stotz, R.W., Controlling the High Cost of Validation. Journal of Validation Technology. Vol. 3, No. 2 (February) 1997: Pp. 108-110. 11 Hargroves, J., Cost-Effective Approaches to Validation. Journal of Validation Technology. Vol. 3, No. 2 (February). 1997. Pp. 131-132. 12 ISPE San Francisco Chapter. Streamlining validation. Journal of Pharmaceutical Engineering. January/February 1998. Pp. 16-17.
Jan du Preez, is Head of Method Development and Validation at the Research Institute for Industrial Pharmacy (Potchefstroom University for Christian Higher Education). He has 25 years experience in product development, analytical chemistry, and physical pharmacy research. References 1 Stocker, A.C., Why Does Validation Cost so Much and Take so Long? (and What we Can do About it). Journal of Validation Technology. Vol. 1, No. 1 (January) 1994. p 5. 2 Gloystein, L., Protocol Structure and IQ/OQ Costs. Journal of Validation Technology. Vol. 3, No. 2 (February). 1997. p 140. 3 Pharmaceutical Inspection Co-operation Scheme (PIC/S). Recommendations on Validation. PIC/S Secretariat, August 2001: 2. 4 Powell-Evans, K. Presentation on Streamlining Validation. Institute of Validation, United Kingdom. 1999. 5 James, P., Integrated Validation: A Way of Streamlining Projects to Reduce Project Validation Time and Cost. Journal of Pharmaceutical Engineering. January/February 1998. p. 78. 6 Signore, A.A., Good Commissioning Practices: Strategic Opportunities for Pharmaceutical Manufacturing. Journal of Pharmaceutical Engineering. May/June 1999. 57, 64 - 65. 7 ISPE Baseline Engineering Guide. Commissioning and Qualification. ISPE; Volume 5, First Edition. March 2001: 12, 25. 8 Odum, J.N. The integration of design, construction, and validation: solving a validation challenge. Journal of Biopharm. Vol. 36, No. 38 (November) 1998. p. 40. 9 Flaherty, W.T., Facility Validation: Management Issues. Journal of Validation Technology. Vol. 2, No. 3 (March) 1996. Pp. 247-248. 10 Stotz, R.W., Controlling the High Cost of Validation. Journal of Validation Technology. Vol. 3, No. 2 (February) 1997: Pp. 108-110. 11 Hargroves, J., Cost-Effective Approaches to Validation. Journal of Validation Technology. Vol. 3, No. 2 (February). 1997. Pp. 131-132. 12 ISPE San Francisco Chapter. Streamlining validation. Journal of Pharmaceutical Engineering. January/February 1998. Pp. 16-17.
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13 Angelucci, L.A., Validation & Commissioning. Journal of Pharmaceutical Engineering. January/February 1998. p. 40. 14 Castilla, B. and Sena, F.J., Validation Documentation: A Winning Approach. Journal of Validation Technology. Vol. 7, No. 2 (February). 2001: 116. 15 Ransdell, T.E., The Cost of Validation. Journal of Validation Technology. Vol. 3, No. 2 (February). 1997. p. 142. Suggested Reading The following specific journal articles have been identified as providing many arguments for scientists to investigate and employ new validation procedures and approaches in the field of facility validation. Angelucci, L., Master Planning. Journal of Validation Technology. Vol. 3, No. 2 (February) 1997. Pp. 167-175. Adamson, J.R., An Approach to Validation. Journal of Pharmaceutical Engineering;. September/October 1992. Pp. 16-22. Buchholz, S., A Rapid Validation Approach: Reducing the Time and Costs Associated with Validation. Journal of Biopharm. January 1997. Pp. 50-53. DeLucia, J.A., Preventative Validation. Journal of Validation Technology. Vol. 3, No. 2 (February) 1997. p. 141. Dominy, K.S. & Fazio, M.A., The Integrated Validation Project Approach. Journal of Pharmaceutical Engineering. July/ August 1995. Pp. 50-58. Goswami, P.E.; Lorenz, D & Lorenz, M.R., Facility Commissioning Basics and Engineering Design Documentation Requirements. Journal of Pharmaceutical Engineering. March/April 1996. Pp. 14-18. Hess, A., An Integrated Approach to Validation. Journal of Biopharm. March 1998. Pp. 42-44. International Society for Pharmaceutical Engineering (ISPE). 2001. Baseline Pharmaceutical Engineering Guides for New and Renovated Facilities: Commissioning and Qualification. Vol. 5 (March). Pp. 11124. International Society for Pharmaceutical Engineering (ISPE). 2001. Baseline Pharmaceutical Engineering Guides for New and Renovated Facilities: Oral Solid Dosage Forms. Vol. 5 (March). Pp. 67-74.
13 Angelucci, L.A., Validation & Commissioning. Journal of Pharmaceutical Engineering. January/February 1998. p. 40. 14 Castilla, B. and Sena, F.J., Validation Documentation: A Winning Approach. Journal of Validation Technology. Vol. 7, No. 2 (February). 2001: 116. 15 Ransdell, T.E., The Cost of Validation. Journal of Validation Technology. Vol. 3, No. 2 (February). 1997. p. 142. Suggested Reading The following specific journal articles have been identified as providing many arguments for scientists to investigate and employ new validation procedures and approaches in the field of facility validation. Angelucci, L., Master Planning. Journal of Validation Technology. Vol. 3, No. 2 (February) 1997. Pp. 167-175. Adamson, J.R., An Approach to Validation. Journal of Pharmaceutical Engineering;. September/October 1992. Pp. 16-22. Buchholz, S., A Rapid Validation Approach: Reducing the Time and Costs Associated with Validation. Journal of Biopharm. January 1997. Pp. 50-53. DeLucia, J.A., Preventative Validation. Journal of Validation Technology. Vol. 3, No. 2 (February) 1997. p. 141. Dominy, K.S. & Fazio, M.A., The Integrated Validation Project Approach. Journal of Pharmaceutical Engineering. July/ August 1995. Pp. 50-58. Goswami, P.E.; Lorenz, D & Lorenz, M.R., Facility Commissioning Basics and Engineering Design Documentation Requirements. Journal of Pharmaceutical Engineering. March/April 1996. Pp. 14-18. Hess, A., An Integrated Approach to Validation. Journal of Biopharm. March 1998. Pp. 42-44. International Society for Pharmaceutical Engineering (ISPE). 2001. Baseline Pharmaceutical Engineering Guides for New and Renovated Facilities: Commissioning and Qualification. Vol. 5 (March). Pp. 11124. International Society for Pharmaceutical Engineering (ISPE). 2001. Baseline Pharmaceutical Engineering Guides for New and Renovated Facilities: Oral Solid Dosage Forms. Vol. 5 (March). Pp. 67-74.
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Lien, E.B. & Schultz, B., A Structured Approach to Validation. Journal of Pharmaceutical Engineering. November/December 1991. Pp. 17-21. Medina, E.M. Project Programming to Start-up. Journal of Pharmaceutical Engineering. July/August 1999. Pp. 62-69. Mitchell, L, Morrison, S. & Veit, E., Determining Criticality and Complexity: A Step-by-Step Approach to Tailoring Appropriate Validation. Journal of Validation Technology. Vol. 2. No. 4. April 1996. Pp. 286-298. Noy, R.J., Validation of a Consumer Healthcare Facility: A Case Study in Time and Cost Reduction. Journal of Validation Technology. Vol. 3, No.1. January 1996. Pp. 30-37. Powell-Evans, K., Streamlining Validation; Value Added Qualifications. Institute of Validation. December 2000. Newsletter. Stoker, A.C. & Embree, J.A., Creating Cost Effective Biotech Facilities. Journal of Pharmaceutical Engineering. May/June 1991. Pp. 37-45. Wheeler, W.P., Commissioning: A Vital Precursor to Validation. Journal of Pharmaceutical Engineering. July/August 1994. Pp. 48-56.
Lien, E.B. & Schultz, B., A Structured Approach to Validation. Journal of Pharmaceutical Engineering. November/December 1991. Pp. 17-21. Medina, E.M. Project Programming to Start-up. Journal of Pharmaceutical Engineering. July/August 1999. Pp. 62-69. Mitchell, L, Morrison, S. & Veit, E., Determining Criticality and Complexity: A Step-by-Step Approach to Tailoring Appropriate Validation. Journal of Validation Technology. Vol. 2. No. 4. April 1996. Pp. 286-298. Noy, R.J., Validation of a Consumer Healthcare Facility: A Case Study in Time and Cost Reduction. Journal of Validation Technology. Vol. 3, No.1. January 1996. Pp. 30-37. Powell-Evans, K., Streamlining Validation; Value Added Qualifications. Institute of Validation. December 2000. Newsletter. Stoker, A.C. & Embree, J.A., Creating Cost Effective Biotech Facilities. Journal of Pharmaceutical Engineering. May/June 1991. Pp. 37-45. Wheeler, W.P., Commissioning: A Vital Precursor to Validation. Journal of Pharmaceutical Engineering. July/August 1994. Pp. 48-56.
process qualification: water used in production of API
process qualification: water used in production of API
Where Purified Water is used for the manufacturing of API, the raw water is generally (i) Treated with Alum to remove colloidal matter. (ii) Filtered through Sand filter, cartridge Filter to remove particulate matter (iii) Treated with Charcoal to remove colouring matter (iv) Passed through resins to remove soluble salts The entire process is carefully designed & validated to convert the raw water into purified water meeting pharmacopoeial requirements. The performance of the purification process is checked as per the following: Test Description Acidity or Alkalinity Requirement It should be clear, colourless, odorless and tasteless liquid. To 10 ml. Freshly boiled and cooled water in a borosilicate glass flask, add 0.05 ml of methyl red solution, the resulting solution should not be red. To 10 ml of water add 0.1 ml of bromothymol blue solution; the resulting solution should not be blue. To 20 ml of water add 1 ml of alkaline potassium mercuric - iodide reagent and allow to stand for 5 minutes. When viewed vertically the solution should not be more intensely coloured than a solution prepared at the same time by adding 1 ml of alkaline potassium mercuric-iodide solution to a mixture of 4 ml of ammonium standard (1 ppm NH4 ) and 16 ml of ammonia-free water (0.2 ppm ) To 100 ml of water add 2 ml of ammonia Magnesium buffer pH 10.0, 50 mg of mordant black II mixture and 0.5 ml of 0.1 M disodium edetate. A blue colour should not be produced.
Where Purified Water is used for the manufacturing of API, the raw water is generally (i) Treated with Alum to remove colloidal matter. (ii) Filtered through Sand filter, cartridge Filter to remove particulate matter (iii) Treated with Charcoal to remove colouring matter (iv) Passed through resins to remove soluble salts The entire process is carefully designed & validated to convert the raw water into purified water meeting pharmacopoeial requirements. The performance of the purification process is checked as per the following: Test Description Acidity or Alkalinity Requirement It should be clear, colourless, odorless and tasteless liquid. To 10 ml. Freshly boiled and cooled water in a borosilicate glass flask, add 0.05 ml of methyl red solution, the resulting solution should not be red. To 10 ml of water add 0.1 ml of bromothymol blue solution; the resulting solution should not be blue. To 20 ml of water add 1 ml of alkaline potassium mercuric - iodide reagent and allow to stand for 5 minutes. When viewed vertically the solution should not be more intensely coloured than a solution prepared at the same time by adding 1 ml of alkaline potassium mercuric-iodide solution to a mixture of 4 ml of ammonium standard (1 ppm NH4 ) and 16 ml of ammonia-free water (0.2 ppm ) To 100 ml of water add 2 ml of ammonia Magnesium buffer pH 10.0, 50 mg of mordant black II mixture and 0.5 ml of 0.1 M disodium edetate. A blue colour should not be produced.
Ammonium
Ammonium
Calcium
Calcium
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Heavy Metals
Chloride
In a glass evaporating dish evaporate 150 ml to 15 ml on a water bath.12 ml of the resulting solution complies with limit test for heavy metals, (limit 0.1 ppm). Use lead standard solution (limit 1 ppm Pb) to prepare the standard. To 10 ml of water add 1 ml of 2M nitric acid & 0.2 ml of 0.1 M silver nitrate. The appearance of the solution does not change within 15 minutes. To 5 ml of water in a test tube immersed in ice add 0.4 ml of a 10% w/v solution of potassium chloride, 0.1 ml of diphenylamine solution and, drop-wise with shaking 5 ml of sulphuric acid. Transfer the tube to a cold water-bath at 50C and allow to stand for 15 minutes. Any blue colour in the solution should not be more intense than that in a solution prepared at the same time and in the same manner using a mixture of 4.5 ml of nitrate free water and 0.5 ml of nitrate standard solution (2 ppm NO4") (0.2 ppm). To 10 ml of water add 0.1 ml of 2M hydrochloric acid and 0.1 ml of 0.25 M Barium Chloride. The solution should show no change in appearance for at least one hour. To 100 ml of water add 10 ml of 1M Sulphuric Acid and 0.1 ml of 0.02 M Potassium Permanganate VS and boil for 5 minutes. The pink colour should be completely discharged. 100 ml of water is evaporated to dryness on a water bath and dried at 100C to 105C. Leaves not more than 0.001 % w/v of residue. If the water intended for use in the manufacture of dialysis solutions, it complies with the test for aluminium. To 400 ml add 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R. The solution complies with the limit test for
Heavy Metals
Chloride
In a glass evaporating dish evaporate 150 ml to 15 ml on a water bath.12 ml of the resulting solution complies with limit test for heavy metals, (limit 0.1 ppm). Use lead standard solution (limit 1 ppm Pb) to prepare the standard. To 10 ml of water add 1 ml of 2M nitric acid & 0.2 ml of 0.1 M silver nitrate. The appearance of the solution does not change within 15 minutes. To 5 ml of water in a test tube immersed in ice add 0.4 ml of a 10% w/v solution of potassium chloride, 0.1 ml of diphenylamine solution and, drop-wise with shaking 5 ml of sulphuric acid. Transfer the tube to a cold water-bath at 50C and allow to stand for 15 minutes. Any blue colour in the solution should not be more intense than that in a solution prepared at the same time and in the same manner using a mixture of 4.5 ml of nitrate free water and 0.5 ml of nitrate standard solution (2 ppm NO4") (0.2 ppm). To 10 ml of water add 0.1 ml of 2M hydrochloric acid and 0.1 ml of 0.25 M Barium Chloride. The solution should show no change in appearance for at least one hour. To 100 ml of water add 10 ml of 1M Sulphuric Acid and 0.1 ml of 0.02 M Potassium Permanganate VS and boil for 5 minutes. The pink colour should be completely discharged. 100 ml of water is evaporated to dryness on a water bath and dried at 100C to 105C. Leaves not more than 0.001 % w/v of residue. If the water intended for use in the manufacture of dialysis solutions, it complies with the test for aluminium. To 400 ml add 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R. The solution complies with the limit test for
