GMP Inspection East Africa PDF

DOCUMENT NO: EAC/TF-MED/GMP/FD/COM/N1R0
COMPENDIUM OF GOOD MANUFACTURING PRACTICES (GMP)

TECHNICAL DOCUMENTS FOR HARMONIZATION OF
MEDICINES REGULATION IN THE EAST AFRICAN COMMUNITY
VERSION SEPTEMBER 2014

DOCUMENTS DEVELOPMENT HISTORY
STEPS DATE
Development of draft harmonized technical 30th July 2012 to 28th June 2013
documents for Good Manufacturing Practices
(GMP) for the East African Community
Medicines Regulatory Harmonization Initiative
Draft harmonized technical documents 3rd September 2013
approved by the Steering Committee
Release of draft harmonized technical 9th September 2013
documents for Public Consultation
End of National Consultation 28th February 2014
(deadline for comments)
Incorporation of national stakeholders inputs 13th to 17th January 2014
by EAC Secretariat in collaboration with EAC
Partner States
Release of revised technical documents for 20th January 2014
regional and international consultation
Draft technical documents reviewed and 12th March 2014
adopted by EAC Technical Working Group on
Medicines and Food Safety
Draft technical documents adopted by the 14th March 2014
18th EAC Sectoral Committee on Health
Draft technical documents finalized by 1st to 4th April 2014
EAC Secretariat in collaboration with
EAC Partner States
Final technical documents approved by the 17th April 2014
9th EAC Sectoral Council on Health
Date for coming into effect 17th April 2014
i
AUTHORS/CONTRIBUTORS Shabani Sifuma

GMP Inspector
Kate Kikule Pharmacy and Poisons Board
Head, Drug Inspectorate Services Nairobi, Kenya
National Drug Authority
Kampala, Uganda Sichei Cheworei
Head, Policy and Planning Unit
Mwesigwa Denis William Nairobi, Kenya
Senior Inspector of Drugs
National Drug Authority Sarah Chesaro
Kampala, Uganda Assistant Chief Pharmacist
Pharmacy and Poisons Board
David Nahamya Nairobi, Kenya
Senior Inspector of Drugs
National Drug Authority Mwesigye John Patrick
Coordinator PTF
Apollo Angole Ministry of Health
National Medicines Regulation Officer Kigali, Rwanda
Kampala, UGANDA Joseph Kabatende
Head of Inspectorate/ Pharmacies
Conrad Mark Mbabazi Ministry of Health
Inspector of Drugs Kigali, Rwanda
Kampala, Uganda Gladys Akimana
Pharmacovigilance Officer
Mpawenimana Servilien Ministry of Health
Head of Production and Laboratories Kigali, Rwanda
Directorate of Pharmacies, Medicines and
Laboratories Alex Gisagara
Bujumbura, Burundi National Medicines Regulatory Officer
Ministry of Health/Rwanda
Nyabenda Bonaventure Kigali, Rwanda
National Medicines Regulation Officer
Directorate of Pharmacies, Medicines and Adonis Bitegeko
Laboratories Senior Drug Inspector- GMP
Bujumbura, Burundi Tanzania Food and Drug Authority
Dar es Salaam, Tanzania
Jacinta N. Wasike
Director Pharmaceutical Manufacturing Kissa W. Mwamwitwa
Services Senior Drug Inspector
Pharmacy and Poisons Board Tanzania Food and Drug Authority
Nairobi, Kenya Dar es Salaam, Tanzania
ii
David Robert Matle Daniel Murenzi

National Medicines Regulation Officer e-Health and Informatics Officer
Tanzania Food and Drugs Authority EAC Secretariat
Dar es Salaam, Tanzania
EAC-MRH PROJECT STEERING
Mohammed Omar Mohammed COMMITTEE AND OTHER MEMBERS
Chief Drug Inspector
Zanzibar Food and Drug Board Kipkerich C. Koskei
Zanzibar, Tanzania Registrar / Chief Pharmacist
Zahran Ali Hamad Nairobi, Kenya
Senior Drug Inspector
Zanzibar Food and Drug Board Fred Moin Siyoi
Zanzibar, Tanzania Deputy Registrar
Hidaya Juma Hamad Nairobi, Kenya
National Medicines Regulation Officer
Zanzibar Food and Drug Board (ZFDB) Hiiti B. Sillo
Zanzibar, Tanzania Director General
Tanzania Food and Drugs Authority (TFDA)
Prat Alain Dar es Salaam, Tanzania
Technical Officer
World Health Organization Burhani Othman Simai
Switzerland Registrar
Zanzibar Food and Drugs Board
Jane Mashingia Zanzibar, Tanzania
Senior Health Officer
EAC Secretariat Joseph Kabatende
Head of Inspectorate/Pharmacy
EDITORIAL TEAM Ministry of Health
Kigali, Rwanda
Apollo Angole
National Medicines Regulation Officer Akimana Gladys
Kampala, Uganda Pharmacovigilance Officer
Ministry of Health
Mwesigye John Patrick Kigali, Rwanda
EAC-MRH-Coordinator Habib Ali Shariff
EAC Secretariat Chief Pharmacist
Ministry of Health
Jane Mashingia Zanzibar, Tanzania
EAC Secretariat
iii
William Reuben Mendy Caroline

Ag. Chief Pharmacist Manager Regulatory, IFPMA
Ministry of Health and social welfare Chemin Lovis Dunant 15
Dar es Salaam, Tanzania 1202 Geneva Switzerland
Gordon KatendeSematiko Dr. Samuel Azatyan

Executive Secretary/Registrar, Programme Manager, Medicines Regulatory
National Drug Authority, Kampala, Uganda Support
World Health Organization, Switzerland
Oteba Olowo Martin Avenue Appia 20, 1211, Switzerland
Assistant Commissioner, Pharmacy
Ministry of Health, Kampala, Uganda Hetzke Juorg
WHO Technical Advisor
Bamenyekanye Emmanuel World Health Organization
Director DPML/MOH Switzerland
Ministry of Health, Bujumbura, Burundi Avenue Appia20, 1211
Geneva, Switzerland
Ramana NV Gandham
Lead Health Specialist Prof. Aggrey Ambali
The World Bank Advisor and Head
Upper Hill Nairobi NEPAD Agency, South Africa
Andreas Seiter Margareth Ndomondo Sigonda

World Bank Pharmaceutical Coordinator
1818H Street NW, G7-701 AU – NEPAD Agency
Washington DC 20043 Midrand, South Africa
South Africa
Apollo. Edson Muhairwe
Senior Operations Officer Mrs. Chimwemwe Chamdimba
World Bank Senior Program Officer
P.O. Box 4463, NEPAD Agency.
Kampala, Uganda
Dr.Vincent Ahonkhai Mr. Paul K. Tanui
Bill and Melinda Gates Foundation, USA Senior Program Officer
NEPAD Agency.
Dr. Stanley Sonoiya P. O BOX 1627
Principal Health Officer (PHO) South Africa.
EAC Secretariat
P.O. Box 1096, Arusha-Tanzania Janet Okero
Senior Programme Officer
Dr. Kamamia Wa Murichu AU – NEPAD Agency
Chairman Kenya Pharmaceutical Distributors Private Bag 218, Halfway Hse
Association Midrand, 1685
P.O. Box 1088-10200 South Africa
Nairobi, Kenya
iv
FOREWORD
This Compendium has been developed to In addition it is also extremely important

provide guidance to National Medicines to recognize the contribution of Clinton
Regulatory Authorities in managing the Health Access Initiative (CHAI) in the
inspection programs for Good Manufacturing conceptualization stage of African Medicines
Practices (GMP) of pharmaceutical Regulatory Harmonization initiative.
manufacturing facilities.
I wish to also thank the EAC Secretariat staff
It was compiled by the East African for their dedicated work and coordination of
Community (EAC) Technical Working the EAC Medicines Regulatory Harmonization
Group (TWG) on GMP. The team relied (MRH) Programme implementation. The
on their experiences and knowledge on oversight role of the EAC MRH Steering
pharmaceutical manufacturing including GMP Committee is also acknowledged.
requirements of their individual Countries,
World Health Organization (WHO) and Finally, I would like to acknowledge regional
Pharmaceutical Inspection Cooperation stakeholders including the respective
Scheme (PIC/S) and other available literature. Ministries responsible for the EAC Affairs and
Health, the EAC pharmaceutical industry and
EAC Secretariat is highly indebted to African associations and the academia for their inputs
Medicines Regulatory Harmonization (AMRH) in this Compendium.
program partners, namely WHO for their
technical support; the World Bank, Bill and
Melinda Gates Foundation (BMGF), the
United Kingdom Department for International
Development (DFID) for their financial
assistance and African Union New Partnership
for Africa’s Development (AU-NEPAD) for high
level advocacy.
Ambassador Dr. Richard Sezibera

Secretary General
EAC Secretariat
v
PREFACE
This Compendium has been prepared to In addition, the Compendium outlines

enable effective implementation of Good procedures to be followed when preparing
Manufacturing Practices (GMP) inspection and planning for joint inspection, reporting
activities under the EAC Regulation requirements including format and
Harmonization Programme. The Compendium classification system adopted for non-
will guide GMP inspectors in preparing for compliances observed during GMP inspection.
and performing GMP inspection activities of
Active Pharmaceutical Ingredients (APIs) and It is also expected that the Compendium
Finished Pharmaceutical Products (FPP). It shall help inspectors to conduct GMP
will serve as one-stop reference on GMP. inspection with integrity and diligence. The
Code of Ethics and Conduct for Inspectors
The Compendium highlights general and confidentiality agreement for performance
conditions and other pertinent requirements have also been outlined with the objective
that are necessary for carrying out GMP to remind inspectors on their ethical and
inspections. It is divided into various moral obligations when engaged in GMP
sections describing the types of inspections, inspection activities.
qualifications, training and experience required
for inspectors as well as code of ethics and Adherence to requirements outlined in
conduct to be observed by inspectors when this Compendium and the referenced
engaged in inspection activities. complementary technical documents will
enable consistent conduct of GMP inspections
including uniform reporting and consequently
amicable decision making that minimizes
complaints from manufacturers. It is therefore
anticipated that the GMP inspectors shall read
this Compendium and diligently apply what
has been documented.
Hon. Jesca Eriyo

Deputy Secretary General for Productive and
Social Sectors
EAC Secretariat
vi
RESPONSIBILITY FOR IMPLEMENTATION AND LEGAL FRAMEWORK
The EAC Treaty Article 118, Chapter 21 on regional cooperation on health provides for harmonization
of medicines regulation among the EAC Partner States. Therefore, this Compendium will be
implemented by National Medicines Regulatory Authorities (NMRAs) in accordance with the
relevant policies, laws, cooperation, guidelines, manuals and procedures existing at national and
regional level.
The 9th EAC Sectoral Council of Ministers of Health has officially approved the operationalization
of this Compendium among the East African Community Partner States’ National Medicines
Regulatory Authorities (NMRAs).
Signed on this ………. Day of ………..2014 by the Honourable Ministers responsible for East
African Community Affairs as here-in:
........................ ........................ ........................ ........................ ........................

Amb. Amina Dr. Abdallah O. Hon. Léontine Hon. Valentine Hon. Shem
C. Mohamed, Kigoda Nzeyimana Rugwabiza Bageine, MP
CBS, CAV
Cabinet Minister of Minister to Minister for Minister of

Secretary: Industry and the Office of East African State Ministry
Ministry of Trade the President Community of East African
Foreign Affairs Responsible for Community
& International EAC Affairs Affairs
Trade 
REPUBLIC OF UNITED REPUBLIC OF REPUBLIC OF REPUBLIC OF

KENYA REPUBLIC OF BURUNDI RWANDA UGANDA
TANZANIA
vii
TABLE OF CONTENTS
AUTHORS/CONTRIBUTORS
FOREWORD
PREFACE

PART ONE: INSPECTION MANUAL FOR GOOD MANUFACTURING PRACTICE
1. ABBREVIATIONS AND ACRONYMS
2. GLOSSARY
3. INTRODUCTION
4. SCOPE
5. TYPES OF INSPECTIONS
5.1. Routine inspection
5.2. Concise inspection
5.3. Follow-up inspection
5.4. Special inspection
6. Frequency of inspections
6.1. LOCAL PHARMACEUTICAL MANUFACTURERS
6.2. FOREIGN PHARMACEUTICAL MANUFACTURERS
7. Planning for GMP Inspections
8. Preparation for GMP inspection
9. JOINT GMP INSPECTION
10. QUALIFICATION OF GMP INSPECTOR
11. CODE OF ETHICS AND CONDUCT FOR GMP INSPECTORS
12. DECLARATION OF CONFLICT OF INTERESTS
13. CONDUCTING GMP INSPECTION
14. SAMPLE COLLECTION AND TESTING
15. INSPECTION REPORT
16. Classification of GMP Inspection Observations
17. RECOMMENDED REGULATORY ACTION(S)
18. PRODUCT RECALL
19. Appeal
20. REFERENCES
21. REVISION HISTORY
22. LIST OF COMPLEMENTARY DOCUMENTS

PART TWO: GUIDELINES ON GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS FOR
USE IN EAC
ABBREVIATIONS AND ACRONYMS
GLOSSARY
1. INTRODUCTION
2. SCOPE
CHAPTER 1: QUALITY MANAGEMENT
Principle
Quality assurance
Good manufacturing practices (GMP)
Quality control
Product Quality Review
Quality Risk Management
Sanitation and hygiene
CHAPTER 2: PERSONNEL
Principle
General
Key personnel
Training
01
Personal hygiene
CHAPTER 3: PREMISES
Principle
General
Production Area
Storage areas
Quality control Areas
Ancillary areas
CHAPTER 4: EQUIPMENT
Principle
General
CHAPTER 5: DOCUMENTATION
Principle
General
Labels
Documents required
Specifications and testing procedures
Specifications for starting and packaging materials
Specifications for intermediate and bulk products
Specifications for finished products
Master formulae and Processing instructions
Packaging instructions
Batch processing records
Batch packaging records
Procedures (SOPs) and records
Receipts
Sampling
Testing
Others
CHAPTER 6: GOOD PRACTICES IN PRODUCTION
Principle
General
Prevention of cross-contamination and bacterial contamination in production
Validation
Starting materials
Processing operations: intermediate and bulk products
Packaging materials
Packaging operations
Finished products
Rejected, Recovered Reprocessed and Returned materials
Waste materials
Miscellaneous
CHAPTER 7: GOOD PRACTICES IN QUALITY CONTROL
Principle
General
Documentation
Sampling
Control of starting materials and intermediate, bulk products
Test requirements
In-process control
Finished products
Batch record review
Stability studies
02
Reagents and culture media

Reference standards
CHAPTER 8: CONTRACT PRODUCTION AND ANALYSIS
Principle
General
The contract giver
The contract accepter
The contract
CHAPTER 9: COMPLAINTS HANDLING AND PRODUCT RECALL
Principle:
Product recall:
CHAPTER 10: SELF-INSPECTION, QUALITY AUDITS, SUPPLIER AUDITS AND APPROVALS
6. REFERENCES
7. REVISION HISTORY
8. LIST OF ANNEXES
ANNEX 1: MANUFACTURE OF STERILE MEDICINAL PRODUCTS

Principle
General
Isolator Technology
Blow/Fill/Seal Technology
Terminally Sterilized Products
Aseptic Preparation
Personnel
Premises
Equipment
Sanitation
Processing
Sterilization
Sterilization by Heat
Moist Heat
Dry Heat
Sterilization by Radiation
Sterilization with Ethylene Oxide
Filtration of Medicinal Products Which Cannot Be Sterilized In Their Final Container
Finishing Of Sterile Products
Quality Control
ANNEX 2:MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE

Scope
Principle
Personnel
Premises and Equipment
Animal Quarters and Care
Production
Labeling
Quality Control

ANNEX 3: QUALIFICATION AND VALIDATION
Principle
Planning for validation
Documentation
Qualification
03
Design qualification
Installation qualification
Operational qualification
Performance qualification
Qualification of established (in-use) facilities, systems and equipment
Process validation
Cleaning validation
Change control
Revalidation
Glossary
ANNEX 4: COMPUTERIZED SYSTEMS

Principle
Personnel
Validation
System
ANNEX 5: WATER FOR PHARMACEUTICAL USE

ANNEX 6: HEATING, VENTILATION AND AIR-CONDITIONING SYSTEMS FOR NON-STERILE
PHARMACEUTICAL DOSAGE FORMS

ANNEX 8: QUALITY RISK MANAGEMENT (QRM)

ANNEX 9: ACTIVE PHARMACEUTICAL INGREDIENTS

ANNEX 10: WASTE MANAGEMENT FOR MEDICINAL PRODUCT MANUFACTURERS

ANNEX 11: MODEL PROCEDURE FOR PLANNING FOR GMP INSPECTION
5.1 Selection of Companies to be Inspected
OFFICER ASSIGNED FOR INSPECTION

ANNEX 12: MODEL PROCEDURE FOR PREPARING FOR GMP INSPECTION
7. REVISION HISTORY

ANNEX 13: MODEL PROCEDURE FOR CONDUCTING GMP INSPCTION
2. REVISION HISTORY

ANNEX 14: MODEL PROCEDURE FOR CONDUCTING JOINT GMP INSPECTION
5.1 Generals
5.2 Initiation of a joint inspection
5.3 Decision regarding the performance of a joint inspection
5.4 Planning for the joint inspection
5.5 Preparation for the joint inspection
5.6 Conducting the joint inspection
5.7 Preparation and validation of the final report
5.8 Follow-up of joint inspection
5.9 Dissemination of the final report
9.2 OFFICER ASSIGNED FOR INSPECTION
ANNEX 15:MODEL PROCEDURE FOR COLLECTING AND HANDLING SAMPLE
04
ANNEX 16: MODEL PROCEDURE FOR PREPARING AND REVIEWING GMP INSPECTION REPORT
5.0 PROCEDURES
6.0 RECORD KEEPING
8.0 REVISION HISTORY
9.0 ATTACHMENTS

ANNEX 17: MODEL PROCEDURE FOR RISK CLASSICATION OF GMP DEFECIENCIES

ANNEX 18: MODEL PROCEDURE FOR FOLLOW UP ON NON COMPLIANCES AFTER GMP INSPECTION
8. DOCUMENT REVISION HISTORY AND AUTHORIZATION

ANNEX 19: MODEL PROCEDURE FOR HANDLING PRODUCT RECALL
PART THREE: GUIDELINES FOR PREPARATION OF SITE MASTER FILE FOR PHARMACEUTICAL
MANUFACTURING FACILITIES
2. GLOSSARY
4. SCOPE
5. LAY OUT OF THE SITE MASTER FILE:
6. CONTENT OF SITE MASTER FILE
6.1 GENERAL INFORMATION
6.1.1 Contact information on the manufacturer
6.1.2 Authorized pharmaceutical manufacturing activities of the site
6.1.3 Any other manufacturing activities carried out on the site.
6.2 QUALITY MANAGEMENT
6.2.1 The quality management system of the manufacturer
6.2.1.1 Brief description of the quality management systems run by the company and reference to the
standards used.
6.2.1.2 Responsibilities related to the maintaining of the quality system including senior
management
6.2.1.3 Information on activities for which the site is accredited and certified, including dates and contents of
accreditations, and names of accrediting bodies.
6.2.2 Release procedure of finished products
6.3 MANAGEMENT OF SUPPLIERS AND CONTRACTORS
6.4 PRODUCT QUALITY REVIEWS
6.4.2 Brief description of methodologies used.
6.5 PERSONNEL
6.5.2 Qualifications, experience, and responsibilities of technical personnel should be included
as Annex 5.
6.5.3 Outline of arrangements for basic and in-service training and how records are maintained.
6.5.5 Personnel hygiene requirements, including clothing.
6.6 PREMISES AND EQUIPMENT
6.6.1 Premises
6.6.1.2 Nature of construction and finishes
6.6.1.6 Brief description of planned preventive maintenance programmes for premises and of the
recording system.
6.6.1.7 Brief description of other relevant utilities, such as steam, compressed air, nitrogen, etc. Schematic
diagrams should be added in annex 9.
6.6.1.8 Availability of written specifications and procedures for cleaning manufacturing areas
6.6.2 Equipment
6.6.2.2 Brief description of the procedures used for cleaning major equipment.
6.6.2.3 Brief description of planned preventive maintenance programmes for equipment and of the
recording system.

05
6.6.2.4 Brief description of the company’s Qualification and calibration policy, including the recording
system. Reference should be made to the Validation master plan.
6.7 DOCUMENTATION
6.7.1 Arrangements for the preparation, revision, distribution and archiving of necessary documentation
for manufacture should be stated.
6.7.2 Brief description of the validation master plan
6.7.3 Brief description of the change control procedure
9.7.4 Any other documentation related to product quality that is not mentioned elsewhere (e.g.,
microbiological controls on air and water).
6.8 PRODUCTION
6.8.1 Type of products
6.8.2 Process validation
6.8.3 Material management and warehousing
6.8.3.2 Arrangements for the handling of rejected materials and products.
6.9 QUALITY CONTROL
6.10 DISTRIBUTION, COMPLAINTS, PRODUCTS DEFECT AND RECALL
6.11 SELF-INSPECTION
6.12 SHELF LIFE / STABILITY DETERMINATION PROGRAM
6.12.1 General policy for the determination of the shelf-life and stability of products manufactured at
the site.
7. REFERENCES:
8. REVISION HISTORY
PART FOUR: GUILDELINES ON TRAINING AND QUALIFICATIONS OF GMP INSPECTORS

GLOSSARY
2. INTRODUCTION
SCOPE
3. GENERAL REQUIREMENTS
4. QUALITIES OF A GMP INSPECTOR
5. EDUCATION AND TRAINING
7.1 QUALIFICATION OF A GMP INSPECTOR
7.2 In-service training
7.3 Continuous training
8. MANAGEMENT CAPABILITIES
9. REPORT WRITING
10. MAINTENANCE OF COMPETENCE AND DISQUALIFICATION
11. INTERNATIONAL AND REGIONAL COLLABORATION
12. REFERENCES
06
PART ONE:
INSPECTION MANUAL FOR GOOD

MANUFACTURING PRACTICE
07

API - Active Pharmaceutical Ingredient
AU-NEPAD - African Union New Partnership for Africa’s Development
EAC - East Africa Community
FPP - Finished Pharmaceutical Product
GMP - Good Manufacturing Practices
MRH - Medicines Regulation Harmonization
NMRA - National Medicines Regulatory Authority
PIC/S - Pharmaceutical Inspection Cooperation Scheme
SOP - Standard Operating Procedure
TWG - Technical Working Group
WHO - World Health Organization
08
2. GLOSSARY Major observation means an observation

describing a situation that may have an impact
The definitions given below apply to the terms on the product but is not as significant as a
used in this guide. They may have different critical observation. It may have an indirect
meanings in other contexts. impact in the strength, identity, purity or safety
of the product. There is reduced usability of
Conflict of interest means any interest in any the product without a probability of causing
business related to medicines declared by harm to the consumer. Observation of a
GMP inspector that may affect or reasonably major deficiency puts a question mark on
perceived to affect the quality or the result of the reliability of the firm’s quality assurance
his/her work or remediation. system.
Critical observation means an observation Minor observation means an observation

describing a situation that will most likely result describing a situation that is a departure
in a non-compliant product or a situation that from GMP but has no significant impact on
may result in an immediate or latent health the product quality. It has low probability of
risk and any observation that involves fraud, affecting the quality or usability of the product.
misrepresentation or falsification of products
or data. Re-qualification implies validation of the
GMP inspector after 24 months absence from
GMP Inspector means a GMP Inspector is conducting GMP inspections to ensure the
an officer appointed by the NMRA of a Partner officer possesses the knowledge and skills to
State in accordance with national regulations carry out GMP inspections
and the provisions of the NMRA to conduct
an inspection or assessment in order to verify Senior GMP Inspector is an officer who
GMP compliance of a manufacturing site on by virtue of experience and competence
behalf of the NMRA. is appointed as such to conduct GMP
inspections and train junior officers in
Lead GMP Inspector is a Senior GMP inspections after evaluation by the NMRA as
Inspector who is charged with the by the criteria outlined in the assessment form.
responsibility for leading a GMP inspection
team to undertake inspection of a specified Specialized GMP Inspector is a GMP
pharmaceutical manufacturing site(s). inspector who possesses specialized
knowledge and experience in conducting
GMP inspections for specialized areas e.g.
Microbiology, HVAC, Biologicals, API, e.t.c.
09
3. INTRODUCTION In order to achieve that goal, EAC GMP

inspectors need to be provided with this
The EAC-MRH Programme was established to Manual which contains sufficient working
improve public health through harmonization tools needed for observing, investigating and
of medicines regulation and all matters reaching conclusions in a particular inspection.
related to improved access to medicines of
acceptable quality, efficacy and safety in the The Manual highlights general conditions
EAC region. and other pertinent requirements that are
necessary for carrying out GMP inspections.
Regulation of medicinal products involves It is divided into various sections which
among other things, inspection of amongst other things outline different types
pharmaceutical plants to verify compliance to of inspections, qualifications, training and
GMP. GMP is that part of quality assurance experience required for inspectors as well as
which ensures that products are consistently code of ethics and conduct to be observed
produced and controlled to meet quality by inspectors when engaged in inspection
standards appropriate for the intended use activities. Moreover, the Manual defines
and as required by marketing authorization. It procedures to be followed when preparing and
is designed to minimize the risks involved in planning for inspection, reporting requirements
any pharmaceutical production that cannot be including format and classification system
eliminated through testing the final product. adopted for non-compliances observed during
GMP inspection.
GMP inspections are conducted as one of
the requirements for registration of medicinal Various working documents are also referred
products in the EAC. Such inspections are to in this Manual to help inspectors to
also conducted for operating as well as comprehend matters related to GMP. It is also
new pharmaceutical plants so as to verify expected that the Manual shall help inspectors
compliance with GMP standards. Inspection to conduct GMP inspection with integrity and
involves review of documents, records, diligence.
facilities and any other resources to assess
their conformity to the requirements of EAC 4. SCOPE
GMP of medicinal products.
The Manual is applicable for all types of GMP
Consistency in conducting GMP inspection inspections for pharmaceutical manufacturing
activities is very important in ensuring quality plants of API and FPP in the EAC Partner
assurance of pharmaceuticals by the NMRA. States NMRAs. This Manual serves as a guide
This results into common decision making by to EAC GMP inspectors in preparing for and
different EAC GMP inspectors at the end of performing GMP inspection activities. It also
inspections and thus avoiding complaints from serves as reference document for inspectors
manufacturers. prior and during GMP inspection.
10
5. TYPES OF INSPECTIONS Collectively, the selected indicators and the

changes identified indicate the manufacturer’s
There are four types of inspection as attitude toward GMP.
indicated below;
A concise inspection is conducted under
a) Routine inspection the following circumstances:
b) Concise inspection
c) Follow-up inspection a) Where a manufacturer has a
d) Special inspection consistent record of compliance with
GMP through routine inspections in
5.1. ROUTINE INSPECTION the past.
b) Where a sample of aspects can be
Routine inspection is a full review of all taken as a good indication of the
aspects and components of GMP within a overall level of compliance with GMP.
facility. Routine inspection is conducted under
the following circumstances: However, if the concise inspection uncovers
evidence that the level of GMP compliance
a) To a newly established has fallen, a more comprehensive or full GMP
manufacturing facility or a inspection should be performed soon after the
manufacturer who has expressed concise inspection. These inspections can be
interest of expanding manufacturing announced or unannounced.
activities e.g. introduction of new
products. 5.3. FOLLOW-UP INSPECTION
b) When there is modification to
manufacturing methods or processes; A follow up inspection is also referred to
or changes in key personnel, as a re-inspection or a reassessment of
premises and/or equipment. the manufacturing facilities. It is performed
c) When GMP certification has specifically to monitor the result of corrective
expired. actions of the manufacturer following a
previous inspection. Depending on the nature
This type of inspection should be announced. of the defects and the work required, the
follow-up inspection could be carried out
5.2. CONCISE INSPECTION within the agreed timeframe after the previous
inspection.
Concise inspection is the evaluation of limited
aspects relating to GMP compliance within a The follow-up inspection is limited to specified
facility. A limited number of GMP requirements GMP non compliances that have been
are selected by the inspector to serve as observed. A follow up inspection shall be
indicators of the overall GMP compliance by unannounced.
the manufacturer. The inspector also has to
identify and evaluate any significant changes
that could have been introduced by the
manufacturer since the last inspection.
11
5.4. SPECIAL INSPECTION 7. PLANNING FOR GMP

A special inspection is undertaken to do spot
INSPECTIONS
checks which could focus on one product,
The planning for GMP inspection shall be
a group of related products, or specific
as per EAC Procedure for Planning for GMP
operations e.g. mixing, or labeling.
Inspections (EAC/TF-MED/GMP/FD/SOP/
N1R0).
Special inspection is conducted under the
following circumstances:
While planning for GMP inspection, the
following categories of manufacturers
a) When there are complaints about
should be considered;
a specific product that suggest there
may be defects.
a) Facilities located within the
b) When there is a product recall due
EAC Region
to events such as adverse drug
reactions.
All applicants with their own and
c) To gather specific information,
contracted manufacturing sites shall
or to investigate specific operations
be inspected at regular intervals
of the manufacturing processes.
in accordance with the EAC NMRAs
recommendation - at least annually
The inspection shall be unannounced.
for routine GMP inspection.
6. FREQUENCY OF b) Facilities located in foreign

INSPECTIONS countries
The frequency of inspection of local and All facilities located in countries

foreign manufacturers shall be as follows: outside the EAC region shall be
subject to GMP Inspection once
6.1 LOCAL PHARMACEUTICAL every three years unless otherwise
notified. Facilities located in
MANUFACTURERS
countries with stringent NMRAs
shall be subject to a first inspection
Local manufacturers shall be inspected once a
and thereafter may be assessed
year or after 2 years depending on the type of
using document review unless
inspection to be performed.
otherwise required.
6.2 FOREIGN PHARMACEUTICAL
MANUFACTURERS
Foreign manufacturers shall be inspected

once after 3 years. A manufacturer may be
inspected more than once within 3 years,
depending on the type of inspection to be
performed.
12
c) Manufacturers of APIs 10. QUALIFICATION OF GMP

Manufacturers of APIs shall be INSPECTOR
inspected on a risk-based basis.
For the purpose of this Manual, high EAC NMRAs shall appoint inspectors to
risk categories shall include, but not inspect domestic and overseas manufacturing
be limited, to the following: facilities where medicines used in EAC
i. Manufacturers of sterile are manufactured. GMP inspectors should
APIs who do not have have the necessary qualification in order
approval of stringent to effectively take part in inspection of
regulatory authorities. pharmaceutical manufacturing facilities.
ii. Manufacturers of APIs The qualification of GMP inspectors should be
for anti-retroviral, anti- in line with the EAC Guidelines on Training
malarial and anti- and Qualification of GMP Inspectors(EAC/
tuberculosis medicinal TF-MED/GMP/FD/GDL/N3R0).
products who do not have
approval of stringent 11. CODE OF ETHICS
regulatory authorities. AND CONDUCT FOR GMP
iii. Manufacturers of
relatively unstable INSPECTORS
APIs who do not have
approval of stringent The code of ethics and conduct for GMP
regulatory authorities. inspectors should be in line with the EAC
iv. Manufacturers of APIs for Code of Ethics and Conduct for GMP
which market complaints Inspectors (EAC/TF-MED/QMS/FD/POL/
have been received N2R0).
8. PREPARATION FOR GMP 12. DECLARATION OF

INSPECTION CONFLICT OF INTERESTS
The preparation for GMP inspection shall The declaration of conflict of interests should
be as per the EAC Model Procedure for be done as per the EAC Code of Ethics and
Preparation for GMP Inspection (EAC/TF- Conduct for GMP Inspectors (EAC/TF-MED/
MED/GMP/FD/SOP/N2R0). QMS/FD/POL/N2R0).
9. JOINT GMP INSPECTION 13. CONDUCTING GMP

INSPECTION
GMP inspection within the EAC shall be
conducted as per the EAC Model Procedure GMP inspection shall be conducted as per the
on Conducting Joint GMP Inspection (EAC/ EAC Model Procedure for Conducting GMP
TF-MED/GMP/FD/SOP/N4R0). Inspection (EAC/TF-MED/GMP/FD/SOP/
N3R0).
13
14. SAMPLE COLLECTION GMP inspection report shall be written

according to the EAC Model Procedure for
AND TESTING Preparing and Reviewing GMP Inspection
Report (EAC/TF-MED/GMP/FD/SOP/
The inspection may include the collection of N6R0). Sufficient details should be provided
samples for verification of quality parameter as to allow for an independent assessment,
deemed necessary by the inspectors as per comprehension and easy decision making.
the Model Procedure for Sample Collection
and Handling (EAC/TF-MED/GMP/FD/SOP/ Observations made that are considered to be
N5R0). Normally, the sample size should be non-compliance with EAC GMP requirements
sufficient to carry out the test for investigated should be listed and cross referenced. Where
parameter(s). Unless otherwise indicated by observations are included in the report,
the laboratory, samples of the following sizes clear distinction should be made between
may be taken, depending on the dosage form “compliances” and “non-compliances”. Non-
of the product: compliance observations should be classified
as “critical”, “major” and “minor”. These
a) tablets and capsules: 100 units classes are detailed below.
per batch;
b) injections (single component): 20
units per batch; 16. CLASSIFICATION OF GMP
c) injections (combination): 20 units INSPECTION OBSERVATIONS
per batch;
d) oral powders for reconstitution: 10 The intention of this part is to help classify
units per batch; the non-compliances observed during GMP
e) liquid formulations: 5 bottles/units inspection. Overall, the evaluation should
per batch. commensurate with the nature and extent
of the deviations (i.e. severity). Situations
15. INSPECTION REPORT involving fraud, misrepresentation or
falsification of source data or records linked
Inspection report should be written with pharmaceutical manufacturing will result
immediately after completing the inspection. in a non-compliance rating.
The compiled report shall be shared within
the NMRA and members of the EAC GMP Non-compliances should be noted by
TWG within fourteen (14) calendar days upon Inspectors and classified as critical,
completion of inspection. The EAC GMP TWG major and minor (refer to the EAC Model
shall make sure that GMP inspection report is Procedure for Risk Classification of GMP
sent to the inspected facility within thirty (30) Deficiencies(EAC/TF-MED/GMP/FD/SOP/
calendar days after receiving the inspection N7R0).
report.
14
17. RECOMMENDED REGULATORY ACTION(S)

Below is a table showing a set of regulatory actions that can be recommended by inspectors when
making decisions on the outcome of inspections.
S/N Category of non- Regulatory action(s)

compliances
1. Minor • Recommend corrective action
within a given timeframe
• Request for compliance report
2. Major • Issue warning letter

• Recommend corrective action
within a given timeframe
• Recommend temporary
withdrawal or suspension of
marketing authorization
• Request for comprehensive
compliance report
• Follow-up inspection to verify
implementation if necessary
1. Critical • Recommend permanent

withdrawal of marketing
authorization in case of
registered products
• Recommend suspension
of marketing authorization in case
of registered products
• Recommend not to grant
marketing authorization for
new application.
Please refer to the ModelProcedure for Follow Up on Non-Compliances After GMP

Inspection (EAC/TF-MED/GMP/FD/SOP/N7R0).
15
18. PRODUCT RECALL 20. REFERENCES

The product recalls should be conducted a) WHO Prequalification Programme
as per the Model Procedure on Handling documents:
Product Recalls (EAC/TF-MED/GMP/FD/ http://apps.who.int/prequal/
SOP/N9R0). b) The Pharmaceutical Inspection
Convention and Pharmaceutical
19. APPEAL Inspection Co-operation Scheme
( PIC/S) guidance documents on
Any manufacturer may appeal against any inspection: www.picscheme.org
decision of the NMRA. c) EAC Partner State guidelines and
SOPs on GMP inspection
When a manufacturer appeals against a
decision of NMRA, the written submission
by the manufacturer will be evaluated by the
NMRA. The NMRA will then decide whether to
accede to the appeal of the manufacturer after
evaluating the submitted reason (s) appeal.
The NMRA may consider the reason (s) and
motivation for appeal and accept or reject the
appeal according to the national and regional
regulations.
16

Revision Date Author(s) Section(s) Description Approvals
No: revised of change
00 17th April EAC TWG All First approved REF: EAC/
2014 GMP version to be SC...../
Members issued DECISION
17TH APRIL
2014
22. LIST OF COMPLEMENTARY DOCUMENTS
a) Code of Conduct for EAC NMRAs (EAC/TF-MED/QMS/FD/POL/N2R0) in

PART V of the Compendium on Quality Management System (QMS)
b) Guidelines on Good Manufacturing Practice for Medicinal Products for Use in
EAC (EAC/TF-MED/GMP/FD/GDL/N1R0) in PART TWO of the Compendium
on Good Manufacturing Practices (GMP)
c) Guidelines on Preparation of Site Master File for Pharmaceutical
Manufacturing Facilities (EAC/TF-MED/GMP/FD/GDL/N2R0) in PART THREE
of the Compendium on Good Manufacturing Practices (GMP)
d) Guidelines on Training and Qualifications of GMP Inspectors
(EAC/TF-MED/GMP/FD/GDL/N3R0) in PART FOUR of the Compendium on
Good Manufacturing Practices (GMP)
e) Model Procedure for Planning for GMP Inspections
(EAC/TF-MED/GMP/FD/SOP/N1R0) - Annex 1
f) Model Procedure for Preparation for GMP Inspection
g) Model Procedure for Conducting GMP Inspections
h) Model Procedure for Conducting Joint GMP Inspections
i) Model Procedure for Sample Collection and Handling
j) Model Procedure for Preparing and Reviewing of GMP Inspection Reports
k) Model Procedure for Risk Classification of GMP Deficiencies
l) Model Procedure for Follow up on Non-compliances after GMP Inspection
m) Model Procedure for Handling Product Recall
17
18
ANNEX 11: MODEL PROCEDURE FOR PLANNING FOR GMP

INSPECTION
1. PURPOSE 5. PROCEDURES
The purpose of this SOPis to ensure that GMP 5.1 Selection of Companies to
Inspectorates follow a standardized procedure be Inspected
when planning for routine GMP inspections.
This should assist with ensuring a consistent 5.1.1 Selection of facilities to be inspected
approach in conducting inspections. is considered an initial and crucial
step in planning for an inspection.
2. SCOPE
5.1.2 The concerned department shall
The scope of thisSOP applies for planning undertake the selection and ensure
GMP inspections of manufacturers of FPPs that:
and of APIs applied within the EAC Partner
States, including joint GMP inspection. 5.1.2.1 The local technical representative or
manufacturer should have filled in
the details of the inspection on a
3. RESPONSIBILITY form with details of actual site to
be inspected, lines and contact
3.1 Head of NMRAs
details of the responsible persons.
3.2 Head GMP department
5.1.2.2 The local technical representative/
manufacturer will also have to pay
3.3 LeadInspectors
the prescribed fee for the GMP
inspection
3.4 GMPinspectors
5.1.2.3 Selection shall ideally be based on
3.6 Procurement department
first application first inspected basis.
3.7 Human Resource Unit
5.1.3 Without unduly contravening the
provision 5.1.5 above, facilities may
4. DISTRIBUTION LIST be selected based on;
4.1 Head of NMRAs 5.1.3.1 Type of activities/products;

Sterile/Non sterile products,
4.2 Head of GMP departments Biological/biotechnological products,
Packaging or API production
4.3 NMROs
5.1.3.2 Need to expedite an ongoing
4.4 Joint GMP Inspection Coordinators regulatory decision process
4.5 Quality assurance departments 5.1.3.3 Public health/interest; Need to meet

a health emergency in the country
Others
19
5.1.3.4 Prevailing Socio-political 5.2.3 The Head of the GMP Inspectorate

atmosphere department shall appoint the
inspection team and designate the
5.1.3.5 Economic/cost effectiveness of lead inspector with the adequate
conducting the inspections competency as per the inspection to
be undertaken.
5.1.3.6 Weather/climatic
5.3 Out-of-Site Planning for the
5.1.3.7 Availability of inspectors with Inspection
specialized expertise in the team
Once the inspection is allocated to a dully-
5.1.3.8 Level of compliance in the previous constituted inspection team, the GMP Unit
inspection (Type/class of findings shall be responsible for planning for the
in the previous inspection, Criminal/ performance of the inspection as follows:
illegal practices)
5.3.1 Inform the manufacturer(s) through
5.1.3.9 Expiry of compliance certification the respective local agents of
the proposed date(s) for the
5.1.3.10 Type of inspection to be carried out inspection and organize letter for
(refer to Types of inspection). invitation to assist in the preparation
for travel.
5.2 Scheduling of Selected
Companies for Inspection 5.3.2 Ensure that the proposed dates for
the inspections are suitable for
5.2.1 Allocation of dates and durations of members of the inspection team.
inspection shall be made based on;
5.3.3 Appropriately fill Form 1 for the
5.2.1.1 Type of inspection to be performed necessary information that will be
and the purpose of the inspection used to organize the inspection and
or visit. facilitate approval.
5.2.1.2 Anticipated duration of inspection 5.3.4 Verify the objective of the inspection
based on plant size, number of that is to be carried out.
blocks/production lines and activities
5.3.5 Determine what the scope and
5.2.1.3 A combination of all, or some of the depth of the inspection will be to
factors for selection as appropriate. enable to prepare properly for
the inspection.
5.2.2 Scheduling to be carried out within
a period of six months and allocate 5.3.6 Scrutinize the relevant documents
tentative dates and will be checked as indicated in SOP for Preparing
and reviewed regularly within the for inspection.
specified period.
20
5.4 Dossier Submission 5.6 Administration
The dossiers have to be submitted before 5.3.7 Inform the administration to

GMP application and inspection should be organize logistics for inspectors
carried out before issuing the Marketing
authorization. 6.0 REFERENCES
5.5 Re-Inspection WHO PQP SOP; PLANNING FOR AN
INSPECTION
The CAPA and/or previous GMP inspection
reports should be reviewed before planning for
the GMP inspection.
Name NMRA Contact (emails & Tel)
21
1. PARTICULARS OF APPLICANT/LICENSE HOLDER
Name________________________________________________________________
Physical Address_______________________________________________________
Country____________________Telephone__________________________________
Fax________________________E-mail_____________________________________
2. PARTICULARS OF SITE TO BE INSPECTED
Name of site___________________________________________________________
Physical Address (if different from 1. above)

_____________________________________________________________________
Country_____________________Tel_______________________________________
Fax____________________E-mail:________________________________________
Note: Separate application to be filled in for each individual site
3. CONTACT PERSON ON SITE
Name of contact person__________________________________________________
Tel: __________________________________Fax:____________________________
E-mail:_______________________________________________________________
4. AUTHORISED REPRESENTATIVE/AGENT IN THE COUNTRY
Name of Local Technical Representative_____________________________________
Tel: __________________________________________________________________
5. TYPE OF MEDICINES
Type of medicines manufactured (Tick where applicable)
(a)Human (b) Veterinary (c) Both (a) and (b)
6. REGISTRATION OF PRODUCTS
Have you registered any products in the country YES NO
Have you submitted dossier for registration? YES NO
If YES, list the products applicable. (Attach a separate sheet if needed)
………………………………………………………………………….....................................
22
7. PRODUCTION LINES TO BE INSPECTED

DOSAGE FORM Tick where *CATEGORY **ACTIVITIES
applicable
Tablets
Capsules
Injections (SVP)
Injections (LVP)
Oral liquids
Creams/Ointments/lotions
Others (specify)
* Category means any of the following;
Beta lactam, Non-beta lactam, Biologicals, Vaccines, Hormones, Cytotoxic products
** Activity means any of the following:
• Formulation(dispensing, mixing, blending)

• Processing(compression, emulsification etc)
• Packing
• Quality Control
• Warehousing(raw material, finished products)
8 DECLARATION
Commitment from manufacturers to welcome inspectors for inspection any time
I hereby certify that the above information is correct and apply for Good Manufacturing Practice
inspection of the above-named site(s).
Signature of applicant……………………………. Date……………………………

Print Name………………………………………....
Notes:
1. Please submit a copy of the Site Master File (not more than 25 pages) together with
this application (refer to Guideline on preparation of a Site Master File)
2. This application must be submitted together with the appropriate fee to the Head
of NMRA
23
FOR OFFICIAL USE ONLY:
INSPECTION TYPE (Please tick where applicable)
First Inspection Re - inspection after failure

Routine Re - inspection Previous inspection date……………….
Joint Inspection
Other (please specify)……………………………………………………………...
Name of the Officers:
24
ANNEX 12: MODEL PROCEDURE FOR PREPARING FOR GMP

INSPECTION
1. PURPOSE 5.2 Once the inspection is allocated

to the inspection team, the Lead
The purpose of this SOP is to ensure that Inspector is responsible for planning
a standardized procedure is followed by for the performance of the
all inspectors when preparing for routine inspection as follows:
inspections in order to ensure a consistent
approach in conducting inspections. 5.2.1 Inform the relevant people meant
to prepare the relevant documents
2. SCOPE at least 14 days before inspection.
The scope of this SOP applies for preparation 5.2.2 Verify the objective of the inspection
of GMP inspections of manufacturers of FPPs that is to be carried out.
and of APIs applied within the EAC Partner
States, including joint GMP inspection. 5.2.3 Verify whether the inspection will
cover the entire factory or just part
of it.
3. RESPONSIBILITY
5.2.4 Determine what the scope and
3.5 Head of NMRAs depth of the inspection will be to
prepare properly for the inspection.
5.2.5 Scrutinize the product dossiers for
3.7 Lead Inspectors the products manufactured in the
respective manufacturing site.
3.8 GMP inspectors
5.2.6 Decide what products will be
4. DISTRIBUTION LIST covered during the inspection.
4.1 Head of NMRAs 5.2.7 Review assessment reports from

the dossier for individual products
4.2 Head of GMP departments including assessment remarks.
4.3 NMROs 5.2.8 Liaise with relevant departments/

officers for any specific information
4.4 Joint GMP Inspection Coordinators related to the selected;
4.5 Quality assurance departments 5.2.8.1 Pharmacovigilance and post market

surveillance reports.
5. PROCEDURE
5.2.8.2 Product dossiers and any
5.1. Inspectors should properly prepare notification/ Amendments
for inspections, including
familiarization with products, sites, 5.2.8.3 Previous inspection reports/CAPAs,
types of technologies. if available
25
5.2.9 Confirm the amount of time that will 5.2.11 If desired, prepare a checklist of
be required to carry out the points to be verified during the
inspection and plan the date when inspection. Prepare notes for
the inspection will take place. verification in the aide memoire
specific to site to be verified during
A routine inspection for one site the inspection.
can be performed over a period of
at least two to five working days. 5.2.12 Prepare a Tentative Inspection
The length of an inspection is Plan (Annex I) which can be used
determined by a number of as a template that can be modified.
factors, including the type of Indicate in the programme which
inspection to be performed, the sections or departments will be
number of inspectors, the size of the inspected, and when.
company and the purpose of the 5.2.13 Distribute the Plan to the team
inspection or visit. Annex: criteria for members for comments and after
deciding the duration. finalization, to the company
approximately 2 weeks before
5.2.9 Study the Site Master File and the inspection.
make notes to be followed up during
the inspection (e.g. available 5.4 Re-Inspection
equipment, SOPs, records).Study
the layout and design of the facility 5.4.1 During preparation for GMP
to get a better understanding of the inspection, the CAPA and/or
flow of material, personnel and previous GMP inspection reports
processes in the facility. Study some should be reviewed.
of the systems the organization has
in place (e.g. HVAC and Water). 6. REFERENCE
5.2.10 If a current SMF does not exist, WHO PQP SOP 402.1;
request for an updated copy from PREPARING FOR AN INSPECTION
the company.
7. REVISION HISTORY
SOP DATE REASON AUTHORISED

VERSION AUTHORISED FOR CHANGE BY
26
27
Notes:
• Tea and lunch breaks will be taken at suitable times
• The inspection will start at approx. 8.30am and finish at approximately 5pm each day
• At the end of each day if need be a brief meeting will be held to review the findings and
discuss the plan for the next day
28
ANNEX 13: MODEL PROCEDURE FOR CONDUCTING GMP

INSPECTION
1. PURPOSE 5.2. All inspections should be started

with an opening meeting. See form
The purpose of this SOP is to ensure that number EAC/TF-MED/GMP/FD/
all inspectors when performing inspections FOM/N3R0 for guidance on what
follow a standardized procedure and to ensure should be covered during
consistency in performance between different the meeting.
inspectors.
5.3 Confirm the inspection plan to the
2. SCOPE company and refer to the
standard(s) against which the
The scope of this SOP applies to conducting inspection will be done.
GMP inspections for manufacturers of FPPs
and of APIs applied within the EAC Partner 5.4. Circulate the attendance record
States, including joint GMP inspection. form EAC/TF-MED/GMP/FD/FOM/
N4R0 to enable all persons present
to record names, positions in the
3. RESPONSIBILITY company and email address.
3.1 Head of NMRAs 5.5 Conduct the inspection through
assessment of compliance with
3.2 Head GMP department GMP according to the inspection
plan. Adjust the inspection plan
3.3 Lead Inspectors if necessary.
3.4 GMP inspectors 5.6 During routine inspections all
aspects described in the GMP
4. DISTRIBUTION LIST guidelines should be assessed as
far as possible. Emphasis should
4.1 Head of NMRAs be placed on specific areas based
on a risk approach and time
4.2 Head of GMP departments allocated accordingly.
4.3 NMROs 5.7 Verify selected source data

where possible. This is done by
4.4 Joint GMP Inspection requesting documentation, records
Coordinators and raw data. It may be helpful to
make a list of documents requested
4.5 Quality assurance departments to ensure that all requested are
provided and reviewed. See form
5. PROCEDURES EAC/TF-MED/GMP/FD/FOM/N5R0.
5.1 The Inspectors should identify 5.8 Maintain notes during the inspection
themselves at the entrance of the and keep this record for filing on
site before entering the site the company files after completion
of the inspection.
29
5.9 Observations should be discussed observed that may lead to

with the company representatives at possible serious risk to patients, the
the time that they are noted. Lead Inspector should immediately
contact the Head, Regulatory
5.10 In addition provide feedback to body and Head of GMP
the company/laboratory / Inspectorate (as appropriate for
organization on the observations each country) to decide what action
(deficiencies) made during the should be taken. The company
inspection. This should normally be should be so informed.
done at the end of each day. No
deficiencies should be included 6. RECORDKEEPING
in the report if these we’re not
mentioned/ discussed with the 6.1. The inspection plan, meeting
company. attendance record, notes made
during the inspection, any
5.11 At the end of the inspection, arrange checklists used, record of
for a closed meeting between documents requested (if used),
inspectors to discuss the copies of any documents requested
deficiencies in preparation for the during the inspection, should be
closing meeting. filed on the company file after the
inspection report has been prepared
5.12. End the inspection with a and sent to the company. See form
closing meeting where the lead EAC/TF-MED/GMP/FD/FOM/N5R0
inspector should summarize the
findings with the representatives 6.2. All documents mentioned in the
of the company. The importance of section 6.1.should be filed in the
the deficiencies should be company file by the relevant
mentioned. See form EAC/TF-MED/ secretary who arranged
GMP/FD/FOM/N3R0 for guidance the inspection.
on what should be covered during
the meeting.
7. REFERENCE
5.13 At any stage during the inspection,
WHO PQP Sop 403.1; Conducting
if serious deficiencies are
an Inspection
8. REVISION HISTORY
SOP DATE REASON AUTHORISED

VERSION AUTHORISED FOR CHANGE BY
30
9.0 ANNEXES ii. Provide brief feedback on some of

the positive points noted in
Annex1: Guidance points for opening and the inspection
closing meeting
iii. Explain the process and time lines
Annex II: Record of persons present in the for the report and corrective action
opening and closing meeting plan
Annex III: Record of documents requested iv. Explain that the closing meeting
during an inspection (optional) allows providing a summary of the
observations made-and the intention
OPENING MEETING is not to list each observation
Opening the meeting should at least include (Note: You should have
but not limited to the following; discussed the observations made
at the end of each day or at some
i. Introduction of the inspectors point during the inspection. No
surprises in the inspection
ii. Ask the company to introduce report!)
the people present and to make a
brief presentation v. Provide a summary of issues of
concern under different areas such
iii. Explain how the inspection is to be as:
conducted
• Quality Assurance
iv. Scope of the inspection • Documentation
• Personnel
v. Inspection plan • Premises
• Equipment
vi. Discuss Inspection Time Table • Materials
• Cleaning/sanitation/Hygiene
vii. How the feedback will be given e.g. • Production
end of each day • Quality control
• Validation
viii. Which are the standards that will be • Utilities
applied(EAC- GMP)
vi. Mention ,if relevant, whether there
are any critical or major deficiencies
CLOSING MEETING
vii. Ask if the company needs
i. Thank the company for their clarification on any point
cooperation
31
32
33
34
ANNEX 14: MODEL PROCEDURE FOR CONDUCTING JOINT GMP

INSPECTION
1. PURPOSE 3.3 The lead inspector has the

following duties:
The purpose is to outline procedures for
EAC NMRAs participating in joint GMP 3.3.1 Setting a reporting deadline in
inspections program, taking into account agreement with all team members
risk based approaches, building on similar taking into account any specific
GMP standards and mutual confidence and deadlines linked to on-going
agreement between regulatory authorities. submissions/applications
or procedures;
2. SCOPE
3.3.2 Technical preparation of the
The scope of this procedure includes EAC inspection with the inspected facility
joint GMP inspections of manufacturers of representative and in liaison with
FPPs and of APIs, which are of common the other inspectors of the team
interest to two or more EAC NMRAs. I
3.3.3 Establishing a draft inspection plan
t is recommended for both pre- and post- in cooperation with the involved
approval inspections. regulators and arranging for a pre-
inspectional preparation meeting;
3. RESPONSIBILITY 3.3.4 Leading the conduct of the
inspection on site;
3.1 Head of NMRAs to allocate
adequate resources 3.3.5 Communication between the
representative of inspected facility
3.2 Head GMP department: and the inspection team;
3.2.1 Ensuring that administrative or 3.3.6 Facilitate the discussion for all the
enforcement actions at national/ findings/observations jointly agreed
regional level are undertaken as with the inspection team
appropriate e.g. database entry,
issuance/update of certificates/
licenses 4. DISTRIBUTION LIST
3.2.2 Act as a contact person at the 4.1 Head of NMRAs

NMRA and to share any information
relevant to joint EAC NMRAs 4.2 Head of GMP departments
inspections.
4.3 NMROs
3.2.3 Appoints and assigns inspectors,
or lead inspector if required, to a 4.4 Joint GMP Inspection
joint EAC NMRAs inspections Coordinators
4.5 Quality assurance departments
35
5. PROCEDURE EAC NMRAs may contact the

concerned EAC NMRAs to express
5.1 GENERALS interest in a joint inspection. The
request should be submitted in the
5.1.1 For this procedure, general prescribed format, adding in the
principles and terms of reference comments the countries/NMRAs
agreement EAC/TF-MED/GMP/FD/ involved.
FOM/N6R0shall apply as necessary.
5.2.2.1 Requests for participation in the
5.1.2 All the NMRAs within the EAC EAC Partner States joint inspections
identify a Joint inspection should be sent by the requesting
coordination within its ranks applicant to the EAC NMRAs so that
specifically for joint inspection the evaluation of the request can be
coordination purposes; preferably efficiently performed by the NMRAs
head of the GMP Department. and any required documentation
provided. See Clause 2.11 of
5.1.3 For the purpose of collaboration and document number EAC/TF-MED/
communication, a joint inspection GMP/FD/FOM/N6R0
coordination committee should
be created with the Joint GMP 5.2.2.2 Applicants should address one
Inspection coordinators as primary single “Request for joint inspection”
members. letter to the concerned NMRAs.
In this letter, the applicant should
5.2 INITIATION OF A JOINT provide countries of interest
INSPECTION together with details of the product,
manufacturing site, manufacturing
5.2.1 A joint inspection can initiate process, inspection history of
through three mechanisms such as: the manufacturer and all other
information considered relevant.
a) An official request from a See Clause 2.12 of document
manufacturer number EAC/TF-MED/GMP/FD/
FOM/N6R0
b) A joint interest of at least two
EAC NMRAs 5.2.2.3 In addition, the applicant should
explicitly authorize in the request
c) A join procedure in the framework the comprehensive exchange
of a multiple application for between the NMRAs of all
marketing authorization to more information relevant to the subject.
than one EAC NMRAs. See Clause 2.13 of document
number EAC/TF-MED/GMP/FD/
Case a) FOM/N6R0
5.2.2 Companies requiring either pre- or

post-registration/approval
inspections from any two or more
36
Case b) will decide or not to perform a joint

inspection in accordance with the
5.2.3 Alternatively, one NMRA can submit principles and procedures outlined
the interest to its counterparts to below.
organize a joint inspection. If this
suggestion is agreed among two 5.3.3.1 The inspection coordinators will
or more NMRAs, they can seek a together decide who the leading
written “no objection” for a joint inspection authority will be, taking
EAC- GMP Inspections to the into account the following:
companies they share interest on.
For manufacturing sites in the EAC;
Case c) the lead inspector will be the
authority other than the country
5.2.4 Finally, in the framework of multiple where the manufacturing site
applications sent to several EAC is located.
NMRAs, the manufacturer
acknowledges the possibility to be For manufacturing sites outside the
inspected by a joint team of EAC EAC: the lead inspector will be
inspectors. The applicant should allocated on a case-by-case
explicitly authorize in the application basis taking into account: the
the comprehensive exchange expertise and competencies, the
between the NMRAs of all inspection history of the site and the
information relevant to the subject. number of concerned finished
pharmaceutical products or active
5.3 DECISION REGARDING THE ingredients in each country. Keeping
PERFORMANCE OF A JOINT a good balance between the various
INSPECTION NMRAs.
5.3.1 The GMP NMRAs Joint Inspection 5.3.4 In case of a request, the decision
coordinators shall share information made is forwarded to the
on manufacturing sites that have manufacturer. If the contacted or
expressed interest in participating in concerned agencies agree to
a joint EAC inspection. conduct a joint inspection, the
applicant should receive an
5.3.2 The GMP Inspection coordinators electronic mail message
shall set up a communication acknowledging such agreement.
platform (e.g teleconference, email, The message should state the
skype call) to agree that a joint EAC primary contact person at each
inspection is warranted, determine agency for the specific inspection.
timelines and identify the inspection See Clause 2.17 of document
team and lead inspector. number EAC/TF-MED/GMP/FD/
FOM/N6R0
5.3.3 Based on the information/response
received and the common areas
of interest, the concerned authorities
37
5.3.5 In the other cases, the letter sent in 5.5.1.4 At least one meeting (VC, Skype,
advance of the inspection will inform Google hangout, etc) should
officially of the joint inspection. be organized by the lead inspector
for discussing the preparation
5.4 PLANNING FOR THE JOINT Works of the joint inspection, which
INSPECTION includes verification of the
scope, the inspection plan,
5.4.1 The joint inspection planned should composition of the team and
be integrated in the planning of allocation of responsibilities.
each NMRAs.
5.6 CONDUCTING THE JOINT
5.4.2 The plan of jointed inspection INSPECTION
is updated by a chair of the
coordination committee. 5.6.1 The joint inspection should be
conducted following the “EAC SOP
5.5 PREPARATION FOR THE JOINT for Conducting GMP Inspection”
INSPECTION with the following particulars;
5.5.1 The joint inspection should 5.6.2 Inspection findings should be

be prepared following the “EAC jointly agreed on site as is with
SOP for Preparation of GMP the EAC requirements. Where
Inspection” with the following applicable, according to the
particulars; procedures of the EAC NMRAs,
the inspection team shall provide
5.5.1.1 The Manufacturer or its the representative of inspected
representatives (e.g. Marketing facility a written list of deficiencies
Authorization/product registration at the conclusion of the inspection
Applicant) provides a name and in a prescribed format. If agreement
contact address and available is not reached at this step see 5.7.
information on the manufacturing
site to be inspected in a prescribed 5.7 PREPARATION AND VALIDATION
format (EAC/TF-MED/GMP/FD/ OF THE FINAL REPORT
FOM/N7R0).The information which
have to be provided are mentioned 5.7.1 The joint inspection report should
in the relevant standard operating be prepared following the “EAC
procedure. SOP for Preparing and Reviewing
GMP Inspection Report” with the
5.5.1.2 The lead inspector should be following particulars;
the contact person for each
particular joint inspection. 5.7.2 The participating NMRAs should
agree in advance establish a
5.5.1.3 Each NMRAs will be in charge of common list of deficiencies and
the logistics arrangements of to write a joint report. If any
its inspectors. deficiency is notified according
to the specific National
38
requirements, this should be 5.8.2 In the case of a negative inspection

captured as annex of the Joint GMP result, the Inspection team will
Inspection Report liaise with each other to ensure
a common understanding following
5.7.3 Taking to account, any applicable “SOP for Follow up on non-
national/regional procedures, compliances” and if possible an
the NMRAs should consider agreed conclusion before closing
developing a common inspection out the inspection and review
report and may find avenues to process.
identify specific failures to specific
national requirements. The Joint 5.8.3 In the unlikely event of a major
inspection report should be sent disagreement on the conclusion of
following the national procedures the inspection, the authorities
asking for Corrective and Preventive should proceed separately and
Action (CAPA) report. conclude the inspection in
accordance with their own national
5.7.3 On receipt of responses of findings/ procedures.
observations, the participating
authorities should discuss and 5.8.4 Any joint follow-up inspection should
agree the responses and any be organized as outlined in this
action plan proposed by the procedure.
representative of inspected facility
taking into account applicable 5.9 DISSEMINATION OF THE FINAL
national/regional procedures. REPORT
If agreement is not reached among
the participating authority at this The final report should be forwarded to the
step see 5.7.2 NMRAs within the EAC.
5.7.4 Unless otherwise agreed, separate 6. REFERENCES

final inspection reports (in English)
in accordance with EAC 6.1 EAC SOP for planning for
requirements will be prepared to an inspection
close out the inspection process, by
each of the parties involved in the 6.2 EAC SOP for preparing for
inspection team. an inspection
5.8 FOLLOW-UP OF JOINT 6.3 EAC SOP for conducting

INSPECTION an inspection
5.8.1 Each participating authority 6.4 EAC SOP for preparing and
is responsible for any follow-up reviewing GMP inspection reports
actions according to their own
regulations and procedures. 6.5 EAC SOP for follow up on
non-compliances.
39
7. REVISION HISTORY
SOP DATE REASON FOR AUTHORISED

VERSION AUTHORISED CHANGE BY
40
ANNEX 14: XIOXXIOXIXOXIXOIXO
1. BACKGROUND 2.4 The national rules for inspection

fees, apply for authorities
1.1 The overall objective of EAC participating in any joint inspection.
NMRAs joint GMP Inspections is
to enhance regional collaboration 2.5 Following a close-out of the
so as to better distribute inspection inspection, each involved
capacity within the EAC Partner authority is responsible for
States, allowing more sites to administrative or enforcement
be inspected/monitored and to actions at national level e.g.
reduce unnecessary duplication. database entry, issuance/update of
certificates/licenses reports.
1.2 The expected advantages from such
interactions are: 2.6 Each authority reserves the right
to perform its “own” inspection.
1.2.1 Increased dialogue between the However, the regulatory authorities
NDRAs in EAC and the applicants will communicate on any
from the beginning of the evaluation deficiencies (or a negative
of a new product, inspection result) found. This will
ensure a common understanding of
1.2.2 A deeper understanding of the the underlying facts and may assist
approaches to GMP inspections by in efforts to try to achieve a joint
either agency, conclusion.
1.2.3 Extending mutual confidence, and 2.7 All the EAC Partner States NMRAs
the opportunity to optimize remain committed to meeting
resources and avoid unnecessary domestic process and review goals
duplication of inspections. and timeframes. The joint inspection
shall not adversely affect either
2.0 PRINCIPLES NMRA’s ability to meet its formal
domestic performance expectations.
2.1 Concerned EAC authorities shall
be responsible for ensuring that 2.8 All NMRAs commit to be cognizant
appropriate confidentiality of the other’s formal domestic
arrangements are in place to allow performance expectations and
them to conduct joint EAC NMRAs to exhibit as much flexibility
GMP inspections. as possible in scheduling meetings
and accommodating the different
2.2 All participating companies shall timeframes for the inspection.
be expected to permit unrestricted
and comprehensive exchange of 2.9 All NMRAs within the EAC will
information between authorities. make these “General Principles”
public on their websites in order to
2.3 The normal rules for national make the joint GMP inspections
coordination of inspections will apply programme, procedures and
goals more transparent and to
41
help answer many questions about 2.12 If an applicant’s request for a joint
the joint inspections programme that inspection within the EAC is
my exist in the general public. declined, this will in no way affect
the processing of any submission
2.10 Exchange of information on FPP/ which will proceed with each agency
APIs, manufacturing sites, individually, following each agency’s
inspection reports and other normal procedures.
detailed information shall be
subject to specific confidentiality 2.12.1 Each authority will follow the SOP
agreements with concerned for GMP inspections in the EAC.
authorities and companies
concerned, as necessary. All 2.12.2 The agencies will assure that
the NMRAs in the EAC will maintain records are maintained to facilitate
the confidentiality of all such the monitoring and evaluation of
information. the program and for the assessment
of the benefits and detriments of
2.11 A request for a joint inspection is the program.
no guarantee that a joint inspection
will be performed. For a variety of
reasons, including scheduling
conflicts and available resources
at any specific time, any of the
NMRAs contacted for joint
inspections may decline to
participate. In which case, the
remaining NMRAs contacted may
proceed with the joint inspection.
42
1. PARTICULARS OF APPLICANT/LICENSE HOLDER
Name______________________________________________________________________
Physical Address_____________________________________________________________
Country____________________Telephone________________________________________
Fax________________________E-mail__________________________________________
2. PARTICULARS OF SITE TO BE INSPECTED
Name of site________________________________________________________________
Physical Address (if different from 1. above)

__________________________________________________________________________
Country_____________________Tel_____________________________________________
Fax____________________E-mail:______________________________________________
Note: Separate application to be filled in for each individual site
3. APPLICATION IN EAC PARTNER STATES
Name of Country Date of Submission
43
4. CONTACT PERSON ON SITE
Name of contact person________________________________________________________
Tel:__________________________________Fax:___________________________________
E-mail:______________________________________________________________________
5. AUTHORISED REPRESENTATIVE/AGENT IN THE COUNTRY
Name of Local Technical Representative___________________________________________
Tel:________________________________________________________________________
6. TYPE OF MEDICINES
Type of medicines manufactured (Tick where applicable)
(a)Human (b) Veterinary (c)Both (a) and (b)
7. REGISTRATION OF PRODUCTS
Have you registered any products in the country YES NO
Have you submitted dossier for registration? YES NO

If YES, list the products applicable. (Attach a separate sheet if needed)
…………………………………………………………………………..................................................
8. LINES TO BE INSPECTED
DOSAGE FORM Tick where *CATEGORY **ACTIVITIES

applicable
Tablets
Capsules
Injections (SVP)
Injections (LVP)
Oral liquids
Creams/Ointments/lotions
Others (specify)
44
*Category means any of the following:

Beta lactam, Non-beta lactam, Biologicals, Vaccines, Hormones, Cytotoxic products.
**Activity means any of the following:

• Formulation (dispensing, mixing, blending)
• Processing (compression, emulsification etc)
• Packing
• Quality Control
• Warehousing (raw material, finished products)
Commitment from manufacturers to welcome inspectors for inspection any time

I hereby certify that the above information is correct and apply for Good Manufacturing Practice
inspection of the above-named site(s).
Signature of applicant……………………………. Date……………………………

Print Name………………………………………....
Notes:
1. Please submit a copy of the Site Master File (not more than 25 pages) together with
this application (refer to Guideline on preparation of a Site Master File)
2. This application must be submitted together with the appropriate fee to the Head
of NMRAs
9. FOR OFFICIAL USE ONLY:
9.1 INSPECTION TYPE (Please tick where applicable)
First Inspection Re - inspection after failure

Routine Re - inspection Previous inspection date……………….
Joint Inspection
Other (please specify)……………………………………………………………...
Name of the Officers:
45
ANNEX 15: MODEL PROCEDURE FOR COLLECTING AND

HANDLING SAMPLES
1. PURPOSE 6.2 The inspector shall look for

anything, in particular its labeling
To outline the procedure that shall be followed and packing, that makes the product
when collecting and handling samples from look different from an original
the manufacturing facilities. reference sample.
2. SCOPE 6.3 Inspectors shall take sample

whenever is necessary.
GMP inspection of pharmaceutical
manufacturing facilities. 6.4 Special precautions to be noted by
the person initiating the sampling or
seizure procedure, with particular
3. RESPONSIBILITY reference to correct legal
procedures to be followed.
GMP Inspectors
6.5 Inspectors shall inform the
4. ACCOUNTABILITY manufacturer reasons for taking
samples
Head of inspection Department
6.6 Inspectors shall make sure that all
5. DISTRIBUTION LIST operations related to sampling
are performed with care. The
5.1 EAC Secretariat Inspectors should have all the tools
needed for sampling according to
5.2 GMP TWG members respective product.
5.3 GMP Inspectors 6.5 The actual number of tablets or

capsules per sample should be
5.4 NMRA Quality Assurance decided on the basis of the type
of laboratory testing to be performed
6. PROCEDURE and by considering the below
sampling plan
6.1 Inspector shall first screen the
product by looking, touching packing
and its contents when examining
a possible suspect of substandard/
spurious/falsified/fasley-labelled/
counterfeit (SSFFC
medicinal product.
46
TABLE 1.SAMPLING PLAN

DOSAGE FORM Minimum Sample Size to Be Taken
from Each Batch for Testing
Tablets/capsules 100 tablets/capsules
Suppositories/ovules 20 suppositories/ovules
Powders/sachets 20 packets/sachets
Injectables (ampules) 20 ampoules
Injectables (vials) 20 vials
Eyedrops 6 bottles
Syrups 6 bottles
IV fluids 6 bottles
6.6 Assign and mark each sample 6.11 Samples should be collected in
collected with a number from their original package. In case a
the respective Sample Receipt product which is not on its
Form. The following sample original package will need to
numbering system is be sampled, then Inspector should
recommended - date, month, year, make sure that all information
country, region, name of required should be recorded on the
manufacturing facility Sampling Form
6.7 Inspector should use appropriate 6.12 Inspector should complete a Sample
type of materials for sealing Receipt FormEAC/TF-MED/GMP/
samples or for embargoing FD/FOM/N8R0 for each
of products sample collected.
6.8 The samples should be in their 6.13 Adequate measures have to be

original packaging material. As a taken to ensure that samples are
general rule, the packaging material transported in good condition from
should be sealed and tamperproof. collection site to the respective
The sample must be properly laboratory for testing. These
labeled. measures should prevent any
physical damage to the samples
6.9 Samples must be kept and stored and should comply with the
according to the manufacturer’s manufacturer’s recommended
recommended storage conditions as storage conditions
prescribed on the product label.
6.10 The Inspector should make

every effort to collect samples that
have an “identifiable” name of
the product, lot or batch number and
the manufacturer’s address bearing
on the label.
47
7.0 ATTACHMENTS
7.1 Sample Receipt Form (SRF)- EAC/TF-MED/GMP/FD/FOM/N8R0
1. Name of Institution/Company (under inspection) ……………………………………………
Physical Address:…………………………………………………………………………........
2. Date of inspection/collecting sampled DD/MM/YYYY………………………………………
3. Reason for collection Routine/investigational/others…………………..............................
4. Product name and description/Identification (e.g. colour, dosage form. Etc)
…………………………………………………………………………………………………....
5. Size of Batch/Lot from which sampled ……………………………………………………....
6. Name and address of Manufacturer. ……………………………………………………..…
7. Batch no……………Manufacturing Date………………..Expiring Date…………………..
8. Place sampled (Warehouse area, Manufacturing plant, etc.) …………………………....
9. No. of samples taken (tins, packets, etc.)……………………………………………………
10. Sample code number……………………………………………………………....................
11. Storage conditions and precautions ………………………………………………………….
Name of Representative(s) of the Signature Date

Inspected Establishment
(1)………………………………………. ………………………… …………………….
Name of Drug Inspector(s) Signature Date

(Sampling Officer).
(1)……………………………............... …………………………. …………………….

