Course Notes

Good Manufacturing Practice
Course : Diploma in Chemical & Pharmaceutical Technology (CLDF02)

Diploma in Biologics & Process Technology (CLDF05)
Module Title : Good Manufacturing Practice
Module Code : CLC326/CLB216
Course Note
TOPIC 1 History of GMP
HISTORY OF GMP Last Date updated: 10 June 2004

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TOPIC 1 History of GMP
1.1 Introduction
Learning Objectives:
 Define Good Manufacturing Practice (GMP and cGMP)
 Explain the need for, importance and applicability of cGMP
1.1.1 What is Good Manufacturing Practice? What do GMP and cGMP stand
for?
GMP is the short form for Good Manufacturing Practice.
Good Manufacturing Practice can be defined as:
The procedures used to make sure that pharmaceutical products, medical devices or
medical device components are made in such a way that it will be pure, safe and of
the right quality. GMP applies to all aspects of manufacturing and testing from receipt
of raw materials to shipment of final product.
What does the “c” stand for?
The GMP procedures are constantly being revised and updated. The “c” stands for
“current”, which means that only the latest and the most current practice is applicable
to the set of procedures. This is important since GMP is a continuously evolving set
of industry practices and all manufacturers should be using the most current and
updated practices.
1.1.2 GMP variations
The overall principles of GMP are similar whether we follow the World Health
Organisation (WHO) Guidelines, the European Union (EU) Guidelines, the US Food
and Drug Administration (FDA), the Australian or Singapore guidelines.
Although the overall principles are the same, the interpretation and applications are
open to interpretation. The differences could take the following forms:
- The approach taken by different regulatory authorities varies.

- The enforcement of the guidelines varies between different regulatory authorities.
- The approach taken by individual inspectors varies.
Harmonisation Efforts
There are efforts being made to harmonise these standards. For example, the
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) brings together the
regulatory authorities of Europe, Japan and the United States and experts from the
pharmaceutical industry in the three regions to discuss scientific and technical aspects
of product registration.
HISTORY OF GMP 1-1 Last Date updated: 10 June 2004

The purpose is to make recommendations on ways to achieve greater harmonisation in
the interpretation and application of technical guidelines and requirements for product
registration in order to reduce or obviate the need to duplicate the testing carried out
during the research and development of new medicines.
Harmonisation of cGMP requirements
The Pharmaceutical Inspection Cooperation Scheme (PIC/S) was established in 1995.

This is a non-legal cooperative arrangement between regulatory countries. PIC/S
provides for GMP inspection reports and GMP certificates to be exchanged; however,
there is no legal obligation that member authorities must accept such reports or
certificates.
The main functions of PIC/S are:
1. to exchange information and experience on GMP (Good

Manufacturing Practice) for medicines, including exchange of GMP
inspection reports and GMP certificates;
2. to facilitate the training of GMP inspectors by means of regular
seminars and a joint inspection training program, with a view to harmonising
GMP inspection activities;
3. to arrange Expert Circle meetings to discuss specific areas of
GMP involving the inspection of manufacturers of medical gases, blood banks,
hospital pharmacy and other specialised areas;
4. to develop guidance documents on different aspects of GMP,
e.g. validation, sterility testing, isolator technology and Quality Systems for
GMP Inspectorates;
5. to facilitate networking and confidence building; and
6. to facilitate international harmonisation on GMP.
About 25 countries are on PIC/S. Singapore became a member of PIC/S in Jan 2000.
1.1.3 What does GMP look at?
GMP encompasses all manufacturing. In general, GMP looks at the following

specifics:
• Inspections and Audits
• Documentation
• Calibration and Preventive Maintenance
• Housekeeping, Buildings and Facilities
• Validation
• Warehousing
• Manufacturing Controls
• Storage and Labels
• Samples and Retains
• Quality Control

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1.1.4 Need for, importance and applicability of GMP
Why is it important to have GMP?
If drugs are wrongly made, labelled or has deteriorated in quality, it may have a
dangerous or even fatal effect on the users. It is just not possible to exchange a
medicine after use. Biomedical products must be FIT for their intended purpose.
GMPs are used by the pharmaceutical manufacturers as they produce products that
people use (drug GMPs also apply to the veterinary drugs). In many countries, the
relevant authorities have issued these regulations as the minimum requirements.
There are many cases in the past where bio-medical products were recalled due to a
lack of testing or not following GMP procedures. For example, in 1999, the
Medicines and Healthcare Products Regulatory Agency in the UK initiated a recall of
an asthma inhaler product because the product had been incorrectly labelled. The
product inside the canister would have been ineffective in treating an asthma attack.
Worse still, the product might cause side effects in some of the users. Consumers rely
on product labels to know what the product is and how to use it. The regulatory
agencies regulate what's on these labels to ensure that they are truthful and that they
provide useable information that helps consumers make healthy, safe decisions when
using the product.
1.1.5 Definitions of Commonly Used Terms
1. Batch means a specific quantity of a drug or other material that

is intended to have uniform character and quality, within specified limits, and
is produced according to a single manufacturing order during the same cycle
of manufacture.
2. Component means any ingredient intended for use in the

manufacture of a drug product, including those that may not appear in such
drug product.
3. Drug product means a finished dosage form, for example,

tablet, capsule, solution, etc., that contains an active drug ingredient generally,
but not necessarily, in association with inactive ingredients. The term also
includes a finished dosage form that does not contain an active ingredient but
is intended to be used as a placebo.
4. Fiber means any particulate contaminant with a length at least

three times greater than its width.
5. Non-fiber-releasing filter means any filter, which after any

appropriatepretreatment such as washing or flushing, will not release
fibersinto the component or drug product that is being filtered. All
filterscomposed of asbestos are deemed to be fiber-releasing filters.
6. Active ingredient means any component that is intended to

furnish pharmacological activity or other direct effect in the diagnosis, cure,

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mitigation, treatment, or prevention of disease, or to affect the structure or
any function of the body of man or other animals. 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.
7. Inactive ingredient means any component other than an active

ingredient.
8. In-process material means any material fabricated,

compounded, blended, or derived by chemical reaction that is produced for,
and used in, the preparation of the drug product.
9. Lot means a batch, or a specific identified portion of a batch,

having uniform character and quality within specified limits; or, in the case of
a drug product produced by continuous process, it is a specific identified
amount produced in a unit of time or quantity in a manner that assures it
having uniform character and quality within specified limits.
10. Lot number, control number, or batch number means any

distinctive combination of letters, numbers, or symbols, or any combination
of them, from which the complete history of the manufacture, processing,
packing, holding, and distribution of a batch or lot of drug product or other
material can be determined.
11. Manufacture, processing, packing, or holding of a drug

product includes packaging and labeling operations, testing, and quality
control of drug products.
12. Quality control unit means any person or organizational

element designated by the firm to be responsible for the duties relating to
quality control.
13. Strength means:

(i) The concentration of the drug substance (for example,
weight/weight, weight/volume, or unit dose/volume basis), and/or
(ii) The potency, that is, the therapeutic activity of the drug
product as indicated by appropriate laboratory tests or by adequately
developed and controlled clinical data (expressed, for example, in terms
of units by reference to a standard).
14. Theoretical yield means the quantity that would be produced at

any appropriate phase of manufacture, processing, or packing of a particular
drug product, based upon the quantity of components to be used, in the
absence of any loss or error in actual production.
15. Actual yield means the quantity that is actually produced at

any appropriate phase of manufacture, processing, or packing of a particular
drug product.

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16. Percentage of theoretical yield means the ratio of the actual
yield (at any appropriate phase of manufacture, processing, or packing of a
particular drug product) to the theoretical yield (at the same phase), stated as
a percentage.
17. Acceptance criteria means the product specifications and
acceptance/rejection criteria, such as acceptable quality level and
unacceptable quality level, withan associated sampling plan, that are
necessary for making a decision to accept or reject a lot or batch (or any other
convenient subgroups of manufactured units).
18. Representative sample means a sample that consists of a

number of units that are drawn based on rational criteria such as random
sampling and intended to assure that the sample accurately portrays the
material being sampled.
19. Gang-printed labeling means labeling derived from a sheet of

material on which more than one item of labeling is printed.
1.2 History of GMP
 Describe the history of GMP regulations
 Understand concept of GMP compliance and its impact on
manufacturing activities
 Understand legal principles of GMP
1.2.1 History of GMP regulations
1937, a public health disaster in the US tragically drove home the need for a stronger
federal law. A new antibiotic preparation, Elixir of Sulfanilamide, was formulated and
marketed for use in children. But the drug contained a poison, the same chemical used
in antifreeze, and it killed 107 people, most of them children. The earlier law did not
require the drug's manufacturer to test the formulation for safety before it was sold.
The US Congress corrected this weakness in the law in 1938 when it passed the
Federal Food, Drug, and Cosmetic Act. This law, for the first time, required
companies to prove the safety of new drugs and therapeutic devices before putting
them on the market.
In 1962, the US Food Drug and Cosmetic act required that drugs must be made in
accordance with GMP.
In 1967, the WHO published its Draft Requirements for GMP in the Manufacture and
Quality control of drugs and pharmaceutical specialties.
In 1976, the US FDA published its proposed cGMPs regulations.
Various revisions to GMP have followed since.

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GMP regulations are constantly being revised and changed. It is thus important to
ensure that the GMP regulations you are using is the “current” version.
1.2.2 Impact of GMP requirements on Manufacturing Activities
Companies that manufacture drugs have to be well versed in GMP regulations. They
have to ensure that their manufacturing facilities and processes are “GMP-enabled”.
These companies have to ensure the following:
• Know the cGMP Regulations.
• Comply with cGMP Regulations.
• Know their products and processes
• Communicate problems to the Quality Control department
• Take responsible actions and document justifications
• Have a system for conducting Failure Investigations. Consumer Protection is the
number one goal.
• Make the product according to cGMP.
The above has to be translated into actual plant procedures. Companies are required
to show proof that they are complying with cGMP regulations. Procedures have to be
recorded and compiled with in the plant-operating environment.
What are some of these procedures that companies have to follow?
Examples of procedures and actions which the company has to ensure are proper
include:
• The right product is pack in the correct container.
• The product and container have the right label on it.
• The product been made correctly so that it is the right quality and strength.
• The product is not contaminated.
• The product has an expiry date on it.
Testing will not improve Quality. At best it can only detect bad or good quality. It is
also not possible to test every product. Therefore Quality must be built in from start to
finish i.e. there should be zero defect in each and every product and all the time.

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1.2.3 Do meeting GMP objectives make good business sense?
Meeting GMP objectives require a lot of documentation and work. So does it make
good business sense since time and money have to be spent? Meeting GMP
regulations make good business sense because of the following reasons:
 The amount of product failure should decrease.
 The process should be more efficient and reproducible.
 The equipment should be well maintained and able to
consistently operate within process specifications resulting in less wastage.
 Future performance should be predictable.
 Amount of recalls and complaints should decrease.
 The right level of documentation should enhance investigations
of deviations (example- reduce the time spent to investigate deviations).
1.2.4 Understanding the legal principles of GMP
Pharmaceutical manufacturing is a highly regulated industry with a universal legal

requirement for it to be authorised and licensed for use by the appropriate regulatory
authorities.
GMP regulatory requirements refer to the country’s regulations with respect to GMP.
For example, in the United States, it is the FDA’s Code of Federal Regulations. The
current FDA’s cGMP are part of FDA regulations, and interpret what the FDA
believes to be good manufacturing practices, providing minimum requirements for the
production of pharmaceutical products/medical devices that are Safe, Pure and
Effective.
Thus, compliance with GMP is a regulatory and legal requirement.
1.2.5 Enforcement
When a problem arises, the regulatory agencies can take a number of actions to
protect the public health. The actions include:
1. Working with the manufacturer to correct the problem

voluntarily.
2. Taking regal remedies including asking the manufacturer to
recall a product, having enforcement personnel seize products if a voluntary
recall is not done, and detaining imports at the port of entry until problems are
corrected.
3. If warranted, the agency can ask the courts to issue injunctions
or prosecute those that deliberately violate the law.

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TOPIC 2 International GMP requirements
Understand the regulatory bodies and their roles:
 Food and Drug Administration, USA
 Therapeutic Goods Administration, Australia
 Medicines and Healthcare Products Regulatory Agency (MHRA), UK
 Centre for Pharmaceutical Administration, Health Science Authority,
Singapore
2.1 The regulatory bodies and their roles
Different countries have their own GMP regulations and have different standards.
The role of the regulatory authorities is in each country is to decide on the appropriate
regulatory standards for safety, quality and efficacy and assess whether the standards
are being met.
The regulatory authorities include:

- The Food and Drug Administration (FDA) in USA.
- The Medicines and Healthcare Products Regulatory Agency (MHRA) in
UK.
- The Therapeutic Goods Administration (TGA) in Australia.
- Centre for Pharmaceutical Administration (CPA), Health Science
Authority (HSA) in Singapore.
The manufacturer must satisfy the regulations of the country in which he will sell his
product. Inspectors from the regulatory agencies will come to his factory to check on
his compliance to GMP.
The relative risks that the products pose to consumers dictate the regulations. At the
heart of the product evaluation decisions is a judgment about whether a new product's
benefits to users will outweigh its risks. No regulated product is totally risk-free, so
these judgments are important. The regulatory agencies will allow a product to
present more of a risk when its potential benefit is great -- especially for products
used to treat serious, life-threatening conditions.
What do the regulatory agencies actually do?
The scope of work of each agency can be generally divided into the following 6 types
of activities:
1. New Product Review

The agency reviews the results of laboratory, animal and human clinical testing done
by companies to determine if the product the company wants to put on the market is
safe and effective. If required, the regulatory agency might perform some of the
laboratory testing itself, to confirm the results.
INTERNATIONAL GMP REQUIREMENTS 2-1 Last Date updated: 20 Mar 2004

2. Keeping Watch
Once products are on the market, the agency keeps track of how they are
manufactured and responds to reports of problems or newly identified risks.
3. Safe manufacturing and handling

To ensure the safety of marketed products, agency staff inspects domestic and foreign
manufacturers, check shipments of imported products, and collect and test product
samples for signs of contamination. For example, in year 2002, FDA staff made more
than 16,000 visits to facilities that handle FDA-regulated products.
4. Monitor for new risks

Because initial testing of products is based on a relatively small number of users, and
because variations in quality can happen in manufacturing, the agency keeps careful
watch on reports of adverse experiences with products after they are marketed. For
example, the FDA receives more than 400,000 problem reports a year.
5. Standards and Regulations

The agency reviews regulations and product standards periodically.
6. Research
The agency’s research activities provide the scientific basis for its regulatory
decisions and the tools needed to identify and assess risks. The agency uses its
research results to guide standards setting, evaluate new products, develop test
methods and to provide support for product monitoring, and to study emerging risks.
GMP guidelines
Each regulatory body has its set of cGMP guidelines. The guidelines adopted by the
regulatory bodies are:
Agency Guidance
USA Food and Drug Administration Chapter 21 Code of Federal
Regulations (CFR) (Parts 210, 211 &
820)
UK Medicines and Healthcare Rules and Guidance for
Products Regulatory Agency, Pharmaceutical Manufacturers and
UK Distributors
Australia Therapeutic Goods Australian Code of GMP
Administration
2.1.1 Food and Drug Administration, USA
Origins
The US Food and Drug Administration (FDA) is funded by the US

government. Its jurisdiction encompasses most food products (other than meat
and poultry), human and animal drugs, therapeutic agents of biological origin,
medical devices, radiation-emitting products for consumer, medical, and
occupational use, cosmetics, and animal feed. In fact, FDA-regulated products
account for more than 20-25 cents of every dollar spent in the United States.
INTERNATIONAL GMP REQUIREMENTS Last Date updated: 10 June 2004

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The agency has approximately 9,100 employees and a budget of US$1.3
billion in 2001, comprising chemists, pharmacologists, physicians,
microbiologists, veterinarians, pharmacists, lawyers, and specialists in public
health education and communication.
Mission
The FDA's mission is to promote and protect the public health by helping safe
and effective products reach the market in a timely way, and monitoring
products for continued safety after they are in use.
FDA methodology and approaches
FDA's regulatory approaches are as varied as the products it regulates. Some

products such as new drugs and complex medical devices must be proven safe
and effective before companies can put them on the market. Other products
such as x-ray machines and microwave ovens must measure up to
performance standards. And some products such as cosmetics and dietary
supplements can be marketed with no prior approval.
2.1.2 Therapeutic Goods Administration, Australia
The Therapeutic Goods Administration (TGA) is a unit of the Federal

Department of Health and Ageing. The TGA carries out a range of assessment
and monitoring activities to ensure therapeutic goods available in Australia are
of an acceptable standard.
The Therapeutic Goods Act 1989, which came into effect in 1991, is to
provide a national framework for the regulation of therapeutic goods in
Australia and ensure their quality, safety and efficacy. The Act set out the
requirements for inclusion of therapeutic goods, including advertising,
labelling, product appearance and appeal guidelines. This is to ensure that
medicines and medical devices in the marketplace are safe and have high
quality, to a standard at least equal to that of comparable countries.
2.1.3 Medicines and Healthcare Products Regulatory Agency (MHRA),

UK
The MHRA is the executive agency of the Department of Health protecting

and promoting public health and patient safety by ensuring that medicines,
healthcare products and medical equipment meet appropriate standards of
safety, quality, performance and effectiveness, and are used safely.
The MHRA was formed from a merger of the Medicines Control Agency
(MCA) and the Medical Devices Agency (MDA) on 1 April 2003. With the
increasing convergence of medicines and medical devices, the Agency serves
to provide a seamless service to healthcare professionals, industry, patients
and the public.
Its key activities are:

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1. Regulating medical devices.
2. Licensing of medicines before marketing and subsequent variations.
3. Regulation of clinical trials.
4. Operating adverse incident reporting system for medical devices.
5. Issuing safety warnings.
6. Responsibility for reporting, assessment and communications of
defective medicines.
7. Monitoring of medicines and acting on safety concerns after marketing.
8. Ensuring compliance to standards of pharmaceutical manufacture and
wholesaling.
9. Enforcement of requirements.
10. Evaluating medical devices and encourage safe use.
11. Providing advice and guidance on medicines and medical devices.
2.1.4 Centre for Pharmaceutical Administration (CPA), Singapore
The CPA is under the jurisdiction of the Health Sciences Authority (HSA).
The HSA is a statutory board under the Ministry of Health (MOH). HSA's
mission is to safeguard public health and contribute to the development of
biomedical science in Singapore by administrating a robust, scientific and
responsive regulatory framework, which ensures that pharmaceuticals and
health-related products in Singapore meet appropriate standards of safety,
quality and efficacy.
Key milestones of CPA
Date Milestones
Jun 1987 Implementation of drug registration to ensure medicines on sale in
Singapore are safe, efficacious and of good quality. The initial exercise
to register all pharmaceutical products sold in Singapore within the first
four years was successfully completed in July 1991.
Apr 1994 Singapore acceded to the WHO Certification Scheme on the Quality of
Pharmaceutical Products Moving in International Commerce. The
accession to the scheme helps to promote Singapore's international
standing and improve Singapore’s international cooperation with other
countries on pharmaceutical matters. It will also facilitate Singapore's
exports of pharmaceutical products.
Apr 1997 The Pharmaceutical Department operated as an Autonomous Agency
under the Ministry of Health.
Apr 1997 Formation of the Good Manufacturing Practice (GMP) Unit.
Apr 1999 Change of name from Pharmaceutical Department to National
Pharmaceutical Administration (NPA).
Jan 2000 Singapore became a member of the Pharmaceutical Inspection
Cooperation Scheme (PICS).
Feb 2001 Establishment of Mutual Recognition Agreement (MRA) on GMP
Inspection with Australia.
Apr 2001 NPA was renamed as the Centre for Pharmaceutical Administration
under the Health Sciences Authority.

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Manufacturing and Quality Audit Division
The Division of Manufacturing and Quality Audit (MQA) in CPA regulates cGMP
requirements and enforces it. A GMP Certificate would only be issued by HSA when
the manufacturing facilities have been audited and found to comply with the required
PIC/S GMP standards. A GMP Certificate would normally be valid for 2 years.
International Accreditation and Liaisons
With effect from 1 January 2000, Singapore has become the first Asian country to
accede to Pharmaceutical Inspection Co-operation Scheme (PICS). Accession to PICS
(which is based in Geneva, Switzerland) would enhance the status of Singapore as a
regional pharmaceutical and life sciences hub and will result in the global acceptance
of the quality of bio-medical products manufactured and exported from Singapore.
Product Licence
All medicinal products imported or sold in Singapore are required to be licensed by
the CPA, HSA. All factories engaged in the manufacture or assembly of medicinal
products must be licensed with Health Sciences Authority. In application for a
manufacturer's licence, the applicant should submit a formal application form and a
Site Master File for initial assessment. A Manufacturer’s Licence would only be
granted when the manufacturing facilities has been audited and found to comply with
Pharmaceutical Inspection Convention/Co-operation Scheme (PIC/S) Guide to Good
Manufacturing Practice (GMP) for Medicinal Products.
2.2 Code of Federal Regulations, FDA, USA
 Review Code of Federal Regulations (CFR) Chapter 21
The GMP regulations set forth in parts 210 and 211 and 820 are relevant for
pharmaceutical manufacturers. These regulations contain the minimum cGMP for
these manufacturers. The failure to comply with the regulations shall render such drug
to be adulterated under the act and such drug or medical component, as well as the
person who is responsible for the failure to comply, shall be subject to regulatory
action.
2.2.1 Code of Federal Regulations Part 210
CFR Parts 210 and 211 is titled “Current Good Manufacturing Practice In
Manufacturing, Processing, Packing, Or Holding Of Drugs; General”.
Parts 210 and 211 include the following subparts and sections:
210.1 Status of current good manufacturing practice regulations.
210.2 Applicability of current good manufacturing practice regulations.
210.3 Definitions.
Subpart A -- General Provisions

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211.1 Scope.
211.3 Definitions.
Subpart B -- Organization and Personnel

211.22 Responsibilities of quality control unit.
211.25 Personnel qualifications.
211.28 Personnel responsibilities.
211.34 Consultants.
Subpart C -- Buildings and Facilities

211.42 Design and construction features.
211.44 Lighting.
211.46 Ventilation, air filtration, air heating and cooling.
211.48 Plumbing.
211.50 Sewage and refuse.
211.52 Washing and toilet facilities.
211.56 Sanitation.
211.58 Maintenance.
Subpart D -- Equipment
211.63 Equipment design, size, and location.
211.65 Equipment construction.
211.67 Equipment cleaning and maintenance.
211.68 Automatic, mechanical, and electronic equipment.
211.72 Filters.
Subpart E -- Control of Components and Drug Product Containers and Closures

211.80 General requirements.
211.82 Receipt and storage of untested components, drug product containers, and closures.
211.84 Testing and approval or rejection of components, drug product containers, and
closures.
211.86 Use of approved components, drug product containers, and closures.
211.87 Retesting of approved components, drug product containers, and closures.
211.89 Rejected components, drug product containers, and closures.
211.94 Drug product containers and closures.
Subpart F -- Production and Process Controls

211.100 Written procedures; deviations.
211.101 Charge in of components.
211.103 Calculation of yield.
211.105 Equipment identification.
211.110 Sampling and testing of in-process materials and drug products.
211.111 Time limitations on production.
211.113 Control of microbiological contamination.
211.115 Reprocessing.
Subpart G -- Packaging and Labelling Controls