Nitrate
Nitrate
Sulphate
Sulphate
Oxidisable matter
Oxidisable matter
Non-volatile matter
Non-volatile matter
Aluminium
Aluminium
process qualification of water used in production of API
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Microbial load
Pour-Plate Method
Test for E. Coli
Primary Test
aluminium (10 ug/l). Use as the reference solution a mixture of 2 ml of aluminium standard solution (2 ppm Al) R, 10 ml of acetate buffer solution pH 6.0 R and 98 ml of distilled water R. To prepare the blank, use a mixture of 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R. Total viable aerobic count should not be more than 100 micro-organisms per millilitre, determined by membrane filtration, using agar medium B. Using Petri dishes 9 cm in diameter, add to each dish 1 ml of the sample prepared as described and 15 ml to 20 ml of a liquefied agar medium suitable for the cultivation of bacteria (such as medium B), prepare for each medium at least two Petri dishes for each level of dilution. Incubate the plates at 30 to 35C (20 to 25C for fungi) for five days, unless a reliable count is obtained in a shorter time. Select the plates responding to one dilution and showing the highest number of colonies less than 300 (100 colonies for fungi). Take the arithmetic average of the counts and calculate the number of colony forming units per gram or millilitre. Aseptically transfer 1 ml of water sample in sterile screw capped container, add 100 ml Nutrient broth, shake, allow it to stand for 1 hour, and shake again. Loosen the cap and incubate at 37C for 18 to 24 hours. Aseptically transfer 1 ml of enriched culture prepared as above to the tubes containing positive and negative controls and to the tube containing sterile 5 ml Maconkeys broth with inverted Durhams tube. Incubate for 48 hours at 37C. Acid formation (change in colour from red
Microbial load
Pour-Plate Method
Test for E. Coli
Primary Test
aluminium (10 ug/l). Use as the reference solution a mixture of 2 ml of aluminium standard solution (2 ppm Al) R, 10 ml of acetate buffer solution pH 6.0 R and 98 ml of distilled water R. To prepare the blank, use a mixture of 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R. Total viable aerobic count should not be more than 100 micro-organisms per millilitre, determined by membrane filtration, using agar medium B. Using Petri dishes 9 cm in diameter, add to each dish 1 ml of the sample prepared as described and 15 ml to 20 ml of a liquefied agar medium suitable for the cultivation of bacteria (such as medium B), prepare for each medium at least two Petri dishes for each level of dilution. Incubate the plates at 30 to 35C (20 to 25C for fungi) for five days, unless a reliable count is obtained in a shorter time. Select the plates responding to one dilution and showing the highest number of colonies less than 300 (100 colonies for fungi). Take the arithmetic average of the counts and calculate the number of colony forming units per gram or millilitre. Aseptically transfer 1 ml of water sample in sterile screw capped container, add 100 ml Nutrient broth, shake, allow it to stand for 1 hour, and shake again. Loosen the cap and incubate at 37C for 18 to 24 hours. Aseptically transfer 1 ml of enriched culture prepared as above to the tubes containing positive and negative controls and to the tube containing sterile 5 ml Maconkeys broth with inverted Durhams tube. Incubate for 48 hours at 37C. Acid formation (change in colour from red
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Secondary Test
Test for Salmonellae
Primary Test:
to yellow) and gas liberation (gas bubbles in inverted Durhams tube) should not be seen. Add 1 ml of contents of the tube showing acid and gas to each of two tubes containing (a) 5 ml of sterile Maconkeys broth, and (b) 5 ml of sterile peptone water. Incubate for 24 hours and examine tube (a) for acid and gas formation, and tube (b) for presence of indole formation. To test for presence of indole add 0.5ml of Kovacs reagent. Shake well and allow to stand for 1 minute. If a red colour is produced in the reagent layer, indole is present. The presence of acid, gas and indole in the secondary test indicates the presence of E. Coli. Aseptically transfer 1 ml of water sample in sterile screw capped container, add 100 ml Nutrient broth, shake, allow to stand for 1 hour, and shake again. Loosen the cap and incubate at 37C for 18 to 24 hours. Add 1.0 ml of the enriched culture prepared as above to each of two tubes containing (a) 10 ml of salenite F broth and (b) 10 ml of Tetrathionate Broth and incubate at 36C to 38C for 48 hours. From each of these two culture inoculate three plates containing a layer of (i) Brilliant Green Agar, (ii) Desoxycholate Citrate Agar, and (iii) Bismuth Sulphate Agar. Incubate the plates at 36C to 38C for 18 to 24 hours. Colonies confirming to following description shall be absent: 1.Brilliant Green Agar: Small, transparent & colourless, or opaque, pinkish or white (frequently surrounded by a pink or red zone) 2. Deoxycholate Citrate: Colourless and opaque, Agar or without black centres with 3. Bismuth Sulphite Agar: Black or green
Secondary Test
Test for Salmonellae
Primary Test:
to yellow) and gas liberation (gas bubbles in inverted Durhams tube) should not be seen. Add 1 ml of contents of the tube showing acid and gas to each of two tubes containing (a) 5 ml of sterile Maconkeys broth, and (b) 5 ml of sterile peptone water. Incubate for 24 hours and examine tube (a) for acid and gas formation, and tube (b) for presence of indole formation. To test for presence of indole add 0.5ml of Kovacs reagent. Shake well and allow to stand for 1 minute. If a red colour is produced in the reagent layer, indole is present. The presence of acid, gas and indole in the secondary test indicates the presence of E. Coli. Aseptically transfer 1 ml of water sample in sterile screw capped container, add 100 ml Nutrient broth, shake, allow to stand for 1 hour, and shake again. Loosen the cap and incubate at 37C for 18 to 24 hours. Add 1.0 ml of the enriched culture prepared as above to each of two tubes containing (a) 10 ml of salenite F broth and (b) 10 ml of Tetrathionate Broth and incubate at 36C to 38C for 48 hours. From each of these two culture inoculate three plates containing a layer of (i) Brilliant Green Agar, (ii) Desoxycholate Citrate Agar, and (iii) Bismuth Sulphate Agar. Incubate the plates at 36C to 38C for 18 to 24 hours. Colonies confirming to following description shall be absent: 1.Brilliant Green Agar: Small, transparent & colourless, or opaque, pinkish or white (frequently surrounded by a pink or red zone) 2. Deoxycholate Citrate: Colourless and opaque, Agar or without black centres with 3. Bismuth Sulphite Agar: Black or green
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Secondary Test
Perform this test as secondary /confirmatory test: Subculture any colonies showing the characteristics given in Table 1 in Triple Sugar Iron Agar, by first inoculating the surface of the slope and then making a stab culture with the same inoculating needle and at the same time inoculate a tube of Urea Broth. Incubate at 36C to 38C for 18 to 24 hours. The formation of acid and gas in the stab culture ( with or without concomitant blackening ) and the absence of acidity from the surface growth in the triple sugar, iron agar, together with absence of a red colour in the urea broth, indicates the presence of Salmonellae. If acid but no gas is produced in the stab culture, the identity of the organisms should be confirmed by agglutination tests. Control Test : Carry out a control test by repeating the primary and secondary test using 1.0 ml of the enriched culture and a column of broth containing 10 to 50 Salmonellas Abony (NCTC 6017), prepared from a twenty four hour culture in Nutrient Broth, for the inoculation of tubes (a) and (b). The test is invalid if the results do not indicates that the control contains Salmonellae. Test for Pseudomonas Place 1 ml of water in sterile screw - capped jar containing 100 ml of Cetrimide Broth, and incubate at 30C to 32C for 72 hours. Subculture on a plate containing a layer of Cetrimide Agar and incubate at 30C to 32C for 48 hours. Examine the resulting growth by Grams stain. Gram negative bacilli shall be absent. Oxidase test Place 2 or 3 drops of a freshly prepared 1%w/v solution of N,N,N,N-tetramethyl-P Phynylendediammonium dichloride on a piece of filter paper. Whatman No. 1 is suitable) and smear with the suspect colony The purple
Secondary Test
Perform this test as secondary /confirmatory test: Subculture any colonies showing the characteristics given in Table 1 in Triple Sugar Iron Agar, by first inoculating the surface of the slope and then making a stab culture with the same inoculating needle and at the same time inoculate a tube of Urea Broth. Incubate at 36C to 38C for 18 to 24 hours. The formation of acid and gas in the stab culture ( with or without concomitant blackening ) and the absence of acidity from the surface growth in the triple sugar, iron agar, together with absence of a red colour in the urea broth, indicates the presence of Salmonellae. If acid but no gas is produced in the stab culture, the identity of the organisms should be confirmed by agglutination tests. Control Test : Carry out a control test by repeating the primary and secondary test using 1.0 ml of the enriched culture and a column of broth containing 10 to 50 Salmonellas Abony (NCTC 6017), prepared from a twenty four hour culture in Nutrient Broth, for the inoculation of tubes (a) and (b). The test is invalid if the results do not indicates that the control contains Salmonellae. Test for Pseudomonas Place 1 ml of water in sterile screw - capped jar containing 100 ml of Cetrimide Broth, and incubate at 30C to 32C for 72 hours. Subculture on a plate containing a layer of Cetrimide Agar and incubate at 30C to 32C for 48 hours. Examine the resulting growth by Grams stain. Gram negative bacilli shall be absent. Oxidase test Place 2 or 3 drops of a freshly prepared 1%w/v solution of N,N,N,N-tetramethyl-P Phynylendediammonium dichloride on a piece of filter paper. Whatman No. 1 is suitable) and smear with the suspect colony The purple
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colour shall not be obtained within 5 to 10 seconds. Control Test: Carry out a control test by repeating the test adding the prescribed quantity and a volume of broth containing 10 to 50 Pseudomonas Aeruginosa (NCTC 6750 ), prepared from twenty four hour culture in Nutrient Broth, to a sterile, screwcapped jar containing 100 ml of Cetrimide Broth. The test must show Gram negative Bacilli and must also show purple colour when treated with 1.0 % w/v solution of N,N,N,Ntetramethyl-P-Phyenylendediammonium dichloride on a piece of filter paper. Test for Staph. Aureus Place 1 ml of Water sample in a sterile screwcapped jar containing 100 ml of fluid Soyabean Casein digest medium and incubate at 30C to 32C for 72 hours. Subculture on a plate containing a layer of Mannitol Salt Agar medium or Vogel Johnson Agar medium and incubate at 30C to 32C for 48 hours. Examine the resulting growth by Grams stain . Gram positive cocci ( in clusters ) in yellow colonies (in mannitol salt agar medium ) should be absent. Gram positive cocci Black colonies surrounded by yellow zones ( in Vogel Johnson agar medium ) shall be absent. Coagulase Test Transfer representative suspect colonies from the agar surfaces of the mannitol salt agar medium or Vogel Johnson agar medium to individual tubes, each containing 0.5 ml of mammalian, preferably rabbit or horse plasma with or without suitable additives. Incubate in a water bath at 37C examining the tubes at three hours and subsequently at suitable intervals up to 24 hours. The coagulation to any degree shall be absent. Positive Control: Carry out a control test by repeating the test, adding the prescribed quantity and a volume of
colour shall not be obtained within 5 to 10 seconds. Control Test: Carry out a control test by repeating the test adding the prescribed quantity and a volume of broth containing 10 to 50 Pseudomonas Aeruginosa (NCTC 6750 ), prepared from twenty four hour culture in Nutrient Broth, to a sterile, screwcapped jar containing 100 ml of Cetrimide Broth. The test must show Gram negative Bacilli and must also show purple colour when treated with 1.0 % w/v solution of N,N,N,Ntetramethyl-P-Phyenylendediammonium dichloride on a piece of filter paper. Test for Staph. Aureus Place 1 ml of Water sample in a sterile screwcapped jar containing 100 ml of fluid Soyabean Casein digest medium and incubate at 30C to 32C for 72 hours. Subculture on a plate containing a layer of Mannitol Salt Agar medium or Vogel Johnson Agar medium and incubate at 30C to 32C for 48 hours. Examine the resulting growth by Grams stain . Gram positive cocci ( in clusters ) in yellow colonies (in mannitol salt agar medium ) should be absent. Gram positive cocci Black colonies surrounded by yellow zones ( in Vogel Johnson agar medium ) shall be absent. Coagulase Test Transfer representative suspect colonies from the agar surfaces of the mannitol salt agar medium or Vogel Johnson agar medium to individual tubes, each containing 0.5 ml of mammalian, preferably rabbit or horse plasma with or without suitable additives. Incubate in a water bath at 37C examining the tubes at three hours and subsequently at suitable intervals up to 24 hours. The coagulation to any degree shall be absent. Positive Control: Carry out a control test by repeating the test, adding the prescribed quantity and a volume of
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broth containing 10 to 50 Staphylococcus aureus ( ATCC 6538, NCTC 10788 ), prepared from a twenty four hour culture in fluid Soyabean Casein digest medium to a sterile screwcapped jar containing 100 ml of fluid Soyabean Casein digest medium. The test shall show the evidence of Staphyllo coccus aureus
broth containing 10 to 50 Staphylococcus aureus ( ATCC 6538, NCTC 10788 ), prepared from a twenty four hour culture in fluid Soyabean Casein digest medium to a sterile screwcapped jar containing 100 ml of fluid Soyabean Casein digest medium. The test shall show the evidence of Staphyllo coccus aureus
Prerequisites for Successful Validation