(2)……………………………............... …………………………. …………………….
(3)……………………………............... …………………………. …………………….
48
ANNEX 16: MODEL PROCEDURE FOR PREPARING AND

REVIEWING GMP INSPECTION REPORTS
1. PURPOSE 5. PROCEDURES
The purpose of this procedure is to guide 5.1 PREPARING A GMP INSPECTION
GMP inspectors and Peer review committees REPORT
on how to prepare and review an inspection
report respectively. 5.1.1 The GMP inspection report shall be
in Times Roman 12; line spacing 1.5
2. SCOPE and in the format attached herewith.
It shall comprise the sections
The scope of this SOP applies to the indicated in form EAC/TF-MED/
preparation and review of the GMP GMP/FD/FOM/N9R0. The
inspections reports of manufacturers of FPPs inspection reports should be written
and of APIs applied within the EAC Partner in 3rd person passive style and I
States, including joint GMP inspection. past tense.
5.1.2 GMP audit reports should be written

3. RESPONSIBILITY before a team proceeds to inspect
the next manufacturing facility.
3.13 Head of NMRAs
5.1.3 The inspection team shall
collectively prepare and agree
upon the final GMP inspection
3.15 LeadInspectors
report. Any differences of opinion
should be resolved by discussion.
3.16 GMPinspectors
5.1.4 The Lead Inspector assisted by
3.17 Peer review committees
the other inspector (s), must prepare
an exit inspection report using
4. DISTRIBUTION LIST the relevant template EAC/TF-MED/
GMP/FD/FOM/N10RO.The
4.1 Head of NMRAs inspectors and the inspected
company should agree upon the
4.2 Head of GMP departments findings and sign the exit inspection
report. Any differences of opinion
4.3 NMROs should be resolved by discussion
and reevaluation of the finding in
4.4 Joint GMP Inspection Coordinators question. In case of any objection
to sign the exit inspection report, the
a. Quality assurance departments lead inspector should note this on
the report
4.5 Peer review committees
5.1.5 To prepare a GMP report, consider
the documented information in the
site master file, product dossier,
inspection checklist, notebook,
49
inspection exit report, and any other review technical team within seven
document as may be necessary (7) days before discussion of report.
5.1.6 The GMP inspection report should 5.2 REVIEWS AND APPROVAL OF
be balanced, unbiased and factual. THE GMP INSPECTION REPORT
It shall be detailed enough to enable
GMP peer review technical 5.2.1 The GMP peer review technical
team make an informed opinion of team, procedurally selected, shall
the recommendation made by read the reports, assess their text,
the inspectors. The observations context and facts and agree or
should be referenced to the relevant disagree with the recommendations
applicable clause in the EAC of the GMP audit team. The head
GMP guideline. An observation that of inspection to convene a meeting
can’t be reasonably referenced to discuss and approve the
should not be listed as inspection report.
an observation.
5.2.2 The signed report must then
5.1.7 Where more than one observation be scanned and emailed by the
relate to the same basic quality Head of the NMRA to the applicant
system failure, they should be and/ or contact person in the
grouped and listed as a single manufacturing facility within
observation, under a heading that forty five (45) days from the last
reflects the basic system failure. day of the inspection. As necessary,
the local technical representative
5.1.8 The observations identified shall be may have a copy of the report.
classified according to standard
procedure number EAC/TF-MED/ 5.2.3 In case the facility complies
GMP/FD/SOP/N7R0. with current EAC GMP
requirements, the respective
5.1.9 The inspection team should prepare NMRAs will issue Certificate of
finalize, sign and submit the final Compliance as per form EAC/TF-
GMP Inspection report within MED/GMP/FD/FOM/N12R0.
fourteen (14) working days after the
date of return to office. 6.0 RECORD KEEPING
5.1.10 All inspection team members should 6.1 The GMP department/Unit/Division
sign the inspection report. shall keep both an electronic copy
and hard copy of the reports in PDF
5.1.11 The Lead Inspector shall submit or any other protected format in a
the inspection reports to the Head designated folder and prepare the
GMP Inspectorate /division certificates or cover letters of
non-compliance or approval as per
5.1.12 The Head of GMP Inspectorate shall the GMP Inspection
circulate copies of the report to
every member of the GMP peer
50
6.2 The GMP inspection outcomes 7.0 REFERENCE

shall be shared with the drug
registration, drug quality control WHO ; preparing and reviewing a
and drug information department GMP Inspection report
and other NMRAs in the EAC.

9.0 ATTACHMENTS
9.1 Template for FPP/API Inspection Report: EAC/TF-MED/GMP/FD/N6RO
9.2 EAC GMP Inspection Exit Points: EAC/TF-MED/GMP/FD/FOM/N10RO
9.3 Covering letter for Inspection Reports Compliance: EAC/TF-MED/GMP/FD/FOM/N11R0
9.4 Certificate of Compliance to GMP: EAC/TF-MED/FD/FOM/N12R0
51
COVER PAGE
The page should bear the name of the Regulatory Authority
Name and details of the company/facility inspected
Details of the audited manufacturing site;
Name of the site, geographical location (district, state and country),

inspection dates; (Date/s, Month and Year)
1.0 INTRODUCTION
1.1 General information
Name of Manufacturer:
Physical address:
Unit number:
Production Block:
Contact person and email address (full Postal address, Tel numbers, faxes and email address)
Manufacturing license:
GMP certificate:
1.2 Inspection date(s) Date(s), Month………Year…………
1.3 Type of inspection:
1.4 Abbreviations used
All the abbreviations used in the report should be included in this section.
1.5 Inspection Teams-
Name of the GMP Inspectors involved. The team leader should be specified.
1.6 Names, titles and qualifications of key personnel of the facility that participated
Other people met during the inspection should also be mentioned. Key personnel
52
PART 2: SUMMARY
2.1 General information about the company and site
Short description of the company and the activities undertaken.
Dosage forms(s) included in the inspection

1.5 Summary of the activities performed by the manufacturer
(Manufacturing, packaging etc)
2.2 History of regulatory agency inspections
Where applicable, the date of previous inspection by the regulatory authority
Conclusion of other inspections
Where applicable, State major changes made on the facility, equipment, products, and senior
personnel since the previous inspection should be stated.
2.3 Scope of the inspection
Brief description of the objective/reason for the Inspection. State the type of inspection and
whether it was product related inspection.
What you planned to do, areas inspected.
3.1 INSPECTION - OBSERVATIONS AND FINDINGS

Specify each area of the facility that was inspected. Use headings from the checklist relevant to
the scope of the inspection. New headings may be introduced where necessary. The following
area should however be covered adequately.
Add Appendixes if relevant

Refer to applicable clause in GMP Guideline
QUALITY ASSURANCE
GOOD MANUFACTURING PRACTICES (GMPs) FOR PHARMACEUTICAL PRODUCTS
SANITATION AND HYGIENE
QUALIFICATION AND VALIDATION
COMPLAINTS
PRODUCT RECALLS
53
CONTRACT PRODUCTION AND ANALYSIS
SELF INSPECTION AND QUALITY AUDIT
PERSONNEL
TRAINING
PERSONAL HYGIENE
PREMISES
EQUIPMENT
MATERIALS
DOCUMENTATION
GOOD PRACTICES IN PRODUCTION
GOOD PRACTICES IN QUALITY CONTROL
3.2 SUMMARY OF SIGNIFICANT DEFICIENCIES

Where observation of non-compliance to GMP are made they shall be listed in order of
importance and classified as critical, major, minor as in Appendix E
4.0 RECOMMENDATIONS AND CONCLUSION

Recommendations
State any recommendations or actions to be taken by against the facility.
Conclusion
Make conclusion of your assessment of the acceptability of the facility’s GMP status for the range
of products manufactured.
Consider the examples below from EAC PPQ
Based on the areas inspected, the people met and the documents reviewed, and considering
the findings of the inspection, including the observations listed in the inspection report, were
considered to be operating at an acceptable level of compliance with EAC GMP guidelines.
54
However, the observations (non-compliances with guidelines) listed below must be addressed in a
timely manner. The manufacturer is expected to respond to all observations and for each include
a description of the corrective action implemented or planned to be implemented, and the date of
completion or target date for completion. The acceptability of corrective actions will be assessed
through evaluation of the response to each observation and will be followed up during the next
inspection.
or
Based on the areas inspected, the people met and the documents reviewed, and considering the
findings of the inspection, including the observations listed in the Inspection Report, a decision
on the compliance of with WHO GMP will be made after the manufacturer’s response to the
observations has been assessed.
The manufacturer is expected to respond to all observations and for each include a description
of the corrective action implemented or planned to be implemented, and the date of completion
or target date for completion. In addition, for observations classified as “major”, supporting
documentation should be submitted with the response as objective evidence of completion of
corrective actions. The acceptability of corrective actions will be assessed through evaluation of
the response to each observation and will be followed up during the next inspection. If considered
necessary, an on-site follow up inspection may be conducted to verify effective implementation of
corrective actions.
or
Based on the areas inspected, the people met and the documents reviewed, and considering
the findings of the inspection, including the observations listed in the Inspection report,
was considered to be operating at an unacceptable level of compliance with EACGMP
guidelines.
Another inspection will be required to verify the implementation of corrective actions before the
manufacturer’s level of GMP compliance can be reconsidered.
5.0 APPENDIXES
Attach the necessary Appendixes to the report, chronologically numbered in Roman numerals.
The following Appendixes should appear:
Manufacturing certificate
GMP certificate of the local regulatory authority
6.0 NAMES, DESIGNATION, SIGNATURES AND DATE

The report should be signed and dated by the GMP Inspectors involved.
55
Date: ………………………..
56
Your Ref:……………………………………… Date……………………………….
ADDRESS OF THE FACILITY

…………………………….......
…………………………..........
Attn: PLANT COORDINATOR
REPORT OF cGMP INSPECTION REPORT
The manufacturing facility of ………………………………………………………

……………………………………………………………….. (physical address), of
………………………………………………………………. (Country), inspected on
……………………………… (dates), complied with cGMP requirements as per ………………………
NMRA GMP Guidelines at the time of inspection for the following dosage ………………………….
(category) production lines:
Mention the lines

…………………………………..
…………………………………..
…………………………………..
Attached please find the inspection report. Attention should be given to the noted deficiencies and
corrective action taken on the major and minor defiencies observed in due course. Please send
the corrective action schedule and documentation of what has been done.
Please note:
1. That each product must be registered with NMRA (mention the name) before export to
………............. (Country name)
2. NMRA (mention name) can inspect your facility at any time as long as your product is
on the……………. (country name) market.
3. Approval for GMP compliance is valid for three years from the date of inspection.
The company has to apply for re-inspection six months prior to the expiry date if interested in
maintaining products on the NMRA (mention name of NMRA) register.
…………………………………………………...
Head of NMRA (name & Signature)
Copy: Local Agent
57
CERTIFICATE OF GOOD MANUFACTURING PRACTICES
(Issued under …… NMRA regulations)
On the basis of the inspection carried out on [date] ................. we certify that the site indicated
on this certificate complies with Good Manufacturing Practices for dosage forms, categories and
activities listed in Table 1.
1. Name and physical address of site :…………………………………………………...

2. Manufacturer’s license number :……………………………………………………
Table 1:
Dosage form (s) Categories of medicines Activity i.e. Packaging, manufacture of finished
pharmaceutical products
The responsibility for the quality of the individual batches of the pharmaceutical products
manufactured lies with the manufacturer/applicant.
This certificate remains valid until [date] .............. It becomes invalid if the dosage forms, activities
and/or categories certified herewith are changed or if the site is no longer considered to be in
compliance with GMP.
Name of Head of NMRA
.................................... ................................
Signature Stamp and date:
Note: 1.This certificate certifies the status of the site listed in point 1 of the certificate
2. This certificate shall remain valid for a period of 3 years from the date of issue, but
can be revoked at any time if there is evidence that the facility is no longer complies
with then current EAC GMP regulations.
58
ANNEX 17: MODEL PROCEDURE FOR RISK CLASSICATION OF

GMP DEFECIENCIES
1. PURPOSE 2.4.1 Narrow therapeutic window
The purpose of this guide is to ensure 2.4.2 High toxicity

uniformity among the EAC GMP inspectors in
classifying observations and in determining 2.4.3 Sterile product
the compliance status of pharmaceutical
industries following GMP inspection. 2.4.4 Biological product
2. DEFINITIONS 2.4.5 Complex manufacturing process:

process for which slight deviations
2.1 Critical observation: in the control of parameters could
result in a non-uniform product or
An observation describing a situation that will a product not meeting its
most likely result in a non-compliant product specifications. As examples,
or a situation that may result in an immediate powder mixing or granulation for low
or latent health risk and any observation dosage solid forms, long acting/
that involves fraud, misrepresentation or delayed action products, sterile
falsification of products or data. products.
2.2 Major observation: 2.5 Non- compliant product:
An observation describing a situation that is a product that does not meet the
may have an impact on the product but is manufacturer’s specifications or those in the
not as significant as a critical observation. It authorized pharmacopeia
may have an indirect impact in the strength,
identity, purity or safety of the product. There 3. GUIDE
is reduced usability of the product without a
probability of causing harm to the consumer. Whereas it is recognized that it is impossible
Observation of a major deficiency puts a to encompass every situation that may
question mark on the reliability of the firm’s generate a risk, the following principles should
quality assurance system. be considered:
2.3 Minor observation: 3.1 Classification of the observation

is based on the assessed risk level
An observation describing a situation that is and the number of occurrences.
a departure from GMP but has no significant This may vary depending on
impact on the product quality. It has low the nature of the product, eg in
probability of affecting the quality or usability some circumstances an example
of the product. of major deficiency may be
categorized as critical.
2.4 Critical product:
3.2 A deficiency that was reported
A critical product is one for which one or more at a previous inspection and
of the following criteria apply:
59
not corrected may be reported in a 3.5 Critical Observations

higher classification of observation.
3.5.1 Premises:
3.3 Generally, a GMP non-compliance
(NC) rating is assigned when 3.5.1.1 No air filtration system to eliminate
a critical observation is noted during airborne contaminants that are
an inspection. likely to be generated during
manufacture or packaging.
3.4 Generally, a GMP compliance (C)
rating is assigned when major 3.5.1.2 Generalized malfunctioning of
observations are noted during an the ventilation system(s) with
inspection after submission and evidence of widespread cross-
satisfactory review of Corrective contamination.
Action and Preventive Action.
However, a NC rating may be 3.5.1.3 Design of premises does not allow
assigned in the following situations; unidirectional flow of material
and personnel thus posing a risk of
3.4.1 When numerous major observations cross contamination
are noted during an inspection
indicating that the company 3.5.1.4 The building material for premises
does not control its process and not fit for pharmaceutical industry
operations sufficiently. e.g asbestos roofing
3.4.2 Repetition of major observations 3.5.1.5 Inadequate segregation of

noted during previous inspections manufacturing and of testing areas
indicating that the company did not: from other manufacturing areas for
products that pose serious health
a) Implement the corrective actions hazards such as:
submitted following the previous
inspections. a) Highly sensitizing drugs
b) Did not put in place adequate b) Biologicals

preventive actions in a timely
manner to avoid recurrence of c) Hormones
such deviations.
d) Cytotoxic drugs
3.4.3 A compliance rating of GMP
compliance will be assigned in all e) Highly active drugs
situations where only minor
observations are noted. 3.5.2 Equipment:
3.5.2.1 Equipment used for manufacturing

operations of critical products not
qualified with evidence of
malfunctioning.
60
3.5.2.2 Evidence of contamination of deviations or significant calculation

products by foreign materials errors.
such as grease, oil, rust particles
from the equipment. 3.5.6.3 Line clearance not properly done
leading to cross contamination
3.5.2.3 Equipment made of inappropriate
material. 3.5.6.4 Inappropriate status labelling and
identification of materials in
3.5.3 Personnel production leading to mix ups
3.5.3.1 Individual in charge of Quality 3.5.6.5 Lack of proper controls in handling

Control/ Quality Assurance starting materials, in process bulk
or production does not hold a materials and materials in
university degree in a science quarantine or rejected areas
related to the work being conducted
and does not have sufficient 3.5.7 Quality Control Department
practical experience in their area of
responsibility. 3.5.7.1 No full-time person in charge of QC.
3.5.4 Sanitation 3.5.7.2 QC department not a distinct and

independent unit, lacking decisional
3.5.4.1 Evidence of widespread power, with evidence that QC
accumulation of residues/ decisions are overruled by
extraneous matter indicative of production department or
inadequate cleaning. management.
3.5.4.2 Evidence of gross infestation. 3.5.7.3 Poor quality control methods

such as analytical methods used in
3.5.5 Raw material testing the analysis of starting and finished
products are not appropriate,
3.5.5.1 Evidence of falsification or analytical methods not validated,
misrepresentation of analytical major equipment for analysis has no
results. installation and/or operation
qualification
3.5.5.2 No evidence of certificate of
analysis (CoA) available from the 3.5.8 Finished Product Testing
supplier/synthesizer and no testing
done by the manufacturer. 3.5.8.1 Finished product not tested
for compliance with specifications
3.5.6 Manufacturing control by the manufacturer before release
for sale.
3.5.6.1 No written Master Formula.
3.5.8.2 Evidence of falsification or
3.5.6.2 Master Formula or manufacturing misrepresentation of testing results/
batch document showing gross forgery of CoA.
61
3.5.9 Records 3.5.11.8 Aseptic manufacturing suites under

negative pressure compared to
3.5.9.1 Evidence of falsification or clean (C-D) areas. Clean (C-D)
misrepresentation of records. areas under negative pressure to
unclassified areas.
3.5.10 Stability
3.6 Major Observations
3.5.10.1 No data available to establish the
shelf-life of products. 3.6.1 Premises
3.5.10.2 Evidence of falsification or 3.6.1.1 Malfunctioning of the ventilation

misrepresentation of stability data/ system that could result in possible
forgery of CoA. localized or occasional cross-
contamination.
3.5.11 Sterile Products
3.6.1.2 Maintenance/periodic verification
3.5.11.1 Critical sterilization cycle based on such as air filter replacement,
probability of survival not validated. monitoring of pressure differentials
not performed.
3.5.11.2 Water for injection (WFI) systems
not validated with evidence of 3.6.1.3 Accessory supplies (steam, air,
problems such as microbial/ nitrogen, dust collection etc) not
endotoxin counts not within qualified.
specifications.
3.6.1.4 Heating Ventilation Air Conditioning
3.5.11.3 No media fills performed to (HVAC) and purified water (PW)
demonstrate the validity of aseptic system not qualified.
filling operations.
3.6.1.5 Temperature and humidity not
3.5.11.4 No environmental controls/no controlled or monitored when
monitoring of viable microorganisms necessary.
during filling for aseptically filled
products. 3.6.1.6 Damages to walls/ceilings
immediately adjacent or above
3.5.11.5 Aseptic filling operations maintained manufacturing areas or equipment
following unsatisfactory results where the product is exposed.
obtained for media fills.
3.6.1.7 Un-cleanable surfaces created by
3.5.11.6 Batches failing initial sterility test pipes, fixtures or ducts directly
released for sale on the basis of a above products or manufacturing
second test without proper equipment.
investigation.
3.6.1.8 Surface finish (floors, walls, ceilings)
3.5.11.7 Inadequate room classification for that do not permit effective
processing /filling operations. cleaning.*
62
3.6.1.9 Unsealed porous finish in 3.6.2.8 Equipment location does not

manufacturing areas with evidence prevent cross-contamination or
of contamination (mould, powder possible mix ups for operations
from previous productions etc).* performed in common area.
3.6.1.10 Insufficient manufacturing space 3.6.2.9 PW not maintained or operated to

that could lead to mix ups.* provide water of adequate quality.*
3.6.1.11 Quarantine areas accessible to 3.6.2.10 Leaking gaskets.

unauthorized personnel and not well
marked.* 3.6.2.11 No calibration program for
measuring equipment /no records
3.6.1.12 No separate area/Insufficient maintained.*
precautions to prevent
contamination or cross- 3.6.2.12 No equipment usage logs.
contamination during RM sampling.
3.6.3 Personnel
3.6.2 Equipment
3.6.3.1 Delegation of responsibilities for
3.6.2.1 Equipment does not operate within QC or production to insufficiently
its specifications.* qualified persons.
3.6.2.2 Equipment used for complex 3.6.3.2 Insufficient personnel in QC

manufacturing operation not production resulting in a high
qualified. possibility of error.
3.6.2.3 Clean in place (CIP) equipment not 3.6.3.3 Insufficient training for personnel
validated. involved in production and QC
resulting in related GMP violations.
3.6.2.4 Tanks for manufacturing of liquids
and ointments not equipped with 3.6.3.4 No medical check-ups for personnel
sanitary clamps. involved in critical areas of
production and quality control
3.6.2.5 Stored equipment not protected
from contaminations.* 3.6.4 Sanitation
3.6.2.6 Inappropriate equipment for 3.6.4.1 Sanitation program not in writing but
production: surfaces porous and premises in acceptable state of
non-cleanable/material to shed cleanliness.
particles.*
3.6.4.2 No Standard Operating Procedure
3.6.2.7 No covers for tanks, hoppers or (SOP) for microbial/environmental
similar manufacturing equipment. monitoring, no action limits for areas
where susceptible non-sterile
products are manufactured.
63
3.6.4.3 Cleaning procedure for production 3.6.6.4 Line clearance between productions
equipment not validated (including of different products not covered by
analytical methods). SOP and not documented.
3.6.4.4 Incomplete health requirements. 3.6.6.5 No regular checks for measuring

devices/no records.
3.6.5 Raw Material Testing
3.6.6.6 Lack of proper identification of in-
3.6.5.1 Water used in the formulation is not process materials and products
of acceptable quality. resulting in a high probability of
mix-ups.
3.6.5.2 No testing done on materials by the
manufacturer. 3.6.6.7 Inadequate labelling /storage of
rejected materials and products that
3.6.5.3 COA showing incomplete testing. could generate mix-ups.
3.6.5.4 Incomplete specifications. 3.6.6.8 Upon receipt, bulk and in-process

drugs, raw materials and packaging
3.6.5.5 Specifications not approved by QC. materials not held in quarantine until
released by QC.
3.6.5.6 Testing methods not validated.
3.6.6.9 Production personnel using bulk
3.6.5.7 Use of materials after retest date and in-process drugs, RM and
without retesting. packaging materials without prior
authorization by QC.*
3.6.5.8 Multiple lots comprising one
consignment not considered as 3.6.6.10 Inadequate/inaccurate labelling
separate for sampling, testing of bulk/in-process drugs, raw
and release. materials and packaging materials.
3.6.5.9 No SOP for conditions of 3.6.6.11 Raw materials dispensing not done
transportation and storage. by qualified persons, according
to SOP.
3.6.6 Manufacturing Control
3.6.6.12 Master Formulae incomplete or
3.6.6.1 Master Formulae prepared/verified showing inaccuracies in the
by unqualified personnel. processing operations.
3.6.6.2 Deviations from instructions during 3.6.6.13 Changes in batch size not prepared/
production not documented and not verified by qualified personnel
approved.
3.6.6.14 Inaccurate/incomplete information in
3.6.6.3 Discrepancies in yield or manufacturing/packaging batch
reconciliation following production document.
not investigated.
64
3.6.6.15 Although documented, combination 3.6.8.3 No SOP approved and available for
of batches done without QC sampling, inspection and testing of
approval/not covered by SOP. materials.
3.6.6.16 No written procedures for packaging 3.6.8.4 Products made available for sale
operations. without approval of QC department.*
3.6.6.17 Non-standard occurrences during 3.6.8.5 Products released for sale by QC

packaging not investigated by without proper verification of
qualified personnel. manufacturing and packaging
documentation.
3.6.6.18 Inadequate control of coded and
non-coded printed PM (including 3.6.8.6 Deviations and borderline
storage, dispensing, printing and conformances not properly
disposal). investigated and documented,
according to an SOP.
3.6.6.19 No or inadequate self-inspection
program does not address all 3.6.8.7 Raw materials and packaging
applicable sections of GMPs/ materials used in production without
Records incomplete or not prior approval of QC.
maintained.
3.6.8.8 Reprocessing/Reworking done
3.6.7 Recall without prior approval of QC.*
3.6.7.1 Absence of recall procedure 3.6.8.9 No system for complaint handling

combined with distribution practices and returned goods.
that would not permit and adequate
recall (distribution records 3.6.8.10 SOPs covering operations that
unavailable or not kept). can affect the quality of a product
such as transportation, storage etc
3.6.7.2 Improper quarantine and disposal not approved by QC / not
practices that would allow recalled/ implemented
rejected units to be returned
for sale. 3.6.8.11 Absence of a change control
system.
3.6.8 Quality Control/Quality
Assurance Department 3.6.8.12 The systems and controls in
place for the proper qualification,
3.6.8.1 Inadequate facilities, personnel and operation, calibration and
testing equipment. maintenance of equipment,
standards, solutions, and records
3.6.8.2 No authority for QC/QA personnel to keeping do not assure that the
enter production areas.* results and conclusions generated
are accurate, precise and reliable.
65
3.6.9 Packaging Material Testing 3.6.13.3 No stability studies pertaining

to changes in manufacturing
3.6.9.1 Absence of testing of packaging (formulation) packaging materials.
materials.
3.6.13.4 Testing methods not validated.
3.6.9.2 Specifications not approved by QC.
3.6.10 Finished Product Testing
3.6.14.1 Aqueous based products not
3.6.10.1 Incomplete/inadequate subjected to terminal steam
specifications. sterilization without proper
justification or approval through the
3.6.10.2 Finished products specifications not marketing authorization.
approved be QC.
3.6.14.2 Insufficient number of samples
3.6.10.3 Incomplete testing. for room classification/inadequate
sampling methods.*
3.6.10.4 Test methods not validated.
3.6.14.3 Insufficient environmental controls/
3.6.11 Records insufficient monitoring of viable
micro-organisms during filling for
3.6.11.1 Absence of Master Production aseptically filled products.*
Documents.
3.6.14.4 Premises and equipment not
3.6.11.2 Lack of standard operating designed or maintained to minimize
procedures for the operations contamination/generation of
undertaken particles.*
3.6.12 Samples 3.6.14.5 Inadequate maintenance of purified

water and water for injection
3.6.12.1 Retention samples not kept for systems.
finished products.
3.6.14.6 Inadequate re-validation of purified
3.6.13 Stability water and water for injection
systems after maintenance,
3.6.13.1 Insufficient number of batches/ upgrading, out-of-specs trends.
insufficient data to establish shelf
life. 3.6.14.7 Inadequate training of personnel.
3.6.13.2 No action taken when data 3.6.14.8 Inadequate gowning practices for
shows that the products do not meet clean and aseptic areas.
their specifications prior to the
expiry date. 3.6.14.9 Inadequate practices/precautions to
minimize contamination or prevent
mix-ups.
66
3.6.14.10 Non-validated time lapse between components are not depyrogenated

start of manufacturing and subsequently.
sterilization or filtration. *May be elevated to critical
observation
3.6.14.11 Inadequate procedures for media-
fills. 3.7 Minor Observations
3.6.14.12 Insufficient number of units filled 3.7.1 Premises

during media-fills.
3.7.1.1 Doors giving direct access to
3.6.14.13 Media-fills do not simulate actual exterior from manufacturing and
operations. packaging areas used by personnel.
3.6.14.14 Capability of media to grow a wide 3.7.1.2 Un-screened/un-trapped floor

range of microorganisms not drains.
demonstrated.
3.7.1.3 Outlets for liquids and gases not
3.6.14.15 Misinterpretation of results for identified.
media-fills.
3.7.1.4 Damages to surfaces not directly
3.6.14.16 Absence of leak test for ampoules. adjacent or above exposed
products.
3.6.14.17 Samples for sterility testing
insufficient in number or not 3.7.1.5 Non-production activities performed
representative of the entire in production areas.
production run.
3.7.1.6 Inadequate rest, change, wash-up
3.6.14.18 Each sterilizer load not considered and toilet facilities.
as a separate batch for sterility
testing. 3.7.2 Equipment
3.6.14.19 Purified water is not used as the 3.7.2.1 Insufficient space between
feed water for water for injection equipment and walls to permit
system and the clean steam cleaning.
generator.
3.7.2.2 Base of immovable equipment not
3.6.14.20 The water for injection used in the adequately sealed at points of
preparation of parenterals is not contact.
tested for endotoxins.
3.7.2.3 Use of temporary means or devices
3.6.14.21 The water for injection used for final for repair.
rinsing of containers and
components used for parenteral 3.7.2.4 Defective or unused equipment
drugs is not tested for endotoxins used for non-critical products not
when those containers and qualified.
67
3.7.3 Sanitation 3.7.7 Finished Product Testing
3.7.3.1 Incomplete written sanitation 3.7.7.1 Incomplete testing of physical

program but premises in acceptable parameters.
state of cleanliness.
3.7.8 Records
3.7.3.2 Sanitation or Health and hygiene
programs not properly implemented 3.7.8.1 Incomplete records/documentation
or followed by employees. for a product.
3.7.4 Raw Material Testing 3.7.8.2 Incomplete plans and specification

for the manufacturing buildings.
3.7.4.1 Incomplete validation of test
methods. 3.7.8.3 Incomplete documentation
pertaining to supervisory personnel.
3.7.5 Manufacturing Control
3.7.8.4 Insufficient retention time for
3.7.5.1 Incomplete SOPs for handling of evidence and records to be
materials and products. maintained.
3.7.5.2 Access to production areas not 3.7.8.5 No organization charts.

restricted to authorized personnel.
3.7.8.6 Incomplete records for the sanitation
3.7.5.3 Inadequate checks for incoming program.
materials.
3.7.9 Samples
3.7.5.4 Written procedures incomplete for
packaging operations. 3.7.9.1 Samples of raw materials not
available.
3.7.5.5 Incomplete recall procedure.
3.7.9.2 Incomplete testing parameters.
3.7.6 Packaging Material Testing
3.7.9.3 Improper storage conditions.
3.7.6.1 Inadequate procedures of
transportation and storage. 3.7.10 Stability
3.7.6.2 Inadequate handling of outdated/ 3.7.10.1 Insufficient number of batches in

obsolete packaging materials. continuing stability program.
3.7.6.3 Incomplete testing. 3.7.10.2 Incomplete testing parameters.
3.7.6.4 Inadequate specifications. 3.7.10.3 Improper storage conditions.
68
3.7.11.1 Steam used for sterilization not

monitored to assure suitable quality
and absence of additives.
3.7.11.2 Inadequate control on the maximum

number of personnel present in
clean and aseptic areas.
3.7.11.3 Gases used to purge solutions

or blanket products not passed
through a sterilizing filter.
3.7.11.4 Inadequate inspection for particles

and defects.
69
ANNEX 18: MODEL PROCEDURE FOR FOLLOW UP ON

NON-COMPLIANCES AFTER GMP INSPECTION
5. PURPOSE 7.4.1 To review the inspection report and

make a final conclusion on the
The purpose is to outline procedures for submitted GMP inspection report
National Medicines Regulatory Authorities
(NMRAs) to follow up on non-compliances 7.5 GMP unit/division/section
observed after GMP inspections of administrative staff
manufacturing facilities and implement
administrative actions where necessary. 7.5.1 Update databases and prepare
communication by letter or email
6. SCOPE
8. DISTRIBUTION LIST
The scope of this SOP applies to EAC GMP
inspections of manufacturers of FPPs and 4.1 Head of NMRA
of APIs.
4.2 Head of GMP inspectors
7. RESPONSIBILITY
4.3 GMP inspectors
7.1 Head of NMRA
4.4 The peer review/technical
7.1.1 Ensure decisions on all committee members
manufacturing facilities are
implemented in a timely manner and 4.5 GMP unit/division/section
in accordance with the legislation to administrative staff
protect human health
9. PROCEDURE
7.2 Head GMP Inspectorate:
5.1 After generation of a GMP
7.2.1 Ensuring that administrative or inspection report with
enforcement actions are undertaken classification of all non-
as appropriate compliances as critical, major
and minor therein and peer
7.3 The lead and/or co-inspector: review; a site shall be considered
compliant if it has:
7.3.1 To generate a GMP inspection
report with conclusion on the status 5.1.1 No critical noncompliance.
of the manufacturing facility
5.1.2 Minor non compliances
7.3.2 To review the CAPA and submit
comments 5.1.3 Major non compliances that are
rectified and Corrective And
7.4 The Peer Review/Technical Preventive Action (CAPA) submitted
Committee: by the manufacturer; review of
CAPA by the NMRA and found
satisfactory
70
5.2 A site shall be considered non- 5.8 Manufacturing facilities that fail
compliant if it has: to comply with GMP shall have:
5.2.1 One or more critical non 5.8.1 their products removed from the
compliances national medicine register thus
halting further manufacture or
5.2.2 Several major non compliances that importation of the products
imply a failure in the quality
assurance system 5.8.2 Their products recalled from the
market depending on the criticality
5.3 The NMRA shall issue a GMP of the findings (see SOP on recall of
certificate and /or a products from the market annex
manufacturing license where VI H).
applicable for a site that is
compliant i.e has no critical or 5.9 The NMRA may decide to close
has minor observations down the whole site by
withdrawing the GMP certificate
5.4 The NMRA shall demand for a and/or manufacturing license or a
corrective and preventive action section of the site depending on
report for review and where the critical observations
possible a follow up inspection identified by the inspection team
for a site that has major non
compliances may be done prior 5.10 Upon careful consideration of
to issue of a GMP certificate and the findings in the inspection
close out of the inspection. report and where these affect the
health of patients in a critical
5.5 The NMRA shall not issue manner; the NMRA may consider
a GMP certificate to a non- raising a rapid alert to EAC
compliant manufacturing facility NMRAs, health care workers
that has critical or several major and patients
non compliances
6. RECORDS
5.6 Local manufacturers shall require
physical re-inspection for a 6.1 The quality manuals, master
site that has critical or several distribution list file, obsolete
major non compliances until a documents file and general list of
satisfactory report is achieved documents shall be kept and
maintained by HQM for a period
5.7 The re-inspection of a non- specified in the respective
compliant facility shall be after document
submission of corrective action
report and an application
together with payment of the
inspection fee.
71
6.2 Department list of documents 7. REFERENCES

shall be kept and maintained by
respective Head Department 7.1. Inspection procedures NDA-Uganda
6.3 Records shall be destroyed by 7.2. EMA Compilation of Community

tearing/shredding/burning or any procedures on Inspection and
other appropriate means. exchange of information, 16 July
2012, EMA/INS/GMP/321252/2012
Rev 15, Compliance and Inspection

(Name, Sign & (Name, Sign &
Date) Date)
72
ANNEX 19: MODEL PROCEDURE FOR HANDLING PRODUCT

RECALL
1. PURPOSE 6. PROCEDURE
To outline the procedure for classification and 6.1 OCCASIONS UNDER WHICH
communications involved in a product recall or A PRODUCT MAY BE RECALLED
withdrawal OR WITHDRAWN
2. SCOPE 6.1.1. The withdrawal/recall of a particular

batch or batches of a product
This SOP is applicable for use at EAC from the market may be occasioned
headquarter and individual Partner States by the following:
NMRAs for handling product recalls occurring
in their operations. They are also applicable 6.1.1.1. Serious reports of adverse drug
to all authorized and marketed products for reactions not included in the
which there is an evidence or potential that package insert
the product is noncompliant with the marketing
authorization and, therefore can have 6.1.1.2. Unexpected frequency of adverse
undesirable effects to the patient’s health. reaction stated in the package
inserts
3. RESPONSIBILITY 6.1.1.3. Incorrect labeling of a product
It is the responsibility of the head of NMRA
6.1.1.4. Incorrect formulation of a product
and the pharmaceutical Inspectorate
secretariat to initiate and supervise the
6.1.1.5. Unfavorable result from post
product recall or withdrawal.
marketing surveillance
It is also the responsibility of the
6.2. CLASSIFICATIONOF DEFECTS
manufacturer/or distributor /or Local Technical
Representative to inform the NMRA of any
It is necessary to assign/indicate the relative
product defect and conduct the recall of the
degree of health hazard presented by the
defected products
product being recalled, namely:
4. ACCOUNTABILITY 6.2.1. Situation in which there is

reasonable probability that the use
• Head NMRA (HNMRA) of or exposure to a suspect
product will cause serious adverse
5. DISTRIBUTION health consequences or death
• Head of NMRA 6.2.2. Situation in which the use of or

exposure to a suspect product
• Head of Inspectorate will cause temporary adverse
health consequences or where
• Head of registration the probability of serious adverse
health consequences is remote.
• Head of Medicines Information
73
6.2.3. Situation in which the use of or Action: Recall Notification to all distribution
exposure to a suspect product points plus Media release.
is not likely to cause any adverse
health consequences 6.3.2. Type B
A type B recall is designed to reach
The following classification criterion is wholesalers throughout the country,
recommended: directors of hospital services
(private as well as state hospitals),
Class I retail outlets, doctors, nurses,
pharmacists, authorized prescribers
Class I is for defective/dangerous/potentially and dispensers.
life threatening medicines that predictably or
probably could result into serious health risk/ Action: Recall letter to all distribution points.
adverse events or even death.
6.3.3. Type C
Class II A type C recall is designed to reach
wholesale level and other
Class II is for medicines that possibly could distribution points (e.g. pharmacies,
cause temporary or medically reversible doctors, hospitals). This can be
adverse health problem or mistreatment. achieved by means of
representatives calling on
Class III wholesalers and/or retail outlets. If
it is known where the product in
Class III is for medicine that is defective and is question had been distributed to,
unlikely to cause any adverse health reaction specific telephone calls or recalls
or which do not comply with the requirements letters to arrange for the return of
of the NMRA Laws of the individual partner the product could be made.
States and regional bidding laws and
regulations of the EAC Action: Specific telephone calls, recall letters/
representatives calling at distribution points
6.3. TYPES OF RECALL if known where the medicines have been
distributed.
6.3.1. Type A
A type A recall is designed to reach 6.4. RECALL NOTIFICATION
all suppliers of medicines (all
distribution points) i.e. wholesalers It is imperative that before or upon initiating a
throughout the country, directors recall, the company immediately on becoming
of hospital services (private as well aware of the problem, notifies the head NMRA
as state hospitals), retail outlets, or, in his absence, his designate
doctors, nurses, pharmacists,
authorized prescribers and If the notification fails and there is urgent
dispensers and individual customers need to recall the product then the company
or patients through media release may proceed according to their discretion
(radio, television, internet, regional and follow up contact with the NMRA to be
and national press). pursued in the process.
74
6.5. BASIC INFORMATION REQUIRED or considered for recall will also be conducted
FOR RECALL by the NMRA and will take into account, but
need not be limited to, assessment of the
6.5.1. Name, strength, pack size, batch/ following factors:
lot number and means of
identification of the recalled product 6.6.1. Whether any disease or injuries
have already occurred from the use
6.5.2. Total quantity of the product being of the product
re called originally in possession of
the company 6.6.2. Hazard to various segments of the
population e.g. children, surgical
6.5.3. The date distribution of the product patients etc, who are expected to
began be exposed to the product, with
particular attention to those
6.5.4. The total quantity of the product individuals who may be at greatest
being re called that had been risk
distributed up to the time of the
recall should be indicated. 6.6.3. The degree of seriousness of the
health hazard to which the
6.5.5. Area of distribution of the product population at greatest risk would
and, if exported, the country to be exposed.
where it was exported.
6.6.4. The likelihood of occurrence of
6.5.6. List of customers to whom product that hazard
was issued
6.6.5. The consequences (immediate
6.5.7. The quantity of the recalled product or long-term) of occurrence of
still in their possession the hazard. The recalling company
will be given every opportunity
6.5.8. The reason for initiating the recall; to contribute to the information
nature of defect on which the health hazard
evaluation is made by the NMRA,
6.5.9. Suggested action to be taken and who, on the basis of this
its urgency determination, classifies it based on
the relative degree of health hazard
6.5.10. Indication of the health risk together posed by the product being recalled
with reasons or considered for recall.
6.6. HEALTH HAZARD EVALUATION 6.7. RECALL STRATEGY
Before initiating a recall, the company will In formulating a recall strategy, the following
gather, correlate and evaluate all known should be taken into consideration:
information on the nature and extent of the
reputed health risk. An evaluation of the health
hazard presented by a product being recalled
75
6.7.1. Result of health hazard evaluation with the hazard of the product and the
strategy developed for that recall. Recall
6.7.2. Ease in identifying the product communication should convey:
6.7.3. Extent to which the product 6.9.1. That the product in question is
deficiency is obvious to the subject to recall
consumer/user
6.9.2. That further distribution or use
6.7.4. Continued availability of essential of any remaining product should
products (risk: benefit) cease immediately
6.8. ELEMENTS OF A RECALL 6.9.3. The instructions on what to do with

STRATEGY the product

6.8.1. Depth of recall 6.10. IMPLEMENTATION OF
RECALL COMMUNICATION
Depending on the product’s degree of hazard
and extent of distribution, the recall strategy The following may be used in a recall
has to specify the level in the distribution chain communication:
in which the recall is to extend, as follows:
6.10.1. Telephone
6.8.2. Consumer or user level including
any intermediate wholesale and/ 6.10.2. Telex
or distribution or retail level, and or
all government and military 6.10.3. Telegram
hospitals; or
6.10.4. Public media
6.8.3. Retail level, including any
intermediate wholesale and/ or 6.10.5. Special delivery
distribution level; or
6.10.6. Conspicuous marking e.g.
6.8.4. Manufacturer, Wholesale and/ or “MEDICINE RECALL” in bold red on
distributor level. the letter and envelope, and also
“URGENT” for serious cases
6.8.5. Recall communication from
recalling company to all affected 6.10.7. A public warning may be necessary
parties for products that pose serious health
hazards. However, this should be
6.9. RECALL COMMUNICATION reserved for urgent situations where
other means of preventing use of
A recalling entity is responsible for promptly the recalled product appear
notifying involved parties about the recall and inadequate.
the same information notified to the Board.
The format, content, and extent of recall
communication should be commensurate
76
NMRA to decide if necessary and who to issue 6.12. POST RECALL PROCEDURES
such a warning and the type of public warning
should be specified in the recall strategy for The NMRA must be furnished with a report
the product e.g. within a specified period (2 weeks) of the
recall or withdrawal being instituted. The
General public warning in the general media report should contain the following information:
as appropriate and a public warning through
specialized news media to professionals or 6.12.1. Name of the product
to specific segments of the population like
physicians, hospitals etc. 6.12.2. Strength of the product
6.11. CONTENTS OF RECALL 6.12.3. Pack size

COMMUNICATION
6.12.4. Batch/ lot number
A recall communication should:
6.12.5. Nature of the defect
6.11.1. Be brief and to the point
6.12.6. Action that was taken
6.11.2. Name the product, strength, pack
size, and any other pertinent 6.12.7. Urgency of the action taken
descriptive information of
the product 6.12.8. Reason for the action
6.11.3. Indicate nature of the defect 6.12.10. Indication of the health risk and
reported clinical problems
6.11.4. Specify urgency of the action
6.12.11. Copies of all the recall
6.11.5. Indicate reason for the action correspondence; and
6.11.6. Indicate the health risk; and 6.12.12. Steps taken to prevent re-
occurrence of the problem
6.11.7. Provide specific instructions on what
should be done with the recalled 6.12.13. After termination of a recall and
product. not later than 90 days after a recall
has been instituted, a full
Note: Where necessary, follow-up reconciliation must be submitted.
communication should be sent to those
who fail to respond to the initial recall A recall will be terminated when the NMRA
communication. This should be done within a and the recalling company are in agreement
reasonable time depending on the urgency of that the non-compliant product has been
the recall. removed and proper disposal or correction
has been made.
77
DEFINITIONS Holder of a certificate of registration

- means a person in whose name a
Recall - means the removal of specific batch/ registration certificate has been granted
batches of a medicinal product from the and who is responsible for all aspects of the
market for reasons relating to deficiencies in medicine, including quality and safety and
the quality, safety or efficacy. compliance with conditions of registration.
This terminology will also include the agent/
Withdrawal - means the total withdrawal of a distributor of a drug.
medicinal product from the market
78
RECALL ASSESSMENT FORM

* The information below could be provided verbally but should be confirmed in writing
within 3 working days.
79
80
81
PART TWO:
GUIDELINES ON GOOD MANUFACTURING

PRACTICE FOR MEDICINAL PRODUCTS FOR USE IN EAC
82

AHU - Air Handling Unit
BAS - Building Automation System
BCG - Bacillus Calmette Guerin
BMGF - Bill and Melinda Gates Foundation
BMR - Batch Manufacturing Record
BMS - Building Management System
BOD - Biochemical Oxygen Demand
BP - British Pharmacopoeia
CAPA - Corrective Action and Preventive Action
COD - Chemical Oxygen Demand
CPPs - Critical Process Parameters
CQAs - Critical Quality Attributes
CTD - Common Technical Document
DNA - Deoxyribononucleic Acid
DQ - Design Qualification
EAC - East African Community
EAC-MRH - East African Community Medicines Regulation
Harmonization project
eCTD - Electronic Common Technical Document
EMA - European Pharmaceutical products Agency
EN - European Norm
ETP - Effluent Treatment Plant
EU - European Union
FEAPM - Federation of East African Pharmaceutical Manufacturers
FMEA - Failure Modes Effects Analysis
GCP - Good Clinical Practice
GDP - Good Distribution Practice
GEP - Good Engineering Practice
GLP - Good Laboratory Practice
GMP - Good Manufacturing Practice
GxP - Good (x- variable replaced with manufacturing, clinical,
laboratory, storage, distribution and review) Practice
HACCP - Hazard Analysis and Critical Control Point Harmonization
HAZOP - Hazard Operability Analysis
HEPA - High Efficiency Particulate Air
HPW - Highly Purified Water
HVAC - Heating Ventilation and Air Conditioning
ICH - International Conference on Harmonization of Technical
IQ - Installation Qualification
ISO - International Standard Organization
83
MA - Marketing Authorization
MAL - Material Air Lock
MRA - Medicines Regulatory Authority
MTC - Manufacturing Technology Committee
NEPAD - New Partnership for Africa’s Development
OQ - Operational Qualification
OSD - Oral Solid Dosage
PAL - Personnel Air Lock
pH - Power of Hydrogen
Ph. Eur - European Pharmacopoeia
Ph. Int. - International Pharmacopoeia
PP - Process Parameter
PQ - Performance Qualification
PQRI - Product Quality Research Institute
PQS - Pharmaceutical Quality System
PW - Purified Water
QA - Quality Assurance
QC - Quality Control
QRM - Quality Risk Management
QTPP - Quality Target Product Profile
Requirements for Registration of Pharmaceuticals for Human Use
RMP - Risk Management Plan
SCADA - System Control and Data Acquisition
UDAF - Unidirectional Air Flow
USP - United State Pharmacopoeia
VMP - Validation Master Plan
WFI - Water for Injection
84
GLOSSARY Batch records: All documents associated with

the manufacture of a batch of bulk product
The definitions given below apply to the terms or finished product. They provide a history of
used in this guide. They may have different each batch of product and of all circumstances
meanings in other contexts. pertinent to the quality of the final product.
Active pharmaceutical ingredient: A Bulk product: Any product that has

substance or compound that is intended to be completed all processing stages up to, but not
used in the manufacture of a pharmaceutical including, final packaging.
product as a pharmacologically active
compound (ingredient). Calibration: The set of operations that
establish, under specified conditions, the
Authorized person: A person responsible relationship between values indicated by an
for the release of batches of finished product instrument or system for measuring (especially
for sale or distribution. Such a person weighing), recording, and controlling, or the
is recognized by the national medicines values represented by a material measure,
regulatory framework as having the and the corresponding known values of a
responsibility for ensuring that each of the reference standard. Limits for acceptance
finished products has been manufactured, of the results of measuring should be
tested and approved for release in compliance established.
with the laws and regulations in force in each
of the member states. Certification: The final review and formal
approval of a validation or revalidation,
Batch (or lot): A defined quantity of starting followed by approval of a process for routine
material, packaging material, or product use.
processed in a single process or series of
processes so that it could be expected to Challenge tests/worst case: A condition or
be homogeneous. In the case of continuous set of conditions encompassing upper and
manufacture, the batch must correspond lower processing limits and circumstances,
to a defined fraction of the production, within standard operating procedures, that
characterized by its intended homogeneity. pose the greatest chance of process or
It may sometimes be necessary to divide a product failure when compared with ideal
batch into a number of sub-batches, which conditions.
are later brought together to form a final
homogeneous batch. Clean area: An area with defined
environmental control of particulate and
Batch number (or lot number): A distinctive microbial contamination; constructed and used
combination of numbers and/or letters which in such a way as to reduce the introduction,
specifically identifies a batch on the labels, the generation and retention of contaminants
batch records, the certificates of analysis, etc. within the area.
Batch numbering system: standard Consignment (or delivery): The quantity of

operating procedure describing the details of starting material, or of a drug product, made
the batch numbering. by one manufacturer and supplied at one time
in response to a particular request or order.
85
A consignment may comprise one or more Large-volume parenterals: Sterile solutions

packages or containers and may include intended for parenteral application with a
material belonging to more than one batch. volume of 100 ml or more in one container of
the finished dosage form.
Critical process: A process that may cause
variation in the quality of the pharmaceutical Manufacture: All operations of purchase
product. of materials and products, production,
packaging, quality control, release, storage,
Cross-contamination: Contamination of a shipment of finished products, and the related
starting material, intermediate product, or controls.
finished product with another starting material
or product during production. Manufacturer: A company that carries out at
least one step of manufacture.
Finished product: A product that has
undergone all stages of production, including Manufacturing process: The transformation
packaging in its final container and labeling. of starting materials into finished products
(drug substances or pharmaceutical dosage
Hazardous substance/product: A product or forms) through a single operation or a
substance that may present a substantial risk sequence of operations involving installations,
of injury, to health or to the environment personnel, documentation and environment.
In-process control: Checks performed Marketing authorization (product license,

during production in order to monitor and if registration certificate): A legal document
necessary to adjust the process to ensure issued by the competent drug regulatory
that the product conforms to its specifications. authority that establishes the detailed
The control of the environment or equipment composition and formulation of the product
may also be regarded as a part of in-process and the pharmacopoeial or other recognized
control. specifications of its ingredients and of the
final product itself, and includes details of
Installation qualification: The performance packaging, labeling and shelf-life.
of tests to ensure that the installations (such
as machines, measuring devices, utilities, Master formula: A document or set of
manufacturing areas) used in a manufacturing documents specifying the starting materials
process are appropriately selected and with their quantities and the packaging
correctly installed and operate in accordance materials, together with a description of the
with established specifications. procedures and precautions required to
produce a specified quantity of a finished
Intermediate product: Partly processed product as well as the processing instructions,
material that must undergo further including the in-process controls.
manufacturing steps before it becomes a bulk
product.
86
Master record: A document or set of Production: All operations involved in the

documents that serve as a basis for the batch preparation of a pharmaceutical product,
documentation (blank batch record). from receipt of materials, through processing
and packaging, to completion of the finished
Medicinal product: Any medicine or similar product.
product intended for human use, which is
subject to control under national legislation Qualification of equipment: The act of
in the manufacturing or importing State. (see planning, carrying out and recording the
also Pharmaceutical product) results of tests on equipment to demonstrate
that it will perform as intended. Measuring
Operational qualification: Documented instruments and systems must be calibrated.
verification that the system or subsystem
performs as intended over all anticipated Quality assurance: See Chapter 1
operating ranges.
Quality control: See Chapter 1
Packaging: All operations, including filling and
labeling, that a bulk product has to undergo Quality unit (s): An organizational unit
in order to become a finished product. Sterile independent of production which fulfils both
filling would not normally be regarded as part quality assurance (QA) and quality control
of packaging, the bulk product being the filled, (QC) responsibilities. This can be in form
but not the finally packaged, primary container. of a separate QA and QC units or a single
individual or group, depending upon the size
Packaging material: Any material, including and structure of the organization.
printed material, employed in the packaging of
a pharmaceutical product, excluding any outer Quarantine: The status of starting or
packaging used for transportation or shipment. packaging materials, intermediates, or bulk
Packaging materials are referred to as primary or finished products isolated physically or
or secondary according to whether or not they by other effective means while a decision
are intended to be in direct contact with the is awaited on their release, rejection, or
product. reprocessing.
Pharmaceutical product: Any medicine Reconciliation: A comparison, making due

intended for human use or veterinary allowance for normal variation, between the
product administered to food-producing amount of product or materials theoretically
animals, presented in its finished dosage produced or used and the amount actually
form or as a starting material for use in such produced or used.
a dosage form, that is subject to control
by pharmaceutical legislation in both the Recovery (or blending): The introduction of
exporting state and the importing state. all or part of previous batches (or of redistilled
solvents and similar products) of the required
quality into another batch at a defined stage of
manufacture.
87
Reprocessing: The reworking of all or part of Validation protocol (or plan): A document
a batch of product of an unacceptable quality describing the activities to be performed in a
from a defined stage of production so that its validation, including the acceptance criteria for
quality may be rendered acceptable by one or the approval of a manufacturing process - or a
more additional operations. part thereof - for routine use.
Returned product: Finished product sent Validation report: A document in which the
back to the manufacturer. records, results and evaluation of a completed
Revalidation: Repeated validation of an validation program are assembled. It may
approved process (or a part thereof) to also contain proposals for the improvement of
ensure continued compliance with established processes and/or equipment.
requirements.
Specification: A document describing in detail

the requirements with which the products or
materials used or obtained during manufacture
have to conform. Specifications serve as a
basis for quality evaluation.
Standard operating procedure (SOP):

An authorized written procedure giving
instructions for performing operations not
necessarily specific to a given product or
material but of a more general nature (e.g.,
equipment operation, maintenance and
cleaning; validation; cleaning of premises
and environmental control; sampling and
inspection). Certain SOPs may be used to
supplement product-specific master and batch
production documentation.
Starting material: Any substance of a

defined quality used in the production of
a pharmaceutical product, but excluding
packaging materials.
System: A regulated pattern of interacting

activities and techniques that are united to
form an organized whole.
Validation: The documented act of proving

that any procedure, process, equipment,
material, activity, or system actually leads to
the expected results.
88
1. INTRODUCTION 2. SCOPE
The quality of medicinal products in the EAC This guideline and its annexes shall be used
region has always been a concern of National as a basis for the inspection of medicinal
Medicine Regulatory Authorities. EAC NMRAs products manufacturing facilities and as a
strive to ensure quality, safety and efficacy standard to justify GMP status during the
of human and veterinary medicines and assessment of applications for manufacturing
other health care products through regulation authorizations. The annexes provide details
and control of their production, importation, on specific areas which include; sterile
distribution and use. preparations, biological medicinal products
and vaccines for human use, computerized
Through the medicine regulation systems, water for pharmaceutical use,
harmonization initiative in the EAC region, heating ventilation and air conditioning
the GMP guidelines have been developed systems, qualification & validation, GMP
to ensure that medicinal products marketed for manufacture of active pharmaceutical
in the Partner States meet uniform and ingredients, waste management for
acceptable quality, safety and efficacy. medicinal product manufacturers, quality risk
management and authorized persons.
The EAC Guide on Good Manufacturing
Practices (GMP) is based on the World Health This guideline is applicable to all
Organization (WHO) Good Manufacturing manufacturers (local and foreign) of finished
Practices guidelines in the WHO Technical pharmaceutical product formulations
Report Series No. 961, 2011. This guide and active pharmaceutical ingredients
also refers to the Pharmaceutical Inspection manufactured and marketed in the EAC region
Convention Scheme (PIC/S) guide PE 009-9. for human use.
The national drug laws across all Partner CHAPTER 1: QUALITY