211.122 Materials examination and usage criteria.
211.125 Labelling issuance.
211.130 Packaging and labelling operations.
211.132 Tamper -resistant packaging requirements for over-the-counter human drug products.
211.134 Drug product inspection.
211.137 Expiration dating.
Subpart H -- Holding and Distribution

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211.142 Warehousing procedures.
211.150 Distribution procedures.
Subpart I -- Laboratory Controls

211.165 Testing and release for distribution.
211.166 Stability testing.
211.167 Special testing requirements.
211.170 Reserve samples.
211.173 Laboratory animals.
211.176 Penicillin contamination.
Subpart J -- Records and Reports

211.182 Equipment cleaning and use log.
211.184 Component, drug product container, closure, and labelling records.
211.186 Master production and control records.
211.188 Batch production and control records.
211.192 Production record review.
211.194 Laboratory records.
211.196 Distribution records.
211.198 Complaint files.
Subpart K -- Returned and Salvaged Drug Products

211.204 Returned drug products.
211.208 Drug product salvaging.
2.3 Therapeutic Goods Administration, Australia
 Review Australian Code of Good Manufacturing Practice for Medicinal
Products
The GMP regulations “Australian Code of Good Manufacturing Practice for

Medicinal Products” serves as the regulatory guidelines.
The contents of the GMP regulations are:
Chapter 1 – Quality management

 Principle
 Quality assurance
 Good manufacturing practice for medicinal products
 Quality control
Chapter 2 – Personnel
 Principle
 General
 Key personnel
 Training
 Personnel hygiene

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Chapter 3 – Premises and equipment
 Principle
 Premises
o General
o Production area
o Storage areas
o Quality control areas
o Ancillary areas
 Equipment
Chapter 4 – documentation
 Principle
 General
 Documents required
o Specifications
o Specifications for starting and packaging materials
o Specifications for intermediate and bulk products
o Specifications for finished products
 Manufacturing formula and processing instructions
 Packaging instructions
 Batch processing records
 Batch packaging records
 Procedures and records
o Receipt
o Sampling
o Testing
o Other
Chapter 5 – Production
 Principle
 General
 Prevention of cross-contamination in production
 Validation
 Starting materials
 Processing operations – intermediate and bulk products
 Packaging materials
 Packaging operations
 Finished products
 Rejected, recovered and returned materials
Chapter 6 – Quality control

 Principle
 General
 Good quality control laboratory practice
 Documentation
 Sampling
 Testing

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Chapter 7 – Contract manufacture and analysis
 Principle
 General
 The contract giver
 The contract acceptor
 The contract
Chapter 8 – Complaints and product recall

 Principle
 Complaints
 Recalls
Chapter 9 – Self inspection

 Principle

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TOPIC 3 Quality Management
3.1 GMP Organisation
 Understand principles of quality management
 Understand principles of GMP organisation
 Describe organisational structure
 Describe roles of key personnel
3.1.1 Definition of quality
Quality can be defined as “the totality of features and characteristics that bear on the
ability of a component to meet the specified requirements of the customer, satisfy
fitness-for-use, including safety and performance”.
The companies can define quality in a way which best fits the products the company
is selling. Quality can thus be defined by the company in various ways, such as:
1. Fitness for use
2. Conformance to specifications
3. Producing the very best products
4. Excellence in product and services
5. Total customer satisfaction
6. Exceeding customer expectations
3.1.2 Principles of quality management
A Quality management system is composed of an organization that executes a quality

program according to documented policy and specifications in order to achieve stated
objectives as shown in the figure below.
Elements of a Quality System
Every company should have a quality policy stating the overall intentions and
directions of an organisation with respect to quality, as established by management
with executive responsibility.
QUALITY MANAGEMENT 3-1 Last Date updated: 10 June 2004

The system of quality control that is adopted should ensure that:
(a) Products are designed and developed in a way that takes account of the
requirements of GMP.
(b) Production and control operations are clearly specified in a written form and GMP
requirements are adopted.
(c) Managerial responsibilities are clearly specified in job descriptions.
(d) Arrangements are made for the manufacture, supply, and use of the correct
starting and packaging materials.
(e) All necessary controls on starting materials, intermediate products, and bulk
products and other in-process controls, calibrations, and validations are carried out.
(f) The finished product is correctly processed and checked, according to the defined
procedures.
(g) Products are not sold or supplied before the authorised persons have certified that
each production batch has been produced and controlled in accordance with the
requirements of the marketing authorization and any other regulations relevant to the
production, control and release of pharmaceutical products.
(h) Satisfactory arrangements exist to ensure, as far as possible, that the

pharmaceutical products are stored by the manufacturer, distributed, and subsequently
handled so that quality is maintained throughout their shelf-life.
(i) There is a procedure for self-inspection and/or quality audit that regularly
appraises the effectiveness and applicability of the quality assurance system.
Prevention versus detection

One of the major problems in manufacturing today is that some companies’ version of
quality control is simply to find defective items after they are made and remove them
before shipment to the customer. This is known as trying to achieve quality through
the detection method.
What is the problem with the detection method?
Repair or
Rework
Process Inspection
Shipment
Scrap or
Waste
The Detection Model
QUALITY MANAGEMENT Last Date updated: 10 June 2004

3-2
Detection models usually rely on a group of inspectors to check the product at various
stages of production and catch errors. This quality control method is inadequate and
wasteful. Money, time and materials are invested in products or services that are not
always usable or satisfactory. After-the-fact inspection is uneconomical and
unreliable.
The quality of the system has not improved, even though some inferior products were
weeded out or some mistakes were found and corrected.
Can such a system be used in a drug manufacturing plant?
Inspection cannot find all the defective items. If a defective item is found, then the
whole batch has to be reworked or thrown away. The detection model is thus not an
acceptable method of quality control for a drug manufacturing plant. Unless action is
taken to correct a faculty process, the percentage of the output that is defective will
remain constant.
Prevention Method
In a drug manufacturing plant, the principle of prevention is important. Statistical
signals are used to improve a process systematically so that the production of poor
quality drugs is prevented or the procedure that led to mistakes is improved.
The prevention model uses statistical signals at appropriate points in the process to
improve the procedure and to maintain control at the improved level. Statistical
signals provide an efficient method for analysing a process to indicate where
improvements should be made to prevent the manufacture of defective items and to
improve the quality of the items produced.
output
Process Shipment
Improve Inspect with SPC
Analyse
The Prevention Model
Statistical Process Control
A major obstacle to achieving high quality is product variability. Design quality may
differ between products. Statistical Process Control (SPC) can improve quality by
reducing product variability and can lead to improvements in production efficiency by
decreasing scrap and rework. It can be used to monitor a process to determine when

3-3
substandard items are about to be produced so that adjustments can be made to
prevent the production of defective items.
Basic tools for SPC
The following tools are commonly used in SPC:
1. Flowchart
The entire process is diagrammed from start to finish with each step of the process
clearly indicated. All involved in the process should know their position(s) on the
flowchart and at least a partial upstream and downstream trace from their position(s).
All should know who their suppliers are and who their customers are in the process
flow.
2. Pareto chart
The number of occurrences or the costs of occurrences of specific problems are
charted on a bar graph. The largest bars indicate the major problems and are used to
determine the priorities of problem solving.
3. Checksheet
A data-gathering sheet is prepared that categorises problems or defects. Checksheet
information may be put on a Pareto chart or, if a time analysis is included, may be
used to investigate problems trends over time.
4. Cause-and-effect diagram
A problem (the effect) is systematically tracked back to possible causes. The diagram
organises the search for the root cause of the problem. A similar diagram can be used
to systematically search for solutions to a problem.
5. Histogram
A bar graph shows the comparative frequency of specific measurements. The shape of
the histogram can indicate that a problem exists at a specific point in a process.
6. Control chart
A broken-line graph illustrates how a process or a point in the process behaves over
time. Samples are periodically taken, checked, or measured, and the results plotted
over time. The charts can show how the specific measurement changes, how the
variation in measurements changes, or how the proportion of defective pieces changes
over time. Control charts are used to find sources of special-cause variation (variation
that is caused by specific, fixable occurrences), to measure the extent of common-
cause variation (variation that is inherent in the process), and to maintain control of a
process that is operating effectively.
7. Scatterplot
Pairs of measurements are plotted on a two-dimensional coordinate system to
determine if a relationship exists between the measurements.

3-4
3.1.3 Principles of GMP organisation
The organisation should clearly identify senior executives with executive

responsibilities. Executive responsibility means those senior employees of a company
who have the authority to establish or make changes to the manufacturer’s quality
policy and quality system.
These executives play an important role as it is their responsibility to ensure the

following:
 Establish the company’s policy and objectives for, and commitment to,
quality.
 Ensure that the quality policy is understood, implemented, and maintained at
all levels of the organisation.
3.1.4 Organisational structure
The company should establish and maintain an adequate organisational structure for
the reporting responsibilities within the company to ensure that components are
designed and produced that meet the organisation goals and customers’ requirements.
What is an adequate organizational structure?

1. The structure should have clearly indicated lines of authority to ensure that the
technical, administrative, and human functions affecting the quality of the component
will be controlled. All such controls should be orientated towards the reduction,
elimination, or prevention of quality non-conformances.
2. An adequate number of personnel with the necessary qualifications and practical

experience. The responsibilities placed on any one individual should not be so
extensive as to present any risk to quality.
3. All responsible staff should have their specific duties recorded in written
descriptions and adequate authority to carry out their responsibilities. Their duties
may be delegated to designate deputies of a satisfactory qualification level. There
should be no gaps or unexplained overlaps in the responsibilities of personnel
concerned with the application of cGMP.
4. All personnel should be aware of the principles of cGMP that affect them and
receive initial and continuing training, including hygiene instructions, relevant to their
needs. All personnel should be motivated to support the establishment and
maintenance of high-quality standards.
5. The structure should be reviewed regularly to ensure that it remains current.
Examples of two typical organizational structures are shown below.
What are the pros and cons of each of the organizational structure shown?

3-5
Management
board
Core business Cross-functional Regional management

process team coordinating councils
committee
Business Regional business

Quality teams
team(s) units
Typical Organisation Structure (1)
CEO
Quality Operations Financial R&D

manager manager & Services manager
Documentation
manager Production
QC manager engineering
In-coming warehouse
In-process
Out-going
Typical Organisation Structure (2)
3.1.5 Roles of key personnel
The establishment and maintenance of a satisfactory system of quality assurance and

the correct manufacture and control of bio-medical products rely upon PEOPLE. For
this reason there must be sufficient qualified personnel to carry out all the tasks for
which the manufacturer is responsible.
Each manufacturer shall have the following:
1. Establish the appropriate responsibility, authority and interrelation of all personnel

who manage, perform and assess work affecting quality, and provide the
independence and authority necessary to perform these tasks.
2. Provide adequate resources, including the assignment of trained personnel, for

management, performance of work, and assessment activities, including internal
quality audits.

3-6
3. Sufficient personnel with the necessary education, background, training, and
experience to assure that their roles in production, technical functions, quality
assurance, customer complaint handling and management are correctly performed.
4. Manufacturer should conduct regular review of the suitability of the personnel

qualification and experience relative to the skills and qualification required for each
role. The review will identify what training is required for which personnel and by
when.
Who are the key personnel?

Key personnel include the heads of the following departments:
1. Production,
2. Quality control,
3. Sales/distribution,
4. Other heads as required by the organisation.
Normally, full-time personnel should occupy key posts. The heads of production and
quality control should be independent of each other. In large organizations, it may be
necessary to delegate some of the functions; however, the responsibility cannot be
delegated.
Key personnel responsible for supervising the manufacture and quality control of
pharmaceutical and medical components should:
1. Possess the qualifications of a scientific education and practical experience.
2. Have adequate practical experience in the manufacture and quality assurance of

pharmaceutical and medical components. In order to gain such experience, a
preparatory period may be required, during which they should exercise their duties
under professional guidance.
3.2 Responsibilities of the quality units
 Describe roles of QC
 Understand importance of separation of production and QC
 Describe role of management representative
 Describe management review
 Describe master control of GMP documents
3.2.1 Roles of Quality Control
A Quality Control department should be present in the organisation.
Quality control (QC) is the part of GMP concerned with sampling, specifications,
and testing and with the organisation, documentation, and release procedures which
ensure that the necessary and relevant tests are actually carried out and that materials
are not released for use, nor products released for sale or supply, until their quality has

3-7
been judged to be satisfactory. Quality control is not confined to laboratory operations
but must be involved in all decisions concerning the quality of the product.
The basic requirements for quality control are as follows:
(a) Adequate facilities, trained personnel and approved procedures must

be available for sampling, inspecting, and testing all materials, and where appropriate
for monitoring environmental conditions for GMP purposes.
(b) Samples of starting materials, packaging materials, intermediate products, bulk

products and finished products must be taken by methods and personnel approved of
by the quality control department.
(c) Test methods must be validated.
(d) Records must be made (manually and/or by recording instruments) demonstrating

that all the required sampling, inspecting, and testing procedures have actually been
carried out and that any deviations have been fully recorded and investigated.
(e) The finished products must contain ingredients complying with the qualitative and
quantitative composition of the product described in the marketing authorization; the
ingredients must be of the required purity, in their proper container, and correctly
labelled.
(f) No batch of product is to be released for sale or supply prior to certification by the
authorized person(s) that it is in accordance with the requirements of the marketing
authorization.
(h) Sufficient samples of starting materials and products must be retained to permit
future examination of the product if necessary; the retained product must be kept in its
final pack unless the pack is exceptionally large.
(i) Quality systems utilising tools like Statistical Process Control (SPC) must be in
place to ensure that quality is being monitored all the times in the plant and remedial
action can be taken promptly if the situation deteriorates.
3.2.2 Separation of Production and QC
The independence of quality control from production is considered fundamental. The

quality control department should be independent of other departments and under the
authority of a person with appropriate qualifications and experience, who has one or
several control laboratories at his or her disposal. Adequate resources must be
available to ensure that all the quality control arrangements are effectively and
reliably carried out.
The head of the production department generally has the following responsibilities:
(a) to ensure that products are produced and stored according to the appropriate
documentation in order to obtain the required quality;

3-8
(b) to approve the instructions relating to production operations, including the in-
process controls, and to ensure their strict implementation;
(c) to ensure that the production records are evaluated and signed by a designated
person before they are made available to the quality control department;
(d) to check the maintenance of the department, premises, and equipment;
(e) to ensure that the appropriate process validations and calibrations of

control equipment are performed and recorded and the reports made available;
(f) to ensure that the required initial and continuing training of production personnel is
carried out and adapted according to need.
The head of the quality control department generally has the following
responsibilities:
(a) to approve or reject starting materials, packaging materials, and intermediate, bulk,
and finished products;
(b) to evaluate batch records;
(c) to ensure that all necessary testing is carried out;
(d) to approve sampling instructions, specifications, test methods, and other quality
control procedures;
(e) to approve and monitor analyses carried out under contract;
(f) to check the maintenance of the department, premises and equipment;
(g) to ensure that the appropriate validations, including those of analytical procedures,
and calibrations of control equipment are done;
(h) to ensure that the required initial and continuing training of quality control
personnel is carried out and adapted according to need.
3.2.3 Role of management representative
There should be a management representative who, irrespective of other

responsibilities, shall have authority over and responsibility for the following:
1. Ensuring that quality system requirements are effectively established and
effectively maintained
2. Reporting on the performance of the quality system to management with
executive responsibility for review
3.2.4 Management Review
Management with executive responsibility shall review the suitability and

effectiveness of the quality system at defined intervals and with sufficient frequency

3-9
according to established procedures to ensure that the quality system satisfies the
quality requirements as established by the quality policy and objectives.
Dates and results of quality system reviews shall be documented.
3.2.5 Master control of GMP documents
A quality system can be defined as the organisational structure, responsibilities,

procedures, processes and resources for implementing quality management.
Documentation is thus required for the following:
1. Policies
2. Standard Operating Procedures (SOPs)
3. Batch Records
4. Rework Procedures
5. Product Specifications
6. Analytical Methods
7. Calibration and Maintenance Documentation
8. Change Control Records
9. Housekeeping Logs
10. Equipment Cleaning and Use Logs
11. Validation Documentation
12. Certificates of analysis of raw materials
13. Information on all components, closures and labelling
14. Complaint Files
15. Annual Product Reviews
3.3 Quality audit
Teaching Objectives:
 Understand quality audit
 Understand quality reaudit
3.3.1 What is quality audit?
Quality audit is defined as a systematic, independent examination of a

manufacturer’s quality system that is performed at defined intervals and at sufficient
frequency to determine whether both quality system activities and the results of such
activities comply with quality system procedures, that these procedures are
implemented effectively, and that these procedures are suitable to achieve quality
system objectives.
A quality audit is usually conducted by outside or independent specialists or a team

designated by the management for this purpose. Such audits may also be extended to
suppliers and contractors. Quality audits shall be conducted by individuals who do
not have direct responsibility for the matters being audited. Corrective actions shall
be taken when necessary.
A report of the results of each quality audit where taken, shall be made and such
reports shall be reviewed by management having responsibility for the matters
audited. The dates and results of the quality audits shall be documented.

3-10
Regulatory inspections
Quality audits can also be carried out by the regulatory agencies. In this instance,
they are known as Regulatory Inspections.
3.3.2 What is quality reaudit?
In the event that non-conformances are highlighted in the quality audit, corrective
actions shall be taken. After the corrective actions have been taken, it is necessary to
conduct a quality reaudit to ensure that the quality system is now in compliance with
the established quality system requirements.
The dates and results of the quality reaudits shall be documented.
3.4 Personnel
 Understand need for training
 Understand procedures for identifying training needs
3.4.1 Training
The manufacturer should provide training in accordance with a written programme for
all the personnel whose duties take them into production areas or into control
laboratories (including the technical, maintenance, and cleaning personnel), and for
other personnel whose activities could affect the quality of the product.
Training should include the following:
1. Basic training on the theory and practice of cGMP.

2. Newly recruited personnel should receive training appropriate to the duties
assigned to them.
3. Continuing training should also be given, and its practical effectiveness should be
periodically assessed.
4. Training programmes should be available, approved by the head of either
production or quality control, as appropriate.
5. Training records should be kept.
6. Personnel working in areas where contamination is a hazard, e.g., clean areas or
areas where highly active, toxic, infectious, or sensitising materials are handled
should be given specific training.
7. The concept of quality assurance and all the measures capable of improving its
understanding and implementation should be fully discussed during the training
sessions.
8. Personnel should be made aware of component defects which may occur from the
improper performance of their specific jobs.
9. Personnel who perform verification and validation activities shall be made aware
of defects and errors that may be encountered as part of their job functions

3-11
3.4.2 Identifying training needs
Procedures should be in place to identify training needs and ensure that all personnel
are trained to adequately perform their assigned responsibilities.
Each manufacturer shall establish procedures for evaluating the effectiveness of

training conducted in terms of enhanced competency of people, and measurement of
the effectiveness against expectation.
Training shall be documented. Records, specific for each member of staff, shall be
made and retained.

3-12
TOPIC 4 Building and Facilities
Understand general requirements of Design and Construction of the following:
 Materials
 Construction and finishes
 Utility lines
4.1 Design and construction
4.1.1 Materials
1. The quality of materials used shall be confirmed from the purchasing specification
and the materials receiving reports.
2. Generally, the use of wooden materials is not recommended.
Floor
Expoxy resin-welded PVC sheets and epoxy terrazzo are generally recommended for
floor construction.
Walls
Generally acceptable materials for walls are:
a. Epoxy coating
b. Polyester coating
c. Seamless PVC coating
d. Welded sheets of PVC
e. Prefabricated wall panels
Ceilings
Commonly used materials for ceilings are gypsum board with epoxy, polyester
coating, and seamless PVC coating.
Doors
The following materials are generally used for doors:
a. Standard painted timber
b. Timber with plastic lamination
c. Stainless steel
d. Glass
4.1.2 Construction and finishes
1. The area of each room shall be checked to ensure that it meets specifications
(length, width and height).
2. Rooms shall be designed and constructed so that air leakage through openings or
penetration is kept to a minimum.
3. All surfaces must be completely cleanable and resistant to germicidal solutions.
4. Horizontal and other surfaces on which dust can accumulate shall be kept to an
absolute minimum, and they shall be completely avoided above areas where the
product containers are exposed.
BUILDING AND FACILITIES 4-1 Last Date updated: 10 June 2004

Floors
1. The material used for the construction of floor shall be free from seams, cracks, or
holes and shall be durable, washable and cleanable.
2. Floor-wall joints, building columns, equipment pads and other obstructions should
be completely sealed.
3. Floor drains should be provided only where large volumes of liquids are
anticipated.
4. The floor should be pitched toward the drain (if available) to prevent
accumulation of liquids.
5. The floor drain should not be located in the aseptic clean room because of
concerns about microbiological growth in the trap.
6. Trapped floor drains should be provided.
Walls
1. Construction materials shall be free from seams, cracks or holes and also
washable, cleanable and free from rust or corrosion.
2. Walls should be smooth, rigid, and resistant to impact and abrasion.
3. Walls should be protected by physical barriers such as stainless steel subrails (if
necessary).
4. Wall surfaces should be easy to clean and resistant to repeated exposure to
disinfectants.
5. Floor-wall, wall-wall, and ceiling-wall intersections should be properly sealed to
prevent dirt accumulation and pest entry.
6. Floor-wall and wall-wall joints should be coved.
7. Ledges should be sloped to reduce dust accumulation.
Ceiling
1. Construction materials shall be durable, cleanable, and washable.
2. Ceilings should be smooth, non-perforated, and properly sealed to the framing.
3. All penetration through ceilings must be designed to establish and maintain the
integrity of a 100% sealed system.
4. The suspension system should be heavy-duty aluminum with anodized even-finish
stainless steel.
Entryway, doors, and airlocks

1. Construction materials, door openings and door gaskets should be satisfactory.
2. Glass fixing should be satisfactory.
3. Entry of all personnel, materials and equipment should be through a suitable air
lock.
4. The design and arrangement should minimize migration of particulate and other
contaminants into the controlled process area.
5. Door should have automatic closing systems.
6. Locks and latches should be avoided.
Windows
1. Materials should be durable, washable and cleanable.
2. Windows between class 100 areas and other areas should have sloping sills on
both sides of glass to facilitate cleanliness.
BUILDING AND FACILITIES Last Date updated: 10 June 2004

4-2
Illumination
The units of lux should be comparable with the standard of each room.
4.1.3 Utility lines
The following should be checked to ensure that utilities are installed as per the room
requirement list:
1. Industrial steam
2. Pure steam
3. Chilled water
4. Tap water (warm and cold)
5. Distilled water
6. Water for injection
7. Compressed air
8. Nitrogen gas
9. Exposed piping and conduit should be avoided as much as possible
10. Exposed piping should be completely cleanable by being set out approximately 1
to 1.5 inches from the wall or other surfaces
11. All piping should be properly labelled with flow directions
4.1.4 Safety features
The safety equipment should be installed as per room requirement list:

1. Location, condition and number of water showers available.
2. Location and number of fire extinguishers available.
3. Location, condition and number of smoke detectors available.
4. Location and number of emergency doors available.
4.1.5 Drainage system
1. Drainage should be designed and constructed per approved layout.