Charlie Neal Validation was hinted in the 1960s, almost four decades ago. What has changed over the last 30 to 40 years? Has the overall understanding of the term improved? Have all responsible firms truly embraced validation? Are they doing everything within their power to make validations a success? Unfortunately not. While validation is a very necessary element of any firm that falls under the scrutiny of the governing regulatory agencies both United States and foreign it has not received the recognition it deserves. So often, departments charged with conducting validations are forced into an exiled status, as opposed to being embraced. How can validation professionals bring about a change? How can they assure that proper events occur to achieve successful validation? Why has validation been so misunderstood for the last four decades? How can validation resources go about planning and executing validations? How can a firm be assured that its resources have what it takes to successfully complete a validation? There are thirteen tools or elements that are required for conducting effective validations. Each are presented and discussed in the following sections of this article.
Prerequisites for Successful Validation

Charlie Neal Validation was hinted in the 1960s, almost four decades ago. What has changed over the last 30 to 40 years? Has the overall understanding of the term improved? Have all responsible firms truly embraced validation? Are they doing everything within their power to make validations a success? Unfortunately not. While validation is a very necessary element of any firm that falls under the scrutiny of the governing regulatory agencies both United States and foreign it has not received the recognition it deserves. So often, departments charged with conducting validations are forced into an exiled status, as opposed to being embraced. How can validation professionals bring about a change? How can they assure that proper events occur to achieve successful validation? Why has validation been so misunderstood for the last four decades? How can validation resources go about planning and executing validations? How can a firm be assured that its resources have what it takes to successfully complete a validation? There are thirteen tools or elements that are required for conducting effective validations. Each are presented and discussed in the following sections of this article.
1. UNDERSTANDING
Perhaps the single most important element required is a good understanding of what validation is. This understanding actually goes beyond the basic definitions of validation, beyond the concept of requiring a minimum of three runs. This understanding must be anchored by sufficient years of practical experience and knowledge. It will permit sound and logical decisions, even under the most intense situations. Given the fact that regulated drug manufacturers must perform validations, it is very important that this understanding be shared throughout the
1. UNDERSTANDING
Perhaps the single most important element required is a good understanding of what validation is. This understanding actually goes beyond the basic definitions of validation, beyond the concept of requiring a minimum of three runs. This understanding must be anchored by sufficient years of practical experience and knowledge. It will permit sound and logical decisions, even under the most intense situations. Given the fact that regulated drug manufacturers must perform validations, it is very important that this understanding be shared throughout the
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organization. Afirm derives little benefit if a thorough understanding of validation remains within the validation department, and there is absolutely no concept of the term within the department responsible for approving the validation budget. So often, validation becomes alienated from the rest of the company due to a lack of thorough understanding. Why cant the laboratory use the piece of equipment undergoing validation? Why cant the facility be used before the laboratory has completed analysis of the microbiological data? Why are validations so expensive? Naturally, if the entire company is fairly educated on what validation entails, less time will be required defending validations actions. Good understanding has to be disseminated throughout the entire organization. Of course, it has to begin with the group charged with performing validations. In the end, it is up to the firm to realize the importance of assuring that this understanding is shared among the key groups.
organization. Afirm derives little benefit if a thorough understanding of validation remains within the validation department, and there is absolutely no concept of the term within the department responsible for approving the validation budget. So often, validation becomes alienated from the rest of the company due to a lack of thorough understanding. Why cant the laboratory use the piece of equipment undergoing validation? Why cant the facility be used before the laboratory has completed analysis of the microbiological data? Why are validations so expensive? Naturally, if the entire company is fairly educated on what validation entails, less time will be required defending validations actions. Good understanding has to be disseminated throughout the entire organization. Of course, it has to begin with the group charged with performing validations. In the end, it is up to the firm to realize the importance of assuring that this understanding is shared among the key groups.
2. COMMUNICATION
One of the best methods of improving environmental understanding is through communication. Communication is essential for any activity that requires more than one resource to complete. Hopefully this point is understandable considering that conducting effective validations involve multi-departments. When is validation of unit xyz scheduled to begin? How many resources will be required? When do protocols have to be approved? At what sites will sampling occur? These are typical questions that can best be answered through communication. One of the keys to proper communication is locating the right communication vehicle. Most organizations communicate through one or more of the following methods: Conversations Memos Periodic meetings
2. COMMUNICATION
One of the best methods of improving environmental understanding is through communication. Communication is essential for any activity that requires more than one resource to complete. Hopefully this point is understandable considering that conducting effective validations involve multi-departments. When is validation of unit xyz scheduled to begin? How many resources will be required? When do protocols have to be approved? At what sites will sampling occur? These are typical questions that can best be answered through communication. One of the keys to proper communication is locating the right communication vehicle. Most organizations communicate through one or more of the following methods: Conversations Memos Periodic meetings
templates and tips for qualification protocols
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Training sessions While adequate communication can be obtained through either one of the above, the ideal environment would have all of the above. The point is that s o m e communication is better than n o c o m m u n i c a t i o n .
Training sessions While adequate communication can be obtained through either one of the above, the ideal environment would have all of the above. The point is that s o m e communication is better than n o c o m m u n i c a t i o n .
3. EXPERIENCE
A firm must have resources with solid validation experience in order for their validation program to be successful. Can the average person be expected to perform open heart surgery without proper study/preparation? More simply, can the average person be expected to win a bike race if they have not yet learned to ride a bike? If one has not shouldered the responsibility of performing an Installation Qualification (IQ) on a pump, will they be able to execute the Operational Qualification (OQ)? Well, this same concept holds true for a person charged with planning or executing validations. The point is that the more responsibility a person has shouldered for validation, the greater his experience will be. Likewise, the greater his knowledge, understanding and logic will be. For example, a seasoned validation resource, in the midst of completing a validation, encounters a failure that will necessitate validation to be repeated in its entirety. Working through this series of events will undoubtedly provide the resource with experience in dealing with failure and resolving problems. Now, is it reasonable to expect an inexperienced staff to perform a solid validation? In most cases, no. However, with proper coaching and consultation, some successes can indeed be realized.
3. EXPERIENCE
A firm must have resources with solid validation experience in order for their validation program to be successful. Can the average person be expected to perform open heart surgery without proper study/preparation? More simply, can the average person be expected to win a bike race if they have not yet learned to ride a bike? If one has not shouldered the responsibility of performing an Installation Qualification (IQ) on a pump, will they be able to execute the Operational Qualification (OQ)? Well, this same concept holds true for a person charged with planning or executing validations. The point is that the more responsibility a person has shouldered for validation, the greater his experience will be. Likewise, the greater his knowledge, understanding and logic will be. For example, a seasoned validation resource, in the midst of completing a validation, encounters a failure that will necessitate validation to be repeated in its entirety. Working through this series of events will undoubtedly provide the resource with experience in dealing with failure and resolving problems. Now, is it reasonable to expect an inexperienced staff to perform a solid validation? In most cases, no. However, with proper coaching and consultation, some successes can indeed be realized.
4. COOPERATION AND FOCUS

Why is there a need for cooperation in order for personnel to conduct effective validations? Let us first understand the multitude of departments that sometimes interact during the course of executing validation- Program/ Project Management, Accounting, Validat ion , Quality Control (QC), Project Engineering, Process Engineering, Quality Assurance (QA), M e t r o l o g y,
4. COOPERATION AND FOCUS

Why is there a need for cooperation in order for personnel to conduct effective validations? Let us first understand the multitude of departments that sometimes interact during the course of executing validation- Program/ Project Management, Accounting, Validat ion , Quality Control (QC), Project Engineering, Process Engineering, Quality Assurance (QA), M e t r o l o g y,
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Facilities, Regulatory, etc. It is safe to assume that these departments have an array of priorities, and typically they are not the same as validations. Let us focus on the example of a professional basketball team. Their objective parallels that of a multidisciplined / inter-departmental validation team-both strive for success. The assumption is that each team member is critical to the overall success of the team. Assume that both teams are in the fourth quarter or final phase of their event-the basketball team in the championship game, and the validation team executing the final event prior to initiating product commercialization. If the center on the basketball team loses his desire to play defense, and/or pass to his teammates, how successful will that team be? The same concept applies to the validation team. If someone fails to approve the protocol or to sample per the protocol, the cost of validation will undoubtedly increase. Why? Simply because more time will be spent seeking approvals. Likewise, time will be spent justifying and writing the explanation for why a sample was not initially collected. Cooperation is essential and critical. Therefore, each member must be focused on the overall tasks, and willing to cooperate 100%.
Facilities, Regulatory, etc. It is safe to assume that these departments have an array of priorities, and typically they are not the same as validations. Let us focus on the example of a professional basketball team. Their objective parallels that of a multidisciplined / inter-departmental validation team-both strive for success. The assumption is that each team member is critical to the overall success of the team. Assume that both teams are in the fourth quarter or final phase of their event-the basketball team in the championship game, and the validation team executing the final event prior to initiating product commercialization. If the center on the basketball team loses his desire to play defense, and/or pass to his teammates, how successful will that team be? The same concept applies to the validation team. If someone fails to approve the protocol or to sample per the protocol, the cost of validation will undoubtedly increase. Why? Simply because more time will be spent seeking approvals. Likewise, time will be spent justifying and writing the explanation for why a sample was not initially collected. Cooperation is essential and critical. Therefore, each member must be focused on the overall tasks, and willing to cooperate 100%.
5. RESOURCES
In reality, it does not matter how much knowledge, experience, and understanding a firm has, if they dont allocate the proper resources for conducting effective validations. What do we mean by resources? By resources, we of course mean personnel who will plan and execute, equipment on which validations will be performed on, materials, with which to conduct validations, laboratories that will perform necessary analyses, funding to pay for the validations, and TIME in which to perform validations. Validations can often begin, but cannot be completed if any one of these resources are missing. As an example, consider an autoclave on which a new load configuration requires validation. A w i n d o w has been created by the equipment owner (time, equipment), the owners department has provided all the human resources required (personnel), and the lab is ready for samples (laboratories). However, the validation team has been advised that the laboratory does not have the requ i r e d spore strips (materials) in inventory. Can validation be completed? No, since spore strips are required in order to
5. RESOURCES
In reality, it does not matter how much knowledge, experience, and understanding a firm has, if they dont allocate the proper resources for conducting effective validations. What do we mean by resources? By resources, we of course mean personnel who will plan and execute, equipment on which validations will be performed on, materials, with which to conduct validations, laboratories that will perform necessary analyses, funding to pay for the validations, and TIME in which to perform validations. Validations can often begin, but cannot be completed if any one of these resources are missing. As an example, consider an autoclave on which a new load configuration requires validation. A w i n d o w has been created by the equipment owner (time, equipment), the owners department has provided all the human resources required (personnel), and the lab is ready for samples (laboratories). However, the validation team has been advised that the laboratory does not have the requ i r e d spore strips (materials) in inventory. Can validation be completed? No, since spore strips are required in order to
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assess the efficacy of the cycle. The same holds true for any resource required for validation.
assess the efficacy of the cycle. The same holds true for any resource required for validation.
6. BUDGET
It is important to understand that a successful validation must be done to completion. Typically, it should not be limited by a budget assembled by personnel who have no appreciation for what is required to successfully complete validation. Further, it is important to understand that validations cost money. A rule of thumb has been that equipment qualifications, which are integral parts of validations, are typically 10-20% of the cost of the capital equipment. Where do these charges come from? Typically, these charg e s are related to the time to execute the following cost initiatives: Investigate/acquire information Conduct meetings Plan Put the plan into words (protocol) Execute the plan Troubleshoot and/or resolve problems Summarize the effort Consider how projects are funded within corporations. Each department has to prepare an annual budget for anticipated expenses. It is very important that the anticipated costs are shared with upper management to assure that ample support-or fundingexists. Now consider validation and the bulleted activities listed above. From a corporate standpoint, each one of these elements require time, and therefore have an associated cost. Thus, it is essential that they are reflected in the validation budget.
6. BUDGET
It is important to understand that a successful validation must be done to completion. Typically, it should not be limited by a budget assembled by personnel who have no appreciation for what is required to successfully complete validation. Further, it is important to understand that validations cost money. A rule of thumb has been that equipment qualifications, which are integral parts of validations, are typically 10-20% of the cost of the capital equipment. Where do these charges come from? Typically, these charg e s are related to the time to execute the following cost initiatives: Investigate/acquire information Conduct meetings Plan Put the plan into words (protocol) Execute the plan Troubleshoot and/or resolve problems Summarize the effort Consider how projects are funded within corporations. Each department has to prepare an annual budget for anticipated expenses. It is very important that the anticipated costs are shared with upper management to assure that ample support-or fundingexists. Now consider validation and the bulleted activities listed above. From a corporate standpoint, each one of these elements require time, and therefore have an associated cost. Thus, it is essential that they are reflected in the validation budget.
7. PLAN
A professional sports team cannot be expected to win the championship without a plan. Most of these teams refer to their plans as plays. Without plays, a good offensive football team cannot hope for success against another good teams defense. For example, if the quarterback does not know where his receivers will be, how often would he be able to complete a
7. PLAN
A professional sports team cannot be expected to win the championship without a plan. Most of these teams refer to their plans as plays. Without plays, a good offensive football team cannot hope for success against another good teams defense. For example, if the quarterback does not know where his receivers will be, how often would he be able to complete a
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pass? If a running back did not know his teams blocking strategy, how many yards would he average per play? Per game? Per year? Bear in mind, that conducting validations within most companies will involve a number of departments and disciplines. These disciplines need a plan in order to get good team synerg y. Further, this plan must be communicated in order to be accepted and successful. When should the analytical laboratory receive the samples? How should a deviation be handled? How will chamber temperatures be monitored? When will the first event occur? Will manufacturing assistance be required to execute the validation protocols? It is essential that the lead validation resource know the answer to each of the above questions, and assure that they are shared in pre-validation planning sessions.
pass? If a running back did not know his teams blocking strategy, how many yards would he average per play? Per game? Per year? Bear in mind, that conducting validations within most companies will involve a number of departments and disciplines. These disciplines need a plan in order to get good team synerg y. Further, this plan must be communicated in order to be accepted and successful. When should the analytical laboratory receive the samples? How should a deviation be handled? How will chamber temperatures be monitored? When will the first event occur? Will manufacturing assistance be required to execute the validation protocols? It is essential that the lead validation resource know the answer to each of the above questions, and assure that they are shared in pre-validation planning sessions.
8. TRAINING
Training is essential for any successful validation. Even though the group charged with gathering routine Water-for-Injection (WFI) samples from the plant distillation system knows how to collect regular samples, chances are they will not inherently know how and when to gather samples in support of a new sample port. Thus, the need for training. Typically, this training initiates within the validation group. It is essential that the lead validation resource for a given validation project initiate, facilitate, coordinate, and/or communicate the need for resource training. In some companies, the expectation is that validation resources provide training as required by the validation event. A c t u a l l y, the requirement for training goes beyond the act of mere teaching. The regulating bodies require proper documentation be assembled and maintained to serve as proof that key resources have undergone required training. Proper documentation should minimally include employee identification, a description of the training course, and the date on which training occurred.
8. TRAINING
Training is essential for any successful validation. Even though the group charged with gathering routine Water-for-Injection (WFI) samples from the plant distillation system knows how to collect regular samples, chances are they will not inherently know how and when to gather samples in support of a new sample port. Thus, the need for training. Typically, this training initiates within the validation group. It is essential that the lead validation resource for a given validation project initiate, facilitate, coordinate, and/or communicate the need for resource training. In some companies, the expectation is that validation resources provide training as required by the validation event. A c t u a l l y, the requirement for training goes beyond the act of mere teaching. The regulating bodies require proper documentation be assembled and maintained to serve as proof that key resources have undergone required training. Proper documentation should minimally include employee identification, a description of the training course, and the date on which training occurred.
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9. STANDARD OPERATING PROCEDURES (SOPS)

