Pharmaceutical Quality Assurance and Management
By K. P. Bhusari and U. D. Shivhare
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About this ebook
Salient Features:
- Presented the information in condensed and cohesive form
- Covers different validation protocols for various processes, methods and equipments involved in the manufacturing
- Involved pharmaceutical inspections, various regulatory acts
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Pharmaceutical Quality Assurance and Management - K. P. Bhusari
CHAPTER 1
Introduction to Clinical Pharmacy
1.1 Introduction
GMP refers to the Good Manufacturing Practice Regulations promulgated by the US Food and Drug Administration under the authority of the Federal Food, Drug, and Cosmetic Act (See Chapter IV for food, and Chapter V, Sub chapters A, B, C, D, and E for drugs and devices.) These regulations, which have the force of law, require that manufacturers, processors, and packagers of drugs, medical devices, some food, and blood take proactive steps to ensure that their products are safe, pure, and effective. GMP regulations require a quality approach to manufacturing, enabling companies to minimize or eliminate instances of contamination, mixups, and errors. This in turn, protects the consumer from purchasing a product which is not effective or even dangerous. Failure of firms to comply with GMP regulations can result in very serious consequences including recall, seizure, fines, and jail time.
GMP regulations address issues including recordkeeping, personnel qualifications, sanitation, cleanliness, equipment verification, process validation, and complaint handling. Most GMP requirements are very general and open-ended, allowing each manufacturer to decide individually how to best implement the necessary controls. This provides much flexibility, but also requires that the manufacturer interpret the requirements in a manner which makes sense for each individual business.
Fig. 1.1 Illustrates how we approach creating and maintaining a GMP lifestyle in a company.
GMP is also sometimes referred to as cGMP
. The c
stands for current,
reminding manufacturers that they must employ technologies and systems which are up-to-date in order to comply with the regulation, systems and equipment used to prevent contamination, mixups, and errors, which may have been top-of-the-line
20 years ago. may be less than adequate by today's standards.
At the GMP Institute, it may be believed that GMP is a good business tool which will help to refine both compliance and performance at your company. GMP requirements are largely common sense practices which will help your company better itself as it moves toward a quality approach using continuous improvement. The Fig. 1.1 illustrates how we approach creating and maintaining a GMP lifestyle in a company. First, set standards of performance. These include GMP regulations and other standards which are necessary for your company. Then, train to those standards. All departments in the company should be trained (to varying degrees) on GMP and other standards. The diagram lists four types of employees which are especially critical to train: top management, managers and supervisors, operators and technicians, and support staff. Because training is such an important part of maintaining a GMP Lifestyle, the GMP Institute focuses heavily on training.
The next step in the GMP Lifestyle is to reinforce what was learned in training. This falls on the managers and supervisors in a plant. Therefore, it is important that managers and supervisors be involved in training, so that they can support it through reinforcement. The same four job categories are listed as being the most critical in promoting and receiving reinforcement.
The third stage is to audit to ensure that your efforts have provided adequate controls by auditing. Audits fall in the following three categories: personal, whereby every individual does a self-check to make sure that he/she is complying with all appropriate standards: internal audit, which should be performed by the quality assurance department as required by GMP, and external audits, which can consist of an FDA audit, a consultant checking your compliance status, or you performing a supplier audit. The GMP Institutes also offers workshops for auditors needing training.
Finally, the results of audits will help you to know if you need to modify your standards of performance. Of course, no procedures should be changed without appropriate change control and approval from quality assurance. The glue that sticks the whole process together is commitment. Commitment to GMP and quality is critical at all levels of the organization, starting with top management. If you foster commitment, use this process, and attend GMP Institute workshops when necessary, you will help you make GMP a Lifestyle, Not Just a Regulation in your company. You will then improve the overall performance of your workforce, as well as your FDA compliance.
