WHO TRS 996 Web PDF

996
W H O Te c h n i c a l R e p o r t S e r i e s
996
WHO Expert Committee on Specifications for Pharmaceutical Preparations

The Expert Committee on Specifications for Pharmaceutical
Preparations works towards clear, independent and practical
WHO Expert Committee

standards and guidelines for the quality assurance of
medicines. Standards are developed by the Committee through
worldwide consultation and an international consensus-
building process. The following new guidelines were adopted
and recommended for use. Good pharmacopoeial practices;
FIP-WHO technical guidelines: points to consider in the
on Specifications
provision by health-care professionals of children-specific
preparations that are not available as authorized products; for Pharmaceutical
Preparations
Guidance on good manufacturing practices for biological
products; Guidance on good manufacturing practices:
inspection report, including Appendix 1: Model inspection
report; Guidance on good data and record management
practices; Good trade and distribution practices for starting
materials; Guidelines on the conduct of surveys of the quality
of medicines; Collaborative procedure between the World
Health Organization (WHO) prequalification team and
Fiftieth report
national medicines regulatory authorities in the assessment
and accelerated national registration of WHO-prequalified
pharmaceutical products and vaccines; Guidance for
organizations performing in vivo bioequivalence studies;
and World Health Organization (WHO) general guidance on
variations to multisource pharmaceutical products.
WHO Technical Report Series
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on Specifications
for Pharmaceutical
Preparations
Fiftieth report
This report contains the views of an international group of experts, and

does not necessarily represent the decisions or the stated policy of the World Health Organization
WHO Library Cataloguing-in-Publication Data
Fiftieth report of the WHO Expert Committee on specifications for pharmaceutical preparations.
(WHO technical report series ; no. 996)
1.Pharmaceutical Preparations - standards. 2.Technology, Pharmaceutical - standards.
3.Drug Industry - legislation. 4.Quality Control.
I.World Health Organization. II.Series.
ISBN 978 92 4 120996 0 (NLM classification: QV 771)
ISBN 978 92 4 069548 1 (PDF)
ISSN 0512-3054
World Health Organization 2016

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Printed in Italy
Contents
WHO Expert Committee on Specifications for Pharmaceutical Preparations vi
Declarations of interest xii
1. Introduction 1
2. General policy 3
2.1 Cross-cutting pharmaceutical quality assurance issues 3
2.2 International collaboration 4
3. Quality control specifications and tests 7
3.1 The International Pharmacopoeia 7
3.1.1 Updates 7
3.1.2 Workplan 20152016 7
3.2 Specifications for medicines, including childrens medicines and
radiopharmaceuticals 10
3.2.1 Maternal, newborn, child and adolescent health medicines 10
3.2.2 Antimalarial medicines 11
3.2.3 Antituberculosis medicines 12
3.2.4 Medicines for tropical diseases 12
3.2.5 Medicines for chronic diseases and for mental health 12
3.2.6 Other anti-infective medicines 13
3.2.7 Other medicines 13
3.2.8 Radiopharmaceuticals 14
3.3 General policy 15
4. Quality control international referencematerials (International
Chemical Reference Substances and Infrared Reference Spectra) 19
4.1 Update on International Chemical ReferenceSubstances (ICRS), including report
of the ICRS Board 19
4.2 General policy 20
4.2.1 Chapter on reference substances and reference spectra 20
5. Quality control national laboratories 21
5.1 External quality assurance assessment scheme 21
5.2 Guidance on testing of suspect substandard/spurious/falsely-labelled/falsified/
counterfeit medicines 21
6. Prequalification of quality control laboratories 22
6.1 Update on the prequalification of quality control laboratories 22
6.2 Update on WHO quality monitoring projects 22
7. Quality assurance collaboration initiatives 23
7.1 International meetings of world pharmacopoeias 23
7.2 Good pharmacopoeial practices 23
7.3 FIPWHO technical guidelines: points to consider in the provision by
health-care professionals of children-specific preparations that are not available
as authorized products 24
iii
8. Quality assurance good manufacturing practices 26
8.1 Update of WHO good manufacturing practices for biologicals 26
8.2 Update of questions and answers for WHO good manufacturing practices for
active pharmaceutical ingredients 26
8.3 Update of WHO good manufacturing practices: validation 27
8.4 Update of model inspection report 27
8.5 Update and recommendations from the inspectors meeting 28
8.5.1 Supplementary guidelines on good manufacturing practices for heating,
ventilation and air-conditioning systems for non-sterile pharmaceutical
dosage forms 28
8.5.2 Risk classification of inspection observations 28
8.6 Guidance on good data and record management practices 29
9. Quality assurance distribution and trade of pharmaceuticals 30
9.1 Good trade and distribution practices for starting materials 30
9.2 WHO Certification scheme on the quality of pharmaceutical products moving in
international commerce questions and answers 30
9.3 Guidance on medicines quality surveys 31
9.4 Update on the monitoring and surveillance project 32
10. Prequalification of priority essential medicines and active
pharmaceutical ingredients 33
10.1 Update on the Prequalification Team managed by WHO 33
10.2 Collaborative procedure between the World Health Organization (WHO)
Prequalification Team and national regulatory authorities in the assessment
and accelerated national registration of WHO-prequalified pharmaceutical
products and vaccines 34
11. Regulatory guidance 35
11.1 Guidance for organizations performing in vivo bioequivalence studies 35
11.2 WHO general guidance on variations to multisource pharmaceutical products 35
11.3 Update of biowaiver principles for assessment of interchangeable multisource
(generic) products 36
11.4 Update of biowaiver list based on the WHO Model List of Essential Medicines 37
11.5 Update of international comparator products list for equivalence assessment of
interchangeable multisource (generic) products 37
11.6 Good regulatory practices 38
12. Nomenclature, terminology and databases 40
13. Summary and recommendations 42

Acknowledgements 48
Annex 1
Good pharmacopoeial practices 67
Annex 2
FIPWHO technical guidelines: Points to consider in the provision by
health-care professionals of children-specific preparations that are not available
as authorized products 87
iv
Annex 3
WHO good manufacturing practices for biological products 111
Annex 4
Guidance on good manufacturing practices: inspection report 149
Annex 5
Guidance on good data and record management practices 165
Annex 6
Good trade and distribution practices for pharmaceutical starting materials 211
Annex 7
Guidelines on the conduct of surveys of the quality ofmedicines 227
Annex 8
Collaborative procedure between the World Health Organization (WHO)
Prequalification Team and national regulatory authorities in the assessment and
accelerated national registration of WHO-prequalified pharmaceutical products
and vaccines 263
Annex 9
Guidance for organizations performing in vivo bioequivalence studies 305
Annex 10
WHO general guidance on variations to multisource pharmaceutical products 347
v
WHO Expert Committee on Specifications for Pharmaceutical Preparations Fiftieth report
WHO Expert Committee on Specifications

for Pharmaceutical Preparations
Geneva, 1216 October 2015
Members1
Professor Saleh A. Bawazir, Consultant, College of Pharmacy, King Saud Unit, Riyadh,
Saudi Arabia (Rapporteur)
Professor Theo G. Dekker, Professor Emeritus, Research Institute for Industrial Pharmacy,
North-West University, Potchefstroom, South Africa
Professor Jos Hoogmartens, Leuven, Belgium (Co-chairperson)
Professor Jin Shaohong, Chief Expert for Pharmaceutical Products, National Institutes for
Food and Drug Control, Beijing, Peoples Republic of China
Professor Henning G. Kristensen, Vedbaek, Denmark
Ms Gugu N. Mahlangu, Director-General, Medicines Control Authority of Zimbabwe,
Harare, Zimbabwe (Chairperson)
Dr Justina A. Molzon, Bethesda, MD, USA
Mrs Lynda Paleshnuik, Arnprior, Ontario, Canada
Dr Jitka Sabartova, Prague, Czech Republic (Rapporteur)
Temporary advisers2
Professor Erwin Adams, Laboratorium voor Farmaceutische Analyse, Leuven, Belgium
Dr Marius Brits, Director, WHO Collaborating Centre for the Quality Assurance of Medicines,
North-West University, Potchefstroom, South Africa
Dr Mnica da Luz Carvalho Soares, Expert Health Regulation, Brazilian Health Surveillance
WHO Technical Report Series, No. 996, 2016
Agency (ANVISA), Brasilia, Brazil

Mr David Churchward, Expert Good Manufacturing and Distribution Practice Inspector,
Inspection, Enforcement and Standards, Medicines & Healthcare products Regulatory
Agency (MHRA), London, England
1
Unable to attend: Ms Nilka M. Guerrero Rivas, Technical Director, Radiopharmacy, Radiofarmacia de
Centroamrica, SA, Ciudad del Saber, Panama; Dr Toru Kawanishi, Director General, National Institute of
Health Sciences, Tokyo, Japan; Dr Adriaan J. van Zyl, Cape Town, South Africa.
2
Unable to attend: Dr Jean-Louis Robert, Luxembourg; Dr Jan Welink, Medicines Evaluation Board, Utrecht,
Netherlands.
vi
Dr Alfredo Garca Arieta, Head of Service on Pharmacokinetics and Generic Medicines,

Division of Pharmacology and Clinical Evaluation, Department of Human Use
Medicines, Agencia Espaola de Medicamentos y Productos Sanitarios (AEMPS),
Madrid, Spain
Dr John Gordon, Wolfville, Nova Scotia, Canada
Dr Olivier Le Blaye, Inspector, Trials and Vigilance Inspection Department, Agence
nationale de scurit du mdicament (ANSM) et des produits de sant, Saint-
Denis, France
Dr John Miller, Ayr, Scotland
Professor Alain Nicolas, Radiopharmacist, Pharmacie, Hpital Brabois Adultes, Vandoeuvre,
France
Mr Salim Akbaralli Veljee, Director, Food and Drugs Administration, Directorate of Food
and Drugs Administration, Goa, India
Mr John Wilkinson, Director of Devices, Medicines & Healthcare products Regulatory
Agency (MHRA), London, England
Ms Caroline Munyimba-Yeta, Director, Operations (Plant), NRB Pharma Zambia Limited,
Lusaka, Zambia
Representation from United Nations offices3

United Nations Childrens Fund (UNICEF)
Dr Peter Svarrer Jakobsen, Quality Assurance Specialist, UNICEF Supply Division,
Copenhagen, Denmark
Representation from specialized agencies and related organizations4

World Trade Organization (WTO)
Ms Daria Novozhilkina, Research Associate, Intellectual Property Division, Geneva,
Switzerland
Representation from intergovernmental organizations5

Council of Europe
Dr Stefan Almeling, Deputy Head, Laboratory Department, European Directorate for the
Quality of Medicines & HealthCare (EDQM), Strasbourg, France
3
Unable to attend: United Nations Development Programme (UNDP), New York, NY, USA.
4
Unable to attend: United Nations Industrial Development Organization (UNIDO), Vienna, Austria; World
Intellectual Property Organization (WIPO), Geneva, Switzerland; World Bank, Washington, DC, USA;
International Atomic Energy Agency (IAEA), Vienna, Austria.
5
Unable to attend: World Customs Organization (WCO), Brussels, Belgium; European Commission (EC),
Directorate-General for Health and Consumer Protection, Brussels, Belgium.
vii
European Medicines Agency (EMA)

Mr Andrei Spinei, London, England
Representation from nongovernmental organizations6

Active Pharmaceutical Ingredients Committee (APIC)
Dr Landry Le Chevanton, Team Leader, Global Regulatory Affairs and Quality Management,
DSM Nutritional Products Ltd, Switzerland
The Stop TB Partnership
Dr Nigorsulton Muzafarova, Product Quality Officer, Global Drug Facility (GDF), Geneva,
Switzerland
Dr Kaspars Lunte, Team Leader, Sourcing and Special Project, GDF, Geneva
International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)
Dr Betsy Fritschel, Director, Quality & Compliance, Johnson & Johnson, New Brunswick,
NJ, USA
Ms Valrie Faillat-Proux, Regulatory Affairs Senior Director, Access to Medicines & Malaria
Programme, Sanofi, Gentilly, France
International Generic Pharmaceutical Alliance (IGPA)
Dr Koen Nauwelaerts, Quality and Regulatory Affairs Manager, EGA-European Generic
and Biosimilar Medicines Association, Brussels, Belgium
International Pharmaceutical Excipients Council (IPEC)
Dr Eckart Krmer , SE Tylose GmbH & Co., Cologne, Germany
International Pharmaceutical Federation (FIP)
Ms Zuzana Kusynov, Policy Analyst and Project Coordinator, The Hague, Netherlands
Observers7
Dr C. Michelle Limoli, Senior International Health Advisor, Center for Biologics Evaluation
and Research, US Food and Drug Administration, Silver Spring, MD, USA
Ms Wei Ningyi, Associate Researcher, Division of Chemical Drugs, National Institutes for
Food and Drug Control, Beijing, Peoples Republic of China
Dr Gabriela Zenhusern, Senior Case Manager, Sector Authorisation, Swissmedic, Berne,
Switzerland
6
Unable to attend: Commonwealth Pharmacists Association (CPA), London, England; Global Fund to Fight
AIDS, Tuberculosis and Malaria, Geneva, Switzerland; International Society for Pharmaceutical Engineering
(ISPE), Tampa, FL, USA; World Self-Medication Industry (WSMI), Ferney-Voltaire, France.
7
Unable to attend: Pharmaceutical Inspection Co-operation Scheme (PIC/S), Geneva, Switzerland.
viii
Professor Zhang Mei, Deputy Director and Vice Chairman, Institutes for Food and Drug
Control, Jiangsu, Peoples Republic of China/Antibiotic Subcommittee, Chinese
Pharmacopoeia Commission, Peoples Republic of China
Pharmacopoeias8
Farmacopia Brasileira
Mr Varley Dias Sousa, Coordinator, Coordination of Brazilian Pharmacopoeia, Brazilian
Health Surveillance Agency (ANVISA), Brasilia, Brazil
British Pharmacopoeia
Ms Helen Corns, British Pharmacopoeia and Laboratory Services, Medicines & Healthcare
products Regulatory Agency (MHRA), London, England
Pharmacopoeia of the Peoples Republic of China
Dr Wang Fei, Beijing, Peoples Republic of China
European Pharmacopoeia 9
Council of Europe, Strasbourg, France
Japanese Pharmacopoeia
Dr Yoshihiro Matsuda, Deputy Director, Pharmaceutical and Medical Devices Agency,
Division of Pharmacopoeia and Standards for Drugs, Office of Standards and
Guidelines Development, Pharmaceuticals and Medical Devices Agency, Tokyo,
Japan
Pharmacopoeia of the Republic of Korea
Dr Kwangmoon Lee, Deputy Director, Drug Research Division, Pharmaceutical
Standardization Research and Drug Research Division, National Institute of Food
and Drug Safety Evaluation, Ministry of Food and Drug Safety, Chungcheongbuk-do,
Republic of Korea
State Pharmacopoeia of the Russian Federation
Dr Elena Sakanyan, Director, Centre of Pharmacopoeia and International Collaboration,
Scientific Centre for Expert Evaluation of Medicinal Products of the Ministry of Health
of the Russian Federation, Moscow, Russian Federation
Ms Olga Gubareva, Head, International Cooperation Department, Moscow, Russian
Federation
United States Pharmacopeia
Dr Kevin Moore, Manager, Pharmacopeial Harmonization, Rockville, MD, USA
Dr Kelly S. Willis, Senior Vice President, Global Public Health, Rockville, MD, USA
8
Unable to attend: Farmacopea Argentina; Indian Pharmacopoeia Commission; Indonesian Pharmacopoeia
Commission; Pharmacopoeia of Ukraine.
9
See under Council of Europe.
ix
Representation from WHO Regional Offices10

Regional Office for the Western Pacific
Ms Uhjin Kim, Essential Medicines and Health Technology, Division of Health Systems,
WHO Regional Office for the Western Pacific, Manila, Philippines
WHO Secretariat 11
Health Systems and Innovation (HIS)
Dr M.-P. Kieny, Assistant Director-General
Essential Medicines and Health Products (HIS/EMP)
Mr C. de Joncheere, Director, Essential Medicines and Health Products (EMP)
Regulation of Medicines and other Health Technologies (EMP/RHT)
Dr L. Rgo, Head
Technologies, Standards and Norms (EMP/RHT/TSN)
Dr D.J. Wood, Coordinator
Medicines Quality Assurance (EMP/RHT/TSN)
Dr S. Kopp, Group Lead, Medicines Quality Assurance (Secretary)
Dr H. Schmidt, TSN
Dr H. Chen, TSN (volunteer)
International Nonproprietary Name (INN/RHT/TSN)
Dr R.G. Balocco, Group Lead
Policy, Access and Use (EMP/PAU)
Ms Bernadette Cappello
Prequalification Team (EMP/RHT/PQT)
Mr M. McDonald, Coordinator
Mr J.R.H. Kuwana
Mr D. Mubangizi, Group Lead, Inspections

Ms T. Muvirimi
Regulatory Systems Strengthening (RSS/RHT/RHT)
Dr M. Ward, Coordinator
Safety and Vigilance Team (EMP/RHT/SAV)
Miss P. Bourdillon-Esteve, Analyst
10
Unable to attend: Regional Office for Africa; Regional Office for the Americas; Regional Office for the
Eastern Mediterranean; Regional Office for Europe; Regional Office for South-East Asia.
11
Unable to attend: Traditional and Complementary Medicine (HIS/Service Delivery and Safety (SDS)/TCM).
x
Global TB Programme (GTB)

Dr C. Gilpin, Laboratories, Diagnostics and Drug-Resistance (LDR)
Dr L. Nguyen, LDR
Prevention of Noncommunicable Diseases (PND)
Dr Dongbo Fu, Technical Officer, National Capacity
Ms M. Zweygarth (report writer)
xi
Declarations of interest
Members of the WHO Expert Committee on Specifications for Pharmaceutical Preparations
and temporary advisers reported the following:
Dr E. Adams, Dr M. Brits, Mr D. Churchward, Dr T. Dekker, Dr A. Garcia Arieta, Dr J. Gordon,
Professor J. Hoogmartens, Professor Jin S., Dr O. Le Blaye, Dr J. Molzon, Dr A. Nicolas,
MsL. Paleshnuik, Dr J. Sabartova, Dr M. Da Luz Carvalho Soares and Mr S. Akbaralli
Veljee reported no conflict of interest.
Professor S. Bawazir reported that he is in the process of establishing a new consultancy.
Professor H.G. Kristensen reported that he has provided testimonies as an independent
expert in questions on validity and for infringement of patents at courts in Denmark,
Norway and Sweden. In all cases testimony related to drug formulations. No items
conflict with the subjects of the meeting.
Ms G.N. Mahlangu reported that she would receive an out-of-pocket allowance from her
current employer, the Medicines Control Authority of Zimbabwe, in accordance with
the travel allowances schedule for sponsored travel.
Dr J. Miller reported that he has acted as a consultant for national authorities.
Ms C. Munyiamba-Yeta reported that she was employed by the Zambian Regulatory
Authority for seven years until 2014. For the moment she works as an independent
consultant.
Mr J. Wilkinson reported that he was employed with the European Medical Devices
Industry Association until December 2012.
The interests summarized above do not give rise to a conflict of interest such that the
expert concerned should be partially or totally excluded from participation in the Expert
Committee on Specifications for Pharmaceutical Preparations. However, following WHOs
policy, they were disclosed within the Committee so that other members were aware
ofthem. All other members of the Expert Committee declared no relevant interests.
Many of the Expert Committee Members have extensive governmental

experience and expertise including consulting with WHO in the areas that are the
subject of the Expert Committee agenda, and which were considered very relevant and
important for the challenging tasks faced by the Committee. It was suggested that
the Secretariat should provide more detail on the type of conflict to be reported in the
declarations of interest for regulatory authorities. The Secretariat agreed to follow up
this suggestion with the WHO Office of the Legal Counsel.
xii
1. Introduction
The World Health Organization (WHO) Expert Committee on Specifications
for Pharmaceutical Preparations met in Geneva from 12 to 16 October 2015.
MrCornelius de Joncheere, Director of the Department of Essential Medicines
and Health Products (EMP) at WHO, welcomed participants on behalf of the
Director-General.
Mr de Joncheere welcomed the experts and advisers from all WHO
regions, as well as observers and representatives from international organizations.
He thanked them and their teams for their major contributions to the work of
WHO in setting standards in the area of pharmaceuticals. He mentioned that this
was the fiftieth anniversary of the Expert Committees meetings. The Committee
held its first meeting in 1947 under the name of Expert Committee on Unification
of Pharmacopoeias to continue the work of technical experts of the League of
Nations. The Committees scope of work was extended from the maintenance of
international pharmacopoeial standards to good manufacturing practices (GMP)
and subsequently to other topics. Today it covers all aspects of medicines quality,
with a strong focus on building quality assurance into the life cycle of products,
from development to the supply to patients. A press event titled Promoting
quality medicines and saving lives Commemorating the 50th anniversary of
WHO programme to improve medicines quality worldwide had been organized
for 15 October 2015.
WHOs standard-setting work today is more important than ever, and is
conducted under strengthened rules for selection of experts and for declarations
of interests. The Expert Committee system is the backbone of WHOs
normative function. The technical guidance is provided online and is widely
used. The website, with the 75 medicines quality assurance-related guidelines
adopted through the Committee and the online version of The International
Pharmacopoeia, is at the top of the Organizations list for web queries.1
The Expert Committee has strong links with other WHO groups such as
the Expert Committee on Biological Standardization (ECBS), the International
Nonproprietary Names (INN) expert consultation, which met concurrently
with this Committee, and the Expert Committee on the Selection and Use of
Expert Medicines. Strong links also exist with global groups such as the world
pharmacopoeias.
Health systems were a focus of the 2015 World Health Assembly.
Besides the extensive work done to sustain the emergency response to the Ebola
outbreak and to step up preparedness for future public health emergencies, other
achievements included the adoption of a global action plan to combat antibiotic
http://www.who.int/medicines/areas/quality_safety/quality_assurance/en/.
1
1
resistance, and the adoption of the Global Vaccine Action Plan. In the area of
medicines, innovative ways of developing new medicines are an important
topic, as is the work of the mechanism to combat substandard/spurious/falsely-
labelled/falsified/counterfeit (SSFFC) products. Health has also been recognized
as a central topic for global development in the Sustainable Development Goals
(SDGs) launched in September 2015. The health-related goal SDG 3, Ensure
healthy lives and promote well-being for all at all ages includes targets for
improving access to good quality, affordable medicines and promoting research
for needed medicines.
The Committee elected Ms G.N. Mahlangu as Chairperson, Professor J.
Hoogmartens as Co-chairperson, and Professor S.A. Bawazir and Dr J. Sabartova
as Rapporteurs. Ms Mahlangu then took the chair. Declarations of interest as
shown on page 10 of this report were presented to the meeting participants in
accordance with strengthened WHO rules for Expert Committees.
Open session
The Chairperson welcomed the members, technical advisers and observers to
the open session of the Expert Committee. The open session had been arranged
in response to earlier expressions of interest by the diplomatic missions. It was
noted that there were no representatives from the missions.
The Secretary of the Expert Committee described the Committees role
in fulfilling WHOs normative mandate, and explained how WHOs Expert
Committee system works. In its normative work the Committee sets rules for
medicines quality assurance, and acts in response to global health emergencies
and the needs of international organizations. An Expert Committee is the highest
advisory body to the Director-General and is established in the constitution of
the Organization. A set of strengthened rules and procedures, including new
procedures for declaration of interests, govern invitations to and participation
in an Expert Committee. The WHO Expert Committee on Specifications for
Pharmaceutical Preparations maintains The International Pharmacopoeia and

provides guidance on all topics relating to medicines quality assurance. The
guidelines are developed in consultation with a wide range of international
partners, including Collaborating Centres, international associations and
organizations. Participants were reminded that they were acting in their personal
capacity as experts.
The Secretary thanked all the partners for their major contributions to
WHOs standard-setting work.
2
2. General policy
2.1 Cross-cutting pharmaceutical quality assurance issues
Expert Committee on the Selection and Use of Essential Medicines
The Expert Committee on the Selection and Use of Essential Medicines selects
the medicines that satisfy the priority health-care needs of the population, taking
into account disease prevalence, efficacy and safety, and comparative cost-
effectiveness. However, the absolute cost of treatment will not constitute a reason
to exclude a medicine that is shown to otherwise meet the established selection
criteria. The WHO Model Lists of Essential Medicines (EML) for adults and for
children are updated every two years.
The current EMLs include 416 medicines for adults and 289 medicines
for children. Important additions in 2015 include 16 new medicines for
treatment of cancer, four single-ingredient antivirals and two combination
antivirals to treat hepatitis C, as well as four medicines to treat multidrug-
resistant tuberculosis and one medicine to treat latent tuberculosis infection.
Other additions included new contraceptive formulations, medicines affecting
coagulation, medicines for hepatitis B, and some new formulations of existing
medicines. Notably, it was decided not to recommend inclusion on the EML
of ranibizumab for neovascular eye diseases, novel oral anticoagulants and
socalled polypill therapy for cardiovascular disease.
The EML includes a number of biological medicines, and a process for
adding biosimilars will need to be defined in the future. All applications and
recommendations of this Expert Committee are published on the WHO website.
The Committee noted the report.
Regulatory support
An update was provided about WHOs regulatory support activities conducted
on the basis of the Organizations normative guidance. WHO is one of the
largest global providers of regulatory training, covering all aspects of regulation,
including inspections, assessment of product data and post-marketing control of
medicines. The wide implementation of a common basis of norms and standards
has facilitated the creation of a number of successful harmonization initiatives
and cooperative networks, such as the East African Community harmonization
project and similar initiatives in the Southern African Development Community
region and elsewhere. Joint assessment and inspection activities are also
increasing. These developments are further supported by good practices (GXP)
documents for regulatory authorities that are being developed through the
Committee, such as the good review practice document developed under the
leadership of the Asia-Pacific Economic Cooperation Regulatory Harmonization
3
Steering Committee and adopted by the Committee in 2014. A further

overarching framework guidance document on good regulatory practices is
being developed to promote regulatory consistency and collaboration.
Expert Committee on Biological Standardization (ECBS)

The ECBS met concurrently with the Expert Committee on Specifications for
Pharmaceutical Preparations. Directions in biological standardization have been
driven by three strategic aims that have shaped WHOs work in the past year,
namely to:
1) ensure preparedness for public health emergencies;
2) step up access to biotherapeutic products; and
3) strengthen global regulatory systems.
With regard to public health emergencies, lessons learnt during the
Ebola outbreak have led to thought being given to the development of rapid
regulatory pathways to make needed products available to affected populations.
WHO has played a critical role in accelerating clinical trials for candidate
products in Ebola-affected countries. With unprecedented support from the
global regulatory community, efficacy data for vaccines, diagnostic products and
potential treatments were generated in record time. Based on the lessons learnt
during the Ebola outbreak a blueprint has been prepared for a new research
and development (R&D) framework, with appropriate prioritization of suitable
candidate products, enabling a swift and concerted global response in case of
future emergencies. The development of a road map on R & D for Middle East
respiratory syndrome (MERS) coronavirus will serve as a pilot. The blueprint
was intended to be presented to the World Health Assembly (WHA) in 2016.
2.2 International collaboration

United Nations Childrens Fund (UNICEF)
UNICEF was established in 1946 to promote and protect childrens rights.
Health and nutrition and the fight against HIV/AIDS are among UNICEFs
core commitments. The Supply Division in Copenhagen, Denmark, ensures
that high-quality, good value medicines and other supplies reach children
and their families quickly. In 2014, UNICEF supplied goods with a total
value of US$ 3.38 billion, including US$ 1.48 billion worth of vaccines and
US$251million worth of pharmaceuticals. A web-based catalogue of products
procured, including a wide range of medicines for all major health needs, is
publicly available on the Internet.
4
General policy
UNICEF applies the WHO model quality assurance system for

procurement agencies (MQAS) in inspections, assessment of product data
and monitoring of supplier performance. The Committee was provided with
a description of UNICEFs systems for qualifying products and suppliers,
which is based on product assessment and inspections. Products are assessed
using a product questionnaire as published in the MQAS guidance. Vaccines,
antiretrovirals, antimalarials and medicines for treatment of tuberculosis must
be WHO-prequalified, with measures in place to verify that the goods supplied
do in fact meet prequalification standards. UNICEF inspects manufacturers
to verify compliance with WHO GMP guidelines and participates in joint
inspections with the WHO prequalification team (WHO/PQT) and other
organizations. Since 2006 UNICEF has been a partner of the Pharmaceutical
Inspection Co-operation Scheme (PIC/S).
Priority areas of UNICEFs work in 2015 included performance
management to ensure timely delivery, measures to support sourcing and
regulation in recipient countries, long-term arrangements with suppliers,
participation in meetings on essential medicines and relevant WHO disease
programmes, targeted activities to ensure the availability and quality of
specific products or product groups for use in WHO Member States, and the
implementation of the outputs of the Expert Committee on Specifications for
Pharmaceutical Preparations. The Committee noted the report.
Pharmacopoeial Discussion Group (PDG)

The PDG consisting of the European Pharmacopoeia, the United States
Pharmacopeia (USP) and the Japanese Pharmacopoeia (JP) met in Tokyo, Japan,
from 30 June to 1 July 2015. It was reported that 29 of the 36 general chapters
and 48 of the 62 excipient monographs on the current work programme had
been harmonized and that in-depth discussions on a number of additional items
currently on the PDG work programme had taken place. Significant progress had
been made, for example, with the harmonization of chromatographic methods
for certain products. Chapters on colour, conductivity and protein determination
had reached PDG Stage 4 (public consultation phase); a chapter on uniformity
of delivered dose was being harmonized between the European Pharmacopoeia
and the Japanese Pharmacopoeia. Methods for biotechnology products were also
being harmonized. Stage 4 documents are posted on the websites of all three
participating pharmacopoeias. WHO is an observer to PDG.
To provide increased transparency on its activities, PDG will offer an easy
way to access information on its work programme to its sister pharmacopoeias,
including the possibility to provide comments on draft texts during the
consultation period. Information with respect to increasing transparency was
shared at the sixth WHO international meeting of world pharmacopoeias.
5
Model regulatory framework for medical devices

Over the past 20 years, medical devices have become an extremely diverse and
complex product group, with a significant manufacturer base and large global
sales. Resolution WHA 67.20 urges Member States to strengthen national
regulatory systems for medical products, including medical devices. A survey
on the current status of regulatory systems in Member States has shown that
regulatory systems for medical devices are nonexistent in almost half of the
countries and very limited in many others.
Medical devices differ in several important ways from pharmaceuticals,
although they are often regulated by the same national authorities. Opportunities
exist for collaboration between regulatory authorities. There is currently limited
WHO guidance available for medical devices, aside from that originating
from the WHO/PQT for in vitro diagnostics (IVDs). To support Member
States in establishing systems to regulate medical devices, WHO has initiated
the development of a model regulatory framework for use by national
regulatoryauthorities.
It has been proposed that the Expert Committee on Specifications for
Pharmaceutical Preparations oversees the development of a model regulatory
framework for medical devices. The Expert Committee noted that it does not
currently have sufficient expertise and resources to perform this additional
work. It was therefore suggested that a subgroup of suitably qualified experts
should be created. The Secretariat will follow up accordingly and seek to identify
the required expertise from the existing WHO Expert Advisory Panels.
6
3. Quality control specifications and tests
3.1 The International Pharmacopoeia
3.1.1 Updates
Fifth edition of The International Pharmacopoeia
The fifth edition of The International Pharmacopoeia was published on the WHO
website in August 2015 and has been made available on CD. The new edition
includes 32 new or revised monographs on pharmaceutical substances and dosage
forms as listed in the preface. Other updates include two texts reproduced with
the permission of the European Pharmacopoeia. A function has been added to
the electronic interface enabling users to generate PDF documents for saving or
printing. The Secretariat expressed its sincere thanks to all who had contributed
to this fifth edition.
The Committee noted the report and congratulated the Secretariat on
this achievement.
Trade names of stationary phases