SOPs capture activities that routinely occur within an organization. Departments charged with abiding by or following these SOPs must first be trained against these SOPs. Many SOPs are typically the offspring of a successful validation. In most cases, equipment operation SOPs are drafted for use during the initial phases of qualification. These SOPs often are not finalized until after the equipments OQ event. A case in point would be an SOP for the set-up and operation of a new piece of equipment. Often, the vendor manuals or the specifications will convey how the equipment is operated. In the OQ phase, this information is usually transcribed for use in the form of a draft SOP. Once the OQ steps are completed, the result should be an SOP that is finalized, approved, trained upon, and implemented for routine use. The expectation is that these SOPs are finalized before the equipment is used to support process validation.
9. STANDARD OPERATING PROCEDURES (SOPS)

SOPs capture activities that routinely occur within an organization. Departments charged with abiding by or following these SOPs must first be trained against these SOPs. Many SOPs are typically the offspring of a successful validation. In most cases, equipment operation SOPs are drafted for use during the initial phases of qualification. These SOPs often are not finalized until after the equipments OQ event. A case in point would be an SOP for the set-up and operation of a new piece of equipment. Often, the vendor manuals or the specifications will convey how the equipment is operated. In the OQ phase, this information is usually transcribed for use in the form of a draft SOP. Once the OQ steps are completed, the result should be an SOP that is finalized, approved, trained upon, and implemented for routine use. The expectation is that these SOPs are finalized before the equipment is used to support process validation.
10. SOLID QUALITY CONTROL (QC)/LAB SUPPORT

During most validations, some laboratory testing will be required. In most cases, this testing is handled by the QC group. In most organizations, QC will shoulder the responsibility to develop and validate the analytical methods used. QC is also expected to provide results in a timely manner. So often, the wait for the receipt of analytical results causes the entire validation project to come to a halt. Why? Because validations are based upon the results obtained. In addition, QC input is required during protocol preparation. If the QC lab lacks organization, maturity, technical competency, appropriated methods, etc. an initiative has to be undertaken to attain laboratory support through a contract laboratory.
10. SOLID QUALITY CONTROL (QC)/LAB SUPPORT

During most validations, some laboratory testing will be required. In most cases, this testing is handled by the QC group. In most organizations, QC will shoulder the responsibility to develop and validate the analytical methods used. QC is also expected to provide results in a timely manner. So often, the wait for the receipt of analytical results causes the entire validation project to come to a halt. Why? Because validations are based upon the results obtained. In addition, QC input is required during protocol preparation. If the QC lab lacks organization, maturity, technical competency, appropriated methods, etc. an initiative has to be undertaken to attain laboratory support through a contract laboratory.
11. SOLID QA SUPPORT

All validation resources may not be the best for adhering to compliance procedures. It is therefore up to Q A to thoroughly police the protocols before, during, and after execution.
11. SOLID QA SUPPORT

All validation resources may not be the best for adhering to compliance procedures. It is therefore up to Q A to thoroughly police the protocols before, during, and after execution.
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This policing must be against internal SOPs and external regulations. The expectation is that QA will enforce any relevant compliance issues, and will thereby prevent an unwanted discovery by auditing bodies. If an auditor uncovers a number of compliance issues, the department that will often be held accountable is QA. It must be understood that a good QAresource often is not a resource that most other operating departments would choose as their best buddy during working hours. However, their value to the success of the organizations validations must not be minimized.
This policing must be against internal SOPs and external regulations. The expectation is that QA will enforce any relevant compliance issues, and will thereby prevent an unwanted discovery by auditing bodies. If an auditor uncovers a number of compliance issues, the department that will often be held accountable is QA. It must be understood that a good QAresource often is not a resource that most other operating departments would choose as their best buddy during working hours. However, their value to the success of the organizations validations must not be minimized.
12. PERMISSION TO CONDUCT PRELIMINARY RUNS

( Trials/Engineering Runs, Demonstrations, etc.) Could one be expected to drive from Maine to California without a map? Would a map exist without some preliminary explorations? Why does an infant crawl before walking? Why do they undergo a period where they will make only one to three steps? With time, they of course, progressively make more steps until they ultimately learn to walk. Walking then becomes natural, and for the most part, faultless. When a system undergoes validation, the desire is that its operation is then faultless. Like walking, validations require practice. Given the fact that validations are typically expensive, it should be understood that anything that would assure that the costs are minimized would be an asset. Therefore, it is advisable that permission be attained to perform some form of preliminary runs. These runs can be used to provide operator training, to investigate values recommended by specifications or vendor equipment manuals, and/or to explore any limits proposed for validation. These trial runs have to be factored into the validation budget. While each will bear a cost, the focus should be the cost of the overall or entire validation program. Consider the OQ effort. Assume that the requisite specifications are generated, and the protocols are then assembled and approved. During execution, it is discovered that the specifications are incorrect, and therefore, multiple deviations will be generated, each requiring time to resolve. Each resolution will minimally require QAs approval. Each approval will require time for explaining the fix to QA ( and / or other approving departments). Typically, the result is a budget that is severely over spent and a black eye for validation.
12. PERMISSION TO CONDUCT PRELIMINARY RUNS

( Trials/Engineering Runs, Demonstrations, etc.) Could one be expected to drive from Maine to California without a map? Would a map exist without some preliminary explorations? Why does an infant crawl before walking? Why do they undergo a period where they will make only one to three steps? With time, they of course, progressively make more steps until they ultimately learn to walk. Walking then becomes natural, and for the most part, faultless. When a system undergoes validation, the desire is that its operation is then faultless. Like walking, validations require practice. Given the fact that validations are typically expensive, it should be understood that anything that would assure that the costs are minimized would be an asset. Therefore, it is advisable that permission be attained to perform some form of preliminary runs. These runs can be used to provide operator training, to investigate values recommended by specifications or vendor equipment manuals, and/or to explore any limits proposed for validation. These trial runs have to be factored into the validation budget. While each will bear a cost, the focus should be the cost of the overall or entire validation program. Consider the OQ effort. Assume that the requisite specifications are generated, and the protocols are then assembled and approved. During execution, it is discovered that the specifications are incorrect, and therefore, multiple deviations will be generated, each requiring time to resolve. Each resolution will minimally require QAs approval. Each approval will require time for explaining the fix to QA ( and / or other approving departments). Typically, the result is a budget that is severely over spent and a black eye for validation.
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Abenefit of a dry run is less time and money spent troubleshooting or explaining issues. This is true because the debugging is planned on the front end and the impact to the manufacturing schedule should be minimized.
Abenefit of a dry run is less time and money spent troubleshooting or explaining issues. This is true because the debugging is planned on the front end and the impact to the manufacturing schedule should be minimized.
13. REALISTIC COMPLETION DATES

Typically, the expectation is that once the requisite time has been allotted to complete three (3) runs, the system under validation is released and ready for use. Unfortunately, this is rarely the case. For example, a cleaning validation activity will require time to complete the following activities, including: Training Conducting cleaning events Gather cleaning samples (swabs or rinse samples) Obtain the microbial challenge results Evaluate results, Write conclusions Seek and attain post-execution approval Therefore, it should be relatively easy to see that it requires much longer than the three, basic runs. This is where a Gantt Chart or other time management tool is assembled. Validation resources typically provide input on validation tasks. The firm must understand that this is often a lose/lose situation because if the (validation) planning resource is overly optimistic, disappointment will result when the completion date is not met. Oftentimes, commercial campaigns are planned, based upon the projected completion date. These campaigns may involve contractical commitments. If the dates are not met, money will be forfeited. If the resource is overly pessimistic, chances are that the environment will not be ready to react when validation is completed well before the projected date. In this case, campaigns may not be pursued in a timely manner, and therefore, the opportunity to earn money may be lost. Either one of these extremes causes some degree of disarray. Thus, it is the responsibility of
13. REALISTIC COMPLETION DATES

Typically, the expectation is that once the requisite time has been allotted to complete three (3) runs, the system under validation is released and ready for use. Unfortunately, this is rarely the case. For example, a cleaning validation activity will require time to complete the following activities, including: Training Conducting cleaning events Gather cleaning samples (swabs or rinse samples) Obtain the microbial challenge results Evaluate results, Write conclusions Seek and attain post-execution approval Therefore, it should be relatively easy to see that it requires much longer than the three, basic runs. This is where a Gantt Chart or other time management tool is assembled. Validation resources typically provide input on validation tasks. The firm must understand that this is often a lose/lose situation because if the (validation) planning resource is overly optimistic, disappointment will result when the completion date is not met. Oftentimes, commercial campaigns are planned, based upon the projected completion date. These campaigns may involve contractical commitments. If the dates are not met, money will be forfeited. If the resource is overly pessimistic, chances are that the environment will not be ready to react when validation is completed well before the projected date. In this case, campaigns may not be pursued in a timely manner, and therefore, the opportunity to earn money may be lost. Either one of these extremes causes some degree of disarray. Thus, it is the responsibility of
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the lead validation resource to accurately plan, communicate, and realistically reflect the time required to complete validation.
the lead validation resource to accurately plan, communicate, and realistically reflect the time required to complete validation.
CONCLUSION
Validation has been, and continues to be, greatly misunderstood after approximately four decades. Thirteen remedies have been discussed that can help make validations more successful within any organization possessing a desire to be compliant with the regulatory agencies. While some of these tools may appear to be insignificant, all are necessary. It is therefore important that firms seeking to properly execute validations, conduct a self-assessment to determine which of these tools exist within their organization , and which of these could use some form of improvement. Once this self-assessment has been completed, the firm can then take the necessary steps to bring about an improvement in the manner that validations are conducted. The time required to affect change within the organization will be dependent upon the amount of interest that exists within the corporations upper management team. This is, after all, the team that is ultimately responsible for allocating and funding validation resources.
CONCLUSION
Validation has been, and continues to be, greatly misunderstood after approximately four decades. Thirteen remedies have been discussed that can help make validations more successful within any organization possessing a desire to be compliant with the regulatory agencies. While some of these tools may appear to be insignificant, all are necessary. It is therefore important that firms seeking to properly execute validations, conduct a self-assessment to determine which of these tools exist within their organization , and which of these could use some form of improvement. Once this self-assessment has been completed, the firm can then take the necessary steps to bring about an improvement in the manner that validations are conducted. The time required to affect change within the organization will be dependent upon the amount of interest that exists within the corporations upper management team. This is, after all, the team that is ultimately responsible for allocating and funding validation resources.
ABOUT THE AUTHOR

Charlie Neal, Jr. is the Equipment Validation and Requalification Manager for Diosynth-RTP (an Akzo Nobel company), located in Research Triangle Park, North Carolina. He has been involved with validation for over 22 years, and has authored articles for both the Journal of Validation Technology and the Journal of cGMP Compliance. He can be reached at 919-678-4387. Article Acronym Listing I Q : Installation Qualification O Q : Operational Qualification QA: Quality Assurance QC: Quality Control W F I : Water-for-Injection SOP: Standard Operating Procedure
ABOUT THE AUTHOR

Charlie Neal, Jr. is the Equipment Validation and Requalification Manager for Diosynth-RTP (an Akzo Nobel company), located in Research Triangle Park, North Carolina. He has been involved with validation for over 22 years, and has authored articles for both the Journal of Validation Technology and the Journal of cGMP Compliance. He can be reached at 919-678-4387. Article Acronym Listing I Q : Installation Qualification O Q : Operational Qualification QA: Quality Assurance QC: Quality Control W F I : Water-for-Injection SOP: Standard Operating Procedure
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templates for qualification protocols
developing qualification/validation protocols
Validation Master Plan

Principle Validation in general requires a meticulous preparation and careful planning of the various steps in the process. In addition, all work involved should be carried out in a structured way according to formally authorised, standardised working and administrative procedures. These factors require a well organised and structured approach that should be adequately described in a Validation Master Plan (VMP). Definition A Validation Master Plan is a document that summarises the firms overall philosophy, intentions and approach to be used for establishing performance adequacy: The validation policy of company is that no API/ drug product manufactured should be released for further processing or commercial distribution without approved and appropriate validation of processes, facilities, equipment and systems. Purpose The VMP should present an overview of the entire validation operation, its organisational structure, its content and planning. The core of the VMP being the list / inventory of the items to be validated and the planning schedule. It serves as a road map for validation: The objective for the master validation plan is to have documented evidence to assure that a plan exists for the validation of existing facilities, systems, procedures, equipment and personnel are capable of and delivering product meeting approved quality standards. VMP helps management to know what the validation programme involves with respect to time, people and money and to understand the necessity for the programme; helps all members of the validation team to know their tasks and responsibilities; helps GMP inspectors to understand the firms approach to validation and the set up and organisation of all validation activities. Scope All validation activities relating to critical technical operations, relevant to product and process controls within a firm should be included in a VMP.
Validation Master Plan