2. Verify the drainage locations using building specification.
3. The floor should be pitched toward drain holes to prevent accumulation of liquids.
4. All surfaces should be cleanable.
5. All drains should have deep seal traps to avoid back-flow (non-return valves).
6. Open drains should be avoided in manufacturing and packaging areas.
7. Process and sanitary drains should be separate to avoid the possibility of
introducing sanitary waste into process systems.
8. Drains must be covered with secured lids.
9. Check that drain’s flushing procedure is established and identified.
10. Check that drainage lines are sanitized according to procedure and that records are
available.
11. Check that drainpipe’s slope is toward outside.
4.2 Space, layout and compatibility
Describe specific requirements of the following:
 Premises

4-3
 Ancillary areas
 Storage areas
 Weighing areas
 Production areas
 Quality control areas
 Cleanability
 Contamination prevention
4.2.1 Premises
The following principles should be observed:
1. Premises must be located, designed, constructed, adapted, and maintained to suit

the operations to be carried out.
2. Their layout and design must aim to minimise the risk of errors and permit
effective cleaning and maintenance in order to avoid cross-contamination, build-
up of dust or dirt, and, in general, any adverse effect on the quality of products.
3. General housekeeping, buildings and related facilities have to be in the most
hygienic condition.
4. Certain areas that require clean room environment has to meet specification in
relation to their particles count in the air - premises should be situated in an
environment that, when considered together with measures to protect the
manufacturing process, presents minimum risk of causing any contamination of
materials or products.
5. Premises used for the manufacture of products should be suitably designed and
constructed to facilitate good sanitation.
6. Premises should be designed and equipped so as to afford maximum protection
against the entry of insects or other animals.
7. Premises should be carefully maintained, and it should be ensured that repair and
maintenance operations do not present any hazard to the quality of products.
Premises should be cleaned and, where applicable, disinfected according to
detailed written procedures.
8. The quality of utilities supply by the relevant facilities has to meet the stringent
specifications.
9. Electrical supply, lighting, temperature, humidity, and ventilation should be
appropriate and such that they do not adversely affect, directly or indirectly, either
the pharmaceutical products during their manufacture and storage, or the accurate
functioning of equipment.
4.2.2 Ancillary areas
1. Rest and refreshment rooms should be separate from other areas.

2. Facilities for changing and storing clothes and for washing and toilet purposes
should be easily accessible and appropriate for the number of users. Toilets should
not communicate directly with production or storage areas.
3. Maintenance workshops should, if possible, be separated from production areas.
Whenever parts and tools are stored in the production area, they should be kept in
rooms or lockers reserved for that use.

4-4
4.2.3 Storage areas
1. Storage areas should be of sufficient capacity to allow orderly storage of the

various categories of materials and products: starting and packaging materials,
intermediates, bulk and finished products, products in quarantine, and released,
rejected, returned, or recalled products.
2. Storage areas should be designed or adapted to ensure good storage conditions. In
particular, they should be clean and dry and maintained within acceptable
temperature limits. Where special storage conditions are required (e.g.,
temperature, humidity) these should be provided, checked, and monitored.
3. Receiving and dispatch bays should protect materials and products from the
weather. Reception areas should be designed and equipped to allow containers of
incoming materials to be cleaned if necessary before storage.
4. Where quarantine status is ensured by storage in separate areas, these areas must
be clearly marked and their access restricted to authorized personnel. Any system
replacing the physical quarantine should give equivalent security.
5. There should normally be a separate sampling area for starting materials. If
sampling is performed in the storage area, it should be conducted in such a way as
to prevent contamination or cross-contamination.
6. Segregation should be provided for the storage of rejected, recalled, or returned
materials or products.
7. Highly active materials, narcotics, other dangerous drugs, and substances
presenting special risks of abuse, fire, or explosion should be stored in safe and
secure areas.
8. Printed packaging materials are considered critical to the conformity of the
pharmaceutical product to its labelling, and special attention should be paid to the
safe and secure storage of these materials.
4.2.4 Weighing areas (may belong to either storage or production areas)
The weighing of starting materials and the estimation of yield by weighing should
usually be carried out in separate weighing areas designed for that use, for example
with provisions for dust control.
4.2.5 Production areas
1. In order to minimize the risk of cross-contamination, dedicated and self-contained

facilities must be available for the production of particular products, such as
highly sensitising materials (e.g., penicillin) or biological preparations (e.g., live
microorganisms).
2. Premises should preferably be laid out in such a way as to allow the production to
take place in areas connected in a logical order corresponding to the sequence of
the operations and to the requisite cleanliness levels.
3. The adequacy of the working and in-process storage space should permit the
orderly and logical positioning of equipment and materials so as to minimize the
risk of confusion between different products or their components, to avoid cross-
contamination, and to minimize the risk of omission or wrong application of any
of the manufacturing or control steps.
4. Where starting and primary packaging materials and intermediate or bulk products
are exposed to the environment, interior surfaces (walls, floors, and ceilings)

4-5
should be smooth and free cracks and open joints, should not shed particulate
matter, and should permit easy and effective cleaning and, if necessary,
disinfection.
5. Pipe work, light fittings, ventilation points, and other services should be designed
and sited to avoid the creation of recesses that are difficult to clean. As far as
possible, for maintenance purposes, they should be accessible from outside the
manufacturing areas.
6. Drains should be of adequate size and equipped to prevent back-flow. Open
channels should be avoided where possible, but if they are necessary they should
be shallow to facilitate cleaning and disinfection.
7. Production areas should be effectively ventilated, with air-control facilities
(including control of temperature and, where necessary, humidity and filtration)
appropriate to the products handled, to the operations undertaken, and to the
external environment. These areas should be regularly monitored during
production and non-production periods to ensure compliance with their design
specifications.
8. Premises for the packaging of pharmaceutical products should be specifically
designed and laid out so as to avoid mix-ups or cross-contamination.
9. Production areas should be well lit, particularly where visual on-line controls are
carried out.
4.2.6 Quality control areas
1. Quality control laboratories should be separated from production areas. Areas

where biological, microbiological, or radioisotope test methods are employed
should be separated from each other.
2. Control laboratories should be designed to suit the operations to be carried out in
them. Sufficient space should be given to avoid mix-ups and cross-contamination.
There should be adequate suitable storage space for samples, reference standards
(if necessary, with cooling), and records.
3. The design of the laboratories should take into account the suitability
of construction materials, prevention of fumes, and ventilation. Separate air-
handling units and other provisions are needed for biological, microbiological, and
radioisotope laboratories.
4. A separate room may be needed for instruments to protect them against electrical
interference, vibration, contact with excessive moisture, and other external factors,
or where it is necessary to isolate the instruments.
A Typical Drug Manufacturing Facility Layout

4-6
4.2.7 Cleanability
Cleanability refers to the ability to rid an equipment or surface of dirt and impurities.
The general principles are:

1. Process equipment selection, design and surface that contain product contact
surfaces or potentially contaminating surfaces should be specified such that
cleanability is maximised.
2. Where possible, equipment should be dedicated to specific products.
3. Equipment should be designed such that areas that would collect or retain drug
or component residues are minimised. All surfaces should be smooth and free
of pitting.
4. Where possible, cleaning apparatus should be incorporated into the equipment.
This can be accomplished with spray nozzles and spray ball diffusers.
5. Drains should be carefully placed in the equipment so that rinse water and
solvents are allowed to fully drain.
6. Sanitary fittings and valves should be used for product contact applications.
4.2.8 Contamination prevention
The cGMP regulation requires that every manufacturer establish and maintain
procedures to prevent contamination of product or equipment. Drugs should not be
contaminated with contaminated with microbes, detergents, body oils and pyrogens.
Sanitation
(a) Any building used in the manufacture, processing, packing, or holding of a drug
product shall be maintained in a clean and sanitary condition, Any such building shall
be free of infestation by rodents, birds, insects, and other vermin (other than
laboratory animals). Trash and organic waste matter shall be held and disposed of in a
timely and sanitary manner.
(b) There shall be written procedures assigning responsibility for sanitation and
describing in sufficient detail the cleaning schedules, methods, equipment, and
materials to be used in cleaning the buildings and facilities; such written procedures
shall be followed.
(c) There shall be written procedures for use of suitable rodenticides, insecticides,
fungicides, fumigating agents, and cleaning and sanitizing agents. Such written
procedures shall be designed to prevent the contamination of equipment, components,
drug product containers, closures, packaging, labelling materials, or drug products and
shall be followed. Rodenticides, insecticides, and fungicides shall not be used unless
registered and used in accordance with the Federal Insecticide, Fungicide, and
Rodenticide Act (7 U.S.C. 135).

4-7
(d) Sanitation procedures shall apply to work performed by contractors or temporary
employees as well as work performed by full time employees during the ordinary
course of operations.
Personnel Sanitation Practices
Adequate bathroom, dressing, storage, and waste facilities should be provided, as

appropriate, for personnel to maintain the needed level of cleanliness. Such facilities
should be maintained on a regularly scheduled basis. Where necessary, such as in a
clean room, special clothing and an area to don and store the garments should be
provided. Clean room clothing should not be worn into uncontrolled rooms or outside
the facility.
Personal Practices
Eating, drinking, or smoking should be confined to specially designated areas such as

a lunchroom or employees lounge. Directions and containers or equipment should be
provided for timely and safe disposal of trash, by-products, effluents and other refuse.
Cross-Contamination
The application of good design practices, if applied and monitored throughout the
development of construction documents, will help prevent a high degree of cross-
contamination. The considerations for reducing the risk of contamination include:
1. Whenever product or material is exposed, adequately designed localised
containment should be carefully considered, for example, through use of local
exhaust ventilation and containment booths.
2. Limit the dispersal of product around manufacturing facilities through adequately
designed air handling system zoning, air locks, and room pressure differentials.
3. Limit spread of product around manufacturing facilities via the proper cleaning
and maintenance of environmental and process air handling units.
Prevent Contamination by Hazardous Substances
If rodenticides, insecticides, or other hazardous substances are used, written

procedures to limit their use or for their removal from work surfaces should be
established to prevent any adverse affect on the manufacturing process or the drug.
Waste materials
Provision should be made for the proper and safe storage of waste materials awaiting
disposal. Toxic substances and flammable materials should be stored in suitably
designed, separate, enclosed cupboards.
Waste material should not be allowed to accumulate. It should be collected in suitable

receptacles for removal to collection points outside the buildings and disposed of
safely and in a sanitary manner at regular and frequent intervals.

4-8
4.3 Air control
 Air ducts
 Air flow pattern
 Air zones
 Air pressure differentials
 Air locks
4.3.1 Air ducts
General specifications
1. The air duct must be constructed with galvanised steel.
2. Other materials are authorized if specific uses (i.e. chemical resistance) are
required.
3. The perimeter of the duct must be constructed with the same material.
4. The inside surface of the ducts must be smooth, except if specific equipment
are required (e.g. noise attenuator, damper).
Design of ducts
1. The use of ducts with circular section is preferred.
2. The duct system must be airtight.
3. The rectangular sections must be reinforced with folds or reinforcement to
resist deformations and vibrations.
4. The duct system must be designed to allow the cleaning of the ducts (e.g.
provide access doors).
5. Obturable openings (diameter 25 mm) must be located in the ducts to allow
the measurement of the air velocity (minimum 2 m of straight duct for
accurate air velocity measurements).
6. The section of the duct must be designed to provide ≤ 5 m/s in the blow ducts.
4.3.2 Airflow pattern
Air changes/hour
The number of air changes/hour in a room refers to the number of times/hour that the
volume of air in the room undergoes a complete change. For example, an air change
of 20/hour means that the air in the room will be replaced 20 times every hr.
The number of air changes/hr is determined by the following considerations:
1. Particulate levels – refers to the amount of particulates in the room. To maintain a

low particulate level in the room, the air changes must be more frequent. In
general, the following are recommended for the different room classifications
(refer to section 5.3 for definitions of room classifications):

4-9
Class Air change/ hour
100 200 to 400
1000 80 to 120
10000 40 to 60
100000 20 to 30
2. Heat and humidity generation – if a large amount of heat and humidity are
generated, more frequent air changes are required.
3. Activity levels – the higher the activity level, the more frequent the air changes
required.
Once-through and recirculated air
An air handling system can be designed for one of the following:

1. Once-through air – air entering the room is purged out completely and not
recirculated. In general, solvent use areas, filter areas and loading areas might
require once-through air.
The advantages of a once-through air are:

1. Maximum protection
2. Maximum heat and humidity removal
The disadvantages are:

1. High utility cost
2. Recirculated air – part of the air entering the room is recirculated.
The advantages are:

1. Lower utility cost
The disadvantages are:

1. Not as high a protection as once-through air
Example
Assume a process that includes controlled areas for general laboratory work,
equipment, storage, decontamination and sterilization. These areas might be divided
into 4 modules, each with an independent air handling system. This design allows for
4 separate production runs to occur in the facility simultaneously and minimises the
chance of cross contamination between different processes.
The mechanical room might be located outside the facility and routine maintenance
operations such as waste disposal and replacement of gas supply tanks (e.g. CO2
tanks) can be performed without entering the laboratory. Air supply to the facility is
filtered through high efficiency particulate air (HEPA) filters. In critical areas, e.g. the
4 modules used for production, the particle count/ft3 is not more than 10,000 in a size
range of 0.5 micron and larger. Air in the immediate vicinity of exposed chemical
preparations has an upstream airflow and a particle count of no more than 100/ft3 in a
size range of 0.5 micron and larger.

4-10
4.3.3 Air zones
There might be a need for separate process areas to have a dedicated air handling
systems. Considerations for the need for dedicated air handlers would include:
1. Segregation of production versus support spaces - separate air handling systems
for manufacturing and non-manufacturing operations. For example, the following
areas could have their own separate air handling systems – manufacturing,
packing areas, QC laboratories, administration building etc.
2. Separation between products - dedicated air handling system for specific
manufacturing departments for example, dry, liquid and sterile product
manufacture.
3. Separation between process steps
4.3.4 Air pressure differentials
Why should rooms be operated at different pressures?
Air and contaminants in the air will travel from a region of higher pressure to a region
of lower pressure. If the objective is to prevent dust and containments from entering
the room, then the process room has to be kept at a higher differential pressure versus
the surrounding areas/rooms.
This difference in pressure (differential pressure) is important as it serves the

following purposes:
1. Airflow direction
Air will flow from a region of higher pressure to a region of lower pressure.
2. Containment of dust and contaminants

To contain dust and contaminants within a room, that room should be operated at a
lower differential pressure so that air will flow INTO the room, thus containing the
dust and contaminants within the room. This is esp. important if the contaminants are
harmful.
In general, a pressure of 0.05 inches water (12.5 Pa) differential between areas of
separate classification should be maintained.
4.3.5 Airlocks
An airlock is simply a mechanism consisting of doors and/or curtains that control air-
flow patterns in the doorway such that the air flows only towards the inside of the
enclosure to which the decontamination system is attached.
Airlocks allow people to enter and leave a room without changing the internal static
pressure. Airlocks thus provide a transition between pressures. A simple airlock
design is that of a centre-pivot, side-swing door which opens outward without force
and automatically closes against the structure's internal.
For example, a clean room, shower room, and equipment room can each be separated
from the other and from the containment area by airlocks accessible through

4-11
doorways. The rooms where gowning and degowning take place would be an airlock
place.
4.4 Clean utilities
 Critical utilities
 Clean steam system
 Clean water system
 Clean air system
4.4.1 Critical utilities
Utilities that are in contact with product contact surfaces have to be sanitary. These
are critical utilities. These would include purified water, water for injection (WFI),
process water and clean steam. These utilities may not be used until the plant,
processes and procedures used in producing and distributing it have been tested and
approved by the quality control unit as capable of consistently producing air or water
meeting the requirements as set forth in the process documents.
In addition, the utilities’ quality must be monitored according to the required

schedule.
Procedures designating schedules, assigning responsibilities and describing in detail

the action to be taken to assure that the systems produce and deliver air and water that
conform to the requirements shall be written. Such procedures shall also specify the
corrective action to be taken when testing reveals that the established standards are
not being met. Records of corrective actions shall be maintained.
Non-critical systems would include plant steam, process air, instrument air, chilled
water (e.g. glycol system) and cooling tower water.
4.4.2 Clean steam system
Clean (pure) steam systems are normally constructed of non-rusting (stainless steel)
materials and typically are produced by the steam generator using purified water. No
additives are allowed to be used due to contact with products. The steam generator
shall be located at a suitable place per approved plant layout. From this, the steam is
pumped via tubings to the different points of use. A system to collect the condensate
must be provided.
The main characteristics of the clean steam system are:

1. It is obtained from purified water.
2. The condensate must have the qualities required for water for injection.
4.4.3 Clean water system
Clean water should be free of microbial contaminations and high particulate count.

4-12
Water for cleaning or initial rinsing
Water used to cleanse or initially rinse product contact surfaces such as containers and
equipment shall:
1. be subjected to a process such as chlorination for control of microbial population.
2. contain not more than 50 microorganisms per 100 millimetres of sample in 3
consecutive samples from the sampling site.
Water for manufacturing or final rinsing

Water used as a component or as a final rinse for equipment or product contact
surfaces shall:
1. contain not more than 10 microorganisms per 100 millimetres of sample in 3
consecutive samples from the sampling site. When the microbial quality falls
below that specified, use of such water shall cease and corrective action shall be
taken to clean and sterilise the system so that the water conforms to the limit.
2. be stored in a suitable vessel or system including a piping network for distribution
to points of use:
- at a temperature of at least 80 oC under continuous circulation or
- at ambient or lower temperature for not longer than 24 hours, after which time
such water shall be discarded to drain.
Boiler feed water

Feed water for boilers supplying steam that contacts components, in-process
materials, medical components and product contact surfaces shall not contain volatile
additives such as amines or hydrazines.
Water quality programme

Water quality monitoring shall include:
1. Sampling and testing of water for manufacturing or final rinsing at least once a
day. All sampling ports or points of use in the distribution system shall be
sampled at least weekly.
2. Sampling and testing of water for cleaning or initial rinsing at least once a week.
All sampling ports or points of use in the distribution system shall be sampled at
least monthly.
3. Boiler feed water shall be sampled and tested periodically for the presence of
volatile additives.
Equipment used to produce clean water include:

1. multi-media filter
2. activated carbon bed
3. ultrafiltration
4. reverse osmosis
5. deionisation
6. ultraviolet light (UV)
4.4.4 Clean air system
Air handling units should be provided with prefilters, 2 inches thick at minimum, and
80 to 85% efficient filter. If HEPA filters are located within the air handling unit, they
should be the last component in the direction of the airflow into the room.

4-13
Note: Air filters are normally constructed of a cotton and synthetic media, support
grid and enclosing frame.
To assure filtration, several types of filters must be used:

1. Prefilter – to be placed on the inlet of mixed air (fresh air and recycled air).
2. Filters – to be placed directly after the fan section before the outlet of the
AHU.
3. Terminal filters – to be placed directly after the fan section before the outlet of
the AHU.
4. Terminal filters – to be placed in the room.
The filters must be designed and fastened to allow an easy removal to change the
filter and to keep perfect peripheral air tightness. The number of terminal filters must
be calculated to guarantee the same air velocity out of the different filter of the same
AHU. When the pressure drop across the filter exceeds the recommended change
point, the filter must be replaced.
HEPA filters
High efficiency particulate air (HEPA) filters are commonly used for room
classification of 100,000 or less. HEPA filters are also used for terminal filtration
(last line of defense against emission of unwanted contaminants into the room or out
into the atmosphere).
HEPA filter
HEPA filters are normally made of metallic materials or pleated fibrous filter media.
HEPA filters are the highest efficiency air filters available for the filtration of small
particles. As defined by the Institute of Environmental Science, a certified HEPA
filter must capture a minimum of 99.97% of contaminants at 0.3 microns in size.
HEPA filters will become clogged or plugged with time. In general, for non-critical
usage, HEPA filters are replaced once every 2 to 3 years. The pressure drop across
the HEPA filters can also be used to indicate replacement. When the pressure drop is
excessive (the pressure drop is indicated in the filter specification), the HEPA filters
will have to be replaced.

4-14
TOPIC 5 Environmental Control
5.1 Air Con Mechanical Ventilation (ACMV) System
 Introduce environmental control
 Describe ACMV system
5.1.1 Environmental control
One of the variables that can significantly affect product quality and employee
performance is the environment. A controlled environment is, to various degrees, an
integral part of most production facilities.
Goals of environmental control
Environmental control is to control the following parameters:

1. Temperature
2. Humidity
3. Ventilation – heat, vapour, dust removal
4. Particulate amount (including microorganisms)
5. Room relative pressures
6. Air flow patterns/ minimization of cross contamination
When should the environment be controlled?
If the environment in which drugs are manufactured or stored can have an adverse
effect on the devices' fitness for use, that environment shall be controlled.
For example, in the manufacture of sterile devices such as implants, the environment
should be controlled to reduce viable microorganisms and particulate matter. The
packaging for sterile devices should be stored in a clean, dry, insect-free area.
When analysing the production of a drug to determine the degree of control needed,
the manufacturer should identify exactly what needs to be controlled:
1. The drug itself;

2. The area for one task; or
3. The large production area.
Considerations include also the need to reduce environmental facility and equipment
costs and reduce the activities required to maintain and monitor the controlled area
and operations.
Examples
1. If the drug is stored in clean containers or are immediately packaged, the
environment should be controlled where the drug is being packaged.
ENVIRONMENTAL CONTROL 5-1 Last Date updated: 10 June 2004

2. A HEPA filtered laminar flow bench maintains a low particulate environment
that is large enough for many small tasks or operations - a small laminar flow
unit and curtains can create a small, but very clean area.
3. If a larger area is needed, then it may be possible to set a broad environmental
specification for most of the room or area.
5.1.2 ACMV system
Environmental control is achieved, in many instances, through the installation and

operation of an ACMV system. The ACMV system provides conditioned air to
building occupants and is essential to the comfort of building occupants, and
necessary to the operation of the building. An ACMV system should be energy
efficient in order to minimise operating cost. The ACMV system, including the air
handling unit and the air-duct, is often insulated with fiberglass and other insulation
materials.
Most ACMV systems consist of four components:

1. Controls
2. Fuel supply
3. Heating or cooling unit
4. Distribution system
Some air ducts are insulated internally or externally. Internal insulation materials with
a rough porous surface will trap particles and particulates from the air stream.
Materials trapped include paper fibres, pollen grains, plant matter, fungal spores,
insect parts, skin flakes, and other organic matter. These materials are often
gyroscopic and can absorb moisture from the air. With sufficient moisture content in
the accumulated dust, fungal spores germinate and grow. The condensation from the
cooling coils and water in the drain also allow fungi and bacteria to proliferate.
5.2 Pressure, Temperature, Humidity Control
Define critical requirements of environmental control of the following:
 Temperature
 Relative humidity
 Airborne particulates
5.2.1 Temperature
ACMV systems are designed mainly for cooling (in Singapore). During the cooling
cycle, warm air is cooled by passing through the cooling coils. Excessive moisture in
the warm air is condensed into liquid water when passing through the coils. Air
discharged from the cooling coils often has elevated relative humidity. Therefore, the
capacity of an existing heating or cooling system, as measured by its ability to heat or
cool a specific building or space, can be determined in either of two ways:
Field test
ENVIRONMENTAL CONTROL Last Date updated: 10 June 2004

5-2
Properly sized heating and cooling systems should operate at full capacity at normal
yearly outside temperature extremes. The system is operated on the warmest possible
day (within the limitations of the inspection period). The system is observed to
determine how “hard” the system is working to maintain the preset indoor
temperature, as indicated by how often the system cycles on and off.
Design calculation
An ACMV system’s capacity can be more accurately determined by noting its heating
or cooling output (in tons or BTUs) from information on the manufacturer’s data plate
and comparing it to the building’s heating and cooling loads. A rough estimate of a
building’s required cooling capacity in BTUs per hour (BTUH) can be obtained by
using the following formula:
BTUH = .33 x [square footage of building to be heated] x [difference between outside

and inside design temperatures]. The factor of .33 in this formula is based on a 3”
exterior wall, a 6” ceiling at the top floor or roof, and double-glazed windows.
5.2.2 Relative humidity
Humidity is the amount of water vapour in the air and can be described in different
ways, including "relative humidity," which is the term used most often.
Relative humidity is the amount of water vapour in the air compared with the amount
of vapour needed to make the air saturated at the air's current temperature.
The warmer air is, the more water vapour it can "hold." Dew point is a measure of
how much water vapour is actually in the air.
Air temperature in degrees C Water vapour air can hold at this temperature
30 degrees 30 grams per cubic meter of air
Note: these numbers apply to air at sea level pressure
Example of dew point and relative humidity
Imagine, that at 3 p.m. you measure the air's temperature at 30 degrees and you
measure its humidity at 9 grams per cubic meter of air. What would happen if this air
cooled to 10 degrees with no water vapour being added or taken away? As it cools to
10 degrees the air becomes saturated; that is, it can't hold any more water vapour than
9 grams per cubic meter. Cool the air even a tiny bit more and its water vapour will
begin condensing to form clouds, fog or dew - depending on whether the air is high
above the ground, just above the ground, or right at the ground. Back at 3 p.m., when
we made the measurements, we could say that the air's dew point is 10 degrees C.
That is, if this particular air were cooled to 10 degrees at ground level, its humidity
would begin condensing to form dew.