States require medicinal products to be
manufactured only by manufacturers MANAGEMENT PRINCIPLE
whose activities are regularly inspected and
authorized by the EAC NMRAs or competent The manufacturer’s responsibility is to
inspectorates recognized by EAC NMRAs. ensure the quality of medicinal products
manufactured is fit for their intended use,
All manufacturers of medicinal products shall comply with the requirements of market
demonstrate, during a factory inspection, authorization and do not place patients at
compliance with manufacturing principles risk due inadequate safety, quality or efficacy.
specified in these guidelines. Local and The achievement of this objective is the
foreign manufacturers of pharmaceutical responsibility of management and requires
products to be marketed in the EAC region the participation and commitment by staff in
shall be subjected to GMP conformity different departments and at all levels within
assessment following these guidelines and the company, by the company’s suppliers and
are required to meet an acceptable standard distributors.
of GMP.
89
To achieve the quality objective reliably there QUALITY ASSURANCE

must be a comprehensively designed and
correctly implemented system of Quality 1.3 “Quality assurance” is a wide-
assurance incorporating GMP and thus ranging concept covering all matters
Quality control. It should be fully documented that individually or collectively
and its effectiveness monitored. All parts influence the quality of a product. It
of the Quality Assurance systems should is the totality of the arrangements
be adequately resourced with competent made with the objective of ensuring
personnel and suitable and sufficient that pharmaceutical products are
premises, equipment and facilities. of the quality required for their
intended use. Quality assurance
1.1 The basic concepts of Quality therefore incorporates GMP and
assurance, GMP, and Quality other factors, including those
control are inter-related aspects of outside the scope of this guide such
Quality management. They are as product design and development.
described here in order to
emphasize their relationship and The system of quality assurance
their fundamental importance to appropriate to the manufacture of
the production and control of pharmaceutical products should
pharmaceutical products. ensure that:
1.2 Quality management is defined (a) Medicinal products are designed

as the aspect of management and developed in a way that takes
function that determines and account of the requirements of
implements the “quality policy” GMP, GLP and GCP;
that is, the overall intention and (b) Production and control operations
direction of an organization as are clearly specified in a written
formally expressed and authorized form and GMP requirements are
by top management. adopted;
(c) Managerial responsibilities are
The basic elements of quality management clearly specified in job descriptions;
are: An appropriate infrastructure or “quality (d) Arrangements are made for the
system” encompassing the organizational manufacture, supply and use of the
structure, procedures, processes and correct starting and packaging
resources; and systematic actions necessary materials;
to ensure adequate confidence that a product (e) All necessary controls on starting
(or service) will satisfy given requirements for materials, intermediate products,
quality. and bulk products and any other in-
process controls, calibrations, and
validations are carried out;
(f) The finished product is correctly
processed and checked, according
to the defined procedures;
90
(g) Medicinal products are not sold and as required by the marketing
or supplied before the authorized authorization and product
persons have certified that each specifications. GMP rules are
production batch has been directed primarily to diminishing
produced and controlled in the risks, inherent in any
accordance with the requirements pharmaceutical production that
of the marketing authorization cannot be prevented completely
and any other regulations relevant through the testing of final
to the production, control and products. Such risks are essentially
release of medicinal products; of two types: cross-contamination
(h) Satisfactory arrangements exist (in particular by unexpected
to ensure, as far as possible, that contaminants) and mix-ups
the medicinal products are stored, (confusion) caused by false
distributed, and subsequently labels being put on containers. The
handled so that quality is maintained basic requirements of GMP are that:
throughout their shelf-life;
(i) There is a procedure for self- (a) all manufacturing processes are
inspection and/or quality audit that clearly defined, systematically
regularly appraises the reviewed in the light of experience,
effectiveness and applicability of the and shown to be capable of
quality assurance system; consistently manufacturing
(j) Deviations are reported, medicinal products of the required
investigated and recorded; quality that comply with their
(k) There is a system for approving specifications;
changes that may have an impact (b) critical steps of manufacturing
on product quality; processes and any significant
(l) Regular evaluation of the quality of changes made to the processes
pharmaceutical products should be are validated;
conducted with the objective of (c) all necessary facilities are provided,
verifying the consistency of including:
the process and ensuring its
continuous improvement; (i) appropriately qualified
(m) And there is a system for quality risk and trained personnel;
management (QRM); (ii) adequate premises
and space;
GOOD MANUFACTURING PRACTICES (iii) suitable equipment
(GMP) and services;
(iv) correct materials,
1.4 Good manufacturing practice is containers,
that part of quality assurance and labels;
which ensures that products (v) approved procedures
are consistently produced and and instructions;
controlled to the quality standards (vi) suitable storage and
appropriate to their intended use transport, and;
91
(vii) adequate personnel, QUALITY CONTROL

laboratories, and
equipment for in-process 1.5 Quality control is the part of GMP
controls under the concerned with sampling,
responsibility of specifications, and testing and with
the production the organization, documentation,
management. and release procedures which
ensure that the necessary and
(d) instructions and procedures are relevant tests are actually carried
written in clear and unambiguous out and that materials are neither
language, specifically applicable to released for use, nor for sale or
the facilities provided; supply, until their quality has
(e) operators are trained to carry out been judged to be satisfactory.
procedures correctly; Quality control should not be
(f) records are made (manually and/or confined to laboratory operations
by recording instruments) during but must be involved in all decisions
manufacture to show that all the concerning the quality of the
steps required by the defined product.
procedures and instructions have
in fact been taken and that the Each manufacturer should have a
quantity and quality of the product quality control department.
are as expected; any significant The independence of quality control
deviations are fully recorded from production is considered
and investigated; fundamental. The quality control
(g) records covering manufacture and department should be independent
distribution, which enable the of other departments and under
complete history of a batch to be the authority of a person with
traced, are retained in a appropriate qualifications and
comprehensible and accessible experience, who has one or
form; several control laboratories at his
(h) the proper storage and distribution or her disposal. Adequate resources
of the products minimizes any risk must be available to ensure that
to their quality; all the quality control arrangements
(i) a system is available to recall any are effectively and reliably carried
batch of product from sale or supply; out. The basic requirements for
(j) complaints about marketed products quality control are as follows:
are examined, the causes of
quality defects investigated, and (a) Adequate facilities, trained
appropriate measures taken in personnel and approved procedures
respect of the defective products must be available for sampling,
and to prevent recurrence. inspecting, and testing starting
materials, packaging materials,
intermediate, bulk, and finished
products, and where appropriate for
monitoring environmental conditions
92
for GMP purposes. together with the authorized person

(b) Samples of starting materials, from the quality control department.
packaging materials, intermediate (h) Sufficient reference samples of
products, bulk products and finished starting materials and products must
products must be taken by methods be retained to permit future
and personnel approved of by the examination of the product if
quality control department. necessary; the retained product
(c) Test methods must be well must be kept in its final pack unless
documented and validated. the pack is exceptionally large.
(d) Records must be made
(manually and/or by recording 1.6 The quality control department as a
instruments) demonstrating that all whole will also have other duties,
the required sampling, inspecting, such as to establish, validate, and
and testing procedures have implement all quality control
actually been carried out and that procedures, to evaluate, maintain,
any deviations have been fully and store the reference standards
recorded and investigated. for substances, to ensure the
(e) The finished products must contain correct labeling of containers
ingredients complying with the of materials and products, to ensure
qualitative and quantitative that the stability of the active
composition of the product pharmaceutical ingredients and
described in the marketing products is monitored, to participate
authorization; the ingredients in the investigation of complaints
must be of the required purity, in related to the quality of the product,
their proper container, and and to participate in environmental
correctly labeled. monitoring. All these operations
(f) Records must be made of the should be carried out in accordance
results of inspecting and testing with written procedures and, where
starting materials, intermediate, necessary, recorded.
bulk, and finished products against
specifications; product assessment 1.7 Assessment of finished products
must include a review and should embrace all relevant factors,
evaluation of the relevant production including the production
documentation and an assessment conditions, the results of in-
of deviations from specified process testing, the manufacturing
procedures. (including packaging)
(g) No batch of product is to be documentation, compliance with the
released for sale or supply prior specification for the finished
to certification by the authorized product, and an examination of the
person(s) that it is in accordance finished pack.
with the requirements of the
marketing authorization. In certain 1.8 Quality control personnel must have
countries, by law, the batch release access to production areas for
is a task of the authorized person sampling and investigation as
from the production department appropriate.
93
PRODUCT QUALITY REVIEW (i) a review of adequacy of any other

previous corrective actions on
1.9 Regular, periodic or rolling quality product process or equipment;
reviews of all medicinal products, (j) for new dossiers and variations
including export-only products, to the dossiers, a review of post-
should be conducted with the marketing commitments;
objective of verifying the (k) the qualification status of relevant
consistency of the existing process, equipment and utilities, e.g. heating,
the appropriateness of current ventilation and air-conditioning
specifications for both starting (HVAC), water, or compressed
materials and finished product gases; and
to highlight any trends and to (l) a review of technical agreements to
identify product and process ensure that they are up to date.
improvements. Such reviews should
normally be conducted and The manufacturer and marketing
documented annually, taking into authorization holder, where
account previous reviews, and different, should evaluate the
should include at least: results of this review and an
assessment should be made
(a) review of starting materials and whether corrective and preventive
packaging materials used for the action or any revalidation should
product, especially those from be undertaken. Reasons for such
new sources; corrective actions should be
(b) a review of critical in-process documented.
controls and finished product
results; Agreed corrective and preventive
(c) a review of all batches that failed actions should be completed in a
to meet established specification(s) timely and effective manner.
and their investigation; There should be management
(d) a review of all significant procedures for the ongoing
deviations or non-conformances, management and review of these
the related investigations and the actions and the effectiveness of
effectiveness of resultant corrective these procedures should be verified
and preventive actions taken; during self-inspection.
(e) a review of all changes made to the
processes or analytical methods; Quality reviews may be grouped by
(f) a review of dossier variations product type, e.g. solid dosage
submitted, granted or refused; forms, liquid dosage forms, or
(g) a review of the results of the stability sterile products, where scientifically
monitoring programme and any justified. Where the marketing
adverse trends; authorization holder is not the
(h) a review of all quality-related manufacturer, there should be a
returns, complaints and recalls and technical agreement in place
the investigations performed at the between the various parties that
time; defines their respective
94
responsibilities in producing CHAPTER 2: PERSONNEL

the quality review. The authorized
person responsible for final batch PRINCIPLE
certification, together with the
marketing authorization holder, The establishment and maintenance of a
should ensure that the quality satisfactory system of quality assurance
review is performed in a timely and the correct manufacture and control
manner and is accurate. of pharmaceutical products and active
ingredients rely upon people. For this
QUALITY RISK MANAGEMENT reason there must be sufficient qualified
personnel to carry out all the tasks for which
Quality risk management is a systematic the manufacturer is responsible. Individual
process for the assessment, control, responsibilities should be clearly understood
communication and review of risks to by the individuals concerned and recorded.
the quality of a pharmaceutical product.
It can both be applied proactively and GENERAL
retrospectively.
2.1 The manufacturer should have
The quality risk management system should an adequate number of personnel
ensure that: evaluation of the risk is based with the necessary qualifications
on scientific knowledge, experience with the and practical experience. The
process and ultimately links to the protection responsibilities placed on any one
of the patient; and The level of effort, formality individual should not be so
and documentation of the quality risk extensive as to present any risk
management process is commensurate with to quality.
the level of risk
2.2 The manufacturer must have an
SANITATION AND HYGIENE organization chart. All responsible
staff should have their specific
A high level of sanitation and hygiene duties recorded in written
should be practiced in every aspect of the descriptions and adequate authority
manufacture of drug products. The scope to carry out their responsibilities.
of sanitation and hygiene covers personnel, Their duties may be delegated
premises, equipment and apparatus, to designated deputies of a
production materials and containers, products satisfactory qualification level. There
for cleaning and disinfection, and anything should be no gaps or unexplained
that could become a source of contamination overlaps in the responsibilities of
to the product. Potential sources of personnel concerned with the
contamination should be eliminated through application of GMP.
an integrated comprehensive programme
of sanitation and hygiene. (For hygiene, 2.3 All personnel should be aware of
please refer to chapter 2, “Personnel”, and for the principles of GMP that affect
sanitation to chapter 3, “Premises”.) them and receive initial and
continuing training, including
95
hygiene instructions, relevant to (a) Pharmacy

their needs. All personnel should be (b) pharmaceutical sciences and
motivated to support the technology
establishment and maintenance of (c) chemistry (analytical or organic) or
high-quality standards. biochemistry,
(d) chemical engineering,
2.4 Steps should be taken to prevent (e) microbiology
unauthorized people from entering
production, storage, and quality The education for head of
control areas. Personnel who do not production should include at least
work in these areas should not use bachelor in any of the following:
them as a passageway.
(a) Pharmacy
KEY PERSONNEL (b) pharmaceutical sciences and
technology,
2.5 Key personnel include the head (c) chemistry (analytical or organic) or
of production, the head of the biochemistry,
quality unit; the head of Quality (d) chemical engineering,
Assurance, the head of quality
control, and the authorized The education for head of quality
person(s). Normally, key posts unit should include at least bachelor
should be occupied by full-time in any of the following:
personnel. The heads of production
and quality control should (a) Pharmacy
be independent of each other. In (b) pharmaceutical sciences and
large organizations, it may be technology,
necessary to delegate some of the (c) chemistry (analytical or organic)
functions; however, the or biochemistry,
responsibility cannot be delegated.
The education for head of quality
2.6 Key personnel responsible for control should include at least
supervising the manufacture and bachelor in any of the following:
quality unit including quality
assurance and quality control for (a) Pharmacy
the manufacture of pharmaceutical (b) pharmaceutical sciences and
products should possess the technology,
qualifications of a scientific (c) chemistry (analytical or organic)
education and practical experience or biochemistry,
required by the partner states drug (d) microbiology
legislations. Their education
should include the study of an 2.7 They should also have adequate
appropriate combination of at least practical experience in the
bachelors in: manufacture and quality assurance
of pharmaceutical products. In
order to gain such experience, a
96
preparatory period may be required, (l) the inspection, investigation, and

during which they should exercise taking of samples, in order to
their duties under professional monitor factors that may affect
guidance. The scientific education product quality.
and practical experience of experts
should be such as to enable them to 2.9 The head of the production
exercise independent professional department generally has the
judgment, based on the application following responsibilities:
of scientific principles and
understanding to the practical (a) to ensure that products are
problems encountered in produced and stored according to
the manufacture and quality control the appropriate documentation in
of pharmaceutical products. order to obtain the required quality;
(b) to approve the instructions relating
2.8 The heads of the production to production operations, including
and quality control departments the in-process controls, and to
generally have some shared, or ensure their strict implementation;
jointly exercised, responsibilities (c) to ensure that the production
relating to quality. These may records are evaluated and signed
include, depending on national by a designated person before
regulations: they are made available to the
quality control department;
(a) the authorization of written (d) to check the maintenance of the
procedures and other documents, department, premises, and
including amendments; equipment;
(b) the monitoring and control of the (e) to ensure that the appropriate
manufacturing environment; process validations and calibrations
(c) plant hygiene; of control equipment are performed
(d) process validation and calibration of and recorded and the reports made
analytical apparatus; available;
(e) training, including the application (f) to ensure that the required
and principles of quality assurance; initial and continuing training of
(f) the approval and monitoring of production personnel is carried out
suppliers of materials; and adapted according to need.
(g) the approval and monitoring of
contract manufacturers; 2.10 The head of the quality unit
(h) the designation and monitoring of including quality assurance and
storage conditions for materials and quality control department generally
products; has the following responsibilities:
(i) the performance and evaluation of
in process controls (a) to approve or reject starting
(j) the retention of records; materials, packaging materials, and
(k) the monitoring of compliance with intermediate, bulk, and finished
GMP requirements; products;
(b) to evaluate batch records;
97
(c) to ensure that all necessary testing assigned to them. Continuing

is carried out; training should also be given, and
(d) to approve sampling instructions, its practical effectiveness should
specifications, test methods, and be periodically assessed. Training
other quality control procedures; programs should be available,
(e) to approve and monitor analyses approved by the head of either
carried out under contract; production or quality control, as
(f) to check the maintenance of the appropriate. Training records should
department, premises and be kept.
equipment;
(g) to ensure that the appropriate 2.13 Personnel working in areas where
validations, including those of contamination is a hazard, e.g.,
analytical procedures, and clean areas or areas where
calibrations of control equipment highly active, toxic, infectious, or
are done; sensitizing materials are handled
(h) to ensure that the required initial should be given specific training.
and continuing training of quality
control personnel is carried out and 2.14 The concept of quality assurance
adapted according to need; and all the measures capable
(i) establishment, implementation and of improving its understanding and
maintenance of the quality system; implementation should be fully
(j) supervision of regular internal audits discussed during the training
or self-inspections; sessions.
(k) participation in external audits
(vendor audits); 2.15 Visitors or untrained personnel
(l) participation in validation should preferably not be taken
programmes. to production and quality control
areas. If this is unavoidable
TRAINING they should be given relevant
information in advance (particularly
2.11 The manufacturer should provide about personnel hygiene) and the
training in accordance with a written prescribed protective clothing. They
programme for all the personnel should be closely supervised.
whose duties take them into
production areas or into control 2.16 Consultants and contract staff
laboratories (including the technical, should be qualified for the services
maintenance, and cleaning they provide. Evidence of this
personnel), and for other personnel should be included in the training
whose activities could affect the records.
quality of the product.
2.12 Besides basic training on the

theory and practice of GMP, newly
recruited personnel should receive
training appropriate to the duties
98
PERSONAL HYGIENE 2.22 To ensure protection of the product

from contamination, personnel
2.17 All personnel, prior or and during should wear clean body coverings
employment, as appropriate, should appropriate to the duties they
undergo health examinations. perform, including appropriate hair
Personnel conducting visual covering. Used clothes, if reusable,
inspections should also undergo should be stored in separate closed
periodic eye examinations. containers until properly laundered
and, if necessary, disinfected or
2.18 All personnel should be trained sterilized.
in the practices of personal
hygiene. A high level of personal 2.23 Eating, drinking, smoking, chewing,
hygiene should be observed by and storage of plants, food, drinks,
all those concerned with smoking material, and personal
manufacturing processes. In medicines should not be permitted
particular, personnel should be in production, laboratory, and
instructed to wash their hands storage areas or in any other areas
before entering production areas. where they might adversely
Signs to this effect should be posted influence product quality.
and instructions observed.
2.24 Personal hygiene procedures
2.19 Any person shown at any time to including the use of protective
have an apparent illness or open clothing should apply to all persons
lesions that may adversely affect the entering production areas, whether
quality of products should not they are temporary or full-time
be allowed to handle starting employees or non-employees -
materials, packaging materials, e.g., contractors’ employees,
in-process materials, or drug visitors, senior managers,
products until the condition is no and inspectors.
longer judged to be a risk.
2.25 Any specific requirements for the
2.20 All employees should be instructed manufacture of special groups of
and encouraged to report to their products, for example sterile
immediate supervisor any conditions preparations, are covered in the
(relating to plant, equipment, or guidelines under annexes.
personnel) that they consider may
adversely affect the products. CHAPTER 3: PREMISES
2.21 Direct contact should be avoided
PRINCIPLE
between the operator’s hands
and starting materials, primary
Premises must be located, designed,
packaging materials, and
constructed, adapted, and maintained to
intermediate or bulk product.
suit the operations to be carried out. Their
layout and design must aim to minimize the
99
risk of errors and permit effective cleaning 3.6 Premises should be designed
and maintenance in order to avoid cross- and equipped so as to provide
contamination, build-up of dust or dirt, and, in maximum protection against the
general, any adverse effect on the quality of entry of insects, birds or other
products. animals. There should be a
procedure for rodent and pest
GENERAL control.
3.1 Premises should be situated in an PRODUCTION AREA

environment that, when considered
together with measures to protect 3.7 In order to minimize the risk of
the manufacturing process, presents a serious medical hazard due to
minimum risk of causing any cross-contamination, dedicated,
contamination of materials separate and self-contained
or products. facilities must be available for
the production of particular
3.2 Premises used for the manufacture pharmaceutical products, such as
of drug products should be suitably highly sensitizing materials (e.g.,
designed and constructed to penicillins, cephalosporins)
facilitate good sanitation. or biological preparations (e.g., live
microorganisms). The production
3.3 Premises should be carefully of certain additional products, such
maintained, and it should be as certain antibiotics, hormones,
ensured that repair and cytotoxic substances, highly active
maintenance operations do not medicinal products, and non-
present any hazard to the quality medicinal products, should not
of products. be conducted in the same facilities.
The manufacture of technical
3.4 Premises should be cleaned and, poisons, such as pesticides and
where applicable, disinfected herbicides, should not be allowed
according to detailed written in premises used for the
procedures and records should manufacture of pharmaceutical
be maintained. products.
3.5 Electrical supply, lighting, 3.8 Premises should preferably be laid

temperature, humidity, and out in such a way as to allow the
ventilation should be appropriate production to take place in areas
and such that they do not connected in a logical order
adversely affect, directly or corresponding to the sequence
indirectly, either the pharmaceutical of the operations, materials flow,
products during their manufacture personnel movement and to the
and storage, or the accurate requisite cleanliness levels.
functioning of equipment.
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3.9 The adequacy of the working and to the products handled, to the
in-process storage space should operations undertaken, and to the
permit the orderly and logical external environment. These
positioning of equipment and areas should be regularly monitored
materials so as to minimize the risk during production and non-
of confusion between different production periods to ensure
pharmaceutical products or their compliance with their design
components, to avoid cross- specifications.
contamination, and to minimize the
risk of omission or wrong application 3.14 Where dust is generated (e.g.
of any of the manufacturing or during sampling, weighing, mixing,
control steps. processing operations and
packaging of powders) measures
3.10 Where starting and primary should be taken to avoid cross
packaging materials and contamination and facilitate
intermediate or bulk products are cleaning.
exposed to the environment, interior
surfaces (walls, floors, and ceilings) 3.15 Premises for the packaging of
should be smooth and free from medicinal products should be
cracks and open joints, should not specifically designed and laid out so
shed particulate matter, and should as to avoid mix-ups or cross-
permit easy and effective cleaning contamination.
and, if necessary, disinfection.
3.16 Production areas should be well lit,
3.11 Pipe work, light fittings, ventilation particularly where visual on-line
points, and other services should controls are carried out.
be designed and sited to avoid the
creation of recesses that are difficult STORAGE AREAS
to clean. As far as possible, for
maintenance purposes, they should 3.17 Storage areas should be of
be accessible from outside the sufficient capacity to allow
manufacturing areas. orderly storage of the various
categories of materials and
3.12 Drains should be of adequate size products: starting and packaging
and equipped to prevent back-flow. materials, intermediates, bulk and
Open channels should be avoided finished products, products in
where possible, but if they are quarantine, and released, rejected,
necessary they should be shallow to returned, or recalled products.
facilitate cleaning and disinfection.
3.18 Storage areas should be
3.13 Production areas should be designed or adapted to ensure good
effectively ventilated, with air-control storage conditions. In particular,
facilities (including control of they should be clean and
temperature and, where necessary, dry, sufficiently lit and maintained
humidity and filtration) appropriate within acceptable temperature limits.
101
Where special storage conditions should be paid to sampling, the safe

are required (e.g., temperature, and secure storage of these
humidity) these should be provided. materials.
The conditions should be controlled,
monitored and records maintained. WEIGHING AREAS
3.19 Receiving and dispatch bays 3.25 The weighing of starting materials
should be separate and protect and the estimation of yield by
materials and products from the weighing should usually be carried
weather. Reception areas should be out in separate weighing areas
designed and equipped to allow designed for that use, for example
containers of incoming materials to with provisions for dust control.
be cleaned if necessary before
storage. QUALITY CONTROL AREAS
3.20 Where quarantine status is ensured 3.26 Quality control laboratories
by storage in separate areas, these should be separated from
areas must be clearly marked production areas. Areas where
and their access restricted to biological, microbiological, or
authorized personnel. Any system radioisotope test methods are
replacing the physical quarantine employed should be separated
should give equivalent security. from each other.
3.21 There should normally be a 3.27 Control laboratories should be

separate sampling area for starting designed to suit the operations
materials. If sampling is performed to be carried out in them. Sufficient
in the storage area, it should space should be given to avoid
be conducted in such a way as to mix-ups and cross-contamination.
prevent contamination or There should be adequate suitable
cross-contamination. storage space for samples,
reference standards (if necessary,
3.22 Segregation should be provided for with cooling), and records.
the storage of rejected, recalled, or
returned materials or products. 3.28 The design of the laboratories
should take into account the
3.23 Highly active materials, narcotics, suitability of construction materials,
other dangerous drugs, and prevention of fumes, and ventilation.
substances presenting special risks There should be separate air supply
of abuse, fire, or explosion should to laboratories and production
be stored in safe and secure areas. areas. Separate air-handling units
and other provisions are needed for
3.24 Printed packaging materials are biological, microbiological, and
considered critical to the conformity radioisotope laboratories.
of the pharmaceutical product to its
labeling, and special attention
102
3.29 A separate room may be needed GENERAL

for instruments to protect them
against electrical interference, 4.1 Manufacturing equipment must be
vibration, contact with excessive located, designed, constructed,
moisture, and other external adapted, and maintained to suit the
factors, or where it is necessary to operations to be carried out.
isolate the instruments.
4.2 Repairs and maintenance
ANCILLARY AREAS operations should not present any
hazard to the quality of the products.
3.30 Rest and refreshment rooms should
be separate from other areas. 4.3 Manufacturing equipment should
be designed so that it can be easily
3.31 Facilities for changing and storing and thoroughly cleaned. It should
clothes and for washing and be cleaned according to detailed
toilet purposes should be easily and written procedures and stored
accessible and appropriate for only in clean and dry condition.
the number of users. Toilets should
not communicate directly with 4.4 Non-dedicated equipment should
production or storage areas. be cleaned according to validated
cleaning procedures between
3.32 Maintenance workshops should if productions of different
possible be separated from pharmaceutical products to avoid
production areas. Whenever parts cross contamination.
and tools are stored in the
production area, they should be kept 4.5 Cleaning and drying equipment
in rooms or lockers reserved for should be chosen and used so as
that use. not to be a source of contamination.
3.33 Animal houses should be well 4.6 Equipment should be installed in

isolated from other areas, with such a way as to minimize any risk
separate entrance (animal access) of error or of contamination.
and air-handling facilities.
4.7 Production equipment should not
present any hazard to the products.
CHAPTER 4: EQUIPMENT
The parts of the production
PRINCIPLE equipment that come into contact
with the product must not be
The layout, design and location of equipment reactive, additive, or absorptive to
must aim to minimize the risk of errors and an extent that would affect the
permit effective cleaning and maintenance in quality of the product.
order to avoid cross-contamination, build-up of
dust or dirt, and, in general, any adverse effect 4.8 Closed equipment should be used
on the quality of products. whenever appropriate. Where open
equipment is used or equipment is
103
open, precautions should be taken 4.14 Water for pharmaceutical use

to minimize contamination. (PW, WFI) and other water pipes
should be sanitized, according to
4.9 Balances and other measuring written procedures that detail the
equipment of an appropriate action limits for microbial
range and precision should be contamination and the measures to
available for production and control be taken.
operations and should be calibrated
and checked at defined intervals 4.15 Control-laboratory equipment and
using appropriate methods. instruments should be suited to the
Adequate records of such tests testing procedures undertaken.
should be maintained.
4.16 Defective equipment should, if
4.10 Measuring, weighing, recording, possible, be removed from
and control equipment and production and quality control areas,
instruments should be serviced or at least be clearly labeled
and calibrated at pre-specified as defective.
intervals and records maintained. To
ensure satisfactory functioning, CHAPTER 5: DOCUMENTATION
instruments should be checked
daily or prior to use for performing
PRINCIPLE
analytical tests. The date of
calibration and servicing and the
Good documentation constitutes an essential
date when recalibration is due
part of the quality assurance system and,
should be clearly indicated on
as such, should be related to all aspects of
the equipment.
GMP. Its aims are to define the specifications
for all materials and methods of manufacture
4.11 Current drawings of critical
and control, to ensure that all personnel
equipment and support systems
concerned with manufacture know what to do
should be maintained.
and when to do it, to ensure that authorized
persons have all the information necessary
4.12 Fixed pipework should be clearly
to decide whether or not to release a batch of
labeled to indicate the contents and,
a drug for sale, and to provide an audit trail
where applicable, the direction
that will permit investigation of the history of
of flow.
any suspected defective batch. It ensures
the availability of data needed for validation,
4.13 All service pipings and devices
review and statistical analysis. Documents
should be adequately marked and
must be free from errors and available in
special attention paid to the
writing. The design and use of documents
provision of non-interchangeable
depend upon the manufacturer. In some cases
connections or adaptors for
some or all of the documents described below
dangerous gases and liquids.
may be brought together, but they will usually
be separate.
104
GENERAL 5.6 Any alteration made to a document

should be signed and dated; the
5.1 Documents should be designed, alteration should permit the reading
prepared, reviewed, and distributed of the original information. Where
with care. They should comply with appropriate, the reason for the
the relevant parts of the alteration should be recorded.
manufacturing and marketing
authorizations. 5.7 Records should be made or
completed when any action is taken
5.2 Documents should be approved, and in such a way that all significant
signed, and dated by appropriate activities concerning the
authorized persons. No document manufacture of pharmaceutical
should be changed without products are traceable. Records
authorization. and associated standard operating
procedures should be retained for
5.3 Documents should have at least one year after the expiry
unambiguous contents: the title, date of the finished product.
nature, and purpose should be
clearly stated. They should be 5.8 Data may be recorded by electronic
laid out in an orderly fashion and data-processing systems or by
be easy to check. Reproduced photographic or other reliable
documents should be clear means. Master formulae and
and legible. The reproduction of detailed standard operating
working documents from master procedures relating to the
documents must not allow any error system in use should be available
to be introduced through the and the accuracy of the records
reproduction process. should be checked. If
documentation is handled by
5.4 Documents should be regularly electronic data-processing methods,
reviewed and kept up to date. When only authorized persons should be
a document has been revised, a able to enter or modify data
system should exist to prevent in the computer, and there should
inadvertent use of the superseded be a record of changes and
version. Superseded documents deletions; access should be
should be retained for a specified restricted by passwords or other
period of time means and the entry of critical
data should be independently
5.5 Where documents require the entry checked. Batch records
of data, these entries should be electronically stored should be
clear, legible, and indelible. protected by back-up transfer on
Sufficient space should be provided magnetic tape, microfilm, paper
for such entries. print-outs, or other means. It is
particularly important that, during
the period of retention, the data are
readily available.
105
LABELS DOCUMENTS REQUIRED

SPECIFICATIONS AND TESTING
5.9 Labels applied to containers, PROCEDURES
equipment, or premises should be
clear, unambiguous, and in the 5.12 There should be appropriately
company’s agreed format. It is often approved and dated specifications
helpful in addition to the wording on and testing procedures for identity,
the labels to use colours to indicate content, purity, and quality for
status (for example: quarantined, starting and packaging materials,
accepted, rejected, or clean). and finished products; where
appropriate, they should also be
5.10 All finished drug products should available for intermediate and bulk
be identified by labeling, as required products. Specifications for water,
by the national legislation, bearing solvents, and reagents (e.g., acids
at least the following information: and bases) used in production
should be included.
(a) the name of the drug product;
(b) a list of the active ingredients 5.13 Testing procedures described in
(if applicable, with the International documents should be validated
Non-proprietary Names), showing in the context of available facilities
the amount of each present, and a and equipment before they are
statement of the net contents, e.g., adopted for routing testing.
number of dosage units, weight,
or volume; 5.14 Each specification and test
(c) the batch number assigned by the procedure should be approved and
manufacturer; maintained by the quality control
(d) the expiry date in an uncoded form; unit.
(e) any special storage conditions or
handling precautions that may be 5.15 Periodic revisions of the
necessary; specifications may be necessary
(f) directions for use, and warnings and to comply with new editions of
precautions that may be necessary; the national pharmacopoeia or other
and official compendia.
(g) the name and address of the
manufacturer or the company or the 5.16 Pharmacopoeias, reference
person responsible for placing the standards, reference spectra, and
product on the market. other reference materials should be
available in the quality control
5.11 For reference standards, the label laboratory.
or accompanying document should
indicate concentration, date of
manufacture, expiry date, date the
closure is first opened, and storage
conditions, where appropriate.
106
SPECIFICATIONS FOR STARTING SPECIFICATIONS FOR INTERMEDIATE

AND PACKAGING MATERIALS AND BULK PRODUCTS
5.17 Specifications for starting and 5.19 Specifications for intermediate

primary or printed packaging and bulk products should be
materials should provide, if available. The specifications
applicable description of the should be similar to specifications
materials, including: for starting materials or for finished
products, as appropriate.
a) the designated name (if applicable,
the International Nonproprietary SPECIFICATIONS FOR FINISHED
Name) and internal code reference; PRODUCTS
b) the reference, if any, to a
pharmacopoeial monograph; 5.20 Specifications for finished products
c) qualitative and quantitative should include:
requirements with acceptance limits.
(a) the designated name of the product
Depending on the company’s and the code reference where
practices other data may be added applicable;
to the specifications such as: (b) the designated name(s) of the active
ingredient(s) (if applicable, the
a) the approved supplier; International Nonproprietary
b) a specimen of printed materials; Name(s));
c) directions for sampling and testing, (c) the formula or a reference to the
or a reference to procedures; formula;
(d) storage conditions and precautions; (d) a description of the dosage form
(e) the maximum period of storage and package details;
before re-examination. (e) directions for sampling and testing
or a reference to procedures;
Packaging material should conform (f) the qualitative and quantitative
to specifications, with emphasis requirements, with acceptance
placed on the compatibility of the limits;
material with the drug product it (g) the storage conditions and
contains. The material should precautions, where applicable; and
be examined for defects as well as (h) the shelf-life.
for the correctness of identity
markings. MASTER FORMULAE AND
PROCESSING INSTRUCTIONS
5.18 Documents describing testing
procedures should state the
5.21 A formally approved master formula
required frequency for re-assaying
should exist for each product and
each starting material, as
batch size to be manufactured.
determined by its stability.
107
5.22 The master formula should include: (e) where necessary, the requirements
for storage of the products, including
(a) the name of the product, with the container, the labelling, and any
a product reference code relating to special storage conditions;
its specification; (f) any special precautions to be
(b) a description of the dosage form, observed.
strength of the product, and batch
size; PACKAGING INSTRUCTIONS
(c) a list of all starting materials to
be used (if applicable, with the 5.24 There should be formally approved
International Nonproprietary packaging instructions for each
Names), with the amount of each, product pack size and type. These
described using the designated should normally include, or make
name and a reference that is unique reference to the following:
to that material (mention should be
made of any substance that may (a) the name of the product;
disappear in the course of (b) a description of its pharmaceutical
processing); form, strength, and method of
(d) a statement of the expected final application where applicable;
yield with the acceptable limits, (c) the pack size expressed in terms of
and of relevant intermediate yields, the number, weight, or volume of
where applicable. the product in the final container;
(d) a complete list of all the packaging
5.23 The processing Instructions should materials required for a standard
include: batch size, including quantities,
sizes, and types, with the code or
(a) a statement of the processing reference number relating to the
location and the principal equipment specifications for each packaging
to be used; material;
(b) the methods, or reference to the (e) where appropriate, an example or
methods, to be used for preparing reproduction of the relevant printed
the critical equipment, e.g., cleaning packaging materials and specimens,
(especially after a change in indicating where the batch number
product), assembling, calibrating, and expiry date of the product have
sterilizing; been marked;
(c) detailed stepwise processing (f) special precautions to be observed,
instructions (e.g., checks on including a careful examination of
materials, pretreatments, the packaging area and equipment
sequence for adding materials, in order to ascertain the line
mixing times, temperatures); clearance before and after
(d) the instructions for any in-process operations ;
controls with their limits; (g) a description of the packaging
operation, including any significant
subsidiary operations, and
equipment to be used;
108
(h) details of in-process controls with production and, where appropriate,

instructions for sampling and of the person(s) who checked each
acceptance limits. of these operations (e.g., weighing);
(f) the batch number and/or analytical
BATCH PROCESSING RECORDS control number and the quantity
of each starting material actually
5.25 A batch processing record should weighed (including the batch
be kept for each batch processed. number and amount of any
It should be based on the relevant recovered or reprocessed material
parts of the currently approved added);
master formula. The method (g) any relevant processing operation
of preparation of such records or event and the major equipment
should be designed to avoid used;
transcription errors. The record (h) the in-process controls performed,
should carry the number of the the initials of the person(s) carrying
batch being manufactured. them out, and the results obtained;
(i) the amount of product obtained at
5.26 Before any processing begins, a different and pertinent stages of
check should be made that the manufacture (yield), together with
equipment and work station are comments or explanations for
clear of previous products, significant deviations from the
documents, or materials not expected yield;
required for the planned process, (j) notes on special problems including
and that the equipment is clean details, with signed authorization for
and suitable for use. This check any deviation from the master
should be recorded. formula.
5.27 During processing, the following BATCH PACKAGING RECORDS

information should be recorded
at the time each action is taken, and 5.28 A batch packaging record should be
after completion the record kept for each batch or part batch
should be dated and signed by processed. It should be based
the person responsible for the on the relevant parts of the
processing operations: packaging instructions, and the
method of preparing such records
(a) the name of the product; should be designed to avoid
(b) the number of the batch being transcription errors.
manufactured;
(c) dates and times of commencement, 5.29 Before any packaging operation
of significant intermediate stages, begins, checks should be made that
and of completion of production; the equipment and work station
(d) the name of the person responsible are clear of previous products,
for each stage of production; documents, or materials not
(e) the initials of the operator(s) of required for the planned packaging
different significant steps of operations, and that equipment
109
is clean and suitable for use. These (h) notes on any special problems,
checks should be recorded. including details of any deviation
from the packaging instructions, with
5.30 The following information should written authorization by an
be recorded at the time each action appropriate person;
is taken and, after completion, the (i) the quantities and reference number
date and the person responsible or identification of all printed
should be clearly identified by packaging materials and bulk
signature or electronic password: product issued, used, destroyed, or
returned to stock and the quantities
(a) the name of the product, the batch of product obtained to permit an
number, and the quantity of bulk adequate reconciliation.
product to be packed, as well as
the batch number and the planned PROCEDURES (SOPS) AND
quantity of finished product that will RECORDS RECEIPTS
be obtained, the quantity actually
obtained, and the reconciliation; 5.31 There should be written standard
(b) the date(s) and time(s) of the procedures and records for the
packaging operations; receipt of each delivery of each
(c) the name of the responsible person starting material and primary and
carrying out the packaging printed packaging material.
operation;
(d) the initials of the operators of the 5.32 The records of the receipts should
different significant steps; include:
(e) the checks made for identity and
conformity with the packaging (a) the name of the material on the
instructions, including the results of delivery note and the containers;
in-process controls; (b) the “in-house” name and/or code of
(f) details of the packaging operations material if different from (a);
carried out, including references (c) the date of receipt;
to equipment and the packaging (d) the supplier’s name and, if possible,
lines used, and, when necessary, manufacturer’s name;
the instructions for keeping the (e) the manufacturer’s batch or
product unpacked or a record of reference number;
returning product that has not been (f) the total quantity, and number of
packaged to the storage area; containers received;
(g) whenever possible, samples of the (g) the batch number assigned after
printed packaging materials used, receipt;
including specimens bearing (h) any relevant comment (e.g., state of
approval of the printing, the batch the containers).
number, expiry date, and any
additional overprinting;
110
5.33 There should be written standard 5.37 Analysis records should include at
operating procedures for the internal least the following data:
labeling, quarantine, and storage of
starting materials, packaging (a) the name of the material or product
materials, and other materials, as and, where applicable, dosage form;
appropriate. (b) the batch number and, where
appropriate, the manufacturer and/
SAMPLING or supplier;
(c) references to the relevant
5.34 There should be standard operating specifications and testing
procedures for sampling, which procedures;
specify the person(s) authorized to (d) test results, including observations
take samples. and calculations, and reference to
any specifications (limits);
5.35 The sampling instructions should (e) dates and reference number of
include: testing;
(f) the initials of the persons who
(a) the method of sampling and the performed the testing;
sampling plan; (g) the dates and initials of the persons
(b) the equipment to be used; who verified the testing and the
(c) any precautions to be observed to calculations, where appropriate;
avoid contamination of the material (h) a clear statement of release or
or any deterioration in its quality; rejection (or other status decision)
(d) the amount(s) of sample(s) to be and the dated signature of the
taken; designated responsible person.
(e) instructions for any required
subdivision of the sample; OTHERS
(f) the type of sample container(s) to
be used, and whether they are for 5.38 There should be a standard
aseptic sampling or for normal operating procedure describing the
sampling; details of the batch (lot) numbering
(g) any specific precautions to be system, with the objective of
observed, especially in regard to the ensuring that each batch of
sampling of sterile or noxious intermediate, bulk, or finished
material. product is identified with a specific
batch number.
TESTING
The standard operating procedures
5.36 There should be written procedures for batch numbering that are applied
for testing materials and products at to the processing stage and to the
different stages of manufacture, respective packaging stage should
describing the methods and be related to each other.
equipment to be used. The tests
performed should be recorded.
111
5.39 The standard operating procedure 5.44 Logbooks should be kept with major
for batch numbering should and critical equipment and should
assure that the same batch record, as appropriate, any
numbers will not be repeatedly validations, calibrations,
used; this applies also to maintenance, cleaning, or repair
reprocessing. operations, including dates and
the identity of the people who
5.40 Batch-number allocation should carried these operations out.
be immediately recorded, e.g., in
a logbook. The record should 5.45 Clear standard operating
include date of allocation, product procedures should be available
identity, and size of batch. for major items of manufacturing
and test equipment and placed in
5.41 Written release and rejection close proximity to the equipment.
procedures should be available for
materials and products, and in 5.46 The use of major and critical
particular for the release for sale of equipment and the areas where
the finished product by an products have been processed
authorized person. should be appropriately recorded in
chronological order.
5.42 Records should be maintained for
the distribution of each batch of a 5.47 There should be written procedures
product in order to facilitate the assigning responsibility for cleaning
recall of the batch if necessary. and sanitation and describing
in sufficient detail the cleaning
5.43 Standard operating procedures and schedules, methods, equipment,
associated records of actions taken and materials to be used and
or, where appropriate, conclusions facilities to be cleaned. Such written
reached should be available for: procedures should be followed.
• Validation CHAPTER 6: GOOD

• equipment assembly and
qualification PRACTICES IN PRODUCTION
• analytical apparatus and calibration;
• maintenance, cleaning, and PRINCIPLE
sanitization;
• personnel matters including Production operations must follow clearly
qualification, training, clothing, and defined procedures in accordance with
hygiene; manufacturing and marketing authorizations,
• environmental monitoring; with the objective of obtaining products of the
• pest control; requisite quality.
• complaints;
• recalls;
• returns.
112
GENERAL 6.6 At all times during processing, all

materials, bulk containers, major
6.1 Production should be performed items of equipment, and where
and supervised by competent appropriate the rooms and
people. packaging lines used should
be labeled or otherwise identified
6.2 All handling of materials and with an indication of the product or
products, such as receipt and material being processed, its
cleaning, quarantine, sampling, strength (where applicable), and
storage, labeling, dispensing, the batch number. Where
processing, packaging, and applicable, this indication should
distribution should be done in also mention the stage of
accordance with written procedures production.
or instructions and, where
necessary, recorded. Materials 6.7 Access to production premises
include starting materials, packaging should be restricted to authorized
materials, gases, solvents, process personnel.
aids, reagents and labeling
materials. 6.8 Normally, non-medicinal products
should not be produced in areas or
6.3 Any deviation from instructions with equipment destined for the
or procedures should be avoided as production of pharmaceutical
far as possible. If deviations occur, products.
they should be done in accordance
with an approved procedure; the 6.9 In-process controls are mostly
authorization of the deviation performed within the production
should be approved in writing by a area. They should not carry any risk
designated person, with the for the quality of the product.
involvement of the quality control
department, when appropriate. PREVENTION OF CROSS-
CONTAMINATION AND BACTERIAL
6.4 Checks on yields and reconciliation CONTAMINATION IN PRODUCTION
of quantities should be carried out
as necessary to ensure that there 6.10 When dry materials and products
are no discrepancies outside are used in production, special
acceptable limits. pre-cautions should be taken to
prevent the generation and
6.5 Operations on different products dissemination of dust. Provision
should not be carried out should be made for proper air
simultaneously or consecutively in control (e.g supply and extraction of
the same room or area unless there air of suitable quality)
is no risk of mix-up or cross-
contamination. 6.11 Contamination of a starting
material or of a product by another
113
material or product has to be of untreated or insufficiently treated

avoided. This risk of accidental air;
cross-contamination arises from (e) wearing protective clothing in areas
the uncontrolled release of dust, where products with special risk of
gases, vapours, sprays, or cross-contamination are processed;
organisms from materials and (f) using cleaning and decontamination
products in process, from residues procedures of known effectiveness,
on equipment, from intruding as ineffective cleaning of equipment
insects, and from operators’ is a common source of cross-
clothing, skin, etc. The significance contamination;
of this risk varies with the type (g) using a “closed system” of
of contaminant and of the product production;
being contaminated. Among the (h) testing for residues;
most hazardous contaminants (i) using cleanliness status labels on
are highly sensitizing materials, equipment.
biological preparations such as
living organisms, certain hormones, 6.13 Measures to prevent cross-
cytotoxic substances, and other contamination and their
highly active materials. Products effectiveness should be checked
in which contamination is likely to periodically according to standard
be most significant are those operating procedures.
administered by injection or applied
to open wounds and those given in 6.14 Production areas where susceptible
large doses and/or over a long time. products are processed should
undergo periodic environmental
6.12 Cross-contamination should monitoring (e.g for microbiological
be avoided by appropriate technical monitoring and particulate matter
or organizational measures, for where appropriate.
example:
6.15 No materials used for operations
(a) production in dedicated and self such as cleaning, lubrication of
-contained areas (which may be equipment and pest control, should
required for products such as come into direct contact with the
penicillins, live vaccines, live product. Where possible, such
bacterial preparations and certain materials should be of a suitable
other biologicals), grade (e.g food grade) to minimize
(b) conducting campaign production health risks.
(separation in time) followed by
appropriate cleaning in accordance 6.16 Water used in the manufacture of
with a validated cleaning procedure; pharmaceutical products should be
(c) providing appropriate airlocks, suitable for its intended use.
pressure differentials, and air
extraction;
(d) minimizing the risk of contamination
caused by recirculation or re-entry
114
VALIDATION specifications established by

the manufacturer for the starting
6.17 Validation studies should reinforce materials be discussed and
Good Manufacturing Practices and agreed upon with the suppliers. It
be conducted in accordance with is of benefit that all aspects of the
defined procedures. Results and production and control of the
conclusions should be recorded. starting material in question,
including handling, labeling, and
6.18 Whenever a new manufacturing packaging requirements as well
formula or method of preparation as complaints and rejection
is adopted, steps should be taken procedures, are discussed and
to demonstrate its suitability for agreed upon between the
routine processing. The defined manufacturer and the supplier.
process, using the materials and
equipment specified, should be 6.23 For each consignment, the
shown to consistently yield a containers should be checked
product of the required quality. for integrity of package and seal and
for correspondence between the
6.19 Significant amendments to the order, the delivery note, and the
manufacturing process, including supplier’s labels.
any change in equipment or
materials, which may affect product 6.24 All incoming materials should be
quality and/or the reproducibility of checked to ensure that the
the process, should be validated. consignment corresponds to the
order. Containers should be cleaned
6.20 Processes and procedures should where necessary and labeled, if
undergo periodic critical revalidation required, with the prescribed data.
to ensure that they remain capable Where additional labels are
of achieving the intended results. attached to containers, the original
information should not be lost.
STARTING MATERIALS
6.25 Damage to containers and any
6.21 The purchase of starting materials other problem that might adversely
is an important operation that affect the quality of a material
should involve staff who have a should be recorded and reported
particular and thorough knowledge to the quality control department
of the products and suppliers. and investigated.
6.22 Starting materials should be 6.26 If one delivery of material is made

purchased only from suppliers up of different batches, each batch
named in the relevant specification must be considered as separate for
and, where possible, directly from sampling, testing, and release.
the producer. It is also
recommended that the 6.27 Starting materials in the storage
area should be appropriately
115
labeled. Labels should bear at least 6.32 Materials dispensed for each batch
the following information: of the final product should be kept
together and conspicuously labeled
(a) the designated name of the product as such.
and the internal code reference
where applicable; 6.33 All incoming materials and finished
(b) the batch number(s) given by the products should be quarantined
supplier and on receipt by the immediately after receipt or
manufacturer, if any; processing, until they are released
(c) where appropriate, the status of for use or distribution.
the contents (e.g., on quarantine, on
test, released, rejected, returned, 6.34 All materials and products should
recalled); be stored under the appropriate
(d) where appropriate, an expiry date or conditions established by the
a date beyond which retesting is manufacturer and in an orderly
necessary. fashion to permit batch segregation
and stock rotation by a first-expiry,
When fully computerized storage first-out rule.
systems are used, not all of the
above information need be in a PROCESSING OPERATIONS:
legible form on the label. INTERMEDIATE AND BULK
PRODUCTS
6.28 There should be appropriate
procedures or measures to ensure 6.35 Before any processing operation is
the identity of the contents of each started, steps should be taken to
container of starting material. Bulk ensure that the work area and
containers from which samples have equipment are clean and free from
been drawn should be identified. any starting materials, products,
product residues, labels, or
6.29 Only starting materials released by documents not required for the
the quality control department and current operation.
within their shelf-life should be used.
6.36 Intermediate and bulk products
6.30 Starting materials should be should be kept under appropriate
dispensed only by designated conditions.
persons, following a written
procedure, to ensure that the correct 6.37 Intermediate and bulk products
materials are accurately weighed purchased as such should be
or measured into clean and properly handled on receipt as though they
labeled containers. were starting materials.
6.31 Each dispensed material and its 6.38 Any necessary in-process controls
weight or volume should be and environmental controls should
independently checked and the be carried out and recorded.
check recorded.
116
6.39 Means should be instituted of avoid mix-ups. Packaging materials

indicating failures of equipment or should be issued for use only by
of services (e.g., water, gas) to designated personnel following an
equipment. Defective equipment approved and documented
should be withdrawn from use until procedure.
the defect has been rectified.
6.46 Each delivery or batch of printed or
6.40 Time limits for storage of equipment primary packaging material should
after cleaning and before use should be given a specific reference
be stated and based on data. number or identification mark.
6.41 Containers for filling should be 6.47 Outdated or obsolete primary

cleaned before filling. Attention packaging material or printed
should be given to avoiding and packaging material should be
removing any contaminants such as destroyed and its disposal recorded.
glass fragments and metal particles.
PACKAGING OPERATIONS
6.42 Any significant deviation from
the expected yield should be 6.48 When the program for packaging
recorded and investigated. operations is being set up, particular
attention should be given to
6.43 Checks should be carried out minimizing the risk of cross-
to ensure that pipelines and contamination, mix-ups, or
other pieces of equipment used for substitutions. Different products
the transportation of products from should not be packaged in close
one area to another are connected proximity unless there is physical
in a correct manner. segregation or the use of electronic
surveillance.
PACKAGING MATERIALS
6.49 Before packaging operations are
6.44 The purchase, handling, and control begun, steps should be taken to
of primary and printed packaging ensure that the work area,
materials shall be as for starting packaging lines, printing machines,
materials. and other equipment are clean
and free from any products,
6.45 Particular attention should be paid materials, or documents previously
to printed packaging materials. They used and not required for the
should be stored in secure current operation. The line
conditions so as to exclude the clearance should be performed
possibility of unauthorized access. according to an appropriate
Roll feed labels should be used procedure, checklist and recorded.
wherever possible. Cut labels
and other loose printed materials
should be stored and transported in
separate closed containers so as to
117
6.50 The name and batch number of the to ensure that any electronic code
product being handled should be readers, label counters, or similar
displayed at each packaging station devices are operating correctly.
or line. When labels are attached manually,
in-process control checksshould be
6.51 All products and packaging performed more frequently.
materials to be used should
be checked on delivery to 6.56 Checks should be made to ensure
the packaging department for that any electronic code readers,
quantity , identity and conformity label counters, or similar devices
with the packaging instructions. are operating correctly.
6.52 Containers for filling should be clean 6.57 Printed and embossed information
before filling. Attention should on packaging materials should be
be given to avoiding and removing distinct and resistant to fading
any contaminants such as glass or erasing.
fragments and metal particles.
6.58 On-line control of the product during
6.53 Normally, filling and sealing should packaging should include at least
be followed as quickly as possible checks on:
by labeling. If labeling is delayed,
appropriate procedures should (a) the general appearance of the
be applied to ensure that no mix-ups packages;
or mislabeling can occur. (b) whether the packages are complete;
(c) whether the correct products and
6.54 The correct performance of any packaging materials are used;
printing (for example of code (d) whether any overprinting is correct;
numbers or expiry dates) done (e) the correct functioning of line
separately or in the course of the monitors.
packaging should be checked and
recorded. Attention should be Samples taken away from the
paid to printing by hand, which packaging line should not be
should be rechecked at regular returned.
intervals.
6.59 Products that have been involved in
6.55 Special care should be taken when an unusual event during packaging
cut labels are used and when should be reintroduced into
overprinting is carried out off-line, the process only after special
and in hand-packaging operations. inspection, investigation, and
Roll-feed labels are normally approval by authorized personnel.
preferable to cut labels in helping to A detailed record should be kept of
avoid mix-ups. Online verification of this operation.
all labels by automated electronic
means can be helpful in preventing
mix ups, but checks should be made
118
6.60 Any significant or unusual and stored separately in restricted

discrepancy observed during areas. They should either
reconciliation of the amount of be returned to the suppliers or,
bulk product and printed packaging where appropriate, reprocessed or
materials and the number of destroyed in a timely manner.
units produced should be Whatever action is taken should
investigated and satisfactorily be approved by authorized
accounted for before release. personnel and recorded.
6.61 Upon completion of a packaging 6.65 The reprocessing of rejected

operation, any unused batch-coded products should be exceptional. It is
packaging materials should be permitted only if the quality
destroyed and the destruction of the final product is not affected,
recorded. Upon completion of a if the specifications are met, and if
packaging operation, any unused it is done in accordance with a
batch-coded packaging materials defined and authorized procedure
should be destroyed and the after evaluation of the risks involved.
destruction recorded. A documented A record should be kept of the
procedure requiring checks to be reprocessing. A reprocessed batch
performed before returningunused should be given a new batch
materials should be followed if number.
uncoded printed materials are
returned to stock 6.66 The introduction of all or part of
earlier batches, conforming to the
FINISHED PRODUCTS required quality, into a batch
of the same product at a defined
6.62 Finished products should be held in stage of manufacture should be
quarantine until their final release, authorized beforehand. This
after which they should be stored as recovery should be carried out in
usable stock under conditions accordance with a defined
established by the manufacturer. procedure after evaluation of the
risks involved, including any
6.63 The evaluation of finished products possible effect on shelf-life. The
and the documentation necessary recovery should be recorded.
for release of a product for sale are
described in Chapter 7, “Good 6.67 The need for additional testing
practices in quality control”. of any finished product that has
been reprocessed, or into which
REJECTED, RECOVERED a recovered product has been
REPROCESSED AND RETURNED incorporated, should be considered
by the quality control department.
MATERIALS
6.68 Products returned from the market
6.64 Rejected materials and products
should be destroyed unless it is
should be clearly marked as such
certain that their quality is
119
satisfactory; they may be MISCELLANEOUS

considered for resale, re-labelling,
or bulking with a subsequent 6.71 Rodenticides, insecticides,
batch only after they have been fumigating agents, and sanitizing
critically assessed by the quality materials should not be permitted
control department in accordance to contaminate equipment, staring
with a written procedure. The nature materials, packaging materials, in-
of the product, any special storage process materials, or finished
conditions it requires, its condition products.
and history, and the time elapsed
since it was issued should all be
taken into account in this
CHAPTER 7: GOOD
assessment. Where any doubt PRACTICES IN QUALITY
arises over the quality of the CONTROL
product, it should not be considered
suitable for reissue or reuse, PRINCIPLE
although basic chemical
reprocessing to recover the active Quality control is concerned with sampling,
ingredient may be possible. Any specifications, and testing as well as with the
action taken should be appropriately organization, documentation, and release
recorded. procedures that ensure that the necessary
and relevant tests are carried out, and that
WASTE MATERIALS materials are not released for use, nor
products released for sale or supply, until
6.69 Provision should be made for the their quality has been judged satisfactory.
proper and safe storage of waste Quality control is not confined to laboratory
materials awaiting disposal. Toxic operations, but must be involved in all
substances and flammable decisions that may concern the quality of the
materials should be stored in product. The independence of quality control
suitably designed, separate, from production is considered fundamental to
enclosed cupboards, as required by the satisfactory operation of Quality control.
national legislation.
GENERAL
6.70 Waste material should not be
allowed to accumulate. It should be 7.1 Each holder of manufacturing
collected in suitable receptacles authorization should have a Quality
for removal to collection points Control Department. This
outside the buildings and disposed department should be independent
of safely and in a sanitary manner at from other departments and under
regular and frequent intervals. the authority of a person with
appropriate qualifications and
experience, who has one or several
control laboratories at his disposal.
Adequate resources must be
120
available to ensure that all the recommended that records be kept

Quality Control arrangements are in a manner permitting trend
effectively and reliably carried out. evaluation.