Principle Validation in general requires a meticulous preparation and careful planning of the various steps in the process. In addition, all work involved should be carried out in a structured way according to formally authorised, standardised working and administrative procedures. These factors require a well organised and structured approach that should be adequately described in a Validation Master Plan (VMP). Definition A Validation Master Plan is a document that summarises the firms overall philosophy, intentions and approach to be used for establishing performance adequacy: The validation policy of company is that no API/ drug product manufactured should be released for further processing or commercial distribution without approved and appropriate validation of processes, facilities, equipment and systems. Purpose The VMP should present an overview of the entire validation operation, its organisational structure, its content and planning. The core of the VMP being the list / inventory of the items to be validated and the planning schedule. It serves as a road map for validation: The objective for the master validation plan is to have documented evidence to assure that a plan exists for the validation of existing facilities, systems, procedures, equipment and personnel are capable of and delivering product meeting approved quality standards. VMP helps management to know what the validation programme involves with respect to time, people and money and to understand the necessity for the programme; helps all members of the validation team to know their tasks and responsibilities; helps GMP inspectors to understand the firms approach to validation and the set up and organisation of all validation activities. Scope All validation activities relating to critical technical operations, relevant to product and process controls within a firm should be included in a VMP.
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This includes qualification of critical manufacturing and control equipment. It should comprise all Prospective, Concurrent, Retrospective Validations as well as Revalidations. In case of large projects like the construction of a new facility, often the best approach is to create a separate VMP. (In such situations the VMP should be part of the total project management.): The Master Validation Plan (MVP) includes all relevant aspects relating to the production of API/ drug product in the production facilities. The principles of validation, the organization of qualification and validation, and the design and nomenclature of the documentation equipment and training requirements are also included Format & Content The VMP should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but refer to existing documents such as Policy Documents, SOPs and Validation Protocols/Reports. The VMP should be agreed by management. A VMP should contain data on the subjects / proposed chapters that follow. Introduction Firms validation policy, general description of the scope of those operations covered by the VMP, location and schedule (including priorities). Organisation Clearly identify personnel and their respective responsibilities with respect to: the VMP protocols of individual validation projects validation work report and document preparation and control approval/authorisation of validation protocols and reports in all stages of validation excercises tracking system for reference and review training needs in support of validation.
This includes qualification of critical manufacturing and control equipment. It should comprise all Prospective, Concurrent, Retrospective Validations as well as Revalidations. In case of large projects like the construction of a new facility, often the best approach is to create a separate VMP. (In such situations the VMP should be part of the total project management.): The Master Validation Plan (MVP) includes all relevant aspects relating to the production of API/ drug product in the production facilities. The principles of validation, the organization of qualification and validation, and the design and nomenclature of the documentation equipment and training requirements are also included Format & Content The VMP should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but refer to existing documents such as Policy Documents, SOPs and Validation Protocols/Reports. The VMP should be agreed by management. A VMP should contain data on the subjects / proposed chapters that follow. Introduction Firms validation policy, general description of the scope of those operations covered by the VMP, location and schedule (including priorities). Organisation Clearly identify personnel and their respective responsibilities with respect to: the VMP protocols of individual validation projects validation work report and document preparation and control approval/authorisation of validation protocols and reports in all stages of validation excercises tracking system for reference and review training needs in support of validation.
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Description of Plant/Process/Product: Provide cross references to other documents. A rationale for the inclusion or exclusion of validations, for the validation approach and the extent of validation should be included. Specific Concerns Under this heading specific characteristics / requirements of the plant / process etc. that are critical for yielding a quality product and need extra attention may be briefly outlined here. List of activities Products / Processes / Systems to be Validated: All validation activities comprised in the VMP should be summarised and compiled in a matrix format . Such matrix should provide an overview and contain: all items covered by the VMP that are subject to validation describing the extent of validation required [i.e. IQ, OQ and/or PQ]. It should include validation of analytical techniques which are to be used in determining the validation status of other processes or systems, the validation approach, i.e. Prospective, Retrospective or Concurrent, the Re-validation activities, actual status and future planning.
Description of Plant/Process/Product: Provide cross references to other documents. A rationale for the inclusion or exclusion of validations, for the validation approach and the extent of validation should be included. Specific Concerns Under this heading specific characteristics / requirements of the plant / process etc. that are critical for yielding a quality product and need extra attention may be briefly outlined here. List of activities Products / Processes / Systems to be Validated: All validation activities comprised in the VMP should be summarised and compiled in a matrix format . Such matrix should provide an overview and contain: all items covered by the VMP that are subject to validation describing the extent of validation required [i.e. IQ, OQ and/or PQ]. It should include validation of analytical techniques which are to be used in determining the validation status of other processes or systems, the validation approach, i.e. Prospective, Retrospective or Concurrent, the Re-validation activities, actual status and future planning.
Acceptance Criteria General statement on key acceptance criteria for the items listed above. Documentation Format The format to be used for protocols and reports should be described or referred to. Required SOPs List of relevant SOPs should be presented. Planning & Scheduling An estimate of staffing (including training needs), equipment and other specific requirements to complete the validation effort should be described in the VMP. A time plan of the project with detailed
Acceptance Criteria General statement on key acceptance criteria for the items listed above. Documentation Format The format to be used for protocols and reports should be described or referred to. Required SOPs List of relevant SOPs should be presented. Planning & Scheduling An estimate of staffing (including training needs), equipment and other specific requirements to complete the validation effort should be described in the VMP. A time plan of the project with detailed
planning of subprojects. This time plan could be included in the above mentioned matrix. A VMP requires regular updating. Change Control A statement of the companys commitment to controlling critical changes to materials, facilities, equipment or processes (including analytical techniques), should be included.
planning of subprojects. This time plan could be included in the above mentioned matrix. A VMP requires regular updating. Change Control A statement of the companys commitment to controlling critical changes to materials, facilities, equipment or processes (including analytical techniques), should be included.
Procedure for Validation of a System/ Equipment: QP Checklist

Step 1:: Step 2: Step 3: Step 4: Step 5: Step 6: Step 7: Step 8: Step 9: Define quality attributes on fitness for use or purpose basis Design Qualification Source and procure Factory Acceptance Tests Site Acceptance Tests Installation Qualification - As built phase Operational Qualification - At rest phase Performance Qualification - Operating phase Confirm appropriateness of critical process parameters establish reproducibility and reliability of system establish stability under seasonal or other changes confirm appropriateness of target, alert, alarm levels and corrective action plan Prospective/Concurrent/Retrospective validation Change control Periodic review/Revalidation
Procedure for Validation of a System/ Equipment: QP Checklist

Step 1:: Step 2: Step 3: Step 4: Step 5: Step 6: Step 7: Step 8: Step 9: Define quality attributes on fitness for use or purpose basis Design Qualification Source and procure Factory Acceptance Tests Site Acceptance Tests Installation Qualification - As built phase Operational Qualification - At rest phase Performance Qualification - Operating phase Confirm appropriateness of critical process parameters establish reproducibility and reliability of system establish stability under seasonal or other changes confirm appropriateness of target, alert, alarm levels and corrective action plan Prospective/Concurrent/Retrospective validation Change control Periodic review/Revalidation
Step 10:
Step 10:
Protocol stages: Checklist 1 Protocol approval 2 Overview Objective Purpose Reason for validation Responsibility Revalidation Design Qualification defining inputs Acceptance Criteria References Installation Qualification Operational Qualification Performance Qualification Approvals
Protocol stages: Checklist 1 Protocol approval 2 Overview Objective Purpose Reason for validation Responsibility Revalidation Design Qualification defining inputs Acceptance Criteria References Installation Qualification Operational Qualification Performance Qualification Approvals
3 4 5 6 7 8 9
3 4 5 6 7 8 9
Protocol Format
1 Protocol approval Identify people who will be jointly responsible for * System design * System validation * Checking and approving validation documentation Functional Area Name Signature
Protocol Format
1 Protocol approval Identify people who will be jointly responsible for * System design * System validation * Checking and approving validation documentation Functional Area Name Signature
Date
Date
2 Overview 2.1 Objective To assure that the system will consistently produce_______ of predictable quality when operated in prescribed manner: all physical aspects, related procedures, process monitoring and control all function as per specifications. 2.2 Purpose To demonstrate that the design, construction, commissioning and operation of the system is suitable for the intended purpose and possesses the quality attributes to render it cGMP compliant and meets regulatory obligations. 2.3 Reasons for validation * To demonstrate that system design (with all components) is compatible with system functions * To demonstrate that system has the capacity to achieve specified quality levels * To verify that operation, cleaning, sanitation, and maintenance procedures for system are acceptable * To establish that sampling plan has the capacity to determine whether or not the system is under control * To establish that operating and maintenance people are adequately trained
2 Overview 2.1 Objective To assure that the system will consistently produce_______ of predictable quality when operated in prescribed manner: all physical aspects, related procedures, process monitoring and control all function as per specifications. 2.2 Purpose To demonstrate that the design, construction, commissioning and operation of the system is suitable for the intended purpose and possesses the quality attributes to render it cGMP compliant and meets regulatory obligations. 2.3 Reasons for validation * To demonstrate that system design (with all components) is compatible with system functions * To demonstrate that system has the capacity to achieve specified quality levels * To verify that operation, cleaning, sanitation, and maintenance procedures for system are acceptable * To establish that sampling plan has the capacity to determine whether or not the system is under control * To establish that operating and maintenance people are adequately trained
* To verify that a proper system of documentation and record maintenance exists 2.4 Responsibility * Production Manager * QA Manager * Validation Manager * Engineering Manager * Process Development Manager 2.5 Revalidation System to be revalidated on: * Substitution of existing system or sub-system with new system or sub-system * Major modification to existing system or sub-system since commissioning or after last validation * Excursions from nominal set point observed during routine continuous monitoring 3 Reference documents 1 SOPs for assemblies and sub-assemblies 2 Calibration of motors, gauges, indicators, meters 3 Utilities required 4 Sampling plan and procedures 5 Test procedures
* To verify that a proper system of documentation and record maintenance exists 2.4 Responsibility * Production Manager * QA Manager * Validation Manager * Engineering Manager * Process Development Manager 2.5 Revalidation System to be revalidated on: * Substitution of existing system or sub-system with new system or sub-system * Major modification to existing system or sub-system since commissioning or after last validation * Excursions from nominal set point observed during routine continuous monitoring 3 Reference documents 1 SOPs for assemblies and sub-assemblies 2 Calibration of motors, gauges, indicators, meters 3 Utilities required 4 Sampling plan and procedures 5 Test procedures
Design Qualification Format for a System/ Equipment

1. Pre-approval/post-approval joint responsibilities of protocol Functional Area Name Signature Date
Design Qualification Format for a System/ Equipment

2. Purpose To provide an outline for the design of the equipment/system to be procured and ensure that it meets cGMP and Regulatory expectations 3. Design input * Overview of system, sub-assemblies, and components - how they function and recommended materials of construction; raw material data; finished material expectations * Special concerns, if any, and recommended care during manufacture and installation 4. Design basis * Specifications in terms of bill of materials 5. Acceptance criteria * Parametric definitions with tolerances 6. System description * Sketch or line diagram 7. Reference documents * SOPs for operation, regeneration, maintenance, cleaning, sanitation, testing etc for system/sub-systems/components 8. Manufacturers communication * Description of system offered
2. Purpose To provide an outline for the design of the equipment/system to be procured and ensure that it meets cGMP and Regulatory expectations 3. Design input * Overview of system, sub-assemblies, and components - how they function and recommended materials of construction; raw material data; finished material expectations * Special concerns, if any, and recommended care during manufacture and installation 4. Design basis * Specifications in terms of bill of materials 5. Acceptance criteria * Parametric definitions with tolerances 6. System description * Sketch or line diagram 7. Reference documents * SOPs for operation, regeneration, maintenance, cleaning, sanitation, testing etc for system/sub-systems/components 8. Manufacturers communication * Description of system offered
Installation Qualification Format for a System/Equipment

Installation Qualification Format for a System/Equipment

2. Purpose To verify that 1 System is installed as per approved drawings 2 System meets cGMP and Regulatory expectations 3 SOPs have been identified, drafted and listed 4 Instruments have been identified for calibration of system 5 Support utilities properly connected 6 Peripherals and electricals properly connected 7 Safety features and aspects accounted 3. Recording instructions 1 Record requested information in ink. 2 Use separate data sheet for separate components/systems, even if there are more than one of a type, so that identity of each is preserved 3 Sign and assign date in ink 4. System description 1 Name of system/Model/Serial No/ Manufacturers name, address and contact nos/ Suppliers name, address and contact nos 2 Identification number/location 3 Use of the system/equipment and its capacity 4 Components Component DQ specs Manufacturers specs Actual observation
2. Purpose To verify that 1 System is installed as per approved drawings 2 System meets cGMP and Regulatory expectations 3 SOPs have been identified, drafted and listed 4 Instruments have been identified for calibration of system 5 Support utilities properly connected 6 Peripherals and electricals properly connected 7 Safety features and aspects accounted 3. Recording instructions 1 Record requested information in ink. 2 Use separate data sheet for separate components/systems, even if there are more than one of a type, so that identity of each is preserved 3 Sign and assign date in ink 4. System description 1 Name of system/Model/Serial No/ Manufacturers name, address and contact nos/ Suppliers name, address and contact nos 2 Identification number/location 3 Use of the system/equipment and its capacity 4 Components Component DQ specs Manufacturers specs Actual observation
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5 S/N a b c d e f g
Tabulation of physical details: Description Overall dimensions Weight Colour code Surface finish Motor/gearbox/belts/pulleys etc Electrical ratings Details of auxiliary equipment, if any
Particulars
5 S/N a b c d e f g
Tabulation of physical details: Description Overall dimensions Weight Colour code Surface finish Motor/gearbox/belts/pulleys etc Electrical ratings Details of auxiliary equipment, if any
Particulars
5. SOPs
S/N Function a b c d e f Operating Cleaning & sanitizing Calibration Preventive maintenance Testing & requalification Comments & observations S O P Date of No issue Revn No Title and date Next revn due on
5. SOPs
S/N Function a b c d e f Operating Cleaning & sanitizing Calibration Preventive maintenance Testing & requalification Comments & observations S O P Date of No issue Revn No Title and date Next revn due on
6. Calibration review a. Process Instruments

S/N Instrument Location Date of Calibrated C h e c k e d Next calibrn calibrn by by due on
6. Calibration review a. Process Instruments