The Secretariat has started publishing trade names of stationary phases
found suitable during monograph elaboration, for the information of users
of the monographs. The list is available on the WHO website 2 and will be
updated continuously in accordance with new monographs included in The
International Pharmacopoeia. It was agreed that a cross-reference to the list
would be provided in The International Pharmacopoeia to direct users to this
useful additional information.
3.1.2 Workplan 20152016

Priorities for new monographs
The International Pharmacopoeia specifies primarily the quality of essential
medicines that are included on the WHO EML, on the invitations for expressions
of interest for WHO prequalification, or in other United Nations (UN) and/or
WHO documents recommending the use of medicines for treatment of specific
diseases and/or for use by treatment programmes.
The Committee heard a description of the process used to establish
a workplan for elaboration of monographs, which, while acknowledging
limited resources, aimed to meet the expectations of the Member States, WHO
http://www.who.int/entity/medicines/publications/pharmacopoeia/2015-08-26trade-names_
2
stationary_phases-QAS15-640_04092015N.pdf?ua=1.
7
programmes and other partners. For future monograph elaboration, priority

has been assigned to medicines belonging to the categories covered by the
WHO/PQT and to medicines considered as life-saving commodities for women
and children as identified by the UN Commission on Life-Saving Commodities
for Women and Children (UNCoLSC) and for which public standards are not
yet available. General texts will be developed as the need arises in connection
with the prioritized monographs.
The Secretariat will follow up on an earlier collaboration between WHO/
PQT and the Chinese Pharmacopoeia under the Global Fund project, during
which some 50 monographs were developed, with a view to making these
available to WHO for possible inclusion in The International Pharmacopoeia.
Monographs proposed for elaboration or suppression

In line with the above-mentioned priorities, a list of 31 high priority monographs
for finished pharmaceutical products (FPPs) was proposed for elaboration
(Table 1). Additional monographs for the corresponding active pharmaceutical
ingredient (API) will be required. Ten monographs were identified for
suppression (Table 2) following their deletion from the WHO EML. As the
medicines concerned may still be part of national lists of essential medicines,
it was agreed that suppressed monographs should be transferred to a publicly
accessible Archived section of The International Pharmacopoeia.
Table 1
Dosage form monographs proposed for elaboration with high priority
abacavir, efavirenz and lamivudine tablets

abacavir, lamivudine and nevirapine dispersible tablets
artemether and lumefantrine dispersible tablets
artenimol and piperaquine phosphate dispersible tablets

artesunate and amodiaquine tablets
artesunate and mefloquine tablets
artesunate and pyronaridine tablets
artesunate rectal capsules
atazanavir and ritonavir tablets
dolutegravir tablets
efavirenz, lamivudine and tenofovir tablets
entecavir oral solution
entecavir scored tablets
estradiol valerate and norethisterone enantate injection
8
Quality control specifications and tests
Table 1 continued
etravirine tablets
flucytosine slow release tablets
lamivudine and tenofovir tablets
linezolid oral suspension
moxifloxacin tablets
norethisterone enantate injection
p-aminosalicylic acid granules for oral solution
protionamide tablets
pyrazinamide dispersible tablets
raltegravir tablets
ribavirin syrup
ritonavir oral solution
simeprevir capsule
sofosbuvir tablet
terizidone capsules
terizidone tablets
zanamivir powder for inhalation
Table 2
Monographs proposed for suppression
ampicillin capsules
colchicine tablets
ergometrine hydrogen maleate tablets
indometacin tablets
pethidine hydrochloride tablets
piperazine adipate tablets
piperazine citrate tablets
prednisolone sodium phosphate injection
prednisolone sodium succinate powder for injections
probenecid tablets
The Committee endorsed the workplan as presented.
9
3.2 Specifications for medicines, including childrens

medicines and radiopharmaceuticals
3.2.1 Maternal, newborn, child and adolescent health medicines
Chlorhexidine digluconate solution and chlorhexidine
digluconate topical solution/gel
The Committee was informed that work is ongoing to elaborate monographs
for chlorhexidine digluconate solution and topical solution/gel for umbilical
cord care. These medicines are listed in the 2010 report of the UNCoLSC as
an important, low-cost intervention to reduce newborn mortality; the 7.1%
chlorhexidine gluconate-containing solution or gel was added to the WHO EML
for children in 2013. The Committee will be updated on the progress of the two
monographs.
Estradiol cypionate
In accordance with the agreed workplan for The International Pharmacopoeia
it was proposed to include a monograph on estradiol cypionate. A draft was
received from a WHO Collaborating Centre in February 2015. The draft
was discussed at the consultation on screening technology, sampling and
specifications for medicines in April 2015 and circulated for comment in May
2015. Comments received were incorporated and the revised draft monograph
was presented to the Committee.
The Committee adopted the monograph subject to the amendments
agreed.
Levonorgestrel
Revision of the monograph on levonorgestrel in The International Pharmacopoeia
was proposed in January 2015. A revised draft was discussed at the consultation
on screening technology, sampling and specifications for medicines in April 2015

and sent out for public consultation in May 2015; comments were particularly
sought on whether the monograph should include a limit test for dextronorgestrel.
The revised monograph was presented to the Committee for discussion.
The monograph was adopted subject to the amendments agreed.
The Committee also authorized the intended use of the reference substances
Levonorgestrel for system suitability 1 CRS and Levonorgestrel for system
suitability 2 CRS issued by the European Pharmacopoeia (see also 4.2.1).
Magnesium sulfate and magnesium sulfate injection

The Committee was informed that the suitability of the monographs on
magnesium sulfate and magnesium sulfate injection had been re-evaluated by a
10
WHO Collaborating Centre, leading to the conclusion that the monographs are
up to date and do not need revision.
The Committee endorsed this conclusion.
Misoprostol, misoprostol dispersion and misoprostol tablets

Access to monographs on misoprostol, misoprostol dispersion and misoprostol
tablets is important for WHO Member States; misoprostol tablets have been
identified as a life-saving product by the UNCoLSC. The first draft monograph
on misoprostol was received from a WHO Collaborating Centre in 2014
and a preliminary version was presented to the Committee at its forty-ninth
meeting. The draft was circulated for public consultation in January 2015, and
was discussed and further revised at the informal consultation on screening
technology, sampling and specifications for medicines in April 2015. At the
same time, draft monographs for misoprostol tablets and dispersion were
developed. All three drafts were presented to the Expert Committee at its fiftieth
meeting, noting that it was proposed to send out all three texts again for public
consultation after the Expert Committee meeting and to review the comments
received with a subgroup of experts.
The Committee adopted the three monographs subject to amendments
as agreed at the meeting and subject to the outcome of a further round of public
consultation and subsequent review by a subgroup of experts as proposed. This
will enable the Secretariat to publish the monographs in the next edition of
TheInternational Pharmacopoeia.
It was agreed that the monograph for misoprostol dispersion should be
published in the section on monographs for pharmaceutical substances.
Norethisterone and norethisterone tablets

At the forty-ninth Expert Committee meeting in 2014 it was proposed to revise
the monograph on norethisterone and to include a monograph on norethisterone
tablets in The International Pharmacopoeia. Drafts were developed between
October 2014 and June 2015 and were sent out for public consultation in
July 2015. The drafts were revised according to comments received, and were
presented to the Expert Committee.
The Committee accepted the two monographs and authorized the
proposed intended use of the reference substance Norethisterone for system
suitability issued by the European Pharmacopoeia (see also 4.2.1).
3.2.2 Antimalarial medicines

Artemether injection
The Committee was consulted regarding a proposed change that would widen
the assay limits in the monograph on artemether injection in order to align
11
them with limits specified in similar monographs. The Committee was further
informed of a proposal received from a manufacturer for improvement of the
related substances test. A WHO Collaborating Centre kindly agreed to perform
further investigations in this regard, and the Committee will be informed of
theresults.
The Committee supported the proposed widening of the assay limits and
endorsed their inclusion in the next edition of The International Pharmacopoeia.
3.2.3 Antituberculosis medicines

Cycloserine and cycloserine capsules
Following up on information received from a manufacturer it was proposed
to revise the monographs on cycloserine and cycloserine capsules. Extensive
additional tests were performed by a collaborating laboratory to evaluate the
proposed changes. Revised drafts of the two monographs were received from
the collaborating laboratory in July 2015 and circulated for public comment
in August 2015. The revised monographs were presented to the Committee
fordiscussion.
The Expert Committee adopted the monographs subject to the
amendments agreed.
3.2.4 Medicines for tropical diseases

Mebendazole and mebendazole chewable tablets
The Committee was informed of a number of planned revisions to the
monographs on mebendazole and mebendazole chewable tables. The Committee
will be informed of progress.
The experts took note of this information.
3.2.5 Medicines for chronic diseases and for mental health

Carbamazepine, carbamazepine tablets, carbamazepine

chewable tablets and carbamazepine oral suspension
Draft monographs on carbamazepine and related dosage forms were provided by
a WHO Collaborating Centre in December 2014. The drafts were discussed at an
informal consultation on screening technology, sampling and specifications for
medicines held in April 2015. The text was published for comment in July 2015;
comments were sought in particular as to whether the impurities listed under
the section Impurities are degradation products or synthesis impurities.
The draft monograph on carbamazepine and the related dosage form
monographs were presented to the Expert Committee. However, in light of
new information about the nature of potential impurities, the Secretariat of The
International Pharmacopoeia proposed to redesign the impurity specifications
12
and to circulate the monographs again for public consultation after the meeting,
with a subsequent review of comments by a subgroup of experts in early 2016.
The Committee adopted the monographs, subject to the amendments
agreed and subject to a further round of consultation and revision as proposed.
3.2.6 Other anti-infective medicines

Clindamycin hydrochloride and clindamycin hydrochloride capsules
Initial draft monographs on clindamycin hydrochloride and clindamycin
hydrochloride capsules were received from the responsible WHO Collaborating
Centre in December 2014. The drafts were circulated for public comment in
January 2015 and discussed at the informal consultation on screening technology,
sampling and specifications for medicines in April 2015 before being presented
to theCommittee.
The Committee adopted the monographs subject to the amendments
agreed.
Flucytosine and flucytosine intravenous infusion

Draft monographs on flucytosine and flucytosine intravenous infusion were
circulated for comment in December 2014. The comments received were
discussed at the consultation on screening technology, sampling and
specifications for medicines in April 2015. The revised drafts were presented to
the Committee.
The Committee adopted the proposed monographs.
3.2.7 Other medicines

Dextromethorphan hydrobromide and dextromethorphan oral solution
At the forty-ninth meeting of the Expert Committee it had been decided to
revise the monograph on dextromethorphan hydrobromide in response to
serious incidents that occurred after the consumption of dextromethorphan
cough syrups contaminated with levomethorphan. As a result of these events, the
Committee adopted a revised monograph on dextromethorphan hydrobromide,
which included a statement that the substance must comply with a limit of not
more than 0.1% levomethorphan hydrobromide using a suitable chiral method.
A suitable test for levomethorphan had been elaborated and was included
in the draft revised monograph on dextromethorphan hydrobromide. The draft
was sent out for public consultation in January 2015 and was revised further
at an informal consultation in April 2015. At the same time, a monograph on
dextromethorphan oral solution was developed, and was sent out for public
consultation in August 2015.
The limit test for levomethorphan is not part of the routine release
testing of the dosage form, and was therefore not included in the monograph
13
itself. Instead, the monograph includes a statement that samples, if tested, must
comply with a levomethorphan limit of not more than 0.1%, and provides a
reference to the levomethorphan limit test to be published in the Supplementary
information section of The International Pharmacopoeia (see below).
The Committee adopted both monographs subject to the amendments
agreed.
Levomethorphan limit test for dextromethorphan-containing finished products

An additional limit test for levomethorphan in dextromethorphan-containing
dosage forms is to be included in the Supplementary information section of
The International Pharmacopoeia, enabling quality control laboratories to
test suspicious finished product samples for levomethorphan. In 2014 the
Expert Committee members reviewed a laboratory report describing the
elaboration of suitable procedures. A reference substance containing a mixture
of levomethorphan and dextromethorphan is still under establishment. The
proposed test was further discussed at an informal consultation in April 2015
and was confirmed by a national quality control laboratory before the proposed
text was sent out for comment in August 2015. No comments had been received
by 25September2015.
The Committee adopted the proposed text.
3.2.8 Radiopharmaceuticals3
Review and update of radiopharmaceutical monographs by the International
Atomic Energy Agency (IAEA) had been undertaken according to the update
and submission process adopted by the Committee at its 2013 meeting.
A coordination meeting was held at IAEA in 2014. In early 2015, the work
priorities and time lines were aligned with the available expert time and
resources. The final schedule for the updating of monographs was expected to
be completed in October 2015.

A status update was provided on progress made in updating
radiopharmaceutical monographs and associated documentation in The
International Pharmacopoeia. A number of monographs had been submitted
and circulated for comment in accordance with the Committees consultation
process, namely those for technetium (99m Tc) exametazime, thallous (201Tl)
chloride and sodium iodine (131I) solution, as well as a general monograph on
radiopharmaceuticals. The following monographs had been reviewed by the
experts and were ready for submission to WHO for consultation: technetium
The representative from the IAEA was unable to attend the meeting; the WHO Secretariat presented a
3
written report received from IAEA to the Committee.

14
(99m Tc) bicitate, technetium ( 99m Tc) succimer, technetium ( 99m Tc) sulfur colloid
and technetium ( 99m Tc) mebrofenin. The following monographs were ready for
final verification by designated experts and expected to be completed in January
2016: technetium (99m Tc) sestamibi, technetium ( 99m Tc) tin colloid, technetium
( 99m Tc) pertechnate, technetium ( 99m Tc) pyrophosphate, technetium ( 99m Tc)
pentetate, technetium (99m Tc) tetrafosmin, technetium (99m Tc) medronate and
technetium (99m Tc) mertiatide.
Based on the outcome of the recent IAEA Coordinated Research
Project (CRP), the IAEA planned to arrange a review, with help from the CRP
participants, of the monograph on cyclotron-produced 99m Tc. Furthermore, a
new monograph on extemporaneous preparation of radiopharmaceuticals
would be drafted by the experts.
The Expert Committee noted the report.
3.3 General policy

Microbiological assay of antibiotics
There are currently five International Chemical Reference Substances (ICRS)
which were established as secondary reference standards for tests according
to Chapter 3.1, Microbiological assay of antibiotics, in The International
Pharmacopoeia. To ensure the continuous fitness for purpose of these reference
substances, their assigned potencies have to be monitored regularly in extensive,
resource-consuming collaborative trials. In addition, a total of 21 monographs
prescribe a microbiological assay for antibiotics, but no suitable reference
substance has yet been established.
At its meeting in 2009 the Expert Committee had decided that in
monographs for antibiotics which specify a microbiological assay, this test should
be replaced by a chromatographic method where possible and appropriate.
Since 2009, significant progress has been achieved in developing
physicochemical assay methods for pharmaceutical products. In view of the
information provided above, the Secretariat of The International Pharmacopoeia
proposed to:
(1) discontinue the use of five ICRS in microbiological assays of
antibiotics and to delete the potency assignments in the ICRS
leaflets;
(2) revise four monographs in order to replace the microbiological
assay with liquid chromatography methods, considering methods
already published in pharmacopoeias;
(3) revise four monographs in order to replace the ICRS by WHO
International Standards for Antibiotics (ISA) or, preferably,
15
secondary standards derived from them and established by another

pharmacopoeia for use in microbiological assay, which could foster
work-sharing between pharmacopoeias;
(4) develop a concept document for the possible transition from
microbiological to physicochemical assay in 14 monographs,
considering in particular chromatographic methods published in
the scientific domain, for discussion and possible endorsement
by this Committee and the Expert Committee on Biological
Standardization; and
(5) suppress the monographs for substances containing any of five
active ingredients. Medicines containing these substances are no
longer included in the WHO EML (19th edition) or in the relevant
invitations for expression of interest to manufacturers.
The Committee agreed to the proposals described under points (1), (2),
(4) and (5) above (see Table 3). With regard to the proposal outlined in point (3),
the Committee agreed that the experts should be given more time to identify
possible reference standards that can be referred to in each of the monographs.
The relevant ICRS and monographs affected by these decisions are listed in
Table3.
Table 3
Recommendations relating to the use of microbiological assays for antibiotics
(1) ICRS no longer to be used for microbiological assays of antibiotics, and potency
assignments to be deleted
nystatin (ICRS0369)
framycetin sulfate (neomycin B) (ICRS0355)
gentamicin sulfate (ICRS0319)

spectinomycin hydrochloride (ICRS0415)
streptomycin sulfate (ICRS0416)
(2) Monographs in which microbiological assay should be replaced by liquid
chromatography methods
erythromycin ethylsuccinate
erythromycin lactobionate
erythromycin stearate
tetracycline hydrochloride
16
Table 3 continued
(3) Monographs for which suitable standards other than ICRS should be identified a
amphotericin B
amphotericin B for injection
bleomycin sulfate
kanamycin for injection
kanamycin monosulfate
(4) Monographs for which a concept paper should be developed on the possible
transition from microbiological to physicochemical methods
amphotericin B kanamycin acid sulfate gentamicin sulfate
amphotericin B for kanamycin for injection streptomycin sulfate
injection kanamycin monosulfate streptomycin for injection
bleomycin sulfate nystatin paromomycin sulfate
erythromycin nystatin tablets
ethylsuccinate tablets
erythromycin stearate
tablets
(5) Monographs that should be suppressed
bacitracin chlortetracycline oxytetracycline
bacitracin zinc hydrochloride dehydrate
bleomycin erythromycin (base) oxytetracycline
hydrochloride neomycin sulfate hydrochloride
a
The Committee agreed that the experts should be given more time to identify possible reference standards
that can be referred to in the monographs.
Replacement of mercuric acetate

The Secretariat of The International Pharmacopoeia is committed to eliminating
the use of mercury salts in currently recommended methods in order to
reduce the risk to analysts and the environment. In the past, mercuric acetate
was used to titrate weak bases; however, such titrations are now obsolete
and can be replaced with safer and better titration techniques, such as the
direct titration with perchloric acid in anhydrous acetic acid. As a first step
in phasing out mercury-based methods, a WHO Collaborating Centre has
identified 47 monographs in which mercuric acetate is used as a reagent and
has listed alternative methods used in other pharmacopoeias. As a possible
next step, the Secretariat proposed that a concept should be developed to guide
the replacement of obsolete titrations of pharmaceutical substances in The
International Pharmacopoeia and the elaboration of the related assays.
The Committee took note of the update.
17
Draft note for guidance on organic impurities in active pharmaceutical

ingredients and finished pharmaceutical products
Taking into account current practices in the use of The International
Pharmacopoeia and available guidance on how to establish limits for impurities,
anote for guidance on organic impurities in active pharmaceutical substances
and FPPs was drafted.
The proposed note for guidance is intended to replace the text on
Related substances in finished pharmaceutical product monographs in the
Supplementary information section of The International Pharmacopoeia. The
first draft was prepared by the Secretariat of The International Pharmacopoeia
in JanuaryMarch 2015 with input from a group of experts, and was discussed
at the consultation on screening technology, sampling and specifications for
medicines in April 2015. The draft was sent out for public consultation in April
2015, and the comments received were collated by the Secretariat. The revised
proposed draft was presented to the Committee.
The Committee reviewed the proposed revised draft and provided
further feedback. It was agreed to form a small working group to address a
number of specific comments raised in the discussion. The working group met
during the meeting and reported back to the Committee with a proposal for
further revisions. The Committee agreed that the revised document should be
discussed further within the small working group and with relevant experts. It
should then be discussed at an informal consultation before being sent out again
for public consultation, together with a brief explanatory note about the nature
of the revisions. The Committee will review a revised draft at its next meeting.
18
4. Quality control international referencematerials
(International Chemical Reference Substances
and Infrared Reference Spectra)
4.1 Update on International Chemical ReferenceSubstances
(ICRS), including report of the ICRS Board
International Chemical Reference Substances (ICRS) are used as primary
standards in physical and chemical tests that are described in The International
Pharmacopoeia, as well as for setting official secondary standards. ICRS are used
to identify and determine the purity or assay of pharmaceutical substances and
preparations or to verify the performance of test methods. The standards are
officially adopted by the Expert Committee.
The European Directorate for the Quality of Medicines & HealthCare
(EDQM) is the custodian centre in charge of establishment, storage, distribution
and monitoring of ICRS in The International Pharmacopoeia. Three steering
committee telephone conferences were held in 2014, and two in 2015. In
accordance with the work programme as agreed in March 2014, the ICRS listed
below were established and released by the ICRS Board.
Routine monitoring of fitness for purpose was done on 17 ICRS in
2014, and no negative findings were reported; for 2015, 13 substances had been
monitored with no negative findings. The EDQM welcomed the decisions to add
dates and version numbers to monographs in The International Pharmacopoeia,
as this facilitates quality assurance verification of ICRS batches in relation to
their intended International Pharmacopoeia use.
Work is in progress to establish reference substances for capreomycin
sulfate, enabling testing according to the recently adopted monographs on
capreomycin, and for dextromethorphan for system suitability, enabling the
performance of the limit test for levomethorphan adopted by the Committee
at this meeting.
The Secretariat expressed its sincere thanks to EDQM for establishing,
storing and distributing ICRS and providing related guidance, to the ICRS Board
for reviewing establishment reports and releasing ICRS, and to the laboratories
that participated in collaborative trials. The Expert Committee noted the report
and joined the Secretariat in thanking the custodian centre for this major
contribution. The Expert Committee noted the report and endorsed the release
of the ICRS shown in Table 4.
19
Table 4
ICRS released by the ICRS Board
-artemether ICRS 1
efavirenz ICRS 2
efavirenz impurity B ICRS 1
ritonavir ICRS 2
abacavir sulfate ICRS 2
paracetamol ICRS 3
artemether ICRS 2
rifampicin ICRS 3
stavudine impurity F ICRS 1
4.2 General policy

4.2.1 Chapter on reference substances and reference spectra
Following up on a recommendation made by the Expert Committee at its forty-
ninth meeting to use in The International Pharmacopoeia, where appropriate,
ultraviolet (UV) absorptivity values for assays and other quantification purposes
with a view to limiting reference to ICRS, it was proposed to revise the chapter
on reference substances and reference spectra.
Additional changes were proposed to reflect recent discussions within
the ICRS Board and with the custodian centre for ICRS. A draft revised chapter
was prepared by the Secretariat of The International Pharmacopoeia in January
March 2015 with feedback from a group of experts. The draft was discussed at the
consultation on screening technology, sampling and specifications for medicines
held from 13 to 15 April 2015 before being circulated for public consultation
in May 2015. Comments received were duly collated before presentation of the
draft to the Expert Committee at its meeting in October 2015.

Besides other changes, the revised chapter sets out the principles to be
applied when reference substances are included in monographs that have been
established by other pharmacopoeias for use according to The International
Pharmacopoeia. A list of reference standards found suitable for such a use
is included as an appendix to the draft revised chapter. The list includes the
reference substances mentioned in the monographs on norethisterone and
levonorgestrel (see 3.2.1). To facilitate continuous updating, the Committee
recommended that the list should be maintained as a living document on the
WHO website and referred to in the chapter on reference substances.
The Committee adopted the text subject to the amendments agreed.
20
5. Quality control national laboratories
5.1 External quality assurance assessment scheme
The external quality assurance assessment scheme (EQAAS) is a proficiency
testing scheme offered by WHO for the external evaluation of quality control
management systems in chemical quality control laboratories. Since 2010 it has
been organized with assistance from the EDQM.
The Committee was given an update on Phase 6 of the EQAAS studies.
Unlike in Phase 5 studies, the samples sent out were used for two studies, reducing
the burden of sending and receiving samples. Approximately 40 laboratories
participated in Phase 6 studies. Analysis of samples was ongoing, with results
expected at the end of 2015.
The Secretariat maintains close links with the WHO/PQT prequalifying
quality control laboratories when carrying out the EQAAS studies. Preparations
were beginning for Phase 7 of the EQAAS scheme.
5.2 Guidance on testing of suspect substandard/spurious/

falsely-labelled/falsified/counterfeit medicines
In October 2014, the Committee had provided advice and endorsed a draft
outline for Guidance on testing of suspect substandard/spurious/falsely-
labelled/falsified/counterfeit (SSFFC) medicines.
Various related texts were reviewed at the informal consultation on
screening technology, sampling and specifications for medicines held in April
2015, and work is in progress to draft concise guidelines on testing of suspect
SSFFC medicines. A first draft was produced after the consultation and circulated
for comment among the relevant experts.
The Committee noted the update and recommended that work on
developing the guidelines be continued.
21
6. Prequalification of quality control laboratories
6.1 Update on the prequalification of quality control laboratories
The prequalification procedure for quality control laboratories was established
in 2004. Participation is voluntary and is open to both public and private quality
control laboratories. In October 2015 there were a total of 38 WHO-prequalified
laboratories distributed among all six WHO regions. Two laboratories became
prequalified in 2015, one in Uganda and one in India.
A peer audit scheme has been introduced as a capacity-building measure
for laboratories involved in the prequalification procedure. Training has been
conducted under this scheme in Armenia, Ghana and Nigeria and a further
training programme is planned in Madagascar. Applications are currently also
being received from manufacturer-linked laboratories, and in any future revision
of the procedures consideration should be given to whether the prequalification
procedure should be applicable to this type of laboratory.
6.2 Update on WHO quality monitoring projects

A quality monitoring survey of antiretrovirals started in the third quarter of
2015 and is ongoing, with samples being collected in five countries. A survey
on antimalarials would start in the first quarter of 2016. It is planned that this
survey will include artemisinin combination therapies in the initial phase of
developing a spectral library for FPPs to support the use of screening methods
for the detection of potential SSFFC products.
The Expert Committee expressed its appreciation for the report.
22
7. Quality assurance collaboration initiatives
7.1 International meetings of world pharmacopoeias
In 2012, WHO brought together representatives from 23 national and regional
pharmacopoeia authorities at the first meeting of world pharmacopoeias. The
participants committed to working towards harmonization of pharmacopoeial
standards in the global context by developing a guidance text on good
pharmacopoeial practices (GPhP) aiming at convergence of approaches in
defining pharmacopoeial standards (see7.2). Harmonization of standards
has become increasingly important for public health for several reasons. It
will support the global fight against falsified and substandard medicines and
will reduce the costs arising from meeting the different standards used in the
production and testing of medicines, thus making good quality medicines
accessible to more people.
The international meeting of world pharmacopoeias has become
a recurring event which is co-hosted by WHO and a pharmacopoeia.
Two meetings were held in 2015: the fifth International Meeting of World
Pharmacopoeias cohosted by the United States Pharmacopeia (USP) and
WHO from 20 to 22April 2015 in Rockville, USA, and the sixth International
Meeting of World Pharmacopoeias co-hosted by the Chinese Pharmacopoeia
(ChP) and WHO in Suzhou, China on 2122 September 2015. Achieving global
standards to expand access to medicines globally was key to the discussions
at the September meeting, which was held in connection with the 2015 ChP
Annual Scientific Symposium.
Representatives from 12 WHO Member States pharmacopoeias attended,
and more than 30 official pharmacopoeial authorities were represented. During
this sixth international meeting the new guidelines on GPhP were prepared for
finalization, based on feedback received during wide global consultation (see7.2).
The representative of the Japanese Pharmacopoeia (JP) announced that
the seventh WHO International Pharmacopoeia meeting would be co-hosted
by the JP and WHO, and would be held in Tokyo from 13 to 15 September 2016
inconjunction with the 130th anniversary of the JP.
The Expert Committee noted the report and thanked the pharmacopoeias
and the Secretariat for their major contributions to this achievement.
7.2 Good pharmacopoeial practices

The primary objective of the GPhP is to define approaches and policies on
establishing pharmacopoeial standards with the ultimate goal of harmonization.
The GPhP describe a set of guiding principles for national pharmacopoeial
authorities and regional pharmacopoeial authorities, which facilitates the
appropriate design, development and maintenance of pharmacopoeial standards.
23
A GPhP text has been drafted over the past three years at successive
meetings of world pharmacopoeias (see 7.1). In view of the length of the third
draft it was decided in 2014 to split it into a main text and a detailed technical
annex to be developed by a separate drafting group. A technical annex was
drafted on the basis of parts of the previous GPhP text with input from the JP, the
European Pharmacopoeia and other pharmacopoeias. The significantly shortened
fourth draft of the main text was then circulated for comments in September
2014, and was discussed at the fourth meeting of world pharmacopoeias held in
Strasbourg, France, in October 2014. It was subject to further consultation with
world pharmacopoeias from October 2014 to March 2015 and was discussed at
the fifth international meeting of world pharmacopoeias, held in Washington,
DC, USA in April 2015. Feedback received on the draft text at that meeting was
discussed from 20 to 22 April 2015, leading to preparation of a fifth draft, which
was circulated for further consultation among world pharmacopoeias. Comments
were received from 15 parties, including five international associations, and were
discussed at the sixth international meeting of world pharmacopoeias held in
China in September 2015, leading to a sixth draft, which was subjected to the
usual public consultation process.
At its forty-ninth meeting, the Expert Committee had been briefed on
progress made on developing a GPhP text and had endorsed a concept paper
onthe purpose and benefits of GPhP. The final revised draft of the main guidance
text and comments received during the public consultation process were
presented to the Expert Committee at its fiftieth meeting.
The Committee provided its feedback in response to the comments
received. The Committee adopted the guidance (Annex1) with agreed
amendments reflecting the comments received, subject to final concurrence
being granted by the pharmacopoeias. Work will continue on drafting possible
additional chapters and to develop the technical annex further, taking into
account its complexity and the resources available. The Committee congratulated
the Secretariat on facilitating the development of this document, which is a major

step forward towards prospective harmonization of pharmacopoeial practices.
7.3 FIPWHO technical guidelines: points to consider in the

preparations that are not available as authorized products
The draft of a guidance document on extemporaneous preparation of medicines
for children, which had been commissioned by WHO, was considered in 2011 by
the WHO Expert Committee on the Selection and Use of Essential Medicines,
which has a subcommittee on paediatric medicines. The Committee felt that
extemporaneous preparation of medicines for children may be necessary in
some situations but was concerned about the risks of inappropriate preparations.
24
Quality assurance collaboration initiatives
Revisions of the document were submitted to the forty-sixth, forty-seventh,

forty-eighth and forty-ninth meetings of the Expert Committee on Specifications
for Pharmaceutical Preparations.
The draft was brought into balance with the contents of the WHO
document Development of paediatric medicines: points to consider in formulation
and includes parts from earlier drafts, e.g. the draft appendix on potential
problemsin compounding, a section on aspects of GMP and a glossary intended
to facilitate a common interpretation of the guidance by a wide audience of
practitioners. At its 2014 meeting the Expert Committee reviewed the draft
and the comments received, and decided that a further meeting should be held
between WHO, the International Pharmaceutical Federation (FIP) and other
interested parties in order to discuss the text. The draft was then discussed
at the informal consultation on paediatric formulations for medicines from
13to 14 May 2015, and a revised draft was sent out for comment in June 2015.
Feedback was received and collated and the draft was further revised in line
with comments received. The proposed revised draft was presented to the
Committee at its fiftieth meeting in October 2015, with a note that some points
raised in the comments would require expert advice beyond the scope of advice
from the Committee.
The Committee discussed the proposed draft and the comments, and
adopted the guidance with amendments as agreed (Annex2), subject to a
future revision of remaining points with input from suitably qualified experts.
The Committee thanked the main author and the experts who contributed to
this very useful and relevant guidance. FIP expressed its appreciation to WHO
for facilitating the preparation and adoption of this guidance through the
ExpertCommittee.
25
8. Quality assurance good manufacturing practices
8.1 Update of WHO good manufacturing
practices for biologicals
The guidance on Good manufacturing practices (GMP) for biological products
was first adopted by the Expert Committee on Biological Standardization
(ECBS) as an annex to the GMP for pharmaceutical products, and was
published in the WHO Technical Report Series in 1992. The guidance is widely
used by regulators and is mandatory for prequalification of vaccines. To reflect
the considerable developments since the adoption of the guidelines as well as
current perspectives regarding GMP for manufacturers of biological products,
a preliminary draft revision was prepared in 2008. A revised draft was prepared
by a drafting group and was discussed at a consultation on GMP for biological
products held in July 2014. The text was circulated for public consultation in
2015 before being presented to the ECBS at its October 2015 meeting, held
concurrently with the meeting of the Expert Committee on Specifications for
Pharmaceutical Preparations.
The proposed guidelines are intended to be an annex to WHO Good
manufacturing practices for pharmaceutical products: main principles (WHO
Technical Report Series, No.986, 2014, Annex2), and should be read in
conjunction with other specific WHO guidelines and recommendations for
specific classes of biological products (e.g. vaccines). An outline of the proposed
revised guidelines and key changes and updates was presented to the Committee.
The draft was also presented to the ECBS during its meeting.
The Expert Committee noted the report, and adopted the guidance text
(Annex 3) following its adoption by the ECBS.
8.2 Update of questions and answers for WHO good

manufacturing practices for active pharmaceutical ingredients
The WHO good manufacturing practices for active pharmaceutical ingredients