7.2 The principle duties of the head 7.6 In addition to the information which
of Quality Control and the is part of the batch record, other
Quality Control department as original data such as laboratory
a whole are summarized in Chapter notebooks and/or records should be
1. All these operations should retained and readily available.
be carried out in accordance with
written procedures and, where SAMPLING
necessary, recorded.
7.7 The sample taking should be
DOCUMENTATION done in accordance with approved
written procedures that describe:
7.3 Laboratory documentation should
follow the principles given in chapter • the method of sampling;
5. An important part of this • the equipment to be used;
documentation deals with Quality • the quantity of sample to be taken;
Control and the following details • instructions for any required sub-
should be readily available to the division of the sample;
Quality Control Department. • the type and condition of the sample
container to be used;
• Specifications; • the identification of containers
• Sampling procedures; sampled;
• Testing procedures and records • any special precautions to be
(including analytical worksheets observed, especially with regard to
and/or laboratory notebooks) the sampling of sterile or noxious
• Analytical reports and/or certificates; materials
• Data from environmental monitoring, • the storage conditions
where required; • instructions for the cleaning and
• Validation records of test methods, storage of sampling equipment.
where applicable;
• Procedures for and record for 7.8 Reference samples should be
calibration of instruments and representative of the batch of
maintenance of equipment. materials or products from which
they are taken.
7.4 Any Quality Control documentation
relating to a batch record should be 7.9 Reference samples from each batch
retained for one year after the expiry of finished products should be
date of the batch. retained till one year after the
expiry date. Finished products
7.5 For some kinds of data (e.g. should usually be kept in their final
analytical test results, yields, packaging and stored under the
environmental controls) it is recommended conditions. If
121
exceptionally large packages are 7.13 Care should be taken during

produced, smaller samples might be sampling to guard against
stored in appropriate containers. contamination or mix-up of, or by,
Samples of starting materials (other the material being sampled. All
than solvents, gases and water) sampling equipment that comes
should be retained for at least one into contact with the material
year beyond the expiry date of the should be clean. Some particularly
product if their stability allows. This hazardous or potent materials may
period may be shortened if their require special precautions.
stability, as mentioned in the
relevant specification, is shorter. 7.14 Sampling equipment should be
Reference samples of materials cleaned and, if necessary, sterilized
and products should be of a before and after each use and
size sufficient to permit at least two stored separately from other
full examination. laboratory equipment.
CONTROL OF STARTING MATERIALS 7.15 Each sample container should bear

AND INTERMEDIATE, BULK a label indicating:
PRODUCTS
(a) the name of the sampled material;
7.10 All tests should follow the (b) the batch or lot number;
instructions given in the relevant (c) the number of the container from
written test procedure for each which the sample has been taken;
material or product. The result (d) the number of the sample
should be checked by the (e) the signature of the person who has
supervisor before the material or taken the sample; and
product is released or rejected. (f) the date of sampling.
7.11 Samples should be representative TEST REQUIREMENTS

of the batches of material from STARTING AND PACKAGING
which they are taken. Other MATERIALS
samples may also be taken to
monitor the most stressed part of a 7.16 Before releasing a starting or
process (e.g. beginning or end of a packaging material for use, the
process). quality control manager should
ensure that the materials have
7.12 Sampling should be carried out so been tested for conformity with
as to avoid contamination or other specifications for identity, strength,
adverse effects on quality. The purity, and other quality parameters.
containers that have been sampled
should be marked accordingly and 7.17 An identity test should be conducted
carefully resealed after sampling. on a sample from each container of
starting material.
122
7.18 In lieu of testing by the satisfactory conformity to its finished

manufacturer, a certificate of product specification prior to
analysis may be accepted from release.
the supplier, provided that the
manufacturer establishes the 7.21 Products failing to meet the
reliability of the supplier’s analysis established specifications or any
through appropriate periodic other relevant quality criteria should
validation of the supplier’s test be rejected. Reprocessing may be
results (see sections 10.7 and performed, if feasible, but the
10.8) and through on-site audits reprocessed product should meet all
of the supplier’s capabilities. (This specifications and other quality
does not affect section 7.18). criteria prior to its acceptance and
Certificates must be originals release.
(not photocopies) or otherwise have
their authenticity assured. BATCH RECORD REVIEW
Certificates must contain the
following information: 7.22 Production and control records
should be reviewed and any
(a) identification of the issuing supplier, divergence or failure of a batch to
signature of the competent official, meet its specifications should be
and statement of his or her thoroughly investigated. The
qualifications; investigation should, if necessary,
(b) the name and batch number of the extend to other batches of the
material tested; same product and other products
(c) a statement of specifications and that may have been associated with
methods used; and the specific failure or discrepancy.
(d) a statement of test results obtained A written record of the investigation
and the date of testing. should be made and should include
the conclusion and follow-up action.
Each batch (lot) of printed
packaging materials must be 7.23 Out-of-specification results obtained
examined following receipt during testing of materials or
products should be investigated
IN-PROCESS CONTROL in accordance with an approved
procedure. Records should be
7.19 In-process control records should maintained.
be maintained and form a part of the
batch records (see section 6.24). STABILITY STUDIES
FINISHED PRODUCTS 7.24 After marketing, the stability of

the medicinal product should
7.20 For each batch of drug product, be monitored according to a
there should be an appropriate continuous appropriate programme
laboratory determination of that will permit the detection of
123
any stability issue (e.g. changes (stability chambers among others)

in levels of impurities, or dissolution should be qualified and maintained.
profile) associated with the
formulation in the marketed 7.28 The number of batches and
package. frequency of testing should provide
a sufficient amount of data to
7.25 The purpose of the on-going stability allow for trend analysis. Unless
programme is to monitor the product otherwise justified, at least one
over its shelf life and to determine batch per year of product
that the product remains, and can manufactured in every strength
be expected to remain, within and every primary packaging type,
specifications under the labeled if relevant, should be included in
storage conditions. the stability programme (unless
none are produced during that
7.26 This mainly applies to the medicinal year). For products where on-going
product in the package, in which stability monitoring would normally
it is sold, but consideration require testing using animals and no
should also be given to the inclusion appropriate alternative, validated
in the programme of bulk product. techniques are available, the
For example, when the bulk frequency of testing may take
product is stored for a long period account of a risk-benefit approach.
before being packaged and/ The principle of bracketing
or shipped from a manufacturing and matrixing designs may be
site to a packaging site, the impact applied if scientifically justified in the
on the stability of the packaged protocol.
product should be evaluated and
studied under ambient conditions. 7.29 In certain situations, additional
In addition, consideration should batches should be included in the
be given to intermediates that are on-going stability programme. For
stored and used over prolonged example, an on-going stability study
periods. Stability studies on should be conducted after any
reconstituted product are performed significant change or significant
during product development and deviation to the process or package.
need not be monitored on an on- Any reworking, reprocessing or
going basis. However, when recovery operation should also be
relevant, the stability of considered for inclusion.
reconstituted product can also be
monitored. 7.30 Results of on-going stability studies
should be made available to key
7.27 The on-going stability programme personnel and, in particular, to the
should be described in a written Authorised Person(s). Where on-
protocol following the general rules going stability studies are carried
of Chapter 5 and results formalised out at a site other than the site of
as a report. The equipment used manufacture of the bulk or finished
for the on-going stability programme product, there should be a written
124
agreement between the parties (a) a complete description of the drug

concerned. Results of on-going involved in the study;
stability studies should be available (b) the complete testing parameters
at the site of manufacture for review and methods describing all tests for
by the competent authority. potency, purity, and physical
characteristics and documented
7.31 Out of specification or significant evidence that these tests indicate
atypical trends should be stability;
investigated. Any confirmed out of (c) provision for the inclusion of a
specification result, or significant sufficient number of batches;
negative trend, should be reported (d) the testing schedule for each drug;
to the relevant competent (e) provision for special storage
authorities. The possible impact on conditions;
batches on the market should be (f) provision for adequate sample
considered in accordance retention; and
with chapter 9 of the GMP Guide (g) a summary of all the data
and in consultation with the NMRA generated, including the evaluation
in the member state. and the conclusions of the study.
7.32 A summary of all the data 7.36 Stability should be determined prior
generated, including any interim to marketing and following any
conclusions on the programme, significant changes in processes,
should be written and maintained. equipment, packaging materials,
This summary should be subjected etc.
to periodic review.
REAGENTS AND CULTURE MEDIA
7.33 The quality control department
should evaluate the quality and 7.37 All reagents and culture media
stability of finished pharmaceutical should be recorded upon receipt or
products and, when necessary, of preparation.
starting materials and intermediate
products. 7.38 Reagents made up in the laboratory
should be prepared according to
7.34 The quality control department written procedures and
should establish expiry dates and appropriately labeled. The
shelf-life specifications on the basis label should indicate the
of stability tests related to storage concentration, standardization
conditions. factor, shelf-life, the date when
re-standardization is due, and
7.35 A written programme for ongoing the storage conditions. The label
stability determination should should be signed and dated by the
be developed and implemented to person preparing the reagent.
include elements such as:
125
7.39 Both positive and negative controls

should be applied to verify the 7.44 Secondary or working standards
suitability of culture media. The may be established by the
size of the inoculum used in application of appropriate tests
positive controls should be and checks at regular intervals to
appropriate to the sensitivity ensure standardization.
required.
7.45 All in-house reference standards
REFERENCE STANDARDS should be standardized against an
official reference standard, when
7.40 Reference standards may be available, initially and at regular
available in the form of official intervals thereafter.
reference standards. Official
reference standards are 7.46 All reference standards should be
those obtained from official stored and used in a manner that
recognized pharmacopeia source will not adversely affect their quality.
for example B.P, Ph. Eur, Ph. Int.,
USP CHAPTER 8: CONTRACT
7.41 Reference standards prepared PRODUCTION AND ANALYSIS
by the producer should be tested,
released, and then stored in PRINCIPLE
the same way as official standards.
They should be kept under the Contract production and analysis must be
responsibility of a designated correctly defined, agreed, and controlled in
person in a secure area. order to avoid misunderstandings that could
result in a product or work or analysis of
7.42 Reference standards should be unsatisfactory quality. There must be a written
properly labelled with at least the contract between the contract giver and the
following information: contract accepter which clearly establishes
the duties of each party. The contract must
(a) name of the material; clearly state the way in which the authorized
(b) batch or lot number and control person, in releasing each batch of product
number; for sale or issuing the certificate of analysis,
(c) date of preparation; exercises his or her full responsibility.
(d) shelf-life;
(e) potency; GENERAL
(f) storage conditions.
8.1 All arrangements for contract
7.43 Official reference standards should manufacture and analysis, including
be used only for the purpose any proposed changes in technical
described in the appropriate or other arrangements, should be in
monograph. accordance with the marketing
authorization for the product
concerned.
126
8.2 There should be a written contract specifications or that the product

covering the manufacture and/or has been released by the authorized
analysis arranged under contract person(s).
and any technical arrangements
made in connection with it. THE CONTRACT ACCEPTER
8.3 The contract should permit the 8.8 The contract accepter must have
contract giver to audit the facilities adequate premises, equipment,
of the contract accepter. knowledge, and experience and
competent personnel to carry
8.4 In the case of contract analysis, the out satisfactorily the work ordered
final approval for release must by the contract giver. Contract
be given by the authorized manufacture may be undertaken
person(s) of the contract giver. only by a manufacturer who holds a
manufacturing authorization.
THE CONTRACT GIVER
8.9 The contract accepter should not
8.5 The contract giver is responsible pass to a third party any of the
for assessing the competence of work entrusted to him or her under
the contract accepter in successfully the contract without the contract
carrying out the work or tests giver’s prior evaluation and approval
required and for ensuring by means of the arrangements. Arrangements
of the contract that the principles of made between the contract accepter
GMP described in this guide are and any third party should ensure
followed. that the manufacturing and
analytical information is made
8.6 The contract giver should provide available in the same way as
the contract accepter with all between the original contract giver
the information necessary to carry and contract accepter.
out the contracted operations
correctly in accordance with the 8.10 The contract accepter should refrain
marketing authorization and any from any activity that may adversely
other legal requirements. The affect the quality of the product
contract giver should ensure that manufactured and/or analyzed for
the contract accepter is fully aware the contract giver.
of any problems associated with
the product, work, or tests that THE CONTRACT
might pose a hazard to premises,
equipment, personnel, other 8.11 A contract should be drawn up
materials, or other products. between the contract giver and
the contract accepter that specifies
8.7 The contract giver should ensure their respective responsibilities
that all processed products and relating to the manufacture and
materials delivered by the contract control of the product. Technical
accepter comply with their
127
aspects of the contract should be 8.15 The contract should describe the
drawn up by competent persons handling of starting materials,
suitably knowledgeable in intermediate and bulk products, and
pharmaceutical technology, finished products if they are
analysis, and GMP. All rejected. It should also describe
arrangements for production and the processing of information if
analysis must be in accordance with the contract analysis shows that the
the marketing authorization and tested product must be rejected.
agreed by both parties.
8.16 Technical aspects of the contract
8.12 The contract should specify the should be drawn up by
way in which the authorized person competentpersons suitably
releasing the batch for sale ensures knowledgeable in pharmaceutical
that each batch has been technology, analysis and GMP.
manufactured in, and checked
for, compliance with the 8.17 All arrangements for production
requirements of the marketing and analysis must be in
authorization. accordance with the marketing
authorization and agreed by both
8.13 The contract should describe parties.
clearly who is responsible for
purchasing, testing, and releasing CHAPTER 9: COMPLAINTS
materials and for undertaking
production and quality controls, HANDLING AND PRODUCT
including in-process controls, and RECALL
who has responsibility for sampling
and analysis. In the case of contract PRINCIPLE
analysis, the contract should
state whether or not the contract All complaints and other information
accepter should take samples at the concerning potentially defective products
premises of the manufacturer. must be carefully reviewed according to
written procedures. In order to provide for all
8.14 Manufacturing, analytical, and contingencies, a system should be designed
distribution records and reference to recall, if necessary, promptly and effectively
samples should be kept by, or be products known or suspected to be defective
available to, the contract giver. from the market complaints.
Any records relevant to assessing
the quality of a product in the event 9.1 A person responsible for handling
of complaints or a suspected defect the complaints and deciding the
must be accessible and specified measures to be taken should be
in the defect/recall procedures of designated, together with sufficient
the contract giver. supporting staff to assist him or her.
If this person is different from the
authorized person, the latter
128
should be made aware of any should be recorded and referenced

complaint, investigation, or recall. to the corresponding batch records.
9.2 There should be written procedures 9.8 Complaints records should be

describing the action to be taken, regularly reviewed for any indication
including the need to consider a of specific or recurring problems that
recall, in the case of a complaint require attention and might justify
concerning a possible product the recall of marketed products.
defect.
9.9 The competent authorities should
9.3 Any complaint concerning a product be informed if a manufacturer is
defect should be recorded with considering action following possibly
all the original details and faulty manufacture, product
thoroughly investigated. The person deterioration, or any other serious
responsible for quality control quality problems with a product.
should normally be involved in the
study of such problems. PRODUCT RECALL
9.4 If product defect is discovered or 9.10 A person responsible for the
suspected in a batch, consideration execution and coordination of
should be given to whether other recalls should be designated, as
batches should be checked in order well as sufficient staff to handle all
to determine whether they are also aspects of the recalls with the
affected. In particular, other batches appropriate degree of urgency.
that may contain reprocessed This person should normally
product from the defective batch be independent of sales and
should be investigated. marketing department. If this person
is different from the authorized
9.5 Immediate corrective actions person, the latter should be made
should be taken to address the aware of any recall operation.
root cause of the problem, and
actions should be taken to prevent it 9.11 There should be established written
from recurring. There should be procedures, regularly checked and
active follow-up of the updated, for the organization of
implementation of corrective any recall activity. Recall operations
actions. should be capable of being initiated
promptly at least down to the level
9.6 Where necessary, appropriate of an hospital or pharmacy or any
follow-up action, possibly including authorized drug outlet.
product recall, should be taken after
investigation and evaluation of the 9.12 All competent authorities of all
complaint. countries to which a given product
may have been distributed should
9.7 All the decisions and measures be promptly informed of any
taken as a result of a complaint intention to recall the product
129
because it is, or is suspected of designed to detect any Shortcomings in the

being, defective. implementation of GMP and to recommend
the necessary corrective actions. Self-
9.13 The distribution records should be inspections should be performed routinely,
readily available to a person and may be, in addition, performed on special
responsible for recalls, and they occasions, e.g. in the case of product recalls
should contain sufficient information or repeated rejections, or when an inspection
on wholesalers and directly supplied by the health authorities is announced. The
customers (including, for exported team responsible for self-inspection should
products, those who have received consist of personnel who can evaluate
samples for clinical tests and the implementation of GMP objectively. All
medical samples) to permit an recommendations for corrective action should
effective recall. be implemented. The procedure for self-
inspection should be documented, and there
9.14 The progress of the recall process should be an effective follow-up programme.
should be monitored and recorded.
Records should include the Items for self-inspection
disposition of the product. A
final report should be issued, 10.2 Written instructions for self-
including reconciliation between inspection should be established
the delivered and recovered to provide a minimum and uniform
quantities of the products. standard of requirements. These
may include questionnaires on GMP
9.15 The effectiveness of the requirements covering at least the
arrangements for recalls should be following items:
tested and evaluated from time
to time. (a) personnel;
(b) premises including personnel
9.16 Recalled products should be facilities;
identified and stored separately in a (c) maintenance of buildings and
secure area until a decision is taken equipment;
on their fate. The decision should be (d) storage of starting materials and
made as soon as possible. finished products;
(e) equipment;
CHAPTER 10: SELF - (f) production and in-process controls;
(g) QC;
INSPECTION, QUALITY (h) documentation;
AUDITS, SUPPLIER AUDITS (i) sanitation and hygiene;
(j) validation and revalidation
AND APPROVALS programmes;
(k) calibration of instruments or
The purpose of self-inspection is to evaluate
measurement systems;
the manufacturer’s compliance with GMP
(l) recall procedures;
in all aspects of production and QC. The
(m) complaints management;
self-inspection programme should be
(n) labels control;
130
(o) results of previous self-inspections of all or part of a quality system

and any corrective steps taken. with the specific purpose of
improving it. A quality audit is
Self-inspection team usually conducted by outside or
independent specialists or a team
10.3 Management should appoint a self- designated by the management
inspection team consisting of for this purpose. Such audits may
experts in their respective fields and also be extended to suppliers
familiar with GMP. The members and contractors (see section 8,
of the team may be appointed from “Contract production and analysis”).
inside or outside the company.
Vendors’/Suppliers’ audits and approval
Frequency of self-inspection
10.8 The person responsible for QC
10.4 The frequency at which self- should have responsibility together
inspections are conducted may with other relevant departments for
depend on company requirements approving vendor/suppliers who
but should preferably be at least can reliably supply starting and
once a year. The frequency should packaging materials that meet
be stated in the procedure. established specifications.
Self-inspection report 10.9 Before suppliers are approved

and included in the approved
10.5 A report should be made at the supplier’s list or specifications, they
completion of a self-inspection. The should be evaluated. The evaluation
report should include: should take into account a
vendor’s/supplier’s history and
(a) self-inspection findings; the nature of the materials to be
(b) evaluation and conclusions; and supplied. If an audit is required,
(c) recommended corrective actions. it should determine the supplier’s
ability to conform with GMP
Follow-up action standards.
10.6 There should be an effective follow- 6. REFERENCES

up programme. The company
management should evaluate both a) WHO TRS GMP Guide: Basic
the self-inspection report and the requirements 2011
corrective actions as necessary. b) Guide to Good Manufacturing
Practices Part 1: PEE-009-9
Quality audit September 2009, Pharmaceutical
Inspection Cooperation Scheme
10.7 It may be useful to supplement (PIC/S)
self-inspections with a quality audit.
A quality audit consists of an
examination and assessment
131
7. REVISION HISTORY
Revision Date Author(s) Section(s) Description of Approvals

No: revised change
00 17th April EAC TWG All First approved REF: EAC/SC/

2014 GMP version to be DECISION----
Members issued --/17TH APRIL
2014
8. LIST OF ANNEXES
Annex 1: Manufacture of Sterile Medicinal Products

Annex 2: Manufacture of Biological Medicinal Products for Human Use
Annex 3: Qualification and Validation
Annex 4: Computerized Systems
Annex 5: Water for Pharmaceutical Use
Annex 6: Heating, Ventilation and Air Conditioning Systems for Non-sterile
Pharmaceutical Dosage Forms
Annex 7: Authorized Persons
Annex 8: Quality Risk Management
Annex 9: GMP for Manufacture of Active Pharmaceutical Ingredients
Annex 10: Waste Management for medicinal product manufacture
132
ANNEX 1: MANUFACTURE OF STERILE MEDICINAL

PRODUCTS
PRINCIPLE 3. Clean areas for the manufacture of

sterile products are classified
The manufacture of sterile products is subject according to the required
to special requirements in order to minimize characteristics of the environment.
risks of microbiological contamination, and Each manufacturing operation
of particulate and pyrogen contamination. requires an appropriate
Much depends on the skill, training and environmental cleanliness level in
attitudes of the personnel involved. Quality the operational state in order to
Assurance is particularly important and minimize the risks of particulate
this type of manufacture must strictly follow or microbial contamination of the
carefully established and validated methods product or materials being handled.
of preparation and procedure. Sole reliance
for sterility or other quality aspects must not In order to meet “in operation” conditions
be placed on any terminal process or finished these areas should be designed to reach
product test. certain specified air-cleanliness levels in the
“at rest” occupancy state. The “at rest” state is
Note: This guidance does not lay down the condition where the installation is installed
detailed methods for determining the and operating, complete with production
microbiological and particulate cleanliness of equipment but with no operating personnel
air, surfaces, etc. present. The “in operation” state is the
condition where the installation is functioning
GENERAL in the defined operating mode with the
specified number of personnel working.
1. The manufacture of sterile products The “in operation” and “at rest” states should
should be carried out in clean areas, be defined for each clean room or suite of
entry to which should be through clean rooms.
airlocks for personnel and/or for
equipment and materials. Clean For the manufacture of sterile medicinal
areas should be maintained to an products 4 grades can be distinguished.
appropriate cleanliness standard
and supplied with air which has Grade A: The local zone for high risk
passed through filters of an operations, e.g. filling zone, stopper bowls,
appropriate efficiency. open ampoules and vials, making aseptic
connections. Normally such conditions are
2. The various operations of provided by a laminar air flow work station.
component preparation, product Laminar air flow systems should provide a
preparation and filling should be homogeneous air speed in a range of 0.36
carried out in separate areas within – 0.54 m/s (guidance value) at the working
the clean area. Manufacturing position in open clean room applications.
operations are divided into two The maintenance of laminarity should be
categories; firstly those where the demonstrated and validated. A uni-directional
product is terminally sterilized, air flow and lower velocities may be used in
and secondly those which are closed isolators and glove boxes.
conducted aseptically at some or
all stages.
133
Grade B: For aseptic preparation and filling, this is the background environment for grade A zone.
Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile
products.
The airborne particulate classification for these grades is given in the following table.
Notes:
(a) Particle measurement based on the use of a discrete airborne particle counter to
measure the concentration of particles at designated sizes equal to or greater than
the threshold stated. A continuous measurement system should be used for monitoring
the concentration of particles in the grade A zone, and is recommended for the
surrounding grade B areas. For routine testing the total sample volume should not be
less than 1 m³ for grade A and B areas and preferably also in grade C areas.
(b) The particulate conditions given in the table for the “at rest” state should be achieved
after a short “clean up” period of 15-20 minutes (guidance value) in an unmanned state
after completion of operations. The particulate conditions for grade A “in operation”
given in the table should be maintained in the zone immediately surrounding the product
whenever the product or open container is exposed to the environment. It is accepted
that it may not always be possible to demonstrate conformity with particulate standard
at the point of fill when filling is in progress, due to the generation of particles or droplets
from the product itself.
(c) In order to reach the B, C and D air grades, the number of air changes should be
related to the size of the room and the equipment and personnel present in the room.
The air system should be provided with appropriate terminal filters such as HEPA for
grades A, B and C.
(d) The guidance given for the maximum permitted number of particles in the “at rest”
and “in operation” conditions correspond approximately to the cleanliness classes in the
EN/ISO 14644-1 at a particle size of 0.5 µm.
134
(e) These areas are expected to be completely free from particles of size greater than
5 micrometer. As it is impossible to demonstrate the absence of particles with any
statistical significance, the limits are set to 1 particle /m3. During the clean room
qualification it should be shown that the areas can be maintained within the defined
limits.
(f) The requirements and limits will depend on the nature of the operations carried out.
Examples of operations to be carried out in the various grades are given in the table below
(see also para. 11 and 12):
4. The areas should be monitored during operation in order to control the particulate
cleanliness of the various grades.
5. Where aseptic operations are performed monitoring should be frequent using methods
such as settle plates, volumetric air and surface sampling (e.g. swabs and contact
plates). Sampling methods used in operation should not interfere with zone protection.
Results from monitoring should be considered when reviewing batch documentation for
finished product release. Surfaces and personnel should be monitored after critical
operations.
Additional microbiological monitoring is also required outside production operations, e.g.

after validation of systems, cleaning and sanitization.
135
Recommended limits for microbiological monitoring of clean areas during operation:
Notes:
(a) These are average values.
(b) Individual settle plates may be exposed for less than 4 hours.
6. Appropriate alert and action limits should be set for the results of particulate and
microbiological monitoring. If these limits are exceeded operating procedures should
prescribe corrective action.
ISOLATOR TECHNOLOGY
7. The utilization of isolator technology to minimize human interventions in processing

areas may result in a significant decrease in the risk of microbiological contamination
of aseptically manufactured products from the environment. There are many possible
designs of isolators and transfer devices. The isolator and the background environment
should be designed so that the required air quality for the respective zones can be
realized. Isolators are constructed of various materials more or less prone to puncture
and leakage. Transfer devices may vary from a single door to double door designs to
fully sealed systems incorporating sterilization mechanisms.
The transfer of materials into and out of the unit is one of the greatest potential
sources of contamination. In general the area inside the isolator is the local zone for
high risk manipulations, although it is recognized that laminar air flow may not exist
in the working zone of all such devices. The air classification required for the
background environment depends on the design of the isolator and its application. It
should be controlled and for aseptic processing be at least grade D.
8. Isolators should be introduced only after appropriate validation. Validation should take
into account all critical factors of isolator technology, for example the quality of the air
inside and outside (background) the isolator, sanitation of the isolator, the transfer
process and isolator integrity.
136
9. Monitoring should be carried out TERMINALLY STERILIZED PRODUCTS

routinely and include frequent
leak testing of the isolator and 11. Preparation of components and
glove/sleeve system. most products should be done
in at least a grade D environment
BLOW/FILL/SEAL TECHNOLOGY in order to give low risk of microbial
and particulate contamination,
10. Blow/fill/seal units are purpose suitable for filtration and sterilization.
built machines in which, in one Where there is unusual risk to the
continuous operation, containers product because of microbial
are formed from a thermoplastic contamination, for example,
granulate, filled and then sealed, because the product actively
all by the one automatic machine. supports microbial growth or must
Blow/fill/seal equipment used be held for a long period before
for aseptic production which is fitted sterilization or is necessarily
with an effective grade A air processed not mainly in closed
shower may be installed in at vessels, preparation should be done
least a grade C environment, in a grade C environment.
provided that grade A/B clothing is
used. The environment should Filling of products for terminal sterilization
comply with the viable and non- should be done in at least a grade C
viable limits “at rest” and the viable environment.
limit only when in operation. Blow/
fill/seal equipment used for the Where the product is at unusual risk of
production of products for terminal contamination from the environment, for
sterilization should be installed in at example because the filling operation is slow
least a grade D environment. or the containers are wide-necked or are
necessarily exposed for more than a few
Because of this special technology seconds before sealing, the filling should
particular attention should be paid be done in a grade A zone with at least a
to at least the following: equipment grade C background. Preparation and filling
design and qualification, validation of ointments, creams, suspensions and
and reproducibility of cleaning-in- emulsions should generally be done in a grade
place and sterilization-in-place, C environment before terminal sterilization.
background clean room
environment in which the equipment ASEPTIC PREPARATION
is located, operator training and
clothing, and interventions in the 12. Components after washing should
critical zone of the equipment be handled in at least a grade
including any aseptic assembly prior D environment. Handling of sterile
to the commencement of filling. starting materials and components,
unless subjected to sterilization
or filtration through a micro-
organism-retaining filter later in
137
the process, should be done 14. All personnel (including those

in a grade A environment with grade concerned with cleaning and
B background. maintenance) employed in such
areas should receive regular
Preparation of solutions which are training in disciplines relevant to
to be sterile filtered during the the correct manufacture of sterile
process should be done in a grade products, including reference
C environment; if not filtered, the to hygiene and to the basic
preparation of materials and elements of microbiology. When
products should be done in a grade outside staff who have not received
A environment with a grade B such training (e.g. building or
background. maintenance contractors) need
to be brought in, particular care
Handling and filling of aseptically should be taken over their
prepared products should be done instruction and supervision.
in a grade A environment with a
grade B background. 15. Staff who have been engaged in
the processing of animal tissue
Transfer of partially closed materials or of cultures of micro-
containers, as used in freeze drying, organisms other than those used in
should, prior to the completion the current manufacturing process
of stoppering, be done either in a should not enter sterile-product
grade A environment with grade B areas unless rigorous and clearly
background or in sealed transfer defined entry procedures have
trays in a grade B environment. been followed.
Preparation and filling of sterile 16. High standards of personnel

ointments, creams, suspensions hygiene and cleanliness are
and emulsions should be done essential. Personnel involved in the
in a grade A environment, with a manufacture of sterile preparations
grade B background, when the should be instructed to report any
product is exposed and is not condition which may cause the
subsequently filtered. shedding of abnormal numbers or
types of contaminants; periodic
PERSONNEL health checks for such conditions
are desirable. Actions to be taken
13. Only the minimum number of about personnel who could be
personnel required should be introducing undue microbiological
present in clean areas; this hazard should be decided by a
is particularly important during designated competent person
aseptic processing. Inspections
and controls should be conducted
outside the clean areas as far
as possible.
138
17. Changing and washing should and sterilized or disinfected

follow a written procedure designed footwear should be worn. Trouser-
to minimize contamination of clean bottoms should be tucked inside the
area clothing or carry-through of footwear and garment sleeves into
contaminants to the clean areas. the gloves. The protective clothing
should shed virtually no fibres or
18. Wristwatches, make-up and particulate matter and retain
jewellery should not be worn in particles shed by the body.
clean areas.
20. Outdoor clothing should not be
19. The clothing and its quality should brought into changing rooms leading
be appropriate for the process and to grade B and C rooms. For
the grade of the working area. It every worker in a grade A/B
should be worn in such a way as to area, clean sterile (sterilized or
protect the product from adequately sanitized) protective
contamination. garments should be provided at
each work session. Gloves should
The description of clothing required for be regularly disinfected during
each grade is given below: operations. Masks and gloves
should be changed at least at every
Grade D: Hair and, where relevant, working session.
beard should be covered. A general
protective suit and appropriate 21. Clean area clothing should be
shoes or overshoes should be worn. cleaned and handled in such a way
Appropriate measures should be that it does not gather additional
taken to avoid any contamination contaminants which can later be
coming from outside the clean area. shed. These operations should
follow written procedures. Separate
Grade C: Hair and, where relevant, laundry facilities for such clothing
beard and moustache should be are desirable. Inappropriate
covered. A single or two-piece treatment of clothing will damage
trouser suit, gathered at the wrists fibres and may increase the risk of
and with high neck and appropriate shedding of particles.
shoes or overshoes should be
worn. They should shed virtually no PREMISES
fibres or particulate matter.
22. In clean areas, all exposed
Grade A/B: Headgear should totally surfaces should be smooth,
enclose hair and, where relevant, impervious and unbroken in order
beard and moustache; it should be to minimize the shedding or
tucked into the neck of the suit; accumulation of particles or
a face mask should be worn to micro-organisms and to permit the
prevent the shedding of droplets. repeated application of cleaning
Appropriate sterilized, non- agents, and disinfectants where
powdered rubber or plastic gloves used.
139
23. To reduce accumulation of dust facilities should be provided only in

and to facilitate cleaning there the first stage of the changing
should be no uncleanable recesses rooms.
and a minimum of projecting
ledges, shelves, cupboards and 28. Both airlock doors should not be
equipment. Doors should be opened simultaneously. An
designed to avoid those interlocking system or a visual and/
uncleanable recesses; sliding doors or audible warning system should
may be undesirable for this reason. be operated to prevent the opening
of more than one door at a time.
24. False ceilings should be sealed to
prevent contamination from the 29. A filtered air supply should maintain
space above them. a positive pressure and an air flow
relative to surrounding areas of a
25. Pipes and ducts and other utilities lower grade under all operational
should be installed so that they do conditions and should flush the
not create recesses, unsealed area effectively. Adjacent rooms
openings and surfaces which are of different grades should have
difficult to clean. a pressure differential of 10-
15 pascals (guidance values).
26. Sinks and drains should be Particular attention should be paid
prohibited in grade A/B areas used to the protection of the zone
for aseptic manufacture. In other of greatest risk, that is, the
areas air breaks should be fitted immediate environment to which
between the machine or sink and a product and cleaned components
the drains. Floor drains in lower which contact the product are
grade clean rooms should be fitted exposed. The various
with traps or water seals to prevent recommendations regarding air
back-flow. supplies and pressure differentials
may need to be modified where
27. Changing rooms should be it becomes necessary to contain
designed as airlocks and used to some materials, e.g. pathogenic,
provide physical separation of the highly toxic, radioactive or live
different stages of changing viral or bacterial materials or
and so minimize microbial and products. Decontamination of
particulate contamination of facilities and treatment of air leaving
protective clothing. They should be a clean area may be necessary for
flushed effectively with filtered air. some operations.
The final stage of the changing
room should, in the “at rest” state, 30. It should be demonstrated that air-
be the same grade as the area into flow patterns do not present a
which it leads. The use of separate contamination risk, e.g. care should
changing rooms for entering and be taken to ensure that air flows
leaving clean areas is sometimes do not distribute particles from
desirable. In general hand washing a particle-generating person,
140
operation or machine to a zone of reliable source of water of an

higher product risk. appropriate quality. They should not
be operated beyond their designed
31. A warning system should be capacity. Water for injections
provided to indicate failure in the should be produced, stored and
air supply. Indicators of pressure distributed in a manner which
differences should be fitted between prevents microbial growth,
areas where these differences for example by constant circulation
are important. These pressure at a temperature above 70°C.
differences should be recorded
regularly or otherwise documented. 36. All equipment such as sterilizers,
air handling and filtration systems,
EQUIPMENT air vent and gas filters, water
treatment, generation, storage
32. A conveyor belt should not pass and distribution systems should
through a partition between a grade be subject to validation and planned
A or B area and a processing area maintenance; their return to use
of lower air cleanliness, unless the should be approved.
belt itself is continually sterilized
(e.g. in a sterilizing tunnel). SANITATION
33. As far as practicable, equipment, 37. The sanitation of clean areas is

fittings and services should be particularly important. They should
designed and installed so that be cleaned thoroughly in
operations, maintenance and accordance with a written
repairs can be carried out outside programme. Where disinfectants
the clean area. If sterilization are used, more than one type
is required, it should be carried out should be employed. Monitoring
after complete reassembly wherever should be undertaken regularly in
possible. order to detect the development of
resistant strains.
34. When equipment maintenance
has been carried out within the 38. Disinfectants and detergents should
clean area, the area should be be monitored for microbial
cleaned, disinfected and/or sterilized contamination; dilutions should be
where appropriate, before kept in previously cleaned
processing recommences if the containers and should only be
required standards of cleanliness stored for defined periods unless
and/or asepsis have not been sterilised. Disinfectants and
maintained during the work. detergents used in Grades A and B
areas should be sterile prior to use.
35. Water treatment plants and
distribution systems should be 39. Fumigation of clean areas may
designed, constructed and be useful for reducing
maintained so as to ensure a
141
microbiological contamination in to the HVAC system, equipment,

inaccessible places. process and number of shifts.
Normally process simulation tests
PROCESSING should be repeated twice a year per
shift and process. The number
40. Precautions to minimize of containers used for media
contamination should be taken fills should be sufficient to enable
during all processing stages a valid evaluation. For small
including the stages before batches, the number of containers
sterilization. for media fills should at least equal
the size of the product batch.
41. Preparations of microbiological The target should be zero growth
origin should not be made or filled but a contamination rate of less than
in areas used for the processing of 0.1% with 95% confidence limit
other medicinal products; however, is acceptable. The manufacturer
vaccines of dead organisms or should establish alert and
of bacterial extracts may be filled, action limits. Any contamination
after inactivation, in the same should be investigated.
premises as other sterile medicinal
products. 43. Care should be taken that
any validation does not compromise
42. Validation of aseptic processing the processes.
should include a process simulation
test using a nutrient medium 44. Water sources, water treatment
(media fill). Selection of the nutrient equipment and treated water should
medium should be made based on be monitored regularly for chemical
dosage form of the product and and biological contamination and,
selectivity, clarity, concentration as appropriate, for endotoxins.
and suitability for sterilization of Records should be maintained of
the nutrient medium. The process the results of the monitoring and of
simulation test should imitate any action taken.
as closely as possible the routine
aseptic manufacturing process 45. Activities in clean areas and
and include all the critical especially when aseptic operations
subsequent manufacturing steps. are in progress should be kept
It should also take into account to a minimum and movement
various interventions known to of personnel should be controlled
occur during normal production and methodical, to avoid excessive
as well as worst case situations. shedding of particles and organisms
Process simulation tests should due to over-vigorous activity. The
be performed as initial validation ambient temperature and humidity
with three consecutive satisfactory should not be uncomfortably high
simulation tests per shift and because of the nature of the
repeated at defined intervals and garments worn.
after any significant modification
142
46. Microbiological contamination immediately before sterilization

of starting materials should be which are related to the efficiency of
minimal. Specifications should the method to be used. Where
include requirements for appropriate the absence of
microbiological quality when pyrogens should be monitored. All
the need for this has been indicated solutions, in particular large volume
by monitoring. infusion fluids, should be passed
through a micro-organism-retaining
47. Containers and materials liable to filter, if possible sited immediately
generate fibres should be minimized before filling.
in clean areas.
53. Components, containers, equipment
48. Where appropriate, measures and any other article required
should be taken to minimize the in a clean area where aseptic work
particulate contamination of the takes place should be sterilized
end product. and passed into the area through
double-ended sterilizers sealed into
49. Components, containers and the wall, or by a procedure which
equipment should be handled after achieves the same objective of not
the final cleaning process in such a introducing contamination.
way that they are not re- Noncombustible gases should be
contaminated. passed through micro-organism
retentive filters.
50. The interval between the washing
and drying and the sterilization of 54. The efficacy of any new procedure
components, containers and should be validated, and the
equipment as well as between their validation verified at scheduled
sterilization and use should intervals based on performance
be minimized and subject to a time- history or when any significant
limit appropriate to the storage change is made in the process
conditions. or equipment.
51. The time between the start of the STERILIZATION

preparation of a solution and its
sterilization or filtration through 55. All sterilization processes should
a micro-organism-retaining filter be validated. Particular attention
should be minimized. There should should be given when the adopted
be a set maximum permissible time sterilization method is not described
for each product that takes into in the current edition of the
account its composition and the European Pharmacopoeia, or when
prescribed method of storage. it is used for a product which is
not a simple aqueous or oily
52. The bioburden should be monitored solution. Where possible, heat
before sterilization. There should be sterilization is the method of choice.
working limits on contamination In any case, the sterilization process
143
must be in accordance with the 60. There should be a clear means of

marketing and manufacturing differentiating products which have
authorizations. not been sterilized from those
which have. Each basket, tray
56. Before any sterilization process is or other carrier of products or
adopted its suitability for the product components should be clearly
and its efficacy in achieving the labelled with the material name, its
desired sterilizing conditions in all batch number and an indication of
parts of each type of load to be whether or not it has been sterilized.
processed should be demonstrated Indicators such as autoclave tape
by physical measurements and by may be used, where appropriate, to
biological indicators where indicate whether or not a batch (or
appropriate. The validity of the sub-batch) has passed through a
process should be verified at sterilization process, but they do not
scheduled intervals, at least give a reliable indication that the lot
annually, and whenever significant is, in fact, sterile.
modifications have been made to
the equipment. Records should be 61. Sterilization records should be
kept of the results. available for each sterilization run.
They should be approved as part of
57. For effective sterilization the whole the batch release procedure.
of the material must be subjected to
the required treatment and the STERILIZATION BY HEAT
process should be designed to
ensure that this is achieved. 62. Each heat sterilization cycle
should be recorded on a time/
58. Validated loading patterns should be temperature chart with a suitably
established for all sterilization large scale or by other appropriate
processes. equipment with suitable accuracy
and precision. The position of the
59. Biological indicators should be temperature probes used for
considered as an additional controlling and/or recording should
method for monitoring the have been determined during the
sterilization. They should be stored validation and, where applicable,
and used according to the also checked against a second
manufacturer’s instructions, and independent temperature probe
their quality checked by positive located at the same position.
controls.
63. Chemical or biological indicators
If biological indicators are used, strict may also be used, but should not
precautions should be taken to avoid take the place of physical
transferring microbial contamination from measurements.
them.
144
64. Sufficient time must be allowed for 67. The items to be sterilized, other
the whole of the load to reach the than products in sealed containers,
required temperature before should be wrapped in a material
measurement of the sterilizing which allows removal of air and
time-period is commenced. This penetration of steam but which
time must be determined for each prevents recontamination after
type of load to be processed. sterilization. All parts of the load
should be in contact with the
65. After the high temperature phase of sterilizing agent at the required
a heat sterilization cycle, temperature for the required time.
precautions should be taken against
contamination of a sterilized load 68. Care should be taken to ensure
during cooling. Any cooling fluid that steam used for sterilization is of
or gas in contact with the product suitable quality and does not
should be sterilized, unless it can be contain additives at a level which
shown that any leaking container could cause contamination of
would not be approved for use. product or equipment.
MOIST HEAT DRY HEAT
66. Both temperature and pressure 69. The process used should include
should be used to monitor the air circulation within the chamber
process. Control instrumentation and the maintenance of a positive
should normally be independent pressure to prevent the entry of non-
of monitoring instrumentation and sterile air. Any air admitted should
recording charts. Where automated be passed through a HEPA filter.
control and monitoring systems Where this process is also intended
are used for these applications they to remove pyrogens, challenge tests
should be validated to ensure using endotoxins should be used as
that critical process requirements part of the validation.
are met. System and cycle faults
should be registered by the system STERILIZATION BY RADIATION
and observed by the operator.
The reading of the independent 70. Radiation sterilization is used mainly
temperature indicator should be for the sterilization of heat sensitive
routinely checked against the chart materials and products. Many
recorder during the sterilization medicinal products and some
period. For sterilizers fitted with a packaging materials are radiation-
drain at the bottom of the chamber, sensitive, so this method is
it may also be necessary to record permissible only when the absence
the temperature at this position, of deleterious effects on the product
throughout the sterilization period. has been confirmed experimentally.
There should be frequent leak tests
on the chamber when a vacuum
phase is part of the cycle.
145
Ultraviolet irradiation is not normally STERILIZATION WITH ETHYLENE

an acceptable method of OXIDE
sterilization.
76. This method should only be used
71. During the sterilization procedure when no other method is
the radiation dose should be practicable. During process
measured. For this purpose, validation it should be shown that
dosimetry indicators which are there is no damaging effect on
independent of dose rate should the product and that the conditions
be used, giving a quantitative and time allowed for degassing
measurement of the dose received are such as to reduce any residual
by the product itself. Dosimeters gas and reaction products to defined
should be inserted in the load in acceptable limits for the type of
sufficient number and close product or material.
enough together to ensure that
there is always a dosimeter in the 77. Direct contact between gas and
irradiator. Where plastic dosimeters microbial cells is essential;
are used they should be used within precautions should be taken to
the time-limit of their calibration. avoid the presence of organisms
Dosimeter absorbances should be likely to be enclosed in material
read within a short period after such as crystals or dried protein.
exposure to radiation. The nature and quantity of
packaging materials can
72. Biological indicators may be used significantly affect the process.
as an additional control.
78. Before exposure to the gas,
73. Validation procedures should ensure materials should be brought into
that the effects of variations in equilibrium with the humidity and
density of the packages are temperature required by the
considered. process. The time required for this
should be balanced against the
74. Materials handling procedures opposing need to minimize the time
should prevent mix-up between before sterilization.
irradiated and non-irradiated
materials. Radiation-sensitive colour 79. Each sterilization cycle should be
disks should also be used on each monitored with suitable biological
package to differentiate between indicators, using the appropriate
packages which have been number of test pieces distributed
subjected to a irradiation and those throughout the load. The information
which have not. so obtained should form part of the
batch record.
75. The total radiation dose should be
administered within a predetermined
time span.
146
80. For each sterilization cycle, records the filtration process with some
should be made of the time taken degree of heat treatment.
to complete the cycle, of the
pressure, temperature and humidity 83. Due to the potential additional risks
within the chamber during the of the filtration method as compared
process and of the gas with other sterilization processes,
concentration and of the total a second filtration via a further
amount of gas used. The pressure sterilized microorganism retaining
and temperature should be recorded filter, immediately prior to filling, may
throughout the cycle on a chart. The be advisable. The final sterile
record(s) should form part of the filtration should be carried out as
batch record. close as possible to the filling point.
81. After sterilization, the load should be 84. Fibre shedding characteristics of
stored in a controlled manner under filters should be minimal.
ventilated conditions to allow
residual gas and reaction products 85. The integrity of the sterilized filter
to reduce to the defined level. This should be verified before use and
process should be validated. should be confirmed immediately
after use by an appropriate method
FILTRATION OF MEDICINAL such as a bubble point, diffusive
PRODUCTS WHICH CANNOT flow or pressure hold test. The time
BE STERILIZED IN THEIR FINAL taken to filter a known volume of
bulk solution and the pressure
CONTAINER
difference to be used across the
filter should be determined during
82. Filtration alone is not considered
validation and any significant
sufficient when sterilization in
differences during routine
the final container is possible. With
manufacturing from this should
regard to methods currently
be noted and investigated. Results
available, steam sterilization is
of these checks should be included
to be preferred. If the product
in the batch record. The integrity
cannot be sterilized in the final
of critical gas and air vent filters
container, solutions or liquids can
should be confirmed after use. The
be filtered through a sterile filter of
integrity of other filters should be
nominal pore size of 0.22 micron
confirmed at appropriate intervals.
(or less), or with at least equivalent
micro-organism retaining
86. The same filter should not be used
properties, into a previously
for more than one working day
sterilized container. Such filters can
unless such use has been validated.
remove most bacteria and
moulds, but not all viruses or
87. The filter should not affect the
mycoplasma’s. Consideration
product by removal of ingredients
should be given to complementing
from it or by release of substances
into it.
147
FINISHING OF STERILE PRODUCTS QUALITY CONTROL
88. Containers should be closed by 91. The sterility test applied to the
appropriately validated methods. finished product should only be
Containers closed by fusion, e.g. regarded as the last in a series of
glass or plastic ampoules should control measures by which sterility
be subject to 100% integrity testing. is assured. The test should be
Samples of other containers validated for the product(s)
should be checked for integrity concerned.
according to appropriate
procedures. 92. In those cases where parametric
release has been authorized,
89. Containers sealed under vacuum special attention should be paid to
should be tested for maintenance the validation and the monitoring of
of that vacuum after an appropriate, the entire manufacturing process.
pre-determined period.
93. Samples taken for sterility testing
90. Filled containers of parenteral should be representative of the
products should be inspected whole of the batch, but should in
individually for extraneous particular include samples taken
contamination or other defects. from parts of the batch considered
When inspection is done visually, it to be most at risk of contamination,
should be done under suitable e.g.:
and controlled conditions of
illumination and background. a) for products which have been filled
Operators doing the inspection aseptically, samples should include
should pass regular eye-sight containers filled at the beginning
checks, with spectacles if worn, and and end of the batch and after any
be allowed frequent breaks from significant intervention;
inspection. Where other methods b) for products which have been
of inspection are used, the process heat sterilized in their final
should be validated and the containers, consideration should be
performance of the equipment given to taking samples from the
checked at intervals. Results should potentially coolest part of the load.
be recorded.
148
ANNEX 2: MANUFACTURE OF BIOLOGICAL MEDICINAL

PRODUCTS FOR HUMAN USE
SCOPE produced, controlled and administered make

some particular precautions necessary.
The regulatory procedures necessary to Unlike conventional medicinal products,
control biological products are in large part which are reproduced using chemical and
determined by the sources of products and physical techniques capable of a high degree
methods of manufacture. Manufacturing of consistency, the production of biological
procedures with the scope of these guidelines medicinal products involves biological
include: processes and materials, such as cultivation
of cells or extraction of material from living
a. growth of strains of microorganisms organisms. These biological processes may
and eukaryotic cells, display inherent variability, so that the range
and nature of by-products are variable.
b. extraction of substances from Moreover, the materials used in these
biological tissues, including human, cultivation processes provide good substrates
animal and plant tissues (allergens), for growth of microbial contaminants.
c. recombinant DNA (rDNA) Control of biological medicinal products

techniques, usually involves biological analytical
techniques which have a greater variability
d. hybridoma techniques, than physico-chemical determinations. In-
process controls therefore take on a great
e. propagation of microorganisms in importance in the manufacture of biological
embryos or animals. medicinal products.
Biological products manufactured by these The special properties of biological medicinal

methods include allergens, antigens, vaccines, products require careful consideration in any
hormones, cytokines, enzymes, human whole code of Good Manufacturing Practice and the
blood and plasma derivatives, immune sera, development of this annex takes these points
immunoglobulins (including monoclonal into account.
antibodies), products of fermentation
(including products derived from rDNA) and PERSONNEL
diagnostic agents for in vitro use.
1. The manufacturing establishment
This guidance does not lay down detailed and its personnel shall be under the
requirements for specific classes of authority of a person who has
biological products. been trained in the techniques used
in manufacturing biological
PRINCIPLE substances and who possesses
the scientific knowledge upon which
The manufacture of biological medicinal the manufacture of these products
products involves certain specific is based. The personnel shall
considerations arising from the nature of include specialists with training
the products and the processes. The ways appropriate to the products made in
in which biological medicinal products are the establishment.
149
2. Personnel required to work in clean concerned with the production

and aseptic areas should be process should not enter the
selected with care, to ensure production area except for essential
that they may be relied upon to purposes, and in that case they
observe the appropriate codes of shall be supplied with sterile
practice and are not subject to any protective clothing.
disease or condition that could
compromise the integrity of the 5. The staff engaged in the
product microbiologically or manufacturing process should be
otherwise. High standards of separate from the staff responsible
personal hygiene and cleanliness for animal care.
are essential. Staff should be
instructed to report any conditions 6. The names and qualifications of
(e.g. diarrhea, coughs, infected shin those responsible for approving
or hair, wounds, fever of unknown lot processing records (protocols)
origin) that may cause the shedding should be registered with the
of abnormal numbers or types of national control authority.
organisms into the working
environment. Health checks on 7. To ensure the manufacturing of
personnel for such condition high-quality products, personnel
should be required before should be trained in good
employment and periodically manufacturing and laboratory
thereafter. Any changes in health practices I appropriate fields such
status that could adversely affect as bacteriology, virology, biometry,
the quality of the product shall chemistry, medicine, immunology
preclude the person concerned form and veterinary medicine.
working in the production area.
8. Training records should be
3. Only the minimum number of maintained and periodic
personnel required should be assessments of the effectiveness of
presenting clean and aseptic areas training programmes should
when work is in progress. Inspection be made.
and control procedures should be
conducted from outside theses 9. All personnel engaged I production,
areas as for as possible. maintenance, testing and animal
care (all inspectors) should be
4. During the working day, personnel vaccinated with appropriate
shall not pass from areas where vaccines and where appropriate,
live microorganisms or animals are be submitted to regular testing for
handled to premises where other evidence of active tuberculosis.
products or organisms are handled
unless clearly defined
decontamination measures,
including a change of clothing and
shoes, are followed. Persons not
150
Apart from the obvious problem of cleanable traps and with breaks
exposure of staff to infectious to prevent back-flow. The traps may
agents, potent toxins or allergens, it contain electrically operated heating
is necessary to avoid the risk of devices or other means for
contamination of a production batch disinfection. Any floor channels
with these agents. should be open, shallow and easily
cleanable and be connected to
10. Where BCG vaccines are being drains outside the area in a
manufactured, access to production manner that prevents ingress of
areas shall be restricted to staff microbial contaminants.
who are carefully monitored
by regular health checks. In the 13. Sinks shall be excluded from
case of manufacture of products aseptic areas. Any sink installed in
derived from human blood or other clean areas shall be of
plasma, vaccination of workers suitable material such as
against hepatitis is recommended. stainless steel, without an overflow,
and be supplied with water of
PREMISES AND EQUIPMENT potable quality. Adequate
precautions shall be taken to avoid
11. As a general principle, buildings contamination of the drainage
must be located, designed system with dangerous effluents.
constructed, adapted and Airborne dissemination of
maintained to suit the operations pathogenic microorganisms and
to be carried out within them. viruses used for production and the
Laboratories, operating rooms and possibility of contamination by
all other rooms and buildings other types of viruses or substances
(including those for animals) that during the production process,
are used for the manufacture including those from personnel,
of biological products shall be shall be avoided.
designed and constructed of
materials of the highest standard so 14. Lighting, heating, ventilation
that cleanliness, especially freedom and, if necessary, air-conditioning
form dust, insects and vermin, can should be designed to maintain a
be maintained. satisfactory temperature and relative
humidity, to minimize contamination
12. Interior surfaces (walls, floors and and to take account of the comfort
ceilings) shall be smooth and free of personnel working in protective
from cracks; they shall not shed clothing. Buildings shall be in a good
matter and shall permit easy state of repair. The condition of the
cleaning and disinfection. Drains buildings should be reviewed
shall be avoided whenever regularly and repairs carried out
possible and, unless essential, when and where necessary. Special
should be excluded from aseptic care should be exercised to ensure
areas. Where installed they should that building repair or maintenance
be fitted with effective, easily operations do not compromise
151
products. Premises should provide 18. Products such as killed vaccines,

sufficient space to suit the including those made by rDNA
operations carried out, allowing techniques, toxoids and bacterial
an efficient flow of work and extracts may after inactivation
effective communication and be dispensed into containers
supervision. All buildings and on the same premises as other
rooms shall be clean and sanitary sterile biological products, providing
at all times. If rooms intended for that adequate decontamination
the manufacture of biological measures are taken after filling, if
substances are used for other appropriate, sterilization
purposes, they shall be cleaned and washing.
thoroughly and, if necessary,
sanitized before the manufacture 19. Spore-forming organisms shall be
of biological substances is handled in facilities dedicated to this
resumed. Areas used for processing group of products until the
animal tissue materials and inactivation process is
microorganisms must be separated accomplished. For Bacillus
from premises used for anthracis, Clostridium botulinum
manufacturing sterile biological and Clostridium tetani, strictly
products and have completely dedicated facilities should be utilized
separate ventilation systems and for each individual product.
separate staff. Where campaign manufacture of
spore-forming organisms occurs in
15. If certain products are to be a facility or suite of facilities, only
produced on a campaign basis, one product should be processed at
the layout and design of the a time.
premises and equipment shall
permit effective decontamination 20. Dedicated facilities and equipment
by fumigation, where necessary, shall be used for the manufacture of
as well as cleaning and sanitizing medicinal products derived from
after the production campaign. human blood or plasma.
16. Seed lots and cell banks used for 21. All containers of biological
the production of biological substances, regardless of the stage
products should be stored of manufacture, shall be
separately from other material. identified by securely attached
Access should be restricted to labels. Cross-contamination should
authorized personnel. be prevented by adoption of some
or all of the following measures:
17. Live organisms shall be handled
in equipment that ensures that • processing and filling in segregated
cultures are maintained in a pure areas;
state and are not contaminated • avoiding manufacture of different
during processing. products at the same time, unless
they are effectively segregated;
152
• containing material transfer when infectious and potentially

by means of airlocks, air extraction, infectious materials are used
clothing change and careful washing for production.
and decontamination of equipment;
• protecting against the risks of c. Pipe work, valves and vent filters
contamination caused by shall be properly designed to
recirculation of untreated air, or by facilitate cleaning and sterilization.
accidental re-entry of extracted air; Valves on fermentation vessels
• using “closed systems” of shall be completely steam-
manufacture; sterilizable. Air-vent filters shall be
• taking care to prevent aerosol hydrophobic and shall be validated
formation (especially by for their designated use.
centrifugation and blending);
• excluding pathological specimens d. Small stocks of substances that
sent in for diagnosis from areas have to be measured or weighed
used for manufacturing biological during the production process
substances; (e.g. buffers) may be kept in the
• using containers that are sterilized production area, provided that
or are of documented low they are not returned to the general
“bioburden”. stocks. Otherwise, dry materials
used to formulate buffers, culture
22. Positive-pressure areas should be media, etc should be weighed and
used to process sterile products, put into solution in a contained area
but negative pressure is acceptable outside the purification and aseptic
in specific areas where pathogens areas in order to minimize
are processed. In general, any contamination of the product.
organisms to be pathogenic should
be handled within specifically ANIMAL QUARTERS AND CARE
designed areas under negative
pressures, in accordance with 23. Animals are used for the
containment requirements for the manufacture and control of a
product concerned. number of biological products.
Animals shall be accommodated
a. Air-handling units should be in separate buildings with self-
dedicated to the processing area contained ventilation systems. The
concerned. Air from operations buildings’ design and construction
involving pathogens shall not be materials shall permit maintenance
re-circulated and, in the case of in a clean and sanitary condition
organisms in a group above Risk free from insects and vermin.
Group 2 (3), shall be exhausted Facilities for animal care shall
through sterilizing filters that are include isolation units for quarantine
regularly checked for performance. of incoming animals and provision
for vermin-free food storage.
b. Specific decontamination systems Provision shall also be made for
should be considered for effluent animal inoculation rooms, which
153
shall be separate from the carried out where possible by heat.

postmortem rooms. There shall Where necessary, other appropriate
be facilities for the disinfection of methods may also be used for
cages, if possible by steam, and an inactivation of biological materials
incinerator for disposing of waste (e.g. irradiation).
and of dead animals.
c. In order to prevent the unwanted
24. The health status of animals from drift of properties which might
which starting materials are ensue from repeated subcultures
derived and of those used for or multiple generations, the
quality control and safety testing production of biological medicinal
should be monitored and recorded. products obtained by microbial
Staff employed in animal quarters culture, cell culture of propagation
must be provided with special in embryos and animals should be
clothing, changing facilities and based on a system of master and
showers. Where monkeys are working seed lots and/or cell banks.
used for the production or quality
control of biological products, d. The number of generations
special consideration is required, (doublings, passages) between the
as laid down in the revised seed lot or cell bank and the
Requirements for Biological finished product should be
Substances No. 7 (Requirements consistent with the marketing
for Polio-myelitis Vaccine authorization dossier. Scaling
(Oral)) (5). up of the process should not change
this fundamental relationship.
PRODUCTION
e. Seed lots and cell banks should
25. Standard operating procedures shall be adequately characterised and
be available and maintained up to tested for contaminants. Their
date for all manufacturing suitability for use should be further
operations. demonstrated by the consistency
of the characteristics and quality of
a. The source, origin and suitability of the successive batches of
starting materials should be clearly product. Seed lots and cell banks
defined. Where the necessary tests should be established, stored and
take a long time, it may be used in such a way as to minimize
permissible to process starting the risks of contamination
materials before the results of the or alteration.
tests are available. In such cases,
release of a finished product is f. Establishment of the seed lot and
conditional on satisfactory results of cell bank should be performed in a
these tests. suitably controlled environment to
protect the seed lot and the cell
b. Where sterilisation of starting bank and, if applicable,
materials is required, it should be the personnel handling it. During the
154
establishment of the seed lot and j. The growth promoting properties

cell bank, no other living or of culture media should
infectious material (e.g. virus, be demonstrated.
cell lines or cell strains) should be
handled simultaneously in the same k. Addition of materials or cultures to
area or by the same persons. fermenters and other vessels and
the taking of samples should
g. Evidence of the stability and be carried out under carefully
recovery of the seeds and banks controlled conditions to ensure that
should be documented. Storage absence of contamination is
containers should be hermetically maintained. Care should be taken
sealed, clearly labeled and kept to ensure that vessels are correctly
at an appropriate temperature. An connected when addition or
inventory should be meticulously sampling take place.
kept. Storage temperature should
be recorded continuously for l. Centrifugation and blending of
freezers and properly monitored for products can lead to aerosol
liquid nitrogen. Any deviation from formation and containment of
set limits and any corrective action such activities to prevent transfer of
taken should be recorded. live microorganisms is necessary.
h. Only authorized personnel should m. If possible, media should be

be allowed to handle the material sterilized in situ. In-line sterilizing
and this handling should be done filters for routine addition of gases,
under the supervision of a media, acids or alkalis, defoaming
responsible person. Access to agents etc. to fermenters should be
stored material should be controlled. used where possible.
Different seed lots or cell banks
should be stored in such a way to n. Careful consideration should be
avoid confusion or cross- given to the validation of any
contamination. It is desirable to split necessary virus removal or
the seed lots and cell banks and to inactivation undertaken.
store the parts at different locations
so as to minimize the risks of o. In cases where a virus inactivation
total loss. or removal process is performed
during manufacture, measures
i. All containers of master or working should be taken to avoid the risk of
cell banks and seed lots should recontamination of treated products
be treated identically during storage. by non-treated products.
Once removed from storage, the
containers should not be returned to p. A wide variety of equipment is
the stock. used for chromatography, and in
general such equipment should be
dedicated to the purification of one
product and should be sterilized
155
or sanitized between batches. substance used in the preparation

The use of the same equipment of the biological product that is likely
at different stages of processing to give rise to an adverse reaction in
should be discouraged. Acceptance some recipients;
criteria, life span and sanitization • the name and address of the
or sterilization method of columns manufacturer or the company and/
should be defined. or the person responsible for placing
the drug on the market.
LABELING
29. The label on the package shall, in
26. All products shall be clearly addition to the information shown
identified by labels. The labels on the label on the container,
used must remain permanently show at least the nature and amount
attached to the containers under of any preservative or additive in
all storage conditions and an area of the product.
the container should be left
uncovered to allow inspection of the a. The leaflet in the package should
contents. If the final container is not provide instructions for the
suitable for labeling (for example use of the product, and mention
a capillary tube), it should be in a any contraindications or potential
labeled package. adverse reactions.
27. The information given on the label Lot Processing Records (Protocols) And
on the container and the label on Distribution Records
the package shall be approved by
the national control authority. 30. Processing records of regular
production lots must provide a
28. The label on the container shall complete account of the
show:- manufacturing history of each lot of
a biological preparation, showing
• the name of the drug product; that it has been manufactured,
• a list of the active ingredients and tested, dispensed into containers
the amount of each present, with a and distributed in accordance with
statement of the net contents, e.g. the licensed procedures.
number of dosage units, weight
or volume; 31. A separate processing record
• the batch or final lot number should be prepared for each lot of
assigned by the manufacturer; biological product, and should
• the expiry date; include the following information:
• recommended storage conditions or
handling precautions that may • the name and dosage of
be necessary; the product;
• directions for use, and warnings and • the date of manufacture;
precautions that may be necessary; • the lot identification number;
• the nature and amount of any • the complete formulation of the
156
lot, including identification of seed or of all apparatus and materials used

starting materials; in its manufacture. Distribution
• the batch number of each records must be kept in a manner
component used in the formulation; that permits rapid recall of any
• the yield obtained at different stages particular lot, if necessary.
of manufacture of the lot;
• a duly signed record of each QUALITY CONTROL
step followed, precautions taken
and special observations made 33. The quality-assurance and/or
throughout the manufacture of quality-control department should
the lot; have the following principal duties:
• a record of all in-process control
tests and of the results obtained; • to prepare detailed instructions for
• a specimen of the label; each test and analysis;
• identification of packaging materials, • to ensure adequate identification
containers and closures used; and segregation of test samples to
• a dated signature of the expert avoid mix-up and cross-
responsible for approving the contamination;
manufacturing operations; • to ensure that environmental
• an analytical report, dated monitoring and equipment validation
and signed by the responsible are conducted as appropriate for
expert, showing whether the lot evaluating the adequacy of the
complies with the specifications manufacturing conditions;
described in the standard operating • to release or reject raw materials
procedure registered with the and intermediate products,
national control authority; if necessary;
• a record of the decision regarding • to release or reject packaging and
the release or rejection of the lot by labeling materials and the final
the quality-control department and, containers in which drugs are to
if the lot is rejected, a record of its be placed;
disposal or utilization. • to release or reject each lot of
finished preparation;
32. The records shall be of a type • to evaluate the adequacy of
approved by the national control the conditions under which raw
authority. They shall be retained materials, intermediate products and
for at least two years after the expiry finished biological preparations
date of a lot or batch of a biological are stored;
product and be available at all times • to evaluate the quality and stability
for inspection by the national control of finished products and, when
authority. necessary, of raw materials and
intermediate products;
a. Records must make it possible • to establish expiry dates on the
to trace all steps in the manufacture basis of the validity period related to
and testing of a lot, and should specified storage conditions;
include records of sterilization • to establish and, when necessary,
157
revise control procedures and • at least one specific identity test is

specifications; and conducted by the manufacturer of
• to be responsible for the the final product.
examination of returned
preparations to determine whether c. Samples of intermediate and final
such preparations should be products shall be retained in
released; reprocessed or destroyed; sufficient amount and under
adequate records of the distribution appropriate storage conditions to
of such preparations should allow the repetition or confirmation
be maintained. of a batch control. However,
reference samples of certain starting
34. A manufacture’s quality-control materials, e.g. components of
laboratory shall be separated from culture media, need not necessarily
the production area and ideally be retained.
should be in a separate building.
The control laboratory should be d. Certain operations require the
designed and equipped and of continuous monitoring of data during
such a size as to be a self-contained a production process, for example
entity, with adequate provision monitoring and recording of physical
for the storage of documents parameters during fermentation.
and samples, preparation of records
and performance of the necessary e. Special consideration needs to
tests. be given to the quality-control
requirements arising from
a. In-process controls play a special production of biological products by
important role in ensuring the continuous culture.
consistent quality of biological
products. Tests that are crucial for
quality control but that cannot
be carried out on the finished
product shall be performed at an
appropriate stage of production.
b. Performance of all qualitative

and quantitative tests mentioned in
the specifications for starting
materials may be replaced by a
system of certificates issued by the
producer of the starting material,
provided that:
• there is a history of reliable

production,
• the producer is regularly audited,
and
158
ANNEX 3: QUALIFICATION AND VALIDATION
PRINCIPLE f) change control;

g) reference to existing documents.
1. This Annex describes the principles
of qualification and validation which 5. In case of large projects, it may
are applicable to the manufacture of be necessary to create separate
medicinal products. It is a validation master plans.
requirement of GMP that
manufacturers identify what DOCUMENTATION
validation work is needed to prove
control of the critical aspects 6. A written protocol should be
of their particular operations. established that specifies how
Significant changes to the facilities, qualification and validation will be
the equipment and the processes, conducted. The protocol should be
which may affect the quality of reviewed and approved. The
the product, should be validated. A protocol should specify critical steps
risk assessment approach should and acceptance criteria.
be used to determine the scope and
extent of validation. 7. A report that cross-references
the qualification and/or validation
PLANNING FOR VALIDATION protocol should be prepared,
summarizing the results obtained,
2. All validation activities should be commenting on any deviations
planned. The key elements of observed, and drawing
a validation programme should be the necessary conclusions,
clearly defined and documented in including recommending changes
a validation master plan (VMP) or necessary to correct deficiencies.
equivalent documents. Any changes to the plan as defined
in the protocol should be
3. The VMP should be a summary documented with appropriate
document which is brief, concise justification.
and clear.
8. After completion of a satisfactory
4. The VMP should contain data on at qualification, a formal release for the
least the following: next step in qualification and
validation should be made as a
a) validation policy; written authorization.
b) organizational structure of validation
activities; QUALIFICATION
c) summary of facilities, systems,
equipment and processes to Design qualification
be validated;
d) documentation format: the format to 9. The first element of the validation of
be used for protocols and reports; new facilities, systems or equipment
e) planning and scheduling; could be design qualification (DQ).
159
10. The compliance of the design operating and cleaning procedures,

with GMP should be demonstrated operator training and preventative
and documented. maintenance requirements. It should
permit a formal “release” of the
Installation qualification facilities, systems and equipment.
11. Installation qualification (IQ) should Performance qualification

be performed on new or modified
facilities, systems and equipment. 16. Performance qualification (PQ)
should follow successful completion
12. IQ should include, but not be limited of Installation qualification and
to the following: Operational qualification.
a) installation of equipment, piping, 17. PQ should include, but not be

services and instrumentation limited to the following:
checked to current engineering
drawings and specifications; a) tests, using production materials,
b) collection and collation of supplier qualified substitutes or simulated
operating and working instructions product, that have been developed
and maintenance requirements; from knowledge of the process and
c) calibration requirements; the facilities, systems or equipment;
d) verification of materials of b) tests to include a condition or set
construction. of conditions encompassing upper
and lower operating limits.
Operational qualification
18. Although PQ is described as a
13. Operational qualification (OQ) separate activity, it may in some
should follow Installation cases be appropriate to perform it in
qualification. conjunction with OQ.
14. OQ should include, but not be Qualification of established (in-use)

limited to the following: facilities, systems and equipment
a) tests that have been developed 19. Evidence should be available to

from knowledge of processes, support and verify the operating
systems and equipment; parameters and limits for the
b) tests to include a condition or a set critical variables of the operating
of conditions encompassing upper equipment. Additionally,
and lower operating limits, the calibration, cleaning,
sometimes referred to as “worst preventative maintenance, operating
case” conditions. procedures and operator
training procedures and records
15. The completion of a successful should be documented.
Operational qualification should
allow the finalization of calibration,
160
PROCESS VALIDATION (a) short description of the process;

(b) summary of the critical processing
General steps to be investigated;
(c) list of the equipment/facilities to
20. The requirements and principles be used (including measuring /
outlined in this chapter monitoring / recording equipment)
are applicable to the manufacture together with its calibration status
of pharmaceutical dosage forms. (d) finished product specifications
They cover the initial validation for release;
of new processes, subsequent (e) list of analytical methods,
validation of modified processes as appropriate;
and revalidation. (f) proposed in-process controls with
acceptance criteria;
21. Process validation should normally (g) additional testing to be carried
be completed prior to the distribution out, with acceptance criteria and
and sale of the medicinal product analytical validation, as appropriate;
(prospective validation). In (h) sampling plan;
exceptional circumstances, where (i) methods for recording and
this is not possible, it may be evaluating results
necessary to validate processes (j) functions and responsibilities;
during routine production (k) proposed timetable.
(concurrent validation). Processes
in use for some time should also be 25. Using this defined process
validated (retrospective validation). (including specified components) a
series of batches of the final product
22. Facilities, systems and equipment may be produced under routine
to be used should have been conditions. In theory the number
qualified and analytical testing of process runs carried out and
methods should be validated. Staff observations made should be
taking part in the validation work sufficient to allow the normal extent
should have been appropriately of variation and trends to be
trained. established and to provide sufficient
data for evaluation. It is generally
23. Facilities, systems, equipment and considered acceptable that three
processes should be periodically consecutive batches/runs within the
evaluated to verify that they are still finally agreed parameters would
operating in a valid manner. constitute a validation of
the process.
Prospective validation
26. Batches made for process validation
24. Prospective validation should should be the same size as the
include, but not be limited to intended industrial scale batches.
the following:
27. If it is intended that validation
batches be sold or supplied, the
161
conditions under which they 33. The source of data for this validation
are produced should comply fully should include, but not be limited
with the requirements of Good to batch processing and packaging
Manufacturing Practice, including records, process control charts,
the satisfactory outcome of the maintenance log books, records of
validation exercise, and (where personnel changes, process
applicable) the marketing capability studies, finished product
authorization. data, including trend cards and
storage stability results.
Concurrent validation
34. Batches selected for retrospective
28. In exceptional circumstances it may validation should be representative
be acceptable not to complete of all batches made during the
a validation programme before review period, including any batches
routine production starts. that failed to meet specifications,
and should be sufficient in number
29. The decision to carry out concurrent to demonstrate process consistency.
validation must be justified, Additional testing of retained
documented and approved by samples may be needed to obtain
authorized personnel. the necessary amount or type of
data to retrospectively validate
30. Documentation requirements the process.
for concurrent validation are the
same as specified for prospective 35. For retrospective validation,
validation. generally data from ten to thirty
consecutive batches should be
Retrospective validation examined to assess process
consistency, but fewer batches may
31. Retrospective validation is only be examined if justified.
acceptable for well-established
processes and will be inappropriate CLEANING VALIDATION
where there have been recent
changes in the composition of the 36. Cleaning validation should be
product, operating procedures performed in order to confirm the
or equipment. effectiveness of a cleaning
procedure. The rationale for
32. Validation of such processes selecting limits of carryover of
should be based on historical data. product residues, cleaning agents
The steps involved require the and microbial contamination should
preparation of a specific protocol be logically based on the materials
and the reporting of the results of involved. The limits should be
the data review, leading to a achievable and verifiable.
conclusion and a recommendation.
37. Validated analytical methods having
sensitivity to detect residues or
162
contaminants should be used. The CHANGE CONTROL

detection limit for each analytical
method should be sufficiently 43. Written procedures should be in
sensitive to detect the established place to describe the actions to be
acceptable level of the residue taken if a change is proposed to a
or contaminant. starting material, product
component, process equipment,
38. Normally only cleaning procedures process environment (or site),
for product contact surfaces of the method of production or testing
equipment need to be validated. or any other change that may
Consideration should be given to affect product quality or
non-contact parts. The intervals reproducibility of the process.
between use and cleaning as well Change control procedures
as cleaning and reuse should be should ensure that sufficient
validated. Cleaning intervals and supporting data are generated to
methods should be determined. demonstrate that the revised
process will result in a product of the
39. For cleaning procedures for desired quality, consistent with the
products and processes which are approved specifications.
similar, it is considered acceptable
to select a representative range 44. All changes that may affect product
of similar products and processes. A quality or reproducibility of the
single validation study utilizing a process should be formally
“worst case” approach can be requested, documented and
carried out which takes account of accepted. The likely impact of the
the critical issues. change of facilities, systems
and equipment on the product
40. Typically three consecutive should be evaluated, including risk
applications of the cleaning analysis. The need for, and the
procedure should be performed and extent of, requalification and re-
shown to be successful in order to validation should be determined.
prove that the method is validated.
REVALIDATION
41. “Test until clean” is not considered
an appropriate alternative to 45. Facilities, systems, equipment and
cleaning validation. processes, including cleaning,
should be periodically evaluated
42. Products which simulate the to confirm that they remain valid.
physicochemical properties of the Where no significant changes
substances to be removed have been made to the validated
may exceptionally be used instead status, a review with evidence that
of the substances themselves, facilities, systems, equipment and
where such substances are either processes meet the prescribed
toxic or hazardous. requirements fulfils the need for
revalidation.
163
GLOSSARY Installation Qualification (IQ)
Definitions of terms relating to qualification The documented verification that the facilities,
and validation which are not given in the systems and equipment, as installed or
glossary of the current EAC-GMP Guide, but modified, comply with the approved design
which are used in this Annex, are given below. and the manufacturer’s recommendations.
Operational Qualification (OQ)

Change Control
The documented verification that the facilities,
A formal system by which qualified systems and equipment, as installed or
representatives of appropriate disciplines modified, perform as intended throughout the
review proposed or actual changes that anticipated operating ranges.
might affect the validated status of facilities,
systems, equipment or processes. The intent Performance Qualification (PQ)
is to determine the need for action that would
ensure and document that the system is The documented verification that the facilities,
maintained in a validated state. systems and equipment, as connected
together, can perform effectively and
Cleaning Validation reproducibly, based on the approved process
method and product specification.
Cleaning validation is documented evidence
that an approved cleaning procedure will Process Validation
provide equipment which is suitable for
processing medicinal products. The documented evidence that the process,
operated within established parameters,
Concurrent Validation can perform effectively and reproducibly
to produce a medicinal product meeting its
Validation carried out during routine production predetermined specifications and quality
of products intended for sale. attributes.
Design qualification (DQ) Prospective Validation
The documented verification that the proposed Validation carried out before routine
design of the facilities, systems and equipment production of products intended for sale.
is suitable for the intended purpose.