S/N Instrument Location Date of Calibrated C h e c k e d Next calibrn calibrn by by due on
b. Test Instruments
S/N Instrument Location Date of Calibrated Checked Next cal Component calibrn by by due on to be calibrtd
b. Test Instruments
S/N Instrument Location Date of Calibrated Checked Next cal Component calibrn by by due on to be calibrtd
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7. S/N a b c d e f g
System / Equipment Installation check-list Statement Yes or No Observed by Space for installation Power Compressed air Steam Vacuum Water, plumbing and drainage Others
Date
7. S/N a b c d e f g
System / Equipment Installation check-list Statement Yes or No Observed by Space for installation Power Compressed air Steam Vacuum Water, plumbing and drainage Others
Date
Piping and Instrumentation General arrangement/ schematic line diagram Utility Isometric Other S/N Title of Drawing Category Location Drawing No Date
8. Drawings Category:
Piping and Instrumentation General arrangement/ schematic line diagram Utility Isometric Other S/N Title of Drawing Category Location Drawing No Date
8. Drawings Category:
9. Physical verification and listing of materials of construction * Parts in contact with product S/N Description of item Material of construction
9. Physical verification and listing of materials of construction * Parts in contact with product S/N Description of item Material of construction
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* Parts not in contact with product S/N Description of item Material of construction
* Parts not in contact with product S/N Description of item Material of construction
10. Support utilities S/N Utility Facility
Capacity required
Capacity available
Properly connected and identified Yes No
10. Support utilities S/N Utility Facility
Capacity required
Capacity available
Properly connected and identified Yes No
a Power b Comp air c Water* d Steam e Vacuum f Other *state quality 11. Manufacturers submissions 1 Commissioning reports 2 Test reports 3 Calibration certificates 4 Others 12. Deficiency and Corrective Action Report 1 Description of deficiency and observations 2 Assignment of responsibility for corrective action 3 Corrective action taken, comments and observations and date 4 Work carried out by 5 Approved by 13. Final report 1 Summary 2 Analysis and evaluation of data 3 Certification Appendix A: Definitions and abbreviations
a Power b Comp air c Water* d Steam e Vacuum f Other *state quality 11. Manufacturers submissions 1 Commissioning reports 2 Test reports 3 Calibration certificates 4 Others 12. Deficiency and Corrective Action Report 1 Description of deficiency and observations 2 Assignment of responsibility for corrective action 3 Corrective action taken, comments and observations and date 4 Work carried out by 5 Approved by 13. Final report 1 Summary 2 Analysis and evaluation of data 3 Certification Appendix A: Definitions and abbreviations
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Appendix B: Reference documents A Manufacturers brochures/catalogues/manuals B Purchase order C List of essential spares, accessories and consumables and their specification data sheets
Appendix B: Reference documents A Manufacturers brochures/catalogues/manuals B Purchase order C List of essential spares, accessories and consumables and their specification data sheets
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Operational Qualification Format for a System/Equipment

Operational Qualification Format for a System/Equipment

2. Purpose 1 To demonstrate that the equipment/system performs reproducibly and consistently 2 To document performance of the equipment/system for future reference 3 To assure that the equipment /system performance is adequate to support the process for which the system is intended 4 To develop SOPs for start-up, operation, shut-down and sanitisation of the equipment/system 5 To document test procedures and criteria for acceptance 6 To define parameters that should be reproducible 7 To verify performance across full range of operation from minimal to maximal loads, with special evaluation at upper and lower limits 3. SOP verification 1 Is current version in use? 2 Do operating personnel understand and follow SOP methodology and requirements? 3 Does SOP provide adequate direction and control to ensure uniform equipment/system performance? (Comments if answer to above is negative) Final Remarks: SOP verification result: Pass/Fail? 4. Control panel functionality Purpose To demonstrate that the control panel provides proper functionality as per description
2. Purpose 1 To demonstrate that the equipment/system performs reproducibly and consistently 2 To document performance of the equipment/system for future reference 3 To assure that the equipment /system performance is adequate to support the process for which the system is intended 4 To develop SOPs for start-up, operation, shut-down and sanitisation of the equipment/system 5 To document test procedures and criteria for acceptance 6 To define parameters that should be reproducible 7 To verify performance across full range of operation from minimal to maximal loads, with special evaluation at upper and lower limits 3. SOP verification 1 Is current version in use? 2 Do operating personnel understand and follow SOP methodology and requirements? 3 Does SOP provide adequate direction and control to ensure uniform equipment/system performance? (Comments if answer to above is negative) Final Remarks: SOP verification result: Pass/Fail? 4. Control panel functionality Purpose To demonstrate that the control panel provides proper functionality as per description
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Testing 1 Verify that all controls on the panel are properly labeled and identified 2 Verify functionality of each component on the panel against its stated function 3 Observe and record responses with control panel in use Functionality test results: Identification: Eqpmnt No/Make/Serial No/ Location of eqpmnt Control panel serial no/ location of control panel S/N Component of Described Description matches function control panel function Yes No Comments: Reviewed and inspected by: Name/signature/date 5. Safety features review and check list Indicate which of the safety features listed below are applicable, and record the specific measures to be taken for them and verify their completion. (All this should have featured in your URS/DQ. At this stage you are merely reconfirming that your concerns have been satisfactorily addressed in execution.) A Extreme temperatures - Applicable / Not Applicable: Y / N Hot lines / equipment insulated Personal protection available Heat sources identified and shielded Signs posted to alert operators (Surface is Hot!) B Pressure considerations - Applicable / Not Applicable: Y / N All piping properly aligned Pressure ratings of piping components is compatible with operating conditions Pressure release devices provided where applicable Calculations for pressure release devices Compressed air / gas lines can be isolated and blended to zero energy state ASME stamps Vessel registered with site services for insurance registration
Testing 1 Verify that all controls on the panel are properly labeled and identified 2 Verify functionality of each component on the panel against its stated function 3 Observe and record responses with control panel in use Functionality test results: Identification: Eqpmnt No/Make/Serial No/ Location of eqpmnt Control panel serial no/ location of control panel S/N Component of Described Description matches function control panel function Yes No Comments: Reviewed and inspected by: Name/signature/date 5. Safety features review and check list Indicate which of the safety features listed below are applicable, and record the specific measures to be taken for them and verify their completion. (All this should have featured in your URS/DQ. At this stage you are merely reconfirming that your concerns have been satisfactorily addressed in execution.) A Extreme temperatures - Applicable / Not Applicable: Y / N Hot lines / equipment insulated Personal protection available Heat sources identified and shielded Signs posted to alert operators (Surface is Hot!) B Pressure considerations - Applicable / Not Applicable: Y / N All piping properly aligned Pressure ratings of piping components is compatible with operating conditions Pressure release devices provided where applicable Calculations for pressure release devices Compressed air / gas lines can be isolated and blended to zero energy state ASME stamps Vessel registered with site services for insurance registration
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C Hazardous materials of fluid nature - Applicable / Not Applicable: Y / N Material safety data sheet (MSDS) location If required, SOP for handling available Spill retention provided Toxic and flammable chemical risks controlled Biohazards information provided D Electrical hazards - Applicable / Not Applicable: Y / N All wiring properly placed All systems properly grounded Lock-outs available on all equipment emitting ionizing radiations Proper shielding provided E Moving parts - Applicable / Not Applicable: Y / N Guards provided are in place at pinch points Lock nut on shaft Belt tension properly adjusted F Noise level - Applicable / Not Applicable: Y / N Noise level is dB on scale Ambient noise level is Noise reduction equipment /devices in place, if required G Physical environmental factors - Applicable / Not Applicable: Y/N Sharp edges removed or protected Trip/fall hazards eliminated or protected against Low clearance head space clearly indicated or eliminated Equipment properly anchored Eye hazards eliminated Adequate lighting provided in the area Warning and precautionary signs provided wherever required
C Hazardous materials of fluid nature - Applicable / Not Applicable: Y / N Material safety data sheet (MSDS) location If required, SOP for handling available Spill retention provided Toxic and flammable chemical risks controlled Biohazards information provided D Electrical hazards - Applicable / Not Applicable: Y / N All wiring properly placed All systems properly grounded Lock-outs available on all equipment emitting ionizing radiations Proper shielding provided E Moving parts - Applicable / Not Applicable: Y / N Guards provided are in place at pinch points Lock nut on shaft Belt tension properly adjusted F Noise level - Applicable / Not Applicable: Y / N Noise level is dB on scale Ambient noise level is Noise reduction equipment /devices in place, if required G Physical environmental factors - Applicable / Not Applicable: Y/N Sharp edges removed or protected Trip/fall hazards eliminated or protected against Low clearance head space clearly indicated or eliminated Equipment properly anchored Eye hazards eliminated Adequate lighting provided in the area Warning and precautionary signs provided wherever required
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H Ergonomic design - Applicable / Not Applicable: Y / N Ergonomic risks evaluated, operators can safely and conveniently access all areas of equipment Adequate operator visibility Emergency stop buttons visible, accessible, labeled, and operational Warning bells and lights audible, visible and functional Belt/conveyor/table width appropriate for manual operations Hazardous equipment not operational without safety guard Excessive reaching, body bending, weight lifting, pushing and pulling eliminated or minimized Personnel protective equipment to be worn when operating is indicated I Dust levels - Applicable / Not Applicable: Y / N Particulate matter concentration: Results Respiratory equipment / devices in place, if required 6. Final Report Analysis/evaluation of data Certification Reviewed & Inspected by Appendix A: Appendix B: Definitions and abbreviations Reference documents A Manufacturers brochures/catalogues/manuals B Purchase order C List of essential spares, accessories and consumables and their specification data sheets
H Ergonomic design - Applicable / Not Applicable: Y / N Ergonomic risks evaluated, operators can safely and conveniently access all areas of equipment Adequate operator visibility Emergency stop buttons visible, accessible, labeled, and operational Warning bells and lights audible, visible and functional Belt/conveyor/table width appropriate for manual operations Hazardous equipment not operational without safety guard Excessive reaching, body bending, weight lifting, pushing and pulling eliminated or minimized Personnel protective equipment to be worn when operating is indicated I Dust levels - Applicable / Not Applicable: Y / N Particulate matter concentration: Results Respiratory equipment / devices in place, if required 6. Final Report Analysis/evaluation of data Certification Reviewed & Inspected by Appendix A: Appendix B: Definitions and abbreviations Reference documents A Manufacturers brochures/catalogues/manuals B Purchase order C List of essential spares, accessories and consumables and their specification data sheets
Qualification Plan and Acceptance Criteria for HVAC

Early in design, the owner and designer should discuss who will be responsible for as-built drawings, setting up maintenance files, and training. They should create a qualification plan for the HVAC, including: 1 a functional description of what the systems will do; 2 maps of room pressures, airflow diagrams, and cleanliness zones served by each air handler; 3 a list of critical components to be qualified, including the computer controlling the HVAC; 4 a list of owners procedures that must be followed for qualification of equipment and systems that affect critical variables; 5 a list of qualification procedures (IQ/OQ/PQ protocols) written especially for the project; and 6 a list of needed commissioning equipment. The approval procedure should also be defined in the QP. It is important to measure and document the critical variables of a system (such as room pressure), but it is also important to document performance of components that affect that critical variables (e.g., room pressure sensors, temperature sensors, airflow volume monitor) for GMP as well as business records. Documentation helps ensure that replacement parts (e.g., motors) can be specified, purchased, and installed to satisfy critical variables. Critical components must be determined (including instruments) that could affect critical parameters and could, through an undetected failure, lead to product corruption. If performance data are in the qualification records, replacement parts of different manufacture can be installed without major change control approvals, as long as they meet performance requirements. Owner approvals for the qualification plan should be obtained while proceeding with detailed design.
Qualification Plan and Acceptance Criteria for HVAC