(WHO Technical Report Series, No.957, 2010, Annex2), adopted by the
Expert Committee in 2010, are in line with the International Conference on
Harmonisation of Technical Requirements for Registration of Pharmaceuticals
for Human Use (ICH) text adopted by numerous national and regional
authorities. An Appendix 2 to this GMP text approved at the time was intended
to eliminate ambiguities and uncertainties and help harmonize the inspections
of both small molecules and biotech APIs.
To clarify technical issues and harmonize expectations during
inspections, the Pharmaceutical Inspection Co-operation Scheme (PIC/S)
through its Expert Circle on APIs and later the ICH, set up working groups to
develop questions and answers (Q&As) on the API GMP guidance. WHO has
26
Quality assurance good manufacturing practices
been involved both as an observer and through technical advice in the PIC/S
as well as the ICH-related working groups. The ICH Q&As were adopted on
10 June 2015.4 During the consultation on data management, bioequivalence,
GMP and medicines inspection, held from 29 June to 1 July 2015, a draft
working document titled WHO good manufacturing practice guide for active
pharmaceutical ingredients (working document QAS/15.626) was discussed,
and the participants unanimously recommended that the current Appendix 2
should be replaced by a cross-reference to the ICH website with the Q&As on
Q7: Good manufacturing practice guide for active pharmaceutical ingredients.
The Expert Committee endorsed this proposal.
8.3 Update of WHO good manufacturing practices: validation

The need for revision of the published Supplementary guidelines on good
manufacturing practices: validation (WHO Technical Report Series, No. 937, 2006,
Annex 4) had been identified by PQT and a draft document was circulated for
comment in early 2013. The focus of the revision was Appendix 7 (non-sterile
process validation), which had been revised and was adopted by the Committee
at its forty-ninth meeting in October 2014.
The Committee was informed that work is ongoing to revise the
validation guidance and its appendices as relevant. The Committee noted
theupdate and recommended that this work should be continued.
8.4 Update of model inspection report

A draft proposal for updating the Guidance on GMP: inspection report (WHO
Technical Report Series, No.908, 2002, Annex 5) and the Model certificate
of GMP (WHO Technical Report Series, No.908, 2002, Annex 6) in line with
current trends and formats was first discussed at an informal consultation on
inspection, GMP and risk management guidance in medicine manufacturing
held in April 2014. The objectives of the revision were to promote consistency
between formats used by inspectorates, thus facilitating collaborative activities
and information-sharing, and to bring the document into line with current
WHO good manufacturing practices for pharmaceutical products: main principles
(WHO Technical Report Series, No. 986, 2014, Annex 2).
An outline of an update of the model inspection report prepared by
PQT was submitted to the Expert Committee in October 2014; the Committee
discussed the outline and endorsed the proposals of the informal consultation.
A draft proposal for revision was prepared by the inspectors of the WHO/
The ICH Q&As are available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/

4
Quality/Q7/ICH_Q7-IWG_QA_v5_0_14Apr2015_FINAL_for_publication_17June2015.pdf.
27
PQT, and was discussed at an informal consultation on data management,

bioequivalence, GMP and medicines inspection held in Geneva from 29 June
to 1 July 2015. The revised draft guidance and model inspection report format
were sent out for comment in August 2015. The comments received and a
proposed revised draft were presented to the Committee at its fiftieth meeting.
The experts discussed the draft revised guidance and the model
inspection report template and provided their input. It was agreed that the
template should include subsections for inspection observations corresponding
to the subsections of the WHO GMP text with cross-references to the set of six
systems incorporating the general scheme of pharmaceutical manufacturing
operations, as reflected, e.g. in the inspectional approach of the United States
Food and Drug Authority.
The Committee adopted the guidance (Annex4), subject to the
amendments agreed.
8.5 Update and recommendations from the inspectors meeting

8.5.1 Supplementary guidelines on good manufacturing
practices for heating, ventilation and air-conditioning
systems for non-sterile pharmaceutical dosage forms
The Committee was briefed about progress on updating the Supplementary
guidelines on good manufacturing practices for heating, ventilation and air-
conditioning systems for non-sterile pharmaceutical dosage forms (WHO Technical
Report Series, No.961, 2011, Annex 5). A revised draft of these guidelines was
discussed at a consultation on data management, bioequivalence, GMP and
medicines inspection held from 29 June to 1 July 2015. The revision takes into
account current trends in engineering as well as experience gained from the
implementation of this guidance during inspections.
The guidelines were further revised by a consultant, based on the
feedback received during the consultation and from the inspectors of PQT. On
this occasion the text was also aligned with other relevant guidelines, notably
the proposed revisions to Supplementary guidelines on good manufacturing
practices: validation (WHO Technical Report Series, No. 937, 2006, Annex 4).
The revised draft was circulated for public comment in September 2015. A large
number of comments had been received, which will be discussed at a further
technical consultation.
8.5.2 Risk classification of inspection observations

Observations noted during inspections of manufacturing sites, contract research
organizations and quality control laboratories need to be classified according
28
to the risk to patients and level of compliance with relevant GXPs. Guidance
on classification of observations will facilitate harmonization and increase
the uniformity of approaches taken by inspectors, as well as the overall rating
of GXP compliance by the site. During the consultation on data management,
bioequivalence, GMP and medicines inspection held on 29 June1 July 2015,
a draft working document on Risk classification of inspection observations was
discussed. The draft was submitted to the Committee at its fiftieth meeting.
Considering that other organizations were also drafting guidance in this area,
the participants at the informal consultation recommended that WHO should
join in with the ongoing activities in order to enable consistency between
inspectorates, facilitating the sharing of information and inspection reports.
The Committee endorsed this proposal.
8.6 Guidance on good data and record management practices

In recent years the number of observations made regarding good data
management practices during inspections of GMP, good clinical practice (GCP)
and good laboratory practices (GLP) has been increasing. There is increased
regulatory awareness of the need for integrity of data submitted as a basis for
regulatory decisions. Good data management in line with scientific advances
and regulatory developments is crucial for all stakeholders in regulation of
health products, including patients, industry and regulators.
A proposal for a new guidance document on good data management
was first discussed at an informal consultation held in April 2014. At its forty-
ninth meeting the Committee discussed and endorsed a concept paper and
the proposed structure of the guidance. A document was then drafted by the
inspectors of PQT in close cooperation with a data management expert and
national inspectors, and was discussed at the consultation on data management,
bioequivalence, GMP and medicines inspection held from 29 June to 1 July
2015. The draft was further revised on the basis of feedback received during
the consultation, taking into account principles laid down in related WHO
guidance as well as industry norms and regulatory requirements. The guidance
promotes a risk-based approach and provides illustrative examples of good data
management in practice. The draft was sent out for comments in September 2015
before being presented to the Committee at its fiftieth meeting. The Committees
view was sought on future collaboration with PIC/S to enable future revisions of
the proposed guidance, aiming for convergence with PIC/S data management
norms, which are at an early stage of development.
Recognizing the wide interest in and urgent need for this guidance, the
Committee adopted the guidance (Annex 5), subject to the review of current and
forthcoming comments by a subgroup and subject to circulation of the finalized
document to the Expert Committee prior to publication.
29
9. Quality assurance distribution and
trade of pharmaceuticals
9.1 Good trade and distribution practices for starting materials
WHO guidance on good trade and distribution practices (GTDP) was
developed in order to ensure the quality and integrity of starting materials
and pharmaceutical products circulating in the global pharmaceutical market.
The guidance was adopted in 2003. At the forty-seventh meeting of the Expert
Committee in 2012 it was felt that there was a need to include new developments
and concepts in both the WHO guidelines on GTDP for pharmaceutical starting
materials and the good distribution practices (GDP) guide for pharmaceutical
excipients issued by the International Pharmaceutical Excipients Council (IPEC),
which is aligned with the WHO document. In July 2013 the IPEC Federation
provided a proposed revision and update of the WHO guidelines, which then
underwent several rounds of comments and was discussed at the forty-eighth and
forty-ninth meetings of the Expert Committee. The draft document was revised
in line with the experts input and was circulated again for comment in March
2015. Comments were collated and reviewed by a subgroup of the Committee in
July and August 2015. The revised draft was submitted to the Expert Committee
at its fiftieth meeting.
It was agreed that a subgroup of experts should review the comments
received and revise the guidance further. A revised draft was presented to the
Committee members during the meeting. The Committee adopted the guidance
subject to further review by a subgroup of experts. The final revised text is
included in Annex 6.
9.2 WHO Certification scheme on the quality of

pharmaceutical products moving in international
commerce questions and answers
The WHO Certification Scheme for finished pharmaceutical products is an

international voluntary agreement, originally endorsed by the World Health
Assembly in 1969, to provide information about the quality of pharmaceutical
products moving in international commerce to countries which participate
in the Scheme using model format templates provided by WHO, notably the
Certificate of Pharmaceutical Product (CPP).
The Scheme has been revised several times, with each revision being
endorsed by the World Health Assembly. A questions and answers (Q&A)
document was developed as an interim measure in line with recommendations
for revision of the Scheme. In 2010, WHO initiated a survey among its Member
States about their use of the Scheme. The responses received indicated that the
Scheme is appreciated as a valuable tool for exchange of regulatory information
30
Quality assurance distribution and trade of pharmaceuticals
between Member States, but that it may need further adaptation and more active
participation by a number of member countries to enable its useful application
in the current regulatory and industry environment. At its forty-ninth meeting
in 2014, the Expert Committee had therefore recommended that the Q&As
should be updated. The CPP Network team of the International Federation of
Pharmaceutical Manufacturers and Associations (IFPMA) proposed a revised
document, which was circulated for comment in August 2015. The comments
were reviewed by a small working group in September 2015, and the proposed
revision was presented to the Committee in October 2015. The Committee
reviewed the revised Q&As and heard from the WHO Regulatory Systems
Strengthening Team and from a number of organizations represented at the
meeting session about their experience with the use of the Scheme.
The Committee adopted the proposed revised Q&A document.
Furthermore it was recommended that the 17th International Conference of
Drug Regulatory Authorities (ICDRA) to be held in Cape Town, South Africa,
from 27 November to 2 December 2016 should be used as an opportunity to
advocate for active support of the effective functioning of the Scheme by
Member States.
9.3 Guidance on medicines quality surveys

Following recommendations made by the Committee at its meetings in 2010
and 2011, two draft guidance documents were produced. These documents
reflected the extensive experience of the WHO/PQT with the conduct of quality
control testing surveys to monitor the quality of pharmaceutical products
circulating in the markets of Member States. The Proposal for a procedure
on sampling and market surveillance was drafted in 2012 in response to the
Committees recommendation to develop a sampling procedure. A second
draft document entitled Recommendations on the content of a survey protocol
for surveys of the quality of medicines was prepared in 2014. It describes the
steps necessary for conducting quality surveys and proposes examples and
standard operating procedures that can be adapted to different situations. This
document was presented to the Expert Committee at its 2014 meeting. Noting
its comprehensive nature the Committee had recommended in 2014 that
it should be retained as a scientific background reference and that a shorter
practical guide should be prepared.
A concise draft of the guidelines on the conduct of surveys of the quality
of medicines was sent out for public consultation in July 2015. Comments
received were consolidated and presented together with the revised draft text to
the Committee in October 2015.
The Committee reviewed the document and the comments and provided
its input. The Expert Committee adopted the proposed guidance, subject to
amendments agreed (Annex 7).
31
9.4 Update on the monitoring and surveillance project

A pilot study of the WHO global monitoring and surveillance system was
conducted between September 2012 and January 2013 and is now part of the
workplan of the Member States mechanism on substandard/spurious/falsely-
labelled/falsified/counterfeit (SSFFC) medical products established by the World
Health Assembly Resolution WHA65.19. Participation has steadily increased
and was reported to encompass 112 Member States in October 2015.
A rapid alert form with a minimum set of questions is used for reporting.
Reports are submitted to WHO through focal points at national regulatory
authorities (NRAs). Since 2012 there have been 900 reports of potential SSFFC
products, leading to 12 International Drug Alerts being issued for SSFFC
medical products presenting an immediate and significant threat to public
health. Potential SSFFC products have been reported for all types of medicines.
Frequently reported categories include antimalarials and antibiotics. This is a
worrying finding in view of the emerging resistance to both.
Upon receipt of a report, WHO provides immediate technical support
with a response time of 2472 hours. The reports are uploaded to a database, and
the data are analysed in order to detect patterns and to assess the scale, scope,
extent and harm from SSFFC products. Detection and reporting are also used to
prevent future harm. Evidence-driven action is taken to strengthen regulatory
systems, raise awareness and engage stakeholders in combating SSFFC medical
products. Future actions will involve strengthening the communication with
focal points in participating NRAs and strengthening networks of NRAsglobally.
32
10. Prequalification of priority essential medicines
and active pharmaceutical ingredients
10.1 Update on the Prequalification Team managed by WHO
The Prequalification Programme was launched by WHO in 2001 in partnership
with the Joint United Nations Programme on HIV/AIDS (UNAIDS), UNICEF
and the United Nations Population Fund (UNFPA).
The Committee was given an overview of the different workstreams and
activities within PQT.
In terms of pharmaceutical products, medicines for hepatitis B and C
have become eligible for prequalification, with two finished product applications
undergoing screening and preparatory meetings having been held with several
companies. Prequalification may also be opened up to other therapeutic areas
if there is a need. WHO assessment times have decreased substantially in recent
years. Additional guidance to applicants has been provided for specific product
types and specific prequalification requirements. A total of 426 products were
prequalified as of 12 October 2015. A collaborative registration procedure,
which started in 2013, supports speedy registration of prequalified products in
participating countries based on sharing of prequalification information.
Regarding prequalification of APIs, the Committee was informed that
a total of 82 APIs have been prequalified to date. New API manufacturers had
come forward in 2015 thus improving the prospects of continued access and
competitiveness. Three applications for hepatitis C-related APIs are being
processed. In general the number of applications for prequalification of both
APIs and finished products has been stable, demonstrating continued interest.
PQT is involved in a wide range of collaborative initiatives. Within
WHO, PQT maintains close links with many other programmes and units,
including The International Pharmacopoeia. A standard text has been included
in the API prequalification sign-off form to permit access by The International
Pharmacopoeia to relevant data in the API master file. Monographs in The
International Pharmacopoeia strongly support manufacturers working towards
prequalification of their products; for example, the revised cycloserine monograph
has been much appreciated by applicants. PQT offers a rotational fellowship
programme, under which regulators from Member States spend three or six
months working at WHO with the prequalification assessor team or inspectorate.
This programme has greatly contributed to capacity-building and to the success
of collaborative activities.
The Secretariat thanked PQT for its important input to, and feedback
on, the guidance developed through the Expert Committee.
33
10.2 Collaborative procedure between the World Health

Organization (WHO) Prequalification Team and
national regulatory authorities in the assessment and
accelerated national registration of WHOprequalified
pharmaceutical products and vaccines
The Collaborative procedure between the World Health Organization (WHO)
Prequalification Team and national regulatory authorities in the assessment and
aims to make use of work done by the WHO/PQT to support efficient assessment
for granting of marketing authorization by participating regulatory authorities.
It is based on sharing of prequalification assessment and inspection reports with
the consent of the prequalification holder. The procedure was first adopted in
2012 (WHO Technical Report Series, No. 981, 2013, Annex 4), and has been
successfully implemented for medicines.
It was proposed to update the procedure and to extend it to vaccines.
The revision was discussed with stakeholders and the Expert Committee was
informed of the proposed revision at its 2014 meeting. A working document
was sent out for public consultation in July 2015. The revised document,
together with the comments received, was submitted to the Expert Committee
in October2015.
The Expert Committee adopted the proposed revision of the
collaborative procedure, now titled Collaborative procedure between the World
Health Organization (WHO) Prequalification Team and national regulatory
authorities in the assessment and accelerated national registration of WHO-
prequalified pharmaceutical products and vaccines (revision) (Annex8), subject
to the amendments agreed.
34
11. Regulatory guidance
11.1 Guidance for organizations performing
in vivo bioequivalence studies
The performance of a bioequivalence study is usually a requirement for
registration and prequalification of a multisource (generic) product to
ensure interchangeability of the product. Such studies should be undertaken in
compliance with WHO GCP and considering relevant elements from WHO GLP
and good practices for quality control laboratories.
An update of WHOs 2006 Guidance for organizations performing in vivo
bioequivalence studies (WHO Technical Report Series, No. 937, 2006, Annex9)
in line with new developments was discussed at an informal consultation in
April 2014. A working document was presented to the Expert Committee in
October 2014, and the Committee supported the revision of the guidelines.
The draft was then further revised by the inspectors of the WHO/PQT in
collaboration with national inspectors and was circulated for public comment
in May 2015. Comments received were discussed at an information consultation
on data management, bioequivalence, GMP and medicines inspection held from
29June to 1 July 2015. A second draft was prepared taking into consideration
the revised text on Multisource (generic) pharmaceutical products: guidelines
on registration requirements to establish interchangeability (WHO Technical
Report Series, No.992, 2015, Annex7), the new proposed guidelines on good
data management (see 8.6), and PQTs experience of assessing and inspecting
bioequivalence studies since 2006. Guidance was added on bioanalytical analysis,
and areas with recurrent inspection findings were clarified. The updated draft
was presented to the Committee in October 2015. The guidelines emphasize
management responsibilities to ensure that adequate premises, equipment and
quality systems are available to conduct good quality studies.
The Committee discussed the revised guidelines and agreed to the
changes proposed in response to the comments. The revised guidelines (Annex9)
were adopted as presented.
11.2 WHO general guidance on variations to

multisource pharmaceutical products
A marketing authorization holder is responsible for the quality, safety and
efficacy of an FPP that is placed on the market throughout its life cycle. After the
FPP has been authorized for marketing the manufacturer will often wish to make
changes (variations) to the product for a number of reasons. Such changes may
require the approval of the national medicines regulatory authority. The extent
35
and nature of regulatory control of variations to registered pharmaceutical

products varies considerably between WHO Member States.
In October 2013 the Expert Committee endorsed the development of
Guidelines for regulatory authorities on variations for multisource products. A draft
of the guidelines was developed between October 2013 and February 2014 and
circulated for comment and feedback before being discussed by the Committee
at its forty-ninth meeting. Based on feedback received, the guidance was revised
to describe the main principles for variation procedures for implementation by
regulatory authorities in accordance with riskbenefit and legal considerations
specific to each authority. The guidance is intended to assist regulatory authorities
to establish national requirements for the regulation of post-approval changes.
It proposes categories of changes and reporting procedures for adaptation by
regulatory authorities. The revised document was sent out for another round
of comments in June 2015. Feedback was collated and the revised draft was
presented to the Committee at its fiftieth meeting. The Committee discussed the
proposal to revise the title of the guidance and to delete the term multisource,
asit was noted that a wider audience may use the document as written. However,
it was concluded that the original name should be retained.
The Committee reviewed the guidance and the comments received, and
adopted the guidance subject to the amendments agreed (Annex 10).
11.3 Update of biowaiver principles for assessment of

interchangeable multisource (generic) products
Revised guidelines on interchangeability of multisource products were adopted
by the Committee in 2014. The safety and efficacy of a multisource (generic)
product is usually demonstrated through an in vivo bioequivalence study that
establishes its therapeutic equivalence to a comparator product. A biowaiver is a
regulatory approval process based on evidence of equivalence other than through
in vivo bioequivalence testing. Existing guidance on whether a biowaiver can

be granted based on the permeability and solubility of the API according to
the Biopharmaceutics Classification System (BCS) is provided in the Proposal
to waive in vivo bioequivalence requirements for WHO Model List of Essential
Medicines immediate-release, solid oral dosage forms (WHO Technical Report
Series, No. 937, 2006, Annex 8). The proposal includes a section describing the
general biowaiver principles as well as three tables listing information on various
categories of APIs included in the WHO EML.
In 2014 the Committee reviewed progress and endorsed the proposed
approach to separate the guidance text from the tables, which will be maintained
in a separate living document that can be updated in line with each new version
of the EML (see 11.4). This is analogous to the approach suggested for the list of
comparator products (see 11.5).
36
Regulatory guidance
Following these discussions, the WHO Secretariat requested a WHO

Collaborating Centre in Germany to provide a draft revised version of the
guidance on the biowaiver principles. The draft text was presented to the
Committee at its fiftieth meeting.
The Committee discussed the revised guidance and provided its
feedback. The document will be further revised and sent out as a working
document for comment.
11.4 Update of biowaiver list based on the WHO

Model List of Essential Medicines
Following the forty-eighth meeting of the Expert Committee the Secretariat
contacted a WHO Collaborating Centre in Germany to discuss the additional
studies needed for the update of the currently published biowaiver list in line
with successive updates of the WHO EML. A list of all APIs for which additional
studies are necessary in view of the various updates of the EML, was collated
and prioritized. The WHO Collaborating Centre submitted the proposed
tables to be attached as separate, living documents to the revised guidance on
biowaivers (see 11.3). The importance of providing well documented, reliable
references and study data for the BCS classifications assigned in the list was
noted. New references on the outcomes of existing studies have been added. The
Collaborating Centre is continuing to carry out further studies and the list will
be updated accordingly. The tables were presented to the Committee with a view
to obtaining further feedback before the lists are circulated for comment.
The Committee recommended that the list should be further reviewed
in line with comments made at the meeting and should be made available for
public consultation. The list will be presented to the Committee for consideration
at its next meeting.
11.5 Update of international comparator products list

for equivalence assessment of interchangeable
multisource (generic) products
A comparator product is a pharmaceutical product with which the multisource
product is intended to be interchangeable in clinical practice. In 1999 the Expert
Committee adopted a document containing a list of international comparator
pharmaceutical products for bioequivalence testing and included a decision-tree
for use in identifying comparator pharmaceutical products.
In 2014 the Expert Committee endorsed the decision that the guidance
on general principles for selecting comparator products should be separated
from the lists of comparator products and endorsed the revised Guidance on
the selection of comparator pharmaceutical products for equivalence assessment
37
of interchangeable multisource (generic) products (WHO Technical Report Series

No. 992, 2015, Annex 8). The Committee further supported the proposal to seek
the assistance of members of the International Generic Drug Regulators Pilot
(IGDRP) a collaborative network of medicines regulatory authorities aiming
at work-sharing in approval of generic products in validating the entries in the
international comparator products list. Members of the Expert Committee were
also invited to review the current international comparator products list and to
submit comments and amendments to the Secretariat.
Based on these discussions and inputs, the experts prepared an updated
draft list of comparator products, together with explanatory notes on the updating
process and selection criteria for the products listed. The main difference from
the existing approach is that there can be more than one acceptable market from
which to source a comparator product, because many products are marketed in
countries other than their countries of manufacture. The list and explanatory
notes were presented to the Committee for discussion and feedback on the
proposed updating approach.
The Committee recommended that the table should be reviewed and
updated further to ensure its consistency and applicability before it is circulated
for comment to all interested parties, and subsequently posted as a working
document on the WHO website. The Committee will discuss maintenance of
the list at its next meeting.
11.6 Good regulatory practices

Good governance principles and legal frameworks for health product regulation
are critically needed in Member States. Following the recommendation made
in 2010 at the 14th ICDRA to collect examples of best regulatory practice,
and based on feedback gained from national regulatory authorities during
WHO assessments, a project was initiated to develop WHO guidelines on
good regulatory practices (GRP). WHO has facilitated collaborative activities
between regulatory authorities and has reviewed feedback gathered from

national regulatory authorities over more than a decade to identify the
authorities mainneeds.
The scope of the proposed GRP guidelines is intended to include all
health products and health technologies, and set out high-level principles from
which a series of companion documents similar to the Good review practices
document adopted by the Committee in 2014 could be developed according
to need, timing and available resources. The concept of leveraging the work of
other authorities or good cooperation practices will be an important aspect of
this work. The draft guidance will go through the usual consultation process and
it is planned to present it for review to both the ECBS and the Expert Committee
on Specifications for Pharmaceutical Preparations in 2016.
38
Regulatory guidance
The Committee discussed the proposal and noted the importance of

having such a framework. The Committee expressed its support for the plans to
develop this guidance.
39
12. Nomenclature, terminology and databases
Quality assurance terminology
The Secretariat maintains a collection of terms and definitions included in the
guidance documents adopted by the Committee, with references to the respective
guidelines. The Secretariat reported that this database is being kept up to date. An
updated version is in the process of being verified and finalized for publication
on the WHO website.
The Committee took note of the update.
International Nonproprietary Names (INN)

for pharmaceutical substances
The International Nonproprietary Name (INN) Programme assigns unique
names to pharmaceutical substances to enable global consistency and
identification. A record number of 239 requests for assignment of an INN had
been received from manufacturers in 2015. A total of 196 INNs were published
in 2015, 94 of which were for biological substances. The total number of
requests, as well as the proportion of requests received for INNs for biologicals,
has been increasing.
A biological qualifier (BQ) scheme is proposed by the INN Programme
to identify a substance manufactured by a specific process under a specific
quality system. The BQ would be assigned as a second qualifier in addition to
the INN. The scheme is intended to apply to all biological substances, including
both innovators and biosimilars. Discussion is ongoing among a wide range
of partners. The BQ proposal, together with a Q&A document providing the
detailed technical information, was to be presented to the INN Expert Group at
its 61st Consultation in October 2015 for discussion.
Cell therapies are another complex and growing product group for
which there is currently no global naming system. Names have been assigned to
cell therapies in some regulatory systems. The INN Expert Group is discussing a
naming scheme applicable to cell therapies.
Revision of guidance on representation of graphic formulae

Guidance on how to represent graphic formulae in The International
Pharmacopoeia and within the INN list was developed and adopted by the
Expert Committee at its thirty-fourth meeting (TRS 863, Annex 1, 1996).
Adiscussion took place on whether an update of this guidance would be useful
to bring it into line with current practices. Such updated guidance could promote
convergence in this area.
40
Nomenclature, terminology and databases
The Committee supported the proposal and recommended that

work should start promptly to update WHO guidance on representation of
graphicformulae.
41
13. Summary and recommendations
The World Health Organization (WHO) Expert Committee on Specifications
for Pharmaceutical Preparations advises the Director-General of WHO on
pharmaceutical quality assurance. Based on a wide consultation process, it
provides independent expert recommendations and guidance to ensure that
medicines meet identical standards of quality, safety and efficacy in all WHO
Member States. The Committee held its first meeting in 1947 under the name of
the Expert Committee on Unification of Pharmacopoeias. Over time, it expanded
the scope of its standard-setting work from quality-control-testing specifications
to all arrangements that must be made in the development, production, regulation
and supply of medicines to ensure that the medicines reaching the patients are
of the quality required for their intended use.
At its fiftieth meeting from 12 to 16 October 2015, the Expert Committee
heard updates from the WHO Expert Committee on Biological Standardization,
the WHO Expert Committee on the Selection and Use of Essential Medicines
and the International Nonproprietary Names (INN) Expert Group, all of which
met in Geneva. With respect to international collaboration, updates were
presented by the United Nations Childrens Fund (UNICEF) about the supply
and quality assurance of health products in line with WHO guidance, and by
the Pharmacopoeial Discussion Group (PDG) about progress achieved with the
harmonization of pharmacopoeial standards.
In the area of quality control the Expert Committee adopted the
proposed workplan for elaboration of monographs and reviewed new and
revised specifications and general texts for quality control testing of medicines
for inclusion in The International Pharmacopoeia. The Committee was informed
that the fifth edition of The International Pharmacopoeia was published on
the WHO website in August 2015 as well as being made available as a CD. A
total of 22 texts, as listed below, were adopted. The Committee also endorsed
nine International Chemical Reference Substances (ICRS) established by

the custodian centre, the European Directorate for the Quality of Medicines
& HealthCare (EDQM). The Expert Committee further noted the progress
report of the external quality assurance assessment scheme (EQAAS), which
has successfully completed six phases of proficiency testing studies and will
begin Phase 7 in 2016. An update was given on the international meetings of
world pharmacopoeias, which are cohosted in turn by one of the participating
pharmacopoeias together with WHO. These meetings had been instrumental
in developing the good pharmacopoeial practices document adopted by
the Committee at its fiftieth meeting, subject to concurrence of the world
pharmacopoeias. This text provides guidance on the appropriate design,
development and maintenance of pharmacopoeial standards and will facilitate
prospective harmonization of standards among pharmacopoeias globally.
42
Summary and recommendations
In the various quality assurance-related areas, the Expert Committee

adopted new guidance on good data and record management, on establishing
national requirements for the regulation of post-approval changes to
pharmaceutical products and on the conduct of surveys of the quality of
medicines, as well as a guidance text developed in collaboration with the
International Pharmaceutical Federation (FIP) on the provision of children-
specific preparations that are not available as authorized products. The Expert
Committee was briefed on WHO prequalification of medicines, which has
continued to attract the interest of applicants, including additional manufacturers
of APIs. Additional medicines have become eligible for prequalification,
notably treatments for hepatitis B and C. A collaborative procedure for speedy
registration of medicines that have been fully assessed and prequalified by
WHO is currently offered by 26 regulatory authorities in collaboration with
WHO, and a revision of this procedure to extend it to prequalified vaccines
was discussed and adopted at the meeting. Prequalification of quality control
laboratories is also ongoing and two quality monitoring surveys one on HIV/
AIDS medicines and one on antimalarials are under way. The Committee also
heard updates from the WHO regulatory support unit, which offers a modular
assessment tool and capacity-building advice for regulatory systems, and from
the WHO monitoring and surveillance project for reporting of medicines quality
problems by Member States. Acknowledging the need for a model regulatory
framework for medical devices the Committee discussed possibilities for WHO
to oversee this work through its Expert Committee structure.
A list of decisions and recommendations made by the Expert Committee
at its fiftieth meeting is given below.
The following guidelines were adopted and recommended for use:

Good pharmacopoeial practices (Annex 1)
FIPWHO technical guidelines: Points to consider in the provision
by health-care professionals of children-specific preparations that
are not available as authorized products (Annex 2)
Guidance on good manufacturing practices: inspection report,
including Appendix 1: Model certificate of good manufacturing
practices (revision) (Annex 4)
Guidance on good data and record management practices (Annex 5)
Good trade and distribution practices for pharmaceutical starting
materials (revision) (Annex 6)
WHO Certification scheme on the quality of pharmaceutical
products moving in international commerce: questions and answers
(Q&A) (revision)
43
Guidelines on the conduct of surveys of the quality of medicines

(Annex 7)
Collaborative procedure between the World Health Organization
(WHO) prequalification team and national regulatory authorities
in the assessment and accelerated national registration of WHO-
prequalified pharmaceutical products and vaccines (revision)
(Annex 8)
Guidance for organizations performing in vivo bioequivalence
studies (revision) (Annex 9)
WHO general guidance on variations to multisource pharmaceutical
products (Annex 10)
The Committee also adopted the revised guidance on good manufacturing
practices for biological products (Annex 3), following its adoption by the Expert
Committee on Biological Standardization on 16 October 2015.
The following monographs were adopted for inclusion

in The International Pharmacopoeia:
For maternal, newborn, child and adolescent health medicines
estradiol cypionate
levonorgestrel (revision), including the use of the reference
substances Levonorgestrel for system suitability 1 CRS and
Levonorgestrel for system suitability 2 CRS issued by the European
Pharmacopoeia
misoprostol
misoprostol dispersion
misoprostol tablets
norethisterone (revision), including the use of the reference

substance Norethisterone for system suitability issued by the
European Pharmacopoeia
norethisterone tablets, including the use of the reference substance
Norethisterone for system suitability issued by the European
Pharmacopoeia
For antimalarial medicines
artemether injection (revision)
For antituberculosis medicines
cycloserine (revision)
cycloserine capsules (revision)
44
For medicines for chronic diseases and for mental health

carbamazepine
carbamazepine tablets
carbamazepine chewable tablets
carbamazepine oral suspension
For other anti-infective medicines
clindamycin hydrochloride
clindamycin hydrochloride capsules
flucytosine
flucytosine intravenous infusion
For other medicines
dextromethorphan hydrobromide
dextromethorphan oral solution
For the Supplementary section of The International Pharmacopoeia:

levomethorphan limit tests for dextromethorphan-containing
finished products
General policy
Chapter on Reference substances and reference spectra
The Committee also agreed to proposals to discontinue the use of certain
ICRSfor the purpose of microbiological assays, to replace microbiological assays
by physicochemical methods in certain monographs, to suppress a number
of monographs that currently prescribe microbiological assays but pertain to
medicines no longer included in the WHO Model List of Essential Medicines (19th
edition) or in the relevant invitations for expression of interest from manufacturers.
International Chemical Reference Substances (ICRS)

The Committee endorsed the release of the following ICRS newly characterized
by the custodian centre, the European Directorate for the Quality of Medicines
& HealthCare (EDQM) and released by the ICRS Board:
-Artemether ICRS 1
Efavirenz ICRS 2
Efavirenz impurity B ICRS 1
Ritonavir ICRS 2
45
Abacavir sulfate ICRS 2

Paracetamol ICRS 3
Artemether ICRS 2
Rifampicin ICRS 3
Stavudine impurity F ICRS 1.
Recommendations
The Expert Committee made the recommendations listed below in the various
quality assurance-related areas. Progress on the suggested actions will be reported
to the Committee at its next meeting. The Committee recommended that the
Secretariat, in collaboration with experts as appropriate, should carry out the
following activities.
The International Pharmacopoeia

Continue the development of monographs, general methods
and texts and general supplementary information, including
radiopharmaceutical monographs elaborated by the International
Atomic Energy Agency (IAEA), in accordance with the workplan.
Identify possible reference standards that can be referred to in five
specific monographs which currently prescribe microbiological
assays using ICRS, and for which no suitable alternative reference
standard or physicochemical assay method has yet been identified.
Proceed with the revision of the draft Note for guidance on organic
impurities in active pharmaceutical ingredients and finished
pharmaceutical products, intended to replace the text on Related
substances in finished pharmaceutical product monographs in
the Supplementary information section of The International
Pharmacopoeia.
Quality control national laboratories

Continue with the development of guidelines on testing of suspect
substandard/spurious/falsely-labelled/falsified/counterfeit medicines.