5-3
How about relative humidity? At 3 p.m. the air has 9 grams of water vapour per cubic
meter of air. We divide 9 by 30 and multiply by 100 to get a relative humidity of 30%
In other words, the air actually has 30% of the water vapour it could hold at its current
temperature. Cool the air to 20 degrees. Now we divide 9, the vapour actually in the
air, by 17, the vapour it could hold at its new temperature, and multiply by 100 to get
a relative humidity of 53% (rounded off). Finally, when the air cools to 10 degrees,
we divide 9 by 9 and multiply by 100 to get a relative humidity of 100% - the air now
has all the vapour it can hold at its new temperature.
Temperature and humidity control
General air conditioning is normally not regarded as an environmental control in

cGMP context; however, changes in temperature and lighting can have an adverse
effect on employee performance and, in turn, on assuring that the drug is properly
manufactured, packed, inspected, and tested. Production workers are a major source
of particulate contamination and standard operating procedures for personnel are often
necessary in order in ensure that employees are not adversely affected by the
environment.
Air conditioning can control humidity that, in turn, can affect the generation of static
charges. Static charges can damage some electronic components and, in such
situations, need to be controlled.
The temperature and humidity of the room should be controlled within limits where
people feel comfortable. For example, in the process areas where personnel are
working in gowns, the temperature might have to be set lower to maintain conditions
at a comfortable level for these personnel. The normal controlled ranges are:
temperature of 20 to 22 oC, relative humidity of 30-50%.
The temperature and humidity also have to be controlled to process requirements.

Some process might require a higher temperature while others require a lower
temperature. The requirement for the process should take precedence over that for
human comfort.
5.2.3 Airborne particulates
Airborne particulate matter includes solid and liquid matter such as:
1. Dusts
2. Fumes
3. Mists
4. Smoke - smoke consists of carbon or soot particles less than 0.1 micrometer in
size, and suspended in air. Smoke results from the incomplete combustion of
carbonaceous materials such as coal, oil, or wood.
5.3 Classified areas (clean rooms)
 Define Classified Area
 Understand applicability of classified areas

5-4
5.3.1 Definition
Air in controlled areas is generally of acceptable particulate quality if it has a per-

cubic-foot particle count of not more than 100,000 in a size range of 0.5 micron and
larger (Class 100,000) when measured in the vicinity of the exposed articles during
periods of activity. With regard to microbial quality, an incidence of no more than 25
colony forming units per 10 cubic feet is acceptable.
A clean room is a room that is maintained virtually free of contaminants, such as dust
or bacteria.
A clean room is used in laboratory work, in the production of precision parts for
electronic or aerospace equipment or in the manufacture of pharmaceuticals and
medical components.
Clean rooms are classified according to the concentration and the size of particles in
the room. Classification allows the design of an ACMV system that meets the need of
the room.
The areas within a plant can be classified into the following classes:
1. Class 100,000
2. Class 10,000
3. Class 1,000
4. Class 100
The numbers refer to the number of particles per cubic foot of air whose size is
greater or equal to the selected particle size. The number of particulates in the room
should be measured during normal work activities and should be a measurement of
the process-contact air.
The following table shows the standards for room classification. For example, a
Class 1000 room contains no more than 1000 particles 0.5 micron diameter or larger
per cubic foot of air.
Particle size (microns)

Class
0.1 0.2 0.3 0.5 5.0
1 35 7.5 3 1 NA
10 350 75 30 10 NA
100 NA 750 300 100 NA
1 000 NA NA NA 1000 7
10
NA NA NA 10000 70
000

5-5
100
NA NA NA 100000 700
000
Note: If the particle concentration/ft3 is multiple by 35.2, the count is converted to counts/m3
Examples of operations to be carried out in the various grades are given in the table
below. The particulate conditions for a class 100 zone that is in operation should be
maintained in the zone immediately surrounding the product whenever the product or
open container is exposed to the environment.
Examples of cleanroom conditions required for different operations
Class Examples of Operations for Terminally Sterilised Products

100 Filling of products, when unusually at risk
10,000 Preparation of solutions, when unusually at risk. Filling of products
100,000 Preparation of solutions and components for subsequent filling
Class Examples of Operations for Aseptic Preparations

100 Aseptic preparation and filling
10,000 Preparation of solutions to be filtered
100,000 Handling of components after washing.
Measurements
The number of particulates can be measured using air samplers (refer to diagrams
below).
The measurements should be performed at a height of 1.5 m above floor level. The
minimum volume of air required per sample can be calculated using the following
formula:
Volume = 20 particles/class limit (particles/volume) i.e. each sample of air tested at

each location shall be of sufficient volume such that at least 20 particles would be
detected.
The minimum number of sampling points required for measuring the particulate
matter in a clean area is indicated in the following table:
Square feet Square Sampling points

meter
100 9.2 4
200 18.4 8
400 36.8 16
1,000 92.0 40
2,000 184.0 80
4,000 368.0 160
10,000 920.0 400

5-6
At each location, at least 5 measurements of a volume calculated as described should
be performed. Afterwards, the average of the obtained values for each sampling
location should be calculated. The average value of the measurements from each
sampling location should comply with the requirements.
Particulate Air Samplers
5.3.2 Microbial standards
Room classification using microbial count
Microbiological monitoring is also required to demonstrate the microbiological

cleanliness of the cleanroom during production. The recommended limits are given in
the table below.
Room Cfu/ft3 Cfu/m3 Cfu/contact

Classification (air) (air) plate
(surfaces)
100 <0.1 <1 <1
10000 <0.5 <10 5
100000 <2.5 <100 25
Note:
1. Cfu = colony forming unit
Measurements
Contact plates are used in the cleanroom environment to estimate the sanitary quality
of containers, air, equipment and working surfaces.

5-7
The microbial count (numbers) can be measured using RODAC (replicate organisms
detecting and counting) contact plates. These plates contain a solid culture medium
(medium contains approximately 0.7 g/l of lecithin and 5.0 g/l of polysorbate 80) in a
specially designed petri dish. The convex surface extends above the walls of the plate.
These 60 x 15 mm plates feature a grid on the bottom to simplify the estimation of the
number of organisms present.
To use a contact plate, remove the lid, firmly press the exposed agar with a slight
rolling movement against the surface being tested, hold for a few seconds without
moving it, remove the disk, replace the lid immediately and allow to incubate at 35 oC
for 48 hours and subsequently at 25 oC for another 5 days. The amount of bacteria
colonies can be observed using a bacteria colony counter. Disinfect the area of
contact after sampling.
1 to 3 representative samples from the walls at a height of 1 to 2 m, should be taken.
Swabs (sterile, moistened, wool tips) are used for sampling discrete surfaces areas or
difficult to reach locations inaccessible to RODAC plates. Gentle swab 25 cm2 of area
(walls, floor, equipment etc). Subsequent direct inoculation on solid media can be
used to cultivate the microorganisms.
Contact Plates
The amount of microbes in the air can also be measured using the Reuter Centrifugal
Sampling (RCS) sampler. The RCS sampler collects viable airborne particles in
combination with the principle of agar impaction. A known volume of air is drawn by
vacuum through a slit orifice that accelerates the sampled air and its contaminants.
Located below the slit and in the path of airflow is an exposed agar plate that rotates
on a turntable at a selected rate of speed. The contaminants, because of their higher
mass, become impacted on the agar surface, while the rest of the air mass flows
around the plate and exits the air sampler. Sampling time with the RCS sampler
should be 2 minutes. After incubation of the agar plate, colonies can be counted and
identified.
One sample should be taken per room, at a location in the middle of the room at a
height of between 1 to 2 m.

5-8
Biological Air Sampler
5.3.3 Applicability of classified areas
Areas in the plant can be divided into 2 broad categories:

1. Uncontrolled areas - these include office and support areas that are non-operational
related.
2. Controlled areas - areas where the processes are being carried out. These areas
have tighter control limits on temperature, humidity, particulate count, microbial
count and other controlled parameters. The control limits should take into account the
type of processes that are being carried out. Controlled areas would be further
subdivided into the different categories of room classification as needed.
Factors that should be considered when planning and using a controlled environment
include:
1. Controlled use of, and entry into, controlled areas;
2. Prohibiting eating, drinking, smoking, or gum chewing;
3. Preventing use of lead pencils;
4. Regulating the storage of glassware and containers;
5. Preventing or controlling the cutting, tearing or storage of cardboard, debris, etc.;
6. Cleaning the room and production equipment per written procedure;
7. Selecting correct furniture and eliminating all nonessential equipment;
8. Controlling room air quality (amount of particulates, pressure, velocity, and
exchange rate);
9. Eliminating electrostatic charges by controlling work surface composition or
grounding;
10. Ensuring cleanliness of raw materials, components and tools;
11. Controlling the purity, sterility, and nonpyrogenicity of process water; and
12. Maintaining prefilters, HEPA filters, and electrostatic precipitators.
Example
What is the room classification typically used for manufacturing of drugs?
A Class 10,000 room contains no more than 10,000 particles 0.5 micron diameter or
larger per cubic foot of air. During idle periods, the particle count will generally be
much lower than 10,000. Some manufacturers use a Class 10,000 clean room for the

5-9
assembly and packaging of devices that will be terminally sterilized and where a low
particulate count on the devices is desired.
The typical specifications for a controlled room could be:
Maximum of 10,000 of 0.5 micron diameter or larger per

Particulates:
cubic foot of air
Humidity: 45 +/- 5 percent
Temperature: 22 +/- 1.0 oC
Air Velocity: 90 feet/minute +/ 2 percent
Air Pressure: 0.05 inches water between the clean room and other areas
5.4 Environmental monitoring
5.4.1 Importance of environmental monitoring
 Understand importance of environmental monitoring
 Define Planned Monitoring
 Describe use of cleaning and sanitising agents
All types of microorganisms including bacteria, mould spores, yeast, protozoa, algae
and viruses, are floating in the air around us. Many of these microorganisms are
harmful. Microorganisms are tiny living cells. They reproduce by one cell dividing
every 20 minutes. This is a continuous cycle and if left unchecked, one bacterium
would multiply into several billion bacteria within a day.
5.4.2 Planned monitoring
A comprehensive environmental monitoring programme has to be developed to

ensure the environmental conditions are maintained within limits. The programme has
to include critical utility systems, microbiological testing areas, and manufacturing
areas.
Parameters that may affect the integrity of the product or manufacturing process,
personnel safety, or the cleaning and sanitization programme will be monitored. The
parameters include particulate count, microbial count and identity, temperature and
relative humidity.
Alert and action levels for each parameter in each area or critical utility have to be
established based on the results from validation testing and cGMP requirements.
Specific action plans have to be developed for addressing excursions beyond alert and
action limits for each area or utility.
All sampling should be done per written procedure, and the data should be recorded.
Further, periodic inspections of environmental controls and documentation of the

5-10
inspections are required. The inspection check-off form or other record should be kept
simple.
5.4.3 Use of cleaning and sanitizing agents
What is cleaning?
Cleaning is the removal of the source of food for microorganisms. Cleaning is done
through use of cleaning detergents and soaps.
What is sanitising?
Sanitising is the reduction of microbial counts (numbers) on equipment surfaces
through the use of sanitising agents. Microbial control in water systems should be
achieved primarily through sanitisation practices. Systems should be sanitized using
either thermal or chemical means.
Efficiency testing for disinfectants- Surface testing technique

Clean surface (steel strips can be used in place of surface for testing purposes) to be
treated with detergent and rinse well with distilled water. Spot-inoculate with a known
volume of a culture of microbes. Each strip should contain approximately 100
organisms. Allow drying for 30 min at room temperature. After drying, immerse two
strips in sanitizer solution to be tested. Allow the contact for 5, 10 or 15 min. The
recommended disinfectant must be able to establish a 5-log reduction of the
inoculated microorganisms within 5 min.

5-11
TOPIC 6 Control of Components and Drug Product Containers and

Closures
6.1 General control
 Define principles of control of components
 Describe Suppliers Qualification programme
 Understand supplier audit
6.1.1 Principles of control of components
The main objective of a drug manufacturing plant is to produce drugs for patients' use
from a combination of starting materials. Thus, special attention should be given to
the materials.
The purchase of starting materials is an important operation that should involve staff
who have a particular and thorough knowledge of the products and suppliers. Starting
materials should be purchased only from suppliers named in the relevant specification
and, where possible, directly from the producer. It is also recommended that the
specifications established by the manufacturer for the starting materials be discussed
with the suppliers. It is of benefit that all aspects of the production and control of the
starting material in question, including handling, labelling, and packaging
requirements as well as complaints and rejection procedures, are discussed between
the manufacturer and the supplier.
Procedures should be in place to ensure that all purchased or otherwise received

product and services conform to specified requirements. Incoming product shall be
inspected, tested, or otherwise verified as conforming to specified requirements.
Acceptance or rejection shall be documented.
General requirements
(a) There shall be written procedures describing in sufficient detail the receipt,
identification, storage, handling, sampling, testing, and approval or rejection of
components and drug product containers and closures; such written procedures shall
be followed.
(b) Components and drug product containers and closures shall at all times be handled
and stored in a manner to prevent contamination.
(c) Bagged or boxed components of drug product containers, or closures shall be

stored off the floor and suitably spaced to permit cleaning and inspection.
(d) Each container or grouping of containers for components or drug product

containers, or closures shall be identified with a distinctive code for each lot in each
shipment received. This code shall be used in recording the disposition of each lot.
CONTROL OF COMPONENTS 6-1 Last Date updated: 10 June 2004

AND DRUG PRODUCT CONTAINERS
AND CLOSURES
Each lot shall be appropriately identified as to its status (i.e., quarantined, approved,
or rejected).
6.1.2 Suppliers qualification programme
Each manufacturer shall establish and maintain the requirements, including quality
requirements that must be met by suppliers. Each manufacturer shall:
1. Evaluate and select potential suppliers on the basis of their ability to meet
specified requirements, including quality requirements. The evaluation shall
be documented.
2. Define the type and extent of control to be exercised over the product and
suppliers based on the evaluation results.
3. Establish and maintain records of acceptable suppliers.
Selecting and qualifying a supplier has become a critical factor in the overall
manufacture of a product. The purpose of qualification is to verify that a product meet
specified performance, quality, and reliability requirements. Qualification takes place
independent of any contract action.
Benefits of a successful supplier qualification programme
1. Increase the likelihood of product performance, quality and reliability without

delaying a specific contract or procurement action.
2. Assure that a new technology or product can initially meet a specified

performance, quality and reliability level.
3. Assure that a manufacturer’s product design, manufacturing process, and

quality and reliability control program provide items that meet a specified
level of performance on a continuous basis.
4. Reduce redundant product qualifications.
5. Reduces acquisition time and product costs
6. Reduces production delay and time.
7. Reduces duplicate and non-standard testing requirements.
8. Cost effective way to improve the likelihood of continuous product

compliance with specified requirements.
9. Maintains configuration control during product redesigns and manufacturing

process changes.
10. Allows for faster problem identification and resolution for major product
quality problems.
CONTROL OF COMPONENTS Last Date updated: 10 June 2004

AND CLOSURES
6-2
When designing a qualification programme, the performance, quality and reliability
aspects of the products must be fully understood and taken into consideration. The
design and failure modes that would contribute to reduced performance, quality and
reliability must be addressed in the qualification programme to ensure that failures do
not occur.
6.1.3 Supplier audit
The audit should include an evaluation of the following:
1. Product design
2. Manufacturing materials
3. Workmanship
4. Conformance testing
The qualification and on-going quality conformance (both 100% and periodic)
inspection requirements should be defined and documented.
Quality Control should determine the type, depth, scope and frequency (initial or
periodic) of the audits that will be necessary for verification. The product life cycle,
complexity, and criticality should be reviewed to determine the frequency of the
assessments that are needed and whether they should be scheduled assessments,
unannounced assessments, or a combination.
6.2 Identification
Understand importance of receipt and identification requirements:
 Documentation
 Labelling control
 Procedures for identification
 Procedures for traceability
6.2.1 Documentation
Each manufacturer shall establish and maintain purchasing data that clearly describe
or reference the specified requirements, including quality requirements, for purchased
or otherwise received product and services.
Purchasing documents shall include, where possible, an agreement that the suppliers
and contractors agree to notify the manufacturer of changes in the product or service
so that manufacturers may determine whether the changes may affect the quality of a
finished drug
Purchasing data shall be approved in accordance with cGMP requirements.

AND CLOSURES
6-3
6.2.2 Labelling control
1. Each manufacturer shall establish and maintain procedures to control labelling

activities.
2. All incoming materials and finished products should be quarantined immediately
after receipt or processing, until they are released for use or distribution.
3. All materials and products should be stored under the appropriate conditions
established by the manufacturer and in an orderly fashion to permit batch
segregation and stock rotation by a first-in, first-out rule.
4. Labelling and documentation must provide the information needed to use the drug
safely. The label is often the most scrutinised part of the product because it does
the most to inform the user of a drug's use or misuse. Misbranding is a major issue
of legal concern.
5. Some of the information required in the label includes symbols. Symbols and
identification colours should be used where appropriate.
6. When preparing labels, drug manufacturers must consider several variables,
including space for information on the package, properly tested inks, legibility,
text size, easy to understand writing, and a visually appealing, logical layout.
Label integrity
Labels shall be printed and applied so as to remain legible and affixed during the
customary conditions of processing, storage, handling, distribution, and use.
Labelling inspection
Labelling shall not be released for storage or use until a designated individual(s) has
examined the labelling for accuracy including, where applicable, the correct
expiration date, control number, storage instructions, handling instructions, and any
additional processing instructions.
Labelling storage
Each manufacturer shall store labelling in a manner that provides proper identification
and is designed to prevent mix-ups.
Labelling operations
Each manufacturer shall control labelling and packaging operations to prevent
labelling mix-ups.
Label warning
The label should contain a signal word (such as WARNING or CAUTION) followed
by a hazard avoidance directive (beginning with such words as Do not, Never, or
Avoid), an identification of the hazard, and a description of the consequences if the
warning is not observed.
6.2.3 Procedures for identification
Where a control number is required, that control number shall be on or shall

accompany the batch of drugs through distribution.

AND CLOSURES
6-4
6.2.4 Procedures for traceability
Retained samples of all batches have to be stored in the appropriate condition,

properly labelled and sealed. This is to ensure traceability when situation calls for it.
Destruction record for retain samples has to be kept properly.
6.3 Drug Product Containers and Closures
The quality of the packaging of Pharmaceutical product plays a very important role in
the quality of such products. It must:
1. protect against all adverse external influences that can alter the properties of the
product, e.g. moisture, light, oxygen, and temperature variations;
2. protect against biological contamination;
3. protect against physical damage;
4. carry the correct information and identification of the product.
The kind of packaging and the materials used must be chosen in such a way that:
1. the packaging itself does not have an adverse effect on the product(e.g. through
chemical reactions, leaching of packaging materials or absorption);
2. the product does not have an adverse effect on the packaging material, changing
its properties or affecting its protective function.
Glossary of Containers for Pharmaceuticals:
1. Ampoule: A container sealed by fusion and to be opened exclusively by breaking.

The contents are intended for use on one occasion only.
2. Bag: A container consisting of surfaces, whether or not with a flat bottom, made of
flexible material, closed at bottom and at sides by sealing; the top may be closed by
fusion of the material, depending on the intended use.
3. Blister: A multi-dose container consisting of 2 layers, of which one is shaped to

contain the individual doses.

AND CLOSURES
6-5
4. Bottle: A container with a more or less pronounced neck and usually a flat bottom.
5. Cartridge: A container, usually cylindrical, suitable for liquid or solid

pharmaceutical dosage forms; generally for use in a specially designed apparatus
(e.g. a pre filled syringe).
6. Gas cylinder: A container, usually cylindrical, suitable for compressed, liquefied

or dissolved gases, fitted with a device to regulate the spontaneous outflow of gas
at atmospheric pressure and room temperature.
7. Injection Needle: A hollow needle with a locking device intended for the
administration of liquid pharmaceutical dosage forms.
8. Injection Syringe: A cylindrical device with a cannula-like nozzle, with or without

a fixed needle and a movable piston, used for the administration, usually
parenteral, of an accurately measured quantity of a liquid pharmaceutical dosage
form. The syringe can be pre filled and can be for single dosage or multiple
dosages.

AND CLOSURES
6-6
9. Strip: A multi-dose container consisting of 2 layers, usually provided with

perforations, suitable for containing single doses of solids or semi solids preparations.
9. Vial: A small container for parenteral medicinal products, with a stopper and over
seal; the contents are removed after piercing the stopper. Both single and multiple
dosage forms exists.
Closures
Depending on the type of container, closures may have different shapes and sizes e.g.
stoppers for infusion or injection bottles or plungers for prefilled syringes. A special
design of stopper may also be required for some pharmaceutical production process
like Lyophilization.
PP/PE PP PP PE
PP
Normal Closures

AND CLOSURES
6-7
Tamper Resistant Closures
The FDA listed 11 technologies capable of satisfying the definition of Tamper evident
packaging. These include: Film wrappers, blister packs, bubble packs, heat shrunk
bands, paper foils, breakable cap ring system, sealed tubes, sealed cartons, aerosol
containers, and all metal & composite cans.
Child Resistant closures

The use of child resistant packaging has proved effective in reducing child mortality
from intoxication by oral prescription drugs, and it is now recognized worldwide that
children must be protected against such intoxication.
The three most common reclosable child resistant types of closures are the “press
turn”, “squeeze turn” & a combination lock. Most such designs need two hands to
open the closure.
Other Considerations
1. 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.
2. Drug product containers and closures shall not be reactive, additive, or

absorptive so as to alter the safety, identity, strength, quality, or purity of the
drug beyond the official or established requirements.
3. Container closure systems shall provide adequate protection against

foreseeable external factors in storage and use that can cause deterioration or
contamination of the drug product.
4. Drug product containers and closures shall be clean and, where indicated by
the nature of the drug, sterilized and processed to remove pyrogenic properties
to assure that they are suitable for their intended use.
5. Standards or specifications, methods of testing, and, where indicated, methods

of cleaning, sterilizing, and processing to remove pyrogenic properties shall be
written and followed for drug product containers and closures.