Early in design, the owner and designer should discuss who will be responsible for as-built drawings, setting up maintenance files, and training. They should create a qualification plan for the HVAC, including: 1 a functional description of what the systems will do; 2 maps of room pressures, airflow diagrams, and cleanliness zones served by each air handler; 3 a list of critical components to be qualified, including the computer controlling the HVAC; 4 a list of owners procedures that must be followed for qualification of equipment and systems that affect critical variables; 5 a list of qualification procedures (IQ/OQ/PQ protocols) written especially for the project; and 6 a list of needed commissioning equipment. The approval procedure should also be defined in the QP. It is important to measure and document the critical variables of a system (such as room pressure), but it is also important to document performance of components that affect that critical variables (e.g., room pressure sensors, temperature sensors, airflow volume monitor) for GMP as well as business records. Documentation helps ensure that replacement parts (e.g., motors) can be specified, purchased, and installed to satisfy critical variables. Critical components must be determined (including instruments) that could affect critical parameters and could, through an undetected failure, lead to product corruption. If performance data are in the qualification records, replacement parts of different manufacture can be installed without major change control approvals, as long as they meet performance requirements. Owner approvals for the qualification plan should be obtained while proceeding with detailed design.
Design Qualification 1. Prepare User Requirement, Specifications & Functional Specifications Include System ID, Rooms covered, Class to be maintained, Temperature & RH conditions to be maintained within area, Equipment with their loads, diversity factor, Approximate level of filtration, Type of return from room, Lighting in lux, Approximate manpower will be working, Differential pressure, Any ACH requirements, safety systems to be included, concept for controlling & monitoring system 2. Prepare Tender document with the help of Consultant, or External expert, or if expert within Include URS, System designing, Heat Load calculations, Codes to be followed for design & construction, Detailed control & monitoring system with interlocks, Detailed specifications of major items, Guidelines to befollowed, Tentative BOQ, Drawings, documentation requirements etc. 3. Float the tender to selected vendors Includes issuing of tenders, explaining the technical aspects of tender,explaining the documentation requirement, schematics, etc. 4. Receipt & Evaluation of tenders Includes receipt of tender documents, evaluation of received tenders for technical & commercial aspects 5. Decision Making for award of tender Includes technical & commercial evaluation, reasoning/ rationale for selecting vendor for awarding tender. 6. Risk Analysis Detailed technical challenging for HVAC zoning, AHU zoning, control & monitoring system, Equipment & lighting loads given in URS, Differential Pressure, ACH, Air flow & control schematics, Filtration level, Return system from room, etc. User, Consultant or External expert, Selected vendor should jointly carry out the Risk Analysis & minute the decisions taken, changes accepted with reasoning / rationale for it.
Design Qualification 1. Prepare User Requirement, Specifications & Functional Specifications Include System ID, Rooms covered, Class to be maintained, Temperature & RH conditions to be maintained within area, Equipment with their loads, diversity factor, Approximate level of filtration, Type of return from room, Lighting in lux, Approximate manpower will be working, Differential pressure, Any ACH requirements, safety systems to be included, concept for controlling & monitoring system 2. Prepare Tender document with the help of Consultant, or External expert, or if expert within Include URS, System designing, Heat Load calculations, Codes to be followed for design & construction, Detailed control & monitoring system with interlocks, Detailed specifications of major items, Guidelines to befollowed, Tentative BOQ, Drawings, documentation requirements etc. 3. Float the tender to selected vendors Includes issuing of tenders, explaining the technical aspects of tender,explaining the documentation requirement, schematics, etc. 4. Receipt & Evaluation of tenders Includes receipt of tender documents, evaluation of received tenders for technical & commercial aspects 5. Decision Making for award of tender Includes technical & commercial evaluation, reasoning/ rationale for selecting vendor for awarding tender. 6. Risk Analysis Detailed technical challenging for HVAC zoning, AHU zoning, control & monitoring system, Equipment & lighting loads given in URS, Differential Pressure, ACH, Air flow & control schematics, Filtration level, Return system from room, etc. User, Consultant or External expert, Selected vendor should jointly carry out the Risk Analysis & minute the decisions taken, changes accepted with reasoning / rationale for it.
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7. Based on Tender document, Risk Analysis - Vendor to prepare detailed documents & client / consultant to approve it At minimum should include following: AHU & HVAC zoning diagram, Detailed heat load calculations, Detailed duct layout, Air flow with level of filtration & control system schematics, Differential pressure diagram & pressure flow diagram, AHU data sheet with fan selection, Dehumidifier/Recovery wheels etc. data sheets & selection (If applicable), Design specifications for control & monitoring system with selection of control system & components, Typical P & ID for near coil piping of AHU / Dehumidifier etc.. Filter selection & data sheets of filters, Typical drawings - longitudinal, transverse joints, duct support etc. for ducting, Supply & return air systems, Duct insulation etc., Data sheets of all major items like Diff. Pressure gauges & switches, fire dampers, volume control dampers, actuators for dampers, T & P gauges etc. Compilation of all the documents stated above with summary to evaluate across the User Requirement & Risk Analysis for acceptance of design will complete the Design Qualification
7. Based on Tender document, Risk Analysis - Vendor to prepare detailed documents & client / consultant to approve it At minimum should include following: AHU & HVAC zoning diagram, Detailed heat load calculations, Detailed duct layout, Air flow with level of filtration & control system schematics, Differential pressure diagram & pressure flow diagram, AHU data sheet with fan selection, Dehumidifier/Recovery wheels etc. data sheets & selection (If applicable), Design specifications for control & monitoring system with selection of control system & components, Typical P & ID for near coil piping of AHU / Dehumidifier etc.. Filter selection & data sheets of filters, Typical drawings - longitudinal, transverse joints, duct support etc. for ducting, Supply & return air systems, Duct insulation etc., Data sheets of all major items like Diff. Pressure gauges & switches, fire dampers, volume control dampers, actuators for dampers, T & P gauges etc. Compilation of all the documents stated above with summary to evaluate across the User Requirement & Risk Analysis for acceptance of design will complete the Design Qualification
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Installation Qualification The installation qualification (IQ) protocol records construction inspection to verify compliance with contract documents, including completion of punch list work, for critical components. It may include material test reports, receipt verification forms, shop inspection reports, motor rotation tests, and contractor-furnished testing and balancing. It also includes calibration records for instrumentation used in commissioning and for installed instrumentation (e.g., sensors, recorders, transmitters, controllers, and actuators) traceable to National Institute of Standards and Technology (NlST) instruments. Control software should be bench tested, and preliminary (starting) tuning parameters should be entered. Control loops should be dry-loop checked to verify that installation is correct. Equipment and instruments should be tagged and wiring labeled. Commissioning documentation must attest to the completion of these activities and include as-built drawings and installation-operation-maintenance (IOM) manuals from contractors and vendors. 1. Preparing for Installation Qualification Making copy of following documents approved during DQ phase for cross- verification of Installation, Detailed duct layout, Detailed heat load calculations, Air flow with level of filtration & control system schematics, AHU data sheet with fan selection, Dehumidifier/Recovery wheels etc. data sheets & selections (If applicable), Design specifications for control & monitoring system with selection of control system & components, Typical P & ID for near coil piping of AHU / Dehumidifier etc., Filter selection & data sheets of filters, Data sheets of all major items etc. Simultaneously prepare Installation Check Sheet giving ref. of drawings, details etc. approved during DQ, Include items to be checked as per GEP like Flange gaskets, tightening of bolts etc., SOPs - duct leak test, Hydro test, loop check, etc. 2. Verification of Received Material Verify the major items received at site against Data Sheets, Drawings etc. that were approved during DQ phase. Make a summary report for deviations, corrective actions & acceptance
Installation Qualification The installation qualification (IQ) protocol records construction inspection to verify compliance with contract documents, including completion of punch list work, for critical components. It may include material test reports, receipt verification forms, shop inspection reports, motor rotation tests, and contractor-furnished testing and balancing. It also includes calibration records for instrumentation used in commissioning and for installed instrumentation (e.g., sensors, recorders, transmitters, controllers, and actuators) traceable to National Institute of Standards and Technology (NlST) instruments. Control software should be bench tested, and preliminary (starting) tuning parameters should be entered. Control loops should be dry-loop checked to verify that installation is correct. Equipment and instruments should be tagged and wiring labeled. Commissioning documentation must attest to the completion of these activities and include as-built drawings and installation-operation-maintenance (IOM) manuals from contractors and vendors. 1. Preparing for Installation Qualification Making copy of following documents approved during DQ phase for cross- verification of Installation, Detailed duct layout, Detailed heat load calculations, Air flow with level of filtration & control system schematics, AHU data sheet with fan selection, Dehumidifier/Recovery wheels etc. data sheets & selections (If applicable), Design specifications for control & monitoring system with selection of control system & components, Typical P & ID for near coil piping of AHU / Dehumidifier etc., Filter selection & data sheets of filters, Data sheets of all major items etc. Simultaneously prepare Installation Check Sheet giving ref. of drawings, details etc. approved during DQ, Include items to be checked as per GEP like Flange gaskets, tightening of bolts etc., SOPs - duct leak test, Hydro test, loop check, etc. 2. Verification of Received Material Verify the major items received at site against Data Sheets, Drawings etc. that were approved during DQ phase. Make a summary report for deviations, corrective actions & acceptance
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3. Installation verification using Check Sheets & copies of Drawings, Details approved during DQ phase As Installation progress, verify the Installation using check sheets. Mark the deviations if any, corrective action taken & acceptance after corrective action. Simultaneously verify the Installation with respect to drawings, details approved during DQ phase using copy of these documents & marking the respective area. Any deviation beyond corrective action due to site constraint should be marked with reasons, carry out impact w.r.t design & give acceptance if Impact dose not affect the design. If impact does affect the design, carry out Risk Analysis & take the appropriate decision. Compile Calibration /Test certificates for all major components which will have impact on system performance. Compilation of all the documents stated above with summary to evaluate Installation against Design, respective codes etc. will complete Installation Qualification.
3. Installation verification using Check Sheets & copies of Drawings, Details approved during DQ phase As Installation progress, verify the Installation using check sheets. Mark the deviations if any, corrective action taken & acceptance after corrective action. Simultaneously verify the Installation with respect to drawings, details approved during DQ phase using copy of these documents & marking the respective area. Any deviation beyond corrective action due to site constraint should be marked with reasons, carry out impact w.r.t design & give acceptance if Impact dose not affect the design. If impact does affect the design, carry out Risk Analysis & take the appropriate decision. Compile Calibration /Test certificates for all major components which will have impact on system performance. Compilation of all the documents stated above with summary to evaluate Installation against Design, respective codes etc. will complete Installation Qualification.
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Operational Qualification The operational qualification (OQ) protocol documents startup, including critical components. This includes individual performance testing of control loops under full operating pressure performed in a logical order (i.e., fan control before room pressure control). The commissioning agent must verify that operating parameters are within acceptance criteria. The HVAC may be challenged under extremes of design load (where possible) to verify operation of alarms and recorders, to determine (and correct, if significant) weak points, and to verify control and door interlocks. Based on observations, informal alert values of critical parameters, which might signify abnormal operation, may be considered. Files should include an updated description of the HVAC system, describing how it operates, schematics, airflow diagrams, and room pressure maps that accompany it. Copies should be readily accessible and properly filed. Operating personnel should be familiar with the data in these records and be able to explain it to an agency inspector. GMP documents should also include test reports for HEPA filters (efficiency or pinhole-scan integrity tests) at final operating velocities. If the filter installer performed the tests, the data should have been part of the IQ package. 1. Prepare Operation Qualification Protocol Includes checking all the operational parameters like Interlocks, Input Utilities, Fan Performance, Actuations of control system for their correctness. Carry out these checks using protocol & prepare report with any deviations, corrective actions taken & acceptance. Completion of Report with supporting documents like printouts etc. will complete Operation Qualification.
Operational Qualification The operational qualification (OQ) protocol documents startup, including critical components. This includes individual performance testing of control loops under full operating pressure performed in a logical order (i.e., fan control before room pressure control). The commissioning agent must verify that operating parameters are within acceptance criteria. The HVAC may be challenged under extremes of design load (where possible) to verify operation of alarms and recorders, to determine (and correct, if significant) weak points, and to verify control and door interlocks. Based on observations, informal alert values of critical parameters, which might signify abnormal operation, may be considered. Files should include an updated description of the HVAC system, describing how it operates, schematics, airflow diagrams, and room pressure maps that accompany it. Copies should be readily accessible and properly filed. Operating personnel should be familiar with the data in these records and be able to explain it to an agency inspector. GMP documents should also include test reports for HEPA filters (efficiency or pinhole-scan integrity tests) at final operating velocities. If the filter installer performed the tests, the data should have been part of the IQ package. 1. Prepare Operation Qualification Protocol Includes checking all the operational parameters like Interlocks, Input Utilities, Fan Performance, Actuations of control system for their correctness. Carry out these checks using protocol & prepare report with any deviations, corrective actions taken & acceptance. Completion of Report with supporting documents like printouts etc. will complete Operation Qualification.
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Performance Qualification Performance qualification (PQ) is proof that the entire HVAC performs as intended under actual production conditions. PQ is the beginning of the ongoing verification that the system meets acceptance criteria of the product (often called validation). This includes documentation of Maintenance record keeping and final operating and maintenance procedures in place, with recommended frequency of maintenance, and (at the owners option) a procedure for periodic challenge of the controls and alarms Logs of critical parameters that prove the system maintains acceptance criteria over a prescribed time Training records of operators and maintenance personnel Final loop tuning parameters After accepting PQ, the owners change control procedure should limit further modifications to critical components (as shown on IQ and OQ forms) that affect the product. Once the system is operational, pharmaceutical product trial lots are run in the facility (process validation) and the owner should regularly monitor viable (microbial) and nonviable particles in the room. 1. Preparing for Performance Qualification: Vendor to submit following SOPs, to be approved by Client/Consultant: 1. Measuring Velocity, Volume & calculating ACH, 2. DOP test if HEPA filter is used, 3. Particle count measurement, 4. T & RH measurement & recording, 5. Recovery, Fall Out (if applicable), 6. Any additional as per guideline & applicable for specific system. * Client to have SOPs required for Viable checking, approved & effective. 1. Preparing for Performance Qualification: Simultaneously prepare protocol for carrying out Performance Qualification for Viable & Non - Viable with following details: 1. Locations for Particle counts, Air counts & Surface counts ref. to guidelines & expertise 2. Frequencies for checking T & RH & minimum number of readings per day
Performance Qualification Performance qualification (PQ) is proof that the entire HVAC performs as intended under actual production conditions. PQ is the beginning of the ongoing verification that the system meets acceptance criteria of the product (often called validation). This includes documentation of Maintenance record keeping and final operating and maintenance procedures in place, with recommended frequency of maintenance, and (at the owners option) a procedure for periodic challenge of the controls and alarms Logs of critical parameters that prove the system maintains acceptance criteria over a prescribed time Training records of operators and maintenance personnel Final loop tuning parameters After accepting PQ, the owners change control procedure should limit further modifications to critical components (as shown on IQ and OQ forms) that affect the product. Once the system is operational, pharmaceutical product trial lots are run in the facility (process validation) and the owner should regularly monitor viable (microbial) and nonviable particles in the room. 1. Preparing for Performance Qualification: Vendor to submit following SOPs, to be approved by Client/Consultant: 1. Measuring Velocity, Volume & calculating ACH, 2. DOP test if HEPA filter is used, 3. Particle count measurement, 4. T & RH measurement & recording, 5. Recovery, Fall Out (if applicable), 6. Any additional as per guideline & applicable for specific system. * Client to have SOPs required for Viable checking, approved & effective. 1. Preparing for Performance Qualification: Simultaneously prepare protocol for carrying out Performance Qualification for Viable & Non - Viable with following details: 1. Locations for Particle counts, Air counts & Surface counts ref. to guidelines & expertise 2. Frequencies for checking T & RH & minimum number of readings per day
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3. Number of days T & RH readings to be taken 4. Number of consecutive days Viable validation to be continued 5. Acceptance criteria for each parameter. 2. Performance Qualification Activity Carry out all checks as per Protocol, using approved SOPs & Calibrated measuring instruments. Prepare report with acceptance criteria. Any deviations Or out of limit readings, investigate, take corrective actions & repeat the Performance Qualification activity again. Compilation of Protocol, reports, investigation reports, rechecking, final report, along with copy of all SOPs, Calibration certificate of measuring instruments & Summary report will complete Performance Qualification. Validation Overview Report Prepare a Qualification / Validation Overview report giving references of all summary reports, all deviations, corrective actions, impact analysis, risk analysis, acceptance of deviations with reasoning & conclusion. THIS COMPLETES THE QUALIFICATION / VALIDATION ACTIVITY.