Add a cross-reference to the WHO good manufacturing practices
for active pharmaceutical ingredients to the ICH Q7 Guideline: Good
manufacturing practice guide for active pharmaceutical ingredients
questions and answers.
46
Proceed with revising the Supplementary guidelines on good

manufacturing practices: validation including the appendices as
relevant.
Continue with the revision of the Supplementary guidelines on good
manufacturing practices for heating, ventilation and air-conditioning
systems for non-sterile pharmaceutical dosage forms.
Pursue the revision of the draft working document on Risk
classification of inspection observations in collaboration with the
Brazilian Health Surveillance Agency (ANVISA), the European
Medicines Agency (EMA), the Pharmaceutical Inspection
Cooperation Scheme (PIC/S) and other organizations currently
drafting guidance in this area.
Regulation and regulatory collaboration

Continue revising the proposed Prerequisites for waiver of in vivo
bioequivalence requirements for the WHO Model List of Essential
Medicines immediate-release, solid oral dosage forms
Further review the biowaiver list and make the draft updated list
available for public consultation.
Further review the proposed updated international comparator
products list to ensure its consistency and applicability before
circulating it for comment to all interested parties and subsequently
posting it as a working document on the WHO website.
Pursue the ongoing initiative to develop a high-level guidance
document on good regulatory practices for health products
and health technologies, for adoption through both the Expert
Committee on Specifications for Pharmaceutical Preparations and
the Expert Committee on Biological Standardization.
Investigate possibilities to set up an expert group on regulation of
medical devices, composed of suitably qualified experts appointed
to existing Expert Advisory Panels.
Nomenclature, terminology and databases

Continue to provide the database of terms and definitions covered
by this Expert Committee on the WHO website.
Proceed with the proposed update of guidance on graphic
representation of chemical formulae used, for example, in The
International Pharmacopoeia.
47
Acknowledgements
Special acknowledgement was made by the Committee to:
Mrs W. Bonny, Medicines Quality Assurance (MQA), Technologies Standards
and Norms (TSN), Mr H. Chen, MQA, Ms M. Gaspard, MQA, Dr S. Kopp,
Group Lead, MQA, Dr H. Schmidt, MQA; Dr D.J. Wood, Coordinator, TSN;
MrD. Mubangizi, Group Lead, Inspection Services, Prequalification Team (PQT),
Ms J.K. Sawyer, Liaison Officer, PQT, Dr M.M. Stahl, Group Lead, Medicines
Assessment, PQT, Mr I.R. Thrussell, Expert Inspector, PQT; Dr L. Rgo, Head,
Regulation of Medicines and other Health Technologies; Mr C. de Joncheere,
Director, Department of Essential Medicines and Health Products, WHO,
Geneva, Switzerland; and Ms M. Zweygarth, Geneva, Switzerland, who were
instrumental in the preparation and proceedings of the meeting.
Technical guidance included in this report has been produced with the
financial assistance of the European Union, the Bill & Melinda Gates Foundation,
the Reproductive, Maternal, Newborn and Child Health Fund and UNITAID.
The Committee also acknowledged with thanks the valuable contributions
made to its work by the following agencies, institutions, organizations,
pharmacopoeias, WHO Collaborating Centres, WHO Programmes, especially
PQT, and persons:
Active Pharmaceutical Ingredients Committee, European Chemical
Industry Council, Brussels, Belgium; Belgian Association of the Pharmacists
of the Pharmaceutical Industry, Meerbeke, Belgium; Asia-Pacific Economic
Cooperation, Singapore; Brazilian Health Surveillance Agency/ANVISA,
Brasilia, DF, Brazil; Commonwealth Pharmacists Association, London, England;
European Commission, Brussels, Belgium; European Directorate for the
Quality of Medicines & HealthCare on behalf of the European Pharmacopoeia,
Council of Europe, Strasbourg, France; European Federation of Pharmaceutical
Industries and Associations, Brussels, Belgium; European Generic and
Biosimilars Medicines Association, Brussels, Belgium; European Generic

Medicines Association, Brussels, Belgium; European Medicines Agency,
London, England; The Global Fund to Fight AIDS, Tuberculosis and Malaria,
Vernier, Switzerland; International Atomic Energy Agency, Vienna, Austria;
International Federation of Pharmaceutical Manufacturers and Associations,
Geneva, Switzerland; International Generic Pharmaceutical Alliance, Brussels,
Belgium; International Pharmaceutical Excipients Council Americas,
Arlington, VA, USA; International Pharmaceutical Excipients Council Europe,
Brussels, Belgium; International Pharmaceutical Federation, The Hague,
Netherlands; International Society for Pharmaceutical Engineering, Tampa,
Florida, USA; International Society for Pharmaceutical Engineering,Thousand
Oaks, CA, USA; Latin American Association of Pharmaceutical Industries
(ALIFAR), Buenos Aires, Argentina; Medicines and Healthcare Products
48
Acknowledgements
Regulatory Agency, Inspection, Enforcement and Standards Division, London,

England; Pan-American Network for Drug Regulatory Harmonization,
Washington, DC, USA; Parenteral Drug Association, Bethesda, Maryland,
USA; Pharmaceutical Inspection Co-operation Scheme, Geneva, Switzerland;
The Stop TB Partnership, Geneva, Switzerland; Swissmedic, Swiss Agency for
Therapeutic Products, Berne, Switzerland; Therapeutic Goods Administration,
Woden, ACT, Australia; United Nations Childrens Fund, Supply Division,
Copenhagen, Denmark; United Nations Children's Fund, New York, USA; United
Nations Development Programme, New York, USA; United Nations Industrial
Development Organization, Vienna, Austria; The World Bank, Washington, DC,
USA; World Intellectual Property Organization, Geneva, Switzerland; World
Self-Medication Industry, Ferney-Voltaire, France; World Trade Organization,
Geneva, Switzerland.
Laboratoire National de Contrle des Produits Pharmaceutiques, Chraga,
Alger, Algeria; Instituto Nacional de Medicamentos, Buenos Aires, Argentina;
Expert Analytic Laboratory, Centre of Drug and Medical Technology Expertise,
Yerevan, Armenia; Laboratoire national de contrle de qualit des mdicaments
et consommables mdicaux, Cotonou, Benin; Agency for Medicinal Products
and Medical Devices, Control Laboratory, Sarajevo, Bosnia and Herzegovina;
Instituto Nacional de Controle de Qualidade em Sade, Rio de Janeiro, Brazil;
Laboratoire National de Sant Publique, Ouagadougou, Burkina Faso; National
Product Quality Control Centre, Ministry of Health, Phnom Penh, Cambodia;
Laboratoire National de Contrle de Qualit des Mdicaments et dExpertise,
Yaound, Cameroon; Departamento de Control Nacional, Unidad de Control
de Calidad de Medicamentos comercializados, Institutu de Salud Pblica,
Santiago de Chile, Chile; National Institutes for Food and Drug Control, Beijing,
Peoples Republic of China; Medicamentos y Productos Biolgicos del INVIMA,
Bogot, Colombia; Laboratorio de Anlisis y Asesora Farmacutica, Facultad
de Farmacia, Universidad de Costa Rica, San Jos, Costa Rica; Laboratorio
de Normas y Calidad de Medicamentos, Caja Costarricense de Seguro Social,
Universidad de Costa Rica, Alajuela, Costa Rica; Laboratoire National de la Sant
Publique, Abidjan, Cte dIvoire; Oficina Sanitaria Panamericana, OPS/OMS,
Havana, Cuba; National Organization for Drug Control and Research, Cairo,
Egypt; Drug Quality Control and Toxicology Laboratory, Drug Administration
and Control Authority, Addis Ababa, Ethiopia; Centrale Humanitaire Mdico-
Pharmaceutique, Clermont-Ferrand, France; Food and Drugs Board, Quality
Control Laboratory, Accra, Ghana; Laboratoire national de contrle de qualit
des medicaments, Conakry, Guinea; Laboratory for Quality Evaluation and
Control, National Institute of Pharmacy, Budapest, Hungary; Central Drugs
Laboratory, Kolkata, India; Provincial Drug and Food Quality Control Laboratory,
Yogyakarta, Indonesia; Food and Drugs Control Laboratories, Ministry of Health
and Medical Education, Tehran, Islamic Republic of Iran; Caribbean Regional
49
Drug Testing Laboratory, Kingston, Jamaica; Mission for Essential Drugs and
Supplies, Nairobi, Kenya; National Quality Control Laboratory for Drugs and
Medical Devices, Nairobi, Kenya; Food and Drug Quality Control Center,
Ministry of Health, Vientiane, Lao Peoples Democratic Republic; Laboratoire de
Contrle de Qualit des Mdicaments, Agence du Mdicament de Madagascar,
Antananarivo, Madagascar; Centre for Quality Control, National Pharmaceutical
Control Bureau, Petaling Jaya, Selangor, Malaysia; Laboratoire National de la
Sant du Mali, Bamako, Mali; Laboratoire National de Contrle des Mdicaments,
Rabat, Morocco; Quality Surveillance Laboratory, Windhoek, Namibia; National
Medicines Laboratory, Department of Drug Administration, Kathmandu, Nepal;
Laboratoire National de Sant Publique et dExpertise, Niamey, Niger; Central
Quality Control Laboratory, Directorate General of Pharmaceutical Affairs and
Drug Control, Ministry of Health, Muscat, Oman; Drug Control and Traditional
Medicine Division, National Institute of Health, Islamabad, Pakistan; Instituto
Especializado de Anlisis, Universidad de Panam, Panama; Centro Nacional
de Control de Calidad, Instituto Nacional de Salud, Lima, Peru; Bureau of Food
and Drugs, Department of Health, Muntinlupa City, Philippines; Laboratory for
Quality Control of Medicines, Medicines Agency, Ministry of Health, Chisinau,
Republic of Moldova; National Drug and Cosmetic Control Laboratories, Drug
Sector, Saudi Food and Drug Authority, Riyadh, Saudi Arabia; Laboratoire
National de Contrle des Mdicaments, Dakar Etoile, Senegal; Pharmaceutical
Division, Applied Sciences Group, Health Sciences Authority, Singapore; Centre
for Quality Assurance of Medicines, Faculty of Pharmacy, North-West University,
Potchefstroom, South Africa; Research Institute for Industrial Pharmacy,
North-West University, Potchefstroom, South Africa; National Drug Quality
Assurance Laboratory, Ministry of Health, Colombo, Sri Lanka; National Drug
Quality Control Laboratory, Directorate General of Pharmacy, Federal Ministry
of Health, Khartoum, Sudan; Pharmaceutical Analysis Laboratory, R&D, The
School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dares-
Salaam, United Republic of Tanzania; Tanzania Food and Drug Authority,

Dar-es-Salaam, United Republic of Tanzania; Bureau of Drug and Narcotic,
Department of Medical Sciences, Ministry of Public Health, Nonthaburi,
Thailand; Laboratoire National de Contrle des Mdicaments, Tunis, Tunisia;
National Drug Quality Control Laboratory, National Drug Authority, Kampala,
Uganda; Central Laboratory for Quality Control of Medicines of the Ministry
of Health of Ukraine, Kiev, Ukraine; Laboratory of Pharmaceutical Analysis,
State Pharmacological Centre, Ministry of Health of Ukraine, Kiev, Ukraine;
Laboratorio Control de Productos MSP, Comisin Para El Control de Calidad
de Medicamentos, Montevideo, Uruguay; Instituto Nacional de Higiene Rafael
Rangel, Caracas, Venezuela; National Institute of Drug Quality Control, Hanoi,
Viet Nam; Medicines Control Authority, Control Laboratory of Zimbabwe,
Harare, Zimbabwe.
50
Acknowledgements
Farmacopea Argentina, Buenos Aires, Argentina; Farmacopeia

Brasileira, Brasilia, DF, Brazil; British Pharmacopoeia Commission, Medicines
and Healthcare Products Regulatory Agency, London, England; Farmacopea
Chilena, Valparaso, Chile; Pharmacopoeia of the Peoples Republic of China,
Beijing, Peoples Republic of China; Croatian Pharmacopoeia, Zagreb, Croatia;
Czech Pharmacopoeia, Prague, Czech Republic; Danish Pharmacopoeia
Commission, Copenhagen, Denmark; European Pharmacopoeia, European
Directorate for the Quality of Medicines & HealthCare, Council of Europe,
Strasbourg, France; Finnish Medicines Agency, Helsinki, Finland; Pharmacope
franaise, Agence nationale de scurit sanitaire des produits de sant, Saint-
Denis, France; German Pharmacopoeia Commission, Bonn, Germany;
Indian Pharmacopoeia Commission, Raj Nagar, Ghaziabad, India; Indonesian
Pharmacopoeia Commission, Jakarta, Indonesia; Iranian Pharmacopoeia,
Iranian Association of Pharmaceutical Scientists, Tehran, Islamic Republic of
Iran; Committee of the Japanese Pharmacopoeia, Tokyo, Japan; Kazakhstan
Pharmacopoeia, Pharmacopoeia Centre of the Republic of Kazakhastan,
Almaty, Kazakhstan; Pharmacopoeia of the Republic of Korea, Cheongwon-
gun, Chungcheongbuk-do, Republic of Korea; Lithunian Pharmacopoeia
Commission, Vilnius, Lithuania; Mexican Pharmacopoeia, Mxico DF, Mexico;
Philippines Pharmacopoeia, Manila, Philippines; Polish Pharmacopoeia
Commission, Warsaw, Poland, Portuguese Pharmacopoeia, Lisbon, Portugal;
State Pharmacopoeia of the Russian Federation, Moscow, Russian Federation;
Serbian Pharmacopoeia, Belgrade, Serbia; Slovakian Pharmacopoeia Commission,
Bratislava, Slovakia; Spanish Pharmacopoeia, Royal, Madrid, Spain; Swedish
Pharmacopoeia, Uppsala, Sweden; Swiss Pharmacopoeia, Berne, Switzerland; Thai
Pharmacopoeia, Nonthaburi, Thailand; Pharmacopoeia of Ukraine, Ukrainian
Scientific Pharmacopoeial Center for Quality of Medicines, Kharkov, Ukraine;
United States Pharmacopeia, Rockville, MD, USA; Vietnamese Pharmacopoeia,
Hanoi, Viet Nam.
WHO Centre Collaborateur pour la Conformit des Mdicaments,
Laboratoire national de Contrle des Produits Pharmaceutiques, Alger, Algeria;
WHO Collaborating Centre for Drug Quality Assurance, Therapeutic Goods
Administration Laboratories, Woden, ACT, Australia; WHO Collaborating
Centre for Drug Quality Assurance, National Institute for the Control of
Pharmaceutical and Biological Products, Beijing, Peoples Republic of China;
WHO Collaborating Centre for Research on Bioequivalence Testing of Medicines,
Frankfurt am Main, Germany; WHO Collaborating Centre for Drug Information
and Quality Assurance, National Institute of Pharmacy, Budapest, Hungary;
WHO Collaborating Centre for Quality Assurance of Essential Drugs, Central
Drugs Laboratory, Calcutta, India; WHO Collaborating Centre for Regulatory
Control of Pharmaceuticals, National Pharmaceutical Control Bureau, Jalan
University, Ministry of Health, Petaling Jaya, Malaysia; WHO Collaborating
51
Centre for Drug Quality Assurance, Pharmaceutical Laboratory, Centre for

Analytical Science, Health Sciences Authority, Singapore; WHO Collaborating
Centre for Quality Assurance of Drugs, North-West University, Potchefstroom,
South Africa; WHO Collaborating Centre for Quality Assurance of Essential
Drugs, Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry
of Public Health, Nonthaburi, Thailand.
Health Systems and Innovation Cluster, WHO, Geneva, Switzerland;
Department of Essential Medicines and Health Products, WHO, Geneva,
Switzerland; Regulation of Medicines and other Health Technologies, WHO,
Geneva, Switzerland; Prequalification Team, WHO, Geneva, Switzerland;
International Nonproprietary Names, WHO, Geneva, Switzerland; Policy Access
and Use, WHO, Geneva, Switzerland; Regulatory Systems Strengthening, WHO,
Geneva, Switzerland; Safety and Vigilance Team, WHO, Geneva, Switzerland;
Technologies Standards and Norms, WHO, Geneva, Switzerland; Traditional
and Complementary Medicine, WHO, Geneva, Switzerland; Office of the Legal
Counsel, WHO, Geneva, Switzerland; Control of Neglected Tropical Diseases,
WHO, Geneva, Switzerland; Global Malaria Programme, WHO, Geneva,
Switzerland; Global TB Programme, WHO, Geneva, Switzerland; HIV/AIDS
Programme, WHO, Geneva, Switzerland; Prevention of Noncommunicable
Diseases, WHO, Geneva, Switzerland; WHO Regional Office for Africa,
Brazzaville, Congo; WHO Regional Office for the Americas/Pan American
Health Organization, Washington, DC, USA; WHO Regional Office for the
Eastern Mediterranean, Cairo, Egypt; WHO Regional Office for Europe,
Copenhagen, Denmark; WHO Regional Office for South-East Asia, New Delhi,
India; WHO Regional Office for the Western Pacific, Manila, Philippines.
Abbott, Allschwil, Switzerland; Abbott Laboratories, Abbott Quality &
Regulatory, Dept. 03QY, Abbott Park, IL, USA; Dr F. Abiodun, Benin City,
Nigeria; Professor E. Adams, Laboratorium voor Farmaceutische Chemie en
Analyse van Geneesmiddelen, Leuven, Belgium; Dr M. Adarkwah-Yiadom,
Standard Officer, Ghana Standards Board, Drugs, Cosmetics and Forensic

Laboratory Testing Division, Accra, Ghana; Professor I. Addae-Mensah,
Department of Chemistry, University of Ghana, Legon, Ghana; Divisin de
Qumica y Tecnologa Farmacutica, AEMPS. Madrid, Spain; Dr K. Agravat,
Regulatory Affairs, Unimark Remedies Limited, Ahmedabad, India; Ms R.
Ahmad, Centre for Product Registration, National Pharmaceutical Control
Bureau, Ministry of Health, Petaling Jaya, Malaysia; Ajanta Pharma Ltd, Kandivli
(West), Mumbai, India; Apotex Inc., Toronto, Ontario, Canada; Amgen Inc.,
Thousand Oaks, CA, USA; Amgen Inc., Engineering, West Greenwich, RI, USA;
Dr P. Aprea, Director, Directorate of Evaluation and Control of Biologicals and
Radiopharmaceuticals, National Administration of Medicines, Food and Medical
Technology, Buenos Aires, Argentina; Dr N. Aquino, Inspector and Specialist in
GMP and Risk Management, Brazilian Health Surveillance Agency, Brasilia, DF,
52
Acknowledgements
Brazil; Dr A.C. Moreira Marino Araujo, Health Expert, Drugs Office, Post
Approval Changes of Synthetic Drugs, Brazilian Health Surveillance Agency,
Brasilia, DF, Brazil; Dr H. Arentsen, Regulatory Intelligence and Policy Specialist,
Regulatory Development Strategy, H. Lundbeck A/S, Copenhagen-Valby,
Denmark; Astellas Pharma Europe BV, Leiderdorp, Netherlands; AstraZeneca
Pharmaceuticals (China) Co., Ltd, Taizhou City, Jiangsu Province, China;
AstraZeneca, Alderley Park, Cheshire, England; Dr C. Athlan, Quality Reviewer,
Swissmedic, Swiss Agency for Therapeutic Products, Berne, Switzerland; Dr A.
Ba, Directeur, Qualit et Dveloppement, Centrale Humanitaire Medico-
Pharmaceutique, Clermont-Ferrand, France; Dr H. Baio, Infarmed, Portugal;
Dr P. Baker, United States of America Food and Drug Administration, China
Office, USA; Dr J.R. Ballinger, Guys and St Thomas Hospital, London, England;
Dr E. Bamanyekanye, Dpartment de la Pharmacie, du Mdicament et des
Laboratoires (DPML), Burundi; Mr N. Banerjee, Cipla Limited, Goa, India;
DrH. Batista, US Food and Drug Administration, Silver Spring, MD, USA; Mr B.
Baudrand, OTECI, Paris, France; Dr R. Bauer, Head of Institute, Institute
Surveillance, Austrian Federal Office for Safety in Health Care, Austrian Agency
for Health and Food Safety, Vienna, Austria; Dr O.P. Baula, Deputy Director,
State Pharmacological Center, Ministry of Health, Kiev, Ukraine; Professor S.A.
Bawazir, Advisor to the Executive President, Saudi Food and Drug Authority,
Riyadh, Saudi Arabia; Bayer Health Care Pharmaceuticals, Bayer Pharma AG,
Berlin, Germany; Dr M.G. Beatrice, Vice President, Corporate Regulatory and
Quality Science, Abbott, Abbott Park, IL, USA; Dr T.L. Bedane, Drug
Administration and Control, Addis Ababa, Ethiopia; Ms T.J. Bell, WHO Focal
Point, US Food and Drug Administration, Silver Spring, MD, USA; Dr M.
Silvana Bellini, EDQM Laboratory, Strasbourg, France; Dr I.B.G. Bernstein,
Director, Pharmacy Affairs, Office of the Commissioner/Office of Policy, US
Food and Drug Administration, Silver Spring, MD, USA; Mr L. Besanon,
General Secretary and CEO, International Pharmaceutical Federation, The
Hague, Netherlands; Dr R.P. Best, President and CEO, International Society for
Pharmaceutical Engineering, Tampa, FL, USA; Dr A. Bevilacqua, US
Pharmacopeia, Bedford, MA, USA; Dr J. Bishop III, Review Management Staff,
Office of the Director, Center for Biologics Evaluation and Research, United
States Food and Drug Administration,, Silver Spring, MD, USA; Dr L. Bonthuys,
Pretoria, South Africa; Mr M.H. Boon, Deputy Director, Overseas Audit Unit
Audit Branch, Audit & Licensing Division, Health Products Regulation Group,
Singapore; Dr G. Born, Institute of Pharmaceutical Technology, Johann Wolfgang
Goethe-University, Frankfurt, Germany; Professor R. Boudet-Dalbin, Paris,
France; Dr B. Blum, Sandoz, France; Dr G. Bourdeau, Mrville, France; Dr S.K.
Branch, Acting Group Manager, Special Populations Group, Medicines and
Healthcare Products Regulatory Agency, London, England; Dr E. Brendel, Bayer
HealthCare AG, Elberfeld, Germany; Dr M. Brits, Director, WHO Collaborating
53
Centre for the Quality Assurance of Medicines, North-West University,

Potchefstroom Campus, Potchefstroom, South Africa; Mr C. Brown, Inspections
Enforcement and Standards Division, Medicines and Healthcare Products
Regulatory Agency, London, England; Dr W. Bukachi, Project Coordinator,
International Affairs, US Pharmacopeia, Rockville, MD, USA; Ms A. Bukirwa,
National (Food and) Drug Authority, Kampala, Uganda; Bureau of Drug and
Narcotic, Department of Medical Sciences, Ministry of Public Health,
Nonthaburi, Thailand; Dr F. Burnett, Managing Director, Pharmaceutical
Procurement Service, Organization of Eastern Caribbean States, Casties, St Lucia;
Dr W. Cabri, Research and Development, Director, Chemistry and Analytical
Development, Sigma-tau Industrie Farmaceutiche Riunite SpA, Pomezia, Italy;
Dr M.Cahilly, Warren, Vermont, USA; Dr. D. Calam, Wiltshire, England; Dr N.
Cappuccino, Lambertville, NJ, USA; Dr L. Cargill, Director, Caribbean Regional
Drug Testing Laboratory, Kingston, Jamaica; Professor (Madame) R. Jimnez-
Castellanos, Department of Pharmaceutics and Pharmaceutical Technology,
Faculty of Pharmacy, Seville, Spain; Dr A. Castro, Regulatory Affairs Director
and Senior Pharmacist, Roche Servicios SA, Heredia, Costa Rica; Dr D.
Catsoulacos, Scientific Administrator, Manufacturing and Quality Compliance,
Compliance and Inspection, European Medicines Agency, London, England;
European Medicines Agency, London, England; Mr J.-M. Caudron, Braine-le-
Chteau, Belgium; Mr P. Cenizo, Southern African Pharmaceutical Regulatory
Affairs Association (SAPRAA), Randburg, South Africa; Dr A.N.K. Chali,
Chemical and Pharmaceutical Assessor, Uppsala, Sweden; Dr B. Chapart, Pharma
Review Manager, Global Analytical Development, Sanofi-Aventis Pharma,
Anthony, France; Ms Cheah Nuan Ping, Director, Cosmetics & Cigarette Testing
Laboratory, Pharmaceutical Division, Applied Sciences Group, Health Sciences
Authority, Singapore; Dr X. Chen, Director, Division of Drug Distribution
Supervision, State Food and Drug Administration, Beijing, Peoples Republic
of China; Professor Y. Cherrah, Facult de Mdecine et Pharmacie, Rabat,
Morocco; Dr B.K. Choi, Director, Pharmaceutical Standardization, Osong Health

Technology Administration Complex, Research and Testing Division of the
Ministry of Food and Drug Safety, Cheongwon-gun, Chungbuk, Republic of
Korea; Dr Y.H. Choi, Scientific Officer, Korea Food & Drug Administration,
Cheongwon-gun, Chungbuk, Republic of Korea; Dr D. Churchward, Expert
GMPD Inspector, Inspection Enforcement and Standards, Medicines &
Healthcare products Regulatory Agency, London, England; Cipla Limited,
Mumbai, India; Ms I. Clamou, Assistant Manager, Scientific,Technical and
Regulatory Affairs, European Federation of Pharmaceutical Industries and
Associations, Brussels, Belgium; Dr M. Cooke, Senior Manager, Global Quality,
Operations, AstraZeneca, Macclesfield, Cheshire, England; Dr C. Craft, Member,
United States Pharmacopeia International Health Expert Committee, Rockville,
MD, USA; Ms J. Crawford, Inpatients Pharmacy, Waitakere Hospital, Auckland,
54
Acknowledgements
New Zealand; Ms T. Crescenzi, United States of America Food and Drug