AND CLOSURES
6-8
6.3.2 Testing and approval or rejection of drug product containers and
closures
(a) Each lot of components, drug product containers, and closures shall be withheld
from use until the lot has been sampled, tested, or examined, as appropriate, and
released for use by the quality control unit.
(b) Representative samples of each shipment of each lot shall be collected for testing
or examination. The number of containers to be sampled, and the amount of material
to be taken from each container, shall be based upon appropriate criteria such as
statistical criteria for component variability, confidence levels, and degree of
precision desired, the past quality history of the supplier.
(c) Samples shall be collected in accordance with the following procedures:
(1) The containers of components selected shall be cleaned where necessary, by

appropriate means.
(2) The containers shall be opened, sampled, and resealed in a manner designed to
prevent contamination of their contents and contamination of other components, drug
product containers, or closures.
(3) Sterile equipment and aseptic sampling techniques shall be used when necessary.
(4) If it is necessary to sample a component from the top, middle, and bottom of its
container, such sample subdivisions shall not be composited for testing.
(5) Sample containers shall be identified so that the following information can be
determined: name of the material sampled, the lot number, the container from which
the sample was taken, the data on which the sample was taken, and the name of the
person who collected the sample.
(6) Containers from which samples have been taken shall be marked to show that
samples have been removed from them.
(d) Samples shall be examined and tested as follows:

(1) At least one test shall be conducted to verify the identity of each component of a
drug product. Specific identity tests, if they exist, shall be used.
(2) Each component shall be tested for conformity with all appropriate written
specifications for purity, strength, and quality. In lieu of such testing by the
manufacturer, a report of analysis may be accepted from the supplier of a component,
provided that at least one specific identity test is conducted on such component by the
manufacturer, and provided that the manufacturer establishes the reliability of the
supplier's analyses through appropriate validation of the supplier's test results at
appropriate intervals.
(3) Containers and closures shall be tested for conformance with all appropriate
written procedures. In lieu of such testing by the manufacturer, a certificate of testing
AND CLOSURES
6-9
may be accepted from the supplier, provided that at least a visual identification is
conducted on such containers/closures by the manufacturer and provided that the
manufacturer establishes the reliability of the supplier's test results through
appropriate validation of the supplier's test results at appropriate intervals.
(4) When appropriate, components shall be microscopically examined.
(5) Each lot of a component, drug product container, or closure that is liable to
contamination with filth, insect infestation, or other extraneous adulterant shall be
examined against established specifications for such contamination.
(6) Each lot of a component, drug product container, or closure that is liable to
microbiological contamination that is objectionable in view of its intended use shall
be subjected to microbiological tests before use.
(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.
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 or 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.
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.

AND CLOSURES
6-10
TOPIC 7 Production & In-Process Controls
7.1 Documentation
 Define Standard Operating Procedures
 Understand batch record sheets
7.1.1 Standard operating procedures
What are standard operating procedures (SOPs)?
SOPs are used worldwide. Anybody who has served in the military is painfully aware
of the standard operating procedures learned and relearned in boot camp, starting with
the way to properly make a bed or to dismantle and clean his rifle.
In the professional world, SOPs usually refer to the components of a procedures

manual. In a manufacturing plant, there are SOPs for virtually every repeated
procedure for all tasks performed in the process areas, maintenance areas, quality
areas etc, including specific actions by management.
Each SOP has a desired outcome (what you want to happen as a result of following
the SOP) and a measurement (how you know if it is being correctly followed).
SOP format
All SOPs should be uniformly designed and formatted. Information common to all
SOPs is described below:
First Page
1. Company name – at the top of each SOP, the company name is indicated.
2. SOP number – each SOP is assigned a unique number
3. Title – the title of each SOP appears below the SOP number. The title
describes the subject of the SOP.
4. Date – each SOP is assigned an effective date. The date describes the month,
day, and year of implementation.
5. Author – each SOP should provide the author name, title, and the department,
along with signatures and dates.
6. Checked by – each SOP should provide the name, title, and the department,
along with signatures and dates, of the person responsible for checking the
contents of the SOP.
7. Approved by – the signature of the quality control manager or department
manager approving the SOP to prevent unauthorized changes.
8. Revisions – the revision documents the revision number, section, pages,
initials and date.
Inside pages
1. Subject – each SOP begins with the subject to provide key description of the
SOP.
2. Purpose – the purpose of the SOP.
PRODUCTION & IN-PROCESS CONTROL 7-1 Last Date updated: 10 June 2004
3. Responsibility – this clearly identifies who has to follow the procedures and
who is responsible for the overall compliance with the SOP.
4. Procedure – the individual steps of the SOP, arranged in logical order to make
the SOP easy to perform.
5. Reason for revision – at the end of each SOP, the reasons why the SOP is
changed, along with the date, should be stated.
Example
A sample of the first page of the SOP is shown below.
Company ABC
Validation Standard Operating Procedures
SOP No: Val 100.10 Effective Date: 1/4/2003
Title Introduction to validation
Author ___________________________
name/title/department
___________________________
signature/date
Checked by: ___________________________

___________________________
signature/date
Approved by: ___________________________

___________________________
signature/date
Revisions:
Number Section Pages Initials/Date
Example
An example of an SOP for the cleaning of an aseptic filling room is shown below.
TITLE: Cleaning Procedure for the Aseptic Filling Room
APPROVED BY: __________________________ Date: ___________________
PURPOSE: Control of surface contamination within the Aseptic Filling Room.
EQUIPMENT NEEDED:
1. Cleaning solution: See SOP G044
2. Nonlinting wiping cloths
3. Stainless steel basins and pails
4. Dry-wet vacuum cleaner for floors
(should be equipped with a HEPA filter on the exhaust air port to filter the exhaust air)
5. Sponge mops with replaceable sterile heads
6. Mop buckets
7. Stainless steel sponges
8. Powder free latex surgical gloves, sterile
9. Head and shoe covers, sterile
10. Face masks and gowns, sterile
11. Stainless steel cart
12. Sprayer
13. Trash cans plastic liners
14. Stepladder
DAILY CLEANING REQUIREMENTS:
CAUTION: Be careful when using stepladder and when walking in wet areas. USE
EXTREME CARE WHEN CLEANING ELECTRICAL FIXTURES AND
OUTLETS. USE DAMP (NOT WET) CLOTH TO WIPE ELECTRICAL ITEMS.
A. Gowning Room:
Shoe and head covers are required in this area. Begin all cleaning at the top and finish
at the bottom of any equipment or surface to be cleaned.
1. Empty trash containers and replace plastic liners.
2. Replenish stock of shoe covers, masks, head covers, gowns, gloves and put into
proper areas.
3. Fill dispenser with 0.45 u filtered 70% Isopropyl alcohol.
4. Mix cleaning solution of XXXXXXXX using process water (SOP G044).
5. Fill a stainless steel basin with cleaning solution and begin wiping in this order: the
boot box; stool; wash station; top and outsides of all cabinets; counter tops; and the
tops of the trash containers.
6. Remove excess debris and wet mop the floor with cleaning solution.
7. Fill sprayer with cleaning solution and wet the floor; allow it to air dry.
8. Gown according to gowning procedures and go into the filling area (SOP G014).
B. Filling Room:
1. Move any remaining products (devices) to appropriate areas as directed by your

supervisor.
2. Empty all trash containers and replace liners.
3. Remove particulate matter from ledges, cabinets and external surfaces of laminar
flow benches with a wiping cloth and cleaning solution.
4. Perform general cleaning and organization of shelves.
5. Remove debris and wet mop the floor with cleaning solution.
6. Spray the entire floor in the filling room with cleaning solution, using the provided
sprayer. Allow the floor to air dry.
WEEKLY CLEANING REQUIREMENTS:
All daily cleaning requirements are included in the weekly cleaning requirements. The
additions to the weekly cleaning are ceilings, walls, and the internal work surfaces of
the laminar-flow work benches. Rodac plate measurements are taken after cleaning
and before the next production shift.
A. Gowning Room:
1. Use only one entrance and one exit when cleaning. The cleaning direction will flow
from entrance to exit.
2. Remove all nonessential equipment from the room and clean it. Return the
equipment after the entire area is cleaned.
3. Begin cleaning the room by wiping the entire ceiling area with the cleaning
solution.
Frequent changes of the cleaning solution and the wiping cloths are needed for
effective cleaning of large areas such as the ceilings and walls. Make new solution
and change wiping cloths when dirty.
1. Clean air vents, lighting fixtures, and sprinkler heads.
2. Clean the walls next, starting at the top and cleaning toward the floor.
3. When the ceilings and walls are cleaned, follow steps 1, 2, 3 and 5 of the Daily
Cleaning Requirements for the gowning room.
4. Remove debris and wet mop the floor with cleaning solution.
5. Fill the sprayer with cleaning solution and wet the floor. Allow to air dry.
6. Gown according to procedure and go into the Filling room (SOP G014).
B. Filling Room:
1. Follow steps 1, 2, 3 and 4 of Daily Cleaning Requirements for Filling Room.
2. Begin cleaning operation by wiping the entire ceiling area with cleaning solution.
Make new cleaning solution and change wiping cloth when visibly dirty.
3. Clean air vents, ultraviolet and fluorescent lighting fixtures and sprinkler heads.
4. Clean the ultraviolet bulb since any oil or dust on the bulb drastically reduces its
germicidal properties.
5. Clean the walls next, starting at the top and cleaning toward the floor. Make new
cleaning solution, and change wiping cloth when dirty.
6. Empty all shelves and wipe with the cleaning solution. Wipe the removed materials
and put them back onto the cleaned shelf.
7. Wipe all cabinets and equipment with the cleaning solution from top to bottom.
8. Wipe all ledges and surfaces with the cleaning solution.
9. Pay particular attention to the laminar flow workbenches because the cleaning
operation should start in the internal work surface of the hood as it is the cleanest area.
Use a fresh wiping cloth and cleaning solution for the internal work surfaces. Do not
use the same cloth or solution which was used for the external cleaning. Discard
solution and wiping cloths after cleaning each hood.
1. First, switch off the laminar flow hood, then clean all outside surfaces from top of
hood to bottom stand. Discard cleaning cloth.
2. Second, clean all internal work surfaces with a new cleaning cloth in this order:
a. Air diffuser screen
b. Workbench top.
c. Plexiglas sides
d. Light covers
3. Clean the floors. Scrub stains or spills first, with stainless steel sponges, to loosen
debris. Use the sponge mop to clean the loosened debris. Fill the sprayer with
cleaning solution and wet the entire floor area. Allow to air dry. Rodac plate
measurements are made after cleaning and before the next production shift.
7.1.2 Batch Record Sheet
Batch production and control records shall be prepared for each batch of drug product
produced and shall include complete information relating to the production and
control of each batch. These records shall include:
(a) An accurate reproduction of the appropriate master production or control record,
checked for accuracy, dated, and signed;
(b) Documentation that each significant step in the manufacture, processing, packing,
or holding of the batch was accomplished, including:
(1) Dates;
(2) Identity of individual major equipment and lines used;
(3) Specific identification of each batch of component or in process material used;
(4) Weights and measures of components used in the course of processing;
(5) In process and laboratory control results;
(6) Inspection of the packaging and labeling area before and after use;
(7) A statement of the actual yield and a statement of the percentage of theoretical
yield at appropriate phases of processing;
(8) Complete labeling control records, including specimens or copies of all labeling
used;
(9) Description of drug product containers and closures;
(10) Any sampling performed;
(11) Identification of the persons performing and directly supervising or checking

each significant step in the operation;
(12) Any investigation made;
(13) Results of examinations made.
Production record review
All drug product production and control records, including those for packaging and
labeling, shall be reviewed and approved by the quality control unit to determine
compliance with all established, approved written procedures before a batch is
released or distributed. Any unexplained discrepancy (including a percentage of
theoretical yield exceeding the maximum or minimum percentages established in
master production and control records) or the failure of a batch or any of its
components to meet any of its specifications shall be thoroughly investigated, whether
or not the batch has already been distributed. The investigation shall extend to other
batches of the same drug product and other drug products that may have been
associated with the specific failure or discrepancy. A written record of the
investigation shall be made and shall include the conclusions and follow-up.
7.2 Production operations
 Understand equipment cleaning and maintenance
 Describe equipment cleaning and maintenance schedule
 Describe deviation handling
 Describe change control
7.2.1 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.
(7) Records shall be kept of maintenance, cleaning, sanitizing, and inspection.
7.2.2 Equipment Cleaning
Clean in Place (CIP)
CIP is a system that involves cleaning plant and equipment while the plant and
equipment are kept in an assembled state. Circulating or once-through water rinses
and chemical or sanitising solutions are normally used. The rinses and solutions are
used such that all contaminated or soiled product contact surfaces are cleaned to an
acceptably high and consistently reproducible state. Computer control of CIP systems
is common and programmed recipes can help control the consistency and quality of
the cleaning procedure.
CIP systems are commonly used:

1. To eliminate environmental and personnel exposure to the contaminant.
2. When the shutdown and disassembly of equipment in production would
impact manufacturing efficiency.
3. To improve the consistency and reproducibility of the cleaning process.
A typical CIP cycle consists of the following:

1. Process water (PW) pre-rinse
2. Caustic (alkaline) cleaning solution
3. PW rinse
4. Phosphoric acid rinse
5. PW rinse
6. WFI (water for injection) rinse
Clean out of place (COP)
COP is used to describe the removal, disassembly and opening of process equipment
and systems for cleaning. Care should be taken to minimise environmental exposure
leading to cross-contamination and personnel interference.
7.2.3 What is a maintenance schedule?
All equipment relating to the production of the pharmaceutical product e.g. weighing
equipment, has to be certified by accredited bodies to ensure accuracy at all times.
A preventative maintenance program has also to be set in place so that all equipment
are in tiptop condition. Maintenance activities, including the date and individual(s)
performing the maintenance activities, shall be documented.
Periodic inspection of equipment
Each manufacturer shall conduct periodic inspections in accordance with established

procedures to ensure adherence to applicable equipment maintenance schedules. The
inspections, including the date and individual(s) conducting the inspections, shall be
documented.
There are 2 types of maintenance programmes. They are:
1. Preventive Maintenance
 Time-interval maintenance
 Based on calendar time or equipment running hours
 Intervals are based on average deterioration rate
2. Predictive Maintenance
 Condition-based maintenance
 Based on equipment conditions
 Project trends from condition monitoring techniques to determine the trouble-
free service life of equipment
7.2.4 Deviation handling
When a deviation is detected in progress, appropriate corrective action must be taken..

After the corrective action is applied, the processor must assure the application has
been satisfactorily implemented and documented on batch records and in the
deviation file.
Each manufacturer shall establish and maintain procedures for implementing

corrective and preventive action. The procedures shall include requirements for:
1. Analyzing processes, equipment and other source of quality data to identify

existing and potential causes of nonconforming product, or other quality
problems.
2. Identifying the action(s) needed to correct and prevent recurrence of
nonconforming product and other quality problems.
3. Verifying or validating the corrective and preventive action to ensure that such
action is effective and does not adversely affect the device.
4. Submitting relevant information on identified quality problems, as well as
corrective and preventive actions, for management review.
7.2.5 Change control
(1) There 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. Such procedures shall include all requirements
in this subpart. These written procedures, including any changes, shall be drafted,
reviewed, and approved by the appropriate organizational units and reviewed and
approved by the quality control unit.
(2) Written production and process control procedures shall be followed in the
execution of the various production and process control functions and shall be
documented at the time of performance. Any deviation from the written procedures
shall be recorded and justified.
7.3 In-Process Control
 Understand control of inspection, measuring and test equipment
 Describe calibration standards and records
 Understand sampling and testing
7.3.1 Control of inspection, measuring and test equipment
When a company produces a product, it utilises many interrelated processes and each
process involves several to many steps to accomplish a specified task. Measurements
have to be taken and checked to make sure that they are within specified limits or
outcomes. All the different processes are combined to yield the final product or
service.
Statistical process control (SPC) is a procedure in which data is collected, organised,

analysed and interpreted so that a process can be maintained at its present level of
quality or improved to a higher level of quality.
Each manufacturer shall ensure that all inspection, measurement and test equipment,
including mechanical, automated, or electronic inspection and test equipment, is
suitable for its intended purposes and is capable of generating valid results.
Each manufacturer shall establish and maintain procedures to ensure that equipment is
routinely calibrated, inspected, checked and maintained. The procedures shall include
provisions for handling, preservation and storage or equipment, so that its accuracy
and fitness for use are maintained. These activities shall be documented.
7.3.2 Calibration standards
Calibration standards used for inspection, measurement and test equipment shall be
traceable to national or international standards. If national or international
standards are not practical or available, the manufacturer shall use an independent
reproducible standard.
Calibration guidelines
1. Upon receipt, all equipment should be reviewed by the calibration lab manager
and the user department to establish if the equipment has to be kept on a
calibration programme.
2. Inclusion and exclusion lists should be maintained with reasons, location, and
final approval by the QC manager.
3. Classification of equipment as critical or noncritical with regard to calibration
necessities should be maintained.
4. The equipment variables affecting the product quality shall be identified as
critical for calibration.
5. Determination of accuracy requirements of the instrument should be in
consent with the QC and calibration department.
6. New changed or repaired instrument should be calibrated prior to use.
Reference, standards
The reference standards used for calibration of instruments should be checked for
accuracy annually by an authorised measuring institution (e.g. SPRING Singapore).
The reference standard employed should have an uncertainty of measurement which
is 1/10 to 1/5 the uncertainty required in the measurement equipment.
7.3.3 Calibration records
The equipment identification, calibration dates, the individual performing each

calibration and the next calibration date shall be documented. These records shall be
displayed on or near each piece of equipment or shall be readily available to the
personnel using such equipment and to the individuals responsible for calibrating the
equipment.
All critical items should be calibrated every 6 months. Noncritical items should be
calibrated every 12 months. If necessary, recalibration frequency should be reviewed
and revised.
7.3.4 Sampling and Testing of in-process materials and drug products
7.3.4.1 General Principles
(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.
(b) Valid in-process specifications for such characteristics shall be consistent with
drug product final specifications and 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. Examination and
testing of samples shall assure that the drug product and in-process material conforms
to specifications.
(c) In-process materials shall be tested for identity, strength, quality, and purity as
appropriate, and approved or rejected by the quality control unit, during the
production process, e.g., at commencement or completion of significant phases or
after storage for long periods.
(d) Rejected in-process materials shall be identified and controlled under a
quarantine system designed to prevent their use in manufacturing or processing
operations for which they are unsuitable.
7.3.4.2 Understand statistical sampling
Where appropriate, each manufacturer shall establish and maintain procedures for
identifying valid statistical techniques for establishing, controlling and verifying the
acceptability of incoming production materials.
Sampling plans, when used, shall be written and based on a valid statistical rationale.
Each manufacturer shall establish and maintain procedures to ensure that sampling
methods are adequate for their intended use and to ensure that when changes occur,
the sampling plans are reviewed. These activities shall be documented.
The 4 phases in the application of a statistical sampling plan are:
1. Collection of data. The data collected can be all the data in the population or,
as is usually the case, a sample of the data in a population. When a sample is
used, the sample must fairly represent the population because conclusions
about the population depend on the information from the samples.
2. Organisation of data. The data collected must be organised so that the
information they contain can be understood. Tables, charts, graphs are
normally used.
3. Analysis of data. The analysis of data involves concise numerical measures of
the data. The measures fall into two main classifications: a middle value,
called a measure of central tendency, and a data spread indicator, called a
measure of dispersion.
4. Interpretation of the data. Conclusions are made about the population of
measurements based on the charts, graphs and other statistical calculations that
are applied to the samples taken.
7.3.4.3 Sampling quantity and frequency
Where appropriate, each manufacturer shall establish and maintain procedures for
identifying valid statistical techniques for establishing, controlling and verifying the
acceptability of process capability and product characteristics.
Sampling plans, when used, shall be written and based on a valid statistical rationale.
Each manufacturer shall establish and maintain procedures to ensure that sampling
methods are adequate for their intended use and to ensure that when changes occur,
the sampling plans are reviewed. These activities shall be documented.
Sampling does a good job of accepting very good lots and rejecting very bad lots.
Unfortunately, a large area of indecision lies in the middle. The sampling rules in all
the formal sample plans are based on probability, BUT the application of probability
predicts the acceptance of lots with substandard quality.
To select a statistically valid sampling plan, the following should be done:
1. First, the objective of the inspection should be determined based on past

performance, other controls that are in place and potential failure modes.
2. Then, the acceptance standards (acceptable quality level, AQL) should be of
the sampling plan should be documented to demonstrate that the sampling
plan meets this objective.
3. Document sampling plan.
4. Implement sampling plan.
5. Periodically review sampling plan for validity.
7.3.4.4 Describe sampling methods
The samples must represent a true picture of the population in order to accurately
predict the population values. If all the data are stacked up, the distribution will
usually take on a normal shape (normal distribution). Control limits are based on the
assumption of a normal distribution of the sample means.
Small sample size
A small sample size is desirable to minimise the opportunity for within-sample

variation due to special causes. This is important because each sample should be
representative of the state of control at one point in time. In addition, the cost of
sampling should be kept low. The time an operator spends collecting the samples,
taking the sample measurements and plotting a control chart represents time away
from production.
Large sample size
A large sample allows smaller changes in process characteristics to be detected with

higher probability. It is needed for a good statistical analysis. The larger the sample,
the more closely the sample distribution will resemble the population distribution. To
detect process shifts of 2 standard deviation or less, sample sizes of at least 15 to 25
must be used.
Frequency
Measurement
Normal Distribution
Sampling frequency
Taking large samples on a frequent basis is desirable but not economical. No hard-
and-fast rules exist for the frequency of sampling but at the very least, samples should
be taken from every lot or batch of incoming materials. Samples should be close
enough to provide an opportunity to detect changes in the incoming production
materials as soon as possible and reduce the chances of producing a large amount of
nonconforming output.
Why must samples be taken from every batch/lot?
This is required in order to determine if the batch/lot meets specification limits. If the
batch/lot is found to be out of specification, then the batch/lot can be segregated.
7.3.4.5 Testing and releasing principles
Each manufacturer shall establish and maintain procedures for acceptance activities.
Acceptance activities include inspections, tests, or other verification activities.
Receiving acceptance activities

Each manufacturer shall establish and maintain procedures for acceptance of
incoming product. Incoming product shall be inspected, tested, or otherwise verified
as conforming to specified requirements. This is normally done on a batch/lot basis.
Acceptance or rejection shall be documented.
Control limits
The location of control limits is closely related to the risk involved in making an
incorrect assessment about the state of control. A type I error occurs when an
incorrect conclusion is reached that a special cause is present when in fact one does
not exist. This error results in cost incurred and time wasted trying to find a
nonexistent problem.
A type II error occurs when special causes are present but are not signalled in the
control chart because points fall within the control limit by chance. Because
nonconforming products have a greater chance to be produced, a cost will eventually
be incurred as a result.
The tighter the control limits, the greater is the probability that a sample will indicate
that the process is out of control. Hence, a type 1 error increases as control limits are
reduced.
To reduce errors
Source of Sample size Sampling Control
cost frequency limit
Type I error Large High Wide
Type II Large High Narrow
error
7.4 Acceptance
 Describe in-process acceptance activities
 Describe nonconforming product management
 Understand corrective and preventive actions
7.4.1 In-process acceptance activities
Each manufacturer shall establish and maintain acceptance procedures to ensure that
specified requirements for in-process product are met. Such procedures shall ensure
that in-process product is controlled until the required inspection and tests or other
verification activities have been completed, or necessary approvals are received and
documented.
The documentation shall include:
1. The acceptance activities performed.