164
Retrospective Validation
Validation of a process for a product which has been marketed based upon accumulated
manufacturing, testing and control batch data.
Re-Validation
A repeat of the process validation to provide an assurance that changes in the process/equipment
introduced in accordance with change control procedures do not adversely affect process
characteristics and product quality.
Risk analysis
Method to assess and characterize the critical parameters in the functionality of an equipment or
process.
Simulated Product
A material that closely approximates the physical and, where practical, the chemical
characteristics (e.g. viscosity, particle size, pH etc.) of the product under validation. In many
cases, these characteristics may be satisfied by a placebo product batch.
System
A group of equipment with a common purpose.
Worst Case
A condition or set of conditions encompassing upper and lower processing limits and
circumstances, within standard operating procedures, which pose the greatest chance of product
or process failure when compared to ideal conditions. Such conditions do not necessarily induce
product or process failure.
165
ANNEX 4: COMPUTERIZED SYSTEMS
PRINCIPLE system. This cycle includes

the stages of planning, specification,
The introduction of computerized systems programming, testing,
into systems of manufacturing, including commissioning, documentation,
storage, distribution and quality control does operation, monitoring and changing.
not alter the need to observe the relevant
principles given elsewhere in the Guide. SYSTEM
Where a computerized system replaces
a manual operation, there should be no 3. Attention should be paid to the siting
resultant decrease in product quality or quality of equipment in suitable conditions
assurance. Consideration should be given where extraneous factors cannot
to the risk of losing aspects of the previous interfere with the system.
system by reducing the involvement of
operators. 4. A written detailed description of
the system should be produced
PERSONNEL (including diagrams as appropriate)
and kept up to date. It should
1. It is essential that there is the describe the principles, objectives,
closest co-operation between key security measures and scope of
personnel and those involved with the system and the main features
computer systems. Persons of the way in which the computer is
in responsible positions should have used and how it interacts with other
the appropriate training for the systems and procedures.
management and use of systems
within their field of responsibility 5. The software is a critical component
which utilizes computers. This of a computerized system. The user
should include ensuring that of such software should take all
appropriate expertise is available reasonable steps to ensure that
and used to provide advice on it has been produced in accordance
aspects of design, validation, with a system of Quality Assurance.
installation and operation of
computerized system. 6. The system should include, where
appropriate, built-in checks of the
VALIDATION correct entry and processing
of data.
2. The extent of validation necessary
will depend on a number of factors 7. Before a system using a computer
including the use to which the is brought into use, it should be
system is to be put, whether it is thoroughly tested and confirmed as
prospective or retrospective being capable of achieving the
and whether or not novel elements desired results. If a manual system
are incorporated. Validation should is being replaced, the two should be
be considered as part of the run in parallel for a time, as part of
complete life cycle of a computer this testing and validation.
166
8. Data should only be entered or checking, approving and

amended by persons authorized implementing the change. Such
to do so. Suitable methods of an alteration should only be
deterring unauthorized entry of implemented with the agreement
data include the use of keys, pass of the person responsible for
cards, personal codes and restricted the part of the system concerned,
access to computer terminals. There and the alteration should be
should be a defined procedure recorded. Every significant
for the issue, cancellation, and modification should be validated.
alteration of authorization to enter
and amend data, including 12. For quality auditing purposes,
the changing of personal it should be possible to obtain
passwords. Consideration should meaningful printed copies of
be given to systems allowing electronically stored data.
for recording of attempts to access
by unauthorized persons. 13. Data should be secured by
physical or electronic means against
9. When critical data are being entered willful or accidental damage,
manually (for example the weight and this in accordance with item 5.8
and batch number of an ingredient of the Guide. Stored data should
during dispensing), there should be checked for accessibility,
be an additional check on the durability and accuracy. If changes
accuracy of the record which is are proposed to the computer
made. This check may be done by equipment or its programs, the
a second operator or by validated above mentioned checks should be
electronic means. performed at a frequency
appropriate to the storage medium
10. The system should record the being used.
identity of operators entering
or confirming critical data. Authority 14. Data should be protected by
to amend entered data should backing-up at regular intervals.
be restricted to nominated persons. Back-up data should be stored as
Any alteration to an entry of long as necessary at a separate and
critical data should be authorized secure location.
and recorded with the reason for
the change. Consideration should 15. There should be available adequate
be given to the system creating alternative arrangements for
a complete record of all entries and systems which need to be operated
amendments (an “audit trail”). in the event of a breakdown.
The time required to bring the
11. Alterations to a system or to a alternative arrangements into use
computer program should only be should be related to the possible
made in accordance with a urgency of the need to use them.
defined procedure which should
include provision for validating,
167
For example, information required 18. When outside agencies are used to
to effect a recall must be available provide a computer service, there
at short notice. should be a formal agreement
including a clear statement of the
16. The procedures to be followed if the responsibilities of that outside
system fails or breaks down should agency. (see chapter 8)
be defined and validated. Any
failures and remedial action taken 19. When the release of batches
should be recorded. for sale or supply is carried out
using a computerized system,
17. A procedure should be established the system should recognize that
to record and analyze errors and to only an Authorized Person can
enable corrective action to be taken. release the batches and it should
clearly identify and record the
person releasing the batches.
168
ANNEX 5: WATER FOR PHARMACEUTICAL USE
1.1 Scopes 1.2 Background to water

requirements and uses
The guidance contained in this document
is intended to provide information about Water is the most widely used substance, raw
the available specifications for water for material or starting material in the production,
pharmaceutical use (WPU), guidance about processing and formulation of pharmaceutical
which quality of water to use for specific products. It has unique chemical properties
applications, such as the manufacture of due to its polarity and hydrogen bonds. This
active pharmaceutical ingredients (APIs) and means it is able to dissolve, absorb, adsorb
dosage forms, and to provide guidance on the or suspend many different compounds. These
good manufacturing practice (GMP )regarding include contaminants that may represent
the design, installation and operation of hazards in themselves or that may be able
pharmaceutical water systems. Although to react with intended product substances,
the focus of this document is on water for resulting in hazards to health.
pharmaceutical applications, the guidelines
may also be relevant to other industrial or 1.3 Applicable guides
specific uses where the specifications and
practices can be applied. In addition to the specific guidance provided
in this document, the Bibliography lists some
This document refers to available relevant publications that can serve as
specifications, such as the pharmacopoeias additional background material when planning,
and industry guidance for the use, production, installing and using systems intended to
storage and distribution of water in bulk provide WPU.
form. In order to avoid confusion it does not
attempt to duplicate such material. Note:
This document does not cover waters for 2. General requirements for
administration to patients in their formulated pharmaceutical water systems
state or the use of small quantities of water
in pharmacies to compound individually Pharmaceutical water production, storage
prescribed medicines. and distribution systems should be designed,
installed, commissioned, validated and
The guidance provided in this document can maintained to ensure the reliable production
be used in whole or in part as appropriate to of water of an appropriate quality. They
the application under consideration. should not be operated beyond their designed
Where subtle points of difference exist capacity. Water should be produced, stored
between pharmacopoeial specifications, and distributed in a manner that prevents
the manufacturer will be expected to decide unacceptable microbial, chemical or physical
which option to choose in accordance with the contamination (e.g. with dust and dirt).
related marketing authorization submitted to
the national drug regulatory authority. The use of the systems following installation,
commissioning, validation and any unplanned
maintenance or modification work should
be approved by the quality assurance (QA)
department. If approval is obtained for
169
planned preventive maintenance tasks, they Drinking-water is unmodified except for

need not be approved after implementation. limited treatment of the water derived from a
Water sources and treated water should natural or stored source. Examples of natural
be monitored regularly for quality and for sources include springs, wells, rivers, lakes
chemical, microbiological and, as appropriate, and the sea. The condition of the source water
endotoxin contamination. The performance will dictate the treatment required to render
of water purification, storage and distribution it safe for human consumption (drinking).
systems should also be monitored. Records Typical treatment includes softening, removal
of the monitoring results and any actions of specific ions, particle reduction and
taken should be maintained for an appropriate antimicrobial treatment. It is common for
length of time. drinking-water to be derived from a public
water supply that may be a combination of
Where chemical sanitization of the water more than one of the natural sources listed
systems is part of the biocontamination control above. It is also common for public water-
programme, a validated procedure should be supply organizations to conduct tests and
followed to ensure that the sanitizing agent guarantee that the drinking-water delivered is
has been effectively removed. of potable quality.
3. Water quality specifications Drinking-water quality is covered by the WHO

drinking-water guidelines, standards from the
3.1 General International Organization for Standardization
(ISO) and other regional and national
The following requirements concern water agencies. Drinking-water should comply with
processed stored and distributed in bulk the relevant regulations laid down by the
form. They do not cover the specification of competent authority.
waters formulated for patient administration.
Pharmacopoeias include specifications for If drinking-water is used directly in certain
both bulk and dosage-form waters. stages of pharmaceutical manufacture or is
the feed-water for the production of higher
Pharmacopoeial requirements for WPU are qualities of WPU, then testing should be
described in national and international carried out periodically by the water user’s site
pharmacopoeias and limits for various to confirm that the quality meets the standards
contaminants are given. Companies required for potable water.
wishing to supply multiple markets should
set specifications that meet the strictest 3.3 Purified water
requirements from each of the relevant
pharmacopoeias. Purified water (PW) should be prepared from
a potable water source as a minimum-quality
3.2 Drinking water feed-water, should meet the pharmacopoeial
specifications for chemical and microbiological
Drinking-water should be supplied under purity, and should be protected from
continuous positive pressure in a plumbing recontamination and microbial proliferation.
system free of any defects that could lead to
contamination of any product.
170
3.4 Highly purified water 4. Application of specific waters to

processes and dosage forms
Highly purified water (HPW) should be
prepared from potable water as minimum- Product licensing authorities define the
quality feed-water. HPW is a unique requirement to use the specific grades of
specification for water found only in the WPU for different dosage forms or for different
European Pharmacopoeia. This grade of stages in washing, preparation, synthesis,
water must meet the same quality standard manufacturing or formulation.
as water for injections (WFI) including the
limit for endotoxins, but the water-treatment The grade of water used should take into
methods are not considered to be as reliable account the nature and intended use of the
as distillation. HPW may be prepared by intermediate or finished product and the stage
combinations of methods such as reverse in the manufacturing process at which the
osmosis, ultra filtration and deionization. water is used.
3.5 Water for injections HPW can be used in the preparation of

products when water of high quality(i.e. very
Water for injections (WFI) should be low in microorganisms and endotoxins) is
prepared from potable water as a needed, but the process stage or product
minimum-quality feed-water. WFI is not sterile requirement does not include the constraint on
water and is not a final dosage form. It is an the production method defined in some of the
intermediate bulk product. WFI is the highest pharmacopoeial monographs for WFI.
quality of pharmacopoeial WPU.
WFI should be used in injectable product
Certain pharmacopoeias place constraints preparations, for dissolving or diluting
upon the permitted purification techniques substances or preparations for parenteral
as part of the specification of the WFI. administration before use, and for sterile water
The International Pharmacopoeia and the for preparation of injections. WFI should also
European Pharmacopoeia, for example, allow be used for the final rinse after cleaning of
only distillation as the final purification step. equipment and components that come into
contact with injectable products as well as
3.6 Other grades of water for the final rinse in a washing process in
which no subsequent thermal or chemical
When a specific process requires a special depyrogenization process is applied.
non-pharmacopoeial grade of water, this
should be specified and should at least satisfy When steam comes into contact with an
the pharmacopoeial requirements of the grade injectable product in its final container, or
of WPU required for the type of dosage form equipment for preparing injectable products,
or process step. it should conform to the specification for WFI
when condensed.
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5. Water purification methods • tolerance to cleaning and sanitizing

agents (thermal and chemical);
5.1 General considerations • the system capacity and output
requirements; and
The specifications for WPU found in • the provision of all necessary
compendia (e.g. pharmacopoeias) are instruments, test and sampling
generally not prescriptive as to permissible points to allow all the relevant
water purification methods other than those for critical quality parameters of the
WFI (refer to section 3.5). complete system to be monitored.
The chosen water purification method, or The design, configuration and layout of the
sequence of purification steps, must be water purification equipment, storage and
appropriate to the application in question. The distribution systems should also take into
following should be considered when selecting account the following physical considerations:
the water treatment method:
• the space available for the
• the water quality specification; installation;
• the yield or efficiency of the • structural loadings on buildings;
purification system; • the provision of adequate access for
• feed-water quality and the variation maintenance; and
over time (seasonal changes); • the ability to safely handle
• the reliability and robustness of the regeneration and sanitization
water-treatment equipment chemicals.
in operation;
• the availability of water-treatment 5.2 Production of drinking-water
equipment on the market;
• the ability to adequately support and Drinking-water is derived from a raw water
maintain the water purification source such as a well, river or reservoir. There
equipment; and are no prescribed methods for the treatment
• the operation costs. of raw water to produce potable drinking-water
from a specific raw water source.
The specifications for water purification
equipment, storage and distribution systems Typical processes employed at a user plant or
should take into account the following: by a water supply authority include:
• the risk of contamination from • filtration;

leachates from contact materials; • softening;
• the adverse impact of adsorptive • disinfection or sanitization (e.g. by
contact materials; sodium hypochlorite (chlorine)
• hygienic or sanitary design, where injection);
required; • iron (ferrous) removal;
• corrosion resistance; • precipitation; and
• freedom from leakage; • reduction of specific inorganic/
• configuration to avoid proliferation of organic materials.
microbiological organisms;
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The drinking-water quality should be with appropriately protected vents, allow for
monitored routinely. Additional testing should visual inspection and for being drained and
be considered if there is any change in the sanitized. Distribution pipe work should be
raw-water source, treatment techniques or able to be drained, or flushed, and sanitized.
system configuration. If the drinking water
quality changes significantly, the direct use Special care should be taken to control
of this water as a WPU, or as the feed-water microbiological contamination of sand filters,
to downstream treatment stages, should carbon beds and water softeners. Once
be reviewed and the result of the review microorganisms have infected a system, the
documented. contamination can rapidly form biofilms and
spread throughout the system. Techniques
Where drinking-water is derived from an for controlling contamination such as back-
“in-house” system for the treatment of raw flushing, chemical or thermal sanitization and
water, the water-treatment steps used and the frequent regeneration should be considered.
system configuration should be documented. Additionally, all water-treatment components
Changes to the system or its operation should be maintained with continuous water
should not be made until a review has been flow to inhibit microbial growth.
completed and the change approved by the
QA department. 5.3 Production of purified water

Where drinking-water is stored and distributed There are no prescribed methods for the
by the user, the storage systems must not production of PW in the pharmacopoeias. Any
allow degradation of the water quality before appropriate qualified purification technique
use. After any such storage, testing should or sequence of techniques may be used to
be carried out routinely in accordance with a prepare PW. Typically ion exchange, ultra
defined method. Where water is stored, its use filtration and/or reverse osmosis processes
should ensure a turnover of the stored water are used. Distillation can also be used.
sufficient to prevent stagnation. The drinking-
water system is usually considered to be an The following should be considered when
“indirect impact system” and does not need to configuring a water purification system:
be qualified.
• the feed-water quality and its
Drinking-water purchased in bulk and variation over seasons;
transported to the user by tanker presents • the required water-quality
special problems and risks not associated with specification;
potable water delivered by pipeline. Vendor • the sequence of purification stages
assessment and authorized certification required;
activities, including confirmation of the • the energy consumption;
acceptability of the delivery vehicle, should be • the extent of pretreatment required
undertaken in a similar way to that used for to protect the final purification steps;
any other starting material. • performance optimization, including
yield and efficiency of unit
Equipment and systems used to produce treatment- process steps;
drinking-water should be able to be drained
and sanitized. Storage tanks should be closed
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• appropriately located sampling 5.5 Production of water for injections

points designed in such a way as to
avoid potential contamination; and The pharmacopoeias prescribe or limit the
• unit process steps should be permitted final water purification stage in the
provided with appropriate production of WFI. Distillation is the preferred
instrumentation to measure technique; it is considered a more robust
parameters such as flow, pressure, technique based on phase change, and in
temperature, conductivity, pH and some cases, high temperature operation of
total organic carbon. the process equipment.
Ambient-temperature PW systems are The following should be considered when

especially susceptible to microbiological designing a water purification system:
contamination, particularly when equipment
is static during periods of no or low demand • the feed-water quality;
for water. It is essential to consider the • the required water quality
mechanisms for microbiological control and specification;
sanitization. The following techniques should • the optimum generator size to avoid
be considered: over-frequent start/stop cycling;
• blow-down and dump functions; and
• maintenance of flow through water- • cool-down venting to avoid
purification equipment at all times; contamination ingress.
• control of temperature in the system
by pipeline heat exchange or plant- 6. Water purification, storage
room cooling to reduce the risk of and distribution systems
microbial growth (guidance
value <25°C); This section applies to WPU systems for
• provision of ultraviolet disinfection; PW, HPW and WFI. The water storage and
• selection of water-treatment distribution should work in conjunction with the
components that can be thermally purification plant to ensure consistent delivery
sanitized; and/or of water to the user points, and to ensure
• application of chemical sanitization optimum operation of the water purification
(including agents such as ozone). equipment.
5.4 Production of highly purified water 6.1 General
There are no prescribed methods for The storage and distribution system should be
the production of HPW in any major considered as a key part of the whole system,
pharmacopoeia, including the European and should be designed to be fully integrated
Pharmacopoeia. Any appropriate qualified with the water purification components of the
purification technique or sequence of system.
techniques may be used to prepare HPW.
Typically ion exchange, ultrafiltration and/
or reverse osmosis processes are used. The
guidance provided in section 5.3 for PW is
equally applicable to HPW.
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Once water has been purified using an be compatible with the pipe work
appropriate method, it can either be used used. Appropriate sanitary-
directly or, more frequently, it will be fed into specification plastics and stainless
a storage vessel for subsequent distribution steel materials are acceptable for
to points of use. The following text describes WPU systems. When stainless
the requirements for storage and distribution steel is used it should be at
systems. least grade 316 L. The system
should be passivated after initial
The storage and distribution system should be installation or after modification.
configured to prevent recontamination of the When accelerated passivation is
water after treatment and be subjected to a undertaken, the system should be
combination of online and offline monitoring to thoroughly cleaned first, and the
ensure that the appropriate water specification passivation process should be
is maintained. undertaken in accordance with a
clearly defined documented
6.2 Materials that come into contact with procedure.
systems for water for pharmaceutical use
• Smooth internal finish. Once
This section applies to generation equipment water has been purified it is
for PW, HPW and WFI, and the associated susceptible to microbiological
storage and distribution systems. contamination, and the system is
subject to the formation of
The materials that come into contact with biofilms when cold storage and
WPU, including pipe work, valves and fittings, distribution is employed. Smooth
seals, diaphragms and instruments, should be internal surfaces help to avoid
selected to satisfy the following objectives. roughness and crevices within the
WPU system. Crevices are
• Compatibility. All materials used frequently sites where corrosion can
should be compatible with the commence. The internal finish
temperature and chemicals used by should have an arithmetical average
or in the system. surface roughness of not greater
than 0.8 micrometre arithmetical
• Prevention of leaching. All mean roughness (Ra). When
materials that come into contact stainless steel is used, mechanical
with WPU should be non-leaching at and electropolishing techniques
the range of working temperatures. may be employed. Electropolishing
improves the resistance of the
• Corrosion resistance. PW, HPW stainless steel material to surface
and WFI are highly corrosive. To corrosion.
prevent failure of the system and
contamination of the water, the • Jointing. The selected system
materials selected must be materials should be able to be
appropriate, the method of jointing easily jointed by welding in a
must be carefully controlled, and all controlled manner. The control of
fittings and components must the process should include as
175
a minimum, qualification of the or modification. The techniques employed

operator, documentation of the should be considered during the design of
welder set-up, work-session test the system and their performance proven
pieces, logs of all welds and visual during the commissioning and qualification
inspection of a defined proportions activities.
of welds.
Systems that operate and are maintained
• Design of flanges or unions. at elevated temperatures, in the range of
Where flanges or unions are used, 70–80°C, are generally less susceptible to
they should be of a hygienic or microbiological contamination than systems
sanitary design. Appropriate checks that are maintained at lower temperatures.
should be carried out to ensure that When lower temperatures are required due
the correct seals are used and that to the water treatment processes employed
they are fitted and tight- ened or the temperature requirements for the water
correctly. in use, then special precautions should be
taken to prevent the ingress and proliferation
• Documentation. All system of microbiological contaminants (see section
components should be fully 6.5.3 for guidance).
documented and be supported
by original or certified copies of 6.4 Storage vessel requirements
material certificates.
The water storage vessel used in a
• Materials. Suitable materials system serves a number of important
that may be considered for sanitary purposes. The design and size of the vessel
elements of the system include 316 should take into consideration the following.
L (low carbon) stainless steel,
polypropylene, 6.4.1 Capacity
polyvinylidenedifluoride and
perfluoroalkoxy. Other materials The capacity of the storage vessel should
such as unplasticized be determined on the basis of the following
polyvinylchloride (uPVC) may be requirements.
used for treatment equipment
designed for less pure water such • It is necessary to provide a buffer
as ion exchangers and softeners. capacity between the steady-
state generation rate of the water-
6.3 System sanitization and bioburden treatment equipment and the
control potentially variable simultaneous
demand from user points
Water treatment equipment, storage and
distribution systems used for PW, HPW and • The water treatment equipment
WFI should be provided with features to should be able to operate
control the proliferation of microbiological continuously for significant periods
organisms during normal use, as well as to avoid the inefficiencies and
techniques for sanitizing or sterilizing the equipment stress that occur when
system after intervention for maintenance
176
the equipment cycles on and off configured to allow in situ testing of

too frequently. integrity. Offline testing is also
acceptable. The use of heated
• The capacity should be sufficient vent filters should be considered
to provide short-term reserve to prevent condensation within the
capacity in the event of failure of filter matrix that might lead to filter
the water-treatment equipment or blockage and to microbial grow-
inability to produce water due to through that could contaminate the
a sanitization or regeneration cycle. storage vessels.
When determining the size of such
reserve capacity, consideration • Where pressure-relief valves and
should be given to providing bursting discs are provided on
sufficient water to complete a storage vessels to protect them from
process batch, work session or over-pressurization, these devices
other logical period of demand. should be of a sanitary design.
Bursting discs should be provided
6.4.2 Contamination control considerations with external rupture indicators to
prevent accidental loss of system
The following should be taken into account integrity.
for the efficient control of contamination.
6.5 Requirements for water distribution
• The headspace in the storage pipework
vessel is an area of risk where
water droplets and air can come into The distribution of PW, HPW and WFI should
contact at temperatures that be accomplished using a continuously
encourage the proliferation of circulating pipework loop. Proliferation of
microbiological organisms. The contaminants within the storage tank and
water distribution loop should be distribution loop should be controlled.
configured to ensure that the
headspace of the storage vessel is Filtration should not usually be used in
effectively wetted by a flow of water. distribution loops or at takeoff user points to
The use of spray ball or distributor control biocontamination. Such filters are likely
devices to wet the surfaces should to conceal system contamination.
be considered.
6.5.1 Temperature control and heat
• Nozzles within the storage vessels exchangers
should be configured to avoid dead
zones where microbiological Where heat exchangers are employed to
contamination might be harboured. heat or cool WPU within a system, pre-
cautions should be taken to prevent the
• Vent filters are fitted to storage heating or cooling utility from contaminating
vessels to allow the internal level the water. The more secure types of heat
of liquid to fluctuate. The filters exchangers of the double tube plate or double
should be bacteria-retentive, plate and frame configuration should be
hydrophobic and ideally be considered. Where these types are not used,
177
an alternative approach whereby the utility • The system design should ensure
is main- trained and monitored at a lower the shortest possible length
pressure than the WPU may be considered. of pipework.
Where heat exchangers are used they should • For ambient temperature systems,
be arranged in continually circulating loops or pipework should be isolated from
sub-loops of the system to avoid unacceptable adjacent hot pipes.
static water in systems. • Deadlegs in the pipework
installation greater than 1.5 times
When the temperature is reduced for the branch diameter should
processing purposes, the reduction should be avoided.
occur for the minimum necessary time. The • Pressure gauges should be
cooling cycles and their duration should be separated from the system by
proven satisfactory during the qualification of membranes.
the system. • Hygienic pattern diaphragm valves
should be used.
6.5.2 Circulation pumps • Pipework should be laid to falls to
allow drainage.
Circulation pumps should be of a sanitary • The growth of microorganisms can
design with appropriate seals that prevent be inhibited by:
contamination of the system. Where stand-
by pumps are provided, they should be 1. ultraviolet radiation sources
configured or managed to avoid dead zones in pipework;
trapped within the system. 2. maintaining the system heated
(guidance temperature 70–80°C);
6.5.3 Biocontamination control techniques 3. sanitizing the system periodically
using hot water (guidance
The following control techniques may be used temperature >70°C);
alone or more commonly in combination. 4. sterilizing or sanitizing the system
periodically using superheated hot
• Maintenance of continuous turbulent water or clean steam; and
flow circulation within water distribu- 5. routine chemical sanitization using
tion systems reduces the ozone or other suitable chemical
propensity for the formation of agents. When chemical sanitization
biofilms. The maintenance of the is used, it is essential to prove that
design velocity for a specific the agent has been removed prior
system should be proven during the to using the water. Ozone can
system qualification and the be effectively removed by using
maintenance of satisfactory ultraviolet radiation.
performance should be monitored.
During the operation of a distribution
system, short- term fluctuations
in the flow velocity are unlikely to
cause contamination problems
provided that cessation of flow, flow
reversal or pressure loss does
not occur.
178
7. Operational considerations Phase1: A test period of 2–4 weeks should

be spent monitoring the system intensively.
7.1 Start-up and commissioning of water During this period the system should operate
systems continuously without failure or performance
deviation. The following should be included in
Planned, well-defined, successful and well- the testing approach.
documented commissioning is an essential
precursor to successful validation of water • Undertake chemical and
systems. The commissioning work should microbiological testing in
include setting to work, system setup, controls accordance with a defined plan.
loop tuning and recording of all system • Sample the incoming feed-water
performance parameters. If it is intended to daily to verify its quality.
use or refer to commissioning data within • Sample after each step in the
the validation work then the quality of the purification process daily.
commissioning work and associated data and • Sample at each point of use and at
documentation must be commensurate with other defined sample points daily.
the validation plan requirements. • Develop appropriate operating
ranges.
7.2 Qualification • Develop and finalize operating,
cleaning, sanitizing and
WPU, PW, HPW and WFI systems are maintenance procedures.
all considered to be direct impact, quality • Demonstrate production and
critical systems that should be qualified. delivery of product water of the
The qualification should follow the validation required quality and quantity.
convention of design review or design • Use and refine the standard
qualification (DQ), installation qualification operating procedures (SOPs) for
(IQ), operational qualification (OQ) and operation, maintenance, sanitization
performance qualification (PQ). and troubleshooting.
• Verify provisional alert and action
This guidance does not define the standard levels.
requirements for the conventional validation • Develop and refine test-failure
stages DQ, IQ and OQ, but concentrates on procedure.
the particular PQ approach that should be
used for WPU systems to demonstrate their Phase 2: A further test period of 2–4 weeks
consistent and reliable performance. A three- should be spent carrying out further intensive
phase approach should be used to satisfy monitoring while deploying all the refined
the objective of proving the reliability and SOPs after the satisfactory completion of
robustness of the system in service over phase 1. The sampling scheme should be
an extended period. generally the same as in phase 1. Water can
be used for manufacturing purposes during
this phase.
179
The approach should also: of use should be taken in a similar way to

that adopted when the water is being used in
• demonstrate consistent operation service.
within established ranges; and
• demonstrate consistent production Tests should be carried out to ensure that
and delivery of water of the required the selected pharmacopoeia specification
quantity and quality when the has been satisfied, and should include, as
system is operated in accordance appropriate, determination of conductivity,
with the SOPs. pH, heavy metals, nitrates, total organic
carbon, total viable count, presence of specific
Phase 3: Phase 3 typically runs for 1 year pathogens and endotoxins.
after the satisfactory completion of phase
2. Water can be used for manufacturing Monitoring data should be subject to trend
purposes during this phase which has the analysis.
following objectives and features.
7.4 Maintenance of water systems
• Demonstrate extended reliable
performance. WPU systems should be maintained in
• Ensure that seasonal variations are accordance with a controlled, documented
evaluated. maintenance programme that takes into
• The sample locations, sampling account the following:
frequencies and tests should be
reduced to the normal routine • defined frequency for system
pattern based on established elements;
procedures proven during phases 1 • the calibration programme;
and 2. • SOPs for specific tasks;
• control of approved spares;
7.3 Continuous system monitoring • issue of clear maintenance plan
and instructions;
After completion of phase 3 of the qualification • review and approval of systems for
programme for the WPU system, a system use upon completion of work; and
review should be undertaken. Following this • record and review of problems and
review, a routine monitoring plan should be faults during maintenance.
established based on the results of phase 3.
7.5 System reviews
Monitoring should include a combination of
online instrument monitoring of parameters WPU (PW, HPW and WFI) systems should be
such as flow, pressure, temperature, reviewed at appropriate regular intervals. The
conductivity and total organic carbon, and review team should comprise representatives
offline sample testing for physical, chemical from engineering, QA, operations and
and microbiological attributes. Offline samples maintenance.
should be taken from points of use and
specific sample points. Samples from points
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The review should consider matters such as:
• changes made since the last review;

• system performance;
• reliability;
• quality trends;
• failure events;
• investigations;
• out-of-specifications results from
monitoring;
• changes to the installation;
• updated installation documentation;
• log books; and
• the status of the current SOP list.
181
ANNEX 6: HEATING, VENTILATION AND AIR-CONDITIONING

SYSTEMS FOR NON-STERILE PHARMACEUTICAL DOSAGE FORMS
1. Introduction read in conjunction with the parent guide. The

additional standards addressed by the present
Heating, ventilation and air-conditioning guidelines should therefore be considered
(HVAC) play an important role in ensuring supplementary to the general requirements
the manufacture of quality pharmaceutical set out in the parent guide.
products. A well designed HVAC system
will also provide comfortable conditions 2. Scope of document
for operators. These guidelines mainly
focus on recommendations for systems for These guidelines focus primarily on the
manufacturers of solid dosage forms. The design and good manufacturing practices
guidelines also refer to other systems or (GMP) requirements for HVAC systems for
components which are not relevant to solid facilities for the manufacture of solid dosage
dosage form manufacturing plants, but which forms. Most of the system design principles
may assist in providing a comparison between for facilities manufacturing solid dosage forms
the requirements for solid dosage- form plants also apply to other facilities such as those
and other systems. manufacturing liquids, creams and ointments.
These guidelines do not cover requirements
HVAC system design influences architectural for manufacturing sites for the production of
layouts with regard to items such as airlock sterile pharmaceutical products.
positions, doorways and lobbies. The
architectural components have an effect on These guidelines are intended as a basic
room pressure differential cascades and guide for use by GMP inspectors. They are
cross-contamination control. The prevention not intended to be prescriptive in specifying
of contamination and cross-contamination is requirements and design parameters. There
an essential design consideration of the HVAC are many parameters affecting a clean area
system. In view of these critical aspects, condition and it is, therefore, difficult to lay
the design of the HVAC system should be down the specific requirements for one
considered at the concept design stage of a particular parameter in isolation.
pharmaceutical manufacturing plant.
Many manufacturers have their own
Temperature, relative humidity and ventilation engineering design and qualification standards
should be appropriate and should not and requirements may vary from one
adversely affect the quality of pharmaceutical manufacturer to the next.
products during their manufacture and
storage, or the accurate functioning of
equipment.
This document aims to give guidance to

pharmaceutical manufacturers and inspectors
of pharmaceutical manufacturing facilities
on the design, installation, qualification and
maintenance of the HVAC systems. These
guidelines are intended to complement those
provided in Good manufacturing practices for
pharmaceutical products (1) and should be
182
Figure 1: The guidelines address the various system criteria according to the
sequence set out in this diagram
GMP, Good Manufacturing Practice

Design parameters should, therefore, be set realistically for each project, with a view to creating
a cost-effective design, yet still complying with all regulatory standard and ensuring that product
quality and safety are not compromised. The three primary aspects addressed in this manual
are the roles that the HVAC system plays in product protection, personnel protection and
environmental protection (Fig. 1).
183
3. Glossary As-built
The definitions given below apply to terms Condition where the installation is complete
used in these guidelines. They may have with all services connected and functioning
different meanings in other contexts but with no production equipment, materials or
personnel present.
Acceptance criteria
At-rest
Measurable terms under which a test result
will be considered acceptable. Condition where the installation is complete
with equipment installed and operating in a
Action limit manner agreed upon by the customer and
supplier, but with no personnel present.
The action limit is reached when the
acceptance criteria of a critical parameter Central air-conditioning unit (see air-
have been exceeded. Results outside handling unit)
these limits will require specified action and
investigation.
Change control
Air-handling unit (AHU)
A formal system by which qualified
The air-handling unit serves to condition the representatives of appropriate disciplines
air and provide the required air movement review proposed or actual changes that
within a facility. might affect a validated status. The intent is
to determine the need for action that would
Airlock ensure that the system is maintained in a
validated state.
An enclosed space with two or more doors,
which is interposed between two or more Clean area (clean room)
rooms, e.g. of differing classes of cleanliness,
for the purpose of controlling the airflow An area (or room) with defined environmental
between those rooms when they need to be control of particulate and microbial
entered. An airlock is designed for and used contamination, constructed and used in such a
by either people or goods (PAL, personnel way as to reduce the introduction, generation
airlock; MAL, material airlock). and retention of contaminants within the area.
Alert limit Commissioning
The alert limit is reached when the normal Commissioning is the documented process of
operating range of a critical parameter has verifying that the equipment and systems are
been exceeded, indicating that corrective installed according to specifications, placing
measures may need to be taken to prevent the equipment into active service and verifying
the action limit being reached. its proper action. Commissioning takes place
at the conclusion of project construction but
prior to validation.
184
Containment Direct impact system
A process or device to contain product, dust or A system that is expected to have a direct
contaminants in one zone, preventing it from impact on product quality. These systems are
escaping to another zone. designed and commissioned in line with good
engineering practice (GEP) and, in addition,
Contamination are subject to qualification practices.
The undesired introduction of impurities of Facility

a chemical or microbial nature, or of foreign
matter, into or on to a starting material or The built environment within which the clean
intermediate, during production, sampling, area installation and associated controlled
packaging or repackaging, storage or environments operate together with their
transport. supporting infrastructure.
Critical parameter or component Good engineering practice (GEP)
A processing parameter (such as temperature Established engineering methods and

or humidity) that affects the quality of a standards that are applied throughout the
product, or a component that may have a project life-cycle to deliver appropriate, cost-
direct impact on the quality of the product. effective solutions.
Cross-contamination Indirect impact system
Contamination of a starting material, This is a system that is not expected to have

intermediate product or finished product with a direct impact on product quality, but typically
another starting material or material during will support a direct impact system. These
production. systems are designed and commissioned
according to GEP only.
Design condition
Infiltration
Design condition relates to the specified range
or accuracy of a controlled variable used by Infiltration is the ingress of contaminated air
the designer as a basis for determining the from an external zone into a clean area.
performance requirements of an engineered
system. Installation qualification (IQ)
Design qualification (DQ) IQ is documented verification that the

premises, HVAC system, supporting utilities
DQ is the documented check of planning and equipment have been built and installed
documents and technical specifications for in compliance with their approved design
conformity of the design with the process, specification.
manufacturing, GMP and regulatory
requirements.
185
No-impact system its design specifications in its normal operating

range and performs as intended throughout all
This is a system that will not have any anticipated operating ranges.
impact, either directly or indirectly, on product
quality. These systems are designed and Oral solid dosage (OSD)
commissioned according to GEP only.
Usually refers to an OSD plant that
Non-critical parameter or component manufactures medicinal products such as
tablets, capsules and powders to be taken
A processing parameter or component within orally.
a system where the operation, contact, data
control, alarm or failure will have an indirect Performance qualification (PQ)
impact or no impact on the quality of the
product. PQ is the documented verification that the
process and/or the total process related to the
Normal operating range system performs as intended throughout all
anticipated operating ranges.
The range that the manufacturer selects as
the acceptable values for a parameter during Point extraction
normal operations. This range must be within
the operating range. Air extraction to remove dust with the
extraction point located as close as possible to
Operating limits the source of the dust.
The minimum and/or maximum values that will Pressure cascade

ensure that product and safety requirements
are met. A process whereby air flows from one area,
which is maintained at a higher pressure, to
Operating range another area at a lower pressure.
Operating range is the range of validated Qualification

critical parameters within which acceptable
products can be manufactured. Qualification is the planning, carrying out and
recording of tests on equipment and a system,
Operating condition which forms part of the validated process, to
demonstrate that it will perform as intended.
This condition relates to carrying out room
classification tests with the normal production
process with equipment in operation, and the
normal staff present in the room.
Operational qualification (OQ)
OQ is the documentary evidence to verify that

the equipment operates in accordance with
186
Relative humidity Validation
The ratio of the actual water vapour pressure The documented act of proving that any
of the air to the saturated water vapour procedure, process, equipment, material,
pressure of the air at the same temperature activity or system actually leads to the
expressed as a percentage. More simply put, expected results.
it is the ratio of the mass of moisture in the
air, relative to the mass at 100% moisture Validation master plan (VMP)
saturation, at a given temperature.
VMP is a high-level document which
Standard operating procedure (SOP) establishes an umbrella validation plan for
the entire project, and is used as guidance
An authorized written procedure, giving by the project team for resource and
instructions for performing operations, not technical planning (also referred to as master
necessarily specific to a given product or qualification plan).
material, but of a more general nature (e.g.
operation of equipment, maintenance and 4. Protection
cleaning, validation, cleaning of premises
and environmental control, sampling and 4.1 Product and personnel
inspection). Certain SOPs may be used to
supplement product-specific master and batch 4.1.1 Areas for the manufacture of
production documentation. pharmaceuticals, where
pharmaceutical starting materials
Turbulent flow and products, utensils and
equipment are exposed to the
Turbulent flow, or non-unidirectional airflow, environment, should be classified as
is air distribution that is introduced into the “clean areas”.
controlled space and then mixes with room air
by means of induction. 4.1.2 The achievement of a particular
clean area classification depends on
Unidirectional airflow (UDAF) a number of criteria that should
be addressed at the design and
Unidirectional airflow is a rectified airflow over qualification stages. A suitable
the entire cross-sectional area of a clean balance between the different
zone with a steady velocity and approximately criteria will be required in order to
parallel streamlines(see also turbulent flow). create an efficient clean area.
(Modern standards no longer refer to laminar
flow, but have adopted the term unidirectional 4.1.3 Some of the basic criteria to be
airflow.) considered should include:
• building finishes and structure

• air filtration
• air change rate or flushing rate
• room pressure
187
• location of air terminals and 4.1.6 Air change rates normally vary
directional airflow between 6 and 20 air changes per
• temperature hour and are normally determined
• humidity by the following considerations:
• material flow
• personnel flow • level of protection required
• equipment movement • the quality and filtration of the
• process being carried out supply air
• outside air conditions • particulates generated by the
• occupancy manufacturing process
• type of product. • particulates generated by
the operators
4.1.4 Air filtration and air change rates • configuration of the room and air
should ensure that the defined clean supply and extract locations
area classification is attained. • sufficient air to achieve containment
effect
4.1.5 The air change rates should • sufficient air to cope with the room
be determined by the manufacturer heat load
and designer, taking into account • sufficient air to maintain the required
the various critical parameters. room pressure.
Primarily the air change rate should
be set to a level that will achieve the 4.1.7 In classifying the environment, the
required clean area classification. manufacturer should state whether
this is achieved under “as-built” (Fig.
2), “at-rest” (Fig. 3) or “operational”
(Fig. 4) conditions.
Figure 2. “As-built” condition
188
Figure 3. “At-rest” condition
Figure 4. “Operational” condition
189
4.1.8 Room classification tests in the “as- 4.1.11 Materials and products should
built” condition should be carried be protected from contamination
out on the bare room, in the and cross-contamination during
absence of any equipment all stages of manufacture (see
or personnel. also section 5.5 for cross-
contamination control). Note:
4.1.9 Room classification tests in the contaminants may result from
“at-rest” condition should be carried inappropriate premises (e.g. poor
out with the equipment operating design, layout or finishing), poor
where relevant, but without any cleaning procedures, contaminants
operators. Because of the amounts brought in by personnel, and a poor
of dust usually generated in a solid HVAC system.
dosage facility most clean area
classifications are rated for the “at- 4.1.12 Airborne contaminants should be
rest” condition. controlled through effective
ventilation.
4.1.10 Room classification tests in the
“operational” condition should be 4.1.13 External contaminants should be
carried out during the normal removed by effective filtration of
production process with equipment the supply air. (See Fig. 5 for an
operating, and the normal number example of a shell-like building
of personnel present in the layout to enhance containment and
room. Generally a room that is protection from external
tested for an “operational” condition contaminants.)
should be able to be cleaned up to
the “at-rest” clean area classification
after a short clean-up time. The
clean-up time should be determined
through validation and is generally
of the order of 20 minutes.
190
Figure 5. Shell-like containment control concept
Note: The process core is regarded as the most stringently controlled clean zone which is
protected by being surrounded by clean areas of a lower classification.
191
4.1.14 Internal contaminants should 4.2 Air filtration

be controlled by dilution and
flushing of contaminants in the Note: The degree to which air is filtered
room, or by displacement airflow. plays an important role in the prevention
(See Figs 6 and 7 for examples of contamination and the control of cross-
of methods for the flushing of contamination.
airborne contaminants.)
4.2.1 The type of filters required for
4.1.15 Airborne particulates and the different applications depend on
degree of filtration should be the quality of the ambient air and
considered critical parameters with the return air (where applicable) and
reference to the level of product also on the air change rates.
protection required. Table 2 gives the recommended
filtration levels for different levels
4.1.16 The level of protection and air of protection in a pharmaceutical
cleanliness for different areas facility. Manufacturers should deter-
should be determined according to mine and prove the appropriate use
the product being manufactured, of filters.
the process being used and the
product’s susceptibility to
degradation (Table 1).
Figure 6. Turbulent dilution of dirty air
192
Figure 7. Unidirectional displacement of dirty air
Table 1. Examples of levels of protection
Level Condition Example of area

Level 1 General Area with normal housekeeping and maintenance, e.g.
warehousing, secondary packing
Level 2 Protected Area in which steps are taken to protect the exposed
pharmaceutical starting material or product from
contamination or degradation, e.g. manufacturing,
primary packing, dispensing
Level 3 Controlled Area in which specific environmental conditions

are defined, controlled and monitored to
prevent contamination or degradation of the
pharmaceutical starting material or product
193
Table 2. Levels of protection and recommended filtration
Level of Protection Example of area

Level 1 Primary filters only (e.g. EN779 G4 filters)
Level 2 and 3 Production facility operating on 100% outside air:

primary plus secondary filters (e.g. EN779 G4 plus F8
filters)
Level 2 and 3 Production facility operating on recirculated plus
ambient air, where potential for cross-contamination
exists: Primary plus secondary plus tertiary filters
(e.g. EN779 G4 plus F8 plus EN1822 H13 filters)
Note: The filter classifications referred to above relate to the EN1822 and EN779 test standards
(EN 779 relates to filter classes G1 to F9 and EN 1822 relates to filter classes H10 to U16).
4.2.2 Filter classes should always be linked to the standard test method because
referring to actual filter efficiencies can be very misleading (as different test
methods each result in a different value for the same filter) (Fig. 8).
4.2.3 In selecting filters, the manufacturer should have considered other factors,
such as particularly contaminated ambient conditions, local regulations
and specific product requirements. Good pre-filtration extends the life of the
more expensive filters downstream.
4.2.4 Materials for components of an HVAC system should be selected with care
so that they do not become the source of contamination. Any component with
the potential for liberating particulate or microbial contamination into the air
stream should be located upstream of the final filters.
4.2.5 Ventilation dampers, filters and other services should be designed and
positioned so that they are accessible from outside the manufacturing areas
(service voids or service corridors) for maintenance purposes.
194
Figure 8. Comparison of filter test standards
EN, European norm (Euronorm); EU, European Union.
This figure gives a rough comparison between the different filter standards (filter classes should
always be connected to the standard test method).
195
4.2.6 Personnel should not be a source of should where possible not be

contamination. used in clean areas where dust is
liberated. Air diffusers should be
4.2.7 Directional airflow within production of the non-induction type,
or packing areas should assist in introducing air with the least amount
preventing contamination. Airflows of induction so as to maximize the
should be planned in conjunction flushing effect. (See Figs 9–11 for
with operator locations, so as to illustrations of the three types
minimize contamination of the of diffuser.)
product by the operator and also to
protect the operator from dust 4.2.10 Whenever possible, air should be
inhalation. exhausted from a low level in rooms
to help provide a flushing effect.
4.2.8 HVAC air distribution components
should be designed, installed and 4.3 Unidirectional airflow
located to prevent contaminants
generated within the room from 4.3.1 Unidirectional airflow (UDAF) should
being spread. be used where appropriate to
provide product protection by
4.2.9 Supply air diffusers of the high supplying a clean air supply
induction type (e.g. those typically over the product, minimizing the
used for office-type air-conditioning) ingress of contaminants from
surrounding areas.
Figure 9. Induction diffuser (not recommended)
196
Figure 10. Perforated plate diffuser (recommended)
Figure 10. Perforated plate diffuser (recommended)
197
4.3.2 Where appropriate, the 4.3.5 A dispensary or weighing booth

unidirectional airflow should also should be provided with
provide protection to the operator unidirectional airflow for protection
from contamination by the product. of the product and operator.
4.3.3 Sampling of materials such 4.3.6 The source of the dust and the
as starting materials, primary position in which the operator
packaging materials and normally stands should be
products, should be carried out determined before deciding on the
in the same environmental direction of unidirectional flow.
conditions that are required for the
further processing of the product.
Example: In Fig. 12 the dust generated at
4.3.4 In a weighing booth situation, the the weighing station is immediately extracted
aim of the design using UDAF through the perforated worktop, thus
should be to provide dust protecting the operator from dust inhalation,
containment. but at the same time protecting the product
from contamination by the operator by means
of the vertical unidirectional airflow stream.
Figure 12. Operator protection at weighing station
198
4.3.7 The unidirectional flow velocity Fig. 16 shows that a solid worktop can
should be such that it does not sometimes cause deflection of the vertical
disrupt the sensitivity of balances in unidirectional airflow resulting in a flow
weighing areas. Where necessary reversal. A possible solution would be to have
the velocity may be reduced a 100 mm gap between the back of the table
to prevent inaccuracies during and the wall, with the air being extracted here.
weighing, provided that sufficient
airflow is maintained to provide 4.3.11 The manufacturer should select
containment. either vertical or horizontal
unidirectional flow (Fig. 17) and an
4.3.8 The position in which the operator appropriate airflow pattern to
stands relative to the source of dust provide the best protection for the
liberation and airflow should be particular application.
determined to ensure that the
operator is not in the path of an 4.4 Infiltration
airflow that could lead to
contamination of the product 4.4.1 Air infiltration of unfiltered air into a
(Fig. 13). pharmaceutical plant should not be
the source of contamination.
4.3.9 Once the system has been
designed and qualified with a 4.4.2 Manufacturing facilities should
specific layout for operators and be maintained at a positive pressure
processes, this should be relative to the outside, to limit the
maintained in accordance with ingress of contaminants. Where
an SOP. facilities are to be maintained at
negative pressures relative to the
4.3.10 There should be no obstructions in ambient pressure to prevent the
the path of a unidirectional flow air escape of harmful products to the
stream that may cause the operator outside (such as penicillin and
to be exposed to dust. hormones), special precautions
should be taken.
Fig. 14 illustrates the incorrect use of a
weighing scale which has a solid back. The 4.4.3 The location of the negative
back of the weighing scale should not block pressure facility should be carefully
the return air path as this causes air to rise considered with reference to the
vertically, resulting in a hazardous situation for areas surrounding it, particular
the operator. attention being given to ensuring
that the building structure is
Fig. 15 illustrates a situation where an open well sealed.
bin is placed below a vertical unidirectional
flow distributor. The downward airflow should
be prevented from entering the bin, and then
being forced to rise again, as this would carry
dust up towards the operator’s face.
199
Figure 13. Operator protection by horizontal airflow
200
Figure 14. Operator subject to powder inhalation due to obstruction
Figure 15. Operator subject to powder contamination due to airflow reversal in

bin
201
Figure 16. Operator subject to powder inhalation due to worktop obstruction
Figure 17. Diagram indicating horizontal and vertical unidirectional flow
202
4.4.4 Negative pressure zones should, 4.5.6 Highly potent products should be
as far as possible, be encapsulated manufactured under a pressure
by surrounding areas with clean cascade regime that is negative
air supplies, so that only clean air relative to atmospheric pressure.
can infiltrate into the controlled
zone. 4.5.7 The pressure cascade for each
facility should be individually
4.5 Cross-contamination assessed according to the product
handled and level of protection
4.5.1 Where different products are required.
manufactured at the same time, in
different areas or cubicles, in 4.5.8 Building structure should be
a multiproduct OSD manufacturing given special attention to
site, measures should be taken accommodate the pressure cascade
to ensure that dust cannot move design.
from one cubicle to another.
4.5.9 Airtight ceilings and walls, close
4.5.2 Correct directional air movement fitting doors and sealed light fittings
and a pressure cascade system should be in place.
can assist in preventing cross-
contamination. The pressure Displacement concept (low pressure
cascade should be such that differential, high airflow)
the direction of airflow is from the
clean corridor into the cubicles, Note: This method of containment is not
resulting in dust containment. the preferred method, as the measurement
and monitoring of airflow velocities in
4.5.3 The corridor should be maintained doorways is difficult. This concept should
at a higher pressure than the ideally be applied in production processes
cubicles, and the cubicles at a where large amounts of dust are generated.
higher pressure than atmospheric
pressure. 4.5.10 Under this concept the air should
be supplied to the corridor, flow
4.5.4 Containment can normally be through the doorway, and be
achieved by application of extracted from the back of the
the displacement concept (low cubicle. Normally the cubicle door
pressure differential, high airflow), should be closed and the air
or the pressure differential concept should enter the cubicle through
(high pressure differential, low a door grille, although the concept
airflow), or the physical barrier can be applied to an opening
concept. without a door.
4.5.5 The pressure cascade regime and 4.5.11 The velocity should be high enough
the direction of airflow should be to prevent turbulence within the
appropriate to the product and doorway resulting in dust escaping.
processing method used.
203
4.5.12 This displacement airflow should be 4.5.16 The pressure differential between
calculated as the product of the door adjacent rooms could be considered
area and the velocity, which a critical parameter, depending on
generally results in fairly large the outcome of risk analysis. The
air quantities. limits for the pressure differential
between adjacent areas should be
Pressure differential concept (high such that there is no risk of overlap,
pressure differential, low airflow) e.g. 5 Pa to 15 Pa in one room and
15 Pa to 30 Pa in an adjacent room,
Note: The pressure differential concept may resulting in no pressure cascade, if
normally be used in zones where little or no the first room is at the maximum
dust is being generated. It may be used alone tolerance and the second room is
or in combination with other containment at the minimum tolerance.
control techniques and concepts, such as a
double door airlock. 4.5.17 Low pressure differentials may be
acceptable when airlocks (pressure
4.5.13 The high pressure differential sinks or pressure bubbles) are used.
between the clean and less clean
zones should be generated by 4.5.18 The effect of room pressure
leakage through the gaps of the tolerances are illustrated in Fig. 18.
closed doors to the cubicle.
4.5.19 The pressure control and monitoring
4.5.14 The pressure differential should be devices used should be calibrated
of sufficient magnitude to ensure and qualified. Compliance with
containment and prevention of specifications should be regularly
flow reversal, but should not be so verified and the results recorded.
high as to create turbulence Pressure control devices should be
problems. linked to an alarm system set
according to the levels determined
4.5.15 In considering room pressure by a risk analysis.
differentials, transient variations,
such as machine extract systems,
should be taken into consideration.
Note: The most widely accepted pressure

differential for achieving containment between
two adjacent zones is 15 Pa, but pressure
differentials of between 5 Pa and 20 Pa may
be acceptable. Where the design pressure
differential is too low and tolerances are at
opposite extremities, a flow reversal can take
place. For example, where a control tolerance
of 3 Pa is specified, the implications of the
upper and lower tolerances on containment
should be evaluated.
204
Figure 18. Examples of pressure cascades
4.5.20 Manual control systems, where used, should be set up during commissioning and
should not change unless other system conditions change.
4.5.21 Airlocks can be important components in setting up and maintaining pressure cascade
systems.
4.5.22 Airlocks with different pressure cascade regimes include the cascade airlock, sink
airlock and bubble airlock (Figs 19–21).
• Cascade airlock: high pressure on one side of the airlock and low pressure on the other.
• Sink airlock: low pressure inside the airlock and high pressure on both outer sides.
• Bubble airlock: high pressure inside the airlock and low pressure on both outer sides.
4.5.23 Doors should open to the high pressure side, and be provided with self- closers. Door
closer springs, if used, should be designed to hold the door closed and prevent the
pressure differential from pushing the door open. Sliding doors are not recommended.
4.5.24 Central dust extraction systems should be interlocked with the appropriate air handling
systems, to ensure that they operate simultaneously.
205
Figure 19. Example of cascade airlock
Figure 20. Example of sink airlock
206
Figure 21. Example of bubble airlock
4.5.25 Room pressure imbalance between 4.5.28 Spot ventilation or capture hoods
adjacent cubicles which are linked may be used as appropriate.
by common dust extraction ducting
should be prevented. 4.6 Temperature and relative
humidity
4.5.26 Air should not flow from the room
with the higher pressure to the room 4.6.1 Temperature and relative humidity
with the lower pressure, via the dust should be controlled, monitored
extract ducting (this would normally and recorded, where relevant,
occur only if the dust extraction to ensure compliance with
system was inoperative). requirements pertinent to the
materials and products, and to
Physical barrier concept provide a comfortable environment
for the operator where necessary.
4.5.27 Where appropriate, an impervious
barrier to prevent cross- 4.6.2 Maximum and minimum room
contamination between two zones, temperatures and relative humidity
such as barrier isolators or pumped should be appropriate.
transfer of materials, should
be used. 4.6.3 Temperature conditions should be
207
adjusted to suit the needs of the means such as the injection

operators while wearing their of steam into the air stream. A
protective clothing. product-contamination assessment
should be done to determine
4.6.4 The operating band, or tolerance, whether pure or clean steam is
between the acceptable minimum required for the purposes
and maximum temperatures should of humidification.
not be made too close.
4.6.11 Where steam humidifiers are
4.6.5 Cubicles, or suites, in which used, chemicals such as corrosion
products requiring low humidity inhibitors or chelating agents, which
are processed, should have well- could have a detrimental effect on
sealed walls and ceilings and should the product, should not be added to
also be separated from adjacent the boiler system.
areas with higher humidity by
means of suitable airlocks. 4.6.12 Humidification systems should
be well drained. No condensate
4.6.6 Precautions should be taken to should accumulate in air-handling
prevent moisture migration that systems.
increases the load on the
HVAC system. 4.6.13 Other humidification appliances
such as evaporative systems,
4.6.7 Humidity control should be achieved atomizers and water mist sprays,
by removing moisture from the air, should not be used because of the
or adding moisture to the air, potential risk of microbial
as relevant. contamination.
4.6.8 Dehumidification (moisture 4.6.14 Duct material in the vicinity of the

removal) may be achieved by humidifier should not add
means of either refrigerated contaminants to air that will not be
dehumidifiers or chemical filtered downstream.
dehumidifiers.
4.6.15 Air filters should not be
4.6.9 Appropriate cooling media for installed immediately downstream
dehumidification such as low of humidifiers.
temperature chilled water/glycol
mixture or refrigerant should 4.6.16 Cold surfaces should be insulated to
be used. prevent condensation within the
clean area or on air-handling
4.6.10 Humidifiers should be avoided if components.
possible as they may become a
source of contamination (e.g. 4.6.17 When specifying relative humidity,
Microbiological growth). Where the associated temperature should
humidification is required, this also be specified.
should be achieved by appropriate
208
or a fixed extraction hood.