Peruse the GMP regulations
21 CFR Parts 210 and 211 (For Drug Industry)
21 CFR Part 820 (For Medical Device Industry)
21 CFR Part 110 (For Food Industry)
21 CFR Part 606 (For Blood Industry)
1.2 Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General
(21 CFR Part 210: 43 FR 45076, Sept. 29, 1978)
1. Status of Current good manufacturing practice regulations
2. Applicability of current good manufacturing practice regulations
1.3 Current Good Manufacturing Practice for Finished Pharmaceuticals
(21 CFR Part 211: 43 FR 45077, Sept. 29, 1978)
1.3.1 General Provisions
1. Scope
1.3.2 Organization and Personnel
1. Responsibilities of quality control unit
2. Personnel qualifications
3. Personnel responsibilities
4. Consultants
Consultants advising on the manufacture, processing, packing, or holding of dmg products shall have sufficient education, training, and experience, or any combination thereof, to advise on die subject for which they are retained. Records shall be maintained stating die name, address, and qualifications of any consultants and the type of service diey provide.
1.3.3 Buildings and Facilities
1. Design and construction features
1. Receipt, identification, storage, and withholding from use of components, drug product containers, closures, and labeling, pending the appropriate sampling, testing, or examination by the quality control unit before release for manufacturing or packaging;
2. Holding rejected components, drug product containers, closures, and labeling before disposition;
3. Storage of released components, drug product containers, closures, and labeling;
4. Storage of in-process materials;
5. Manufacturing and processing operations;
6. Packaging and labeling operations;
7. Quarantine storage before release of drug products;
8. Storage of drug products after release;
9. Control and laboratory operations;
10. Aseptic processing, which includes as appropriate:
2. Ventilation, air filtration, air heating and cooling
3. Plumbing
4. Sewage and refuse
Sewage, trash, and other refuse in and from the building and immediate premises shall be disposed of in a safe and sanitary manner.
5. Washing and toilet facilities
Adequate washing facilities shall be provided, including hot and cold water, soap or detergent, air driers or single-service towels, and clean toilet facilities easily accessible to working areas.
6. Sanitation
7. Maintenance
Any building used in the manufacture, processing, packing, or holding of a drug product shall be maintained in a good state of repair.
1.3.4 Equipment
1. Equipment design, size, and location
Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.
2. Equipment construction
(a) Equipment shall be constructed so that surfaces that contact components, in-process materials, or dmg products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the dmg product beyond the official or other established requirements.
(b) Any substances required for operation, such as lubricants or coolants, shall not come into contact with components, dmg product containers, closures, in-process materials, or dmg products so as to alter the safety, identity, strength, quality, or purity of the dmg product beyond the official or other established requirements.
3. Equipment cleaning and maintenance
(a) Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.
(b) Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall include, but are not necessarily limited to, the following:
1. Assignment of responsibility for cleaning and maintaining equipment;
2. Maintenance and cleaning schedules, including, where appropriate, sanitizing schedules;
3. A description in sufficient detail of the methods, equipment, and materials used in cleaning and maintenance operations, and the methods of disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance;
4. Removal or obliteration of previous batch identification;
5. Protection of clean equipment from contamination prior to use;
6. Inspection of equipment for cleanliness immediately before use.
(c) Records shall be kept of maintenance, cleaning, sanitizing, and inspection as specified in cGMP for finished pharmaceutical products.
4. Automatic, mechanical, and electronic equipment
5. Filters
Filters for liquid filtration used in the manufacture, processing, or packing of injectable drag products intended for human use shall not release fibers into such products. Fiber-releasing filters may not be used in the manufacture, processing, or packing of these injectable drag products unless it is not possible to manufacture such drag products without the use of such filters. If use of a fiber-releasing filter is necessary, an additional non-fiber-releasing filter of 0.22 micron maximum mean porosity (0.45 micron if the manufacturing conditions so dictate) shall subsequently be used to reduce the content of particles in the injectable drag product. Use of an asbestos-containing filter, with or without subsequent use of a specific non-fiber-releasing filter, is permissible only upon submission of proof to the appropriate bureau of the Food and Drag Administration that use of a non-fiber-releasing filter will, or is likely to, compromise the safety or effectiveness of the injectable drug product.