2. The dates acceptance activities are performed.
3. The results.
4. The signature of the individual(s) conducting the acceptance activities.
5. The equipment used.
Each manufacturer shall identify by suitable means the acceptance status of product,
to indicate the conformance or non-conformance of product with acceptance criteria.
The identification of acceptance status shall be maintained throughout manufacturing,
packing, and labelling of the product to ensure that only product which has passed the
required acceptance activities is used, or delivered.
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.
(5) 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:
(a) The component was released by the quality control unit;
(b) The weight or measure is correct as stated in the batch production records;
(6) The containers are properly identified.
(a) Each component shall be added to the batch by one person and verified by a
second person.
7.4.2 Nonconforming product management
Each manufacturer shall establish and maintain procedures to control product that
does not conform to specified requirements. The procedures shall address the
identification, documentation, evaluation, segregation and disposition of
nonconforming product. The evaluation of non-conformance shall include a
determination of the need for an investigation and notification of the persons or
organisations responsible for the non-conformance. The evaluation and any
investigation shall be documented.
Each manufacturer shall establish and maintain procedures that define the
responsibility for review and the authority for the disposition of nonconforming
product.
Disposition of nonconforming product shall be documented. Documentation shall

include the justification for use of nonconforming product and the signature of the
individual(s) authorising the use. Nonconforming product is normally evaluated and
dispositioned by members of the Nonconforming Product Review Board. The
Purchasing Manager, Manufacturing Manager, members of QC, Production
Supervisor, and Engineering Manager are members of the Review Board.
Identification and Documentation

QC inspectors and production personnel are responsible for the identification of
nonconforming product in the course of their inspection activities.
All nonconforming products can be documented through the use of a reject tag and a
Nonconforming Product Form. The nonconforming condition is noted on the form.
The form remains with the nonconforming product until the nonconforming condition
is resolved.
Nonconforming product is typically segregated along with its associated tag and form.
Nonconforming product may, however, remain with the job if it is clearly and
individually marked as nonconforming. Segregation areas include rejected materials
quarantine areas and separate, clearly identified areas on the production floor.
7.4.3 Rework
There are four possibilities for the disposition of nonconforming product. They
include the following:
Rework/Repair
The nonconforming product is placed back into the manufacturing process to be
reworked or repaired. The rework or repair must be completed successfully before its
associated nonconforming tag or form is removed. The individual performing the
rework or repair shall indicate completion on the tag or form. The reworked/repaired
item is subject to all existing standards. This disposition shall be authorized by the
Review Board members.
Scrap
The nonconforming product is discarded. This disposition shall be authorized by the
Review Board members.
Use As Is
The nonconforming product is used in the manufacturing process without being
reworked or repaired. When required by contract, the customer is contacted to obtain
permission to use the nonconforming product. This disposition shall be authorized by
QC. Sales provide a second disposition signature when the form, fit, or function is
affected and when the customer must be contacted. The rationale for the use of the
nonconforming product must be stated with the disposition.
Return
The nonconforming product is returned to its supplier. It is accompanied by return
paperwork which, among other things, specifies the reason for the return. It may also
be accompanied by a Supplier Corrective Action Request. This disposition shall be
authorized by the Review Board members.
Re-test
Product is marked this way if the condition is uncertain and the product must be
evaluated again. Ultimately, one of the above four dispositions will be assigned. A
rejection tag or nonconforming form may be marked VOID if the rejection was in
error.
Each manufacturer shall establish and maintain procedures for rework, to include
retesting and re-evaluation of the nonconforming product after rework, to ensure that
the product meets its current approved specifications. These activities shall be
documented in the DHR.
7.4.4 Corrective and preventive actions
Each manufacturer shall establish and maintain procedures for implementing

corrective and preventive action. The procedures shall include requirements for:
1. Analyzing processes, work operations, concessions, quality audit reports,

quality records, service records, complaints, returned product, and other
sources of quality data to identify existing and potential causes of
nonconforming product, or other quality problems. Appropriate statistical
methodology shall be employed where necessary to detect recurring quality
problems.
2. Investigating the cause of nonconformities relating to product, processes, and

the quality system.
3. Identifying the action(s) needed to correct and prevent recurrence of

nonconforming product and other quality problems;
Verifying or validating the corrective and preventive action to ensure that such
action is effective and does not adversely affect the finished device.
4. Implementing and recording changes in methods and procedures needed to

correct and prevent identified quality problems.
5. Ensuring that information related to quality problems or nonconforming

product is disseminated to those directly responsible for assuring the quality of
such product or the prevention of such problems.
6. Submitting relevant information on identified quality problems, as well as

corrective and preventive actions, for management review.
TOPIC 8 Labelling, Packaging and Storage
 Define labelling integrity
 Describe labelling inspection
 Understand use of control number
General Requirements – labels and packing materials
(a) There shall be written procedures describing in sufficient detail the receipt,
identification, storage, handling, sampling, examination, and/or testing of labelling
and packaging materials; such written procedures shall be followed. Labelling and
packaging materials shall be representatively sampled, and examined or tested upon
receipt and before use in packaging or labelling of a drug product.
(b) Any labelling or packaging materials meeting appropriate written specifications

may be approved and released for use. Any labelling or packaging materials that do
not meet such specifications shall be rejected to prevent their use in operations for
which they are unsuitable.
(c) Records shall be maintained for each shipment received of each different
labelling and packaging material indicating receipt, examination or testing, and
whether accepted or rejected.
8.1 Labelling
8.1.1 Labelling integrity
The term "label" is defined as "a display of written, printed, or graphic matter upon
the immediate container of any article . . ." Any word, statement, or other information
appearing on the immediate container should also appear on the outside container or
wrapper, if any, of the retail package or be easily legible through the outside container
or wrapper. The label is not required to appear on the shipping carton.
cGMP requires that device labelling bear adequate directions for use, operating and
servicing instructions, and either adequate warnings against uses dangerous to health,
or information necessary for the protection of users.
Guidelines are:
1. Labels and other labeling materials for each different drug product, strength,
dosage form, or quantity of contents shall be stored separately with suitable
identification. Access to the storage area shall be limited to authorized
personnel.
2. Obsolete and outdated labels, labeling, and other packaging materials shall be
destroyed.
LABELLING, PACKAGING AND STORAGE 8-1 Last Date updated: 10 June 2004
3. Use of gang-printed labeling for different drug products, or different strengths
or net contents of the same drug product, is prohibited unless the labeling
from gang-printed sheets is adequately differentiated by size, shape, or color.
4. If cut labeling is used, packaging and labeling operations shall include one of
the following special control procedures:
(1) Dedication of labeling and packaging lines to each different strength of

each different drug product;
(2) Use of appropriate electronic or electromechanical equipment to conduct a

100-percent examination for correct labeling during or after completion of
finishing operations; or
(3) Use of visual inspection to conduct a 100-percent examination for correct

labeling during or after completion of finishing operations for hand-applied
labeling. Such examination shall be performed by one person and independently
verified by a second person.
5. Printing devices on or associated with, manufacturing lines used to imprint

labeling upon the drug product unit label or case shall be monitored to assure
that all imprinting conforms to the print specified in the batch production
record.
Labeling issuance
(a) Strict control shall be exercised over labeling issued for use in drug
product labeling operations.
(b) Labeling materials issued for a batch shall be carefully examined for
identity and conformity to the labeling specified in the master or
batch production records.
(c) Procedures shall be used to reconcile the quantities of labeling issued,
used, and returned, and shall require evaluation of discrepancies
found between the quantity of drug product finished and the quantity
of labeling issued when such discrepancies are outside narrow preset
limits based on historical operating data.
(d) All excess labeling bearing lot or control numbers shall be destroyed.
(e) Returned labeling shall be maintained and stored in a manner to
prevent mix-ups and provide proper identification.
(f) Procedures shall be written describing in sufficient detail the control
procedures employed for the issuance of labeling; such written
procedures shall be followed.
What is misbranding?
A device is misbranded under a number of different circumstances, including:
1. Its labelling is false or misleading.
2. Its packaging does not bear a label containing the name and place of business
of the manufacturer, packer, or distributor, and an accurate statement of the
quantity of contents.
3. Words, statements, or other required information are not prominent on the
labelling or are not stated clearly.
4. Its label does not contain adequate directions for use. These include warnings
against use in certain pathological conditions; against use by children where
its use may be dangerous to health; and against unsafe dosage, methods,
duration of administration or application unless exempt as unnecessary to
protect the public health.
5. It is dangerous to health when used in the dosage or manner, or with the
frequency or duration prescribed, recommended, or suggested in the labelling.
6. False representations including:
a. incorrect, inadequate or incomplete identification;
b. unsubstantiated claims of therapeutic value;
c. inaccuracies concerning condition, state, treatment, size, shape, or
style; substitution of parts or material;
d. subjective or unsubstantiated quality or performance claims; and,
e. use of government prefixes e.g. U.S. or other similar indication
suggesting government or agency approval or endorsement of the
product.
It is not a necessary condition that the labelling should be flatly and blatantly false for
regulatory authority to take action. The word "misleading" means that labelling is
deceptive if it creates or leads to a false impression in the mind of a reader.
Sterile Devices
Special attention should be given to the labelling of sterile devices. For example,
sterility may be needed only for a portion of certain devices and this condition should
clearly be identified in the labelling. Devices that are not sterile in their entirety
should be labelled to properly inform users what is actually intended to be "sterile" in
the package.
For example, a possible limiting statement might be:
"Caution: Only the fluid path of this set is sterile and non-pyrogenic. Do not use in a
sterile or aseptic area without proper precautions."
Unused Labels
Unused labelling that contains pre-coded serial numbers, manufacturing dates,

expiration dates, control numbers, etc., should be destroyed and not returned to the
label storage area. The GMP requirements do not include reconciliation of the number
of labels used with the number issued, although, this control is recommended.
Design of labelling
The physical design applications of labelling should assure legibility under normal
conditions of use over the expected life of the device. It also helps assure the proper
inspection, handling, storage, and distribution of labelling.
Labelling includes equipment labels, control labels, package labels, directions for use,
maintenance manuals, etc. The displays on CRTs and other electronic message panels
are considered labelling if instructions, prompts, caution, or parameter identification
information is given.
Labels should bear at least the following information:
1. The designated name of the product and the internal code reference where
applicable;
2. The batch number(s) given by the supplier and on receipt by the manufacturer,
if any;
3. Where appropriate, the status of the contents (e.g., on quarantine, on test,
released, rejected, returned, recalled);
4. Where appropriate, an expiry date or a date beyond which retesting is
necessary.
8.1.2 Labelling inspection
Upon receipt, all packaging and labelling materials, including pre-printed containers,
inserts, and pre-printed packaging materials, should be examined and, if deemed
necessary by the company, tested to assure conformance with specifications.
Also, samples of labels shall be proof-read by a designated individual(s). After being

accepted by a responsible individual, these components may be placed into inventory
or into production. These inspections shall be recorded in the device history record as
required to show that inspection and proof reading were performed. The inspection
record for device labelling should be kept simple.
Labelling should be carefully examined to assure that the contents of the labelling
comply with the labelling specifications in the device master record. This examination
should include any control numbers or expiration dates used on the labels. A record of
this check, including the date and name of the person performing the examination,
should be made in the device history record.
If label mix-ups cannot occur, for example a manufacturer makes only one device or
uses only one label and there are no control numbers or expiration dates, the original
inspection when the labelling was placed into inventory is an adequate check for
compliance with the device master record specifications. A second check need not be
performed because it serves no purpose. If, however, there is any possibility that
incorrect labelling can be used, a second check should be made when the labelling is
issued for application, packaging, or shipping.
Examples of labelling mistakes
C Manufact Product Reason for recall

ou urer
ntr
y
Be B. Braun, Ampoules Wrong labelling – potassium
lgi Melsung chloride incorrectly labelled
u en as glucose
m/
G
er
m
an
y
U America Methotrexa The product is labelled with
S n te for the wrong National Drug
A Pharmac injection Code and has a miss-spelt
eutical name
U Aventis Vials of Contains active ingredients
S Pharma docetaxel but labelled as diluent
A
U Chattem Sunscreen Sunscreen factor indicated is
S gel wrong
A
U Summer Triple Mislabelling – product used
S Laborato Paste, Zinc as labelled may cause skin
A ries Oxide irritation
8.1.3 Use of control number
Lot number, control number, or batch number means any distinctive combination of
letters, numbers, or symbols, or any combination of them, from which the complete
history of the manufacture, processing, packing, holding, and distribution of a batch
or lot of drug product or other material can be determined.
8.2 Packaging
 Understand packaging requirements
 Understand use of tamper resistant packaging
8.2.1 Packaging requirements
Tamper-evident packaging requirements are required for over-the-counter (OTC)
human drug products. This is to improve the security of OTC drug packaging and
help assure the safety and effectiveness of OTC drug products.
An OTC drug product (except a dermatological, dentifrice, insulin, or lozenge

product) for retail sale that is not packaged in a tamper-resistant
package or that is not properly labeled under this section is
considered to be adulterated.
Requirements for tamper-evident package
(1) Each manufacturer and packer who packages an OTC drug product (except a
dermatological, dentifrice, insulin, or lozenge product) for retail sale shall package the
product in a tamper-evident package, if this product is accessible to the public while
held for sale. A tamper-evident package is one having one or more indicators or
barriers to entry which, if breached or missing, can reasonably be expected to provide
visible evidence to consumers that tampering has occurred. To reduce the likelihood
of successful tampering and to increase the likelihood that consumers will discover if
a product has been tampered with, the package is required to be distinctive by design
or by the use of one or more indicators or barriers to entry that employ an identifying
characteristic (e.g., a pattern, name, registered trademark, logo, or picture).
The term ``distinctive by design'' means the packaging cannot be duplicated with
commonly available materials or through commonly available processes. A tamper-
evident package may involve an immediate-container and closure system or
secondary-container or carton system or any combination of systems intended to
provide a visual indication of package integrity. The tamper-evident feature shall
be designed to and shall remain intact when handled in a reasonable
manner during manufacture, distribution, and retail display.
(2) In addition to the tamper-evident packaging feature described above, any two-
piece, hard gelatin capsule covered by this section must be sealed using an
acceptabletamper-evident technology.
(c) In order to alert consumers to the specific tamper-evident feature(s) used, each
retail package of an OTC drug product covered by this section (except ammonia
inhalant in crushable glass ampoules, containers of compressed medical oxygen, or
aerosol products that depend upon the power of a liquefied or compressed gas to expel
the contents from the container) is required to bear a statement that:
(i) Identifies all tamper-evident feature(s) and any capsule sealing technologies
used to comply with paragraph (b) of this section;
(ii) Is prominently placed on the package; and
(iii) Is so placed that it will be unaffected if the tamper-evident feature of the

package is breached or missing.
(2) If the tamper-evident feature chosen to meet the requirements in paragraph (b)
of this section uses an identifying characteristic, that characteristic is required to be
referred to in the labeling statement. For example, the labeling statement on a bottle
with a shrink band could say ``For your protection, this bottle has an imprinted seal
around the neck.''
8.3 Storage
8.3.1 Expiration dating
(a) To assure that a drug product meets applicable standards of identity, strength,
quality, and purity at the time of use, it shall bear an expiration date determined by
appropriate stability testing.
(b) Expiration dates shall be related to any storage conditions stated on the
labeling, as determined by stability studies.
(c) If the drug product is to be reconstituted at the time of dispensing, its labeling
shall bear expiration information for both the reconstituted and unreconstituted drug
products.
(d) Expiration dates shall appear on labeling.
8.3.2 Warehousing
Written procedures describing the warehousing of drug products shall

be established and followed. They shall include:
(a) Quarantine of drug products before release by the quality control unit.
(b) Storage of drug products under appropriate conditions of temperature,

humidity, and light so that the identity, strength, quality, and purity of the drug
products are not affected.
Proper records of warehousing inventory information must be kept and the records
themselves tally with the amount being out or consumed for production. This is to
ensure that no excess amount or under consumption of raw materials is used in the
production process.
First in First Out of materials have to be strictly followed so that there is no dead
stock of old materials in the warehouse.
Typical Drug Storage Warehouse Layout
1. Any building or buildings used in the holding of a drug product shall be of

suitable size, construction and location to facilitate cleaning, maintenance, and
proper operations.
2. Any such building shall have adequate space for the orderly placement of
equipment and materials to prevent mix-ups between different components, drug
product containers, closures, labeling, in-process materials, or drug products, and
to prevent contamination.
3. The flow of personnel, and drug products through the building or buildings shall
be designed to prevent contamination.
4. There should be defined areas or other control systems for the following activities:
 Receipt, identification, sampling & quarantine materials pending release or

rejection.
 Separate storage areas for highly sensitizing products like Penicillin.
 Separate storage areas for highly infectious/toxic products like steroids or
cytotoxic agents.
 Separate Holding area for rejected goods
 Separate Holding area for returned goods or scrap goods
 Sampling areas
 Storage of released material
 Re-packing/Labelling areas
5. Dedicated AHU (Air handling units) should be used for storage areas used for
storing sensitizing products like Penicillin.
6. Dedicated AHU (Air handling units) should be used for storage areas used for
storing highly infectious / toxic products like steroids or cytotoxic agents.
7. AHU’s must include equipment for control of -- air pressure, micro-organisms,
dust, humidity and temperature.
8. Containment / Prevention of Cross contamination should be built into the facility
design
• Once Thru AHU should be used for storage areas used for storing sensitizing
products like Penicillin.( No re-circulation of air )
• Once Thru AHU should be used for storage areas used for storing highly
infectious / toxic products like steroids or cytotoxic agents.
( No re-circulation of air )
9. Drains should be of adequate size and should be provided with an air break or a
suitable device to prevent back-siphonage.
10. Special Storage facilities design
a. Availability of cold room storage or refrigerator for vaccines and
biological products.(-40 0c to + 4 0C)
Temperature
Cold Rooms:......4 °C
Warm Rooms: 20 to 50 °C
Stability Rooms: 15 to 30°C
Freezers:.......... -25 to 0 °C
Low Temperature: -40 °C
Humidity
Standard: .....20 -90%RH
With Dew Point... 4 0C to 5 0C
Control: ± 3%;Accuracy: ± 1%
8.3.3 Distribution
Written procedures shall be established, and followed, describing

the distribution of drug products. They shall include:
(a) A procedure whereby the oldest approved stock of a drug product is distributed
first. Deviation from this requirement is permitted if such deviation is temporary and
appropriate.
(b) A system by which the distribution of each lot of drug product can be readily
determined to facilitate its recall if necessary.
Packaging materials
The purchase, handling, and control of primary and printed packaging materials shall
be as for starting materials.
Particular attention should be paid to print packaging materials. They should be stored
in secure conditions so as to exclude the possibility of unauthorized access. Cut labels
and other loose printed materials should be stored and transported in separate closed
containers so as to avoid mix-ups. Packaging materials should be issued for use only
by designated personnel following an approved and documented procedure.
Each delivery or batch of printed or primary packaging material should be given a
specific reference number or identification mark.
Intermediate and bulk products
Intermediate and bulk products should be kept under appropriate conditions.
Intermediate and bulk products purchased as such should be handled on receipt as

though they were starting materials.
Finished products
Finished products should be held in quarantine until their final release, after which
they should be stored as usable stock under conditions established by the
manufacturer.
Rejected and recovered materials
Rejected materials and products should be clearly marked as such and stored
separately in restricted areas. They should either be returned to the suppliers or, where
appropriate, reprocessed or destroyed. Whatever action is taken should be approved
by authorized personnel and recorded.
The reprocessing of rejected products should be exceptional. It is permitted only if the

quality of the final product is not affected, if the specifications are met, and if it is
done in accordance with a defined and authorized procedure after evaluation of the
risks involved. A record should be kept of the reprocessing. A reprocessed batch
should be given a new batch number.
The introduction of all or part of earlier batches, conforming to the required quality,
into a batch of the same product at a defined stage of manufacture should be
authorized beforehand. This recovery should be carried out in accordance with a
defined procedure after evaluation of the risks involved, including any possible effect
on shelf-life. The recovery should be recorded.
The need for additional testing of any finished product that has been reprocessed, or
into which a recovered product has been incorporated, should be considered by the
quality control department.
Recalled products
Recalled products should be identified and stored separately in a secure area until a
decision is taken on their fate. The decision should be made as soon as possible.
Returned goods
Products returned from the market should be destroyed unless it is certain that their
quality is satisfactory; they may be considered for resale, relabelling, or bulking with
a subsequent batch only after they have been critically assessed by the quality control
department in accordance with a written procedure. The nature of the product, any
special storage conditions it requires, its condition and history, and the time elapsed
since it was issued should all be taken into account in this assessment. Where any
doubt arises over the quality of the product, it should not be considered suitable for
reissue or reuse, although basic chemical reprocessing to recover the active ingredient
may be possible. Any action taken should be appropriately recorded.
TOPIC 9 Laboratory Controls
 Need for and general requirements for laboratory controls
 Describe good laboratory practices
9.1 Introduction
9.1.1 Need for and general requirements for laboratory controls
(a) The establishment of any specifications, standards, sampling plans, test

procedures, or other laboratory control mechanisms required, including any change in
such specifications, standards, sampling plans, test procedures, or other laboratory
control mechanisms, shall be drafted by the appropriate organizational unit and
reviewed and approved by the quality control unit. The requirements shall be
followed and shall be documented at the time of performance. Any deviation from the
written specifications, standards, sampling plans, test procedures, or other laboratory
control mechanisms shall be recorded and justified.
(b) Laboratory controls shall include the establishment of

scientifically sound and appropriate specifications, standards, sampling plans, and test
procedures designed to assure that components, drug product containers, closures, in-
process materials, labelling, and drug products conform to appropriate standards of
identity, strength, quality, and purity.
(c) Determination of conformance to appropriate written

specifications for the acceptance of each lot within each shipment of
components, drug product containers, closures, and labelling used in the
manufacture, processing, packing, or holding of drug products should be conducted.
The specifications shall include a description of the sampling and testing
procedures used. Samples shall be representative and adequately
identified. Such procedures shall also require appropriate retesting of
any component, drug product container, or closure that is subject to
deterioration.
(d) Determination of conformance to written specifications and a

description of sampling and testing procedures for in-process materials.
Such samples shall be representative and properly identified.
(e) Determination of conformance to written descriptions of sampling

procedures and appropriate specifications for drug products. Such
samples shall be representative and properly identified.
(f) The calibration of instruments, apparatus, gauges, and recording

devices at suitable intervals in accordance with an established written
program containing specific directions, schedules, limits for accuracy
and precision, and provisions for remedial action in the event accuracy
and/or precision limits are not met. Instruments, apparatus, gauges, and
recording devices not meeting established specifications shall not be
LABORATORY CONTROLS 9-1 Last Date updated: 10 June 2004

used.
9.1.2 Good Laboratory Practices
This is covered under 21CFR PART 58 -- GOOD LABORATORY PRACTICE FOR

NONCLINICAL LABORATORY STUDIES.
21CFR Part 58 prescribes good laboratory practices for conducting nonclinical

laboratory studies that support or are intended to support applications for research or
marketing permits for products regulated by the Food and Drug Administration,
including food and colour additives, animal food additives, human and animal drugs,
medical devices for human use, biological products, and electronic products.
GLP covers the following areas:
1. personnel
2. testing facility management
3. quality assurance unit
4. facilities for handling test and control articles
5. laboratory operation areas
6. specimen and data storage facilities
7. equipment design
8. SOP
9. reagents and solutions
10. storage and retrieval of records and data
etc.
9.2 Testing
 Testing and release procedures
 Stability testing
 Reserve samples
9.2.1 Testing and release for distribution
(a) For each batch of drug product, there shall be appropriate laboratory
determination of satisfactory conformance to final specifications for the drug product,
including the identity and strength of each active ingredient, prior to release. Where
sterility and/or pyrogen testing are conducted on specific batches of short-lived

radiopharmaceuticals, such batches may be released prior to completion of sterility
and/or pyrogen testing, provided such testing is completed as soon as possible.
(b) There shall be appropriate laboratory testing, as necessary, of each batch of

drug product required to be free of objectionable microorganisms.
(c) Any sampling and testing plans shall be described in written procedures that
shall include the method of sampling and the number of units per batch to be tested;
such written procedure shall be followed.
(d) Acceptance criteria for the sampling and testing conducted by the quality
control unit shall be adequate to assure that batches of drug products meet each
appropriate specification and appropriate statistical quality control criteria as a
condition for their approval and release. The statistical quality control criteria shall
include appropriate acceptance levels and/or appropriate rejection levels.
(e) The accuracy, sensitivity, specificity, and reproducibility of test methods

employed by the firm shall be established and documented.
(f) Drug products failing to meet established standards or specifications and any
other relevant quality control criteria shall be rejected. Reprocessing may be
performed. Prior to acceptance and use, reprocessed material must meet appropriate
standards, specifications, and any other relevant criteria.