3. Number of days T & RH readings to be taken 4. Number of consecutive days Viable validation to be continued 5. Acceptance criteria for each parameter. 2. Performance Qualification Activity Carry out all checks as per Protocol, using approved SOPs & Calibrated measuring instruments. Prepare report with acceptance criteria. Any deviations Or out of limit readings, investigate, take corrective actions & repeat the Performance Qualification activity again. Compilation of Protocol, reports, investigation reports, rechecking, final report, along with copy of all SOPs, Calibration certificate of measuring instruments & Summary report will complete Performance Qualification. Validation Overview Report Prepare a Qualification / Validation Overview report giving references of all summary reports, all deviations, corrective actions, impact analysis, risk analysis, acceptance of deviations with reasoning & conclusion. THIS COMPLETES THE QUALIFICATION / VALIDATION ACTIVITY.
Typical considerations in finalising the URS and DQ for machinery and analytical instruments
Machinery 1. Component specifications. To be stated for all types and size(s) of components to be handled. 2. Parametric range(s) 3. Filling or packaging rate. 4. Whether regular changes to different components sizes are required (this is important if the change-over takes a long time for a machine). 5. The location and environment in which the machine is to be used, e.g., sterile area, clean room, etc. 6. The filling or packaging- line layout if the equipment is to connect to other machinery. The infeed and outfeed positions on equipment forming a long packaging line need to be considered. This should include a layout drawing of the line. 7. Careful consideration by production staff is required to determine what monitoring gauges and devices are required to help ensure that product quality is maintained. These are classed as critical devices. When the requirements have been defined, the accuracy limits (or acceptable limits) must be determined for each device. 9. Consideration must be given to safeguards to prevent products or components from becoming trapped in the equipment. It is better to design out the areas for rogue entrapment rather than have packaging machine operators search dozens of locations for rouges at the end of each batch produced. with inevitable missed rogue items due to human error . 10. Easy cleaning of equipment should be possible. The ability to easily completely dismantle filling equipment to ensure effective cleaning and sterilizing will help reduce the risk of bacteriological continuation and minimize the batch/product changeover time. 11. Easy access for maintenance and calibration is required 12. Lubrication
Typical considerations in finalising the URS and DQ for machinery and analytical instruments
Machinery 1. Component specifications. To be stated for all types and size(s) of components to be handled. 2. Parametric range(s) 3. Filling or packaging rate. 4. Whether regular changes to different components sizes are required (this is important if the change-over takes a long time for a machine). 5. The location and environment in which the machine is to be used, e.g., sterile area, clean room, etc. 6. The filling or packaging- line layout if the equipment is to connect to other machinery. The infeed and outfeed positions on equipment forming a long packaging line need to be considered. This should include a layout drawing of the line. 7. Careful consideration by production staff is required to determine what monitoring gauges and devices are required to help ensure that product quality is maintained. These are classed as critical devices. When the requirements have been defined, the accuracy limits (or acceptable limits) must be determined for each device. 9. Consideration must be given to safeguards to prevent products or components from becoming trapped in the equipment. It is better to design out the areas for rogue entrapment rather than have packaging machine operators search dozens of locations for rouges at the end of each batch produced. with inevitable missed rogue items due to human error . 10. Easy cleaning of equipment should be possible. The ability to easily completely dismantle filling equipment to ensure effective cleaning and sterilizing will help reduce the risk of bacteriological continuation and minimize the batch/product changeover time. 11. Easy access for maintenance and calibration is required 12. Lubrication
13. If the equipment available is computer controlled, define exactly what type of computer system is required (try to standardize) and what security measures are required, for example, access codes, back up systems, and alarms. 14. Standardization, wherever possible, will alleviate problems with replacement stock holding. 15. Safety 16. Fitting unnecessary gauges and devices that do not serve either production operation or troubleshooting requirements should be avoided 17. Specifications should slate that critical and non-critical devices must be sited to enable easy access for maintenance and calibration 18. Service Manuals Reaction vessels Before design of the equipment following requirements shall be considered: o Reaction Volume o MOC of the contact parts o Maximum and Minimum Temperature o Stirring Speed o Need for vacuum distillation facilities o Need for reflux facilities o Need for slow charging of one of the reactant o Need for protection of the content from moisture o Need for maintaining inert gas environment in the vessel. o Need for handling hazardous materials in the reactor o Need for handling hazardous gaseous eflfluents from the reaction vessel o Need for scrapping the reaction product after the reaction is over o Need for phase separation after the reaction is over o Need for precise control of temperature and pressure during the reaction
13. If the equipment available is computer controlled, define exactly what type of computer system is required (try to standardize) and what security measures are required, for example, access codes, back up systems, and alarms. 14. Standardization, wherever possible, will alleviate problems with replacement stock holding. 15. Safety 16. Fitting unnecessary gauges and devices that do not serve either production operation or troubleshooting requirements should be avoided 17. Specifications should slate that critical and non-critical devices must be sited to enable easy access for maintenance and calibration 18. Service Manuals Reaction vessels Before design of the equipment following requirements shall be considered: o Reaction Volume o MOC of the contact parts o Maximum and Minimum Temperature o Stirring Speed o Need for vacuum distillation facilities o Need for reflux facilities o Need for slow charging of one of the reactant o Need for protection of the content from moisture o Need for maintaining inert gas environment in the vessel. o Need for handling hazardous materials in the reactor o Need for handling hazardous gaseous eflfluents from the reaction vessel o Need for scrapping the reaction product after the reaction is over o Need for phase separation after the reaction is over o Need for precise control of temperature and pressure during the reaction
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o Need for transfer of all inputs via vacuum and transfer all the reaction products by vacuum o Need for safeguarding against the accidental explosion . o Need for observation for change in colour and state o Need for continous monitoring of pH o Need for rapid stirring o Need for disallowing settling of material at the bottom o Need for handling low boiling point liquids o Need for maintaining at high temperature for prolonged time o Need for gas purging during the reaction Based on the above requirements the equipment design shall include following Parameters : o Detailed Diagram drawn to scale and labelled to show following features ; o Height and Diameter of the vessel o Position of Baffles o Position and design of the stirring device o Position of motor and gearbox o Position of steam jacket o Locations of all openings, valves,joints (Type and size of the valves shall be specified) o Location of thermowell o Location of Pressue gauzes,temperature recorders,flow meters, level tubes o Steam, chilled water, brine inlet and outlet points o Height and Diameter of Condenser,its location and piping o Location of Electrical Points o Design of the scrubber attached (if any) o Details on Vacuum line o Design of Online Cleaning Facilities provided In addition to the above MOC of the contact and non contact parts and all valves shall be specified. Also, limits for hydrostatic pressure which the system can sustain without cracking shall be specified.
o Need for transfer of all inputs via vacuum and transfer all the reaction products by vacuum o Need for safeguarding against the accidental explosion . o Need for observation for change in colour and state o Need for continous monitoring of pH o Need for rapid stirring o Need for disallowing settling of material at the bottom o Need for handling low boiling point liquids o Need for maintaining at high temperature for prolonged time o Need for gas purging during the reaction Based on the above requirements the equipment design shall include following Parameters : o Detailed Diagram drawn to scale and labelled to show following features ; o Height and Diameter of the vessel o Position of Baffles o Position and design of the stirring device o Position of motor and gearbox o Position of steam jacket o Locations of all openings, valves,joints (Type and size of the valves shall be specified) o Location of thermowell o Location of Pressue gauzes,temperature recorders,flow meters, level tubes o Steam, chilled water, brine inlet and outlet points o Height and Diameter of Condenser,its location and piping o Location of Electrical Points o Design of the scrubber attached (if any) o Details on Vacuum line o Design of Online Cleaning Facilities provided In addition to the above MOC of the contact and non contact parts and all valves shall be specified. Also, limits for hydrostatic pressure which the system can sustain without cracking shall be specified.
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Analytical instruments Steps in Design Qualification of Analytical Equipment Description of the analysis problem Selection of the analysis technique Description of the intended use of the equipment Description of the intended environment Preliminary selection of the functional and performance specifications (technical, environmental, safety) Preliminary selection of the supplier Instrument tests (if the technique is new) Final selection of the equipment Final selection of the supplier and equipment Development and documentation of final functional and operational specifications Steps in Vendor Qualification of Analytical Equipment 1. Develop a vendor qualification checklist. Does the vendor have a documented and certified quality system, e.g., ISO 9001 (please note: ISO 9002 or 9003 is insufficient because they dont cover development!)? For products that include software: does the vendor comply with ISO 9000-3 (Guidelines for the application of ISO 9001 to the development, supply and maintenance of software) or an equivalent standard or guide? Is equipment hardware and computer software developed and validated according to a documented procedure, e.g., according to a product life cycle? Is the vendor prepared to make product development and validation records and source code accessible to regulatory agencies ? Does the vendor provide declaration of conformity to documented specifications ? Does the vendor provide assistance in design qualification, equipment installation, qualification, maintenance and timely repair through qualified people?
Analytical instruments Steps in Design Qualification of Analytical Equipment Description of the analysis problem Selection of the analysis technique Description of the intended use of the equipment Description of the intended environment Preliminary selection of the functional and performance specifications (technical, environmental, safety) Preliminary selection of the supplier Instrument tests (if the technique is new) Final selection of the equipment Final selection of the supplier and equipment Development and documentation of final functional and operational specifications Steps in Vendor Qualification of Analytical Equipment 1. Develop a vendor qualification checklist. Does the vendor have a documented and certified quality system, e.g., ISO 9001 (please note: ISO 9002 or 9003 is insufficient because they dont cover development!)? For products that include software: does the vendor comply with ISO 9000-3 (Guidelines for the application of ISO 9001 to the development, supply and maintenance of software) or an equivalent standard or guide? Is equipment hardware and computer software developed and validated according to a documented procedure, e.g., according to a product life cycle? Is the vendor prepared to make product development and validation records and source code accessible to regulatory agencies ? Does the vendor provide declaration of conformity to documented specifications ? Does the vendor provide assistance in design qualification, equipment installation, qualification, maintenance and timely repair through qualified people?
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Is there a customer feedback and response system in case the user reports a problem or enhancement request? Is there a change control system with suitable notification of users after the changes? 2. Send the checklist to the vendor If the vendor answers all the questions satisfactorily within a given time frame, the vendor is qualified. 3. If the vendor does not answer the questions satisfactorily, another vendor should be considered. If there is no other vendor who could provide an instrument that meets the operational and functional specifications, a direct audit should be considered. Steps in Installation Qualification of Analytical Equipment Before installation Obtain manufacturers recommendations for installation site requirements. Check the site for the fulfillment of the manufacturers recommendations (utilities such as electricity, water and gases and environmental conditions such as humidity, temperature, vibration level and dust). Allow sufficient shelf space for the equipment, SOPs, operating manuals and software. During installation Compare equipment, as received, with purchase order (including software, accessories, spare parts) Check documentation for completeness (operating manuals, maintenance instructions, standard operating procedures for testing, safety and validation certificates) Check equipment for any damage Install hardware (computer, equipment, fittings and tubings for fluid connections, columns in HPLC and GC, power cables, data flow and instrument control cables) Switch on the instruments and ensure that all modules power up and perform an electronic self-test Install software on computer following the manufacturers recommendation
Is there a customer feedback and response system in case the user reports a problem or enhancement request? Is there a change control system with suitable notification of users after the changes? 2. Send the checklist to the vendor If the vendor answers all the questions satisfactorily within a given time frame, the vendor is qualified. 3. If the vendor does not answer the questions satisfactorily, another vendor should be considered. If there is no other vendor who could provide an instrument that meets the operational and functional specifications, a direct audit should be considered. Steps in Installation Qualification of Analytical Equipment Before installation Obtain manufacturers recommendations for installation site requirements. Check the site for the fulfillment of the manufacturers recommendations (utilities such as electricity, water and gases and environmental conditions such as humidity, temperature, vibration level and dust). Allow sufficient shelf space for the equipment, SOPs, operating manuals and software. During installation Compare equipment, as received, with purchase order (including software, accessories, spare parts) Check documentation for completeness (operating manuals, maintenance instructions, standard operating procedures for testing, safety and validation certificates) Check equipment for any damage Install hardware (computer, equipment, fittings and tubings for fluid connections, columns in HPLC and GC, power cables, data flow and instrument control cables) Switch on the instruments and ensure that all modules power up and perform an electronic self-test Install software on computer following the manufacturers recommendation
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Verify correct software installation, e.g., are all files loaded. Utilities to do this should be included in the software. Make back-up copy of software Configure peripherals, e.g. printers and equipment modules Identify and make a list with a description of all hardware, include drawings where appropriate. Make a list with a description of all software installed on the computer List equipment manuals and SOPs Prepare an installation report Analytical Equipment Characterization In-house identification number (asset number) Name of the item of equipment The manufacturers name, address and phone number for service calls, service contract number, if there is one Serial number and firmware revision number of equipment Computer hardware with information on the processor, hard disk space, memory and the monitor `Software with product and revision number Date received Date placed in service Current location Size, weight Condition when received, for example, new, used, reconditioned List with authorized users and responsible person Steps in Performance Qualification of Analytical Equipment 1. Define the performance criteria and test procedures. 2. Select critical parameters with some allowance to drift out of predefined specifications. For a liquid chromatography system this can be precision of the amounts precision of retention times resolution between two peaks
Verify correct software installation, e.g., are all files loaded. Utilities to do this should be included in the software. Make back-up copy of software Configure peripherals, e.g. printers and equipment modules Identify and make a list with a description of all hardware, include drawings where appropriate. Make a list with a description of all software installed on the computer List equipment manuals and SOPs Prepare an installation report Analytical Equipment Characterization In-house identification number (asset number) Name of the item of equipment The manufacturers name, address and phone number for service calls, service contract number, if there is one Serial number and firmware revision number of equipment Computer hardware with information on the processor, hard disk space, memory and the monitor `Software with product and revision number Date received Date placed in service Current location Size, weight Condition when received, for example, new, used, reconditioned List with authorized users and responsible person Steps in Performance Qualification of Analytical Equipment 1. Define the performance criteria and test procedures. 2. Select critical parameters with some allowance to drift out of predefined specifications. For a liquid chromatography system this can be precision of the amounts precision of retention times resolution between two peaks
peak width at half height or peak tailing limit of detection and limit of quantitation wavelength accuracy of a UV/Visible wavelength detector. 3. Define the test intervals, e.g., every day every time the system is used before, between and after a series of runs 4. Define corrective actions on what to do if the system does not meet the criteria, in other words if the system is out of specification Post-Qualification Documentation of Analytical Equipment On completion of equipment qualification, documentation should be available that consists of: Design qualification document A vendor qualification checklist Installation qualification document (includes description of hardware and software) Procedures for testing Qualification test reports with signatures and dates Entries on instrument ID in the laboratorys instrument data base PQ test procedures and representative results How much validation is too much validation? The challenge is to find a good compromise between not doing enough and doing too much. Validation is an excellent example.
Incremental benefit Optimal band
peak width at half height or peak tailing limit of detection and limit of quantitation wavelength accuracy of a UV/Visible wavelength detector. 3. Define the test intervals, e.g., every day every time the system is used before, between and after a series of runs 4. Define corrective actions on what to do if the system does not meet the criteria, in other words if the system is out of specification Post-Qualification Documentation of Analytical Equipment On completion of equipment qualification, documentation should be available that consists of: Design qualification document A vendor qualification checklist Installation qualification document (includes description of hardware and software) Procedures for testing Qualification test reports with signatures and dates Entries on instrument ID in the laboratorys instrument data base PQ test procedures and representative results How much validation is too much validation? The challenge is to find a good compromise between not doing enough and doing too much. Validation is an excellent example.
Incremental benefit Optimal band
Incremental costs
Incremental costs
When complying right at the beginning of the validation process the additional value to each 0% Validation efforts 100% validation step is tremendous. However, there is no added value in trying to validate each and every step and the incremental costs for validation goes up with each validation effort. The question is: where is the optimum or how much validation is enough. The challenge is to find the optimum and this requires a thorough risk analysis.
When complying right at the beginning of the validation process the additional value to each 0% Validation efforts 100% validation step is tremendous. However, there is no added value in trying to validate each and every step and the incremental costs for validation goes up with each validation effort. The question is: where is the optimum or how much validation is enough. The challenge is to find the optimum and this requires a thorough risk analysis.

CK Murthy

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