1.3.5 Control of Components and Drug Product Containers and Closures
1. General requirements
2. Receipt and storage of untested components, drug product containers, and closures
3. Testing and approval or rejection of components, drug product containers, and closures
(d) Samples shall be examined and tested as follows:
(e) Any lot of components, drug product containers, or closures that meets the appropriate written specifications of identity, strength, quality, and purity and related tests under paragraph (d) of this section may be approved and released for use. Any lot of such material that does not meet such specifications shall be rejected.
[43 FR 45077, Sept. 29, 1978, as amended at 63 FR 14356, Mar. 25, 1998]
4. Use of approved components, drug product containers, and closures
Components, drug product containers, and closures approved for use shall be rotated so that the oldest approved stock is used first. Deviation from this requirement is permitted if such deviation is temporary and appropriate.
5. Retesting of approved components, drug product containers, and closures
Components, drug product containers, and closures shall be retested or reexamined, as appropriate, for identity, strength, quality, and purity and approved or rejected by the quality control unit in accordance with requirements as necessary, e.g after storage for long periods or after exposure to air, heat or other conditions that might adversely affect the component, drug product container, or closure.
6. Rejected components, drug product containers, and closures
Rejected components, drug product containers, and closures shall be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable.
7. Drug product containers and closures
1.3.6 Production and Process Controls
1. Written procedures; deviations
2. Charge-in of components
Written production and control procedures shall include the following, which are designed to assure that the drug products produced have the identity, strength, quality, and purity they purport or are represented to possess:
(a) The batch shall be formulated with the intent to provide not less than 100 percent of the labeled or established amount of active ingredient.
(b) Components for drug product manufacturing shall be weighed, measured, or subdivided as appropriate. If a component is removed from the original container to another, the new container shall be identified with the following information:
1. Component name or item code:
2. Receiving or control number;
3. Weight or measure in new container;
4. Batch for which component was dispensed, including its product name, strength, and lot number.
(c) Weighing, measuring, or subdividing operations for components shall be adequately supervised. Each container of component dispensed to manufacturing shall be examined by a second person to assure that:
1. The component was released by the quality control unit;
2. The weight or measure is correct as stated in the batch production records;
3. The containers are properly identified.
(d) Each component shall be added to the batch by one person and verified by a second person.
3. Calculation of yield
Actual yields and percentages of theoretical yield shall be determined at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product. Such calculations shall be performed by one person and independently verified by a second person.
4. Equipment identification
(a) All compounding and storage containers, processing lines, and major equipment used during the production of a batch of a drug product shall be properly identified at all times to indicate their contents and, when necessary, the phase of processing of the batch.
(b) Major equipment shall be identified by a distinctive identification number or code that shall be recorded in the batch production record to show the specific equipment used in the manufacture of each batch of a drug product. In cases where only one of a particular type of equipment exists in a manufacturing facility, the name of the equipment may be used in lieu of a distinctive identification number or code.
5. Sampling and testing of in-process materials and drug products
(a) To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall 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. Such control procedures shall include, but are not limited to, the following, where appropriate:
1. Tablet or capsule weight variation;
2. Disintegration time;
3. Adequacy of mixing to assure uniformity and homogeneity;
4. Dissolution time and rate;
5. Clarity, completeness, or pH of solutions.
6. Time limitations on production
When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product. Deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product. Such deviation shall be justified and documented.
7. Control of microbiological contamination
8. Reprocessing
1.3.7 Packaging and Labeling Control
1. Materials examination and usage criteria
2. Labeling issuance
3. Packaging and labeling operations
There shall be written procedures designed to assure that correct labels, labeling, and packaging materials are used for drug products; such written procedures shall be followed. These procedures shall incorporate the following features:
4. Tamper-evident packaging requirements for over-the-counter (OTC) human drug products