9.2.2 Stability testing
(a) There shall be a written testing program designed to assess the stability
characteristics of drug products. The results of such stability testing shall be used in
determining appropriate storage conditions and expiration dates. The written program
shall be followed and shall include:
(1) Sample size and test intervals based on statistical criteria for each attribute
examined to assure valid estimates of stability;
(2) Storage conditions for samples retained for testing;
(3) Reliable, meaningful, and specific test methods;
(4) Testing of the drug product in the same container-closure system as that in
which the drug product is marketed;
(5) Testing of drug products for reconstitution at the time of dispensing (as
directed in the labelling) as well as after they are reconstituted.
(b) An adequate number of batches of each drug product shall be tested to

determine an appropriate expiration date and a record of such
data shall be maintained. Accelerated studies, combined with basic stability
information on the components, drug products, and container-closure system, may be
used to support tentative expiration dates provided full shelf life studies are not
available and are being conducted. Where data from accelerated studies are used to
project a tentative expiration date that is beyond a date supported by actual shelf life
studies, there must be stability studies conducted, including drug product testing at
appropriate intervals, until the tentative expiration date is verified or the appropriate
expiration date determined.
9.2.3 Special testing requirements
(a) For each batch of drug product purporting to be sterile and/or pyrogen-free,
there shall be appropriate laboratory testing to determine conformance to such
requirements. The test procedures shall be in writing and shall be followed.
(b) For each batch of ophthalmic ointment, there shall be appropriate testing to
determine conformance to specifications regarding the presence of foreign particles
and harsh or abrasive substances. The test procedures shall be in writing and shall be
followed.
(c) For each batch of controlled-release dosage form, there shall be appropriate
laboratory testing to determine conformance to the specifications for the rate of
release of each active ingredient. The test procedures shall be in writing and shall be
followed.

9.2.4 Reserve samples
(a) An appropriately identified reserve sample that is representative of each lot in

each shipment of each active ingredient shall be retained. The reserve sample consists
of at least twice the quantity necessary for all tests required to determine whether the
active ingredient meets its established specifications, except for sterility and pyrogen
testing. The retention time is as follows:
(1) For an active ingredient in a drug product other than those described in
paragraphs (a) (2) and (3) of this section, the reserve sample shall be retained for 1
year after the expiration date of the last lot of the drug product containing the active
ingredient.
(2) For an active ingredient in a radioactive drug product, except for non-
radioactive reagent kits, the reserve sample shall be retained for:
(i) Three months after the expiration date of the last lot of the drug product
containing the active ingredient if the expiration dating period of the drug product is
30 days or less; or
(ii) Six months after the expiration date of the last lot of the drug product
containing the active ingredient if the expiration dating period of the drug product is
more than 30 days.
(3) For an active ingredient in an OTC drug product that is exempt from bearing an
expiration date under Sec. 211.137, the reserve sample shall be retained for 3 years
after distribution of the last lot of the drug product containing the active ingredient.
(b) An appropriately identified reserve sample that is representative of each lot or

batch of drug product shall be retained and stored under conditions consistent with
product labelling.
The reserve sample shall be stored in the same immediate container-closure system in
which the drug product is marketed or in one that has essentially the same
characteristics.
Reserve samples from representative sample lots or batches

selected by acceptable statistical procedures shall be examined visually
at least once a year for evidence of deterioration unless visual
examination would affect the integrity of the reserve sample. Any
evidence of reserve sample deterioration shall be investigated. The results of the
examination shall be recorded and maintained with other stability data on the drug
product.
9.2.5 Laboratory animals
Animals used in testing components, in-process materials, or drug products for

compliance with established specifications shall be maintained and controlled in a

manner that assures their suitability for their intended use. They shall be identified,
and adequate records shall be maintained showing the history of their use.

TOPIC 10 Records and Reports
10.1 Records and Reports
10.1 .1 General requirements
(a) Any production, control, or distribution record that is required to be maintained

in compliance with this part and is specifically associated with a batch of a drug
product shall be retained for at least 1 year after the expiration date of the batch
or, in the case of certain OTC drug products lacking expiration dating because they
meet the criteria for exemption under Sec. 211.137, 3 years after distribution of the
batch.
(b) Records shall be maintained for all components, drug product containers,
closures, and labelling for at least 1 year after the expiration date or, in the case of
certain OTC drug products lacking expiration dating because they meet the criteria for
exemption under Sec. 211.137, 3 years after distribution of the last lot of drug product
incorporating the component or using the container, closure, or labelling.
(c) All records required under this part, or copies of such records, shall be readily
available for authorized inspection during the retention period at the establishment
where the activities described in such records occurred. These records or copies
thereof shall be subject to photocopying or other means of reproduction as part of
such inspection. Records that can be immediately retrieved from another location by
computer or other electronic means shall be considered as meeting the requirements
of this paragraph.
(d) Records required under this part may be retained either as original records or as
true copies such as photocopies, microfilm, microfiche, or other accurate
reproductions of the original records. Where reduction techniques, such as
microfilming, are used, suitable reader and photocopying equipment shall be readily
available.
(e) Written records required by this part shall be maintained so that data therein
can be used for evaluating, at least annually, the quality standards of each drug
product to determine the need for changes in drug product specifications or
manufacturing or control procedures. Written procedures shall be established and
followed for such evaluations and shall include provisions for:
(1) A review of a representative number of batches, whether approved or rejected,

and, where applicable, records associated with the batch.
(2) A review of complaints, recalls, returned or salvaged drug products, and

investigations conducted under Sec. 211.192 for each drug product.
(f) Procedures shall be established to assure that the responsible officials of the
firm, if they are not personally involved in or immediately aware of such actions, are
notified in writing of any investigations conducted, any recalls, reports of inspectional
observations issued by the Food and Drug Administration, or any regulatory actions
RECORDS AND REPORTS 10-1 Last Date updated: 10 June 2004

relating to good manufacturing practices brought by the Food and Drug
Administration.
10.1.2 Equipment cleaning and use log
1. A written record of major equipment cleaning, maintenance (except routine

maintenance such as lubrication and adjustments), and use shall be included in
individual equipment logs that show the date, time, product, and lot number of
each batch processed.
2. If equipment is dedicated to manufacture of one product, then individual

equipment logs are not required, provided that lots or batches of such product
follow in numerical order and are manufactured in numerical sequence. In
cases where dedicated equipment is employed, the records of cleaning,
maintenance, and use shall be part of the batch record. The persons
performing and double-checking the cleaning and maintenance shall date
and sign or initial the log indicating that the work was performed.
3. Entries in the log shall be in chronological order.
10.1.3 Component, drug product container, closure, and labelling records
These records shall include the following:
(a) The identity and quantity of each shipment of each lot of components, drug
product containers, closures, and labelling; the name of the supplier; the supplier's lot
number(s) if known; the receiving code as specified in Sec. 211.80; and the date of
receipt. The name and location of the prime manufacturer, if different from the
supplier, shall be listed if known.
(b) The results of any test or examination performed and the conclusions derived
therefrom.
(c) An individual inventory record of each component, drug product container, and
closure and, for each component, a reconciliation of the use of each lot of such
component. The inventory record shall contain sufficient information to allow
determination of any batch or lot of drug product associated with the use of each
component, drug product container, and closure.
(d) Documentation of the examination and review of labels and labelling for
conformity with established specifications
(e) The disposition of rejected components, drug product containers, closure, and
labelling.
10.1.4 Master production and control records
(a) To assure uniformity from batch to batch, master production and control
records for each drug product, including each batch size thereof, shall be prepared,
dated, and signed (full signature, handwritten) by one person and independently

checked, dated, and signed by a second person. The preparation of master production
and control records shall be described in a written procedure and such
writtenprocedure shall be followed.
(b) Master production and control records shall include:
(1) The name and strength of the product and a description of the
dosage form;
(2) The name and weight or measure of each active ingredient per dosage unit or
per unit of weight or measure of the drug product, and a statement of the total weight
or measure of any dosage unit;
(3) A complete list of components designated by names or codes sufficiently

specific to indicate any special quality characteristic;
(4) An accurate statement of the weight or measure of each component, using the
same weight system for each component. Reasonable variations may be permitted,
however, in the amount of components necessary for the preparation in the dosage
form, provided they are justified in the master production and control records;
(5) A statement concerning any calculated excess of component;
(6) A statement of theoretical weight or measure at appropriate phases of

processing;
(7) A statement of theoretical yield, including the maximum and minimum

percentages of theoretical yield beyond which investigation is required;
(8) A description of the drug product containers, closures, and packaging

materials, including a specimen or copy of each label and all other labelling signed
and dated by the person or persons responsible for approval of such labelling;
(9) Complete manufacturing and control instructions, sampling and testing

procedures, specifications, special notations, and precautions to be followed.
10.1.5 Batch production and control records
Batch production and control records shall be prepared for each batch of drug product
produced and shall include complete information relating to the production and
control of each batch. These records shall include:
(a) An accurate reproduction of the appropriate master production or control

record, checked for accuracy, dated, and signed;
(b) Documentation that each significant step in the manufacture, processing,

packing, or holding of the batch was accomplished, including:
(1) Dates;

(2) Identity of individual major equipment and lines used;
(3) Specific identification of each batch of component or in-process material used;

(4) Weights and measures of components used in the course of processing;
(5) In-process and laboratory control results;
(6) Inspection of the packaging and labelling area before and after use;
(7) A statement of the actual yield and a statement of the percentage of theoretical
yield at appropriate phases of processing;
(8) Complete labelling control records, including specimens or copies of all

labelling used;
(9) Description of drug product containers and closures;
(10) Any sampling performed;
(11) Identification of the persons performing and directly supervising or checking

each significant step in the operation;
(12) Any investigation made
(13) Results of examinations made
10.1.6 Production record review
Refer to chapter 7.
10.1.7 Laboratory records
(a) Laboratory records shall include complete data derived from all tests necessary
to assure compliance with established specifications and standards, including
examinations and assays, as follows:
(1) A description of the sample received for testing with identification of source
(that is, location from where sample was obtained), quantity, lot number or other
distinctive code, date sample was taken, and date sample was received for testing.
(2) A statement of each method used in the testing of the sample. The statement
shall indicate the location of data that establish that the methods used in the testing of
the sample meet proper standards of accuracy and reliability as applied to the product
tested. The suitability of all testing methods used shall be verified under actual
conditions of use.
(3) A statement of the weight or measure of sample used for each test, where
appropriate.

(4) A complete record of all data secured in the course of each test, including all
graphs, charts, and spectra from laboratory instrumentation, properly identified to
show the specific component, drug product container, closure, in-process material, or
drug product, and lot tested.
(5) A record of all calculations performed in connection with the test, including
units of measure, conversion factors, and equivalency factors.
(6) A statement of the results of tests and how the results compare with established
standards of identity, strength, quality, and purity for the component, drug product
container, closure, in-process material, or drug product tested.
(7) The initials or signature of the person who performs each test and the date(s) the
tests were performed.
(8) The initials or signature of a second person showing that the original records
have been reviewed for accuracy, completeness, and compliance with established
standards.
(b) Complete records shall be maintained of any modification of an established

method employed in testing. Such records shall include the reason for the
modification and data to verify that the modification produced results that are at least
as accurate and reliable for the material being tested as the established method.
(c) Complete records shall be maintained of any testing and standardization of
laboratory reference standards, reagents, and standard solutions.
(d) Complete records shall be maintained of the periodic calibration of laboratory
instruments, apparatus, gauges, and recording devices required.
(e) Complete records shall be maintained of all stability testing performed.
10.1.8 Distribution records
Distribution records shall contain the name and strength of the

product and description of the dosage form, name and address of the
consignee, date and quantity shipped, and lot or control number of the
drug product. For compressed medical gas products, distribution records
are not required to contain lot or control numbers.
10.1.9 Complaint files
Refer to chapter 12

TOPIC 11 Validation
11.1 Introduction
 Define validation
 Understand validation policy
 Validation team members
 Validation team responsibilities
 Roles of the different departments
11.1.1 What is validation?
Validation is documented evidence that provides a high degree of assurance that a

specific process will consistently produce a product that meets its predetermined
specifications and quality attributes.
11.1.2 Validation policy
Having a validation policy means having proactive regulatory compliance and help in
the prevention of omissions and inappropriate testing, scheduling and tracking of
tasks, identification of personnel qualification, and human resource optimisation.
Benefits of having a validation policy include:
1. Minimise non-compliance cost

2. Reduce rework
3. Reduce rejected lots
4. Avoid recalled lots
5. Help in new drug approval
6. Satisfactory inspections
7. Good corporate image
8. Financial gain
9. Corporate legal protection
11.1.3 Validation team members
The members should include a leader, commonly known as the “validation manager”.
The validation manager is normally from the quality control department. Members
shall include personnel from production; engineering (utilities); laboratory;
maintenance; product development; operations and others as required.
The team members must have the relevant job experience.
11.1.4 Validation team responsibilities
Validation is a team effort that requires the involvement and close interaction of
quality control, production, packaging and maintenance and other appropriate support
such as product development and quality control.
VALIDATION 11-1 Last Date updated: 10 June 2004

The validation team members coordinate the entire validation process by scheduling
meetings and discussions, preparing the validation protocols, monitoring the
validation process, compiling and analysing validation data and test results, and
preparing the final report. All documentation associated with validation should be
reviewed by the validation manager for completeness and compliance with cGMP
requirements.
If test procedures do not fulfil acceptance criteria, the review team must decide if tests
must be repeated or test specifications must be edited. The review team can decide
whether or not test results should be accepted.
11.1.5 Roles of the different departments
Role of quality control
A validation team member from QC is responsible to participate in performing the

validation steps during manufacturing processes and equipment qualification. The
department is also responsible for providing the necessary support for sampling,
testing, and reporting of test results for validation.
Role of Production
This department should prepare the necessary SOPs for the new process or equipment
and assist in the collection of validation data.
Role of Engineering department

This department is responsible for the technical documentation, e.g., manuals,
inspection reports, maintenance reports, and specification sheets. These documents
are stored and updated by personnel from this department.
Role of packaging department

A validation team member from the packaging department is responsible to
participate in the validation steps during packaging processes and equipment
qualification. The packaging department should prepare the necessary SOPs for the
new packaging process or equipment and assist in the collection of validation data.
Role of maintenance department

This department works with the production department to define the necessary
equipment specifications, limitations, capacity, calibration, and maintenance
requirements. In some cases, the maintenance department is required to participate in
equipment installation and operational qualification and provide technical support to
ensure proper and efficient function during the validation process.
Role of product development department

Responsible for defining the process (new product or processes) to be validated and
for providing technical assistance to the validation team by defining specifications,
limits and manufacturing methods.
11.2 Principles of Validation

 Define principles of validation
 Review validation standards
11.2.1 Principles of validation
Good documentation constitutes an essential part of the quality assurance system.

Clearly written documentation prevents errors from spoken communication and
permits tracing of batch history. Specifications, manufacturing formulae and
instructions, procedures, and records must be free from errors and available in
writing. The legibility of documents is of paramount importance.
It is a requirement of cGMP that each pharmaceutical and medical device

manufacturer identify the validation work required to prove control of the critical
aspects of their operations. Any aspect of, including significant changes to, the
premises, the facilities, the equipment or the processes, which may affect the quality
of the product, should be validated.
11.2.2 International validation standards
Documents should be of the following standards:

 Be designed, prepared, reviewed and distributed with care. They should
comply with the relevant parts of the manufacturing and marketing
authorisation dossiers.
 Documents should be approved, signed and dated by appropriate and
authorised persons.
 Documents should have unambiguous contents; title, nature and purpose
should be clearly stated. They should be laid out in an orderly fashion and be
easy to check. Reproduced documents should be clear and legible. The
reproduction of working documents from master documents must not allow
any error to be introduced through the reproduction process.
 Documents should be regularly reviewed and kept up-to-date. When a
document has been revised, systems should be operated to prevent
inadvertent use of superseded documents.
 Documents should not be handwritten; although, where documents require the
entry of data, these entries may be made in clear, legible, indelible
handwriting. Sufficient space should be provided for such entries.
 Any alteration made to the entry on a document should be signed and dated;
the alteration should permit the reading of the original information. Where
appropriate, the reason for the alteration should be recorded.
The records should be made or completed at the time each action is taken and in such
a way that all significant activities concerning the manufacture of drugs are traceable.
They should be retained for at least one year after the expiry date of the finished
product.
Data may be recorded by electronic data processing systems, photographic or other

reliable means, but detailed procedures relating to the system in use should be
available and the accuracy of the records should be checked. Only authorised persons

should be able to enter or modify data in the computer and there should be a record of
changes and deletions; access should be restricted by passwords or other means and
the result of entry of critical data should be independently checked. Batch records
electronically stored should be protected by back-up transfer on magnetic tape,
microfilm, paper or other means. It is particularly important that the data are readily
available throughout the period of retention.
11.3 Validation master plan
 Describe Validation Master Plan
 Know GMP requirements for preparing Validation Master Plan
11.3.1 What is validation master plan (VMP)?
VPM is a comprehensive document describing the applicable validation requirements

for a given facility, and providing a plan for meeting those requirements.
The VMP provides a “road map” for validation, to establish a sequence of events
followed by facilities audit and inspections.
The VMP includes all relevant aspects relating to the production of drugs in the
production facility. The VMP covers all facilities used in the production of the drugs,
the facilities for storing raw materials, interim and finished products, services and the
room for staff.
The plan should contain data on the following subjects:

1. Introduction and validation policy;
2. Organisation and structure of validation activities;
3. Plant, process, and product description;
4. Specific process considerations;
5. List of products, processes, and systems to be validated;
6. High level acceptance criteria;
7. Documentation format;
8. Planning and scheduling;
9. Change control.
11.3.2 GMP requirements for validation master plan
The key elements validation programme should be defined and documented. This
documentation may be referred to as a validation master plan. While the GMP
regulations specifically identifies the validation responsibilities of the production and
quality control departments, in practice, other departments, such as engineering,
research and development, as well as contractors, may be involved. Senior levels of
management within the company should understand the personnel, time and financial
resources required to execute a validation programme and commit the necessary
resources to the work.