4.6.18 Chemical driers using silica gel or 5.3 Dust extraction ducting should be
lithium chloride are acceptable, designed with sufficient transfer
provided that they do not become velocity to ensure that dust is
sources of contamination. carried away, and does not settle in
the ducting.
5. Dust control
5.4 The required transfer velocity should
5.1 Wherever possible, the dust or be determined: it is dependent on
vapour contamination should be the density of the dust (the denser
removed at source. Point-of-use the dust, the higher the transfer
extraction, i.e. as close as possible velocity should be, e.g. 15–20 m/s).
to the point where the dust is
generated, should be employed. 5.5 Airflow direction should be carefully
chosen, to ensure that the operator
5.2 Point-of-use extraction should does not contaminate the product,
be either in the form of a fixed high and so that the operator is not put at
velocity extraction point or an risk by the product.
articulated arm with movable hood
Figure 22. Protective garments
209
5.6 Dust-related hazards to which 5.12 When working with exposed

the operators may be subjected products such as hormones or
should be assessed. An analysis highly potent products, operators
of the type of dust and toxicity should wear totally enclosed
thereof should be done and the garments, as indicated in Fig. 22.
airflow direction determined Operators should also be equipped
accordingly. with an air-breathing system that
provides a supply of filtered and
5.7 Point extraction alone is usually not conditioned air. The air supply
sufficient to capture all of the to this type of breathing apparatus
contaminants, and general should normally be through an
directional airflow should be used to air compressor. Filtration,
assist in removing dust and vapours temperature and humidity need to
from the room. be controlled to ensure operator
safety and comfort.
5.8 Typically, in a room operating with
turbulent airflow, the air should be 5.13 The rates at which fresh air is
introduced from ceiling diffusers and supplied to the facility should
extracted from the room at low level comply with national, regional
to help give a flushing effect in and/or international regulations, to
the room. provide operators with an
acceptable level of comfort and
5.9 The low-level extraction should safety and also to remove odours
assist in drawing air downwards and or fumes.
away from the operator’s face.
The extract grilles should be 5.14 The rate of fresh airflow should also
positioned strategically to draw air be determined by leakage from the
away from the operator, but at building, for pressure control
the same time to prevent the purposes.
operator from contaminating
the product. 6. Protection of the environment
5.10 When planning the system for 6.1 Dust in exhaust air
the extraction of vapours, the
density of the vapour should be 6.1.1 Exhaust air discharge points on
taken into account. If the vapour is pharmaceutical equipment and
lighter than air, the extract grilles facilities, such as from fluid bed
should be at a high level, or possibly driers and tablet-coating equipment,
at both high and low levels. and exhaust air from dust extraction
systems, carry heavy dust loads and
5.11 When dealing with particularly should be provided with adequate
harmful products, additional steps, filtration to prevent contamination of
such as handling the products the ambient air.
in glove boxes or using barrier
isolator technology, should be used.
210
6.1.2 Where the powders are not 6.1.9 Sophisticated computer-based

highly potent, final filters on a dust data monitoring systems may be
exhaust system should be fine dust installed, with which preventive
filters with a filter classification of F9 maintenance is planned by trend
according to EN779 filter standards. logging (This type of system
is commonly referred to as a
6.1.3 Where harmful substances such building management system
as penicillin, hormones, toxic (BMS), building automation system
powders and enzymes are (BAS) or system control and data
manufactured, the final filters on the acquisition (SCADA) system.)
dust exhaust system should be
HEPA filters with at least an H12 6.1.10 An automated monitoring system
classification according to EN1822 should be capable of indicating any
filter standards, as appropriate. out-of-specification condition without
delay by means of an alarm or
6.1.4 For exhaust systems where similar system.
the discharge contaminant is
considered particularly hazardous, 6.1.11 Where reverse-pulse dust
it may be necessary to install two collectors are used for removing
banks of HEPA filters in series, to dust from dust extraction systems,
provide additional protection should they should usually be equipped
the first filter fail. with cartridge filters containing a
compressed air lance, and be
6.1.5 When handling hazardous capable of continuous operation
compounds, safe-change filter without interrupting the airflow.
housings, also called “bag-in-bag-
out” filters, should be used. 6.1.12 Alternative types of dust collectors
(such as those operating with a
6.1.6 All filter banks should be provided mechanical shaker, requiring that
with pressure differential indication the fan be switched off when the
gauges to indicate the filter mechanical shaker is activated)
dust loading. should be used in such a manner
that there is no risk of cross-
6.1.7 Filter pressure gauges should be contamination. There should be no
marked with the clean filter disruption of airflow during a
resistance and the change-out production run as the loss of airflow
filter resistance. could disrupt the pressure cascade.
6.1.8 Exhaust filters should be monitored 6.1.13 Mechanical-shaker dust collectors

regularly to prevent excessive filter should not be used for applications
loading that could force dust where continuous airflow
particles through the filter media, is required.
or could cause the filters to burst,
resulting in contamination of the
ambient air.
211
6.1.14 When wet scrubbers are used, the 6.2.5 The type and quantity of the
dust-slurry should be removed by a vapours to be removed should be
suitable drainage system. known to enable the appropriate
filter media, as well as the volume of
6.1.15 The quality of the exhaust air should media required to be determined.
be determined to see whether the
filtration efficiency is adequate with 7. HVAC systems and components
all types of dust collectors and
wet scrubbers. Note: The required degree of air cleanliness
in most OSD manufacturing facilities can
6.1.16 Where necessary, additional normally be achieved without the use of
filtration may be provided high-efficiency particulate air (HEPA) filters
downstream of the dust collector. provided the air is not re-circulated. Many
open product zones of OSD form facilities
6.2 Fume removal are capable of meeting ISO 14644-1 Class 8,
“at-rest” condition, measured against particle
6.2.1 The systems for fume, dust and sizes of 0.5 cm and 5 cm, but cleanliness may
effluent control should be designed, not be classified as such by manufacturers.
installed and operated in such a
manner that they do not become
possible sources of contamination
or cross- contamination, e.g. an
exhaust-air discharge point located
close to the HVAC system fresh
air inlet.
6.2.2 Fumes should be removed by

means of wet scrubbers or dry
chemical scrubbers (deep-bed
scrubbers).
6.2.3 Wet scrubbers for fume removal

normally require the addition of
various chemicals to the water to
increase the adsorption efficiency.
6.2.4 Deep-bed scrubbers should be

designed with activated carbon
filters or granular chemical
adsorption media. The chemical
media for deep-bed scrubbers
should be specific to the effluent
being treated.
212
Figure 23. Air-handling system with chemical drying
7.1 General by means of passing hot air through

one segment of the wheel).
7.1.1 There should be no failure of a
supply air fan, return air fan, 7.1.4 The figure illustrates the chemical
exhaust air fan or dust extract drier handling part of the fresh
system fan. Failure can cause a air/ return air mixture on a by-pass
system imbalance, resulting in a flow. The location of the chemical
pressure cascade malfunction with drier should be considered in the
a resultant airflow reversal. design phase. Examples of
appropriate locations include:
7.1.2 A schematic diagram of the airflow
for a typical system serving a low • full flow of fresh/return air;
humidity suite is represented • partial handling of fresh/return air
in Fig. 23. (by-pass airflow);
• return air only;
7.1.3 Air should be dried with a chemical • fresh air only; or
drier (e.g. a rotating desiccant wheel • pre-cooled air with any of the
which is continuously regenerated above alternatives.
213
7.1.5 Possible additional components The airflow schematics of the two systems
that may be required should (Figs 24 and 25) indicate air-handling unit
be considered depending on the with return air or re-circulated air, having a
climatic conditions and locations. percentage of fresh air added. Fig. 25 is a
These may include items such as: schematic diagram of an air-handling system
serving rooms with horizontal unidirectional
• frost coils on fresh air inlets in very flow, vertical unidirectional flow and turbulent
cold climates to preheat the air; flow, for rooms A, B and C, respectively.
• snow eliminators to prevent snow
entering air inlets and blocking The airflow diagram in Fig. 24 is an example
airflow; of a typical system with a lower clean area
• dust eliminators on air inlets in arid classification.
and dusty locations;
• moisture eliminators in humid areas Note: There are two basic concepts of air
with high rainfall; and delivery to pharmaceutical production facilities:
• fresh air pre-cooling coils for very a recirculation system, and a full fresh air
hot or humid climates. system (100% outside air supply).
7.1.6 Appropriate alarm systems should 7.2 Recirculation system

be in place to alert personnel if a
critical fan fails. 7.2.1 There should be no risk of
contamination or cross-
7.1.7 Low-level return or exhaust air contamination (including by fumes
grilles are usually preferred. and volatiles) due to recirculation
However, where this is not possible, of air.
a higher air change rate may be
needed to achieve a specified clean 7.2.2 Depending on the airborne
area classification, e.g. where contaminants in the return-
ceiling return air grilles are used. air system it may be acceptable
to use re-circulated air, provided
7.1.8 There may be alternative locations that HEPA filters are installed in the
for return air. For example, referring supply air stream to remove
to Fig. 24, room D (low-level return contaminants and thus prevent
air) and room E (ceiling return air). cross-contamination. The HEPA
filters for this application should
have an EN1822 classification
of H13.
214
Figure 24. Air-handling system with high-efficiency particulate air filters in air-
handling unit
Figure 25. Horizontal unidirectional flow, vertical unidirectional flow and

turbulent flow
215
Figure 26. Full fresh-air systemit
7.2.3 HEPA filters may not be required with toxic products, where
where the air-handling system is recirculation of air with contaminants
serving a single product facility and should be avoided.
there is evidence that cross-
contamination would not 7.2.8 The required degree of filtration
be possible. of the exhaust air depends on
the exhaust air contaminants and
7.2.4 Recirculation of air from areas local environmental regulations.
where pharmaceutical dust is not
generated such as secondary 7.2.9 Energy-recovery wheels should
packing may not require HEPA normally not be used in multiproduct
filters in the system. facilities. When such wheels are
used they should not become
7.2.5 HEPA filters may be located in the a source of possible contamination
air-handling unit or placed (see Fig. 27).
terminally.
Note: Alternatives to the energy-
7.2.6 Air containing dust from highly toxic recovery wheels, such as crossover
processes should never be re- plate heat exchangers and
circulated to the HVAC system. water-coil heat exchangers, may be
used in multiproduct facilities.
7.2.7 Full fresh-air systems
Fig. 26 indicates a system operating
on 100% fresh air and would
normally be used in a facility dealing
216
Figure 27. Full fresh-air system with energy recovery
7.2.10 The potential for air leakage in the user requirement specification
between the supply air and exhaust (URS), and capacities as specified
air as it passes through the wheel by the designer or developer.
should be prevented. The relative
pressures between supply and 8.1.2 The installation records of the
exhaust air systems should be such system should provide documented
that the exhaust air system operates evidence of all measured capacities
at a lower pressure than the supply of the system.
system.
7. Commissioning, qualification and

maintenance
8.1 Commissioning
8.1.1 Commissioning should include the

setting up, balancing, adjustment
and testing of the entire HVAC
system, to ensure that it meets
all the requirements, as specified
217
Figure 28. Qualification is a part of validation
8.1.3 The data should include items 8.1.7 Commissioning should be a

such as the design and precursor to system qualification
measurement figures for airflows, and process validation.
water flows, system pressures
and electrical amperages. These 8.2 Qualification
should be contained in the operating
and maintenance manuals 8.2.1 Validation is a many-faceted and
(O & M manuals). extensive activity and is beyond
the scope of these guidelines.
8.1.4 Acceptable tolerances for all system Qualification and validation
parameters should be specified prior guidelines are included in:
to commencing the physical Expert Committee on Specifications
installation. for Pharmaceutical Preparations.
Fortieth report. Geneva, World
8.1.5 Training should be provided to Health Organization, 2005 (WHO
personnel after installation of the Technical Report Series, No. 937),
system, and should include Annex 4 (see also Fig. 28).
operation and maintenance.
Manufacturers should qualify
HVAC systems using a risk-based
8.1.6 O & M manuals, schematic approach. The basic concepts of
drawings, protocols and reports qualification of HVAC systems are
should be maintained as reference set out below.
documents for any future changes
and upgrades to the system. 8.2.2 The qualification of the HVAC
system should be described in a
validation master plan (VMP).
218
8.2.3 It should define the nature and • A room cleanliness classification is

extent of testing and the test a critical parameter and, therefore,
procedures and protocols to the room air change rates and
be followed. HEPA filters should be critical
parameters and require
8.2.4 Stages of the qualification of the qualification. Items such as the fan
HVAC system should include DQ, generating the airflow and the
IQ, OQ and PQ. primary and secondary filters are
non-critical parameters, and may
8.2.5 Critical and non-critical parameters not require operational qualification.
should be determined by means
of a risk analysis for all HVAC 8.2.8 Non-critical systems and
installation components, components should be subject
subsystems and controls. to GEP and may not necessarily
require qualification.
8.2.6 Any parameter that may affect
the quality of the pharmaceutical 8.2.9 A change control procedure should
product, or a direct impact be followed when changes are
component, should be considered a planned to the direct impact HVAC
critical parameter. system, its components and controls
that may affect critical parameters.
8.2.7 All critical parameters should be
included in the qualification process. 8.2.10 Acceptance criteria and limits
should be defined during the
Note: A realistic approach to design stage.
differentiating between critical and
non-critical parameters is required, 8.2.11 The manufacturer should define
to avoid making the validation design conditions, normal operating
process unnecessarily complex. ranges, operating ranges, and alert
and action limits.
Example:
8.2.12 Design condition and normal
• The humidity of the room where the operating ranges should be
product is exposed should be identified and set to realistically
considered a critical parameter achievable parameters.
when a humidity-sensitive product
is being manufactured. The humidity 8.2.13 All parameters should fall within
sensors and the humidity monitoring the design condition range during
system should, therefore, be system operational qualification.
qualified. The heat transfer system, Conditions may go out of the design
chemical drier or steam humidifier, condition range during normal
which is producing the humidity operating procedures but they
controlled air, is further removed should remain within the operating
from the product and may not range.
require operational qualification.
219
8.2.14 Out-of-limit results (e.g. action limit 8.2.16 A narrow range of relative humidities
deviations) should be recorded and coupled with a wide range of
form part of the batch manufacturing temperatures is unacceptable as
records. changes in temperature will
automatically give rise to variations
8.2.15 The relationships between design in the relative humidity.
conditions, operating range and
qualified acceptance criteria are
given in Fig. 29.
Figure 29. System operating ranges
8.2.17 For a pharmaceutical facility, based • room particle counts

on a risk assessment, some of the • room clean-up rates
typical HVAC system parameters • microbiological air and surface
that should be qualified may include: counts where appropriate
• operation of de-dusting
• temperature • warning/alarm systems where
• relative humidity applicable.
• supply air quantities for all diffusers
• return air or exhaust air quantities
• room air change rates
• room pressures (pressure
differentials)
• room airflow patterns
• unidirectional flow velocities
• containment system velocities
• HEPA filter penetration tests
220
Table 3. Part A: schedule of tests to demonstrate compliance (for reference

purposes only)
Schedule of tests to demonstrate continuing compliance
Test parameter Clean Max. Test procedure

room time
class interval
Particle count test All classes 6 months Dust particle counts to be
(Verification of cleanliness) carried out and printouts of
results produced.
No. of readings and positions
of tests to be in accordance
with ISO
14644-1 Annex B
Air pressure difference All classes 12 months Log of pressure differential

(To verify absence of readings to be produced
cross-contamination) or critical plants should be
logged daily, preferably
continuously. A 15 Pa
pressure differential
between different zones is
recommended.
In accordance with ISO
14644-3
Annex B5*
Airflow volume All classes 12 months Airflow readings for supply

(To verify air change air and return air grilles to be
rioates) measured and air change
rates to be calculated.
14644-3
Annex B13*
Airflow velocity All Classes 12 Months Air velocities for containment

(To verify laminar flow or systems and laminar flow
containment conditions) protection systems to be
measured.
14644-3
Annex B4*
221
8.2.18 The maximum time interval between 8.2.21 Clean-up or recovery times
tests should be defined by the normally relate to the time it takes
manufacturer. The type of facility to “clean up” the room from one
under test and the product level of condition to another, e.g.
protection should be considered. the relationship between “at- rest”
and “operational” conditions in the
Note: Table 3 gives intervals clean area may be used as the
for reference purposes only. The criteria for clean-up tests. Therefore,
actual test periods may be more the clean-up time can be expressed
frequent or less frequent, depending as the time taken to change from an
on the product and process. “operational” condition to an “at
rest” condition.
8.2.19 Periodic requalification of
parameters should be done at
regular intervals, e.g. annually.
8.2.20 Requalification should also be done

when any change, which could
affect system performance,
takes place.
222
Table 3. Part B: recommended optional strategic tests (ISO 14644)

Schedule of tests to demonstrate continuing compliance
Test parameter Clean Max. Test procedure

room time
class interval
Filter leakage tests All classes 24 months Filter penetration tests to be
(To verify filter integrity) carried out by a recognized
authority to demonstrate filter
media and filter seal integrity.
Only required on HEPA filters.

14644-3 Annex B6*
Containment leakage All classes 24 months Demonstrate that contaminant

(To verify absence of is maintained within a room by
cross-contamination) means of:
• airflow direction smoke tests
• room air pressures.
14644-3
Annex B4*
Recovery All classes 24 months Test to establish time that a

(To verify clean- up time) clean room takes to return
from a contaminated condition
to the specified clean room
condition. This should not take
more than 15 min.
14644-3 Annex B13*
Airflow visualization All Classes 24 Months Tests to demonstrate airflows:

(To verify required airflow • from clean to dirty areas
patterns) • do not cause cross-
contamination
• uniformly from laminar
flow units.
Demonstrated by actual or
video- taped smoke tests.
14644-3 Annex B7*
223
8.3 Maintenance 8.3.4 Any maintenance activity should

be assessed critically to determine
8.3.1 There should be a planned any impact on product quality
preventive maintenance program, including possible contamination.
procedures and records for the
HVAC system. Records should 8.3.5 Maintenance activities should
be kept. normally be scheduled to take place
outside production hours, and any
8.3.2 Maintenance personnel should system stoppage should be
receive appropriate training. assessed with a view to the possible
need for requalification of an area
8.3.3 HEPA filters should be changed as a result of an interruption of
either by a specialist or a trained the service.
person.
224
ANNEX 7: AUTHORIZED PERSONS
7.1 The authorized person is defined 7.4 The availability of an authorized

as a person (among key personnel person should be a prerequisite
of a manufacturing establishment) for issue of a manufacturing license
responsible for the release of (authorization). The authorized
batches of finished products person (as well as persons
for sale. responsible for production and
quality control) must be approved
The role and position of the by the NMRA. The marketing
authorized person in the company authorization holder is obliged
to inform the NMRA, or other
7.2 The authorized person as the responsible authority depending on
overall quality controller will be a national (regional) regulations,
member of a team whose function immediately if the authorized person
includes the following major areas: is replaced unexpectedly. Such
provisions will assure to a
• implementation (and, when needed, considerable degree the
establishment) of the quality system; independence of the authorized
• participation in the development of person from the management of the
the company’s quality manual; company in the fulfillment of his
• supervision of the regular internal or her duties even when under
audits or self-inspections; pressure to depart from professional
• oversight of the quality control and technical standards.
department;
• participation in external audit 7.5 More than one authorized persons
(vendor audit); may be designated A company
• participation in validation programs. may have a complex structure, or
operate at several locations, or
7.3 Although authorized persons may both, and sometimes a separate
not have line management authorized person may be
responsibility for many activities designated who is responsible for
within this function (although they the manufacture of clinical trial
should be involved in these activities materials. Consequently it
as much as possible), they must may be necessary to nominate
be aware of any changes that may several authorized persons, one
affect compliance with technical or of them having the responsibilities
regulatory requirements related to of the overall quality controller
the quality of finished products. and the others responsible for site
When any aspect of the company’s or branch operations or specific
operations is not in accordance with products. The person authorizing
GMP guidelines or relevant batch release should be
legislation in force, the authorized independent from production and
person must bring this to the quality control activities.
attention of senior management.
This duty should be reflected in the
authorized person’s job description.
225
7.6 The drug regulatory authority should all relevant requirements. Therefore
approve the authorized person on it is required that the manufacturer
the basis of his or her professional establishes and maintains a
curriculum vitae. Authorized persons comprehensive quality management
have duties not only to their system, covering all aspects
employer but also to the competent of GMP.
authorities such as the drug
regulatory authority. They should 7.9 The Authorized person must ensure
establish good working relations that there is a quality manual
with inspectors and as far as describing the quality policy and
possible provide information on objectives (commitment to quality)
request during site inspections. of the company, the organizational
structure, responsibilities and
7.7 The authorized person depends authorities, together with a
upon many working colleagues for description of or references to
the achievement of quality documented quality system
objectives, and may delegate some procedures.
duties to appropriately trained staff
while remaining the overall quality 7.10 The Authorized person must
controller. It is therefore of ensure that Research and
paramount importance that he or development activities and the
she establish and maintain a good transfer of results of the
working relationship with other developmental work to routine
persons in positions of responsibility, manufacture, including original
especially those responsible for product design, formulation,
production and quality control. processes development and
validation, should observe GMP
Implementation of the quality system principles as guidance. Batches
produced for clinical trials must
7.8 Authorized persons have a personal follow applicable GMP. It is of
and professional responsibility for vital importance that the quality of
ensuring that each batch of routine production batches
finished products has been corresponds to a specification
manufactured in accordance with derived from the composition of
the marketing authorization, GMP development batches. The quality
rules and all related legal and and safety of a pharmaceutical
administrative provisions. This product depend on the application
does not necessarily mean that of appropriate procedures, based
they must have directly supervised on GMP, leading to a product
all manufacturing and quality control within the recognized specification.
operations. They must be Standard procedures and
satisfied either directly or, more recognized specifications cannot
usually, by proper operation of be separated.
quality systems that manufacturing
and testing have complied with
226
Routine duties of an authorized person • All relevant factors have been

considered, including any not
7.11 Before approving a batch for release specifically associated with the
the authorized person doing so output batch directly under review
should always ensure that the (e.g., subdivision of output batches
following requirements have from a common input, factors
been met: associated with continuous
production runs).
• The marketing authorization and
the manufacturing authorization 7.12 In certain circumstances the
requirements for the product have authorized person may be
been met for the batch concerned. responsible for the release of
• The principles and guidelines of intermediates manufactured
GMP have been followed. on contract.
• The principal manufacturing and
testing processes have been Education and training
validated, if different.
• All the necessary checks and tests 7.13 The basic qualifications of a
have been performed and account scientific education and practical
taken of the production conditions experience for key personnel,
and manufacturing records. including authorized persons, are
• Any planned changes or deviations outlined in chapter 2 (Personnel).
in manufacturing or quality control
have been notified in accordance Professional Experience
with a well-defined reporting system
before any product is released. 7.14 Depending on the type of activity
Such changes may need notification and professional knowledge,
to and approval by the drug the required experience shall range
regulatory authority. from a minimum of 1 year up to
• Any additional sampling, inspection, 4 years.
tests and checks have been carried
out or initiated, as appropriate, to The experience expected includes
cover planned changes primarily the following points:
and deviations.
• All necessary production and quality 7.14.1 technical know-how of the
control documentation has been processes an authorized person will
completed and endorsed by be responsible for,
supervisors trained in appropriate
disciplines. 7.14.2 for manufacturing, import and
• Appropriate audits, self-inspections wholesale including market release
and spot-checks are being carried of pharmaceutical products:
out by experienced and trained staff. knowledge and experience of GMP,
• Approval has been given by the
head of the quality control
department.
227
7.14.3 for the import, wholesale, export International Standards ISO

and trade in foreign countries: 9000 - 9004 and relationships
knowledge and experience of GDP, with suppliers, principles and
problems of formulation of
7.14.4 for manufacturing, import and pharmaceutical preparations,
wholesale of blood and blood pharmaceutical microbiology, and
products including market release principles and practice of sampling
of labile blood products: knowledge and testing of starting materials,
and experience of blood collection packaging components and finished
for transfusion, haematology or dosage forms.
blood transfusion.
This experience can be acquired:

• by activities where the individual
is in charge of, or partially
responsible for, the manufacturing
of medicinal products or transplant
products (GMP), or the wholesale of
medicinal products (GDP),
• by involvement in quality assurance

work within a company that
manufactures medicinal products or
transplant products,
• or possibly by means of experience

with regulatory issues, such as the
drafting of the quality modules of
the CTDs /eCTDs within the
framework of authorization
procedures,
• by executing advisory or inspectory

activities in the respective field.
7.15 Additional requirements may

include subjects such as principles
of quality assurance and GMP,
principles of good laboratory
practice as applicable to research
and development as well as to
quality control, detailed knowledge
of the authorized/qualified person’s
duties and responsibilities, of
228
ANNEX 8: QUALITY RISK MANAGEMENT (QRM)
1. INTRODUCTION this WHO guideline has been developed as an

update of WHO advice to the pharmaceutical
1.1 Background and scope industry, taking account of this new guidance.
In most countries compliance with good In order to protect patients, in terms of

manufacturing practices (GMP) (1, 2) quality, safety and efficacy, international
(including validation), drug regulatory activities medicines regulatory authorities (MRAs) are
and inspections, together with supply chain recommending pharmaceutical manufacturers
controls throughout the product life-cycle, to adopt a risk-based approach to the life-
provide good assurance that risks are largely cycle of a pharmaceutical product. Some
controlled. However, where control is less MRAs are requiring the adoption of a risk-
effective, patients may be put at risk through based approach for certain specific areas in
the production of medicines of inadequate the life-cycle of a pharmaceutical product,
quality. The assessment of individual risks e.g. for environmental monitoring for sterile
related to specific products and starting products manufacturing.
materials and the recognition of hazards at
specific stages of production or distribution While the choice of the tools to support the
should permit regulatory authorities to QRM approach is optional and may vary, they
improve control of medicines by increasing need to be appropriate for the intended use.
the effectiveness of their activities within In return for using this approach, there
the limits of the available resources. Quality are potential opportunities for both MRAs
risk management (QRM) is a process that is and pharmaceutical manufacturers(9)as
relevant to all countries and should provide a summarized in the following sections.
rationale to understand risk and mitigate it via
appropriate and robust controls. a) Quality risk management (QRM)
principles can be applied to both
The aim of this guideline is to assist MRAs and pharmaceutical
the development and implementation of manufacturers:
effective QRM covering activities such as
research and development, sourcing of • MRAs: systematic and structured
materials, manufacturing, packaging, testing, planning of reviews and inspections
storage and distribution. In the past, hazard that are risk-based. The submission
analysis and critical control point (HACCP) review and inspection programmes
methodology, traditionally a food safety can also operate in a coordinated
management system but subsequently and synergistic manner.
applied to other industries, has been the
basis of WHO risk management guidance • Manufacturers: design,
to the pharmaceutical industry (3). Since development, manufacture
then international guidance has emerged and distribution, i.e. the life-cycle of
(2, 4-8) that is of specific relevance to the a pharmaceutical product.
pharmaceutical industry and which addresses QRM should be an integral element
the full scope of pharmaceutical industry of the pharmaceutical quality
QRM more effectively than HACCP principles, system (PQS).
including how to structure regulatory filings
using a risk-based approach. Consequently,
229
b) Science-based decision-making can • Manufacturers: evaluation of

be embedded into QRM processes: quality risk through science-based
decisions can be linked ultimately
• MRAs: decisions regarding review, to protection of the patient by
inspection or inspection frequency ensuring the quality, safety and
should consider product risk efficacy of the product. A corporate
and GMP compliance of the culture is supported to produce cost-
manufacturer. The MRA accepts effective medicines, without
residual risks through understanding compromising quality, while
the QRM decisions involved. maintaining focus on the patient as
a primary stakeholder in
• Manufacturers: quality decisions all activities.
and filing commitments can
be based on science-based process d) Restrictive and unnecessary
understanding and QRM (when practices can be avoided:
utilizing the quality by design
approach). Its effective application • MRAs: regulatory scrutiny adjusted
should offer manufacturers greater to level of risk to patients.
freedom on how to meet principles Improvement and innovation by
of GMP, and this, therefore, should manufacturers should
encourage innovation. be encouraged.
The control strategy for the process • Manufacturers: instead of having

focuses on critical quality attributes systems designed to inhibit change
and critical process parameters. and minimize business risk,
Uncertainty can be addressed changes can be managed within
explicitly. a company’s quality management
system. Innovation and the
c) Resources can be focused on risks adoption of the latest scientific
to patients: advances in manufacturing and
technology are supported.
• MRAs: QRM can be used to
determine best allocation of Unnecessary testing can be
inspection resource, both in terms of eliminated, for example, with real-
product types and for specific areas time release testing.
of focus for a given inspection.
This enables the most efficient and e) Communication and transparency
effective scrutiny of the most are facilitated:
significant health risks. Those
manufacturers with poor histories • MRAs: facilitate dialogue with
of GMP compliance can also be pharmaceutical manufacturers and
more closely and frequently clarify to the industry and the
evaluated by on-site inspection than public on how the inspection
those manufacturers with better programme may be adjusted based
records. on the risk to patients. Information-
230
sharing between MRAs will • the capability for continual

contribute to a better risk improvement should be embedded
management approach globally. in the QRM process.
• Manufacturers: matrix team This guidance describes the WHO approach

approach, stakeholders kept to QRM, using the concepts described in ICH
informed via science-based Q9 and illustrated in Figure 1 (reproduced
decisions. Culture of trust and from ICH Q9). The emphasis on each
“one-team” mindset with focus on component of the framework might differ
product and patient. from case to case but a robust process will
incorporate consideration of all the elements
QRM is the overall and continuing process of at a level of detail that is commensurate with
appropriately managing risks to product quality the specific risk.
throughout its life-cycle in order to optimize its
benefit/risk balance. It is a systematic process
for the assessment, control, communication
and review of risks to the quality of the
medicinal product. It can be applied both
proactively and retrospectively.
This guideline will align with the general

framework described within other current
international guidance on this subject.
1.2 Principles of quality

risk management
The two primary principles of QRM are:
• evaluation of the risk to quality

should be based on scientific
knowledge and ultimately linked to
the protection of the patient; and
• the level of effort, formality and
documentation of the QRM process
should be commensurate with the
level of risk.
Beside these the following principles are also

part of the QRM methodology:
• when applied, processes using

QRM methodologiesshould be
dynamic, iterative and responsive to
change; and
231
Figure 1. Overview of a typical quality risk management process
Taken from reference 6: ICH Q9: Quality Risk Management. This figure is
also available on the ICH website www.ich.org
Decision points are not shown in the diagram The approach described in this guideline
above because decisions can occur at any should be used to:
point in the process. These decisions might be
to return to the previous step and seek further • systematically analyze products
information, to adjust the risk models or even and processes to ensure the best
to terminate the risk management process scientific rationale is in place to
based upon information that supports such improve the probability of success;
a decision.
• identify important knowledge gaps
Note: “unacceptable” in the flowchart does not associated with processes that need
only refer to statutory, legislative or regulatory to be understood to properly identify
requirements, but also indicates that the risk risks;
assessment process should be revisited.
232
• provide a communication process attributes (CQAs), thereby contributing to the

that will best interface with all defining and refining of the control strategy.
relevant parties involved in the
QRM activities ; The long process of product development is
inevitably complex and requires the continual
• facilitate the transfer of process exchange of data, decisions and updates
knowledge and product both internally within companies and, where
development history to ease required with external stakeholders, such
product progression along the as MRAs. A very important aspect of product
life-cycle and to supplement already development and QRM is the maintenance
available knowledge about of an effective and secure knowledge
the product; management and documentation system.
Such a system must facilitate transparent
• enable the pharmaceutical communication and the highlighting of key
industry to adopt a risk-based issues to stakeholders and also possess a
approach to development as well-structured archive. Clearly, the ability
described in external regulatory to organize diverse data and information
guidance (4-7). The QRM outputs effectively and then retrieve it as required
will potentially serve as reference for updating and further evaluation, for the
documents to support product purposes of process validation as an example,
development and control strategy would be hugely beneficial.
discussions in regulatory filings.
Finally, it should be noted that QRM
Early in development, the purpose of the QRM activities are focused on the product/process
process is to acquire sufficient product and development and product manufacturing,
process knowledge to assess risks associated ultimately to ensure a robust, safe and
with formulation development of the finished effective FPP. The existence and effectiveness
pharmaceutical product (FPP) according to of the relevant aspects of good clinical
the quality target product profile (QTPP). practices (GCP), good laboratory practices
In recognizing risks and knowledge gaps, (GLP) and GMP should also be assessed
the QRM process plays a significant role in when performing QRM activities.
proactively enabling the prioritization and
mitigation of risks. The objective is to develop 2. QRM PROCESS
the FPP through maximizing product and
process knowledge and risk mitigation. 2.1 Initiating a QRM process
As FPP development progresses, in addition QRM activities should be performed using

to supporting that development, the purpose systematic processes designed to coordinate,
of the QRM process is to determine and facilitate and improve science-based decision-
manage risks to bioavailability, safety, efficacy making with respect to risk.
and product quality. QRM in development
should differentiate process parameters
(PPs) and quality attributes (QAs) from critical
process parameters (CPPs) and critical quality
233
Possible steps used to initiate and plan a The objectives and scope of the QRM
QRM process might include the following (Ref. activities should be clearly defined. The scope
ICH Q9): should describe the segment of the process
involved.
• define the problem and/or risk
question, including pertinent 2.3 Knowledge of the product
assumptions identifying the potential and process
for risk;
• assemble background information Any activity of QRM would need to be based
and/or data on the potential hazard, on knowledge of the product or processes
harm or human health impact concerned, according to the stage of the
relevant to the risk assessment; product life-cycle.
• identify a leader and necessary
resources; and Where necessary, a flow diagram may be
• specify a timeline, deliverables and helpful, covering all operations and controls
appropriate level of decision-making in the process under evaluation. When
for the risk management process. applying QRM to a given operation, the steps
preceding and following that operation should
2.2 Personnel involved in QRM also be considered. A block-type diagram may
be sufficiently descriptive. Amendments to the
The implementing party, i.e. pharmaceutical flow diagram may be made where appropriate,
manufacturer or regulatory authority, should and should be documented.
assure that personnel with appropriate
product-specific knowledge and expertise 2.4 Risk assessment
are available to ensure effective planning
and completion of QRM activities. This may When risk assessment is conducted safety
be best accomplished by assembling a and efficacy need to be considered in addition
multidisciplinary team according to guidance to the quality concerns.
in section 3.2.
During the assessment all the risks that may
The personnel should be able to: be reasonably expected to occur in the activity
under evaluation should be listed. This is
(a) conduct a risk analysis; usually applied during its initiation when there
(b) identify and analyse potential risks; is a change or a concern and may also be
(c) identify, evaluate risks and applied to existing processes. An analysis
determine which ones should should be conducted to identify which risks
be controlled and which ones can are of such a nature that their elimination or
be accepted; reduction to acceptable levels is essential.
(d) recommend and implement
adequate risk control measures; A thorough risk analysis is required to
(e) devise procedures for risk review, ensure an effective risk control. It should
monitoring and verification. review the materials, activities, equipment,
storage, distribution and intended use of the
product. Typically a list of the potential risks
(biological, chemical and physical) which
234
may be introduced, increased or controlled • microbial limits, where applicable;

in each step should be drawn up. In the risk • premises;
analysis the following basic questions should • equipment;
be addressed: • packaging;
• sanitation and hygiene;
• What is the nature of possible risks? • personnel - human error;
• What is the probability of their • utilities;
occurrence and how easy is it to • supply chain.
detect them?
• What are the consequences The output of a risk assessment is either
(the severity)? a quantitative estimate of risk (numeric
probability) or a qualitative description of a
It should then be decided which potential risks range of risk (e.g. high/medium/low) and may
should be addressed by the QRM activities be related to a risk matrix (see section 5). The
and what control measures, if any, should be scoring system and trigger points for mitigating
implemented for each risk. If a risk has been action are subjective so the rationale for score
identified at a step where control is necessary categorization should be defined in as much
for safety, and no control measure exists detail as possible. If supported by factual
at that step or at any other, the product or evidence it should be more obvious what
process should be modified at that step, or mitigating action is required - the mitigating
at an earlier or later stage, to include such action is as important as the score assigned.
a control measure. More than one control Professional judgment should be used in
measure may be required to control a specific interpretation of factual evidence but must be
risk and more than one risk may be controlled subject to justification.
by a specified control measure.
Records of risk assessments should be
Options for risk assessment methodologies maintained according to the document
are described in section 5. management system (see also 2.8).
Risk assessment can be facilitated by the use The expectation of QRM is to assess risks to
of a decision-tree, which facilitates a logical the product quality and to the patient and then
approach. The way that a decision-tree is manage these risks to an acceptable level. It
used will depend on the operation concerned, is appropriate for companies to assess their
e.g. production, packing, reprocessing, control systems to implement the optimum
storage or distribution. The best use of QRM controls to ensure product quality and patient
tools is discussed further in section 5 of this safety. Risk assessment and mitigation in
guidance. order to achieve cost savings but which
could be to the detriment of the patient is an
Normally, potential risks in relation to the unacceptable practice (10).
following should be considered:
2.5 Risk control
• materials and ingredients;
• physical characteristics and Risk control is a decision-making activity
composition of the product; designed to reduce and/or accept risks. It
• processing procedures; usually occurs after risk assessment, and at a
235
fundamental level its purpose is to reduce the occurs, who is responsible for implementing
risk to an acceptable level. the corrective actions, and that a record will be
kept and maintained of the actions taken.
During risk control activities the following key
questions should be asked: 2.6 Risk review
• What can be done to reduce or Appropriate systems should be in place to

eliminate risks? ensure that the output of the QRM process
• What is the appropriate balance is periodically monitored and reviewed, as
among benefits, risks and appropriate, to assess new information that
resources? may impact on the original QRM decision.
• Are new risks introduced as a result Examples of such changes include changes
of the identified risks being to control systems, changes to equipment and
controlled? processes, changes in suppliers or contractors
and organizational restructuring.
Risk control activities usually involve
identifying controls and measures which may Monitoring is the scheduled measurement or
reduce or control the risk associated with a observation of a specific risk control measure
failure mode or negative event. Risk control relative to its acceptance limits. Monitoring
activities can serve to determine critical should be recorded.
process parameters for certain controls,
how they will be monitored, and the level of All records and documents associated with
qualification and validation which may be risk review should be signed and dated by the
required, if any, for such controls. person(s) carrying out the review and by a
responsible official(s) of the quality unit of the
If risk assessments are conducted and company.
risk controls are employed they should be
documented, subject to change control. If 2.7 Verification of QRM process and
conducted for an ongoing activity it should be methodologies
subject to periodic review and the frequency of
review should be appropriate for the nature of The established QRM process and
the activity. methodologiesneed to be verified. Verification
and auditing methods, procedures and tests,
Specific corrective actions should be including random sampling and analysis,
developed to prevent recurrence of instances can be used to determine whether the QRM
where there have been deviations from is working appropriately. The frequency of
established risk control measures, especially verification should be sufficient to confirm the
for high risks. These actions should ensure proper functioning of the QRM process.
that the risk is brought under control as soon
as possible in compliance with the established Verification activities include:
deviation handling procedures.
(a) review of the QRM process and
Specific corrective actions should be its records;
developed in advance for each identified risk (b) review of deviations and product
including what is to be done when a deviation dispositions;
236
(c) confirmation that identified risks is Individuals doing verification should have
kept under control. appropriate technical expertise to perform this
function.
Initial verification of the planned QRM
activities is necessary to determine whether it 2.8 Risk communication and
is scientifically and technically sound, that all documentation
risks have been identified and that, if the QRM
activities are properly completed, these risks Communication of the QRM process should
will be effectively controlled. include key stakeholders. By ensuring that key
stakeholders are engaged in both the data
Information reviewed to verify the QRM collection process for the risk assessment
process should include: and the decision-making for risk control,
this will ensure commitment and support for
(a) expert advice and scientific studies; the QRM. The output of the QRM process
(b) in-plant observations, and associated risk analysis justifying
measurements and evaluations. the approach should be documented and
endorsed by the organization’s quality unit and
Subsequent verifications should be performed management. Additionally, this information
and documented by a QRM team or an should be communicated to stakeholders for
independent expert, as needed. For example, their information and to ensure their support.
verifications may be conducted when there is
an unexplained system failure, a significant There should be a report for every risk
change in product, process or packaging assessment, but the level of effort, formality
occurs or new risks are recognized. Where and documentation will commensurate with
possible verification should include actions the level of risk (2).
to confirm the efficacy of all elements of the
QRM activities. Regarding conclusions to a risk assessment
the mitigation controls should minimize
In addition, a comprehensive review of the the likelihood of risk to patient safety to
QRM process and specific instances of an acceptable level of assurance, on the
QRM application by an independent third understanding that no risk whatsoever is
party may be useful. This would include a unlikely in reality. The degree of risk tolerated
technical evaluation of the risk analysis and very much depends on the circumstances,
each element of the QRM process and its the proximity to the patient and other controls
application as well as an on-site review of that might follow the process being assessed
all flow diagrams and appropriate records before the product reaches the patient (2).
of the operation of the QRM activity. Such a
comprehensive verification is independent of It is expected that risk mitigation plans are
other verification procedures and should be identified and implemented where any risk to
performed in order to ensure that the QRM patient safety is posed. Companies should
process is resulting in the control of the risks. take the holistic view and be mindful that
If the results of the comprehensive verification critical issues often arise where multiple
identify deficiencies the QRM process should failures in systems occur together so
be modified as necessary. mitigation plans should be sufficiently robust
to cover this scenario. Inspectors will assess
237
if risk assessments underrate the likelihood of and responsible authorities is of vital

occurrence and consequences of overrating importance. Opportunities should be
detection such that the patient risk is provided for the joint training of industrial
underestimated. The factual evidence behind staff and MRAs to encourage and maintain a
statements should be robust to challenge by continuous dialogue and create a climate of
inspectors. understanding in the practical application of
QRM.
All risk assessments performed by an
organization should be documented for The success of QRM depends on educating
the purposes of inspection. This should list and training of management and employees
and track all key risks as perceived by the in the importance of QRM in producing and
organization and summarize how these have supplying safe pharmaceuticals.
been mitigated. There should be a clear
reference to risk assessments and a list 3.2 Responsibilities
of risk assessments conducted should be
maintained. A management process should Successful application of QRM is dependent
be in place to review QRM – this may be on a clear understanding of responsibilities
incorporated into the quality management for all staff involved in the QRM activities.
review process. It is recommended that a cross-functional
matrix of assigned responsibilities and
3. QRM APPLICATION FOR accountabilities is drawn up and shared with
all relevant personnel. For example, one
PHARMACEUTICALS may consider the use of techniques such as
RACI (responsibility/accountability/consulted/
3.1 Training and education
informed) grids to illustrate a more complete
picture of the communication pathways.
Training of relevant personnel in industry,
MRAs and universities in QRM principles
The pharmaceutical manufacturer should
and applications is essential for its effective
assure that appropriate knowledge and
implementation. Industry employees should
expertise are available for the effective
understand what QRM is, possess the
planning and completion of QRM activities.
skills necessary to apply it properly, and be
QRM activities are usually, but not always,
appropriately resourced to enable the effective
undertaken by a matrix of interdisciplinary
practice of the QRM principles.
teams. When teams are formed they should
include experts from the appropriate areas
In developing the training programme to
(e.g. quality unit, product development,
support QRM activities, working instructions
engineering, regulatory affairs, production
and procedures should be drawn up which
operations, statistics, clinical and others, such
clarify the strategy and define the tasks of all
as sales, marketing or legal, as applicable), in
involved in these activities. Specific training
addition to individuals who are knowledgeable
should be provided as required to enhance
about the QRM process.
awareness. Staff which has responsibility for
managing and reviewing risks should receive
In this respect it is acceptable for external
formal training in the relevant procedures.
consultants to participate in the QRM matrix
Cooperation between producers, traders
team where they can provide specific
238
expertise or knowledge. Their role should be complete. For this stage of a project there may
justifiable and clearly defined and resultant be significant gaps in knowledge. Therefore,
accountability must be understood. A technical it will be important to apply risk tools that are
agreement or other equivalent document with appropriate for such a situation.
the consultant may be appropriate where a
GMP responsibility is assumed. These might include:
Similarly, contract staff may become involved • cause and effect diagrams (also
to lead or participate in risk assessments, known as Ishikawa or Fishbone
e.g. a contract authorized person. The diagrams);
extent of involvement and responsibility/ • flowcharts (e.g. input-process-output
accountability must be documented in a (IPO));
technical agreement or other equivalent • decision-trees;
document between the individual and the • fault-tree analysis; and
pharmaceutical company. Regarding the • relationship matrices.
authorized person it is important that a
company’s internal procedures are clear on As the product progresses to later stage
where the responsibility lies for final approval development, a more detailed analysis of
of risk acceptance documents. the risks associated with both the API and
FPP becomes a requirement. Risks would
Effective matrix team leadership is required cover concerns associated with stability,
to take responsibility for coordinating QRM bioavailability and patient safety including
across various functions and departments of any challenges to these resulting from
their organization and ensuring that the QRM the manufacturing process (including, for
activities are adequately defined, planned, example, API form conversion under certain
resourced, deployed and reviewed. The conditions of processing).
leader and team will need to identify critical
resources to progress the QRM activities, As product knowledge advances more
and also specify a timeline, deliverables and detailed QRM exercises can be considered,
appropriate levels of decision-making for the concentrating on areas considered to be
QRM process. higher priority risk. As the product’s critical
quality attributes (CQAs) become defined,
3.3 QRM application during product the potential risks arising from each input
development material (API, excipients, any device or pack
components) and each secondary product unit
The application of QRM procedures evolves operation can be investigated.
through the various stages in development of
a product. Eventually, for the developed FPP the
increasingly comprehensive risk assessment
It is important, where possible, to identify risks will support a thorough understanding of the
in the early phases of product development product and will enable all key variables to be
that could challenge the achievement of the identified, understood and controlled.
QTPP. The first QRM exercise should be
performed once the QTPP is defined and
preformulation work on the drug candidate is
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3.4 QRM application during that needs to be made depends on the depth
validation and qualification of knowledge about the process.
In keeping with the principles of QRM, For very low-volume products, e.g. orphan
this guideline recommends that process drugs, this may preclude the need to
validation embraces the product life cycle manufacture multiple batches. It would
concept already mentioned. Accordingly, be beneficial for decisions of this nature
process validation activities should involve the regarding conformance batches to have an
generation and evaluation of data throughout effective company/MRA dialogue to agree
the development process into full-scale on requirements for a regulatory submission.
production that will provide a science-based Until new approaches to demonstrate
assurance of consistent delivery of quality validation mature and become widely used,
product in the production operation the traditional three-batch approach to validate
(10, 11, 12). a process is still acceptable. When applicable
the principles of QRM should also be applied
An important emphasis is that the building for qualification activities.
of scientific assurance begins early in
development. It is obtained through rational Qualification includes four stages (design
design of experiments and robust evaluation qualification (DQ), installation qualification
of data during product/process development (IQ), operational qualification (OQ) and
through to the commercial production phase performance qualification (PQ)) but most
at which time the API and drug product frequently, only IQ, OQ and PQ are performed
CQAs are well understood and controlled. by manufacturers. QRM principles can be
In this scenario, validation or (perhaps used to narrow the scope of IQ, OQ and
more appropriately termed) conformance PQ to cover only the essential elements
batches just serve to reinforce the science- or that can affect product quality. It can also
risk-based decisions that have been made be used to determine the optimal schedule
as product development has advanced for maintenance, monitoring, calibration and
and should demonstrate good control of requalification.
all identified critical sources of variability.
Any unplanned variations within a batch Most importantly, by the time that a
or between batches should be evaluated product is ready for commercialization, the
accordingly, employing suitable statistical manufacturing company will be expected
tools, e.g. trend analysis, to check on process to have derived sufficient knowledge of the
control. commercial production process to support that
commercialization to the optimized benefit of
A potential advantage of this approach is and minimized risk to the patient.
that there can be flexibility in the number of
validation or conformance batches required 3.5 QRM application during
for regulatory scrutiny prior to approval. The commercial manufacturing
traditional number of batches required for
validation has been three but, with QRM QRM principles applied as a process supports
embedded in a product’s development science-based and practical decisions when
process, the number of conformance batches integrated into commercial manufacturing.
In general implementing QRM should not
240
obviate a manufacturer’s obligation to comply Risk review may also include evaluation of,
with regulatory expectations (e.g. regulatory e.g:
requirements, regulatory filings, inspection
commitments, etc.). All QRM activities should • effectiveness of risk control activities
be structured in a way that allows escalation and actions;
of risks to the appropriate management level • changes in observed risk levels or
within the organization. existing controls.
Special focus can be on the risk assessment In principal there are two focuses when
and risk control of, e.g: implementing QRM in commercial
manufacturing: a system focus and a
• product quality risks; product focus.
• adverse impact to patient health
based on product quality defects; 3.5.1 QRM integration with key quality
• product supply interruption to system elements
patients;
• GMP and regulatory compliance Effective QRM can facilitate the “What to
risks; do?” and, therefore, support better and more
• multisite risks; informed decisions. QRM should be integrated
• multiproduct risks; into existing quality system elements and
• new facility and changes to existing related business processes and documented
facility, e.g. start-ups, new appropriately.
commercial manufacturing
processes, technology transfers and Situations in which the use of the QRM
product discontinuation. process might provide information are
beneficial in a variety of operations, e.g:
After completion of the risk assessment and
risk control activities the outcomes must be • integrated quality
summarized and communicated. The results management:documentation;
may be documented in a new or existing training and education; quality
report or they may be included as part of defects; auditing/inspection; change
another document approved by appropriate management/change control
decision-makers (e.g. site or functional (includes equipment, facilities,
management, system owner, quality unit, utilities, control and IT systems);
etc.). A risk review is important if new risks or continual improvement/corrective
changes to existing risk levels are identified and preventive actions (CAPA);
through planned or unplanned events such
as routine operation, changes, complaints, • facilities, equipment and utilities:
product returns, discrepancies/deviations, e.g. design; qualification;
data monitoring, trends, inspections/audits, maintenance and decommissioning
changes in regulatory environment, etc. of facility/equipment; hygiene
aspects; cleaning of equipment and
environmental control; calibration/
preventive maintenance; computer
241
systems and computer-controlled • packaging and labelling: e.g. design

equipment; of packages; selection of container-
closure system; label controls;
• supplier, materials and contract • storage, transport and
service management:e.g. distribution:e.g. cold chain.
assessment and evaluation of
suppliers and contract 4. QRM CONSIDERATIONS
manufacturers; starting material;
use of materials; storage; logistics
FOR MEDICINES
and distribution conditions; REGULATORY
AUTHORITIES(2, 9)
• technology transfer: e.g. from
development to manufacturing; 4.1 Introduction
during commercial manufacturing
between sites; from commercial A key principle of this guideline is that all
manufacturing to product MRAs, developing country manufacturing sites
discontinuation. and API manufacturers should demonstrate,
wherever appropriate, application of
3.5.2 QRM application in product QRM throughout the product life-cycle for
manufacturing operations development and manufacturing facilities.
Inspectors will review this QRM system as part
Effective QRM can facilitate the “How to do?” of the quality systems section of the inspection
and, therefore, ensure products will meet (along with complaints, recalls, deviations,
acceptable standards for safety, quality, and product quality reviews, etc.).
compliance.
Equally, it is recommended that QRM be
QRM methodology can support, beside others, applied by the MRAs themselves (reviewers
the following events to assess and control and inspectorates) as there are clear benefits
quality risks, e.g: of a QRM-based review and inspection plan.
For example, inspectors can allocate time and
• production: e.g. manufacturing resource commensurate with their perceived
process risks; validation; in-process significance of risk in any given situation
sampling and testing controls; and can be pragmatic regarding the level of
production planning; deviation scrutiny and degree of formality required.
and investigation management;
change management; 4.2 QRM application to inspection
strategy
• laboratory control and stability
studies: e.g. out-of-specification 4.2.1 Risk management in inspections
results; retest period/expiration date;
method transfers; The inspection section or unit of a medicines
regulatory authority should operate within a
written, implemented quality management
system (13). Standard operating procedures
(SOPs) should be followed for activities
242
including (but not limited to) inspection Various factors should be considered in
planning, review of corrective and preventive the risk assessment exercise, and may
actions after inspections and complaint be different for the different types of GXP
handling and investigation. Where appropriate, inspections.
the procedures and activities during inspection
should be in line with the principles of QRM. Risk factors to be considered depend on the
type of inspection, and may include:
The unit should have a risk management
plan (RMP) that describes the philosophy, (a) outcome of inspection by another
approach, procedures and implementation of regulatory authority;
risk management. The risk management plan (b) outcome of the previous inspection;
should be reviewed and updated on a rolling (c) complexity of the site (e.g. buildings,
basis, or at least annually and should cover utilities);
all types of inspections (including GMP, GCP, (d) complexity of the product(e.g.
GLP) and other activities. sterile, non-sterile);
(e) type of product (e.g. biological,
Appropriate risk assessment tools should be low dose);
used in the process, and the risk assessment (f) complaints and recalls;
for a site to be inspected should be (g) significance of changes (e.g.
documented in a risk assessment worksheet. equipment, key personnel);
Records should be maintained. (h) results of product testing;
(i) risk to the patient;
A metric system should be used for risk (j) complex route of synthesis (API);
ratings, e.g. on a scale from 1 to 3. (k) polymorphism (API);
(l) biopharmaceutical classification of
4.2.2 Inspection planning and conduct the product;
The frequency and scope of inspections The number of inspectors and number of days
should be determined based on risk required for the inspection, as well as the
assessment that covers product risk and scope of the inspection, should be determined
patient risk. based on the risk rating of the site inspection.
Risk rating should normally be done only for Inspection reports should contain findings and
sites that had been previously inspected. observations. Departures from GXP should be
The risk assessment worksheet should be classified where appropriate, as “critical, major
completed after every inspection. Inspection or minor”.
of a site that had not been inspected
previously may be waived only in cases The unit should have an SOP that describes
where a recognition procedure exists between the classification process. Classification
regulatory inspection units, and where should be based on risk assessment. The
in addition appropriate evidence of GXP level of risk assigned should be in relation to
compliance is available that indicates that the nature of the observation as well as the
there is no or acceptable low risk to products number of occurrences.
and patients.
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4.2.3 Corrective action and preventive The company’s QRM procedure should
action review, and scheduling of be appropriately detailed and should be
routine inspections integrated into the company’s quality
management system.
Corrective actions and preventive actions
(CAPA) should be requested from a site, It should cover at least the following areas:
following an inspection. The CAPAs should
address the observations included in an (a) general approach to both planned
inspection report. and unplanned risk assessment –
and include scope, responsibilities,
Based on the inspection outcome and the controls, approvals, management
acceptability of the CAPA, the risk rating of the systems, applicability and
site should be reviewed and recorded. exclusions;
(b) personnel with appropriate
Inspection frequency should be defined based qualifications, experience and
on the risk rating. For example, a frequency training. Their responsibilities with
can be defined as every 6, 12, 18 or 24 regard to QRM should be clearly
months. (The maximum time interval should defined;
be no more than every 36 months.) (c) senior management should
be involved in the identification and
4.2.4 Complaint handling and implementation of QRM principles
investigation within the company;
(d) the risk management procedure(s)
Handling and investigation of quality for each area of application should
complaints should be done in accordance with be clearly defined;
a written SOP. (e) quality assurance principles should
be applied to QRM-related
The scope and depth of the investigation documentation, e.g. review,
(including whether a desk review or on-site approval, implementation and
inspection will be done) should be based on archiving.
risk assessment.
QRM policies and procedures should be clear
4.3 Inspection of QRM at a and the workflow should be systematic and
manufacturing site conducted in a logical order.
The procedure for risk management should be
Note. During inspections, inspectors implemented. Manufacturers should identify
should assess whether a manufacturer has significant risks and consider all the relevant
appropriate skills, scientific knowledge as well data from reliable sources.
as product and process knowledge for the
QRM procedure being inspected. This is also Personnel should be trained and assessed in
relevant where a company has made use of the principles of QRM.
contracted parties.
Where appropriate, a team of members of
personnel should participate in the QRM
processes.
244
The level of effort and resources used in risk the prioritization of dossiers, the screening
assessment should be appropriate to the process, identification of the specific risk
importance of the identified problem. Critical factors inherent for a given dossier or dosage
issues should be addressed with appropriate form, and allocation of resources to the
urgency and formality. various sections of a dossier for a given
product. In addition, product-related risk
There should be a logical selection of tools factors must be managed throughout the
for risk assessment. Risk acceptance criteria lifecycle of the product, for example through
should be appropriate. Risk assessments effective communication between assessors
should not underrate the severity, nor and inspectors, and by establishing systems
overrate detection of occurrences resulting in for dealing with the products after approval.
underestimating patient risk.
The prioritization of dossiers should consider
The risk acceptance criteria should be the therapeutic needs of the regional
appropriate for the specific situation in population (disease occurrence, the need for
question. paediatric formulations, combination products,
etc.) and the availability of medicines on
Risk controls should be effective. The the market. Prioritization should be a
company should have a review programme to dynamic process in order to accommodate
measure the efficiency of the measures taken. emerging issues such as pandemics. Other
considerations related to prioritization based
Risk-based decision(s) should be science- on medical need may include fixed-dose
based and concordant with the predefined combinations versus single-ingredient or
acceptance criteria. co-packaged products, extended release
products versus twice or thrice daily dosing
All documentation related to the QRM products, second-line versus first-line
activities should be completed in a reasonable products, flexible dosage forms such as
time frame and should be accessible. dispersible tablets and variable dose products
such as oral liquids.
Risk assessments performed should be
reviewed when appropriate, and additional The screening process examines the
controls implemented when required. completeness of a dossier. Screening
ensures that only those dossiers that meet
4.4 QRM applied to dossier review minimum standards for completeness are
(assessment) entered into the full assessment process.
Insufficient screening processes allow a lower
NMRA assessment processes rely on QRM standard of quality of dossiers to be accepted
principles in the management of resources for review, significantly increasing assessment
(time and assessors), as well as in the time.
management of product-related risk factors.
Efficient management of resources minimizes Identification of dossier related and product
the risk that limited resources are not used related risk factors allows for the allocation
to best effect, and ultimately ensures that of proper resources to specific dossiers.
important products are available in a timely Possible risk factors include the experience
manner. Key factors to be considered include and track record of the manufacturer, narrow
245
therapeutic range products, sterile versus Allocation of resources to various aspects/

non-sterile APIs and products, API related sections of the dossier is an important QRM
considerations such as semi-synthetic and consideration, in order to ensure that the
fermentation products, complex routes of resources used are commensurate to the
synthesis, polymorphism, isomerism and associated risk level. An understanding of
potential genotoxic impurities, and product the relative criticality of dossier sections
related considerations such as the use or aspects is necessary for efficient use of
of novel excipients, the complexity of the resources. All aspects of the dossier are
formulation, single-ingredient versus fixed- important to achieve overall quality, safety and
dose combinations, and special delivery efficacy, however some areas are inherently
systems (modified release, transdermal more critical from a risk perspective and
products, inhalation products, etc.). Once warrant more time in the assessment process.
risk factors are identified, resources should Examples include the clinical/bioavailability
be allocated to minimize risk, for example reviews, API synthesis, specifications and
assessors with expertise related to the stability studies, FPP manufacturing details,
identified product-related risk should be pharmaceutical development studies including
assigned to assess the dossier whenever biowaiver justification, process validation,
possible. specifications and stability studies. An
example for most simple solid oral products
When resources allow, organization of is that more time should be allocated to
assessors may be done according to the review of manufacturing steps prior to
specialization, assigning assessors into packaging, compared to the time allotted to
various product categories (e.g. generic review the packaging process.
products, sterile products, solid oral dosage During the assessment process there should
forms, special delivery systems, etc.). This be a standard procedure to communicate to
can facilitate the development of expertise in inspectors those identified issues which may
key areas and promote consistency of review, require consideration during inspection. After
as well as ensuring that products requiring approval of a product, QRM principles should
specialized knowledge are identified and be applied to evaluate the impact of proposed
directed to the appropriate expertise. Where variations or changes. A clear guideline that
a high level of risk is identified for a dossier, outlines possible post-approval changes and
assignment of more experienced assessors is assigns an associated risk level is an effective
required, at minimum on a consultative basis. means to achieve this.
The risk level associated with a dossier may 5. RISK MANAGEMENT

change during the course of assessment,
for example rejection of the bioequivalence
TOOLS
study will result in additional time required to
A variety of tools can be used for the purposes
conduct and assess additional studies and
of QRM, either alone or in combination. It
associated additional quality information. In
is important to note that no single tool or
such a scenario the risk relates both to the use
combination of tools is applicable to every
of additional resources and to increased risk
situation in which a QRM procedure is used.
that the overall product quality may be poor.
Examples of tools are listed in regulatory
guidance (6, 8); neither list is exhaustive.
246
The important criterion for acceptability is that One aspect worth highlighting is the
the tool or tools are used effectively to support development of a risk matrix to facilitate
the key attributes of a good risk assessment. categorization of identified risks during the risk
assessment phase. In order to prioritize a risk,
The Product Quality Research Institute (PQRI) it is essential to agree upon its significance.
Manufacturing Technology Committee (MTC) The risk associated with any situation or event
has produced a summary (10) of common RM can be represented as the impact of that event
principles and best practices, several working multiplied by the probability of its occurrence;
tools to foster consistency in the use of ICH in other words, how likely is it to happen and
Q9 (6) in day-to-day RM decision-making, how severe would it be if it did happen. Impact
and a series of examples of RM applications and probability can each be classified, e.g.
currently in use by major pharmaceutical firms. into 5 levels (1-5) or with a weighting towards
They have also produced very helpful risk tool the higher probability and impact ratings (e.g.
training modules for risk ranking and filtering, 1,3,5,7,10, etc.), so that a grid or matrix can
failure modes effects analysis (FMEA) (14, 15, be constructed.
16), hazard operability analysis (HAZOP) (17)
and HACCP (3)
Table 1. An example of a probability versus impact matrix
The shading in the table represents an example of how the risk values (sometimes called
composite risk indices or risk index values) can be assigned a high, medium or low status. The
definition for each status should be predetermined in the QRM process after consideration of the
specific consequences for the process undergoing risk assessment. These consequences can be
split according to the probability and impact scores, as exemplified in Table 2.
247
Table 2. Example of a consequences table for probability and impact
This table is just a very basic example and would need to be customized for the specific process
in question to enable better and practical definition of the consequence categories. It should be
cautioned that the value of a risk matrix does very much rely upon input information and should
only be used by staff with a good understanding of the embedded judgments and, as such, the
resolution of low/medium/high categorization.
As a summary of the common, well-recognized QRM tool options available for the purposes of
this guideline, the following table has been based on the one from the PQRI-MTC report (10).
The list is not comprehensive but it does include some of the more frequently used approaches.
248
Table 3. Examples of common risk management tools (based on 10)

Risk management Description/attributes Potential applications
tool
Basic tools
Diagram analysis • Simple techniques that are • Compilation of

• Flowcharts commonly used to gather and observations, trends
• Check sheets organize data, structure RM or other empirical
• Process mapping processes and facilitate information to support a
• Cause/effect decision-making variety of less complex
diagrams deviations, complaints,
defaults or other
circumstances
Risk ranking and • Method to compare and rank risks • Prioritize operating
filtering areas or sites for audit/
• Typically involves evaluation of assessment
multiple diverse quantitative and
qualitative factors for each risk, • Useful for situations
• and weighting factors and risk when the risks and
• score underlying
consequences are
diverse and difficult
to compare using a
single tool
Advanced tools
Fault tree analysis • Method used to identify all root causes of • Investigate product
(FTA) an assumed failure or problem complaints
• Used to evaluate system or subsystem • Evaluate deviations

failures one at a time, but can combine
multiple causes of failure by identifying
causal chains
• Relies heavily on full process

understanding to identify causal
factors
249
Hazard operability • Tool assumes that risk events are • Access manufacturing
analysis (HAZOP) caused by deviations from the processes, suppliers,
design and operating intentions facilities and equipment
• Uses a systematic technique to help • Commonly used to evaluate

identify potential deviations from process safety hazards
normal use or design intentions
Hazards analysis • Identify and implement process controls • Better for preventative
and critical control that consistently and effectively prevent applications rather than
points (HACCP) hazard conditions from occurring reactive
• Bottom-up approach that considers • Great precursor or

how to prevent hazards from occurring complement to process
and/or propagating validation
• Emphasizes strength of preventative • Assessment of the efficacy

controls rather than ability to detect of CPPs and the ability to
consistently execute them
for any process
Failure modes • Assumes comprehensive understanding • Evaluate equipment

effects of the process and that critical process and facilities; analyze a
analysis (FMEA) parameters (CPPs) have been defined manufacturing process to
prior to initiating the assessment. Tool identify high risk steps
ensures that CPPs will be met. and/or critical parameters
• Assesses potential failure modes for

processes, and the probable effect on
outcomes and/or product performance
• Once failure modes are known, risk

reduction actions can be applied to
eliminate, reduce or control potential
failures
• Highly dependent upon strong

understanding of product, process and/
or facility under evaluation
• Output is a relative “risk score” for each

failure mode
[Note from the Secretariat: the authors will be contacted regarding copyright of the above table.
250
Another general overview of and references Formal experimental design

for some of the risk tools that might be brought (source: ICH Q8)
to bear in QRM by industry and regulators is
provided in Annex 20 (Annex I) of the EU GMP A structured, organized method for
guideline (2). determining the relationship between
factors affecting a process and the output
6. GLOSSARY of that process. Also known as “design of
experiments”.
[Note from the secretariat: Glossary will be
double-checked against the most up-to- Pharmaceutical product
date definitions in the final version.]
Any preparation for human or veterinary
Control strategy (source: ICH Q8) use that is intended to modify or explore
physiological systems or pathological states
A planned set of controls, derived from current for the benefit of the recipient.
product and process understanding that
assures process performance and product Pharmaceutical product target profile
quality. The controls can include parameters (PPTP)
and attributes related to drug substance
and pharmaceutical product materials and A definition of the target properties of the FPP,
components, facility and equipment operating including dosage form and strength(s), route
conditions, in-process controls, finished of administration and relevant drug release
product specifications, and the associated and pharmacokineticrequirements
methods and frequency of monitoring and
control (ICH Q10). Planned risk assessment
Critical quality attribute (CQA) An assessment that is conducted in

(source: ICH Q8) advance of an activity, either before any
work is conducted or before further work is
A physical, chemical, biological or conducted. This enables quality to be built
microbiological property or characteristicthat into activities and risk reduced, e.g. design of
should be within an appropriate limit, range, high containment facilities for manufacture of
or distribution to ensure thedesiredproduct cytotoxic products.
quality.
Process robustness(source: ICH Q8)
Finished pharmaceutical product (FPP)
Ability of a process to tolerate variability of
The finished pharmaceutical product always materials and changes of the process and
represents a pharmaceutical product after final equipment without negative impact on quality.
release (manufacturing control release, quality
control release, packaging control release). Product quality research institute (PQRI)
A collaborative process involving the United

States Food and Drug Administration (FDA)
Center for Drug Evaluation and Research
251
(CDER), industry and academia. The mission Unplanned risk assessment

of PQRI is to conduct research to generate
specific scientific information that should be An assessment that is conducted to assess
submitted in a regulatory filing to CDER (but the impact of a situation that has already
which will be worth consideration for occurred, e.g. impact of a deviation from
all MRAs). normal ways of working.
PQRI member organizations, representing Validation

industry, academia, and government, cover
a wide array of scientific issues related The collection and evaluation of data,
to pharmaceutical products. Through its beginning at the process development
working groups and technical committees, stage and continuing through the production
PQRI tackles projects to ensure the quality, phase, which ensure that the manufacturing
safety and performance of drug products and processes-including equipment, buildings,
produces publications for the public domain personnel and materials are capable of
based upon the output of those projects. achieving the intended results on a consistent
and continuous basis. Validation is the
Qualification establishment of documented evidence that a
system does what it is supposed to do.
Action of proving and documenting that
any premises, systems and equipment are Verification
properly installed and/or work correctly and
lead to the expected results.Qualification is The application of methods, procedures,
often a part (the initial stage) of validation, but tests and other evaluations, in addition to
the individual qualification steps alone do not monitoring, to determine compliance with the
constitute process validation. quality risk management activities.