Administration, Silver Spring, MD, USA; Critical Paths to TB Regimens (CPTR),
Global Regulatory Pathways Work Group, Tucson, AZ, USA; Dr R.L. Dana,
Senior Vice President, Regulatory Affairs and Parenteral Drug Association
Training and Research Institute, Parenteral Drug Association, Bethesda, MD,
USA; Mr M.M. Das, Barisha, Kolkata, India; Dr V. Davoust, Quality & Regulatory
Policy, Pharmaceutical Sciences, Pfizer Global Research & Development, Paris,
France; Dr D. de Kaste, National Institute for Public Health and the Environment,
Bilthoven, Netherlands; Professor T. Dekker, Research Institute for Industrial
Pharmacy, North-West University, Potchefstroom, South Africa; Dr M. Derecque-
Pois, Director General, European Association of Pharmaceutical Full-line
Wholesalers, Brussels, Belgium; Directorate General of Pharmaceutical Affairs
and Drug Control, Ministry of Health, Muscat, Oman; Dr R. Diyana, Senior
Bioavailability/Bioequivalence Evaluator, National Authority for Food and Drug
Control, Indonesia; DMB (French association of data management professionals),
Suresnes, France; Professor E. Doelker, University of Geneva, Geneva, Switzerland;
Professor J.B. Dressman, Director, Institut fr Pharmazeutische Technologie,
Biozentrum, Johann Wolfgang Goethe-Universitt, Frankfurt am Main,
Germany; Mrs S. Dube-Mwedzi, Consultant Regulatory Officer, Medicines
Control Authority of Zimbabwe, Harare, Zimbabwe; Dr A.T. Ducca, Senior
Director, Regulatory Affairs, Healthcare Distribution Management Association,
Arlington, VA, USA; Dr T.D. Duffy, Lowden International, Tunstall, Richmond,
N. Yorks, England; Dr P. Ellis, Director, External Advocacy, Quality Centre of
Excellence, GlaxoSmithKline, Brentford, Middlesex, England; European
Compliance Academy Foundation, Heidelberg, Germany; European Medicines
Agency, London, England; Fedefarma, Ciudad, Guatemala; F. Hoffman-La Roche
Ltd, Basel, Switzerland; Dr A. Falodun, Department of Pharmaceutical Chemistry,
Faculty of Pharmacy, University of Benin, Benin City, Nigeria; Federal Ministry
of Health, Berlin, Germany; Dr R. Fendt, Head, Global Regulatory & GMP
Compliance Pharma, Care Chemicals Division, BASF, Limburgerhof, Germany;
Mr A. Ferreira do Nascimento, Agncia Nacional de Vigilncia, Braslia, Brazil;
Mr M. FitzGerald, European Association of Pharmaceutical Full-line Wholesalers,
Brussels, Belgium; Dr A. Flueckiger, Head, Corporate Health Protection,
Corporate Safety, Health & Environmental Protection, F. Hoffmann-La Roche,
Basel, Switzerland; Dr G.L. France, Head, Q&A Compliance, EU Region, Novartis
Consumer Health Services SA, Nyon, Switzerland; Dr B. Fritschel, Johnson &
Johnson, New Brunswick, NJ, USA; Dr A. Fuglsang, Haderslev, Denmark; Mr T.
Fujino, Director, International Affairs, Japan Generic Medicines Association,
Tokyo, Japan; Mr A. Garca Arieta, Head, Service on Pharmacokinetics and
Generic Medicines, Division of Pharmacology and Clinical Evaluation,
Department of Human Use Medicines, Spanish Agency of Medicines and Medical
Devices, Madrid, Spain; Miss Y. Gao, Project Manager, Chinese Pharmacopoeia
55
Commission, Beijing, Peoples Republic of China; Dr M. Garvin, Senior Director,

Scientific and Regulatory Affairs, Pharmaceutical Research and Manufacturers
of America, Washington, DC, USA; Dr A. Gayot, Facult de Pharmacie de Lille,
Lille, France; Dr X. Ge, Senior Analytical Scientist, Pharmaceutical Laboratory,
Pharmaceutical Division, Applied Sciences Group, Health Sciences Authority,
Singapore; German Expert Group on Computerized, Darmstadt, Germany; Dr L.
Gibril, Compliance Coordinator, Novartis Pharma SAE, Amiria, Cairo, Egypt;
Gilead Sciences International Ltd, Abington, Cambridge, England; Dr F. Giorgi,
Research and Development, Analytical Development Manager, Sigma-tau
Industrie Farmaceutiche Riunite SpA, Pomezia, Italy; Dr L. Girard, Head, Global
Pharmacopoeial Affairs, Novartis Group Quality, Quality Systems and Standards,
Basel, Switzerland; GlaxoSmithKline, Brentford, Middlesex, England;
GlaxoSmithKline Biologicals SA, Wavre, Belgium; GlaxoSmithKline, Sales
Training Centre, Research Triangle Park, NC, USA; Dr C. Snchez Gonzlez,
Coordinator of Policies and Regulatory Affairs Centro para el Control de
Medicamentos, Equipos y Dispositivos Mdicos, La Habana, Cuba; Dr J. Gordon,
Nova Scotia, Canada; Dr T. Gould, Brighton East, Victoria, Australia; Ms J.
Gouws, Department of Health, Medicines Control Council, Pretoria, South
Africa; Dr M. Goverde, QC Expert Microbiology, Novartis Pharma AG, Basel,
Switzerland; Ms R.Govithavatangaphong, Director, Bureau of Drug and
Narcotics, Department of Medical Sciences, Ministry of Public Health,
Nonthaburi, Thailand; Dr L. Graham, Medicines & Healthcare products
Regulatory Agency, London, England; Dr J. Grande, Manager, Regulatory Affairs,
McNeil Consumer Healthcare, Markham, England; Dr A. Gray, Senior Lecturer,
Department of Therapeutics and Medicines Management and Consultant
Pharmacist, Centre for the AIDS Programme of Research in South Africa
(CAPRISA), Nelson R Mandela School of Medicine, University of KwaZulu-
Natal, Congella, South Africa; Dr M. Guazzaroni Jacobs, Director, Quality and
Regulatory Policy, Pfizer Inc., New York, NY, USA; Ms N.M. Guerrero Rivas,
Radiofarmacia de Centroamrica, SA, Ciudad del Saber, Panam, Panama; Guilin

Pharmaceutical Company Ltd, Guilin, Peoples Republic of China; Dr R. Guinet,
Agence nationale de scurit du mdicament et des produits de sant, Saint-
Denis, France; Dr S. Gupta, Mankind Pharma Limited, Unit-II, Vill. Kishanpura,
Paonta Sahib, Disst. Sirmour, India; Professor R. Guy, Professor of Pharmaceutical
Sciences, Department of Pharmacy & Pharmacology, University of Bath, Bath,
England; Mr L. Gwaza, Medicines Regulation, Evaluations & Registration
Division, Medicines Control Authority of Zimbabwe, Harare, Zimbabwe; Dr N.
Habib, Director General of Medical Supplies, Ministry of Health, Oman; Dr S.
Haidar, Acting Director, Division of Generic Drug Bioequivalence Evaluation,
Office of Study Integrity and Surveillance, Center for Drug Evaluation and
Research, Food and Drug Administration, Silver Spring, MD, USA; Mr B.J.
Hamid, Jakarta, Indonesia; Dr N. Hamilton, Industrial Quality and Compliance,
56
Acknowledgements
Industrial Affairs, Sanofi Aventis, West Malling, Kent, England; Ms J.

Hantzinikolas, Therapeutic Goods Administration, Department of Health,
Woden, ACT, Australia; Dr S. Harada, International Affairs Division, Minister's
Secretariat, Ministry of Health, Labour and Welfare, Tokyo, Japan; Dr B.
Hasselbalch, Acting Associate Director, Policy and Communications, and
Director, Division of Policy, Collaboration & Data Operations, Office of
Compliance, Center for Drug Evaluation and Research, United States Food and
Drug Administration, Silver Spring, MD, USA; Dr A. Hawwa, Lecturer in
Pharmacy (Medicines in Children), Medical Biology Centre, Queens University
Belfast, Belfast, Northern Ireland; Dr M. Hayes-Bachmeyer, Technical Regulatory
Affairs, Pharmaceuticals Division, F. Hoffmann-la Roche, Basel, Switzerland;
Mr Y. Hebron, Manager, Medicines and Cosmetics Analysis Department,
Tanzania Food and Drugs Authority, Dar-es-Salaam, United Republic of
Tanzania; Dr G.W. Heddell, Director, Inspection Enforcement & Standards
Division, Medicines and Healthcare Products Regulatory Agency, London,
England; Dr D. Hege-Voelksen, Swissmedic, Swiss Agency for Therapeutic
Products, Berne, Switzerland; Ms J. Hiep, QA Pharmacist and Auditor, Adcock
Ingram, Bryanston, South Africa; Ms M. Hirschhorn, Head, Quality and
Chemistry Sector, Comisin para el Control de Calidad de Medicamentos
(Drug and Control Commission), Montevideo, Uruguay; Mrs Hong J., Senior
Pharmacist and Director of Hubei Provincial Institutes for Food and Drug
Control, Wuhan Hubei, China; Mrs Hong L., Senior Pharmacist and Director of
Zhejiang Provincial Institutes for Food and Drug Control, Hangzhou, China;
Professor J. Hoogmartens, Leuven, Belgium; Dr K. Horn, Managing Director,
Institute for Pharmaceutical and Applied Analytics, Official Medicines Control
Laboratory, Bremen, Germany; F. Hoffmann-La Roche Ltd, Basel, Switzerland;
Dr K. Hoppu, Director, Poison Information Centre, Helsinki University Central
Hospital, Helsinki, Finland; Dr H. Hoseh, Head of Registration Unit, Drug
Directorate, Jordan Food and Drug Administration, Jordan; Dr X. Hou, Chemical
& Materials, Singapore; Dr N. Ibrahim, National Pharmaceutical Control Bureau,
Ministry of Health, Jalan University, Petaling Jaya, Indonesia; Indian Drug
Manufacturers Association, Mumbai, India; Infarmed, Lisbon, Portugal; Ipsen
Pharma, Dreux, France; Dr J. Isasi Rocas, Pharmaceutical Chemist, Lima, Peru;
Professor R. Jachowicz, Head, Department of Pharmaceutical Technology and
Biopharmaceutics, Jagiellonian University Medical College, Faculty of Pharmacy,
Krakw, Poland; Mr I. Jackson, Operations Manager, GMDP Inspections,
Inspection, Enforcement & Standards Division, Medicines and Healthcare
Products Regulatory Agency, London, England; Dr S.A. Jaffar, Director General,
Directorate General of Pharmaceutical Affairs and Drug Control, Ministry of
Health, Muscat, Oman; Johnson & Johnson, Latina, Italy; Dr R. Jhnke, Global
Pharma Health Fund e.V., Frankfurt, Germany; Dr M. James, GlaxoSmithKline,
Brentford, Middlesex, England; Dr A. Janssen, Manager, Regulatory Affairs,
57
DMV Fonterra Excipients, FrieslandCampina Ingredients Innovation, Goch,

Germany; Professor S. Jin, Chief Expert for Pharmaceutical Products, National
Institutes for Food and Drug Control, Beijing, Peoples Republic of China; Dr P.
Jones, Director, Analytical Control, Pharmaceutical Sciences, Pfizer Global R&D,
Sandwich, England; Dr H. de Jong, International Pharmaceutical Federation, The
Hague, Netherlands; Dr Y. Juillet, Consultant, Paris, France; Mr D. Jnemann,
Teaching Assistant; Institut fr Pharmazeutische Technologie, Biozentrum,
Johann Wolfgang Goethe-Universitt, Frankfurt am Main, Germany; Ms A.
Junttonen, Senior Pharmaceutical Inspector, National Agency for Medicines,
Helsinki, Finland; Dr S. Kafkala, Analytical Development Director, Genepharm
S.A., Pallini, Greece; Dr V. Kamde, Quality Management, Oman Pharmaceuticals,
Oman; Dr M. Kaplan, Director, Institute for Standardization and Control of
Pharmaceuticals, Jerusalem, Israel; Dr M. Karga-Hinds, Director, Barbados Drug
Service, Christchurch, Barbados; Dr A.M. Kaukonen, National Agency for
Medicines, Helsinki, Finland; Ms H. Kavale, Cipla, Mumbai, India; Dr T.
Kawanishi, Director General, National Institute of Health Sciences, Tokyo, Japan;
Dr S. Keitel, Director, European Directorate for the Quality of Medicines and
Healthcare, Strasbourg, France; Dr K. Keller, Director and Professor, Federal
Ministry of Health, Bonn, Germany; Dr M. Keller, Inspector, Division of
Certificates and Licencing, Swissmedic, Swiss Agency for Therapeutic Products,
Berne, Switzerland; Dr L. Kerr, Scientific Operations Adviser, Office of
Laboratories and Scientific Services, Therapeutic Goods Administration, Woden,
ACT, Australia; Mr M. Khan, United States of America Food and Drug
Administration, Silver Spring, MD, USA; Dr M. Khan, Director, Federal Research
Center Life Sciences, US Food and Drug Administration, Silver Spring, MD,
USA; Dr S. Khoja, Vapi, Gujarat, India; Professor K. Kimura, Drug Management
and Policy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa
University, Kanazawa-city, Japan; Dr W. Kongsuk, Bureau of Drug and Narcotic,
Department of Medical Sciences, Nonthaburi, Thailand; Dr H. Kszegi-Szalai,
Head, Department for Quality Assessment and Control, National Institute of

Pharmacy, Budapest, Hungary; Dr S. Kouakap, Ministre de la Sant, Cameroon;
Dr A. Kovacs, Secretariat, Pharmaceutical Inspection Co-operation Scheme,
Geneva, Switzerland; Ms S. Kox, Senior Director Scientific Affairs, European
Generic Medicines Association, Brussels, Belgium; Dr P. Kozarewicz, Scientific
Administrator, Quality of Medicines Sector, Human Unit Pre-Authorization,
European Medicines Agency, London, England; Dr A. Krauss, Principal Chemist,
Office of Laboratories and Scientific Services, Therapeutic Goods Administration,
Woden, ACT, Australia; Professor H.G. Kristensen, Vedbaek, Denmark; Dr J.
Kumar, HLL Lifecare Ltd., Kanagala, Belgaum, India; Mr A. Kupferman, Bangkok,
Thailand; Dr S. Kumar, Assistant Drugs Controller, Central Drugs Standard
Control Organization, Food and Drug Administration Bhawan, New Delhi,
India; Professor S. Ler, Institut fr Klinische Pharmazie und Pharmakotherapie,
58
Acknowledgements
Heinrich-Heine-Universitt, Dsseldorf, Germany; Dr O. Le Blaye, Inspector,

Trials and Vigilance Inspection Department, Agence nationale de scurit du
mdicament et des produits de sant, Saint-Denis, France; Dr L. Lee, Compendial
Compliance Lead, Amgen Inc., Newbury Park, California, USA; LFB
Biomdicaments, Lille Cedex, France; Dr B. Li, Deputy Director General,
National Institutes for Food and Drug Control, Ministry of Public Health, Beijing,
Peoples Republic of China; Dr H. Li, Head, Chemical Products Division, Chinese
Pharmacopoeia Commission, Beijing, Peoples Republic of China; Dr R.
Lichtenstein, Head of Business Analytics and Master Data, Galderma SA,
Lausanne, Switzerland; Dr C.M. Limoli, International Programs, Center for Drug
Evaluation and Research, United States Food and Drug Administration, Silver
Spring, MD, USA; Dr A. Lodi, Head, Laboratory Department, European
Directorate for the Quality of Medicines and HealthCare, Strasbourg, France;
MrM. Lok, Head of Office, Office of Manufacturing Quality, Therapeutic Goods
Administration, Woden, ACT, Australia; Ms M.Y. Low, Director, Pharmaceutical
Division, Applied Sciences Group, Health Sciences Authority, Singapore; Lupin
Ltd, Mumbai, Maharashtra, India; Dr J.C. Lyda, Senior Director, Regulatory
Affairs, Parenteral Drug Association Europe, Glienicke/ Berlin, Germany;
Agence du Mdicament, Madagascar; Mr D. Mader, Compliance Auditor,
GlaxoSmithKline, Cape Town, South Africa; Dr C. Makokha, Kikuyu, Kenya;
Ms G.N. Mahlangu, Director-General, Medicines Control Authority of
Zimbabwe, Harare, Zimbabwe; Mangalam Drugs and Organics Limited,
Mumbai, India; Dr M.A. Mantri, Bicholim, Goa, India; Martindale Pharma,
Brentwood, Essex, England; Dr J.Y. Martey, Accra, Ghana; Dr B. Matthews,
Alcon, Hemel Hempstead, England; Dr Y. Matthews, Regulatory Operations
Executive, GE Healthcare, Amersham, Bucks, England; Dr S.V.M. Mattos,
Especialista em Regulao de Vigilncia Sanitria, Coordenao da Farmacopeia
Brasileira, Brazilian Health Surveillance Agency, Braslia, Brazil; Dr J.L. Mazert,
France; Dr G. McGurk, Executive Inspector, Irish Medicines Board, Dublin,
Ireland; Dr A. Mechkovski, Moscow, Russian Federation; Medicines and
Healthcare Products Regulatory Agency, London, England; Medopharm,
Chennai, Tamilnadu, India; Dr M. Mehmandoust, Agence nationale de scurit
du mdicament et des produits de sant, Saint-Denis, France; Dr D. Mehta,
Vigilance and Risk Management of Medicines, Medicines and Healthcare
Products Regulatory Agency, London, England; Dr C. Mendy, Manager,
Regulatory Policy, International Federation of Pharmaceutical Manufacturers
and Associations, Geneva, Switzerland; Dr K. Mettke, GCP Inspector, Federal
Institute for Drugs and Medical Devices, Bonn, Germany; Micro Labs Ltd,
Kilpauk, Chennai, India; Dr M. Mikhail, Fresenius Kabi, Bad-Homburg,
Germany; Dr J.H.McB. Miller, Ayr, Scotland; Dr O. Milling, Medicines Inspector,
Medicines Control Division, Danish Medicines Agency, Copenhagen, Denmark;
Dr S. Mills, Pharmaceutical Consultant, Ware, England; Ministry of Health,
59
Government of Pakistan, Islamabad, Pakistan; Ministry of Health and Welfare,

Tokyo, Japan; Dr J. Mitchell, GlaxoSmithKline, Belgium; Dr S. Moglate, United
Nations Population Fund, UN City, Copenhagen, Denmark; Dr N.H. Mohd,
Director General of Medical Supplies, Ministry of Health, Muscat, Oman;
MsN.H. Mohd Potri, Senior Assistant, Director, GMP and Licensing Division,
Centre for Compliance and Licensing, National Pharmaceutical Control Bureau,
Ministry of Health Malaysia, Petaling Jaya, Malaysia; Dr J.A. Molzon, Bethesda,
MD, USA; Dr I. Moore, Product and Quality Assurance Manager, Croda Europe,
Snaith, England; Dr J. Mornas, Assistant Director, Inspection and Companies
Department, Agence nationale de scurit du mdicament et des produits de
sant, Saint Denis, France; Dr K. Morimoto, Expert, Office of Review Management,
Review Planning Division, Pharmaceutical and Medical Devices Agency, Tokyo,
Japan; Direction of Medicine and Pharmacy, Ministry of Health, Rabat, Morocco;
Dr J.M. Morris, Irish Medicines Board, Dublin, Ireland; Mr T. Moser, Galenica,
Berne, Switzerland; Dr M. Mugad, HLL Lifecare Ltd, Kanagala, Belgaum,
Karnataka, India; Dr A.E. Muhairwe, Executive Secretary and Registrar, National
Drug Authority, Kampala, Uganda; Dr. S. Mlbach, Director, Senior Regulatory
Counsellor, Vifor Pharma, Glattbrugg, Switzerland; Ms C. Munyimba-Yeta,
Director, Inspectorate and Licensing, Pharmaceutical Regulatory Authority,
Lusaka, Zambia; Dr Murthi, Accutest Research Laboratory Ltd, Navi Mumbai,
Maharashtra, India; Mylan, Allschwil, Switzerland; Mylan Laboratories Limited,
Drug Regulatory Affairs, Jinnaram Mandal, Andhra Pradesh, India; Dr D.A. van
Riet-Nales, Member Quality Working Party, European Medicines Agency, Senior
Assessor, Department of Chemical Pharmaceutical Assessments, College ter
Beoordeling van Geneesmiddelen, Utrecht, Netherlands; Ms N. Nan, Chief
Pharmacist, National Institutes for Food and Drug Control, Beijing, Peoples
Republic of China; Miss X. Nan, Project Officer, China Center for Pharmaceutical
International Exchange, Beijing, Peoples Republic of China; Mr N. Nanerjee,
Cipla Ltd, Goa, India; Dr E. Narciandi, Head, Technology Transfer Department,
Center for Genetic Engineering & Biotechnology, Havana, Cuba; National

Agency of Drug and Food Control, Jakarta Pusat, Indonesia; National Authority
of Medicines and Health Products (INFARMED), Directorate for the Evaluation
of Medicinal Products, Lisbon, Portugal; National Institute of Drug Quality
Control of Vietnam, Hanoi, Viet Nam; NBCD Working Group, Leiden,
Netherlands; Starship Hospital, New Zealand; Dr R. Neri, Sanofi, Antony, France;
Dr E. Nicklikov, Inspector, State Institute for Drug Control, Prague, Czech
Republic; Professor A. Nicolas, Radiopharmacist, Expert analyse, Pharmacie,
Hpital Brabois Adultes, Vandoeuvre, France; Dr H.K. Nielsen, Technical
Specialist, Essential Medicines, Medicines and Nutrition Centre, UNICEF Supply
Division, Copenhagen, Denmark; Professor B. Ning, Deputy Director, Division
of Chemical Drugs, National Institutes for Food and Drug Control, Beijing,
Peoples Republic of China; Dr P. Njaria, Head, Quality Assurance Unit and
60
Acknowledgements
Instrumentation, National Quality Control Laboratory, Nairobi, Kenya; Dr C.

dos Santos Nogueira, Especialista em Regulao e Vigilncia Sanitria, ANVISA,
Brasilia, Brazil; Dr K. Nodop, Inspections, European Medicines Agency, London,
England; Novartis Group Quality, Novartis, Basel, Switzerland; Professor A.
Nunn, Formby, Liverpool, England; Dr A. Ojoo, Technical Specialist, Paediatric
Formulations, United Nations Children's Fund Supply Division, Nordhavn,
Copenhagen, Denmark; Mr S. O'Neill, Managing Director, The Compliance
Group, Dublin, Ireland; Dr L. Oresic, Head, Quality Assurance Department,
Croatian Agency for Medicinal Products and Medical Devices, Zagreb, Croatia;
Dr P.B. Orhii, Director-General, National Agency for Food and Drug
Administration and Control, Abuja, Nigeria; Dr N. Orphanos, International
Programs Division, Bureau of Policy, Science, and International Programs,
Therapeutic Products Directorate, Health Products & Food Branch, Health
Canada, Ottawa, Canada; Professor T.L. Pal, Director-General, National Institute
of Pharmacy, Budapest, Hungary; Dr P.R. Pabrai, New Delhi, India; Dr R. Pai,
Johannesburg, South Africa; Mrs L. Paleshnuik, Arnprior, Ontario, Canada; Dr S.
Parra, Manager, Generic Drugs Quality Division 1, Bureau of Pharmaceutical
Sciences, Therapeutic Products Directorate, Health Canada, Ottawa, Ontario,
Canada; Mr B. Passek, BMG, Germany; Dr D.B. Patel, Secretary-General, Indian
Drug Manufacturers' Association, Mumbai, India; Dr P.S. Patil, Umedica
Laboratories Pvt Ltd, Vapi, Gujarat, India; Dr S.R. Srinivas Patnala, Grahamstown,
South Africa; Dr S. Patnala, Professor, Pharmaceutical Analysis and Coordinator,
University Instrumentation Facility, KLE University, Belgaum, India; Paul-
Ehrlich-Institut, Langen, Germany; Dr A. Pazhayattil, Apotex Inc., Toronto,
Ontario, Canada; Mr C. Perrin, Pharmacist, International Union Against
Tuberculosis and Lung Disease, Paris, France; Dr M. Phadke, Senior Manager,
Analytical Research, IPCA Laboratories, Mumbai, India; Pharmaceutical
Inspection Co-operation Scheme, Geneva, Switzerland; Pharmaceuticals and
Medical Devices Agency (PMDA), Tokyo, Japan; Dr B. Phillips, Medicines and
Healthcare Products Regulatory Agency, London, England; Dr R.D. Pickett,
Supanet, Bucks, England; Dr B. Pimentel, European Chemical Industry
Council, Brussels, Belgium; Polychromix, Inc., Wilmington, MA, USA; Dr A.
Pontn-Engelhardt, Head of Stability Management, Global Quality, Operations,
AstraZeneca, Sdertlje, Sweden; Ms A. Poompanich, Bangkok, Thailand; Dr H.
Potthast, Federal Institute for Drugs and Medical Devices, Berlin, Germany;
Dr R. Prabhu, Regulatory Affairs Department, Cipla, Mumbai, India; Dr J.
Prakash, Principal Scientific Officer, Indian Pharmacopoeia Commission, Raj
Najar, Ghaziabad, India; Dr P.B.N. Prasad, Deputy Drugs Controller (India),
Central Drugs Standard Control Organisation, Bhavan, S.R.Nagr, Hyderabad,
India; Dr R.P. Prasad, Director, Department of Drug Administration,
Kathmandu, Nepal; Ms S.J. Putter, Walmer, Port Elizabeth, South Africa; Quality
Systems and Standards Group Quality, Novartis Pharma AG, Basel, Switzerland;
61
Ms M.-L. Rabouhans, Chiswick, London, England; Dr M. Rafi, Assistant Manager

(Regulatory Affairs), HLL Lifecare Limited, Belgaum, Karnataka, India; Dr A.
Rajan, Director, Celogen Lifescience & Technologies, Mumbai, India; Mr T.L.
Rauber, Specialist in Health Surveillance, Agncia Nacional de Vigilncia
Sanitria Agency, Brasilia, Brazil; Mr N. Raw, Inspection, Enforcement and
Standards Division, Medicines and Healthcare Products Regulatory Agency,
London, England; Mr N. Rech, Brazilian Pharmacopoeia, Brazilian Health
Surveillance Agency, Brasilia, DF, Brazil; Dr J.-L. Robert, Luxembourg; Dr S.
Rnninger, Global Quality Manager, F. Hoffmann-La Roche, Basel, Switzerland;
Dr J. Isasi Rosas, CNCC, Chorrillos, Lima, Peru; Dr N. Ruangrittinon, Bureau of
Drug and Narcotic Department of Medical Sciences, Ministry of Public Health,
Nonthaburi, Thailand; Dr J. Sabartova, Prague, Czech Republic; Dr L.A. Sotelo
Ruiz, Comisin de Control Analtico y Ampliacin de Cobertura, Tlalpan,
Distrito Federal, Mexico; Rusan Pharma Ltd, Selaqui, Dehradun, India; Dr P.L.
Sahu, Indian Pharmacopoeia Commission, Raj Nagar, Ghaziabad, Uttar Pradesh,
India; Dr E.I. Sakanyan, Director, Centre of the Pharmacopoeia and International
Collaboration, Federal State Budgetary Institution, Scientific Centre for Expert
Evaluation of Medicinal Products, Moscow, Russian Federation; Dr C. Snchez
Gonzlez, Adviser, Centre para el Control de Medicamentos, Equipos y
Dispositivos Mdicos, Havana, Cuba; Dr E. Moya Snchez, Radiofarmaceutica-
Evaluadora de Calidad, Divisin de Qumica y Tecnologa Farmacutica,
Departamento de Medicamentos de Uso Umano, Agencia Espaola de
Medicamentos y Productos Sanitarios, Madrid, Spain; Sanofi Aventis, Antony,
France; Sanofi, Bridgewater, NJ, USA; Dr G. Mendes Lima Santos, Coordinator
of Therapeutic Equivalence, Brazilian Health Surveillance Agency, Brasilia, DF,
Brazil; Dr B. Santoso, Sleman, Yogyakarta, Indonesia; Dr T. Sasaki, Pharmaceutical
and Medical Devices Agency, Tokyo, Japan; Dr J. Satanarayana, Matrix
Laboratories, Secunderabad, India; Dr B. Schmauser, Bundesinstitut fr
Arzneimittel und Medizinprodukte, Bonn, Germany; Dr A. Schuchmann, Brazil;
Dr I. Seekkuarachchi, Project Manager, Takeda Pharmaceutical Co., Osaka,

Japan; Dr A. Seiter, Member, United States Pharmacopeia International Health
Expert Committee, Rockville, MD, USA; Ms K. Sempf, Teaching Assistant,
Institut fr Pharmazeutische Technologie, Biozentrum, Johann Wolfgang
Goethe-Universitt, Frankfurt am Main, Germany; Dr U. Shah, Formulation
Research Fellow, Cheshire, Merseyside & North Wales LRN, Medicines for
Children Research Network, Royal Liverpool Children's NHS Trust, Liverpool,
England; Dr R. Shaikh, Pakistan; Shasun Research Centre, Chennai, Tamil Nadu,
India; Dr P.D. Sheth, Vice-President, International Pharmaceutical Federation,
New Delhi, India; Ms R. Shimonovitz, Head of Inspectorates, Institute for
Standardization and Control of Pharmaceuticals, Ministry of Health, Israel; Shin
Poong Pharmaceutical Co. Ltd, Seoul, Republic of Korea: Dr P.G. Shrotriya,
Ambli, Ahmedabad, India; Dr M. Sigonda, Director-General, Tanzania Food and
62
Acknowledgements
Drugs Authority, Dar-es-Salaam, United Republic of Tanzania; Dr G.L. Singal,

Drugs Controller of Haryana, Department of Health Services, Civil Dispensary,
Panchkula, Haryana, India; Dr A.K. Singh, Daman, India; Dr G.N. Singh,
Secretary-cum-Scientific Director, Government of India, Central Indian
Pharmacopoeia Laboratory, Ministry of Health and Family Welfare, Raj Nagar,
Ghaziabad, India; Dr S. Singh, Professor and Head, Department of Pharmaceutical
Analysis, National Institute of Pharmaceutical Education and Research, Nagar,
Punjab, India; Ms K. Sinivuo, Senior Researcher and Secretary, National Agency
for Medicines, Helsinki, Finland; Dr L. Slamet, Jakarta Selatan, Indonesia; Mr D.
Smith, Faerie Glen, Pretoria, South Africa; Dr R. Smith, Wolfson Brain Imaging
Centre, University of Cambridge, Cambridge, England; Dr N. Kumar Soam,
Mankind Pharma Limited, Unit-II, Vill. Kishanpura, Paonta Sahib, Disst.
Sirmour, India; Dr M. Da Luz Carvalho Soares, Expert Health Regulation,
Brazilian Health Surveillance Agency, Brasilia, Brazil; Dr C. Sokhan, Deputy
Director, Department of Drug and Food, Phnom Penh, Cambodia; Dr A.
Spreitzhofer, AGES PharmMed, Vienna, Austria; Mr K. Srinivas, Group Legal
Counsel, Trimulgherry, Secunderabad, Andhra Pradesh, India; State Regulatory
Agency for Medical Activities, Ministry of Labour, Health and Social Affairs,
Tbilisi, Georgia; Dr J.A. Steichen, Manager, Regulatory and Quality Compliance
Services, Safis Solutions, LLC, Indianapolis, IN, USA; Dr Y. Stewart, Scientific,
Technical and Regulatory Affairs, European Federation of Pharmaceutical
Industries and Associations, Brussels, Belgium; Dr L. Stoppa, Inspections &
Certifications Department, Manufacturing Authorisation Office, Italian
Medicines Agency, Rome, Italy; Dr R.W. Stringham, Scientific Director, Drug
Access Team, Clinton Health Access Initiative, Boston, MA, USA; Dr N. Sullivan,
Director, Sensapharm, Sunderland, England; Mr Philip Sumner, Pfizer Global
Engineering, New York, NY, USA; Dr Sun Cuilain D., Senior Analytical Scientist,
Pharmaceutical Laboratory, Pharmaceutical Division, Applied Sciences Group,
Health Sciences Authority, Singapore; Dr V. Suvarna, Medical Director,
Boehringer Ingelheim India Private Limited, India; Dr E. Swanepoel, Head,
Operations, Research Institute for Industrial Pharmacy, North-West University,
Potchefstroom, South Africa; Professor M. Sznitowska, Department of
Pharmaceutical Technology, Medical University of Gdansk, Gdansk, Poland;
DrK. Tadano, Committee of the Japanese Pharmacopoeia, Tokyo, Japan; Dr K.
Takahashi, Senior Policy Advisor, Division of Regulations, Guidance and
Standards, Office of Policy for Pharmaceutical Quality, Center for Drug Evaluation
and Research, Food and Drug Administration, Silver Spring, MD, USA; Tanzania
Food and Drugs Authority, Dar-es-Salaam, United Republic of Tanzania; Dr D.
Teitz, Manager, Bristol-Myers Squibb Company, New Brunswick, NJ, USA; Teva
API Division, Petah Tiqva, Israel; Dr N. Thao, National Institute of Drug Quality
Control, Hanoi, Viet Nam; Dr B.B. Thapa, Chief Drug Administrator, Department
of Drug Administration, Ministry of Health and Population, Kathmandu, Nepal;
63
The Danish Medicines Agency, Denmark; Dr R. Torano, Pharmacopoeial