The observations made during the execution of a VMP provide strength to
significantly reduce the regulatory risks related to the systems and initiation of the
proactive corrective actions required. The VMP can be written for a new or existing
facility. The following information should be established as a minimal requirement.
Information New facility Existing

facility
1 Facility specifications Yes Yes
2 Utilities specifications Yes Yes
3 ACMV specifications Yes Yes
4 List of major SOPs Yes Yes
5 Description of processes Yes Yes
6 Personnel resumes Yes Yes
7 Design review documents Yes Yes
8 Major purchase orders Yes Yes
9 Equipment manuals Yes Yes
10 Review of audit citations Not applicable Yes
11 Review of past validations Not applicable Yes
12 Physical inspection of Not applicable Yes
facility/ equipment
11.4 Validation documents
Understand the following:
 Design Qualification
 Facility Qualification
 Installation Qualification
 Operations Qualification
 Performance Qualification
11.4.1 Design qualification (DQ)
The first element of the validation exercise of a new plant/facility/department is a

review process sometimes referred to as design qualification. The purpose of DQ is to
verify that the design of the process or facility will meet GMP requirements.
The compliance of the basic design with the user requirements and GMP should be
demonstrated and documented.
11.4.2 Facility qualification
The conceptual design of the facility should be available and be compared with the
actual construction. Details should be summarized in a form describing:
1. Room number
2. Activity
3. Room classification (e.g. class 10,000 etc)
4. Utilities required and their quality
5. Room finishes (floor, wall, ceilings)

6. Illumination
7. Safety features
11.4.3 Installation qualification (IQ)
This qualification is a documented demonstration that facilities and operations are

installed as designed and specified and are correctly interfaced with systems.
The IQ protocol should include a statement of the data required and acceptance
criteria to be met for installation of the system or equipment to verify that the
specification has been satisfied. The protocol should include:
1. Engineering drawings and documents
2. Building finishes
3. Process and utilities flow diagrams
4. Piping and instrumentation diagrams
5. Equipment and instrument specifications
6. Manufacturers’ drawings, equipment maintenance and operating manuals
7. Spare lists
8. Maintenance and calibration schedules
11.4.4 Operations qualification (OQ)
The OQ provides a documented demonstration that facilities and operations function

as specified. The OQ should provide documented evidence that the operation of the
equipment and facility conforms to the original design and installation.
OQ should follow an authorised protocol and should include following:

1. A complete description of the purpose, methodology and acceptance criteria
for the operational tests to be performed.
2. Ensure that instrumentation is in current calibration.
3. Ensure that detailed control parameters have been established and recorded for
each instrument loop - studies to include a condition or a set of conditions
encompassing upper and lower operating limits.
4. Ensure change control systems are in operation.
5. Ensure that SOP and maintenance procedures have been developed for each
system, to ensure continued operation under defined conditions.
6. Ensure that training modules and training sessions for production, engineering,
and support personnel have been developed, conducted and documented
during this stage.
Where appropriate and documented in the validation master plan, the IQ and OQ
protocols may form a single document that clearly defines the acceptance of each
test(s).
The completion of a successful OQ should allow the finalisation of operating

procedures.
11.4.5 Performance qualification (PQ)

PQ is a documented programme to demonstrate that an operation (or a piece of
equipment or system), when carried out within defined parameters, will consistently
perform its intended function to meet predetermined acceptance criteria.
Performance qualification is sometimes called Process qualification. Processes may

be proven also by documented verification through appropriate testing that the
finished product produced by a specified process meets all release requirements.
Before commencing PQ, authorised procedures must be in place for routine use of the
facility or operation, training of operators, routine calibration and maintenance,
notification and recording of problems, and for the definition of actions to be taken in
the event of breakdown.
PQ should follow an authorised protocol and should include the following:

1. A complete description of the purpose, methodology and acceptance criteria
for the performance tests to be performed.
2. Ensure that change control systems are in operation.
3. Ensure that, before approval is given to allow PQ testing to proceed, all IQ and
OQ results are reviewed and accepted.
4. Ensure that maintenance and calibration routines are in operation.
5. Ensure that SOPs have been finalized and approved at this stage.
6. Ensure that operating staff have been trained according to the approved SOPs.
7. Ensure that PQ testing has been carried out using the same personnel who will
routinely operate the system or equipment.
8. Ensure that all deviations from the validation protocol are investigated and
documented.
9. Ensure that sufficient lots or samples will be evaluated to demonstrate
adequate process control.
11.4.6 Summary reports
IQ report
The IQ report should include the following:
- results as compared against the protocols
- recommendations for future work
The report must be prepared and accepted by appropriate management, as defined

under management’s responsibilities, before proceeding to the next stage of validation
or implementing the process.
OQ report
The OQ report should include the following:

PQ report

The PQ report should include the following:

11.5 Approach to validation
 Understand principles of cleaning
 Understand clean limits
 Describe validation of cleaning methods
11.5.1 Prospective validation
Prospective validation is defined as the validation conducted prior to distribution

either of a new product, or a product made under a revised manufacturing process.
Validation is completed and the results are approved prior to any product release.
It is preferred that the validation batches made should be the same size as the intended
production scale batches. 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. In
some cases, for example, small batches of high value products, a batch size smaller
than 10% of production scale may be appropriate. When full-scale production starts,
the validity of any assumptions made should be demonstrated.
During the processing of the validation batch, testing should be performed on the
product at appropriate stages. Testing should also be done on the final product and its
package.
Results of the validation study should be documented in a validation report. The

report should include the following:
(a) Batch analytical data
(b) Certificates of analysis
(c) Batch production records
(d) Report on unusual findings
(e) Conclusions and recommendations
(f) Signature of approval
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 written operating procedures.

11.5.2 Concurrent validation
In exceptional circumstances it may not be possible to complete a validation

programme before routine production starts. In these cases, concurrent validation is
performed against an approved protocol but product is released on a lot-by-lot basis. It
is usually used on an existing product not previously validated or insufficiently
validated.
It is important in these cases, however, that the premises and equipment to be used
have been previously qualified and that the decision to carry out concurrent validation
is made by authorised personnel.
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 for the batch to be
released should be reviewed and approved before product is released for sale or
supply.
11.5.3 Retrospective validation
Retrospective validation is defined as validation of a process for a product already in

distribution, based on accumulated production, testing, and control dates. It is in
essence a summary of existing historical data.
Validation of processes that have not undergone a formally documented validation

process is possible using historical data to provide the necessary documentary
evidence that the process is doing what it is purported 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.
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.
The source of data for this validation may include, but not limited to, batch
documents, process control charts, maintenance log books, records of personnel
changes, process capability studies, finished product data, including trend data, and
storage stability results.
11.5.4 Re-validation
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. Re-validation is to
validate changes in equipment, packaging, formulation, operating procedure, or
process that could impact product safety, quality and efficacy. It is important to
establish a revalidation programme for critical equipment to maintain validity.

11.6 Cleaning validation
 Understand principles of cleaning
 Understand clean limits
 Describe validation of cleaning methods
11.6.1 Principles of cleaning
Cleaning Validation is documented evidence that an approved cleaning procedure will

provide equipment which is suitable for processing of products.
Pharmaceutical products and medical components can be contaminated by other

pharmaceutical products, by cleaning agents, by micro-organisms or by other
materials. In many cases, equipment may be used for processing different products.
To avoid contamination, cleaning procedures must follow established and validated
methods.
11.6.2 Cleaning limits
Normally only cleaning procedures for product contact surfaces of the equipment
need to be validated. Consideration should be given to non-contact parts.
Generally in case of batch-to-batch production of the same product, it is not necessary

to clean after each batch. However, cleaning intervals and methods should be
determined as appropriate.
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".
Typically, 3 consecutive applications of the cleaning procedure should be performed

and shown to be successful in order to prove that the method is validated.
Establishment of Limits
The rationale for selecting limits for product residues should be based on a
consideration of the materials involved. The limits should be practical, achievable and
verifiable.
One cannot ensure that the contaminant will be uniformly distributed throughout the
system. It is also incorrect to assume 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.

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.
11.6.3 Validation of cleaning methods
Personnel
Operators carrying out manual cleaning procedures should be adequately supervised.
Equipment
Dedicated equipment may be necessary for products which are difficult to remove, for
equipment which is difficult to clean, or for products with a high safety risk.
Microbiological Aspects
The existence of conditions favourable to microorganisms and the time of storage
should be considered. 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.
Sampling
Samples should be taken according to the cleaning validation protocol. The choice of
sampling methods should be demonstrated to provide accurate information about the
effectiveness of the cleaning process.
2 methods of sampling considered to be acceptable are direct surface sampling (swab

method) and indirect sampling (use of rinse samples).
a. Direct Surface Sampling

The suitability of the material to be used for sampling and of the sampling medium
should be determined to assure predetermined levels of recovery.
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.
Cleaning agents
If cleaning agents are used, acceptable limits should be defined for residue of the
agent after cleaning.
Analytical Methods
Analytical methods should be validated. Analytical methods used to detect residuals
or contaminants should be appropriate for the substance to be tested and provide a
sensitivity that reflects the level of cleanliness determined to be acceptable.

11.7 Computerised system validation
 Explain general principles of Computer System Validation
 Describe validation plan of Computer System
 Understand hardware and software testing
 Understand system acceptance testing
11.7.1 General principles
cGMP applies to computerized systems/software used for the following purposes:
1. Software used as a component, part, or accessory of a drug;

2. Software used in the production of a drug (e.g., programmable logic
controllers in manufacturing equipment); and
3. Software used in implementation of the drug manufacturer's quality system
(e.g., software that records and maintains the device history record).
The purpose of computerised system validation is to verify the documentation of the

system, and to ensure that the system is performing as per documentation. This
documentation must be appropriate, up to date, relevant, and complete.
Is software purchased off-the-shelf required to be validated?
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.
11.7.2 Validation plan
The installation qualification should include the verification that user manuals,
technical manuals, and instrument calibration reports of the computerized system are
available, complete, appropriate, relevant and up to date.
The validation document shall include a paragraph stating the objective of the
document and a paragraph specifying the scope of the document, i.e. the exhaustive
list of the concerned equipment, or categories of equipment. The document should
include:
1. An abbreviated description of the computerized system analysed.
2. For protocols, the pre-approval of the document.
3. For IQ reports, the certification of the document.
4. For IQ reports, a summary of the deviations observed during the installation
qualification.

11.7.3 Hardware and software testing
The general system characteristics shall be reported, including:

- manufacturer, main contractor, customer
- intended purpose
- system identification (serial number, inventory number etc)
- system location
- technical characteristics
- main system limits
- required utilities
The hardware of the system shall be reported, including:

- summary block diagram
- list of main components, processors and modules, memories, storage, signal
converters, networking, communications, and peripherals, including model
and serial numbers when applicable
- list of all fuses (type, rated current, location, protected items)
- operating controls and alarms
- central commands and overrides
- manual controls
The software of the system shall be reported, including:

- software identification (name, version etc)
- operating system (name, version etc)
- source code availability
- language and tools used
11.7.4 System acceptance testing
The purpose is to describe the as-built installation and to compare the findings with
system specifications. Components of the system are compared with those specified.
Any detected discrepancy is mentioned for investigation, correction, justification and
approval. When components found are neither specified nor approved, they will be
mentioned as not specified.
Structural testing
The structural testing section of the installation qualification consists of verifying the
internal integrity of the equipment software and hardware and should be done
separately for each.
Hardware structural testing

This testing consists of a range of verifications pertaining to the hardware of the
equipment. Tests include:
- cabling and wiring
- labelling of wires and components
- grounding of the system
- hardware testing performed by the supplier (normal and stress testing)
- electromagnetic interference compatibility
Software structural testing

This testing consists of assessing the quality of the development process, the produced
code, and the testing process.
The quality of the development process could be verified by auditing the supplier’s
internal development process. The aspects analysed cover:
- specification methodology
- diagramming techniques used
- design verification
- existence and adherence to production SOPs
- enforced naming conventions
The quality of the supplier testing process is verified by auditing the supplier’s
internal testing process. The aspects analysed cover:
1. testing methodology, including stress testing
2. existence of and adherence to testing SOPs
3. testing reports
OQ of computerized equipment
The OQ of computerized systems consist of a group of tests, pooled in functional
checks. The tests are carried out step by step on each component. The input and
output data transmissions at intermediate points are studied.
The OQ document should include the following summary:

- an abbreviated description of the computerized system analysed
- for protocols, the pre-approval of the document
- for OQ reports, the certification of the document
- for OQ reports, a summary of the deviation observed during the OQ
a) Reporting the initial setpoint

Each user-accessible setpoint of the control system will be reported. Results shall be
written in a report. Reporting the initial setpoints enables definition of the
characteristics of the system as it is during qualification and will evidence any
subsequent modifications of the setpoint.
b) Checking the digital/analog transmission: input

Qualification tests shall be carried out in order to check the transmission of
information sent by sensors to the computerized control system, or programmable
logic controller. Each sensor tested is activated or deactivated a few times to visualize
clearly the transmission.
c) Checking the digital/analog transmission: output

The qualification tests consist of checking the transmission of the information sent by
the controller to the contactors, relays, and other digital outputs of the system.
d) Data entry and boundary testing

Tests shall be performed to check the data entry functions and the proper rejection of
out-of-boundaries values. The tests are conducted on critical data entry fields only.
e) Access control testing

Tests shall be performed to check the computer system access control functions,
including access level differentiation. The tests are conducted on critical functions
only. Each tested function is verified against each access level.
Performance qualification computerized equipment

A specific PQ protocol shall be prepared for each piece of equipment undergoing PQ.
The PQ of the computerized equipment consists of accumulating enough evidence
that the computerized system is in compliance with its intended specifications, when
functioning for the concerned process at the production premises.
The PQ shall include the following checks:

a) SOP – the purpose is to verify the SOP at the user’s premises. The procedures
analysed include:
- installation operation SOPs
- installation preventive maintenance SOPs, including virus checks
- installation corrective maintenance SOPs
- change control SOPs
- SOPs for audit and on-going evaluation
b) Training – the purpose is to check that all people involved with the computerized
equipment have received adequate training on operation of the computerized
equipment. The key aspects of the evaluation include checking:
- existence of training programmes for users
- contents of training
- employee training history
c) System recovery procedures – the purpose is to verify the system recovery

procedures. The procedures analysed include:
- periodic backup and archival SOPs
- data restoring SOPs
- programme restoring SOPs
- disaster recovery SOPs
d) Computerized system environment – to qualify the computerized system

environment. The key aspects analysed include:
- quality of the electric power supplied to the equipment
- efficiency of uninterruptible power supply (UPS)
- general environment – temperature, humidity, dust etc.
e) Checking process control and regulation loops – check the efficiency of process
control and regulation loops critical to the process.
f) Checking alarms and safeties –each alarm or safety checked is activated between
one and three times.

TOPIC 12 Non-Compliance and Complaints
12.1 Non-compliance
 Describe types of non-compliance
 Understand consequences of non-compliance
12.1.1 Types of non-compliance
Common critical non-conformances are:
1. There are no written corrective and preventive action procedures for analyzing
processes, work operations, concessions, quality audit reports, quality records,
technical service records, complaints, returned products, and other sources of
quality data to identify existing and potential causes of nonconforming
product, or other quality problems.
2. There are no established written procedures addressing the design verification

and design validation tasks for original designs or existing design changes.
The existing procedures do not address individual responsibilities, criteria for
validation, and documentation requirements.
3. The firm has not established or implemented a written procedure for

identification and control of design input which should include potential
design inputs relating to intended use, safety, risk analysis, human factors,
reliability, limit and tolerances, voluntary standards and manufacturing
processes.
4. The procedure fails to include requirements for conducting Process

Qualification (PQ) with regard to new equipment. There are no established
procedures detailing when PQ is necessary and/or rationale for not conducting
PQ.
5. The validation of the blocking, lathing and milling operations used in the
manufacture of ..... did not include evaluation of finished product
performance. These operations were validated independently, using different
work orders for the validation of each operation. The validations included only
the results of inspections performed during the specific operation. The firm
has not executed a validation protocol using the same work orders to validate
all the manufacturing steps up to and including final product performance.
6. There is no comprehensive testing plan or testing report which identifies the

testing which has been accomplished to demonstrate software is fit for use.
There is no document which provides traceability from the various
specifications, (functional and system requirements, and detailed designs);
documents to associated test cases which assure an intended level of coverage,
(e.g., functional, logical, structural) has not been achieved.
NON-COMPLIANCE AND COMPLAINTS 12-1 Last Date updated: 10 June 2004

7. Failure investigations are inadequate as follows: the root cause of device
failure to meet specifications is not always investigated, technical conclusions
do not describe the root cause of component or device failures; where device
failures have been identified, failure analysis reports do not always document
or reference corrective action; explanations for significant intervals in the
completion of analysis are not provided; unanticipated or nonconforming
results are not always explained; each clinical complaint recorded on return
documentation is not always investigated or additional investigation results are
lacking.
Ten very common GMP violations are:

1. Inadequate and poor procedures for cleaning operations.
2. Maintenance Procedures either non-existent or poorly performed.
3. Equipment either not calibrated or poorly calibrated.
4. Poor documentation for the use of equipment.
5. No stability testing.
6. Protocols for Validation and Qualification not developed.
7. Batch Records Imprecise and Contradictory.
8. Personnel in Laboratory not qualified.
9. SOPs not followed, SOPs not updated.
483
483 Citations
Citations Reported
Reported by
by June
June 1998
1998
Raw
Specifications Mat’ls Cleaning
3% 1%
6% Equip/Facilities 8%
Computers 13% Documentation 1%
Testing <1% Monitoring 19%
Analytical
Methods 3% Training 2%
Failure Record
Investigations 13% Keeping 5%
SOPs 6%
Validation 17% Stability
3%
GMP Presentation 2003 Nanyang Polytechnic
12.1.2 Consequences of non-compliance
The regulatory agency in each country is responsible for administering legislation

relating to medical devices and for ensuring the safety and quality of pharmaceutical
products.
The agencies have a duty to enforce this legislation. This involves establishing that
the cGMP Regulations have been complied with and ensuring that the appropriate
action is taken wherever necessary to prohibit or restrict unsafe products being placed
on the market.

The regulatory agency will investigate any complaints. The investigations will
normally be initiated and resolved in writing by requesting technical and other
information for documentary review. Inspection visits will generally only be
undertaken where the documentation available indicates it is merited to confirm
compliance, or where technical documentation can only be properly reviewed on site,
as for custom-made devices. Immediate enforcement action may be required in some
instances, to protect public health.
Inspection Visits
The regulatory agency has no legal obligation to give prior notice to undertake an
inspection visit. However, manufacturers will normally be informed 14 days before
the date of the proposed visit. One of the aims of the visit is to confirm that the
essential requirements are being complied with in practice. There will therefore, be no
need to disrupt the manufacturing process.
The regulatory officers have the right at any reasonable hour to:
1. Enter premises and inspect goods, other than premises occupied only as a
person's residence.
2. Examine manufacturing procedures and testing arrangements.
3. Require the production of any records for examination and to take copies
of, or copies of any entry in, the records.
4. Seize and/or detain suspect records and/or goods which may be required as
evidence in proceedings for an offence in respect of a contravention.
Enforcement Action
Enforcement action that could be taken includes:

1. Prohibition Notices. These prohibit the supply of any goods that are considered to
be unsafe or are not in compliance with Regulations.
2. Notices to Warn. These require a manufacturer to issue at its own expense a
warning about any relevant goods that are considered unsafe.
3. Suspension Notices. These suspend the supply of any goods for a period of up to
six months, where it is suspected that a safety provision has been contravened.
4. Restriction Notice. Restrict the availability of a particular drug, or drugs of a
particular class or description, in order to protect the health or safety of any
individual or individuals of any class or description, they may serve on any person
a Restriction Notice.
5. Forfeiture Orders. Enforcement authorities may apply for an order for the
forfeiture of goods where there has been a contravention of a safety provision.
12.2 Complaints
 Describe procedure for handling complaints
 Describe the maintenance of complaint files
 Product recalls

12.2.1 Procedure for handling complaints
All complaints and other information concerning potentially defective products must
be carefully reviewed according to written procedures.
A person responsible for handling the complaints and deciding the measures to be
taken should be designated, together with sufficient supporting staff to assist him or
her.
There should be written procedures describing the action to be taken, including the
need to consider a recall, in the case of a complaint concerning a possible product
defect.
Any complaint concerning a product defect should be recorded with all the original
details and thoroughly investigated. The person responsible for quality control should
normally be involved in the study of such problems.
If product defect is discovered or suspected in a batch, consideration should be given

to whether other batches should be checked in order to determine whether they are
also affected. In particular, other batches that may contain reprocessed product from
the defective batch should be investigated.
Where necessary, appropriate follow-up action, possibly including product recall,

should be taken after investigation and evaluation of the complaint.
12.2.2 Maintenance of complaint files
(a) Written procedures describing the handling of all written and

oral complaints regarding a drug product shall be established and
followed. Such procedures shall include provisions for review by the
quality control unit, of any complaint involving the possible failure of
a drug product to meet any of its specifications and, for such drug
products, a determination as to the need for an investigation. Such procedures shall
include provisions for review to determine whether the complaint represents a serious
and unexpected adverse drug experience which is required to be reported to
the Regulatory Authority.
(b) A written record of each complaint shall be maintained in a file

designated for drug product complaints. The file regarding such drug
product complaints shall be maintained at the establishment where the
drug product involved was manufactured, processed, or packed, or such
file may be maintained at another facility if the written records in
such files are readily available for inspection at that other facility.
Written records involving a drug product shall be maintained until at
least 1 year after the expiration date of the drug product, or 1 year
after the date that the complaint was received, whichever is longer. In
the case of certain OTC drug products lacking expiration dating because
they meet the criteria for exemption, such written
records shall be maintained for 3 years after distribution of the drug

product.
(c) The written record shall include the following information,

where known: the name and strength of the drug product, lot number, name
of complainant, nature of complaint, and reply to complainant.
(d) Where an investigation is conducted, the

written record shall include the findings of the investigation and
follow-up. The record or copy of the record of the investigation shall be
maintained at the establishment where the investigation occurred.
(e) Where an investigation is not conducted, the

written record shall include the reason that an investigation was found
not to be necessary and the name of the responsible person making such a
determination.
12.2.3 Product recalls
There should be a system to recall from the market, promptly and effectively,
products known or suspected to be defective.
A person responsible for the execution and coordination of recalls should be

designated, as well as sufficient staff to handle all aspects of the recalls with the
appropriate degree of urgency. This person should normally be independent of the
sales and marketing organization.
There should be established written procedures, regularly checked and updated, for
the organization of any recall activity. Recall operations should be capable of being
initiated promptly at least down to the level of the hospital or pharmacy.
All competent authorities of all countries to which a given product may have been
distributed should be promptly informed of any intention to recall the product because
it is, or is suspected of being, defective.
The progress of the recall process should be recorded and a final report issued,
including reconciliation between the delivered and recovered quantities of the
products.
The effectiveness of the arrangements for recalls should be evaluated from time to
time.
An instruction should be included to store recalled products in a secure segregated

area while their fate is decided.

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Good Manufacturing Practice

Course : Diploma in Chemical & Pharmaceutical Technology (CLDF02)

Module Title : Good Manufacturing Practice

Module Code : CLC326/CLB216

HISTORY OF GMP Last Date updated: 10 June 2004

TOPIC 1 History of GMP

GMP is the short form for Good Manufacturing Practice.

Good Manufacturing Practice can be defined as:

What does the “c” stand for?

1.1.2 GMP variations

- The approach taken by different regulatory authorities varies.

HISTORY OF GMP 1-1 Last Date updated: 10 June 2004

Harmonisation of cGMP requirements

The Pharmaceutical Inspection Cooperation Scheme (PIC/S) was established in 1995.

The main functions of PIC/S are:

1. to exchange information and experience on GMP (Good

1.1.3 What does GMP look at?

GMP encompasses all manufacturing. In general, GMP looks at the following

HISTORY OF GMP Last Date updated: 10 June 2004

Why is it important to have GMP?

1.1.5 Definitions of Commonly Used Terms

1. Batch means a specific quantity of a drug or other material that

2. Component means any ingredient intended for use in the

3. Drug product means a finished dosage form, for example,

4. Fiber means any particulate contaminant with a length at least

5. Non-fiber-releasing filter means any filter, which after any

6. Active ingredient means any component that is intended to

HISTORY OF GMP Last Date updated: 10 June 2004

7. Inactive ingredient means any component other than an active

8. In-process material means any material fabricated,

9. Lot means a batch, or a specific identified portion of a batch,

10. Lot number, control number, or batch number means any

11. Manufacture, processing, packing, or holding of a drug

12. Quality control unit means any person or organizational

13. Strength means:

14. Theoretical yield means the quantity that would be produced at

15. Actual yield means the quantity that is actually produced at

HISTORY OF GMP Last Date updated: 10 June 2004

18. Representative sample means a sample that consists of a

19. Gang-printed labeling means labeling derived from a sheet of

1.2 History of GMP

1.2.1 History of GMP regulations

In 1976, the US FDA published its proposed cGMPs regulations.

Various revisions to GMP have followed since.

HISTORY OF GMP Last Date updated: 10 June 2004

1.2.2 Impact of GMP requirements on Manufacturing Activities

What are some of these procedures that companies have to follow?

HISTORY OF GMP Last Date updated: 10 June 2004

1.2.4 Understanding the legal principles of GMP

Pharmaceutical manufacturing is a highly regulated industry with a universal legal

Thus, compliance with GMP is a regulatory and legal requirement.

1. Working with the manufacturer to correct the problem

HISTORY OF GMP Last Date updated: 10 June 2004

TOPIC 2 International GMP requirements

2.1 The regulatory bodies and their roles

The regulatory authorities include:

What do the regulatory agencies actually do?

1. New Product Review

INTERNATIONAL GMP REQUIREMENTS 2-1 Last Date updated: 20 Mar 2004

3. Safe manufacturing and handling

4. Monitor for new risks

5. Standards and Regulations

2.1.1 Food and Drug Administration, USA