Quality critical process parameter (source:
ICH Q8)
A process parameter whose variability has

an impact on a critical quality attribute and,
therefore, should be monitored or controlled
to ensure the process produces the desired
quality.
Stakeholder
Any individual, group or organization that can

affect, be affected by, or perceive itself to be
affected by a risk. Primary stakeholders are
the patient, healthcare professional, MRAs
and the pharmaceutical industry.
252
7. REFERENCES 5. ICH Harmonised Tripartite

Guideline. ICH Q8(R2):
1. Quality assurance of Pharmaceutical Development.
pharmaceuticals. A compendium August 2008; http://www.ich.org.
of guidelines and related materials.
Vol. 2,Secondupdated edition. 6. ICH Harmonised Tripartite
Good manufacturing practices Guideline. ICH Q9: Quality Risk
and inspection. Geneva, World Management
Health Organization, 2007; Quality June 2006; http://www.ich.org.
assurance of pharmaceuticals.
A compendium of guidelines and 7. Guidance for Industry: PAT - A
related materials. World Health Framework for Innovative
Organization, 2011 (CD-ROM) Pharmaceutical Development,
(http://apps.who.int/medicinedocs/ Manufacturing and Quality
en/q/). Assurance. FDA (CDER),
September 2004; http://www.fda.
2. EudraLex - Volume 4, Good gov/Drugs/default.htm.
manufacturing practice (GMP)
Guidelines; http://ec.europa.eu/ 8. Pharmaceutical cGMPs for the
health/documents/eudralex/vol-4/ 21st Century - A Risk-Based
index_en.htm. Approach. FDA (CDER), September
2004; http://www.fda.gov/Drugs/
3. Application of hazard analysis and default.htm.
critical control point (HACCP)
methodology to pharmaceuticals. 9. MHRA Guidance:GMP-QRM -
In: Quality assurance of Frequently asked questions;
pharmaceuticals. A compendium http://www.mhra.gov.
of guidelines and related materials. uk/Howweregulate/
Vol. 2,Secondupdated edition. Medicines/Inspectionandstandards/
Good manufacturing practices GoodManufacturingPractice/FAQ/
and inspection. Geneva, World QualityRiskManagement/index.htm.
Health Organization, 2007; Quality
assurance of pharmaceuticals. 10. Quality Risk Management
A compendium of guidelines and Principles and Industry case
related materials. World Health Studies. Frank T et al (December
Organization, 2011 (CD-ROM) 2008) sponsored by the
(http://apps.who.int/medicinedocs/ Pharmaceutical Quality Research
en/q/). Institute Manufacturing Technology
Committee (PQRI-MTC).
4. FDA News – GMPs for the 21st
Century; M Anisfeld; Industrial 11. EU GMP Requirements -
Pharmacy, Dec 2004, I4, P20. Quality Systems; Boedecker B,
Germany; Presentation 20-21 Oct
2009, Ankara, Turkey Ministry
of Health.
253
12. WHO guidelines on quality system Further reading

requirements for national GMP
inspectorates: http://www.who. FDA’s New Process Validation Guidance - A
int/medicines/areas/quality_safety/ detailed analysis; European Compliance
quality_assurance/inspections/en/ Academy, Nov 2008; http://www.gmp-
index.html. compliance.org/eca_news_1402_5699,6013.
html.
13. Guidance for Industry -
Process Validation: General Validation of analytical procedures used in the
Principles and Practices; Nov examination of pharmaceutical
2008; http://www.fda.gov/downloads materials. In: WHO Expert Committee on
Drugs/GuidanceCompliance Specifications for Pharmaceutical
RegulatoryInformation/Guidances/ Preparations. Thirty-second report. Geneva,
UCM070336.pdf. World Health Organization, 1992.
14. Failure Mode and Effect Analysis. Annex 5 (WHO Technical Report Series, No.
FMEA from Theory to Execution. 823); Quality assurance of pharmaceuticals.
2ndEdition 2003. D. H. Stamatis, A compendium of guidelines and related
ISBN 0873895983. materials. Vol. 2,Secondupdated edition.
Good manufacturing practices and inspection.
15. Guidelines for Failure Modes and Geneva, World Health Organization, 2007;
Effects Analysis (FMEA) for Quality assurance of pharmaceuticals.
Medical Devices. 2003 Dyadem A compendium of guidelines and related
Press, ISBN 0849319102. materials. World Health Organization, 2011
(CD-ROM) (http://apps.who.int/medicinedocs/
16. McDermott R et al (1996) The en/q/).
Basics of FMEA. ISBN 0527763209.
17. IEC 61882 - Hazard Operability

Analysis (HAZOP).
254
ANNEX 9: ACTIVE PHARMACEUTICAL INGREDIENTS
1. INTRODUCTION 1.2 Scope
1.1 Objective This Guide applies to the manufacture of APIs

for medicinal products for both human and
This document (Guide) is intended to provide veterinary use. It applies to the manufacture
guidance regarding good manufacturing of sterile APIs only up to the point immediately
practice (GMP) for the manufacturing of active prior to the APIs being rendered sterile.
pharmaceutical ingredients (APIs) under an The sterilization and aseptic processing of
appropriate system for managing quality. It is sterile APIs are not covered, but should be
also intended to help ensure that APIs meet performed in accordance with the principles
the requirements for quality and purity that and guidelines of GMP as laid down in
they purport or are represented to possess. national legislations and interpreted in the
GMP Guide including its Annex1.
In this Guide “manufacturing” includes all
operations of receipt of materials, production, In the case of ecto-parasiticides for veterinary
packaging, repackaging, labelling, relabelling, use, other standards than this Guide, that
quality control, release, storage and ensure that the material is of appropriate
distribution of APIs and the related controls. quality, may be used.
In this Guide the term “should” indicates
recommendations that are expected to apply This Guide excludes whole blood and
unless shown to be in applicable, modified in plasmas the PIC/S GMP Guide for Blood
any relevant annexes to the GMP Guide, or Establishments lays down the detailed
replaced by an alternative demonstrated to requirements for the collection and testing
provide at least an equivalent level of quality of blood. However, it does include APIs that
assurance. are produced using blood or plasma as raw
materials. Finally, the Guide does not apply to
The GMP Guide as a whole does not cover bulk-packaged medicinal products.
safety aspects for the personnel engaged in
the manufacture, or aspects of protection of It applies to all other active starting materials
the environment. These controls are inherent subject to any derogations described in the
responsibilities of the manufacturer and are annexes to the GMP Guide, in particular
governed by national laws. Annexes 2 to 7 where supplementary
guidance for certain types of API may be
This Guide is not intended to define found. The annexes will consequently undergo
registration requirements or modify a review but in the meantime and only until
pharmacopoeial requirements and does not this review is complete, manufacturers may
affect the ability of the responsible competent choose to continue to use Part I of the basic
authority to establish specific registration requirements and the relevant annexes for
requirements regarding APIs within the context products covered by those annexes, or may
of marketing/manufacturing authorizations. already apply Part II.
All commitments in registration documents Section 19 contains guidance that only

must be met. applies to the manufacture of APIs used in
the production of investigational medicinal
products although it should be noted
255
that its application in this case, although The guidance in this document would normally
recommended, is not required in PIC/S be applied to the steps showing ray in Table 1.
countries. It does not imply that all steps shown should
be completed. The stringency of GMP in API
An“ API Starting Material” is a raw material, manufacturing should increase as the process
intermediate, or an API that is used in the proceeds from early API steps to final steps,
production of an API and that is incorporated purification, and packaging.
as a significant structural fragment into the Physical processing of APIs, such as
structure of the API. An API Starting Material granulation, coating or physical manipulation
can be an article of commerce, a material of particle size (e.g. milling, micronizing),
purchased from one or more suppliers should be conducted at least to the standards
under contract or commercial agreement, or of this Guide.
produced in-house. API Starting Materials
normally have defined chemical properties This GMP Guide does not apply to steps prior
and structure. to the introduction of the defined “API Starting
Material”.
The manufacturer should designate and
document the rationale for the point at which
production of the API begins. For synthetic
processes, this is known as the point at
which” API Starting Materials” are entered
into the process. For other processes (e.g.
fermentation, extraction, purification, etc), this
rationale should be established on a case-by-
case basis. Table1givesguidanceon the point
at which the API Starting Material is normally
introduced into the process.
From this point on, appropriate GMP as

defined in this Guide should be applied to
these intermediate and/or API manufacturing
steps. This would include the validation of
critical process steps determined to impact the
quality of the API. However, it should be noted
that the fact that a manufacturer chooses to
validate a process step does not necessarily
define that step as critical.
256
Table1: Application of this Guide to API Manufacturing
Increasing GMP requirements
257
2. QUALITY MANAGEMENT 2.16 Any deviation from established

procedures should be documented
2.1 Principles and explained. Critical deviations
should be investigated, and the
2.10 Quality should be the responsibility investigation and its conclusions
of all persons involved in should be documented.
manufacturing.
2.17 No materials should be released
2.11 Each manufacturer should establish, or used before the satisfactory
document, and implement an completion of evaluation by the
effective system for managing quality unit (s )unless there are
quality that involves the active appropriate systems in place
participation of management and to allow for such use (e.g. release
appropriate manufacturing under quarantine as described
personnel. in Section10.20 or the use of raw
materials or intermediates pending
2.12 The system for managing quality completion of evaluation).
should encompass the
organizational structure, 2.18 Procedures should exist for notifying
procedures, processes and responsible management in a timely
resources, as well as activities manner of regulatory inspections,
necessary to ensure confidence that serious GMP deficiencies, product
the API will meet its intended defects and related actions (e.g.
specifications for quality and purity. quality related complaints, recalls,
All quality related activities should regulatory actions, etc.).
be defined and documented.
2.2 Responsibilities of the Quality
2.13 There should be a quality unit(s) Unit(s)
that is independent of production
and that fulfils both quality 2.20 The quality unit(s) should be
assurance (QA) and quality control involved in all quality-related
(QC) responsibilities. This can be matters.
in the form of separate QA and
QC units or a single individual or 2.21 The quality unit(s) should review
group, depending upon the size and and approve all appropriate quality-
structure of the organization. related documents.
2.14 The persons authorized to release 2.22 The main responsibilities of the
intermediates and APIs should independent quality unit(s) should
be specified. not be delegated. These
responsibilities should be described
2.15 All quality related activities should in writing and should include but not
be recorded at the time they necessarily be limited to:
are performed.
258
1. Releasing or rejecting all APIs. 13. Making sure that materials are
Releasing or rejecting intermediates appropriately tested and the results
for use outside the control of the are reported;
manufacturing company;
14. Making sure that there is stability
2. Establishing a system to release or data to support retest or expiry
reject raw materials, intermediates, dates and storage conditions on
packaging and labelling materials; APIs and/or intermediates where
appropriate; and
3. Reviewing completed batch
production and laboratory control 15. Performing product quality reviews
records of critical process steps (as defined in Section 2.5)
before release of the API
for distribution; 2.3 Responsibility for Production
Activities
4. Making sure that critical deviations
are investigated and resolved; The responsibility for production activities
should be described in writing, and should
5. Approving all specifications and include but not necessarily be limited to:
master production Instructions;
1. Preparing, reviewing, approving and
6. Approving all procedures impacting distributing the instructions for the
the quality of Intermediates or APIs; production of intermediates or APIs
according to written procedures;
7. Making sure that internal audits
(self-inspections) are Performed; 2. Producing APIs and, when
appropriate, intermediates
8. Approving intermediate and API according to pre- approved
contract manufacturers; instructions;
9. Approving changes that potentially 3. Reviewing all production batch

impact intermediate or API Quality; records and ensuring that these are
completed and signed;
10. Reviewing and approving validation
protocols and reports; 4. making sure that all production
deviations are reported and
11. making sure that quality related evaluated and that critical deviation
complaints are investigated are investigated and the conclusions
and resolved; are recorded;
12. making sure those effective systems 5. making sure that production facilities
are used for maintaining and are clean and when appropriate
calibrating critical equipment; disinfected;
259
6. making sure that the necessary • A review of critical in-process control

calibrations are performed and and critical API test results;
records kept; • A review of all batches that failed to
meet established specification(s);
7. making sure that the premises and • A review of all critical deviations or
equipment are maintained and non-conformances and related
records kept; investigations;
• A review of any changes carried out
8. making sure that validation to the processes or analytical
protocols and reports are reviewed methods;
and approved; • A review of results of the stability
monitoring program;
9. Evaluating proposed changes in • A review of all quality-related
product, processor Equipment; and returns, complaints and recalls; and
• A review of adequacy of corrective
10. Making sure that new and, when actions.
appropriate, modified facilities and
equipment are qualified. 2.51 The results of this review should
be evaluated and an assessment
2.4 Internal Audits (Self Inspection) made of whether corrective action
or any revalidation should be
2.40 In order to verify compliance with undertaken. Reasons for such
the principles of GMP for APIs, corrective action should be
regular internal audits should be documented. Agreed corrective
performed in accordance with an actions should be completed in a
approved schedule. timely and effective manner.
2.41 Audit findings and corrective actions 3. PERSONNEL

should be documented and brought
to the attention of responsible 3.1 Personnel Qualifications
management of the firm. Agreed
corrective actions should be 3.10 There should be an adequate
completed in a timely and effective number of personnel qualified
manner. by appropriate education, training
and/or experience to perform and
2.5 Product Quality Review supervise the manufacture of
intermediates and APIs.
2.50 Regular quality reviews of APIs
should be conducted with the 3.11 The responsibilities of all
objective of verifying the personnel engaged in the
consistency of the process. Such manufacture of intermediates and
reviews should normally be APIs should be specified in writing.
conducted and documented
annually and should include at least:
260
3.12 Training should be regularly an apparent illness or open lesions

conducted by qualified individuals should be excluded from activities
and should cover, at a minimum, where the health condition could
the particular operations that the adversely affect the quality of
employee performs and GMP as it the APIs until the condition is
relates to the employee’ s functions. corrected or qualified medical
Records of training should be personnel determine that the
maintained. Training should be person’s inclusion would not
periodically assessed. jeopardize the safety or quality of
the APIs.
3.2 Personnel Hygiene
3.3 Consultants
3.20 Personnel should practice good
sanitation and health habits. 3.30 Consultants advising on the
manufacture and control of
3.21 Personnel should wear clean intermediates or APIs should have
clothing suitable for the sufficient education, training, and
manufacturing activity with which experience, or any combination
they are involved and this clothing thereof, to advise on the subject for
should be changed when which they are retained.
appropriate. Additional protective
apparel, such as head, face, hand, 3.31 Records should be maintained
and arm coverings, should be worn stating the name, address,
when necessary, to protect qualifications, and type of service
intermediates and APIs from provided by these consultants.
contamination.
4. BUILDINGS AND
3.22 Personnel should avoid direct
contact with intermediates or APIs.
FACILITIES
4.1 Design and Construction
3.23 Smoking, eating, drinking, chewing
and the storage of food should be
4.10 Buildings and facilities used in
restricted to certain designated
the manufacture of intermediates
areas separate from the
and APIs should be located,
manufacturing areas.
designed, and constructed
to facilitate cleaning, maintenance,
3.24 Personnel suffering from an
and operations as appropriate to
infectious disease or having open
the type and stage of manufacture.
lesions on the exposed surface of
Facilities should also be designed
the body should not engage in
to minimize potential contamination.
activities that could result in
Where microbiological specifications
compromising the quality of
have been established for the
APIs. Any person shown at any
intermediate or API, facilities
time (either by medical examination
should also be designed to limit
or supervisory observation) to have
261
exposure to objectionable These washing facilities should

microbiological contaminants be equipped with hot and cold water
as appropriate. as appropriate, soap or detergent,
air-driers or single service towels.
4.11 Buildings and facilities should have The washing and toilet facilities
adequate space for the orderly should be separate from, but
placement of equipment easily accessible to, manufacturing
and materials to prevent mix-ups areas. Adequate facilities for
and contamination. showering and/or changing clothes
should be provided, when
4.12 Where the equipment itself (e.g., appropriate.
closed or contained systems)
provides adequate protection of 4.16 Laboratory areas/operations should
the material, such equipment can be normally be separated from
located outdoors. production areas. Some laboratory
areas, in particular those used
4.13 The flow of materials and personnel for in-process controls, can be
through the building or facilities located in production areas,
should be designed to prevent mix- provided the operations of the
ups or contamination. production process do not
adversely affect the accuracy of the
4.14 There should be defined areas laboratory measurements, and the
or other control systems for the laboratory and its operations do not
following activities: adversely affect the production
process or intermediate or API.
• Receipt, identification, sampling,
and quarantine of incoming 4.2 Utilities
materials, pending release
or rejection; 4.20 All utilities that could impact
• Quarantine before release or on product quality (e.g. steam,
rejection of intermediates and APIs; gases, compressed air, and heating,
• Sampling of intermediates and APIs; ventilation and air conditioning)
• Holding rejected materials should be qualified and
before further disposition appropriately monitored and action
(e.g., return, reprocessing should be taken when limits are
or destruction); exceeded. Drawings for these utility
• Storage of released materials; systems should be available.
• Production operations;
• Packaging and labelling operations; 4.21 Adequate ventilation, air filtration
and and exhaust systems should be
• Laboratory operations. provided, where appropriate. These
systems should be designed and
4.15 Adequate, clean washing and toilet constructed to minimize risks of
facilities should be provided contamination and cross-
for personnel. contamination and should include
262
equipment for control of air microbiological water quality

pressure, microorganisms (if specifications are called for,
appropriate), dust, humidity, and appropriate specifications for
temperature, as appropriate to the physical/chemical attributes, total
stage of manufacture. Particular microbial counts, objectionable
attention should be given to areas organisms and/or endotoxins should
where APIs are exposed to the be established.
environment.
4.33 Where water used in the process
4.22 If air is recirculated to production is treated by the manufacturer
areas, appropriate measures should to achieve a defined quality, the
be taken to control risks of treatment process should be
contamination and cross- validated and monitored with
contamination. appropriate action limits.
4.23 Permanently installed pipe work 4.34 Where the manufacturer of anon-
should be appropriately identified. sterile API either intends or claims
This can be accomplished by that it is suitable for use in
identifying individual lines, further processing to produce a
documentation, computer control sterile drug (medicinal) product,
systems, or alternative means. water used in the final isolation
Pipe work should be located and purification steps should be
to avoid risks of contamination of monitored and controlled for total
the intermediate or API. microbial counts, objectionable
organisms, and endotoxins.
4.24 Drains should be of adequate size
and should be provided with an air 4.4 Containment
break or a suitable device to prevent
back-siphonage, when appropriate. 4.40 Dedicated production areas,
which can include facilities,
4.3 Water air handling equipment and/or
process equipment, should
4.30 Water used in the manufacture of be employed in the production of
APIs should be demonstrated to be highly sensitizing materials, such as
suitable for its intended use. penicillins or cephalosporins.
4.31 Unless otherwise justified, process 4.41 Dedicated production areas should
water should, at a minimum, also be considered when material of
Meet World Health Organization an infectious nature or high
(WHO) guidelines for drinking pharmacological activity or toxicity
(potable) water quality. is involved (e.g., certain steroids or
cytotoxic anti-cancer agents)
4.32 If drinking (potable) water is unless validated in activation and/
insufficient to assure API quality, or cleaning procedures are
and tighter chemical and/or established and maintained.
263
4.42 Appropriate measures should be 4.71 Written procedures should be

established and implemented to established as signing responsibility
prevent cross-contamination from for sanitation and describing the
personnel, materials, etc. moving cleaning schedules, methods,
from one dedicated area to another. equipment, and materials to be used
in cleaning buildings and facilities.
4.43 Any production activities (including
weighing, milling, or packaging) 4.72 When necessary, written procedures
of highly toxic non-pharmaceutical should also be established for the
materials such as herbicides and use of suitable rodenticides,
pesticides should not be conducted insecticides, fungicides, fumigating
using the buildings and/or agents, and cleaning and sanitizing
equipment being used for the agents to prevent the contamination
production of APIs. Handling of equipment, raw materials,
and storage of these highly toxic packaging/labelling materials,
non-pharmaceutical materials intermediates, and APIs.
should be separate from APIs.
5. PROCESS EQUIPMENT
4.5 Lighting
5.1 Design and Construction
4.50 Adequate lighting should be
provided in all areas to facilitate 5.10 Equipment used in the manufacture
cleaning, maintenance, and proper of intermediates and APIs should
operations. be of appropriate design and
adequate size, and suitably located
4.6 Sewage and Refuse for its intended use, cleaning,
sanitization (where appropriate),
4.60 Sewage, refuse, and other waste and maintenance.
(e.g., solids, liquids, or gaseous
by-products from manufacturing) 5.11 Equipment should be constructed
in and from building sand the so that surfaces that contact raw
immediate surrounding area should materials, intermediates, or APIs do
be disposed of in a safe, timely, and not alter the quality of the
sanitary manner. Containers and/ intermediates and APIs beyond the
or pipes for waste material should official or other established
be clearly identified. specifications.
4.7 Sanitation and Maintenance 5.12 Production equipment should only

be used with in its qualified
4.70 Buildings used in the manufacture operating range.
of intermediates and APIs should be
properly maintained and repaired 5.13 Major equipment (e.g., reactors,
and keep tin a clean condition. storage containers) and
permanently installed processing
264
lines used during the production of procedures should contain sufficient

an intermediate or API should be details to enable operators to clean
appropriately identified. each type of equipment in are
producible and effective manner.
5.14 Any substances associated with the These procedures should include:
operation of equipment, such as
lubricants, heating fluids or coolants, • Assignment of responsibility for
should not contact intermediates cleaning of equipment;
or APIs so as to alter their quality • Cleaning schedules, including,
beyond the official or other where appropriate, sanitizing
established specifications. Any schedules;
deviations from this should be • A complete description of the
evaluated to ensure that there are methods and materials, including
no detrimental effects upon the dilution of cleaning agents used to
fitness for purpose of the material. clean equipment;
Wherever possible, food grade • When appropriate, instructions for
lubricants and oils should be used. disassembling and re assembling
each article of equipment to ensure
5.15 Closed or contained equipment proper cleaning;
should be used whenever • Instructions for the removal or
appropriate. Where open equipment obliteration of previous batch
is used, or equipment is opened, identification;
appropriate precautions should be • Instructions for the protection of
taken to minimize the risk of clean equipment from contamination
contamination. prior to use;
• Inspection of equipment for
5.16 A set of current drawings should cleanliness immediately before use,
be maintained for equipment and if practical; and
critical installations (e.g., • Establishing the maximum time
instrumentation and utility systems). that may elapse between the
completion of processing and
5.2 Equipment Maintenance and equipment cleaning, when
Cleaning appropriate.
5.20 Schedules and procedures 5.22 Equipment and utensils should

(including assignment of be cleaned, stored, and, where
responsibility) should be established appropriate, sanitized or sterilized
for the preventative maintenance to prevent contamination or carry-
of equipment. over of a material that would alter
the quality of the intermediate or
5.21 Written procedures should be API beyond the official or other
established for cleaning of established specifications.
equipment and its subsequent
release for use in the manufacture 5.23 Where equipment is assigned
of intermediates and APIs. Cleaning to continuous production or
265
campaign production of successive 5.34 Instruments that do not meet

batches of the same intermediate calibration criteria should not
or API, equipment should be be used.
cleaned at appropriate
intervals to prevent build-up and 5.35 Deviations from approved standards
carry-over of contaminants (e.g. of calibration on critical instruments
degradants or objectionable levels should be investigated to determine
of micro-organisms). if these could have had an impact
on the quality of the intermediate(s)
5.24 Non-dedicated equipment should or API(s) manufactured using
be cleaned between productions this equipment since the last
of different materials to prevent successful calibration.
cross-contamination.
5.4 Computerized Systems
5.25 Acceptance criteria for residues
and the choice of cleaning 5.40 GMP related computerized systems
procedures and cleaning agents should be validated. The depth and
should be defined and justified. scope of validation depends on
the diversity, complexity and
5.26 Equipment should be identified as criticality of the computerized
to its contents and its cleanliness application.
status by appropriate means.
5.41 Appropriate installation qualification
5.3 Calibration and operational qualification should
demonstrate the suitability of
5.30 Control, weighing, measuring, computer hardware and software to
monitoring and test equipment perform assigned tasks.
that is critical for assuring the quality
of intermediates or APIs should be 5.42 Commercially available software
calibrated according to written that has been qualified does
procedures and an established not require the same level of testing.
schedule. If an existing system was not
validated at time of installation, a
5.31 Equipment calibrations should retrospective validation could be
be performed using standards conducted if appropriate
traceable to certified standards, documentation is available.
if existing.
5.43 Computerized systems should have
5.32 Records of these calibrations should sufficient controls to prevent
be maintained. unauthorized access or changes
to data. There should be controls to
5.33 The current calibration status of prevent omissions in data (e.g.
critical equipment should be known system turned off and not captured).
and verifiable. There should be a record of any
266
data change made, the previous 5.49 Data can be recorded by a second
entry, who made the change, and means in addition to the computer
when the change was made. system.
5.44 Written procedures should be 6. DOCUMENTATION AND

available for the operation and
maintenance of computerized
RECORDS
systems.
6.1 Documentation System
and Specifications
5.45 Where critical data are being
entered manually, there should be
6.10 All documents related to the
an additional check on the accuracy
manufacture of intermediates
of the entry. This can be done by a
or APIs should be prepared,
second operator or by the
reviewed, approved and distributed
system itself.
according to written procedures.
Such documents can be in paper or
5.46 Incidents related to computerized
electronic form.
systems that could affect the quality
of intermediates or APIs or there
6.11 The issuance, revision, superseding
liability of records or test results
and withdrawal of all documents
should be recorded and
should be controlled with
investigated.
maintenance of revision histories.
5.47 Changes to the computerized
6.12 A procedure should be established
system should be made according
for retaining all appropriate
to a change procedure and should
documents (e.g., development
be formally authorized, documented
history reports, scale-up reports,
and tested. Records should be
technical transfer reports, process
kept of all changes, including
validation reports, training records,
modifications and enhancements
production records, control records,
made to the hardware, software and
and distribution records). The
any other critical component of the
retention periods for these
system. These records should
documents should be specified.
demonstrate that the system is
maintained in a validated state.
6.13 All production, control,
and distribution records should
5.48 If system break downs or failures
be retained for atl east 1 year after
would result in the permanent
the expiry date of the batch. For
loss of records, aback-up system
APIs with retest dates, records
should be provided. A means of
should be retained or at least 3
ensuring data protection should be
years after the batch is completely
established for all computerized
distributed.
systems.
267
6.14 When entries are made in records, established and documented for
these should be made indelibly in in-process controls.
spaces provided for such entries,
directly after performing the 6.18 If electronic signatures are used on
activities, and should identify the documents, they should be
person making the entry. authenticated and secure.
Corrections to entries should be
dated and signed and leave the 6.2 Equipment Cleaning and
original entry still readable. Use Record
6.15 During the retention period, originals 6.20 Records of major equipment use,
or copies of records should be cleaning, sanitization and/or
readily available at the sterilization and maintenance should
establishment where the activities show the date, time(if appropriate),
described in such records occurred. product, and batch number of
Records that can be promptly each batch processed in the
retrieved from another location by equipment, and the person who
electronic or other means performed the cleaning and
are acceptable. maintenance.
6.16 Specifications, instructions, 6.21 If equipment is dedicated to

procedures, and record scan be manufacturing one intermediate or
retained either as originals or as API, then individual equipment
true copies such as photocopies, records are not necessary if
micro film, microfiche, or other batches of the intermediate or API
accurate reproductions of the follow in traceable sequence.
original records. Where reduction In cases where dedicated
techniques such as microfilming or equipment is employed, there cords
electronic records are used, suitable of cleaning, maintenance, and use
retrieval equipment and a means can be part of the batch record or
to produce a hard copy should be maintained separately.
readily available.
6.3 Records of Raw Materials,
6.17 Specifications should be established Intermediates, API Labelling and
and documented for raw materials, Packaging Materials
intermediates where necessary,
APIs, and labelling and packaging 6.30 Records should be maintained
materials. In addition, specifications including:
may be appropriate for certain other
materials, such as process aids, • The name of the manufacturer,
gaskets, or other materials used identity and quantity of each
during the production of shipment of each batch of raw
intermediates or APIs that could materials, intermediates or labelling
critically impact on quality. and packaging materials for API’s;
Acceptance criteria should be the name of the supplier; the
268
supplier’s control number(s), if • A complete list of raw materials and

known, or other identification intermediates designated by names
number; the number allocated on or codes sufficiently specific to
receipt; and the date of receipt; identify any special quality
characteristics;
• The results of any test or
examination performed and the • an accurate statement of the
conclusions derived from this; quantity or ratio of each raw material
or intermediate to be used, including
• Records tracing the use of the unit of measure. Where the
materials; quantity is not fixed, the calculation
for each batch size or rate of
• Documentation of the examination production should be included.
and review of API labelling and Variations to quantities should be
packaging materials for conformity provided they are justified;
with established specifications; and
• The production location and major
• the final decision regarding rejected production equipment to be used;
raw materials, intermediates or API
Labelling and packaging materials. • Detailed production instructions,
including the:
6.31 Master (approved) labels should be
maintained for comparison to issued - Sequences to be followed,
labels.
- ranges of process parameters to
6.4 Master Production Instructions be used,
(Master Production and Control
Records) - sampling instructions and in-process
controls with their acceptance
6.40 To ensure uniformity from batch to criteria, where appropriate,
batch, master production
instructions for each intermediate - time limits for completion of
and API should be prepared, dated, individual processing steps and/or
and signed by one person and the total process, where
independently checked, dated, and appropriate; and
signed by a person in the quality
unit(s). - expected yield ranges at appropriate
phases of processing or time;
6.41 Master production instructions
should include: • Where appropriate, special
notations and precautions to be
• The name of the intermediate or followed, or cross-references to
API being manufactured and an these; and
identifying document reference
code, if applicable;
269
• the instructions for storage of the • Dates and, when appropriate, times;
intermediate or API to assure its
suitability for use, including the • Identity of major equipment (e.g.,
labelling and packaging materials reactors, driers, mills, etc.) used;
and special storage conditions with
time limits, where appropriate. • Specific identification of each batch,
including weights, measures,
6.5 Batch Production Records (Batch and batch numbers of raw materials,
Production and Control Records) intermediates, or any reprocessed
Materials used during
6.50 Batch production records should be manufacturing;
prepared for each intermediate and
API and should include complete • Actual results recorded for critical
information relating to the process parameters;
production and control of each
batch. The batch production record • any sampling performed;
should be checked before issuance
to assure that it is the correct • Signatures of the persons
version and a legible accurate performing and directly supervising
reproduction of the appropriate or checking each critical step in
master production instruction. If the the operation;
batch production record is produced
from a separate part of the master • In-process and laboratory test
document, that document should results;
include a reference to the current
master production instruction • Actual yield at appropriate phases
being used. or times;
6.51 These records should be numbered • Description of packaging and label

with a unique batch or identification for intermediate or API;
number, dated and signed when
issued. In continuous production, • Representative label of API or
the product code together with intermediate if made commercially
the date and time can serve as available;
the unique identifier until the final
number is allocated. • any deviation noted, its evaluation,
investigation conducted (if
6.52 Documentation of completion of Appropriate) or reference to that
each significant step in the batch investigation if stored separately;
production records (batch and
production and control records)
should include: • Results of release testing.
270
6.53 Written procedures should be to show the specific material and

established and followed for batch tested;
investigating critical deviations or
the failure of a batch of intermediate • A record of all calculations
or API to meet specifications. The performed in connection with the
investigation should extend to other test, including, for example, units of
batches that may have been measure, conversion factors, and
associated with the specific failure equivalency factors;
or deviation.
• A statement of the test results
6.6 Laboratory Control Records and how they compare with
established acceptance criteria;
6.60 Laboratory control record should
include complete data derived from • The signature of the person who
all tests conducted to ensure performed each test and the date(s)
compliance with established the tests were performed; and
specifications and standards,
including examinations and assays, • The date and signature of a second
as follows: person showing that the original
records have been reviewed for
• A description of samples received accuracy, completeness, and
for testing, including the material compliance with established
name or source, batch number or standards.
other distinctive code, date sample
was taken, and, where appropriate, 6.61 Complete records should also be
the quantity and date the sample maintained for:
was received for testing;
• any modifications to an established
• A statement of or reference to each analytical method,
test method used;
• Periodic calibration of laboratory
• A statement of the weight or instruments, apparatus, gauges,
measure of sample used for each and recording devices;
test as described by the method;
data on or cross-reference to • All stability testing performed on
the preparation and testing of APIs; and
reference standards, reagents and
standard solutions, • Out-of-specification (OOS)
investigations.
• A complete record of all raw data
generated during each test, in 6.7 Batch Production Record Review
addition to graphs, charts, and
spectra from laboratory 6.70 Written procedures should be
instrumentation, properly identified established and followed for the
review and approval of batch
271
production and laboratory control 7.11 Manufacturers of intermediates and/

records, including; or APIs should have a system for
evaluating the suppliers of critical
Packaging and labelling, to materials.
determine compliance of the
intermediate or API with established 7.12 Materials should be purchased
specifications before a batch is against an agreed specification,
released or distributed. from a supplier or suppliers
approved by the quality unit(s).
6.71 Batch production and laboratory
control records of critical process 7.13 If the supplier of a critical material
steps should be reviewed and is not the manufacturer of that
approved by the quality unit(s) material, the name and address of
before an API batch is released or that manufacturer should be known
distributed. Production and by the intermediate and/or API
laboratory control records of non- manufacturer.
critical process steps can be
reviewed by qualified production 7.14 Changing the source of supply
personnel or other units following of critical raw materials should
procedures approved by the be treated according to Section13,
quality unit(s). Change Control.
6.72 All deviation, investigation, and 7.2 Receipt and Quarantine

OOS reports should be reviewed
as part of the batch record review 7.20 Upon receipt and before
before the batch is released. acceptance, each container or
grouping of containers of materials
6.73 The quality unit(s) can delegate should be examined visually for
to the production unit the correct labelling (including
responsibility and authority correlation between the name
for release of intermediates, except used by the supplier and the in-
for those shipped outside the control house name, if these are different),
of the manufacturing company. container damage, broken seals
and evidence of tampering or
7. MATERIALS contamination. Materials should be
held under quarantine until they
MANAGEMENT have been sampled, examined or
tested as appropriate, and released
7.1 General Controls
for use.
7.10 There should be written procedures
7.21 Before incoming materials are
describing the receipt, identification,
mixed with existing stocks (e.g.,
quarantine, storage, handling,
solvents or stocks in silos), they
sampling, testing, and approval or
should be identified as correct,
rejection of materials.
tested, if appropriate, and released.
272
Procedures should be available 7.31 Supplier approval should include

to prevent discharging in coming an evaluation that provides
materials wrongly into the existing adequate evidence (e.g., past
stock. quality history) that the
manufacturer can consistently
7.22 If bulk deliveries are made in non- provide material meeting
dedicated tankers, there should be specifications. Full analyses should
assurance of no cross- be conducted on at least three
contamination from the tanker. batches before reducing in-house
testing. However, as a minimum,
Means of providing this assurance a full analysis should be performed
could include one or more of the at appropriate intervals and
following: compared with the Certificates of
Analysis. Reliability of Certificates
• certificate of cleaning of Analysis should be checked at
• testing for trace impurities regular intervals.
• audit of the supplier.
7.32 Processing aids, hazardous or
7.23 Large storage containers, and their highly toxic raw materials, other
attendant manifolds, filling and special materials, or materials
discharge lines should be transferred to another unit within the
appropriately identified. company’s control do not need to
be tested if the manufacturer’s
7.24 Each container or grouping of Certificate of Analysis is obtained,
containers (batches) of materials showing that these raw materials
should be assigned and identified conform to established
with a distinctive code, batch, or specifications. Visual examination
receipt number. This number should of containers, labels, and recording
be used in recording the disposition of batch numbers should help in
of each batch. A system should be establishing the identity of these
in place to identify the status of materials. The lack of on-site testing
each batch. for these materials should be
justified and documented.
7.3 Sampling and Testing of
Incoming Production Materials 7.33 Samples should be representative
of the batch of material from
7.30 At least one test to verify the which they are taken. Sampling
identity of each batch of material methods should specify the number
should be conducted, with the of containers to be sampled,
exception of the materials described which part of the container to
below in7.32. A supplier’s Certificate sample, and the amount of material
of Analysis can be used in place to be taken from each container.
of performing other tests, provided The number of containers to sample
that the manufacturer has a system and the sample size should
in place to evaluate suppliers. be based upon a sampling plan
273
that takes into consideration the 7.44 Rejected materials should be

criticality of the material, material identified and controlled under a
variability, past quality history of the quarantine system designed
supplier, and the quantity needed to prevent their unauthorized use
for analysis. in manufacturing.
7.34 Sampling should be conducted at 7.5 Re-evaluation

defined locations and by procedures
designed to prevent contamination 7.50 Materials should be re-evaluated
of the material sampled and as appropriate to determine their
contamination of other materials. suitability for use (e.g., after
prolonged storage or exposure to
7.35 Containers from which samples heat or humidity).
are withdrawn should be opened
carefully and subsequently reclosed. 8. PRODUCTION AND
They should be marked to indicate
that a sample has been taken.
IN - PROCESS CONTROLS
8.1 Production Operations
7.4 Storage
8.10 Raw materials for intermediate
7.40 Materials should be handled and
and API manufacturing should
stored in a manner to prevent
be weighed or measured under
degradation, contamination, and
appropriate conditions that do not
cross-contamination.
affect their suitability for use.
Weighing and measuring devices
7.41 Materials stored in fiber drums,
should be of suitable accuracy for
bags, or boxes should be stored
the intended use.
off the floor and, when appropriate,
suitably spaced to permit cleaning
8.11 If a material is subdivided for later
and inspection.
use in production operations, the
container receiving the material
7.42 Materials should be stored under
should be suitable and should be
conditions and for a period that have
so identified that the following
no adverse effect on their quality,
information is available:
and should normally be controlled
so that the oldest stock is used first.
• Material name and/or item code;
• Receiving or control number;
7.43 Certain materials in suitable
• Weight or measure of material in the
containers can be stored outdoors,
new container; and
provided identifying labels remain
• Re-evaluation or retest date if
legible and containers are
appropriate.
appropriately cleaned before
opening and use.
8.12 Critical weighing, measuring, or
subdividing operations should
274
be witnessed or subjected to an (see6.41), these time limits should

equivalent control. Prior to use, be met to ensure the quality of
production personnel should verify intermediates and APIs. Deviations
that the materials are those should be documented and
specified in the batch record for the evaluated. Time limits may be in
intended intermediate or API. appropriate when processing
to a target value (e.g., pH
8.13 Other critical activities should be adjustment, hydrogenation, drying
witnessed or subjected to an to predetermined specification)
equivalent control. because completion of reactions
or processing steps are determined
8.14 Actual yields should be compared by in-process sampling and testing.
with expected yields at designated
steps in the production process. 8.21 Intermediates held for further
Expected yields with appropriate processing should be stored
ranges should be established under appropriate conditions to
based on previous laboratory, pilot ensure their suitability for use.
scale, or manufacturing data.
Deviations in yield associated with 8.3 In-process Sampling
critical process steps should be and Controls
investigated to determine their
impact or potential impact on the 8.30 Written procedures should be
resulting quality of affected batches. established to monitor the progress
and control the performance of
8.15 Any deviation should be processing steps that cause
documented and explained. Any variability in the quality
critical deviation should be characteristics of intermediates
investigated. and APIs. In-process controls and
their acceptance criteria should
8.16 The processing status of major units be defined based on the information
of equipment should be indicated gained during the development
either on the individual units of stage or historical data.
equipment or by appropriate
documentation, computer control 8.31 The acceptance criteria and type
systems, or alternative means. and extent of testing can depend
on the nature of the intermediate
8.17 Materials to be reprocessed or or API being manufactured, the
reworked should be appropriately reaction or process step being
controlled to prevent unauthorized conducted, and the degree to
use. which the process introduces
variability in the product’s quality.
8.2 Time Limits Less stringent in-process controls
may be appropriate in early
8.20 If time limits are specified in the processing steps, whereas
master production instruction tighter controls may be appropriate
275
for later processing steps (e.g., 8.4 Blending Batches of Intermediates

isolation and purification steps). or APIs
8.32 Critical in-process controls (and 8.40 For the purpose of this document,
critical process monitoring), blending is defined as the process
including the control points and of combining materials with in the
methods, should best put in writing same specification to produce a
and approved by the quality unit(s). homogeneous intermediate or API.
In-process mixing of fractions
from single batches (e.g., collecting
8.33 In-process controls can be several centrifuge loads from a
performed by qualified production single crystallization batch)or
department personnel and the combining fractions from several
process adjusted without prior batches for further processing
quality unit(s) approval if the is considered to be part of the
adjustments are made with in production process and is not
pre-established limits approved by considered to be blending.
the quality unit(s). All tests and
results should be fully documented 8.41 Out-Of-Specification batches should
as part of the batch record. not be blended with other batches
for the purpose of meeting
8.34 Written procedures should specifications. Each batch
describe the sampling methods incorporated into the blend should
for in-process materials, have been manufactured using
intermediates, and APIs. Sampling an established process and should
plans and procedures should have been individually tested and
be based on scientifically sound found to meet appropriate
sampling practices. specifications prior to blending.
8.35 In-process sampling should be 8.42 Acceptable blending operations

conducted using procedures include but are not limited to:
designed to prevent contamination
of the sampled material and other • blending of small batches to
intermediates or APIs. Procedures increase batch size
should be established to ensure the • Blending of tailings (i.e., relatively
integrity of samples after collection. small quantities of isolated material)
from batches of the same
8.36 Out-of-specification (OOS) intermediate or API to form a
investigations are not normally single batch.
needed for in- process tests that are
performed for the purpose of 8.43 Blending processes should be
monitoring and/or adjusting adequately controlled and
the process. documented and the blended
batch should be tested for
276
conformance to established carryover should not result in

specifications where appropriate. the carryover of degradants or
microbial contamination that may
8.44 The batch record of the blending adversely alter the established API
process should allow traceability impurity profile.
back to the individual batches that
makeup the blend. 8.51 Production operations should
be conducted in a manner that will
8.45 Where physical attributes of the prevent contamination of
API are critical (e.g., APIs intermediates or APIs by other
intended for use in solid oral dosage materials.
forms or suspensions), blending
operations should be validated to 8.52 Precautions to avoid contamination
show homogeneity of the combined should be taken when APIs are
batch. Validation should include handled after purification.
testing of critical attributes (e.g.,
particle size distribution, bulk 9. PACKAGING AND
density, and tap density) that may
be affected by the blending process.
IDENTIFICATION
LABELLING OF APIS
8.46 If the blending could adversely AND INTERMEDIATES
affect stability, stability testing of the
final blended batches should 9.1 General
be performed.
9.10 There should be written procedures
8.47 The expiry or retest date of the describing the receipt, identification,
blended batch should be based on quarantine, sampling, examination
the manufacturing date of the oldest and/or testing and release, and
tailings or batch in the blend. handling of packaging and labelling
materials.
8.5 Contamination Control
9.11 Packaging and labelling materials
8.50 Residual materials can be should conform to established
carried over into successive specifications. Those that do not
batches of the same intermediate comply with such specifications
or API if there is adequate control. should be rejected to prevent
Examples include residue their use in operations for which
adhering to the wall of a micronizer, they are unsuitable.
residual layer of damp crystals
remaining in a centrifuge 9.12 Records should be maintained
bowl after discharge, and for each shipment of labels
in complete discharge of fluids and packaging materials showing
or crystals from a processing vessel receipt, examination, or testing, and
upon transfer of the material whether accepted or rejected.
to the next step in the process. Such
277
9.2 Packaging Materials Returned labels should be

maintained and stored in a manner
9.20 Containers should provide that prevents mix-ups and provides
adequate protection against proper identification.
deterioration or contamination of
the intermediate or API that may 9.33 Obsolete and outdated labels
occur during transportation and should be destroyed.
recommended storage.
9.34 Printing devices used to print labels
9.21 Containers should be clean for packaging operations should
and, where indicated by the nature be controlled to ensure that all
of the intermediate or API, sanitized imprinting conforms to the print
to ensure that they are suitable for specified in the batch production
their intended use. These containers record.
should not be reactive, additive,
or absorptive so as to alter the 9.35 Printed labels issued for a batch
quality of the intermediate or API should be carefully examined for
beyond the specified limits. proper identity and conformity to
specifications in the master
9.22 If containers are re-used, they production record. The results of
should be cleaned in accordance this examination should be
with documented procedures and documented.
all previous labels should be
removed or defaced. 9.36 A printed label representative of
those used should be included in
9.3 Label Issuance and Control the batch production record.
9.30 Access to the label storage areas 9.4 Packaging and Labelling
should be limited to authorized Operations
personnel.
9.40 There should be documented
9.31 Procedures should be used to procedures designed to ensure that
reconcile the quantities of labels correct packaging materials and
is sued, used, and returned and to labels are used.
evaluate discrepancies found
between the number of containers 9.41 Labelling operations should be
labelled and the number of labels designed to prevent mix-ups. There
issued. Such discrepancies should should be physical or spatial
be investigated, and the separation from operations involving
investigation should be approved by other intermediates or APIs.
the quality unit (s).
9.42 Labels used on containers of
9.32 All excess labels bearing batch intermediates or APIs should
numbers or other batch-related indicate the name or identifying
printing should be destroyed. code, the batch number of the
278
product, and storage conditions, manufacturer’s control should be

when such information is critical to sealed in a manner such that, if the
assure the quality of intermediate seal is breached or missing, the
or API. recipient will be alerted to the
possibility that the contents may
9.43 If the intermediate or API is intended have been altered.
to be transferred outside the control
of the manufacturer’s material 10. STORAGE AND
management system, the name
and address of the manufacturer,
DISTRIBUTION
quantity of contents, and special
10.1 Warehousing Procedures
transport conditions and any special
legal requirements should also
10.10 Facilities should be available for
be included on the label. For
the storage of all materials
intermediates or APIs with an expiry
under appropriate conditions (e.g.
date, the expiry date should be
controlled temperature and
indicated on the label and Certificate
humidity when necessary). Records
of Analysis. For intermediates or
should be maintained of these
APIs with a retest date, there test
conditions if they are critical for the
date should be indicated on the
maintenance of material
label and/or Certificate of Analysis.
characteristics.
9.44 Packaging and labelling facilities
10.11 Unless there is an alternative
should be inspected immediately
system to prevent the un intentional
before use to ensure that all
or un authorized use of quarantined,
materials not needed for the next
rejected, returned, or recalled
packaging operation have been
materials, separates to rage areas
removed. This examination
should be assigned for their
should be documented in the batch
temporary storage until the decision
production records, the facility log,
as to their future use has
or other documentation system.
been taken.
9.45 Packaged and labelled
10.2 Distribution Procedures
intermediates or APIs should be
examined to ensure that containers
10.20 APIs and intermediates should only
and packages in the batch have the
be released for distribution to third
correct label. This examination
parties after they have been
should be part of the packaging
released by the quality unit(s).
operation. Results of these
APIs and intermediates can be
examinations should be recorded in
transferred under quarantine to
the batch production or control
another unit under the company’s
records.
control when authorized by the
quality unit(s) and if appropriate
9.46 Intermediate or API containers that
are transported outside of the
279
controls and documentation are 11.12 All specifications, sampling plans,

in place. and test procedures should be
scientifically sound and appropriate
10.21 APIs and intermediates should to ensure that raw materials,
be transported in a manner that intermediates, APIs, and labels
does not adversely affect their and packaging materials conform
quality. to established standards of
quality and/or purity. Specifications
10.22 Special transport or storage and test procedures should
conditions for an API or intermediate be consistent with those included
should be stated on the label. in the registration/filing. There can
be specifications in addition to
10.23 The manufacturer should ensure those in the registration/filing.
that the contract accept or Specifications, sampling plans,
(contractor) for transportation of the and test procedures, including
API or intermediate knows and changes to them, should be drafted
follows the appropriate transport by the appropriate organizational
and storage conditions. unit and reviewed and approved by
the quality unit(s).
10.24 A system should be in place
by which the distribution of each 11.13 Appropriate specifications should
batch of intermediate and/or API be established for APIs in
can be readily determined to permit accordance with accepted
its recall. standards and consistent with the
manufacturing process. The
11. LABORATORY CONTROLS specifications should include
a control of the impurities (e.g.
11.1 General Controls organic impurities, inorganic
impurities, and residual solvents). If
11.10 The independent quality unit the API has a specification for
(s) should have at its disposal microbiological purity, appropriate
adequate laboratory facilities. action limits for total microbial
counts and objectionable organisms
11.11 There should be documented should be established and met. If
procedures describing sampling, the API has a specification for
testing, approval or rejection of endotoxins; appropriate action limits
materials, and recording and should be established and met.
storage of laboratory data.
Laboratory records should be 11.14 Laboratory controls should be
maintained in accordance with followed and documented at the
Section 6.6. time of performance. Any departures
from the above described
procedures should be documented
and explained.
280
11.15 Any out-of-specification result Appropriate testing should be

obtained should be investigated and performed to establish fully the
documented according to a identity and purity of the
procedure. This procedure should primary reference standard.
require analysis of the data, Appropriate documentation of this
assessment of whether a significant testing should be maintained.
problem exists, allocation of the
tasks for corrective actions, and 11.19 Secondary reference standards
conclusions. Any resampling should be appropriately prepared,
and/or retesting after OOS identified, tested, approved, and
results should be performed stored. The suitability of each batch
according to a documented of secondary reference standard
procedure. should be determined prior to
first use by comparing against
11.16 Reagents and standard solutions a primary reference standard. Each
should be prepared and labelled batch of secondary reference
following written procedures. “Use standard should be periodically
by” dates should be applied as prequalified in accordance with a
appropriate for analytical reagents written protocol.
or standard solutions.
11.2 Testing of Intermediates and APIs
11.17 Primary reference standards
should be obtained as appropriate 11.20 For each batch of intermediate
for the manufacture of APIs. The and API, appropriate laboratory
source of each primary tests should be conducted to
reference standard should be determine conformance to
documented. Records should specifications.
be maintained of each primary
reference standard’s storage 11.21 An impurity profile describing
and use in accordance with the the identified and un identified
supplier’s recommendations. impurities present in a typical batch
Primary reference standards produced by a specific controlled
obtained from an officially production process should normally
recognized source are normally be established for each API. The
used without testing if stored under impurity profile should include
conditions consistent with the the identity or some qualitative
supplier’s recommendations. analytical designation (e.g.
Retention time), the range of each
11.18 Where a primary reference standard impurity observed, and classification
is not available from an officially of each identified impurity (e.g.
recognized source, an “in-house inorganic, organic, solvent). The
primary standard” should be impurity profile is normally
established. dependent upon the production
process and origin of the API.
Impurity profiles are normally not
281
necessary for APIs from herbal 11.42 The Certificate should list each test
or animal tissue origin. performed in accordance with
Biotechnology considerations are compendial or customer
covered in ICH Guideline Q6B. requirements, including the
acceptance limits, and the numerical
11.22 The impurity profile should be results obtained (if test results
compared at appropriate intervals are numerical).
against the impurity profile in the
regulatory submission or 11.43 Certificates should be dated
compared against historical data in and signed by authorized personnel
order to detect changes to the API of the quality unit (s) and should
resulting from modifications in raw show the name, address
materials, equipment operating and telephone number of the
parameters, or the production original manufacturer. Where
process. the analysis has been carried out by
a re-packer or re-processor, the
11.23 Appropriate microbiological tests Certificate of Analysis should show
should be conducted on each batch the name, address and telephone
of intermediate and API where number of the re-packer/reprocess
microbial quality is specified. or and a reference to the name of
the original manufacturer.
11.3 Validation of Analytical
Procedures-see Section 12. 11.44 If new Certificates are issued by or
on behalf of re-packers/re-
11.4 Certificates of Analysis processors, agents’ or brokers,
these Certificates should show the
11.40 Authentic Certificates of Analysis name, address and telephone
should be issued for each batch of number of the laboratory that
intermediate or API on request. performed the analysis. They should
also contain a reference to the
11.41 Information on the name of name and address of the original
the intermediate or API including manufacturer and to the original
where appropriate its grade, the batch Certificate, a copy of which
batch number, and the date of should be attached.
release should be provided on the
Certificate of Analysis. For 11.5 Stability Monitoring of APIs
intermediates or APIs with an expiry
date, the expiry date should be 11.50 A documented, on-going testing
provided on the label and Certificate program should be designed to
of Analysis. For intermediates or monitor the stability characteristics
APIs with a retest date, the retest of APIs, and the results should be
date should be indicated on the used to confirm appropriate storage
label and/or Certificate of Analysis. conditions and retest or expiry
dates.
282
11.51 The test procedures used in stability specific test intervals (e.g.9 month
testing should be validated and be testing) can be considered.
stability indicating.
11.56 Where appropriate, the stability
11.52 Stability samples should be stored storage conditions should be
in containers that simulate the consistent with the ICH guidelines
market container. For example, if on stability.
the API is marketed in bags
within fiber drums, stability samples 11.6 Expiry and Retest Dating
can be packaged in bags of the
same material and in smaller- 11.60 When an intermediate is intended
scale drums of similar or identical to be transferred outside the control
material composition to the market of the manufacturer’s material
drums. management system and an expiry
or retest date is assigned,
11.53 Normally the first three commercial supporting stability information
production batches should be should be available (e.g. published
placed on the stability monitoring data, test results).
program to confirm there test or
expiry date. However, where data 11.61 An API expiry or retest date should
from previous studies show that the be based on an evaluation of data
API is expected to remain stable for derived from stability studies.
at least two years, fewer than three Common practice is to use a retest
batches can be used. date, not an expiration date.
11.54 Thereafter, at least one batch per 11.62 Preliminary API expiry or retest
year of API manufactured (unless dates can be based on pilot scale
none is produced that year) should batches if (1) the pilot batches
be added to the stability monitoring employ a method of manufacture
program and tested at least annually and procedure that simulates the
to confirm the stability. final process to be used on a
commercial manufacturing scale;
11.55 For APIs with short shelf-lives, and (2) the quality of the API
testing should be done more represents the material to be made
frequently. For example, for those on a commercial scale.
biotechnological/biologic and other
APIs with shelf-lives of one year or 11.63 A representative sample should be
less, stability samples should be taken for the purpose of performing
obtained and should be tested a retest.
monthly for the first three months
and at three month intervals after 11.7 Reserve/Retention Samples
that. When data exist that
confirm that the stability of the API 11.70 The packaging and holding of
is not compromised, elimination of reserve samples is for the purpose
of potential future evaluation of the
283
quality of batches of API and not for validation phase, should be

future stability testing purposes. documented.
11.71 Appropriately identified reserve 12.11 The critical parameters/attributes

samples of each API batch should should normally be identified during
be retained for one year after the development stage or from
the expiry date of the batch historical data, and the ranges
assigned by the manufacturer, or necessary for the reproducible
for three years after distribution of operation should be defined. This
the batch, whichever is the longer. should include:
For APIs with retest dates, similar • defining the API in terms of its
reserve samples should be retained critical product attributes;
for three years after the batch is • identifying process parameters that
completely distributed by the could affect the critical quality
manufacturer. attributes of the API;
• determining the range for each
11.72 The reserve sample should be critical process parameter expected
stored in the same packaging to be used during routine
system in which the API is stored or manufacturing and process control.
in one that is equivalent to
or more protective than the
marketed packaging system. 12.12 Validation should extend to those
operations determined to be critical
Sufficient quantities should to the quality and purity of the API.
be retained to conduct at least
two full compendial analyses or, 12.2 Validation Documentation
when there is no pharmacopoeial
monograph, two full specification 12.20 Written validation protocols should
analyses. be established that specifies how
validation of a particular process
12. VALIDATION will be conducted. The protocol
should be reviewed and approved
12.1 Validation Policy by the quality unit (s) and other
designated units.
12.10 The company’s overall policy,
intentions, and approach to 12.21 The validation protocol should
validation, including the validation of specify critical process steps and
production processes, cleaning acceptance criteria as well as
procedures, analytical methods, in- the type of validation to be
process control test procedures, conducted (e.g. retrospective,
computerized systems, and persons prospective, concurrent) and the
responsible for design, review, number of process runs.
approval and documentation of each
284
12.22 A validation report that cross- intended throughout the anticipated

references the validation protocol operating ranges.
should be prepared, summarizing
the results obtained, commenting • Performance Qualification (PQ):
on any deviations observed, documented verification that
and drawing the appropriate the equipment and ancillary
conclusions, including systems, as connected together,
recommending changes to correct can perform effectively and
deficiencies. reproducibly based on the approved
process method and specifications.
12.23 Any variations from the validation
protocol should be documented with 12.4 Approaches to Process Validation
appropriate justification.
12.40 Process Validation (PV) is the
12.3 Qualification documented evidence that
the process, operated within
12.30 Before starting processes validation established parameters, can
activities, appropriate qualification perform effectively and reproducibly
of critical equipment and ancillary to produce an intermediate or API
systems should be completed. meeting its predetermined
specifications and quality attributes.
Qualification is usually carried
out by conducting the following 12.41 There are three approaches to
activities, individually or combined: validation. Prospective validation
is the preferred approach, but there
• Design Qualification (DQ): are exceptions where the other
documented verification that the approaches can be used. These
proposed design of the facilities, approaches and their applicability
equipment, or systems is suitable are listed below.
for the intended purpose.
12.42 Prospective validation should
• Installation Qualification normally be performed for all API
(IQ): documented verification that processes as defined in12.12.
the equipment or systems, Prospective validation performed on
as installed or modified, an API process should be
comply with the approved design, completed before the commercial
the manufacturer’s distribution of the final drug product
recommendations and/or manufactured from that API.
user requirements.
12.43 Concurrent validation can be
• Operational Qualification (OQ): conducted when data from replicate
documented verification that production runs are un available
the equipment or systems, as because only a limited number of
installed or modified, perform as API batches have been produced,
API batches are produced in
285
frequently, or API batches are to obtain data to retrospectively

produced by a validated process validate the process.
that has been modified. Prior to the
completion of concurrent validation, 12.5 Process Validation Program
batches can be released and
used in final drug product for 12.50 The number of process runs for
commercial distribution based on validation should depend on the
thorough monitoring and testing of complexity of the process or the
the API batches. magnitude of the process change
being considered. For prospective
12.44 An exception can be made for and concurrent validation, three
retrospective validation for well- consecutive successful production
established processes that have batches should be used as a
been used without significant guide, but there may be situations
changes to API quality due to where additional process runs
changes in raw materials, are warranted to prove consistency
equipment, systems, facilities, or the of the process (e.g., complex API
production process. This validation processes or API processes with
approach may be used where: prolonged completion times). For
retrospective validation, generally
(1) Critical quality attributes and critical data from ten to thirty consecutive
process parameters have been batches should be examined
identified; to assess process consistency, but
fewer batches can be examined
(2) Appropriate in-process acceptance if justified.
criteria and controls have been
established; 12.51 Critical process parameters should
be controlled and monitored
(3) There have not been significant during process validation studies.
process/product failures attributable Process parameters unrelated
to causes other than operator error to quality, such as variables
or equipment failures unrelated to controlled to minimize energy
equipment suitability; and consumption or equipment use,
need not be included in the process
(4) Impurity profiles have been validation.
established for the existing API.
12.52 Process validation should confirm
12.45 Batches selected for retrospective that the impurity profile for each
validation should be representative API is within the limits specified.
of all batches made during the The impurity profile should be
review period, including any batches comparable to or better than
that failed to meet specifications, historical data and, where
and should be sufficient in number applicable, the profile determined
to demonstrate process consistency. during process development or
Retained samples can be tested
286
for batches used for pivotal clinical and the calculation of residue limits
and toxicological studies. based on potency, toxicity, and
stability.
12.6 Periodic Review of
Validated Systems 12.72 The cleaning validation protocol
should describe the equipment to
12.60 Systems and processes should be cleaned, procedures, materials,
be periodically evaluated to verify acceptable cleaning levels,
that they are still operating in a parameters to be monitored and
valid manner. Where no significant controlled, and analytical methods.
changes have been made to the
system or process, and a quality The protocol should also indicate
review confirms that the system or the type of samples to be obtained
process is consistently producing and how they are collected
material meeting its specifications, and labelled.
there is normally no need for
revalidation. 12.73 Sampling should include swabbing,
rinsing, or alternative methods (e.g.,
12.7 Cleaning Validation direct extraction), as appropriate,
to detect both insoluble and soluble
12.70 Cleaning procedures should residues. The sampling methods
normally be validated. In general, used should be capable of
cleaning validation should be quantitatively measuring levels of
directed to situations or process residues remaining on the
steps where contamination or equipment surfaces after cleaning.
carryover of materials poses the Swab sampling may be impractical
greatest risk to API quality. For when product contact surfaces are
example, in early production it not easily accessible due to
may be un necessary to validate equipment design and/or process
equipment cleaning procedures limitations (e.g., inner surfaces of
where residues are removed by hoses, transfer pipes, reactor tanks
subsequent purification steps. with small ports or handling toxic
materials, and small intricate
12.71 Validation of cleaning procedures equipment such as micronizers
should reflect actual equipment and microfluidizers).
usage patterns. If various APIs or
intermediates are manufactured 12.74 Validated analytical methods having
in the same equipment and the sensitivity to detect residues or
equipment is cleaned by the same contaminants should be used.
process, a representative The detection limit for each
intermediate or API can be selected analytical method should be
for cleaning validation. This sufficiently sensitive to detect
selection should be based on the the established acceptable
solubility and difficulty of cleaning level of the residue or contaminant.
The method’s attainable recovery
287
level should be established. testing methods used should