Technical Expert, GlaxoSmithKline, Co. Durham, England; Dr P. Travis, Team
Leader Compendial Affairs Group, Pfizer Inc., Parsippany, NJ, USA; Ms M.
Treebamroong, Senior Pharmacist, Drug Quality and Safety, Department of
Medical Sciences, Bureau of Drug and Narcotic, Ministry of Public Health,
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Trinh Van Lau, Director, National Institute of Drug Quality Control, Hanoi, Viet
Nam; Professor Tu Guoshi, National Institute for the Control of Pharmaceutical
and Biological Products, Ministry of Public Health, Beijing, Peoples Republic of
China; Dr C. Tuleu, Senior Lecturer and Deputy Director, Department of
Pharmaceutics and Centre for Paediatric Pharmacy Research, School of
Pharmacy, University of London, London, England; Dr Richard Turner, British
Pharmacopoeia Commission, Medicines and Healthcare Products Regulatory
Agency, London, England; United States of America Food and Drug
Administration, Center for Drug Evaluation and Research, Silver Spring, MD,
USA; United States of America Food and Drug Administration, Office of
Pediatric Therapeutics, Office of the Commissioner, Rockville, MD, USA; Ms E.
Uramis, GMP Advisor, Oficina Central Polo Cientfico, Havana, Cuba; Dr A.R.T.
Utami, National Agency for Drugs and Food Control, Jakarta Pusat, Indonesia;
Dr R. Vaillancourt, International Pharmaceutical Federation, The Hague,
Netherlands; Validation and Qualification Department, Pharmaceutical
Laboratory, Esteve, Spain; Mrs M. Vallender, Editor-in-Chief, British
Pharmacopoeia Commission Secretariat, London, England; Mr M. van Bruggen,
EU Liaison Regulatory Intelligence, F. Hoffmann-La Roche, Basel, Switzerland;
Mr F. Vandendriessche, Merck, Sharp and Dohme Europe, Brussels, Belgium;
Mr P. van der Hoeven, APIC, Brussels, Belgium; Dr J.E. van Oudtshoorn,
Pretoria, South Africa; Dr A.J. van Zyl, Sea Point, Cape Town, South Africa;
DrG. Vedoya, CABA, Instituto Nacional de Medicamentos (INAME/ANMAT),
Argentina; Mr S. Akbaralli Veljee, Director, Food and Drugs Administration,
Directorate of Food and Drugs Administration, Government of Goa,

Dhanwantari, Bambolim, Goa, India; Dr A. Kumar Velumury, Cipla Ltd, New
Delhi, India; Mr A. Vezali Montai, Specialist in Regulation and GMP, Agncia
Nacional de Vigilncia, Braslia, Brazil; Mrs L. Vignoli, Regulatory Affairs,
Pharmaceuticals and Cosmetics, Roquette Cie, Lestren, France; Dr O. del Rosario
Villalva Rojas, Executive Director, Quality Control Laboratories, National
Quality Control Center, National Institute of Health, Lima, Peru; Mr L. Viornery,
Agence nationale de scurit du mdicament et des produits de sant, Saint
Denis, France; Dr L. Virgili, USA; Mr J. Wang, Deputy Commissioner, Dalian
Food and Drug Administration, Dalian, Liaoning, Peoples Republic of China;
Mr P. Wang, Deputy Secretary-General, Chinese Pharmacopoeia Commission,
Beijing, Peoples Republic of China; Mrs T. Wang, Deputy Director, Shenzhen
Municipal Institute for Drug Control, Shenzhen, Peoples Republic of China;
64
Acknowledgements
DrG. Wanganga, Head, Microbiological and Medical Devices Units, National

Quality Control Laboratory, Nairobi, Kenya; Dr A. Ward, Regulatory Affairs,
Avecia Vaccines, Billingham, England; Dr D. Waters, Acting Scientific Operations
Advisor, Office of Laboratories and Scientific Services, Therapeutic Goods
Administration, Woden, ACT, Australia; Dr W. Watson, Associate Manager,
CMC Regulatory Affairs, Gilead Sciences International, Cambridge, England;
Dr J. Welink, Medicines Evaluation Board, Utrecht, Netherlands; Ms Wei N.,
Associate Researcher, Division of Chemical Drugs, National Institutes for Food
and Drug Control, Beijing, China; Professor W. Wieniawski, Polish Pharmaceutical
Society, Warsaw, Poland; Mr J. Wilkinson, Director, Devices, Medicines and
Healthcare products Regulatory Agency, London, England; Dr J. Skutnik
Wilkinson, Biogen, Oneco, CT, USA; Dr M. Jiwo Winanti, Senior GMP Inspector,
National Authority for Food and Drug Control, Indonesia; Dr S. Wolfgang, US
Food and Drug Administration, Silver Spring, MD, USA; Mr E. Wondemagegnehu
Biwota, Addis Ababa, Ethiopia; World Self-Medication Industry, Ferney-Voltaire,
France; Dr B. Wright, Group Manager, GMP/GDP, North East Region, Medicines
Inspectorate, Medicines and Healthcare Products Regulatory Agency, York,
England; Professor Z.-Y. Yang, Guangzhou Municipal Institute for Drug Control,
Guangzhou, Peoples Republic of China; Professor Z.-Y. Yang, Member, United
States Pharmacopeia International Health Expert Committee, Rockville, MD,
USA; Ms C. Munyimba-Yeta, Director Operations (Plant), NRB Pharma Zambia
Limited, Lusaka South Multi Facility Economic Zone, Lusaka, Zambia; Dr D. Yi,
Scientist, US Pharmacopeia, Rockville, MD, USA; Dr H. Yusufu, National Agency
for Food and Drug Administration and Control, Abuja, Nigeria; Dr M. Zahn,
Keltern, Germany; Dr H. Zhang, GMP Department Head, Center for Certification
& Evaluation, Shanghai Food and Drug Administration, Shanghai, Peoples
Republic of China; Dr G. Zenhusern, Senior Case Manager, Sector Authorisation,
Swissmedic, Berne, Switzerland; Professor (Mrs) Zhang M., Deputy Director,
Institutes for Food and Drug Control, and Vice Chairman, Antiobiotic
Subcommittee, Chinese Pharmacopoeia Commission, China; Dr T. Zimmer, CD
Safety, Quality & Environmental Protection, Boehringer Ingelheim, Ingelheim,
Germany; Dr N. Zvolinska, Deputy Director, Pharmaceutical Department, State
Pharmacological Centre, Ministry of Health, Kiev, Ukraine.
65
Annex 1
Good pharmacopoeial practices
1. Background 68
2. Purpose and scope of good pharmacopoeial practices 69
3. Glossary 69
4. Benefits of good pharmacopoeial practices 70
5. Implementation 70
6. Monograph development 70
6.1 General considerations 71
6.1.1 Adoption of pharmacopoeial standards 72
6.1.2 Open and transparent process 73
6.1.3 Harmonization 73
6.1.4 Legal recognition 73
6.1.5 Compliance with a pharmacopoeial monograph 74
6.1.6 Analytical requirements 74
6.1.7 Acceptance criteria 74
6.2 Technical guidance 74
6.2.1 Monographs for pharmaceutical substances 75
6.2.2 Monographs for finished pharmaceutical products 80
7. Analytical test procedures and methods 84
67
1. Background
A pharmacopoeias core mission is to protect public health by creating and
making available public standards to help ensure the quality of medicines.
Pharmacopoeia standards support regulatory authorities in controlling the quality
of pharmaceutical substances, their finished pharmaceutical products (FPPs)
and related materials and will provide a tool with which the user or procurer can
make an independent judgement regarding quality, thus safeguarding the health
of the public.
Today there are 49 pharmacopoeias in the world (according to the World
Health Organization (WHO) list of pharmacopoeias, 2015). There are differences
between these pharmacopoeias, including the use of technology reflected in each
pharmacopoeia as well as the breadth of medicines and other articles included.
Pharmacopoeias are embedded in their respective national or regional regulatory
environment and reflect specifications approved by the regulatory body.
Efforts towards pharmacopoeial harmonization started more than a
century ago. When WHO was created in 1948, this was included in its mandate.
This led to the creation of The International Pharmacopoeia, which was the first
global pharmacopoeial activity. Many others followed.
Pharmacopoeial harmonization has been defined by the Pharmacopoeial
Discussion Group (PDG) as when a pharmaceutical substance or product
tested by the documents harmonized procedure yields the same results and the
same accept/reject decision is reached.
Developments in science and medical practice, globalization and the
presence of spurious/falsified/falsely labelled/counterfeit (SFFC) products require
pharmacopoeias to continuously revise their monographs and other text.
Harmonization and reinforced collaboration among pharmacopoeial committees
and regulators, supported by adequate interaction with industry, will assist in
facing new challenges and resource constraints.
WHO Technical Report Series No. 996, 2016
The first initiative to reopen the discussion on international harmonization

of quality control specifications on a global scale was taken in a side meeting of the
10th International Conference of Drug Regulatory Authorities (ICDRA) entitled:
Pharmacopoeial Specifications Need for a Worldwide Approach? in Hong
Kong on 24 June 2002. This led to further discussions among regulators during
the 11th ICDRA meeting held in Madrid in 2004. Other international events
during the following years enabled discussions with and among pharmacopoeias
on this topic.
The main suggestion emerging from all these events was the development
of good pharmacopoeial practices (GPhP) to encourage harmonization,
facilitated by WHO.
It was agreed to develop the GPhP under the auspices of the WHO Expert
Committee on Specifications for Pharmaceutical Preparations, benefiting from
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Annex 1
its well-established international standard-setting processes and procedures.

These processes include an international consultation process, which enables
the participation of all stakeholders and users in the development process. The
final guidance would then be presented, in line with the procedure, to WHOs
194Member States and pharmacopoeial authorities.
2. Purpose and scope of good pharmacopoeial practices

The primary objective of the GPhP guidance is to define approaches and
policies in establishing pharmacopoeial standards with the ultimate goal of
harmonization.
These GPhP describe a set of principles that provide guidance for national
pharmacopoeial authorities (NPAs) and regional pharmacopoeial authorities
(RPAs) that facilitates the appropriate design, development and maintenance of
pharmacopoeial standards.
Although the principles may also apply to other products, the focus
ofthese good practices is pharmaceutical substances and FPPs.
3. Glossary
Terms in this document are used in accordance with WHO terminology,
while recognizing that individual pharmacopoeias may apply their own
nomenclaturepolicies.
active pharmaceutical ingredient. Any substance or mixture of
substances intended to be used in the manufacture of a pharmaceutical dosage
form and that, when so used, becomes an active ingredient of that pharmaceutical
dosage form. Such substances are intended to furnish pharmacological activity
or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention
of disease or to affect the structure and function of the body.
dosage form. The form of the completed pharmaceutical product, e.g.
tablet, capsule, elixir, suppository or injection.
excipient. A substance or compound, other than the active pharmaceutical
ingredient and packaging materials, that is intended or designated to be used in
the manufacture of a pharmaceutical product.
finished pharmaceutical product. A finished dosage form of a
pharmaceutical product that has undergone all stages of manufacture, including
packaging in its final container and labelling.
period of use. Utilization period of multidose products after opening,
reconstitution or dilution of a solution.
pharmaceutical substance. Any substance of a defined quality used in
the production of a pharmaceutical product, but excluding packaging materials.
This includes active pharmaceutical ingredients and pharmaceutical excipients.
69
shelf life. The period of time during which a pharmaceutical product, if

stored as indicated on the label, is expected to comply with the specification as
determined by stability studies on a number of batches of the product. The shelf
life is used to establish the expiry date of each batch.
4. Benefits of good pharmacopoeial practices

GPhP are designed to facilitate collaboration among pharmacopoeias, leading
to possibilities for work-sharing, harmonization of standards and the recognition
of published standards between NPAs and RPAs.
In addition to the above, the establishment of GPhP may result in
thefollowing:
1) strengthening of global pharmacopoeial cooperation;
2) providing stakeholders with a better understanding of how
pharmacopoeial standards are developed and maintained in a
transparent manner;
3) improving cooperation between NPAs/RPAs and stakeholders (e.g.
regulators, pharmaceutical industry) with a view to facilitating
the harmonization of pharmacopoeial standards and reducing
duplication of work;
4) increasing access to and the availability of affordable,
qualitymedicines.
By establishing common practices, GPhP can facilitate adoption or
adaptation of the standards from one pharmacopoeia by another pharmacopoeia,
proactively harmonizing the requirements with considerably less effort than is
currently needed.
GPhP should ultimately enable harmonization of pharmacopoeial
standards.
5. Implementation
While the implementation of the GPhP by NPAs and RPAs is voluntary, it is
recommended and encouraged, as a high level of participation will result in
greater benefit to the stakeholders and ultimately to patients.
6. Monograph development
Development of a monograph requires consideration of information and
candidate materials. This information may come from donors, literature, various
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Annex 1
publicly available sources, from other pharmacopoeias, or may be generated

within the laboratory resources of a pharmacopoeia and/or of a competent
authority (such as an official medicines control laboratory). The draft text should
be displayed for public comments with sufficient time allowed for review and
input by stakeholders.
Pharmacopoeias are encouraged to conform, where possible, to the
work of harmonization initiatives (e.g. WHO, International Conference on
Harmonisation of Technical Requirements for Registration of Pharmaceuticals
for Human Use (ICH) and the PDG)).
6.1 General considerations

Pharmacopoeial monographs provide an important tool for assurance of the
quality of marketed pharmaceutical ingredients and products through testing of
their quality. They generally cover chemical, biological and herbal FPPs and their
ingredients, which have either been approved by national regulatory authorities
or are otherwise legally marketed. Some pharmacopoeias also include standards
for items such as natural products, nutritional products and medical devices.
The principles of GPhP apply equally to substances and products used in both
human and veterinary medicine. It is recognized that different requirements may
be applied to human and veterinary medicines, such as those included in the ICH
and the corresponding Veterinary International Conference on Harmonization
(VICH) requirements.
Specifications in pharmacopoeias are one facet of the overall control
of the quality of FPPs and their ingredients (active pharmaceutical ingredients
(APIs) and excipients). Monographs provide publicly available standards that a
product or a component of a product is expected to meet during its shelf life. Thus,
a substance should be able to demonstrate compliance with a pharmacopoeial
monograph up to the point at which it is used to prepare an FPP. An FPP should
demonstrate compliance with a monograph, if available, throughout its shelf
life. Pharmacopoeial specifications are used within pharmaceutical product
marketing authorization systems and by manufacturers, suppliers, purchasers
and those acting on behalf of patients.
Before developing a monograph it is important to consider the
specifications (tests and acceptance criteria) needed to assure the quality of a
given pharmaceutical substance or FPP. Specifications that limit market access
by, for example, favouring one manufacturer to the exclusion of others should
be avoided.
The ICH guideline Q6A (Specifications: test procedures and acceptance
criteria for new drug substances and new drug products: chemical substances), for
example, could be used as a basis. Whenever possible, specifications should be
applied consistently in monographs across all participating pharmacopoeias,
71
regardless of whether the requirements are specified in the specific monograph

or are incorporated in general monographs. However, there may be situations
where different acceptance criteria are required depending on the national or
regional regulatory authorities. Additional tests might be added by NPAs and
RPAs, depending on national or regional regulations.
Pharmacopoeial standards allow independent testing and are a critical
part of the safety net of standards that help ensure the quality, safety and
efficacy of FPPs. They are closely allied with good manufacturing practice
(GMP) standards.
Pharmacopoeial standards should be available for FPPs and their APIs
and associated materials at an appropriate time to support and benefit patients
through the availability of medicines with consistent quality. They are usually
based on the shelf-life specifications approved by regulatory authorities1 or on the
specifications of unlicensed products (e.g. compounded and other preparations,
as defined by national or regional regulations).
The monographs may employ various validated analytical procedures
for the tests that are designed to be suitable for a competent analyst to perform
using established technologies and facilities.
Pharmacopoeial standards are public standards that are science-based
and data-driven and based on sound analytical measurement and accompanying
validation data.
Pharmacopoeias respect the intellectual property of donors and
recognize the importance of maintaining the confidentiality of proprietary
third-party information. Pharmacopoeias endeavour to work collaboratively
with regulators (including medicines regulatory authorities, official medicines
control laboratories and inspectorates), the pharmaceutical industries (including
manufacturers and trade associations), academia, health-care professionals
and patient advocacy groups (as appropriate), and other stakeholders in the
development of public standards.
6.1.1 Adoption of pharmacopoeial standards

(a) Text in a pharmacopoeial monograph or general chapter is approved by an
expert body of the pharmacopoeia, following publicly available rules and
procedures. This includes public consultation and the application of conflict
of interest and confidentiality rules.
(b) Reference standards cited in a pharmacopoeia are also approved by a
pharmacopoeial expert body.
In the case of The International Pharmacopoeia this relates to the shelf-life specifications evaluated by the
1
WHO Prequalification Team.

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Annex 1
6.1.2 Open and transparent process

Pharmacopoeial standards are based on current scientific knowledge and reflect
the quality of pharmaceutical substances and FPPs available.
Pharmacopoeias ensure openness and transparency throughout the
development and revision of monographs and other texts, which includes:
i. engaging stakeholders in the routine development and revision
of pharmacopoeial standards through adequate and timely public
notice and comment;
ii. engaging stakeholders in the timely development and revision
ofstandards to address major public health concerns;
iii. general transparency of the pharmacopoeial approaches,
including making work programmes publicly available;
iv. good communication with stakeholders through forums,
workshops and other interactions;
v. timely response to user enquiries;
vi. opportunities for user training and education on the
pharmacopoeial process and finalized standards;
vii. rapid correction of errors published in compendial text,
whennecessary;
viii. timely and appropriate revision and/or withdrawal of compendial
standards, when necessary. (The legal status of monographs that
have been withdrawn will depend on the national regulatory
framework.)
6.1.3 Harmonization
Pharmacopoeias should harmonize standards wherever possible through
monographs and general chapters. Harmonization may occur through several
processes including, but not limited to: adoption or adaptation2 of existing
standards; development of a new standard through coordinated consideration
(prospective harmonization); revision of a standard between two or more
pharmacopoeias (bilateral or multilateral harmonization); and creation or
revision of standards through a harmonization initiative (e.g. PDG).
6.1.4 Legal recognition

Pharmacopoeial monographs may acquire legal status and then provide a basis
for enforcement depending on applicable national or regional requirements.
The source of the text should be indicated.

2
73
6.1.5 Compliance with a pharmacopoeial monograph

Any pharmaceutical substance or FPP subject to a monograph must comply with
all of the mandatory requirements within the pharmacopoeia, throughout its
period of use or shelf life.
The assays and tests described are the official methods upon which the
standards of the pharmacopoeia depend. The analyst may not be precluded from
employing alternative methods depending on national and regional legislation.
A validation of the alternative analytical procedure should be done to show at
least an equivalent performance to the analytical procedure described in the
monograph. Subject to regulatory approval an alternative method of analysis may
be used for routine analytical purposes. In this case it is necessary to provide a
rationale for its inclusion, validation data and data comparing results obtained
using the pharmacopoeial method and the alternative method.
In case of doubt or dispute, the official pharmacopoeial methods prevail
and are alone authoritative.
6.1.6 Analytical requirements

Pharmacopoeial procedures and acceptance criteria are set with the intention
that they should be used as compliance requirements and not as requirements to
guarantee total quality assurance.
To achieve maximum benefit from the examination of a product, the
recommended approach is that, wherever possible, a variety of different analytical
techniques should be employed, considering the feasibility and affordability of
the methods.
6.1.7 Acceptance criteria

Acceptance criteria are numerical limits, ranges or other suitable measures
foracceptance of the results of analytical testing to allow determination of pass/
fail criteria. Acceptance criteria indicated in a pharmacopoeial monograph allow

for analytical error, for unavoidable variations in manufacturing processes and for
deviations to an extent considered acceptable under practical storage conditions.
They provide standards with which pharmaceutical substances or FPPs must
comply throughout their shelf life or period of use.
6.2 Technical guidance

The technical guidance provided in this section shall be considered as the
minimum requirements agreed between the participating pharmacopoeias.
They do not preclude national or regional pharmacopoeias from supplementing
such requirements in their monographs in accordance with national or regional
regulations.
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6.2.1 Monographs for pharmaceutical substances

Prior to the preparation of any monograph it is essential to gather as much
information as possible on the substance in question.
In particular it is necessary to ascertain:
the origin of the substance;
the method(s) of preparation of the substance, if needed;
whether the substance is a mixture or a single entity;
whether different entities (e.g. acid, base or salt) are available;
the physicochemical characteristics of the substance that contribute
to its identity and classification, for example, solubility or optical
rotation;
whether there are differences in physical form, for example,
crystallinity or polymorphism, since these properties may affect the
behaviour of the substance;
whether a single optical isomer (e.g. enantiomer) as well as mixtures
of isomers (e.g. racemate) are available;
whether anhydrous or different hydrates or solvates are available.
Substances that are to be described in a monograph may be members of
a group of very similar substances. A general monograph may be drafted stating
the attributes common to all members of the group and that can be used to
identify single members of the group.
6.2.1.1 Monograph title

The International Nonproprietary Name (INN) or modified INN (INNM)
established by WHO should be considered for use wherever it is available,
while recognizing that individual pharmacopoeias may apply their own
nomenclature policies.
6.2.1.2 General information to define the pharmaceutical substance

A pharmacopoeial monograph includes information regarding the pharmaceutical
substance, such as:
graphic formula;
empirical/molecular formula and relative molecular mass (the
latter is calculated based on the figures of the International Table of
Relative Atomic Masses considering, where appropriate, the degree
of hydration);
Chemical Abstracts Service (CAS) registry number, if available;
75
chemical name;
the possible existence of isomers, so as to be able to specify either
which isomer is present or to state that the substance is a mixture
ofisomers;
in the case of an optical isomer, the absolute configuration is
given by the R/S system at the asymmetrical centre(s) or any other
appropriate system (e.g. for carbohydrates and amino acids);
state of hydration or solvation, where relevant, ascertaining thestate
of hydration or solvation by an appropriate technique in order
to distinguish clearly between substances which are well-defined
hydrates and solvates and those that contain variable quantities of
water or solvent(s):
for well-defined hydrates or solvates, water or solvent content
ranges are specified;
for substances containing variable amounts of water or solvents,
only a maximum content is given;
where substances exist as both non-hydrated (or non-solvated)
and hydrated (or solvated) forms, and if all these forms are used
and can be clearly distinguished, they may be treated as individual
substances depending on the regulatory approach prevailing in
the country or region.
In therapeutics, well-defined chemical combinations or even mixtures
are sometimes used. In such cases it is necessary to specify precisely each
component of the combination or mixture, with its chemical structure and the
proportion in which it is present.
6.2.1.3 Content
Assay limits are specified between which the content must fall. In certain
instances the content may be given only as a lower limit. The assay limits take
account of the precision of the method as well as the acceptable purity of the
substance. Assay limits are normally expressed with reference to the dried,
anhydrous and/or solvent-free substance.
In setting limits for the API content, account is taken of:
the method of preparation, which determines the degree of purity
that may be reasonably required;
the precision and accuracy of the analytical method;
where a separation technique is employed both for the test for related
substances and the assay, content limits are set taking into account the
maximum permitted amount of impurities and the analytical error;
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Annex 1
the evaluation of the extent of degradation during storage (since

the limits are intended to apply throughout the shelf life of the
substance and not just at the time of release testing);
a sufficient number of experimental results obtained on several
batches (at least three), if possible, of different origins and ages.
6.2.1.4 Qualitative properties of the pharmaceutical substance

The statements under this heading are not to be interpreted in a strict sense and
are not to be regarded as analytical requirements. Caution statements may be
included here.
The principal characteristics that may be referred to are:
appearance;
solubility;
stability factors;
hygroscopicity;
solid-state properties;
other characteristics, as necessary.
6.2.1.5 Identification
The tests given in the identification section are not designed to give a full
confirmation of the chemical structure or composition of the substance. They
are intended to give confirmation, with an acceptable degree of assurance, that
the substance is the one stated on the label. The specificity of the identification
should be such that pharmaceutical substances exhibiting similar structures
can be distinguished. When an identification series is being investigated it is
desirable that other similar substances, whether or not they are the subject of
monographs of the pharmacopoeia, are examined at the same time to ensure that
a particular combination of tests within a series will successfully distinguish one
similar substance from another. False-positive reactions caused by the presence
of known impurities should be avoided.
Some of the purity tests in a monograph may also be suitable for
identification purposes, possibly in a modified form. A system of cross-references
to the section(s) can be exploited. This is particularly relevant in cases where
distinction between closely related materials depends on properties that are also
parameters in purity or composition control. In some cases an organic impurity
procedure may be introduced to differentiate the analyte from similar, common,
dangerous adulterants.
In the case of monographs for similar pharmaceutical substances,
identification of the type of substances may be supplemented by selective but
discriminating tests to identify individual members of the group.
77
6.2.1.6 Impurities and other tests

Certain tests may apply to special grades (e.g. parenteral preparations, dialysis
solutions) or a test may have a special limit for a particular use: the particular
application of a test/limit is indicated within the test.
6.2.1.6.1 Organic impurities

This section is principally directed at limiting impurities in chemical substances.
In the interests of transparency, information may be included on the
impurities controlled by a test and the approximate equivalent (e.g. percentage
or parts per million) of the prescribed limit in terms of the defined impurities or
class of impurities.
Monographs should include tests and acceptance criteria for impurities
that are likely to occur in substances used in approved medicinal products,
insofar as the necessary information and samples (substance and impurities)
are available from the producers.
Monographs on organic chemicals usually have a test entitled Related
substances (or a test with equivalent purpose under a different title), designed
to control related organic impurities. Impurities to be controlled include
intermediates and by-products of synthesis, co-extracted substances in products
of natural origin and degradation products.
Monographs on pharmaceutical substances should take account of
the principles defined in ICH guideline Q3A (R2) (Impurities in new drug
substances), or comparable guidelines, and follow regulatory decision-making.
Products of fermentation and semi-synthetic products derived therefrom
should be limited applying the same principles, but should be covered by
thresholds considered appropriate for these substances. The same principle
applies to excipients.
Unusually potent or toxic impurities. In addition to the above-mentioned
requirements, impurities that are unusually potent or produce toxic or unexpected
pharmacological effects need to be specifically considered. In this context,

requirements for genotoxic impurities may be followed.
Monographs frequently have to be designed to cover different impurity
profiles because of the use of different synthetic routes and purification
procedures.
For pharmacopoeial purposes the objective of a purity test using a
separation method will usually be the control of impurities derived from one or
more known manufacturing processes and decomposition routes. However, the
experimental conditions, especially the detection system, are chosen for the test
so as not to make it unnecessarily narrow in scope.
Where monographs include a chromatographic method, this should
provide a reliable means of locating all specified impurities on the chromatogram.
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Annex 1
6.2.1.6.2 Inorganic impurities

Inorganic impurities include reagents, ligands and catalysts, elemental impurities,
inorganic salts and other materials such as filter aids (where relevant).
Where known impurities are present, these are typically covered by
specific tests.
6.2.1.6.3 Residual solvents

When applicable, residual solvents need to be controlled, for example, as
outlined in the ICH guideline Q3C (Impurities: guideline for residual solvents).
6.2.1.6.4 Other tests

The following tests should be considered, but are not limited to:
foreign anions and/or cations;
loss on drying;
semi-micro determination of water (Karl Fischer);
micro determination of water (colorimetric titration);
sulfated ash/residue on ignition;
residue on evaporation;
sterility;
microbiological quality;
bacterial endotoxins.
6.2.1.7 Assay
Assays are included in monographs unless, for example:
all the foreseeable impurities can be detected and limited with
sufficient precision;
certain quantitative tests, similar to assays, are carried out with
sufficient precision;
the tests performed are sufficient to establish the quality of the
substance (usually a non-active ingredient, for example, ethanol
andwater).
In certain cases more than one assay may be necessary, for example,
when the substance to be examined consists of a combination of two parts that
are not necessarily present in absolutely fixed proportions, so that the assay of
only one of the two constituents does not make it possible to determine correctly
the content of the substance as a whole.
79
In the case of well-defined salts, the assay of only one of the components,
preferably the pharmacologically active component, is generally considered
sufficient.
6.2.2 Monographs for finished pharmaceutical products

General tests and acceptance criteria that are applied to a specific pharmaceutical
dosage form (and are not specific to a particular formulation) may be grouped
together, for example, uniformity of mass/content, friability and disintegration as
applied to tablet testing. These tests may be included in a general monograph for
a pharmaceutical dosage form, in this example, tablets, as the test procedures
are the same for all tablets.
Specific tests group together those procedures that are required
to provide evidence that an FPP is of a suitable quality, and are specific to a
particular pharmaceutical dosage form. As an example, tests described in tablet
monographs may include identification, related substances, assay and dissolution.
Specific tests are designed to control the purity, composition and release; these
tests are dependent on the pharmaceutical substance.
Prior to the preparation of any monograph it is essential to gather as
much information as possible on the product in question. In particular it is
necessary to ascertain:
if the FPP contains a mixture or a single pharmaceutical substance;
if the FPP can be prepared from different entities (e.g. acid, base
orsalt);
in cases where the pharmaceutical substance exhibits polymorphism,
if the crystallographic form of the entity should be identified in the
FPP monograph;
if the FPP is available in different strengths, whether all strengths
can be controlled under one monograph.
6.2.2.1 Monograph title

The titles of monographs for FPPs combine the name of the pharmaceutical
substance and the pharmaceutical dosage form.
The pharmaceutical substance name should be based on the INN or
national name, wherever it is available (the common name should be used where
an INN or national name is not available). It is supplemented, when required,
by the INNM. The name is followed by the nationally or regionally accepted
pharmaceutical dosage form taxonomy (or published standard term).
For FPPs containing more than one pharmaceutical substance
(combination products), the individual INNs should be used where possible.
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Annex 1
Combination Names (Co-names) may exist in national pharmacopoeias for

prescribing purposes.
6.2.2.2 General information to define the finished pharmaceutical product

Such information may include elements relating to the API, an expression of the
content and other essential features of the dosage form. An appropriate reference
to the relevant general monographs may be included.
The following should be observed:
the pharmaceutical substance will be referred to in this section; it is
not necessary to reproduce the defining information found in the
pharmaceutical substance monograph within this section of the FPP
monograph (e.g. the chemical name);
any reference to producing a salt of the active moiety in situ during
the manufacture of the FPP should be made in this section;
the definition only refers to the name of the pharmaceutical
substance; where the content is expressed in terms other than those
described in the title of the monograph, the limits stated under
Content (see 6.2.2.3) should reflect the label claim.
6.2.2.3 Content
Assay limits are specified between which the content of the pharmaceutical
substance in the FPP must fall. Limits for each pharmaceutical substance (if
more than one) or individual component are included. The assay limits must
take account of the precision of the method as well as the strength of the FPP.
Assay limits are normally expressed with reference to the active moiety or the
label claim in accordance with the national or regional requirements.
Limits should be justified and account should be taken of:
the strength of the FPP;
the stability of the pharmaceutical substance in a specific FPP.
In the case of antibiotics determined by microbiological assay, the content
limit is expressed in International Units (IU); where these exist a content limit is
given in terms of a range, for example:
The precision of the assay is such that the fiducial limits of error
are not less than 95% and not more than 105% of the estimated
potency. The upper fiducial limit of error is not less than 97.0%
and the lower fiducial limit of error is not more than 110.0% of
the stated number of IU.
81
6.2.2.4 Identification
The tests given in the identification section are not designed to give a full
confirmation of the chemical structure or composition of the API in the product.
They are intended to give confirmation, with an acceptable degree of assurance,
that the API(s) in the product is/are the one(s) stated on the label. Special
attention must be given to the sample preparation to ensure that the API is
adequately extracted from the sample matrix.
The minimum number of tests should be included, commensurate with
providing adequate assurance of identity. For example, the monograph may
contain at least two procedures to identify the API(s) in a pharmaceutical dosage
form; one test per API may be sufficient if the technique used is considered to be
a fingerprint of the active moiety (e.g. infrared absorption spectrophotometry).
6.2.2.5 Impurities and other tests