Residue limits should be practical, nonetheless be verified under actual
achievable, and verifiable and conditions of use and documented.
based on the most deleterious
residue. Limits can be 12.81 Methods should be validated
established based on the minimum to include consideration of
known pharmacological, characteristics included within the
toxicological, or physiological ICH guidelines on validation of
activity of the API or its most analytical methods. The degree of
deleterious component. analytical validation performed
should reflect the purpose of the
12.75 Equipment cleaning/sanitization analysis and the stage of the API
studies should address production process.
microbiological and endotoxin
contamination for those processes 12.82 Appropriate qualification of
where there is a need to reduce analytical equipment should be
total microbiological count or considered before starting validation
endotoxins in the API, or other of analytical methods.
processes where such
contamination could be of concern 12.83 Complete records should be
(e.g., non-sterile APIs used to maintained of any modification
manufacture sterile products). of a validated analytical method.
Such records should include the
12.76 Cleaning procedures should be reason for the modification and
monitored at appropriate intervals appropriate data to verify that
after validation to ensure that these the modification produces results
procedures are effective when that are as accurate and reliable as
used during routine production. the established method.
Equipment cleanliness can be
monitored by analytical testing and 13. CHANGE CONTROL
visual examination, where feasible.
Visual inspection can allow 13.10 A formal change control system
detection of gross contamination should be established to evaluate
concentrated in small areas that all changes that may affect the
could otherwise go undetected by production and control of the
sampling and/or analysis. intermediate or API.
12.8 Validation of Analytical Methods 13.11 Written procedures should

provide for the identification,
12.80 Analytical methods should be documentation, appropriate review,
validated unless the method and approval of changes in raw
employed is included in the materials, specifications, analytical
relevant pharmacopoeia or methods, facilities, support systems,
other recognized standard equipment (including computer
reference. The suitability of all
288
hardware), processing steps, intermediate or API produced by

labelling and packaging materials, the modified process can be placed
and computer software. on an accelerated stability program
and/or can be added to the stability
13.12 Any proposals for GMP relevant monitoring program.
changes should be drafted,
reviewed, and approved by the 13.17 Current dosage form manufacturers
appropriate organizational units, should be notified of changes from
and reviewed and approved by the established production and process
quality unit (s). control procedures that can impact
the quality of the API.
13.13 The potential impact of the
proposed change on the quality of 14. REJECTION AND RE-USE
the intermediate or API should be
evaluated. A classification
OF MATERIALS
procedure may help in determining
14.1 Rejection
the level of testing, validation, and
documentation needed to justify
14.10 Intermediates and APIs failing to
changes to a validated process.
meet established specifications
should be identified as such and
Changes can be classified (e.g.as
quarantined. These intermediates
minor or major) depending on the
or APIs can be reprocessed or
nature and extent of the changes,
reworked as described below. The
and the effects these changes may
final disposition of rejected materials
impact on the process. Scientific
should be recorded.
judgment should determine what
additional testing and validation
14.2 Reprocessing
studies are appropriate to justify a
change in a validated process.
14.20 Introducing an intermediate or
API, including one that does not
13.14 When implementing approved
conform to standards or
changes, measures should be taken
specifications, back into the process
to ensure that all documents
and reprocessing by repeating
affected by the changes are revised.
a crystallization step or
other appropriate chemical or
13.15 After the change has been
physical manipulation steps (e.g.,
implemented, there should be an
distillation, filtration,
evaluation of the first batches
chromatography, milling)that are
produced or tested under the
part of the established
change.
manufacturing process is generally
considered acceptable. However,
13.16 The potential for critical changes to
if such reprocessing is used for
affect established retest or expiry
a majority of batches, such
dates should be evaluated. If
necessary, samples of the
289
reprocessing should be included as and the expected results. If there is

part of the standard manufacturing only one batch to be reworked, then
process. a report can be written and
the batch released once it is found
14.21 Continuation of a process step after to be acceptable.
an in-process control test has
shown that the step is incomplete is 14.32 Procedures should provide for
considered to be part of the comparing the impurity profile
normal process. This is not of each reworked batch against
considered to be reprocessing. batches manufactured by the
established process. Where
14.22 Introducing un reacted material routine analytical methods are
back into a process and repeating inadequate to characterize the
a chemical reaction is considered reworked batch, additional methods
to be reprocessing unless it is part should be used.
of the established process. Such
reprocessing should be preceded 14.4 Recovery of Materials
by careful evaluation to ensure and Solvents
that the quality of the intermediate
or API is not adversely impacted 14.40 Recovery (e.g. from mother liquor
due to the potential formation of by- or filtrates ) of reactants,
products and over-reacted intermediates, or the API
materials. is considered acceptable, provided
that approved procedures exist for
14.3 Reworking the recovery and there covered
materials meet specifications
14.30 Before a decision is taken to rework suitable for their intended use.
batches that do not conform to
established standards or 14.41 Solvents can be recovered and
specifications, an investigation into reused in the same processes or in
the reason for non- conformance different processes, provided
should be performed. that the recovery procedures are
controlled and monitored to ensure
14.31 Batches that have been reworked that solvents meet appropriate
should be subjected to appropriate standards before reuse or co-
evaluation, testing, stability testing mingling with other approved
if warranted, and documentation materials.
to show that there worked product
is of equivalent quality to that 14.42 Fresh and recovered solvents
produced by the original process. and reagents can be combined if
Concurrent validation is often the adequate testing has shown their
appropriate validation approach suitability for all manufacturing
for rework procedures. This allows processes in which they may
a protocol to define their work be used.
procedure, how it will be carried out,
290
14.43 The use of recovered solvents, 15.11 Complaint records should include:
mother liquors, and other recovered
materials should be adequately • Name and address of complainant;
documented.
• Name (and, where appropriate, title)
14.5 Returns and phone number of person
submitting the complaint;
14.50 Returned intermediates or APIs
should be identified as such • Complaint nature (including name
and quarantined. and batch number of the API);
14.51 If the conditions under which • Date complaint is received;

returned intermediates or APIs
have been stored or shipped before • Action initially taken (including dates
or during their return or the and identity of person taking
condition of their containers the action);
casts doubt on their quality, the
returned intermediates or APIs • any follow-up action taken;
should be reprocessed, reworked,
or destroyed, as appropriate. • Response provided to the originator
of complaint (including date
14.52 Records of returned intermediates response sent); and
or APIs should be maintained. For
each return, documentation should • Final decision on intermediate or
include: API batch or lot.
• Name and address of the consignee 15.12 Records of complaints should be

retained in order to evaluate trends,
• Intermediate or API, batch number, product- related frequencies, and
and quantity returned severity with a view to taking
additional, and if appropriate,
• Reason for return immediate corrective action.
• Use or disposal of the returned 15.13 There should be a written procedure

intermediate or API that defines the circumstances
under which a recall of an
15. COMPLAINTS AND intermediate or API should
be considered.
RECALLS
15.14 The recall procedure should
15.10 All quality related complaints,
designate who should be involved in
whether received orally or in
evaluating the information, how
writing, should be recorded and
are call should be initiated, who
investigated according to a written
should be informed about the recall,
procedure.
291
and how the recalled material pass to a third party any of the work
should be treated. entrusted to him under the contract
without the contract giver’s prior
15.15 In the event of a serious or evaluation and approval of the
potentially life-threatening situation, arrangements.
local, national, and/or international
authorities should be informed and 16.15 Manufacturing and laboratory
their advices ought. records should be kept at the site
where the activity occurs and be
16. CONTRACT readily available.
MANUFACTURERS 16.16 Changes in the process, equipment,
(INCLUDING test methods, specifications, or
LABORATORIES) other contractual requirements
should not be made unless the
16.10 All contract manufacturers (including contract giver is informed and
laboratories) should comply with approves the changes.
the GMP defined in this Guide.
Special consideration should be 17. AGENTS, BROKERS,
given to the prevention of cross-
contamination and to maintaining
TRADERS,
traceability. DISTRIBUTORS,
REPACKERS AND
16.11 Contract manufacturers (including RELABELLERS
laboratories) should be evaluated by
the contract giver to ensure 17.1 Applicability
GMP compliance of the specific
operations occurring at the contract 17.10 This section applies to any party
sites. other than the original manufacturer
who may trade and/or take
16.12 There should be a written and possession, repack, relabel,
approved contract or formal manipulate, distribute or store an
agreement between the contract API or intermediate.
giver and the contract accept or
that defines in detail the GMP 17.11 All agents, brokers, traders,
responsibilities, including the quality distributors, repackers, and
measures, of each party. relabellers should comply with GMP
as defined in this Guide.
16.13 The contract should permit the
contract giver to audit the contract 17.2 Traceability of Distributed APIs
acceptor’s facilities for compliance and Intermediates
with GMP.
17.20 Agents, brokers, traders,
16.14 Where subcontracting is allowed, distributors, repackers, or relabellers
the contract acceptor should not
292
should maintain complete 17.41 Repackaging should be conducted

traceability of APIs and under appropriate environmental
intermediates that they distribute. conditions to avoid contamination
and cross-contamination.
Documents that should be retained
and available include: 17.5 Stability
• Identity of original manufacturer 17.50 Stability studies to justify assigned

• Address of original manufacturer expiration or retest dates should
• Purchase orders be conducted if the API or
• Bills of lading (transportation intermediate is repackaged in a
documentation) different type of container than that
• Receipt documents used by the API or intermediate
• Name or designation of API or manufacturer.
intermediate
• Manufacturer’s batch number 17.6 Transfer of Information
• Transportation and distribution
records 17.60 Agents, brokers, distributors,
• All authentic Certificates of Analysis, repackers, or relabellers should
including those of the original transfer all quality or regulatory
manufacturer information received from an
• Retest or expiry date API or intermediate manufacturer
to the customer and from the
17.3 Quality Management customer to the API or intermediate
manufacturer.
distributors, repackers, or relabellers 17.61 The agent, broker, trader, distributor,
should establish, document and repacker, or relabeller who supplies
implement an effective system of the API or intermediate to the
managing quality, as specified in customer should provide the
Section2. name of the original API or
intermediate manufacturer and the
17.4 Repackaging, Relabelling and batch number (s) supplied.
Holding of APIs and
Intermediates 17.62 The agent should also provide the
identity of the original API or
17.40 Repackaging, relabelling and intermediate manufacturer to
holding of APIs and intermediates regulatory authorities upon request.
should be performed under The original manufacturer can
appropriate GMP controls, as respond to the regulatory authority
stipulated in this Guide, to avoid directly or through its authorized
mix-ups and loss of API or agents, depending on the legal
intermediate identity or purity. relationship between the authorized
agents and the original API or
intermediate manufacturer. (In this
293
context “authorized” refers to 17.8 Handling of Returns

authorized by the manufacturer.)
17.80 Returns should be handled as
17.63 The specific guidance for specified in Section14.52. The
Certificates of Analysis included in agents, brokers, traders,
Section 11.4 should be met. distributors, repackers, or relabellers
should maintain documentation of
17.7 Handling of Complaints returned APIs and intermediates.
and Recalls
18. SPECIFIC GUIDANCE FOR
distributors, repackers, or relabellers
APIs MANUFACTURED BY
should maintain records of CELL CULTURE/
complaints and recalls, as specified FERMENTATION
in Section 15, for all complaints and
recalls that come to their attention. 18.1 General
17.71 If the situation warrants, the agents, 18.10 Section 18 is intended to address
brokers, traders, distributors, specific controls for APIs or
repackers, or relabellers should intermediates manufactured by
review the complaint with the cell culture or fermentation using
original API or intermediate natural or recombinant organisms
manufacturer in order to determine and that have not been covered
whether any further action, either adequately in the previous sections.
with other customers who may It is not intended to beast and-alone
have received this API or Section. In general, the GMP
intermediate or with the regulatory principles in the other sections of
authority, or both, should be this document apply. Note that
initiated. The investigation in to the the principles of fermentation
cause for the complaint or recall for “classical” processes for
should be conducted and production of small molecules
documented by the appropriate and for processes using
party. recombinant and non-recombinant
organisms for production of
17.72 Where a complaint is referred to proteins and/or polypeptides are the
the original API or intermediate same, although the degree of
manufacturer, the record maintained control will differ. Where practical,
by the agents, brokers, traders, this section will address these
distributors, repackers, or relabellers differences. In general, the degree
should include any response of control for bio technological
received from the original API or processes used to produce proteins
intermediate manufacturer and polypeptides is greater than
(including date and information that for classical fermentation
provided). processes.
294
18.11 The term“biotechnological process. The raw materials used

process” (biotech) refers to the (media, buffer components)
use of cells or organisms that have may provide the potential for growth
been generated or modified by of microbiological contaminants.
recombinant DNA, hybridoma Depending on the source, method
or other technology to produce of preparation, and the intended
APIs. The APIs produced by use of the API or intermediate,
biotechnological processes normally control of bioburden, viral
consist of high molecular contamination, and/or endotoxins
weight substances, such as proteins during manufacturing and
and polypeptides, for which specific monitoring of the process at
guidance is given in this Section. appropriate stages may be
necessary.
Certain APIs of low molecular
weight, such as antibiotics, amino 18.14 Appropriate controls should be
acids, vitamins, and carbohydrates, established at all stages of
can also be produced by manufacturing to assure
recombinant DNA technology. intermediate and/or API quality.
The level of control for these types While this Guide starts at the cell
of API sis similar to that employed culture/fermentation step, prior
for classical fermentation. steps (e.g. cell banking) should be
performed under appropriate
18.12 The term “classical fermentation” process controls. This Guide covers
refers to processes that use cell culture/fermentation from the
microorganisms existing in nature point at which avail of the cell bank
and/or modified by conventional is retrieved for use in manufacturing.
methods (e.g. irradiation or chemical
mutagenesis) to produce APIs. 18.15 Appropriate equipment and
APIs produced by “classical environmental controls should be
fermentation” are normally low used to minimize the risk of
molecular weight products such contamination. The acceptance
as antibiotics, aminoacids, vitamins, criteria for quality of the environment
and carbohydrates. and the frequency of monitoring
should depend on the step in
18.13 Production of APIs or intermediates production and the production
from cell culture or fermentation conditions (open, closed, or
involves biological processes contained systems).
such as cultivation of cells or
extraction and purification of 18.16 In general, process controls should
material from living organisms. take in to account:
Note that there may be additional • Maintenance of the Working Cell

process steps, such as Bank (where appropriate);
physicochemical modification,
that are part of the manufacturing
295
• Proper inoculation and expansion of 18.2 Cell Bank Maintenance and

the culture; Record Keeping

• Control of the critical operating
parameters during fermentation/ 18.20 Access to cell banks should be
cellculture; limited to authorized personnel.
• Monitoring of the process for 18.21 Cell banks should be maintained

cell growth, viability (for most cell under storage conditions
culture processes) and productivity designed to maintain viability and
where appropriate; prevent contamination.
• Harvest and purification procedures 18.22 Records of the use of the vials from
that remove cells, cellular debris the cell banks and storage
and media components while conditions should be maintained.
protecting the intermediate or
API from contamination (particularly 18.23 Where appropriate, cell banks
of microbiological nature) and from should be periodically monitored to
loss of quality; determine suitability for use.
• Monitoring of bioburden and, 18.24 See ICH Guideline Q5D Quality of

where needed, endotoxin levels at Biotechnological Products:
appropriate stages of production; Derivation and Characterization
and of Cell Substrates Used for
Production of Biotechnological/
• Viral safety concerns as Biological Products for a more
described in ICH Guideline Q5A complete discussion of cell banking.
Quality of Biotechnological
Products: Viral Safety Evaluation 18.3 Cell Culture/Fermentation
of Biotechnology Products Derived
from Cell Lines of Human or 18.30 Where aseptic addition of cell
Animal Origin. substrates, media, buffers, and
gases is needed, closed or
18.17 Where appropriate, the removal of contained systems should be
media components, host cell used where possible. If the
proteins, other process-related inoculations of the initial vessel or
impurities, product-related impurities subsequent transfers or additions
and contaminants should be (media, buffers) are performed in
demonstrated. open vessels, there should be
controls and procedures in place to
minimize the risk of contamination.
18.31 Where the quality of the API can

be affected by microbial
contamination, manipulations
296
using open vessels should be processes should be identified as

performed in a biosafety cabinet or appropriate and the effect of
similarly controlled environment. their presence on product quality
should be assessed, if necessary.
18.32 Personnel should be appropriately The results of such assessments
gowned and take special should be taken into consideration
precautions handling the cultures. in the disposition of the material
produced.
18.33 Critical operating parameters (for
example temperature, pH, agitation 18.37 Records of contamination events
rates, addition of gases, pressure) should be maintained.
should be monitored to ensure
consistency with the established 18.38 Shared (multi-product) equipment
process. Cell growth, viability (for may warrant additional testing
most cell culture processes), and, after cleaning between product
where appropriate, productivity campaigns, as appropriate, to
should also be monitored. Critical minimize the risk of cross-
parameters will vary from one contamination.
process to another, and for classical
fermentation, certain parameters 18.4 Harvesting, Isolation
(cell viability, for example) may not and Purification
need to be monitored.
18.40 Harvesting steps either to remove
18.34 Cell culture equipment should cells or cellular components or to
be cleaned and sterilized after collect cellular components after
use. As appropriate, fermentation disruption, should be performed in
equipment should be cleaned, and equipment or are as designed to
sanitized or sterilized. minimize the risk of contamination.
18.35 Culture media should be sterilized 18.41 Harvest and purification procedures
before use when appropriate to that remove or inactivate the
protect the quality of the API. producing organism, cellular debris
and media components (while
18.36 There should be appropriate minimizing degradation,
procedures in place to detect contamination, and loss of
contamination and determines the quality) should be adequate
course of action to be taken. This to ensure that the intermediate or
should include procedures to API is recovered with consistent
determine the impact of the quality.
contamination on the product
and those to decontaminate the
equipment and return it to a
condition to be used in subsequent
batches. Foreign organisms
observed during fermentation
297
18.42 All equipment should be properly 18.53 The same equipment is not normally
cleaned and, as appropriate, used for different purification steps.
sanitized after use. Multiple However, if the same equipment
successive batching without is to be used, the equipment should
cleaning can be used if intermediate be appropriately cleaned and
or API quality is not compromised. sanitized before reuse. Appropriate
precautions should be taken to
18.43 If open systems are used; prevent potential virus carry-over
purification should be performed (e.g. through equipment or
under environmental conditions environment) from previous steps.
appropriate for the preservation of
product quality. 19. APIs FOR USE IN
18.44 Additional controls, such as the
CLINICAL TRIALS
use of dedicated chromatography
19.1 General
resins or additional testing, may
be appropriate if equipment is to be
19.10 Not all the controls in the previous
used for multiple products.
sections of this Guide are
appropriate for the manufacture of
18.5 Viral Removal/Inactivation Steps
a new API for investigational
use during its development. Section
18.50 See the ICH Guideline Q5A Quality
19 provides specific guidance
of Biotechnological Products: Viral
unique to these circumstances.
Safety Evaluation of Biotechnology
Products Derived from Cell Lines
19.11 The controls used in the
of Human or Animal Origin for more
manufacture of APIs for use in
specific information.
clinical trials should be consistent
with the stage of development of the
18.51 Viral removal and viral inactivation
drug product incorporating the
steps are critical processing steps
API. Process and test procedures
for some processes and should be
should be flexible to provide
performed within their validated
for changes as knowledge of the
parameters.
process increases and clinical
testing of a drug product progresses
18.52 Appropriate precautions should be
from pre-clinical stages through
taken to prevent potential viral
clinical stages. Once drug
contamination from pre-viral to post-
development reaches the stage
viral removal/in-activation steps.
where the API is produced for use
in drug products intended for clinical
Therefore, open processing should
trials, manufacturers should ensure
be performed in areas that are
that APIs are manufactured in
separate from other processing
suitable facilities using appropriate
activities and have separate air
production and control procedures
handling units.
to ensure the quality of the API.
298
19.2 Quality 19.31 Procedures for the use of facilities

should ensure that materials are
19.20 Appropriate GMP concepts should handled in a manner that minimizes
be applied in the production of the risk of contamination and cross-
APIs for use in clinical trials with a contamination.
suitable mechanism of approval of
each batch. 19.4 Control of Raw Materials
19.21 A quality unit(s) independent from 19.40 Raw materials used in production
production should be established for of APIs for use in clinical trials
the approval or rejection of each should be evaluated by testing,
batch of API for use in clinical trials. or received with a supplier’s
analysis and subjected to identity
19.22 Some of the testing functions testing. When a material is
commonly performed by the considered hazardous, a supplier’s
quality unit (s) can be performed analysis should suffice.
within other organizational units.
19.41 In some instances, the suitability of
19.23 Quality measures should include a a raw material can be determined
system for testing of raw materials, before use based on acceptability in
packaging materials, intermediates, small-scale reactions (i.e., use
and APIs. testing) rather than on analytical
testing alone.
19.24 Process and quality problems
should be evaluated. 19.5 Production
19.25 Labelling for APIs intended for 19.50 The production of APIs for use
use in clinical trials should be in clinical trials should be
appropriately controlled and documented in laboratory
should identify the material as being notebooks, batch records, or by
for investigational use. other appropriate means. These
documents should include
19.3 Equipment and Facilities information on the use of production
materials, equipment, processing,
19.30 During all phases of clinical and scientific observations.
development, including the use
of small-scale facilities or 19.51 Expected yields can be more
laboratories to manufacture batches variable and less defined than
of APIs for use in clinical trials, the expected yields used in
procedures should be in place to commercial processes.
ensure that equipment is calibrated, Investigations in to yield variations
clean and suitable for its intended are not expected.
use.
299
19.6 Validation after approval, termination, or

discontinuation of an application.
19.60 Process validation for the production
of APIs for use in clinical trials 19.82 Expiry and retest dating as defined
is normally inappropriate, where in Section11.6 applies to existing
a single API batch is produced APIs used in clinical trials. For new
or where process changes during APIs, Section11.6 does not normally
API development make batch apply in early stages of clinical trials.
replication difficult or in exact. The
combination of controls, calibration, 19.9 Documentation
and, where appropriate, equipment
qualification assures API quality 19.90 Asystemshouldbe in place to
during this development phase. ensure that information gained
during the development and the
19.61 Process validation should be manufacture of APIs for use in
conducted in accordance with clinical trials is documented and
Section 12 when batches are available.
produced for commercial use, even
when such batches are produced on 19.91 The development and
a pilot or small scale. implementation of the analytical
methods used to support the
19.7 Changes release of a batch of API for use
in clinical trials should be
19.70 Changes are expected during appropriately documented.
development, as knowledge is
gained and the production is 19.92 A system for retaining production
scaled up. Every change in the and control records and documents
production, specifications, or test should be used. This system should
procedures should be adequately ensure that records and
recorded. documents are retained for
an appropriate length of time
19.8 Laboratory Controls after the approval, termination, or
discontinuation of an application.
19.80 While analytical methods performed
to evaluate a batch of API for clinical
trials may not yet be validated, they
should be scientifically sound.
19.81 A system for retaining reserve

samples of all batches should be
in place. This system should
ensure that a sufficient quantity
of each reserve sample is retained
for an appropriate length of time
300
20. GLOSSARY Batch Number (or Lot Number)
Acceptance Criteria A unique combination of numbers, letters, and/

or symbols that identifies a batch (or lot) and
Numerical limits, ranges, or other suitable from which the production and distribution
measures for acceptance of test results. history can be determined.
Active Pharmaceutical Ingredient (API) (or Bioburden

Drug Substance)
The level and type (e.g. objectionable or not)
Any substance or mixture of substances of micro-organisms that can be present in raw
intended to be used in the manufacture of materials, API starting materials, intermediates
a drug (medicinal) product and that, when or APIs. Bio burden should not be considered
used in the production of a drug, becomes contamination unless the levels have been
an active ingredient of the drug product. exceeded or defined objectionable organisms
Such substances are intended to furnish have been detected.
pharmacological activity or other direct effect
in the diagnosis, cure, mitigation, treatment, or Calibration
prevention of disease or to affect the structure
and function of the body. The demonstration that a particular instrument
or device produces results within specified
API Starting Material limits by comparison with those produced by
a reference or traceable standard over an
A raw material, intermediate, or an API that appropriate range of measurements.
is used in the production of an API and that
is incorporated as a significant structural Computer System
fragment in to the structure of the API. An
API Starting Material can be an article of A group of hardware components and
commerce, a material purchased from one or associated software designed and assembled
more suppliers under contract or commercial to perform a specific function or group of
agreement, or produced in-house. API functions.
Starting Materials are normally of defined
chemical properties and structure. Computerized System
Batch (or Lot) A process or operation integrated with a

computer system.
A specific quantity of material produced in a
process or series of processes so that it is Contamination
expected to be homogeneous within specified
limits. In the case of continuous production, a The undesired introduction of impurities of
batch may correspond to a defined fraction of a chemical or microbiological nature, or of
the production. The batch size can be defined foreign matter, into or onto a raw material,
either by a fixed quantity or by the amount intermediate, or API during production,
produced in a fixed time interval. sampling, packaging or repackaging, storage
or transport.
301
Contract Manufacturer Impurity
A manufacturer performing some aspect Any component present in the intermediate or

of manufacturing on behalf of the original API that is not the desired entity.
manufacturer.
Impurity Profile
Critical
A description of the identified and un identified
Describes a process step, process condition, impurities present in an API.
test requirement, or other relevant parameter
or item that must be controlled within In-Process Control (or Process Control)
predetermined criteria to ensure that the API
meets its specification. Checks performed during production in order
to monitor and, if appropriate, to adjust the
Cross-Contamination process and/or to ensure that the intermediate
or API conforms to its specifications.
Contamination of a material or product with
another material or product. Intermediate
Deviation A material produced during steps of the

processing of an API that undergoes further
Departure from an approved instruction or molecular change or purification before
established standard. it becomes an API. Intermediates may or
may not be isolated. (Note: this Guide only
Drug (Medicinal) Product addresses those intermediates produced after
the point that the company has defined as
The dosage form in the final immediate the point at which the production of the API
packaging intended for marketing. (Reference begins.)
Q1A)
Lot See Batch
Drug Substance
Lot Number see Batch Number
See Active Pharmaceutical Ingredient
See Batch Number
Expiry Date (or Expiration Date)
Manufacture
The date placed on the container/labels of
an API designating the time during which the All operations of receipt of materials,
API is expected to remain within established production, packaging, repackaging, labelling,
shelf life specifications if stored under defined relabelling, quality control, release, storage,
conditions, and after which it should not be and distribution of APIs and related controls.
used.
302
Material Qualification
A general term used to denote raw materials Action of proving and documenting that
(starting materials, reagents, and solvents), equipment or ancillary systems are properly
process aids, intermediates, APIs and installed, work correctly, and actually lead to
packaging and labelling materials. the expected results. Qualification is part of
validation, but the individual qualification steps
Mother Liquor alone do not constitute process validation.
The residual liquid which remains after Quality Assurance (QA)

the crystallization or isolation processes.
A mother liquor may contain un reacted The sum total of the organized arrangements
materials, intermediates, levels of the API made with the object of ensuring that all APIs
and/or impurities. It may be used for further are of the quality required for their intended
processing. use and that quality systems are maintained.
Packaging Material Quality Control (QC)
Any material intended to protect an Checking or testing that specifications are

intermediate or API during storage and met.
transport.
Quality Unit (s)
Procedure
An organizational unit independent of
A documented description of the operations to production which fulfils both Quality Assurance
be performed, the precautions to be taken and and Quality Control responsibilities. This can
me assures to be applied directly or indirectly be in the form of separate QA and QC units or
related to the manufacture of an intermediate a single individual or group, depending upon
or API. Process Aids the size and structure of the organization.
Materials, excluding solvents, used as an aid Quarantine

in the manufacture of an intermediate or API
that do not they participate in a chemical or The status of materials isolated physically or
biological reaction (e.g. filter aid, activated by other effective mean spending a decision
carbon, etc). on their subsequent approval or rejection.
Process Control See In-Process Control Raw Material

Production
A general term used to denote starting
All operations involved in the preparation materials, reagents, and solvents intended for
of an API from receipt of materials through use in the production of intermediates or APIs.
processing and packaging of the API.
303
Reference Standard, Primary Reworking
A substance that has been shown by an Subjecting an intermediate or API that does
extensive set of analytical tests to be authentic not conform to standards or specifications
material that should be of high purity. This to one or more processing steps that are
standard can be: (1) obtained from an different from the established manufacturing
officially recognized source, or (2) prepared by process to obtain acceptable quality
independent synthesis, or (3) obtained from intermediate or API (e.g., recrystallizing with a
existing production material of high purity, or different solvent).
(4) prepared by further purification of existing
production material. Signature (signed)
Reference Standard, Secondary See definition for signed
A substance of established quality and Signed (signature)

purity, as shown by comparison to a primary
reference standard, used as a reference The record of the individual who performed a
standard for routine laboratory analysis. particular action or review. This record can be
initials, full hand written signature, personal
Reprocessing seal, or authenticated and secure electronic
signature.
Introducing an intermediate or API, including
one that does not conform to standards Solvent
or specifications, back into the process
and repeating a crystallization step or An inorganic or organic liquid used as a
other appropriate chemical or physical vehicle for the preparation of solutions
manipulation steps (e.g., distillation, filtration, or suspensions in the manufacture of an
chromatography, milling) that are part of intermediate or API.
the established manufacturing process.
Continuation of a process step after an in- Specification
process control test has shown that the step
is in complete is considered to be part of the A list of tests, references to analytical
normal process, and not reprocessing. procedures, and appropriate acceptance
criteria that are numerical limits, ranges,
Retest Date or other criteria for the test described. It
establishes the set of criteria to which a
The date when a material should be re- material should conform to be considered
examined to ensure that it is still suitable acceptable for its intended use. “Conformance
for use. to specification” means that the material,
when tested according to the listed analytical
procedures, will meet the listed acceptance
criteria.
304
Validation Yield, Expected
A documented program that provides a high The quantity of material or the percentage of
degree of assurance that a specific process, theoretical yield anticipated at any appropriate
method, or system will consistently produce phase of production based on previous
a result meeting pre-determined acceptance laboratory, pilot scale, or manufacturing data.
criteria.
Yield, Theoretical
Validation Protocol
The quantity that would be produced at any
A written plan stating how validation will be appropriate phase of production, based
conducted and defining acceptance criteria. upon the quantity of material to be used, in
For example, the protocol for a manufacturing the absence of any loss or error in actual
process identifies processing equipment, production.
critical process parameters/operating ranges,
product characteristics, sampling, test data to
be collected, number of validation runs, and
acceptable test results.
305
ANNEX 10: WASTE MANAGEMENT FOR MEDICINAL PRODUCT

MANUFACTURERS
10.1 PURPOSE 10.3 SOLID WASTE MATERIALS

These guidelines provide suggestions on 10.3.1 Solid Waste (non- hazardous) -
how to manage pharmaceutical waste, Garbage, refuse, sludge, industrial
maintaining and updating an inventory of waste and other discarded
pharmaceutical waste streams, managing materials. Solid waste management
waste storage sites, and disposing of waste should predominantly regulated at
material. Pharmaceutical waste that exhibits a the local level and be managed
characteristic of hazardous must be managed in accordance with local
and disposed of separately. environmental regulations
10.2 SCOPE 10.3.2 The management of solid waste

should involve its collection,
There are two (2) categories of pharmaceutical transport, processing and recycling
waste that need to be managed and they are or disposal. Collection should
defined as follows: include the gathering of solid waste
and recyclable materials, and the
Hazardous Waste: Waste pharmaceuticals transport of these materials, after
that must be segregated and managed as collection, to the location where the
such. These include antineoplastic agents, collection vehicle is emptied. This
radioactive agents, hormonal products, location may be a material
penicillins, solvents from laboratory. processing facility, a transfer station
or a landfill disposal site.
Non-Hazardous Pharmaceutical Waste: All
other pharmaceutical waste not included in 10.3.3 Waste disposal can be done
one above. primarily by land filling or closure of
existing dump sites. Modern
sanitary landfills are not dumps;
they are engineered facilities used
for disposing of solid wastes on land
without creating hazards to public
health or safety,
10.3.4 Provision should be made for the

proper and safe storage of waste
materials awaiting disposal.
10.3.5 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.
306
10.4 LIQUID WASTE

MATERIALS
10.4.1 If liquid effluent poses a safety or
contamination risk, the effluent
should be treated in Effluent
Treatment Plant before being
discharged to a municipal drain.
10.4.2 After treatment in ETP, water should

be sampled for analysis (pH,
Biochemical oxygen demand
(B.O.D) and chemical oxygen
demand (COD)) to check quality
before being discharged to
municipal drain.
10.4.3 Effluent treatment is the process

of removing contaminants from
waste water . It includes physical,
chemical, and biological processes
to remove physical, chemical and
biological contaminants. Its
objective is to produce an
environmentally safe fluid waste
stream (or treated effluent) and a
solid waste (or treated sludge)
suitable for disposal or reuse
(usually as farm fertilizer).
307
308
PART THREE:
GUIDELINES FOR PREPARATION

FOR SITE MASTER FILE FOR PHARMACEUTICAL
MANUFACTURING FACILITIES
309

DUNS - Data Universal Numbering System
EAC - East Africa Community
EAC-MRH - East African Community Medicines Regulatory Harmonization
GMP - Good Manufacturing Practices
GPS - Global Positioning System
HVAC - Heating Ventilation and Air Condition
PAT - Process Analytical Technology
SMF - Site Master File
310
2. GLOSSARY manufacturing operations carried

out at the named site and any
The definitions given below apply to the terms closely integrated operations at
used in this guide. They may have different adjacent and nearby buildings. If
meanings in other contexts. only part of a pharmaceutical
operation is carried out on the site,
Finished product: A product that has a Site Master File need only
undergone all stages of production, including describe those operations, e.g.
packaging in its final container and labeling. analysis, packaging, etc.
Production: All operations involved in the
preparation of a pharmaceutical product, 3.2 When submitted to a regulatory
from receipt of materials, through processing authority, the Site Master File
and packaging, to completion of the finished should provide clear information on
product. the manufacturer’s GMP related
activities that can be useful in
Qualification of equipment: The act of general supervision and in the
planning, carrying out and recording the efficient planning and undertaking
results of tests on equipment to demonstrate of GMP inspections.
that it will perform as intended. Measuring
instruments and systems must be calibrated. 3.3 A Site Master File should contain
Site master File: is a document containing adequate information but, as
specific information about the activities far as possible, not exceed 25
undertaken in the pharmaceutical pages plus appendices on A4
manufacturing site and is usually prepared by paper sheets. Simple plans outline
the manufacturer. drawings or schematic layouts
are preferred instead of narratives.
System: A regulated pattern of interacting The Site Master File, including
activities and techniques that are united to appendices, should be readable
form an organized whole. when printed on A4 paper sheets.
Validation: The documented act of proving 3.4 The Site Master File should be a
that any procedure, process, equipment, part of documentation belonging
material, activity, or system actually leads to to the quality management system
the expected results. of the manufacturer and kept
updated accordingly. The Site
Master File should have an edition
3. INTRODUCTION number, the date it becomes
effective and the date by which it
3.1 The Site Master File is prepared has to be reviewed. It should be
by the pharmaceutical manufacturer subject to regular review to ensure
and should contain specific that it is up to date and
information about the quality representative of current activities.
management policies and activities Each Appendix can have an
of the site, the production and/ individual effective date, allowing for
or quality control of pharmaceutical independent updating.
311
4. SCOPE to understanding the manufacturing

operations.
These guidelines apply for all kinds of
manufacturing operations such as production, 6.1.1.2 Name and physical address of the
packaging and labelling, testing, relabeling site, including GPS details, DUNS
and repackaging of all types of medicinal number (if available) telephone, fax,
products. The outlines of this guide could 24-hour telephone numbers
also be used in the preparation of a Site
Master File or corresponding document by 6.1.1.3 Name, phone number and e-mail for
manufacturers of Active Pharmaceutical the contact person on the site
Ingredients.
6.1.2 Authorized pharmaceutical
manufacturing activities of the site
5. LAY OUT OF THE SITE
MASTER FILE: 6.1.2.1 Copy of the valid manufacturing
authorization issued by the Local
5.1 Front Page: Drug Regulatory Authority
should be provided in annex 1. If
Name and address of the applicant, Document the local Drug Regulatory Authority
number, Effective date, A bird view of the does not issue manufacturing
manufacturing site (photo), Date, Stamped authorizations, the reason should
be stated.
5.2 Table of contents
6.1.2.2 A copy of current GMP certificate
5.3 Approval page issued by the local regulatory
authority should be provided in
Signed and dated by person(s) as prescribed annex 2
by the Quality Management System
6.1.2.3 Type of products manufactured on
6. CONTENT OF SITE the site, and information about any
specifically toxic or hazardous
MASTER FILE substances handled, mentioning
the way they are manufactured (in
The Site Master File should include the dedicated facilities or on a campaign
following: basis).
6.1 GENERAL INFORMATION 6.1.2.4 Short description of the site (size,

location, and immediate
6.1.1 Contact information on the environment and other
manufacturer manufacturing activities on the site).
6.1.1.1 Brief information on the firm 6.1.2.5 Number of employees engaged

(including name and address), in production, quality control,
relation to other sites and, in storage, and distribution.
particular any information relevant
312
6.1.2.6 Use of outside scientific, analytical, 6.2.2.2 General description of batch

or other technical assistance in certification and releasing
relation to manufacture procedure;
and analysis.
6.2.2.3 Role of authorized person in
6.1.2.7 List of GMP inspections of the site quarantine and release of finished
within the last 3 years; including products and in assessment of
dates and name/country of the compliance with the marketing
Competent Authority having authorization;
performed the inspection.
6.2.2.4 The arrangements between
6.1.3 Any other manufacturing activities authorized persons when several
carried out on the site. authorized persons are involved
6.1.3.1 Description of non-pharmaceutical 6.2.2.5 Statement on the control strategies

activities on site, if any employed to release the different
types of products e.g. process
6.2 QUALITY MANAGEMENT analytical technology (PAT) and/or
real-time release or parametric
6.2.1 The quality management system of release
the manufacturer
6.3 MANAGEMENT OF SUPPLIERS
6.2.1.1 Brief description of the quality AND CONTRACTORS
management systems run by the
company and reference to the The Site Master File should provide
standards used. information on management of suppliers and
contractors as indicated below.
6.2.1.2 Responsibilities related to the
maintaining of the quality system 6.3.1 A brief summary of the
including senior management establishment/knowledge of supply
chain and the external audit
6.2.1.3 Information on activities for which programme;
the site is accredited and certified,
including dates and contents of 6.3.2 A brief description of the
accreditations, and names of qualification system of contractors,
accrediting bodies.
6.3.3 Manufacturers of APIs and other
6.2.2 Release procedure of finished critical materials suppliers;
products
6.3.4 Measures adopted where
6.2.2.1 Detailed description of qualification substandard/spurious/falsely-
(education and work experience) of labelled/falsified/counterfeit medical
the authorized person(s) products, bulk products, APIs or
responsible for batch certification excipients are suspected or
and releasing procedures; identified;
313
6.3.5 Use of outside scientific, analytical 6.5.5 Personnel hygiene requirements,

or other technical assistance in including clothing.
relation to manufacture and
analysis; 6.6 PREMISES AND EQUIPMENT
6.3.6 List of contract manufacturers 6.6.1 PREMISES

and laboratories including the
addresses and contact information 6.6.1.1 Simple plan or description of
and flow-charts of supply chains for manufacturing areas with indication
outsourced manufacturing and QC of scale. Architectural or engineering
activities, e.g. sterilization of primary drawings not required. Plant lay out
packaging material for aseptic should be attached in annex 6.
processes, testing of starting raw
materials, etc., should be presented 6.6.1.2 Nature of construction and finishes
in annex 3
6.6.1.3 Special areas for the handling
6.3.7 Description of the way in which the of highly toxic, hazardous, and
GMP compliance of the contract sensitizing materials.
accepter is assessed.
6.6.1.4 Brief description of ventilation
6.4 PRODUCT QUALITY REVIEWS systems. More details should be
given for critical areas with potential
6.4.2 Brief description of methodologies risks of airborne contamination
used. (schematic drawings of the systems
are desirable). Classification of the
6.5 PERSONNEL rooms used for the manufacture
of sterile products should be
6.5.1 Organization chart showing the mentioned. Principles for defining
arrangements for quality assurance, the air supply, temperature,
quality control and production humidity, pressure differentials and
should be provided in Annex 4 air change rates, policy of air
recirculation (%). Schematic
6.5.2 QUALIFICATIONS, EXPERIENCE, diagrams should be added in
AND RESPONSIBILITIES OF annex 7.
TECHNICAL PERSONNEL
SHOULD BE INCLUDED AS 6.6.1.5 Brief description of water systems
ANNEX 5. with schematic drawings of the
systems, including sanitation
6.5.3 Outline of arrangements for basic should be submitted. Quality
and in-service training and how references of water produced
records are maintained. should be stated. Schematic
diagrams should be added in
6.5.4 Health requirements for personnel annex 8.
engaged in production.
314
6.6.1.6 Brief description of planned 6.7.2 Brief description of the validation

preventive maintenance master plan
programmes for premises and of the
recording system. 6.7.3 Brief description of the change
control procedure
6.6.1.7 Brief description of other relevant
utilities, such as steam, compressed 9.7.4 Any other documentation related
air, nitrogen, etc. Schematic to product quality that is not
diagrams should be added in mentioned elsewhere (e.g.,
annex 9. microbiological controls on air
and water).
6.6.1.8 Availability of written specifications
and procedures for cleaning 6.8 PRODUCTION
manufacturing areas
6.8.1 TYPE OF PRODUCTS
6.6.2 EQUIPMENT
6.8.1.1 Brief description of production
6.6.2.1 Brief description of major equipment operations using, wherever
used in production and control possible, flow sheets and charts
laboratories together with the model, specifying important parameters.
type and identification number. Reference to annex 11 should
The list of equipment is should be be made.
provided in annex 10
6.8.1.2 Policy for reprocessing or reworking
6.6.2.2 Brief description of the procedures should be stated.
used for cleaning major equipment.
6.8.1.3 Production capacities for the various
6.6.2.3 Brief description of planned dosage forms should be provided
preventive maintenance
programmes for equipment and of 6.8.2 PROCESS VALIDATION
the recording system.
6.8.2.1 Brief description of general policy
6.6.2.4 Brief description of the company’s for process validation. Reference
Qualification and calibration policy, should be made to the Validation
including the recording system. master plan.
Reference should be made to the
Validation master plan. 6.8.2.2 Arrangements for computerized
systems validation
6.7 DOCUMENTATION
6.8.3 MATERIAL MANAGEMENT
6.7.1 Arrangements for the preparation, AND WAREHOUSING
revision, distribution and archiving
of necessary documentation for 6.8.3.1 Arrangements for the handling of
manufacture should be stated. starting materials, packaging
materials, and bulk and finished
315
products, including sampling, 6.11 SELF-INSPECTION

quarantine, release, and storage.
6.11.1 Short description of the self-
6.8.3.2 Arrangements for the handling of inspection system with focus on
rejected materials and products. criteria used for selection of
the areas to be covered during
6.9 QUALITY CONTROL planned inspections, practical
arrangements and follow-up
6.9.1 Brief description of the quality activities.
control system: and the quality 6.12 SHELF LIFE / STABILITY
control department activities and DETERMINATION PROGRAM
procedures for the release of
finished products should be stated. 6.12.1 General policy for the determination
of the shelf-life and stability of
6.9.2 Brief description of general products manufactured at the site.
Validation policy
7. REFERENCES:
6.10 DISTRIBUTION, COMPLAINTS,
PRODUCTS DEFECT 7.1. Annex 14-WHO guidelines for
AND RECALL drafting a site master file (2011)
6.10.1 Arrangements and recording system 7.2. Explanatory Notes on the
for distribution. preparation of a Site Master File-
Volume 4 Good Manufacturing
6.10.2 Arrangements for the handling of Practice Medicinal Products for
complaints and product recalls. Human and Veterinary Use,
European Commission Enterprise
6.10.3 Arrangements for handling returned Directorate-General
goods
7.3. PIC/S Explanatory notes on the
preparation of a Site Master File
PE-008-4, (2011)
Revision No: Date Author(s) Section(s) Description Approvals
revised of change
00 September EAC TWG All First REF: EAC/
2013 GMP approved CM...../DECI-
Members version to SION------/dd/
be issued mm/yy
316
PART FOUR:
GUILDELINES ON
TRAINING AND QUALIFICATIONS
317

BMGF - Bill and Melinda Gates Foundation
BMR - Batch Manufacturing Record
EAC - East African Community
EAC-MRH - East African Community Medicines Regulatory Harmonization
EMA - European Pharmaceutical products Agency
EU - European Union
FEAPM - Federation of East African Pharmaceutical Manufacturers
Harmonization
GCP - Good Clinical Practice
GLP - Good Laboratory Practice
GMP - Good Manufacturing Practice
ICH - International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use
MA - Marketing Authorization
NEPAD - New Partnership for African Development
PIC/S - Pharmaceutical Inspection Convention Scheme
QA - Quality Assurance
HVAC - Heating Ventilation and Air Conditioning
QRM - Quality Risk Management
318
1. GLOSSARY Re- qualification implies validation of the

GMP inspector after 24 months absence from
The definitions given below apply to the terms conducting GMP inspections to ensure the
used in this guide. They may have different officer possesses the knowledge and skills to
meanings in other contexts. carry out GMP inspections
GMP Inspector means a GMP Inspector is Senior GMP inspector is an officer who
an officer appointed by the NMRA of Partner by virtue of experience and competence
states in accordance with national regulations is appointed as such to conduct GMP
and the provisions of the NMRA to conduct inspections and train junior officers in
an inspection or assessment in order to verify inspections after evaluation by the NMRA as
GMP compliance of a manufacturing site on by the criteria outlined in the assessment form.
behalf of the NMRA.
Specialized GMP inspector is a GMP
Lead GMP inspector is a Senior GMP inspector who possesses specialized
Inspector who is charged with the knowledge and experience in conducting
responsibility for leading a GMP inspection GMP inspections for specialized areas e.g
team to undertake inspection of a specified Microbiology, HVAC, Biologicals, API
pharmaceutical manufacturing site(s).
319
2. INTRODUCTION Inspectors should be well trained in all the

relevant topics concerning Quality Assurance
EAC NMRAs have a policy to conduct GMP management, manufacturing processes,
inspections of all local and foreign sites control and distribution of medical products
at which medicines used in each member (including investigational medical products)
states are manufactured. This is to ensure and in the way of conducting an inspection
adherence by manufacturers to all licensing (inspection methodology).
provisions and specifically to GMP.
The main objective of GMP is to control and Inspectors should have previous training and
enforce general standards of production and practical experience in the manufacture and/
to provide authorization for the manufacture of or quality control of pharmaceutical products.
specific pharmaceutical products. Graduate pharmacists and chemists or
scientists with an industrial background in
Specifically GMP inspection involves a pharmaceutical production, would qualify for
sequential examination of production and consideration.
control activities on the basis of the GMP
guidelines issued by EAC NMRAs. In The guideline provides information on minimal
addition requires verification that production requirements. They cover inspection of the
and quality control procedures employed production and control of final dosage forms
in the manufacture of specific products are of pharmaceutical products destined for
performed correctly and that they accord human use and of drug substances (active
with data supplied in the relevant licensing pharmaceutical ingredients or bulk drug
applications. substances) employed in their manufacture.
Inspection and licensing of pharmaceutical
Taking into account the paramount importance manufacturing facilities on the basis of
of the management of inspection services, compliance with GMP are a vital element of
this guidance establishes some requirements drug control.
concerning experience, training, assessment
and qualifications of GMP inspectors.
Objectivity and professional integrity,

competence in technical matters and
inspection skills should be the main features
of inspectors.
320
SCOPE of target inspection. However, when needed,

teams of inspectors may be nominated
This guideline applies to the training, comprising with appropriate qualifications
assessment and qualifications required for and experience to collectively fulfill the
an inspector who shall conduct an inspection requirements necessary for conducting the
to verify compliance with GMP for the EAC inspection.
NMRAs.
The inspectors should be made aware of and
maintain confidentiality whenever they gain
3. GENERAL access to confidential information as a result
REQUIREMENTS of GMP-inspections according to EAC and
national laws or international agreements.
EAC NMRAs should appoint inspectors to
inspect the local and foreign manufacturing EAC NMRAs and EAC Secretariat should
sites at which medicines and medical put in place sufficient resources to ensure
products used in EAC member states are availability of competent inspectors to match
manufactured. There should be sufficient the types and numbers of factories/products
resources at all levels to meet, effectively and and frequency of inspection. The possibility
efficiently, the EAC NMRAs requirements of of having part-time inspectors with specialist
verifying compliance with GMP of medicinal knowledge as part of inspection teams should
products. also be considered.
The inspectors shall be officials of or The training of inspectors should regularly

appointed by EAC NMRAs in accordance be assessed within requirements of the
with the current Personnel Manual for each applicable quality system of the Inspectorate
member state and shall follow EAC guidelines and appropriate action taken by EAC NMRA to
on GMP and the EAC standard operating maintain and improve inspection skills.
procedures while preparing for, conducting
and reporting on a GMP inspection. Information on the relevant experience,
training and qualifications of individual
All the inspectors should be competent to inspectors must be documented and
carry out their assigned duties and receive maintained by the Head of GMP Inspectorate
appropriate training. Since the number in each NMRA or his/her designated
of inspectors allocated to a particular representative. These records must be kept
inspection is limited by economic and other up-to-date.
considerations, each inspector should have
all the basic qualifications and experience 4. QUALITIES OF A GMP
necessary to conduct an inspection
independently. INSPECTOR
Moreover, EAC NMRAs shall use the report The personal skills of an inspector are
on observations on all areas of the facility important in helping to achieve the objectives
within the scope of the inspection to make a of the inspections.
judgment on the status of the plant. Thus each
inspector must be able to assess each section During an inspection the inspector should help
321
in creating an open atmosphere. Inspectors 5. EDUCATION AND

need to remain objective during the inspection
and in this context should answer questions or TRAINING
provide clarification but avoid entering into the
role of a consultant. The inspector should have knowledge of
the national and EAC legislation as well as
The inspector should have a high personal systems for applications for marketing and
integrity, maturity, honesty, be open-minded, control of marketed medicines.
understanding of complexity, possess sound
judgment, assertiveness, analytical skills The inspectors should have undergone
and tenacity and have the ability to perceive training to the extent necessary to ensure their
situations in a realistic way. competence in skills required for planning,
carrying out and reporting inspections.
The inspector should have demonstrated The training and experience should be
competence in clearly and fluently expressing documented individually and evaluated within
concepts and ideas orally and in writing in the requirements of the applicable quality
English and/or other languages defined by the system of the GMP Inspectorate of the EAC
EAC NMRA. NMRAs.
The inspector should also possess the 7.1 QUALIFICATION OF A

following attributes: GMP INSPECTOR
• awareness of the probable methods GMP Inspectors should normally be

of using forged or false documents pharmacists preferably with exposure or
for transactions in pharmaceutical working experience in the pharmaceutical
preparations and skill in determining industry. Where persons other than
the genuineness of documents pharmacists are to be employed as GMP
presented for examination inspectors, they should be adequately
experienced in drug control affairs and suitably
• responsible conduct which trained in GMP inspectorate functions.
commands respect
Moreover, in order to be appointed a GMP
• willingness to accept challenges inspector by the respective NMRAs, the
candidate should demonstrate their knowledge
• ability to assess facts quickly and and skills in the relevant pharmaceutical field,
take rational and sound decisions including:
without delay
• Good Manufacturing Practice (Basic
• ability to assess character and principles and annexes)
honesty of persons being
interviewed • Pharmaceutical technology
• commitment to hard work and • Microbiology, process and

ventilation engineering, analytical
• commitment to work for long hours instrumentation, computer systems,
322
process validation, the statistical • Knowledge of and training in

aspects of quality control working according to relevant EAC
NMRAs SOPs for inspections
• Interrelation of inspection, sampling
and analysis, licensing • Structure and principles of operation
of commercial organizations
• Marketing and manufacturing
authorization systems and their • Judiciary procedures
relationships
7.2 IN-SERVICE TRAINING
• Auditing/inspection techniques
After recruitment and in addition to their basic
• Training in inspection technique, training, new inspectors should be trained by
acquired by attending relevant senior inspectors. The theory of inspection
courses and/or by accompanying should be explained and the practice should
and/or be guided by qualified GMP be shown in the field, so that concrete
inspectors during inspections examples of the meaning and of the goals of
inspections are given and can be discussed.
• Training in administration New inspectors should participate, but only as
procedures required for managing observers, in on the spot inspections carried
an inspection, such as planning, out during their initial training.
organizing, communicating or
providing feed back to inspectee Training of inspectors should be a combination
of theoretical and practical training. It should
• Training in evaluation of findings cover both technical and non-technical
and reporting aspects.
• Distribution of medicinal products Prior to assuming responsibility for performing

GMP inspections, the new inspector should
• National and international medicine have gained experience by participation as
legislations a team member in inspections led by senior
inspectors. Preferably, the inspector should
• Communication skills, oral start with national GMP inspections as a
and written member of a team and then deal progressively
with more complex GMP inspections to be
• Organization of the national able to act as a team leader and/or reporting
medicine regulatory authority inspector in international inspections.
• The general principles of Quality This should consist of six phases:

Management Systems (ISO
9000:2000, etc) 1. Initially the trainee is trained in the
basic principles of GMP and good
• Knowledge of the Quality systems inspection techniques.
of the EAC NMRA GMP
Inspectorate
323
2. In addition, the trainee inspector communication, reporting, language, legal

should have assessed at least ten matters and management should be organized
(10) dossiers prior to qualification as by EAC NMRA GMP Inspectorates.
a GMP inspector
7.3 CONTINUOUS TRAINING
3. The trainee inspector would
participate in a GMP inspection with Considering the dynamic nature of
experienced inspector as an manufacturing technologies, the ever
observer in at least three more frequent utilization of automatic and
inspections. computerized systems both in production
and quality control of medicinal products,
4. Secondly, the trainee inspector inspectors should also receive continuous
would participate in inspections training. This could be reached through their
as a junior member of the team (at participation in courses, seminars, scientific
least six inspections). meetings and conferences organized by
either EAC NMRA GMP Inspectorates or by
5. Thirdly, the trainee inspector would national, regional or international scientific
participate in inspections as a co- organizations.
inspector under supervision
of a qualified lead inspector (at When appropriate, joint inspections or training
least three inspections). After visits with other inspectors of the EAC NMRA
assessment and satisfactory or other DRAs may be a useful training
performance, the trainee qualifies method.
as a GMP inspector.
GMP Training in form of courses, symposiums,
6. Finally, the GMP inspector would conferences, or any other mode the NMRA
participate in inspections as a deem suitable) should be arranged by EAC
co-inspector in at least twenty NMRA on annual basis.
inspections at national, regional or
international level taking into
consideration of different dosage 8. MANAGEMENT
forms and expertise acquired
to become a lead GMP inspector CAPABILITIES
after assessment of satisfactory
performance. The inspector should through suitable means
demonstrate their knowledge and capability
At all stages, the performance of the trainee of using the necessary management skills
should be assessed according to the required in execution of an inspection, i.e.
assessment form in annex 1 attached. planning, announcing, conducting and
reporting an inspection.
This should be recorded within the
requirements of the applicable quality system
of the EAC NMRA GMP Inspectorates
Besides this and where needed, training
courses in auditing techniques and
324
9. REPORT WRITING activities, within the requirements of the

applicable quality system of the EAC NMRA
The inspector should document and GMP Inspectorates:
demonstrate their capacity to write inspection
reports according to EAC NMRA requirements • Ensuring that the knowledge
as prescribed in the EAC Model Procedure for of GMP, quality systems standards
Preparing and Reviewing of GMP Inspection and requirements is current,
Reports (EAC/TF-MED/GMP/FD/SOP/N6R0).
An inspection should be regarded as • Ensuring that the knowledge of
an opportunity to assist and motivate a inspection procedures and methods
manufacturer to comply with GMP and to is current,
correct any specific deficiencies. It should not
be limited to compilation of an inventory of EAC NMRAs should arrange annual training
faults, irregularities, and discrepancies. for all GMP inspectors to either refresh the
knowledge of GMP inspection among the
Negative observations (non-compliance inspectors.
with GMP requirements) should distinguish
between whether the defect lies in the system Inspectors should be assessed based on
itself or in a failure to comply with the system. the number of GMP inspections performed,
For instance, when cleaning is found to be trainings undertaken, adherence to the Code
suboptimal, it is important to know whether the of Conducts for GMP inspectors and outcome
standard operating procedures are inadequate thereof on annual basis and this will form a
or lacking, or whether adequate written basis for considering further assignment of
procedures exist but are not being followed by GMP inspection.
personnel.
GMP inspectors should conduct at least
one GMP inspection every year in order to
10. MAINTENANCE OF maintain their status as GMP inspector.
COMPETENCE AND
DISQUALIFICATION A GMP inspector who has not been
performing GMP inspection for more than
Inspectors should have their performance and twenty four months, should be re- qualified
qualifications periodically reviewed within the before one is allowed to conduct further GMP
requirements of the quality system of the EAC inspections. The inspector to be re-qualified
NMRA GMP Inspectorates. should participate in GMP inspection as a
team member.
Their competence should be maintained
and updated by practical experience and Disqualification of a GMP inspector shall
participating in courses, seminars, scientific follow the laid down procedure regarding
meetings, conferences and review of relevant disciplinary action in accordance with
publications. respective NMRAs human resource policy and
Code of Conduct.
This should be documented and its
effectiveness assessed, In quality assurance A GMP inspector shall be assessed by at least
three senior GMP inspectors.
325
11. INTERNATIONAL The management should also facilitate

the exchange of information and practical
AND REGIONAL experience gained by inspectors in the
COLLABORATION fields of GMP, especially on those parts that
are closely related to GCP, e.g. laboratory
In order to promote international facilities, computerized data recording and
harmonization in the interpretation of analyses and requirements in relation to
the principles and compliance, the GMP medicinal products for investigational use.
inspection program management should
facilitate training activities, including on the job 12. REFERENCES
training, at national, regional and international
levels. European Medicines Agency (EMA) Guideline
on Training and qualifications of GMP
Consultations with the staff of the other inspectors, 2008
GMP inspectorates and joint inspection or
training visits may be useful and should be
encouraged.

Revision No: Date Author(s) Section(s) Description Approvals
revised of change
00 17th April EAC TWG All First REF: EAC/SC/
2014 GMP approved DECISION----
Members version to --/17TH APRIL
be issued 2014
326
EAST AFRICAN COMMUNITY SECRETARIAT
EAC CLOSE
P.O.BOX 1096
ARUSHA, TANZANIA

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DOCUMENT NO: EAC/TF-MED/GMP/FD/COM/N1R0

DOCUMENT NO: EAC/TF-MED/GMP/FD/COM/N1R0

COMPENDIUM OF GOOD MANUFACTURING PRACTICES (GMP)

VERSION SEPTEMBER 2014

DOCUMENTS DEVELOPMENT HISTORY

AUTHORS/CONTRIBUTORS Shabani Sifuma

David Robert Matle Daniel Murenzi

William Reuben Mendy Caroline

Gordon KatendeSematiko Dr. Samuel Azatyan

Andreas Seiter Margareth Ndomondo Sigonda

This Compendium has been developed to In addition it is also extremely important

Ambassador Dr. Richard Sezibera

This Compendium has been prepared to In addition, the Compendium outlines

Hon. Jesca Eriyo

RESPONSIBILITY FOR IMPLEMENTATION AND LEGAL FRAMEWORK

........................ ........................ ........................ ........................ ........................

Cabinet Minister of Minister to Minister for Minister of

REPUBLIC OF UNITED REPUBLIC OF REPUBLIC OF REPUBLIC OF

Reagents and culture media

ANNEX 1: MANUFACTURE OF STERILE MEDICINAL PRODUCTS

ANNEX 2:MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE

ANNEX 4: COMPUTERIZED SYSTEMS

ANNEX 15:MODEL PROCEDURE FOR COLLECTING AND HANDLING SAMPLE

PART FOUR: GUILDELINES ON TRAINING AND QUALIFICATIONS OF GMP INSPECTORS

INSPECTION MANUAL FOR GOOD

1. ABBREVIATIONS AND ACRONYMS

2. GLOSSARY Major observation means an observation

Critical observation means an observation Minor observation means an observation

3. INTRODUCTION In order to achieve that goal, EAC GMP

5. TYPES OF INSPECTIONS Collectively, the selected indicators and the

5.4. SPECIAL INSPECTION 7. PLANNING FOR GMP

6. FREQUENCY OF b) Facilities located in foreign

The frequency of inspection of local and All facilities located in countries

Foreign manufacturers shall be inspected

c) Manufacturers of APIs 10. QUALIFICATION OF GMP

8. PREPARATION FOR GMP 12. DECLARATION OF

9. JOINT GMP INSPECTION 13. CONDUCTING GMP

14. SAMPLE COLLECTION GMP inspection report shall be written

17. RECOMMENDED REGULATORY ACTION(S)

S/N Category of non- Regulatory action(s)

2. Major • Issue warning letter

1. Critical • Recommend permanent

Please refer to the ModelProcedure for Follow Up on Non-Compliances After GMP

18. PRODUCT RECALL 20. REFERENCES

21. REVISION HISTORY

a) Code of Conduct for EAC NMRAs (EAC/TF-MED/QMS/FD/POL/N2R0) in

ANNEX 11: MODEL PROCEDURE FOR PLANNING FOR GMP

4.1 Head of NMRAs 5.1.3.1 Type of activities/products;

4.5 Quality assurance departments 5.1.3.3 Public health/interest; Need to meet

5.1.3.4 Prevailing Socio-political 5.2.3 The Head of the GMP Inspectorate

5.4 Dossier Submission 5.6 Administration

The dossiers have to be submitted before 5.3.7 Inform the administration to

7.0 REVISION HISTORY

Name NMRA Contact (emails & Tel)

1. PARTICULARS OF APPLICANT/LICENSE HOLDER

2. PARTICULARS OF SITE TO BE INSPECTED

Physical Address (if different from 1. above)

Note: Separate application to be filled in for each individual site

3. CONTACT PERSON ON SITE

Name of contact person__________________________________________________

4. AUTHORISED REPRESENTATIVE/AGENT IN THE COUNTRY

Name of Local Technical Representative_____________________________________

Type of medicines manufactured (Tick where applicable)

Cabinet Minister of Minister to Minister for Minister of