This section should include all of the specific tests that are required to prove the
quality of the specific FPP.
The Tests section is intended to:
limit the impurities within the FPP. This includes degradation
impurities throughout the shelf life of the FPP and impurities that
occur due to the manufacturing process. In certain circumstances it
is necessary to control FPP impurities resulting from the synthesis
of the pharmaceutical substance;
ensure the homogeneity of the API(s) from dose to dose within
theFPP;
take account of the potential for the sample matrix to restrict the
release of the active moiety in the FPP (i.e. a dissolution test in a
monograph for tablets);
limit the pyrogenic content of a parenteral FPP (i.e. a test for
bacterial endotoxins or a monocyte activation test).
6.2.2.5.1 Impurities: title of test(s)

Where the test is intended to control specified and unspecified impurities, the
title of the test should be related substances or related compounds, or similar,
in line with national or regional practices.
Where the test is intended to control one or a limited number of specified
impurities the title of the test should indicate the impurity or impurities controlled.
6.2.2.5.2 Related substances (or related compounds)

Further to the section on pharmaceutical substance monographs, the following
should be considered for related substances tests specified in FPP monographs:
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Annex 1
specific, quantitative techniques (i.e. high performance liquid

chromatography (HPLC)) are preferred;
non-specific or non-quantitative techniques should be used only if a
specific method is not available or is unsuitable;
methods should be developed with the aim of controlling degradation
products and impurities. In certain circumstances it is necessary to
control impurities from synthesis of the pharmaceutical substance in
the FPP (for example, when they are detected in the test for related
substances at a level greater than the limit for unspecified impurities);
impurities being controlled at a level above the limit for unspecified
impurities should be identified using a reference standard or other
suitable techniques.
The principles outlined in, for example, ICH guideline Q3B (R2)
(Impurities in new drug products) could be used as a starting point.
6.2.2.6 Performance testing

Depending on the dosage form, adequate performance testing may need to
be included in the monograph. Such tests may include, but are not limited to,
dissolution or deposition of the emitted dose.
6.2.2.7 Uniformity
Pharmaceutical preparations presented in single-dose units should comply with
the test(s) as prescribed in the specific dosage form monograph.
Acceptance criteria will be specified regionally for a specific product or
pharmaceutical form.
6.2.2.8 Other tests

The following tests should be considered, but are not limited to:
sterility;
bacterial endotoxins;
microbiological quality;
if necessary, tests for excipients such as antioxidants and
antimicrobial agents.
6.2.2.9 Products of natural origin

Attention needs to be paid to the requirements in the different regions for
minimizing the risk of transmitting animal spongiform encephalopathy agents
via human and veterinary medicinal products.
83
6.2.2.10 Assay
The assay quantifies the amount of API in the FPP. It may also quantify certain
excipients, such as preservatives, depending on national and regional legislation.
Where possible the method used should be harmonized with that in the
pharmaceutical substance monograph, but this may not be possible because of
the sample matrix.
Assays are included in all FPP monographs unless certain quantitative
tests, similar to assays, are carried out with sufficient precision (for example,
uniformity of content, where a mean of individual results could be considered
an accurate assay).
In certain cases more than one assay may be necessary, for example,
where the FPP contains two or more APIs.
For products such as antibiotics, the results of the quantitative tests may
not fully represent the therapeutic activity, in which case a microbiological assay
and a test for composition are included.
Specific assays should be used where possible, for example, liquid
or gas chromatography. Specific assays remove interference from excipients
(formulation matrix) which could lead to significant errors when using non-
specific assays.
Whenever possible, a stability-indicating procedure should be used for
the assay. Generally, chromatographic procedures are preferred. When a non-
stability-indicating assay is proposed, a separate stability-indicating impurity
procedure should be provided.
7. Analytical test procedures and methods

Analytical test procedures and methods are employed to establish quality aspects
such as identity, purity and content of pharmaceutical substances and FPPs.
An analytical method and/or technique specified in a pharmacopoeia should
be robust, reliable, accurate, precise, sensitive, specific and use readily available
materials and equipment.
A pharmacopoeia provides different types of methods, mainly physical,
physicochemical or chemical methods and microbiological tests, for the analysis
of pharmaceutical substances and FPPs. The type of method applied for analysis
depends on the nature of the substance or product.
The principles of method validation apply to all types of analytical
procedures in a pharmacopoeia. However, it is the responsibility of the user
to verify that a particular method is valid for the particular pharmaceutical
substance or FPP being tested.
The validation of analytical procedures described in monographs
should comply with the requirements as laid down, for example, in the WHO
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Annex 1
Supplementary guidelines on good manufacturing practices: validation, Appendix 4

on Analytical method validation, in WHO Technical Report Series, No. 937, 2006,
Annex 4, and ICH guideline Q2 (R1) (Validation of analytical procedures: text
and methodology).
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Annex 2
FIPWHO technical guidelines: Points to consider in
the provision by health-care professionals of children-
specific preparations that are not available as authorized
products
1. Introduction and scope 89

1.1 Background 89
1.2 Purpose 90
1.3 Target audience and health-care settings 90
2. Glossary 90
3. Alternatives to compounding 92
3.1 Sourcing of a commercially-available (marketed) or manufactured product
if available 92
3.2 Dose rounding 93
3.3 Therapeutic alternatives 93
3.4 Manipulation of dosage forms 93
3.4.1 Tablet splitting 94
3.4.2 Tablet/capsule dispersion for oral administration 94
3.4.3 Crushing tablets/opening capsules and mixing powder with food or drink 95
3.4.4 Giving the injectable form by the oral route 96
3.4.5 Splitting suppositories 96
3.4.6 Rectal administration 97
3.4.7 General advice when changing the route of administration 97
4. Compounding 97
4.1 Good manufacturing practices aspects 97
4.2 Some potential problems 98
4.2.1 Oral liquids 99
4.2.2 Microbial contamination 100
4.3 Basic considerations 100
5. Information, availability and access 106
5.1 Standards of practice and guidelines 106
5.2 Formularies and compendia 106
5.3 Source and supply 106
5.4 Networks and information services 107
References 107
Appendix 1 Examples of therapeutic alternatives to extemporaneous formulations 109
87
1. Introduction and scope

1.1 Background
Paediatric patients should have access to authorized, age-appropriate preparations
of medicines that can be administered safely and effectively. Nothing in this
document should detract from this objective. However, it is recognized that
such preparations are not always available and in such cases a safe and effective
alternative must be sought.
In the context of paediatric pharmacy practice, and for the purpose of
this document, compounding is the technique applied by pharmacists to produce
medicines from active pharmaceutical ingredients (APIs) or using authorized
medicines when no commercially available, authorized, age-appropriate or
adequate dosage form exists. Unless stated explicitly in this document, the
compounded medicine is assumed to be dispensed immediately after preparation
and not kept in stock. Compounding does not apply to reconstitution of
authorized medicines prior to dispensing. A clarification of the terminology of
preparation of medicines for children has been proposed by Ernest et al. 2012 (1).
The risks and benefits of compounding and of the alternatives should
be fully understood by practitioners. Practitioners who do not have appropriate
knowledge should seek advice.
Compared to the use of authorized medicines there are significant risks
associated with compounding; quality, safety and efficacy can rarely all be assured,
and many errors have been reported in the preparation of such medicines. In
some situations compounding of a medicine for a child may be the only option,
which may be supported by evidence of quality and occasionally evidence of
bioavailability by industry or other parties, such as academia. There may be
alternatives to compounding, which should also be considered, for example, use
of a commercially available therapeutic alternative or manipulation of authorized
dosage forms.
This points-to-consider document is supported by a literature review

of the evidence available (2). An annex to the report contains an update on the
abstracts and papers published in 20102015.
This document is to be considered as a time-limited document that
addresses current needs for advice in the search for an alternative to an authorized,
age-appropriate dosage form. Wherever possible the guidance is informed
by the relevant evidence. However, the evidence base is weak or non-existent
in most situations. Consequently, the guidance is predominantly informed by
best practice, based on sound scientific and therapeutic principles and expert
consensus. Although the guidance takes the form of a working practical document
it is important to invite comment and input from interested practitioners so that
the guidance can be developed further in response to feedback. The document
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Annex 2
addresses mainly paediatric medicines for oral administration; comments and

proposals concerning other routes of administration are invited as well.
1.2 Purpose
The purpose of the document is to:
provide evidence-based or best practice advice about alternatives to
compounding of medicines for paediatric patients;
describe the main potential problems of compounding and educate
practitioners on how to avoid them;
provide brief advice on compounding;
reduce the risk of providing children-specific preparations without
informed knowledge.
The document will not reproduce guidance and standards that already
exist (e.g. good manufacturing practices (GMP) standards for facilities and
documentation). Where appropriate, reference is made to the relevant resources
and publications.
1.3 Target audience and health-care settings

The document is intended for a wide audience of health-care stakeholders
including:
all practitioners involved in health care of the paediatric population
but mainly pharmacists, physicians, paediatricians and nursing staff;
national medicines regulatory authorities and professional bodies,
e.g. national paediatric organizations and national pharmacy
associations;
general hospitals and health clinics;
specialized paediatric hospitals and primary care clinics;
the pharmaceutical industry, given its role in providing information.
Pharmaceutical manufacturers can often provide useful information
on validated compounded formulas and other information relating to the
manipulations and specific characteristics of formulations.
2. Glossary
The definitions given below apply to the terms used in these guidelines. They
may have different meanings in other contexts.
89
active pharmaceutical ingredient (API). Any substance or mixture

of substances intended to be used in the manufacture or compounding of
a pharmaceutical dosage form and that, when so used, becomes an active
ingredient of that pharmaceutical dosage form. Such substances are intended
to furnish pharmacological activity or other direct effect in the diagnosis, cure,
mitigation, treatment or prevention of disease, or to affect the structure and
function of the body.
authorized dosage form. A pharmaceutical dosage form that has been
authorized by the competent authority to be marketed for the treatment of
specific indications.
beyond-use date. The date after which a compounded preparation should
not be stored, transported or used; the date is determined from the date or time
the preparation is compounded. It is also known as the expiry date.
compounding. Preparation under the supervision of a pharmacist
following national legislation of an unlicensed medicine to meet the specific
needs of a patient when no suitable authorized dosage form is available. This
may involve preparation from the authorized dosage form or from the active
pharmaceutical ingredient and usually involves addition of excipients to produce
an acceptable product.
dispensing pharmacy. The pharmacy receiving the prescription for
a patient and providing the pharmaceutical preparation to the patient. For
compounded medicines, the dispensing pharmacy is not necessarily the
compounding pharmacy.
dose rounding. Amending a dose that has been calculated accurately
on the basis of body weight or surface area to correspond with an amount of
the dosage form that is easy to measure and administer. Account of therapeutic
index should be taken before rounding the dose.
excipient. A substance or compound, other than the active pharmaceutical
ingredient and packaging materials, that is intended or designated to be used in
the manufacture or compounding of a pharmaceutical product.

expiry date. The date after which a compounded preparation should not
be stored, transported or used; the date is determined from the date or time the
preparation is compounded. It is also known as beyond-use date.
good manufacturing practices. A system of practice and processes to
assure the quality and safety of manufactured pharmaceutical products, specified
in, for example, WHO guidelines.
labelling information. Information to the user provided on the container
or package label or in the patient information leaflet.
manipulation of a dosage form. Authorized dosage forms may be
manipulated (or modified), often at the point of administration, to provide the
appropriate dose (e.g. by segmenting tablets) or to facilitate administration (e.g.
by crushing a tablet and adding to food).
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Annex 2
pharmaceutical dosage form. The physical form in which a medicine

is presented; the name of a dosage form combines its physical form and the
intended route of administration, e.g. a tablet (to be swallowed), oral suspension
(liquid suspension of solid particles intended for oral intake and swallowing).
route of administration. The way in which a medicine is given to
a patient, e.g. oral administration (administration via the oral route), rectal
administration (administration to the rectum), parenteral administration
(administration via the blood, muscular or subcutaneous routes).
summary of product characteristics. Summary of product characteristics
approved by the competent authority. The information may alternatively be
presented in the container or package label.
verification. A process of providing any type of adequate evidence,
e.g. new (bio)analytical data, from the literature or by referencing to existing
practices to support that the proposed modification will not change the
pharmaceutical characteristics of the original preparation in a way that will
negatively impact the safety and/or efficacy of the medicine.
3. Alternatives to compounding
Before deciding to compound, consider possible alternatives that will give the
greatest assurance of clinical effectiveness and safety.
The main alternatives to compounding are described below.
3.1 Sourcing of a commercially-available (marketed)

or manufactured product1 if available
A marketed, authorized, age-appropriate finished pharmaceutical preparation
should always be sourced when available. Where appropriate and in accordance
with the national regulations, this could include:
off-label use of a medicine authorized in the country where the
medicine is to be dispensed;
(off-label) use of an imported product authorized in the country
oforigin;
use of a manufactured product made in authorized facilities in the
country where the medicine is to be dispensed.
This includes products prepared to GMP standards, for example, at an accredited hospital manufacturing
1
unit.
91
The logistics of supply, costs and access are obvious factors that might
present obstacles, but practitioners should liaise with suppliers, importers and
regulatory authorities to access these products if possible.
Importation of products may be expensive, and reputable suppliers should
be used to avoid spurious/falsely-labelled/falsified/counterfeit (SFFC) medicines.
Quality assurance systems should be in place, for example, to ensure that recall
systems are available and that information is provided in the local language.
The use of compounded products for children should not be justified
on the grounds that they are cheaper than marketed products. Other
options, including local manufacture in accordance with GMP standards,
should be investigated.
3.2 Dose rounding

If the dose prescribed does not correspond to a dosage form that is commercially
available, consider whether the dose can be suitably amended while maintaining
safety and efficacy.
The therapeutic index of the medicine and patient characteristics need
tobe considered before making a decision.
Some medicine doses are calculated accurately on the basis of body
weight, yet the therapeutic index is such that one dose can be used for a broad
age and weight band. Consult the WHO Model formulary for children.2
3.3 Therapeutic alternatives

If a medicine is prescribed in a formulation that is not available, e.g. in an age-
appropriate form, consider the possibility of using a commercially available
medicine with a similar therapeutic action, which is available in a more suitable
form. Examples are presented in Appendix 1.
3.4 Manipulation of dosage forms

In situations where the prescribed dose is different from what is marketed, or
there are administration-related difficulties, the possibilities for manipulation
of a dosage form as outlined below can be considered. Formularies or
manufacturers information, if available, and the labelling or the summary of
product characteristics (SmPC) should be consulted.
A report with evidence-based guidelines on the manipulation of
medicines to obtain the required dose for children was published by the
Available from: http://apps.who.int/medicinedocs/en/m/abstract/Js17151e/.

2
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Manipulation of Drugs Required in Children (MODRIC) research group in

2013(3).
The practitioner should bear in mind that manipulation, such as tablet
splitting, tablet/capsule dispersion, or tablet crushing and mixing with food
or drink, may increase the potential for inaccurate dosing and may affect the
efficacy, stability and bioavailability of the dosage form, in particular when mixed
with food or drink. Excipients that are safe for adults may not necessarily be so
for children.
When medicines are mixed with food or drink, including breast milk
for very young children, an unpleasant tasting mixture may cause aversion in
the child. In addition, the compatibility of the product with the food, drink or
breast milk will need to be taken into account. Where a child shows signs of
refusal or aversion other options should be considered.
3.4.1 Tablet splitting

Not all tablets should be split. In general, those with a sustained-release or
enteric coating should not be split, but it may be possible to split tablets with
a sustained-release matrix. Formularies or manufacturers information, if
available, and the product label or SmPC should be consulted.
Some tablets allow splitting, either by breaking, if scored, or by using a
tablet cutter designed for the purpose. If the child is able to take solid dosage
forms safely, a tablet segment can be given; otherwise it can be dispersed or
mixed with food or drink as described below in section 3.4.3.
Tablets without a score line cannot, in general, be split into uniform
segments meeting relevant uniformity requirements. Information about possible
splitting of such tablets may however be provided in the SmPC or on the label.
Tablet splitting was reviewed by Freeman et al. (2012) (4).
Consider on a case-by-case basis whether splitting of tablets might lead
to toxicity or reduced effect as a result of inaccurate dosing or an effect on the
release profile. This is especially important in situations where the API is potent
or has a narrow therapeutic index, if there is a lack of appropriate information,
or if an accurate dose cannot be assured.
Consideration should be given to splitting tablets with an appropriate
commercial tablet splitter in the pharmacy. If possible, tablets with score lines
and uniform distribution of the API should be sourced and information sought
on the stability of segments. If carers are cutting segments, they should be given
a suitable tablet splitter and receive adequate instruction on the method for
preparing and storing tablet segments.
3.4.2 Tablet/capsule dispersion for oral administration

It may be possible to disperse immediate-release tablets or the contents of
capsules in water or another liquid. If the tablet disperses, the tablet or a fraction
93
of it can be dispersed in a small volume appropriate for the child concerned and
the whole dose given when a suspension is formed, or mixed with a flavoured
vehicle if required. To ensure that the whole dose is administered the measuring
device should be rinsed and the resulting solution or suspension administered.
It is necessary to consider the impact of dispersion and the risk of interactions
with the vehicle on the bioavailability.
Conventional tablets do not disperse readily but some form a suspension
within a short time. Soluble tablets and dispersible tablets disintegrate and
dissolve or disperse within a short time in water at room temperature.
If the tablet disperses in a known volume of water to form a stable
suspension, a fractional dose can be appropriately measured with a syringe. As
extraction of soluble API from the tablet may be incomplete, the suspension
should be shaken or stirred before measuring the dose and not filtered unless
it has been established that the API is fully dissolved. Dose uniformity of
the prepared suspension cannot be assured and the risk of overdosing or
underdosing must be considered. This may depend on the volume of prepared
suspension that is to be extracted for administration. Any such tablet (whether
a dispersible or conventional-release tablet) compounded to a dispersion
or solution should be administered immediately after preparation and the
remainder should be discarded.
When the dispersion is intended for tube feeding, parameters such as
particle size, viscosity, dosing volume and compatibility of the oral preparation
with the tube material should be considered. Dispersions may be too viscous or
may contain large particles that can mean that administration by feeding tube
is not feasible. Adsorption of API to the tube material results in inappropriate
dosing; this concern is most relevant for lipophilic and low-dose potent APIs.
WHO is promoting the use of flexible solid oral dosage forms such as
dispersible tablets (5). Custom-made dispersible tablets for paediatric dosing
should be used wherever possible but it is still necessary to ensure that carers
understand how they are to be administered.
3.4.3 Crushing tablets/opening capsules and

mixing powder with food or drink
The practice of crushing tablets or opening capsules and adding the powder to a
palatable drink or sprinkling it onto solid food has been reviewed (6). Although
common, there may be little evidence to support the efficacy and safety of this
practice since stability and bioavailability may be altered. With the exception
of multiple-unit preparations, which can be opened and administered without
affecting efficacy and safety, modified-release tablets and capsules cannot be
crushed or opened without affecting bioavailability and/or stability, and this
should therefore not be done. Insoluble tablet excipients are in suspension and
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may compromise product appearance, whereas soluble excipients may alter

stability, for example, by changing the pH of the preparation.
In the case of potent APIs, consider the risks associated with handling of
powdered material to parents or carers.
In general, the decision on whether to crush tablets should be based on
bioavailability and acceptability studies. Information should be sought from
manufacturers (e.g. the label or SmPC and website) and formularies whenever
possible. The process is acceptable only if bioavailability is not affected by food or
drink, and the product has to be used immediately to minimize stability problems.
It is difficult to ensure that a complete dose has been taken and the
practice of nurses and carers handling powdered medicines may present health
concerns. Tablet dispersion may be a simpler, more reliable and potentially
safer method.
Liquid-filled capsules should generally not be opened since it is difficult
to remove and measure the total contents.
3.4.4 Giving the injectable form by the oral route

Oral administration is possible for some injections. If the injectable form of
the API is the same as the oral form (for example, labetalol hydrochloride,
ondansetron hydrochloride) it can be assumed that the API will be absorbed
enterally from the injectable formulation. However, as the API is in solution,
more rapid absorption and higher peak levels may occur than would result
from the slower absorption from a solid oral dosage form. When evaluating
whether an injection is suitable for oral use, specialist advice, e.g. consultation
with a medicines information centre in the region, should be sought because
there are important factors which must be considered, e.g. first-pass effect, oral
bioavailability, gastric acidity (e.g. effect on stability), pH effects (e.g. precipitation
of soluble salts of weak acids) and palatability.
Injections may contain excipients that may have undesirable effects in
some patients, e.g. propylene glycol and ethanol. The pH of some injections may
be high or low and they should therefore not be given orally, or alternatively
should be diluted before administration to avoid irritation. The taste of the
injectable form may not be known and may not be acceptable. Advice should be
sought from the manufacturer and from experts to assist in deciding whether
the injectable form can be administered orally.
3.4.5 Splitting suppositories

There is little information available on the accuracy with which suppositories
can be split. Splitting is usually associated with major problems with regard
to accurate dosing and is therefore generally discouraged. Most commercially
available suppositories are formulated as suspensions, which means that
95
sedimentation of the solid API particles may occur during solidification of

the suppository; therefore, if suppositories need to be split, this should be
donelengthwise.
Therapeutic index and the consequences of over- or underdosing should
be taken into account when determining whether it is safe to split suppositories.
If possible, this should be done in the pharmacy.
3.4.6 Rectal administration

There may be opportunities to give oral or injectable dosage forms by rectal
administration (7).
3.4.7 General advice when changing the route of administration

Whenever a change of the route of administration for an authorized medicine
is considered, advice should be sought from formularies and the literature and
even from specialists. In general, altering the route of administration results in
a different pharmacokinetic profile introducing a high risk of dosing errors and
may compromise safety and efficacy. Hence, this practice is generally discouraged.
4. Compounding
4.1 Good manufacturing practices aspects
The dispensing pharmacy receives the prescription for a patient and provides
the pharmaceutical preparation to the patient. For compounded medicines the
dispensing pharmacy is not necessarily the compounding pharmacy. Regardless
of where the product is compounded the dispensing pharmacy is responsible
for ensuring the safety and quality of the product.
When a batch of non-authorized medicine is prepared, including for
stock, the preparing pharmacy or hospital unit should meet depending on a risk
assessment the GMP or good pharmacopoeial practices (GPhP) requirements

pertaining to personnel, premises and equipment, quality assurance system,
documentation and product dossier. Further, an authorization by the competent
authority to carry out operations may be needed, in accordance with the
national legislation. In this respect, one should refer to the relevant international
and national guidance and to other guidelines, including WHO guidelines on
GMP (8, 9), the Pharmaceutical Inspection Co-operation Scheme (PIC/S) GPP
Guide to good practices for the preparation of medicinal products in healthcare
establishments (10) and corresponding national guidelines.
When compounding is a one-off event, the intended prescription should
be prepared for an identified individual patient for immediate dispensing. In
such cases requirements may be less strict. Nevertheless, certain requirements
need to be met:
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the preparing pharmacy should have appropriate premises

andequipment;
the pharmacist and staff, or entitled persons, must have sufficient
training and background for compounding;
access to relevant literature (e.g. pharmacopoeias, formularies,
handbooks and scientific journals) and the Internet must be
available;
general instructions for the preparation of each dosage form
should be available;
a record on each preparation should be retained showing the
calculations, key processing and packaging steps, and also including
the name of the person responsible for each step.
4.2 Some potential problems

In some situations, for example, if the method of preparation and the stability of
an oral liquid are well documented, e.g. if compounding has been supportedby
evidence of quality, stability data and occasionally evidence of bioavailability
byindustry or other parties, such as academia, and all facilities and ingredients
are available, it may be less pressing to seek an alternative to compounding. On
the other hand, if there are no stability data and, for example, the API forms a
caking suspension in the only available excipients (e.g. a syrup), an alternative
must be considered to ensure safe and effective treatment.
In any case, the decision on how to prepare and/or provide an unlicensed
preparation should be based on an assessment of risks and benefits of the dosing
strategy. On a case-by-case basis, potential benefits from their use should be
weighed against all possible risks arising from preparation and administration
of such medicines. Even in cases where the compounded preparation can be
considered a verified formulation, the impact of compounding on bioavailability
may not be known.
Formulation of a compounded medicine is associated with a number of
potential problems that may impact on its safety and effectiveness. Awareness of
the relative complexity of the formulation and of the things that can go wrong
will help to avoid such problems. Guidance on compounding has been published
(e.g. 11). A review of extemporaneous compounding is also available (12).
Consideration must be given to the properties of the API (e.g. aqueous
solubility, pH effect on solubility, particle size, polymorphism) and stability
of both API and the compounded formulation, i.e. chemical, physical and
microbiological instability.
Care must also be taken in the selection of excipients and their safety
in relation to the age of the child as well as any possible adverse effects of the
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inactive components of the preparation should be considered. The use of

preservatives, ethanol and sugars must be carefully considered. Some guidance
and literature references on the formulation can be found in Development of
paediatric medicines: points to consider in formulation (5).
4.2.1 Oral liquids

Deterioration of an oral liquid may be a result of chemical, physical or
microbiological instability which can lead to a subtherapeutic dose of the
medicine, exposure to toxic degradation products or ingestion of unacceptable
numbers of microorganisms. It is important for pharmacists, clinicians and
nursing staff to be aware of potential problems caused by instability and
microbial contamination to ensure that any medicine used is effective and safe.
APIs in compounded liquids may be susceptible to chemical reactions
leading to degradation. Publications reporting the stability of compounded
paediatric preparations include a review by Glass and Haywood 2013 (13). The
most common reactions are hydrolysis, oxidation and reduction. Usually the
reaction rate or type is influenced by pH. Other factors that may increase
the rate of reaction include the presence of trace metals which catalyse the
oxidation of captopril, methyldopa or exposure to light, which catalyses the
oxidative degradation of 6-mercaptopurine. The rate of chemical degradation
usually increases with temperature.
The API in the preparation may be totally or partially in solution or
predominantly in the solid state as a suspension. APIs in solution are more
susceptible to chemical degradation than APIs in the solid state (i.e. suspensions);
thus suspensions of acetazolamide and chlorothiazide are more stable than
solutions. However, it cannot be assumed that a compounded suspension
is always more stable than a solution. In a suspension, an equilibrium exists
between the API in the solid state and an API in solution, and even though
the amount of API dissolved may be minimal, the conditions could be optimal
for degradation. Furosemide is a notable example: it undergoes hydrolysis in

acidic conditions where the solid state is predominant, but is much more stable
at alkaline pH where it is totally in solution.
Preparations made from tablets contain excipients such as binders
and disintegrating agents in addition to the API. These excipients may reduce
chemical stability by changing the pH to a value at which more rapid degradation
occurs. This probably explains why amiloride solution prepared from pure API
is more stable than an oral liquid prepared from tablets.
Hygroscopicity and/or moisture-sensitivity of the API also play a key
role in degradation. These characteristics of the API(s) should be understood
before compounding from a tablet to a liquid form. A common example of such
an API is tenofovir disoproxil fumurate.
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Annex 2
Dispersions and suspensions of medicine with low therapeutic index

require special consideration with regard to efficient resuspension to avoid
medication error.
4.2.2 Microbial contamination

Microbial growth in an oral liquid may cause a foul odour and turbidity and
adversely affect palatability and appearance. High titres of microorganisms
may be hazardous to health especially in very young or immunocompromised
patients. By-products of microbial metabolism may cause a change in the pH
of the preparation and reduce the chemical stability or solubility of the API.
Microbial contamination during preparation must be minimized by using clean
equipment, water of adequate quality and by avoiding contaminated raw materials
and containers. If sodium benzoate or benzoic acid are used as antimicrobial
preservatives, the final pH must be less than 5 so that the active unionized form
is predominant. Consequently the API must also be stable at this pH.
Many factors can reduce the effectiveness of the preservative, including
use of contaminated materials, chemical degradation, binding of preservative to
suspending agents or tablet excipients, incorrect storage or unhygienic use of the
final product.
4.3 Basic considerations

Quality of API and excipients
It is important to ensure that the API and the excipients meet
pharmacopoeial standards with regard to both identity and purity.
The choice of excipients should be restricted to those that have
been used in authorized medicines intended for the same route of
administration and at similar concentrations.
Consider use of an authorized dosage form as a starting point

It may be safer and more effective to crush tablets or use the
contents of hard capsules with an appropriate suspending vehicle
than to prepare medicines from an API and excipients. There are
many formulations available with a validated shelf life but sourcing
of suspending agents may be difficult and/or expensive.
There might be instances when a pharmacist crushes a number
of tablets or opens a number of capsules, dilutes the powder with a
suitable excipient and doses the powder in ready-to-use single-dose
sachets. Before doing so, consider the stability of the preparation,
including stability with respect to humidity and exposure to air.
99
Consult literature and guidelines if available

Use a validated formulation whenever possible (i.e. based on
literature, stability studies and guidelines). Consult product
information and the latest national and international guidelines
and/or a specialist information centre if possible.
Potential medication error
Medication errors in preparing compounded medicines occur often,
and some have resulted in serious harm to patients or even in death.
The potential for medication error must be recognized and steps
taken to minimize the risk. As a minimum, this will include the use
of a worksheet listing the formulation ingredients and the identity of
the ingredients; quantities, calculations and measurements should
be double-checked by trained personnel and signatures provided.
The pharmacist responsible should check the final product and label
against the signed worksheet, ingredients and prescription.
Exercise caution in extrapolating from other formulations
Caution is required when extrapolating the formulation from a
published study or formulary. Formulations made from APIs may
be more stable than formulations made from solid dose forms and
vice versa. Tablet and capsule excipients can increase or decrease
the stability of the API in an oral liquid preparation. The salt form
of the API used in a published study could be different to the form
locally available and this may affect its solubility, bioavailability
and stability. Consult publications and pharmacopoeias, and seek
specialist advice, if possible.
Similarly, the results of a published study using an API mixed
with a commercial suspending base cannot generally be extrapolated
to a situation where the same API is mixed with a simple base of

syrup or glycerol.
Formulations for compounded medicines based on APIs and
crushed tablets are not interchangeable.
Dose uniformity may be a problem explain the importance of
shaking prior to use
If the API is poorly soluble in water, uniformity of dosing may be a
problem and a suspending agent will be required. Always check that
the finished preparation resuspends under in-use conditions and
explain the importance of resuspension by shaking to patients or
their carers.
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As excipients and other formulation components can affect

solubility, all compounded liquid formulations should be shaken
prior to administration. Some of the API may not be in solution
even if it is highly soluble in water. The only exception would be if
the preparation is made from pure API and it can be assured that
the entire API is in solution.
Suppositories have sometimes been melted and recast
into smaller moulds. This option is associated with a risk of
recrystallization and of affecting the distribution and solubility of the
API, resulting in over- or underdosing. Further, re-melting may affect
degradant levels. Re-melting is therefore generally discouraged.
Exceptionally, when no published formulation is available
When no published formulation is available the pharmacist must
assess the risks associated with the different options and use his or
her knowledge and experience to formulate a product taking into
account the need to:
obtain information on the physicochemical properties of the
API ifavailable.
If possible, obtain basic physicochemical information about
the API, especially its aqueous solubility at the expected pH of
the final preparation. This allows a judgement to be made as to
whether an API solution or suspension is formed at a particular
dose-relevant concentration.
test the physical characteristics before using the preparation to
treata patient.
FPPs of the same medicine may vary worldwide, especially
with respect to the content of excipients. Such differences can
influence the safety, efficacy and acceptability of the preparation.
Basic performance tests should be done before the preparation is
used in a patient, particularly on formulations prepared for the
first time. Tests include ease of resuspension and pouring, degree
of caking on storage, and observation of physical behaviour
andcharacteristics.
consider risk of microbial growth.
All compounded liquid formulations are highly susceptible to
microbial growth. Oral liquids that are not adequately preserved
will support rapid growth of bacteria and fungi especially at warm
to hot temperatures and can pose hazards to patients especially
101
those who are immunosuppressed. An antimicrobial preservative

should be included if the final product is likely to be used beyond
23 days, even when it is stored under refrigeration.
The effects of the addition of the preservative on interactions
between pH, stability and effectiveness of the preservative should
be carefully taken into account.
Compounded liquids should be prepared under conditions
that minimize the introduction of microbial contaminants.
Use appropriate final containers
Final containers and closures should be clean and free from dust and
other residues. Use of new containers is recommended. Containers
that are reused should be thoroughly washed, rinsed with sterile or
freshly boiled water and dried. Light-protective (e.g. dark plastic or
amber glass) containers should generally be used.
Consider the use of a light-protective wrapping such as foil if
a light-protective container is not available. When selecting the final
container, consider the interactions between the container and the
product, for example, the possibility of adsorption to plastic containers.
Dosing device
For liquid preparations, the feasibility of appropriate dosing should
be confirmed bearing in mind that not all dosing devices may allow
delivery of the required volume. Most compounded liquids should
be shaken prior to administration and this may introduce entrapped
air in the liquid, which could cause problems with accurate
measurement of small volumes.
Consider in-use storage
In-use storage conditions may vary considerably from those in a
published study or formulary recommendation. Always consider

whether it will be possible to store and use the preparation
under the optimal conditions described in the study; usually
refrigeration, protection from light and minimal possibility of in-use
contamination. If these conditions are not possible locally it can be
assumed that the preparation will be less stable and more susceptible
to microbial growth. Reduce the shelf life according to professional
judgement. If possible, obtain expert advice.
Expiry date
It is recommended that each compounded preparation be given an
expiry date assigned in a conservative way and taking into account
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API-specific and general stability documentation and relevant

literature when available.
When an authorized medicine is used as the source of the
API, stability information can be obtained from the manufacturer.
Otherwise, applicable information on stability, compatibility
and degradation of ingredients, and use has to be sought in the
literature.
Stability may be formulation-dependent and is likely to change
with any manipulation of the product. Most studies base their
expiry date recommendation on chemical stability but do not
address possible physical or microbiological spoilage which may be
significant during actual use of the product. Whereas compounded
preparations will normally be freshly prepared, the storage and shelf
life during use need to be considered, in particular if it becomes
impractical to prepare the product immediately prior to dispensing
each time it is needed.
The assignment of an expiry date serves to ensure suitability for
use and will encourage regular fresh preparations. It also allows the
practitioner to regularly review the patients use of the preparation.
The following aspects should be considered when determining
an expiry date:
nature of the API and its degradation mechanisms;

dosage form and its components;
potential for microbial proliferation in the preparation;
container in which the preparation is packaged;
expected storage conditions; and
the intended duration of therapy.
The in-use conditions, for example, access to a refrigerator

for storage, should be taken into account when establishing the
expiry date.
Give clear instructions to caregivers and patients

The instructions given to caregivers and patients may include
instructions on storage, resuspension, changes in taste, smell,
appearance, adverse effects and other pharmaceutical advice.
Compounded dosage forms are sometimes added to a small
amount of liquid (e.g. water or juice) or sprinkled onto small
amounts of food. Consideration should be given to the effect of food
103
on bioavailability and to the risk that only part of the dose will be
swallowed. Provide parents and carers with appropriate information.
If an oral syringe or other measuring device is used it is
important to check the technique to ensure that the correct dose
is administered. Advise the use of clean measuring devices and
explain how to avoid contaminating the preparation when preparing
the dose.
Label information
In addition to dosage instructions, include at least the following
information, subject to national regulations for the labelling of
medicines:
if applicable, the name of the pharmaceutical preparation;
the route of administration;
the name(s) of the API(s) and excipients of known
pharmacological action, and adverse effects, e.g.
antimicrobial agents, antioxidants;
if the preparation is a liquid, give the concentration(s) of
the API(s), e.g. in mg/mL, and the amount or volume of
the preparation in the container;
if the preparation is a solid, give amount(s) of the API(s) in
each dose and the number of doses in the container;
reference or batch number (or date of preparation);
expiry date (do not use after ...);
any special storage conditions and handling precautions
that may be necessary, e.g. to be shaken before use, shelf
life during use;
the pharmacy name and contact information;

name of the patient.
Consider adding pictograms to supplement the label
information, e.g. for to be shaken well and store in the refrigerator.
Document concerns and share information
Practitioners are encouraged to maintain a dialogue with regulatory
bodies and international agencies and networks about problems
and concerns associated with the preparation and availability of
age-appropriate medicines for children. The sharing of solutions to
problems is also important.
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5. Information, availability and access

A number of networks, websites and other resources are available which provide
information on standards of practice, formulas for compounded preparations,
manufacturers, suppliers of oral liquid formulations and responsive information
services. These should be consulted by practitioners and regulators to enable
them to provide the safest and most effective treatment options for children who
require an age-appropriate formulation.
5.1 Standards of practice and guidelines

Some national, regional and international guidelines for extemporaneous
formulations and medicines administration to children have been published.
Consulting these documents may assist in forming local policies on practice and
educational activities for practitioners.
5.2 Formularies and compendia

Formularies and compendia may be helpful in providing formulation advice and
general advice on dosage manipulations. The information in these formularies
may be difficult to transfer to a local situation where the base ingredients (e.g.
commercial suspending bases, antimicrobial preservatives, pure API powder)
are not readily available.
In addition to formularies and compendia, information can be sought in:
the eMixt database (www.pharminfotech.co.nz), which provides
comprehensive information for all settings and environments;
Handbook of extemporaneous preparations (11), which contains
formulations and associated stability summaries for oral liquid
preparations;
Improving medicines for children, by the Council of Canadian
Academies, which contains a comprehensive review of paediatric
medicines (14);
The International Journal of Pharmaceutical Compounding,
whichis a general source of information. It is a subscription-only
journal, butthe contents can be searched on the journals website
(http://www.ijpc.com).
5.3 Source and supply

A database of sources and prices of medicines for children has been compiled by
the United Nations Childrens Fund (UNICEF) (15) and the UNICEF catalogue
(https://supply.unicef.org) provides examples without being exhaustive.
105
Countries may also have their own database to use to find suppliers of
age-appropriate formulations for paediatric use.
5.4 Networks and information services

Local, national and international medicines information centres
may respond to questions about formulation. One example is
the WHO Paediatric medicines Regulatory Network (PmRN)
(http://www.who.int/childmedicines/paediatric_regulators/en/).
Partnerships and twinning arrangements between hospitals in
poorly-resourced countries and developed countries can be explored
and are often beneficial.
Questions can be posted via the eMixt website (www.pharminfotech.
co.nz).
Sharing of information and advice on paediatric formulations
should be explored whenever possible.
International discussion lists can be useful for posting questions on
formulations and their archives can be searched for previous questions
and answers. Examples include eDrug and INDICES (accessed via
www.asksource.info/resources/essentialdrugsorg).
References
1. Ernest TB, Craig J, Nunn A, Salunke S, Tuleu C, Breitkreutz J, et al. Preparation of medicines for
children a hierarchy of classification. Int Journal Pharm. 2012;435(2): 12430. doi: 10.1016/j.
ijpharm.2012.05.070.
2. Nunn T, Hill S, Secretary, WHO Expert Committee on the Selection and Use of Essential Medicines.
Report for WHO on findings of a review of existing guidance/advisory documents on how
medicines should be administered to children, including general instructions on extemporaneous
preparations and manipulation of adult dosage forms. Geneva: World Health Organization;
2011 (working document QAS/11.400 available on request) (http://www.who.int/medicines/
areas/quality_safety/quality_assurance/Review-findings-PaediatricMedicnesAdmin_QAS11-
400Rev1_22082011.pdf, accessed 20 November 2015).
3. MODRIC. Manipulation of drugs for children a guideline for health professionals. Liverpool:
Alder Hey Childrens NHS Trust (http://www.alderhey.nhs.uk/wp-content/uploads/MODRIC_
Guideline_FULL-DOCUMENT.pdf, accessed 20 November 2015).
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Consult Pharm. 2012;27(5):34152. doi: 10.4140/TCP.n.2012.341.
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Committee on Specifications for Pharmaceutical Preparations: forty-sixth report. Geneva: World
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7. Smith S, Sharkey I, Campbell D. Guidelines for rectal administration of anticonvulsant medication

in children. Paediatr Perinatal Drug Ther. 2001;4(4):1407.
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10. Pharmaceutical Inspection Co-operation Scheme. PE 010-3 Guide to good practices for the
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picscheme.org/bo/commun/upload/document/pe-010-4-guide-to-good-practices-for-the-
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compounding. London: Pharmaceutical Press; 2010.
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Pharmacophore. 2011;2(2):86103.
13. Glass BD, Haywood A. Liquid dosage forms extemporaneously prepared from commercially
available products Considering new evidence on stability. J Pharm Sci. 2006;9(3):398426.
14. Council of Canadian Academies. Improving medicines for children in Canada. Ottawa: The Expert
Panel on Therapeutic Products for Infants, Children, and Youth; 2014 (http://www.scienceadvice.
ca/uploads/eng/assessments%20and%20publications%20and%20news%20releases/
therapeutics/therapeutics_fullreporten.pdf, accessed 20 November 2015).
15. Sources and prices of selected medicines for children, including therapeutic food, dietary vitamin
and mineral supplementation 2nd edition. Geneva: UNICEF/WHO; 2010 (http://www.who.int/
medicines/publications/sources_prices/en/, accessed 20 November 2015).
Further reading
The International Pharmacopoeia, fifth edition; 2015. Available online and CD-ROM version) (http://
who.int/medicines/publications/pharmacopoeia/en/index.html).
Kastango ES, Trissel LA, Bradshaw BD. An ounce of prevention: Controlling hazards in extemporaneous
compounding practices. Int. J Pharm. Compounding. 2003;7(5):40116.
Pharmaceutical development for multisource (generic) pharmaceutical products. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations: forty-sixth report. Geneva: World
Health Organization; 2012: Annex 3 (WHO Technical Report Series, No. 970) (http://www.who.int/
medicines/areas/quality_safety/quality_assurance/en/).
Pharmaceutical Inspection Co-operation Scheme (http://www.picscheme.org/). In particular the
following documents can be downloaded free of charge: PE 009-9 (Part I); PIC/S GMP guide (Part I:
Basic requirements for medicinal products); PE 010-3 Guide to good practices for the preparation of
medicinal products in healthcare establishments.
Report of the Informal Expert Meeting on Dosage Forms of Medicines for Children. Geneva:
World Health Organization; 2008 (http://www.who.int/selection_medicines/committees/expert/17/
application/paediatric/Dosage_form_report DEC2008.pdf).
The WHO Model formulary for children. Geneva: World Health Organization; 2010 (http://www.who.
int/selection_medicines/list/WMFc_2010.pdf).
107
Appendix 1
Examples of therapeutic alternatives to extemporaneous
formulations
Required Possible alternative Notes

(available)
diclofenac oral naproxen oral suspension; The alternatives are available
liquid (tablet) ibuprofen oral liquid in some countries.
enalapril oral liquid captopril oral liquid Captopril oral liquid is not
(tablet) (losartan oral suspension) available in all countries.
Captopril has a shorter
duration of action than
enalapril. Enalapril tablets can
be crushed and suspended
in water immediately before
use. Captopril tablets can be
easily dispersed in water.
Losartan may be appropriate
for hypertension.
ibuprofen oral paracetamol oral liquid For pain and fever but not as
liquid (tablet) an anti-inflammatory.
levamisole oral albendazole chewable tablet;
liquid (tablet) mebendazole oral liquid;
pyrantel oral liquid
lisinopril oral liquid ramipril oral liquid
(tablet)
omeprazole oral esomeprazole granules;
liquid (capsule) lansoprazole orodispersible
tablet
praziquantel oral niclosamide chewable tablet Niclosamide can also be
liquid (tablet) crushed and mixed with water
to form a vanilla paste.
sertraline oral liquid fluoxetine oral liquid
(tablet)
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Annex 2
Table continued
Required Possible alternative Notes
(available)
tinidazole oral metronidazole oral liquid Very few reasons why
liquid (tablet) tinidazole should be
preferred over metronidazole.
ciprofloxacin/ ciprofloxacin/hydrocortisone
dexamethasone ear drops
eardrops
109
Annex 3
WHO good manufacturing practices for biological products
Replacement1 of Annex 1 of WHO Technical Report Series, No. 822
1. Introduction 114
2. Scope 114
3. Terminology 118
4. Principles and general considerations 122
5. Pharmaceutical quality system and quality risk management 124
6. Personnel 124
7. Starting materials 125
8. Seed lots and cell banks 127
9. Premises and equipment 129
10. Containment 131
11. Clean rooms 133
12. Production 134
13. Campaign production 136
14. Labelling 137
15. Validation 137
16. Quality control 139
17. Documentation (batch processing records) 140
18. Use of animals 141
19. Authors and acknowledgements 143
20. References 145
It also replaces Annex 3 of the report of the Expert Committee on Specifications for Pharmaceutical
1
Preparations, Technical Report Series, No. 834, and forms Annex 2 of the report of the Expert Committee
on Biological Standardization, Technical Report Series, No. 993.
111
Guidelines published by WHO are intended to be scientific and

advisory in nature. Each of the following sections constitutes guidance
for national regulatory authorities (NRAs) and for manufacturers of
biological products. If an NRA so desires, these WHO Guidelines may
be adopted as definitive national requirements, or modifications
maybe justified and made by the NRA.
112
Annex 3
Abbreviations
AEFI adverse event following immunization
ATMP advanced therapy medicinal product
BCG bacille CalmetteGurin
GMP good manufacturing practice(s)
HEPA high-efficiency particulate air
HVAC heating, ventilation and air conditioning
IgE immunoglobulin E
mAb monoclonal antibody
MCB master cell bank
MSL master seed lot
MVS master virus seed
NRA national regulatory authority
PDL population doubling level
PQR product quality review
PQS pharmaceutical quality system
QRM quality risk management
rDNA recombinant DNA
SPF specific pathogen free
TSE transmissible spongiform encephalopathy
WCB working cell bank
WSL working seed lot
WVS working virus seed
113
1. Introduction
Biological products can be defined according to their source material and
method of manufacture. The source materials and methods employed in the
manufacture of biological products for human use therefore represent critical
factors in shaping their appropriate regulatory control. Biological products are
derived from cells, tissues or microorganisms and reflect the inherent variability
characteristic of living materials. The active substances in biological products are
often too complex to be fully characterized by utilizing physicochemical testing
methods alone and may show a marked heterogeneity from one preparation
and/or batch to the next. Consequently, special considerations are needed
when manufacturing biological products in order to maintain consistency in
product quality.
Good manufacturing practices (GMP) for biological products were
first published by WHO in 1992 (1). This current revision reflects subsequent
developments that have taken place in science and technology, and in the
application of risk-based approaches to GMP (214). The content of this
document should be considered complementary to the general recommendations
set out in the current WHO good manufacturing practices for pharmaceutical
products: main principles (2) and in other WHO documents related specifically
to the production and control of biological products.
This document is intended to serve as a basis for establishing national
guidelines for GMP for biological products. If a national regulatory authority
(NRA) so desires, the guidance provided may be adopted as definitive national
requirements, or modifications may be justified and made by the NRA in
light of the riskbenefit balance and legal considerations in each authority.
In such cases, it is recommended that any modification to the principles and
technical specifications set out below should be made only on the condition
that the modifications ensure product quality, safety and efficacy that are at least
equivalent to that recommended in this document.
2. Scope
The guidance provided in this document applies to the manufacture, control
and testing of biological products for human use from starting materials
and preparations (including seed lots, cell banks and intermediates) to the
finished product.
Manufacturing procedures within the scope of this document include:
growth of strains of microorganisms and eukaryotic cells;
extraction of substances from biological tissues, including human,
animal and plant tissues, and fungi;
114
Annex 3
recombinant DNA (rDNA) techniques;

hybridoma techniques;
propagation of microorganisms in embryos or animals.
Medicinal products of biological origin manufactured by these procedures
include allergens, antigens, vaccines, certain hormones, cytokines, monoclonal
antibodies (mAbs), enzymes, animal immune sera, products of fermentation
(including products derived from rDNA), biological diagnostic reagents for in
vivo use and advanced therapy medicinal products (ATMPs) used for example
in gene therapy and cell therapy.
For human whole blood, blood components and plasma-derived products
for therapeutic use separate comprehensive WHO guidance is available and
should be followed (12, 15).
In some countries certain small-molecule medicinal products (for
example, antibiotics) are not defined as biological products. Nevertheless, where
the manufacturing procedures described in this document are used then the
guidance provided may be followed.
The preparation of investigational medicinal products for use in clinical
trials should follow the basic principles of GMP set out in these and other WHO
GMP guidelines (2, 16) as appropriate. However, certain other requirements
(such as process and analytical method validations) could be completed before
marketing authorization (1719).
The current document does not provide detailed recommendations
for specific classes of biological products (for example, vaccines). Attention is
therefore directed to other relevant WHO documents, and in particular to WHO
recommendations to assure the quality, safety and efficacy of specific products.2
Table1 illustrates the typical risk-based application of the current
document (4, 7). It should be noted that this table is illustrative only and is not
intended to describe the precise scope.
See: http://www.who.int/biologicals/en/ (accessed 4 November 2015).

2
115
116
Table A3.1
Scope of the current document (illustrative)
Type and source Example products Application of this document to steps in manufacture
ofmaterial
1. Animal or plant Heparins, insulin, Collection of plant, Cutting, mixing Isolation and Formulation
sources: non- enzymes, proteins, organ, tissue or and/or initial purification andfilling
transgenic allergen extract, ATMPs, fluid processing
animal immune sera
2. Virus or bacteria/ Viral or bacterial Establishment Cell culture Inactivation Formulation
fermentation/cell vaccines, enzymes, and and/or when applicable, andfilling
culture proteins maintenance of fermentation isolation and
MCB, WCB, MSL/ purification
MVS, WSL/WVS
3. Biotechnology Recombinant products, Establishment Cell culture Isolation, Formulation
fermentation/cell mAbs, allergens, and and/or purification and andfilling
culture vaccines, gene therapy maintenance of fermentation modification
(viral and non-viral MCB, WCB, MSL,
vectors, plasmids) WSL
4. Animal sources: Recombinant proteins, Master and Collection, cutting, Isolation, Formulation
transgenic ATMPs working transgenic mixing and/or purification and andfilling
bank initial processing modification

5. Plant sources: Recombinant proteins, Master and Growing and/or Initial extraction, Formulation
transgenic vaccines, allergens working transgenic harvesting isolation, andfilling
bank purification and
modification
Table A3.1 continued
Type and source Example products Application of this document to steps in manufacture
ofmaterial
6. Human sources Urine-derived enzymes, Collection of fluid Mixing and/or Isolation and Formulation
hormones initial processing purification andfilling
7. Human and/or Gene therapy: Donation, Vector Ex vivo genetic Formulation
animal sources genetically modified procurement and manufacture and modification of andfilling
cells testing of starting cell purification cells, establish MCB,
tissue/cellsa and processing WCB or cell stock
Somatic cell therapy Donation, Establishing and Cell isolation, Formulation,
procurement and maintaining MCB, culture purification combination
testing of starting WCB or cell stock and combination andfilling
tissue/cellsa with non-cellular
components
Tissue-engineered Donation, Initial processing, Cell isolation, Formulation,
products procurement and isolation and culture, purification combination
testing of starting purification, and combination andfilling
tissue/cells a establishing and with non-cellular
maintaining MCB, components
WCB, primary cell
stock
a
GMP guidelines, as described in this document, are not applied to this step. Other national regulations, requirements, recommendations and/or guidelines may apply as
deemed necessary by the NRA.
MCB = master cell bank; MSL = master seed lot; MVS = master virus seed; WCB = working cell bank; WSL = working seed lot; WVS = working virus seed.
Annex 3
117
3. Terminology
In addition to the terms defined in WHO good manufacturing practices for
pharmaceutical products: main principles (2) and WHO good manufacturing
practices for sterile pharmaceutical products (3), the definitions given below
apply to the terms as used in the current document. These terms may have
different meanings in other contexts.
Active substance: a defined process intermediate containing the active
ingredient, which is subsequently formulated with excipients to produce the drug
product. This may also be referred to as drug substance or active ingredient
in other documents.
Adventitious agents: contaminating microorganisms of the cell culture
or source materials, including bacteria, fungi, mycoplasmas/spiroplasmas,
mycobacteria, rickettsia, protozoa, parasites, transmissible spongiform
encephalopathy (TSE) agents and viruses that have been unintentionally
introduced into the manufacturing process of a biological product. The source
of these contaminants may be the legacy of the cell line, or the raw materials
used in the culture medium to propagate the cells (in banking, in production or
in their legacy), the environment, personnel, equipment or elsewhere.
Allergen: a molecule capable of inducing an immunoglobulin E (IgE)
response and/or a Type I allergic reaction.
Antibodies: proteins produced naturally by the B-lymphocytes that
bind to specific antigens. Using rDNA technology antibodies are also produced
in other (continuous) cell lines. Antibodies may be divided into two main types
monoclonal and polyclonal antibodies based on key differences in their
methods of manufacture. Also called immunoglobulins.
Antigens: substances (for example, toxins, foreign proteins, bacteria,
tissue cells and venoms) capable of inducing specific immune responses.
Axenic: a single organism in culture which is not contaminated with
any other organism.

Bioburden: the level and type (objectionable or not) of microorganisms
present in raw materials, media, biological substances, intermediates or
finished products. Regarded as contamination when the level and/or type
exceed specifications.
Biohazard: any biological material considered to be hazardous to people
and/or the environment.
Biological starting materials: starting materials derived from a biological
source that mark the beginning of the manufacturing process of a drug, as
described in a marketing authorization or licence application, and from which
the active ingredient is derived either directly (for example, plasma derivatives,
ascitic fluid and bovine lung) or indirectly (for example, cell substrates, host/
vector production cells, eggs and viral strains).
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Annex 3
Biosafety risk group: denotes the containment conditions required for

safe handling of organisms associated with different hazards, ranging from Risk
Group 1 (lowest risk, no or low individual and community risk, and unlikely to
cause disease) to Risk Group 4 (highest risk, high individual and community
risk, usually causes severe disease, and which is likely to spread with no
prophylaxis or treatment available) (20).
Campaign manufacture: the manufacture of an uninterrupted sequence
of batches of the same product or intermediate in a given time period, followed
by strict adherence to accepted control measures before switching to another
product or different serotype. The different products are not run at the same
time but may be run on the same equipment.
Cell bank: a collection of appropriate containers whose contents are
of uniform composition and stored under defined conditions. Each container
represents an aliquot of a single pool of cells.
Cell culture: the process by which cells that are no longer organized into
tissues are grown in vitro under defined and controlled conditions. Cell cultures
are operated and processed under axenic conditions to ensure a pure culture
absent of microbial contamination.
Cell stock: primary cells expanded to a given number of cells to be
aliquoted and used as starting material for production of a limited number of
lots of a cell-based medicinal product.
Containment: the concept of using a process, equipment, personnel,
utilities, system and/or facility to contain product, dust or contaminants in one
zone, preventing them from entering into another zone and/or escaping.
Continuous culture: a process by which the growth of cells is maintained
by periodically replacing a portion of the cells and the medium so that there is
no lag or saturation phase.
Control strategy: a planned set of controls derived from current
product and process understanding that assures process performance and
product quality. The controls can include parameters and attributes related
to active substance and finished product materials and components; facility
and equipment operating conditions; in-process controls; finished product
specifications; and the associated methods and frequency of monitoring
andcontrol.
Cross-contamination: contamination of a starting material, intermediate
product or finished product with another starting material or product during
production. In multi-product facilities, cross-contamination can occur throughout
the manufacturing process, from generation of the master cell bank (MCB)
and working cell bank (WCB) to finished product.
Dedicated: facility, personnel, equipment or piece of equipment used
only in the manufacture of a particular product or group of specified products
of similar risk.
119
Dedicated area: an area that may be in the same building as another

area but which is separated by a physical barrier and which has, for example,
separate entrances, staff facilities and air-handling systems. Also referred to as
self-contained facility in other GMP documents.
Feeder cells: cells used in co-culture to maintain pluripotent stem cells.
For human embryonic stem cell culture, typical feeder layers include mouse
embryonic fibroblasts or human embryonic fibroblasts that have been treated
to prevent them from dividing.
Finished product: a finished dosage form that has undergone all
stagesof manufacture, including packaging in its final container and labelling.
Also referred to as finished dosage form, drug product or final product in
other documents.
Fermentation: maintenance or propagation of microbial cells in vitro
(fermenter). Fermentation is operated and progressed under axenic conditions
to ensure a pure culture absent of contaminating microorganisms.
Harvesting: the procedure by which the cells, inclusion bodies or crude
supernatants containing the unpurified active ingredient are recovered.
Hybridoma: an immortalized cell line that secretes desired (monoclonal)
antibodies and which is typically derived by fusing B-lymphocytes with
tumour cells.
Inactivation: removal or reduction to an acceptable limit of infectivity of
microorganisms or detoxification of toxins by chemical or physical modification.
Master cell bank (MCB): a quantity of well-characterized cells of animal
or other origin, derived from a cell seed at a specific population doubling level
(PDL) or passage level, dispensed into multiple containers and stored under
defined conditions. The MCB is prepared from a single homogeneously mixed
pool of cells. In some cases, such as genetically engineered cells, the MCB may
be prepared from a selected cell clone established under defined conditions.
However, the MCB may not be clonal. The MCB is used to derive a working cell
bank (WCB).
Monoclonal antibodies (mAbs): homogenous antibody population
obtained from a single clone of lymphocytes or by recombinant technology
and which bind to a single epitope.
Pharmaceutical quality system (PQS): management system used by a
pharmaceutical company to direct and control its activities with regard toquality.
Polyclonal antibodies: antibodies derived from a range of lymphocyte
clones and produced in humans and animals in response to the epitopes on
most non-self molecules.
Primary containment: a system of containment that prevents the
escape of a biological agent into the immediate working environment. It
involves the use of closed containers or biological safety cabinets along with
secure operating procedures.
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Quality risk management (QRM): a systematic process for the

assessment, control, communication and review of risks to the quality of
pharmaceutical products across the product life-cycle.
Reference sample: a sample of a batch of starting material, packaging
material, intermediate or finished product which is stored for the purpose of
being analysed should the need arise during the shelf-life of the batch concerned.
Retention sample: a sample of a fully packaged unit from a batch
of finished product. It is stored for identification purposes (for example, of
presentation, packaging, labelling, patient information leaflet, batch number and
expiry date) should the need arise during the shelf-life of the batch concerned.
Seed lot: a quantity of live cells or viruses which has been derived from
a single culture (though not necessarily clonal), has a uniform composition and
is aliquoted into appropriate storage containers from which all future products
will be derived, either directly or via a seed lot system. The following derived
terms are used in this document master seed lot (MSL): a lot or bank of
cells or viruses from which all future vaccine production will be derived. The
MSL represents a well-characterized collection of cells or viruses or bacteria of
uniform composition. Also referred to as master virus seed (MVS) for virus
seeds, master seed bank, master seed antigen or master transgenic bank in
other documents; and working seed lot (WSL): a cell or viral or bacterial seed
lot derived by propagation from the MSL under defined conditions and used to
initiate production of vaccines on a lot-by-lot basis. Also referred to as working
virus seed (WVS) for virus seeds, working seed bank, working seed antigen
or working transgenic bank in other documents.
Specific pathogen free (SPF): denoting animals or animal materials
(such as chickens, embryos, eggs or cell cultures) derived from groups of animals
(for example, flocks or herds) free from specified pathogens, and used for the
production or quality control of biological products. Such flocks or herds are
defined as animals sharing a common environment and having their own
caretakers who have no contact with non-SPF groups.
Starting materials: any substances of a defined quality used in the
production of a pharmaceutical product, but excluding packaging materials. In
the context of biological products manufacturing, examples of starting materials
may include cryo-protectants, feeder cells, reagents, growth media, buffers,
serum, enzymes, cytokines, growth factors and amino acids.
Transgenic: denoting an organism that contains a foreign gene in its
normal genetic component for the expression of biological pharmaceutical
materials.
Vaccine: a preparation containing antigens capable of inducing an
active immune response for the prevention, amelioration or treatment of
infectiousdiseases.
121
Working cell bank (WCB): a quantity of well-characterized cells of

animal or other origin, derived from an MCB at a specific PDL or passage
level, dispensed into multiple containers and stored under defined conditions.
The WCB is prepared from a single homogeneously mixed pool of cells
(often,this is the MCB). One or more of the WCB containers is used for each
production culture.
4. Principles and general considerations

The manufacture of biological products should be undertaken in accordance with
the basic principles of GMP. The points covered by the current document should,
therefore, be considered as complementary to the general recommendations
set out in the current WHO good manufacturing practices for pharmaceutical
products: main principles (2) and associated specialized guidelines and
recommendations (3, 4, 10, 13, 14) as well as other WHO documents related
specifically to the production and control of biological products established by
the WHO Expert Committee on Biological Standardization.3
The manufacture, control and administration of biological active
substances and finished products require certain specific considerations and
precautions arising from the nature of these products and their processes.
Unlike conventional pharmaceutical products which are manufactured using
chemical and physical techniques capable of a high degree of consistency, the
manufacture of biological active substances and finished products involves
biological processes and materials, such as cultivation of cells or extraction from
living organisms. As these biological processes may display inherent variability,
the range and nature of by-products may also be variable. As a result, quality
risk management (QRM) principles are particularly important for this class of
materials and should be used to develop the control strategy across all stages
of manufacture so as to minimize variability and reduce the opportunity for
contamination and cross-contamination.

Materials and processing conditions used in cultivation processes are
designed to provide conditions for the growth of target cells and microorganisms
therefore, extraneous microbial contaminants have the opportunity to grow.
Furthermore, many biological products have limited ability to withstand certain
purification techniques, particularly those designed to inactivate or remove
adventitious viral contaminants. The design of the processes, equipment, facilities,
utilities, the conditions of preparation and addition of buffers and reagents,
sampling, and training of the operators are key considerations in minimizing
See: http://www.who.int/biologicals/en/ (accessed 4 November 2015).

3
122
Annex 3
such contamination events. Specifications outlined in WHO guidelines and

recommendations will determine whether and to what stage of production
substances and materials can have a defined level of bioburden or need to be
sterile. Similarly, manufacturing should be consistent with other specifications
set out in the product summary files, marketing authorization or clinical trial
approvals (for example, number of generations (expressed as doublings or
passages) between the seed lot or cell bank and the finished product).
Many biological materials (such as live-attenuated bacteria and
viruses) cannot be terminally sterilized by heat, gas or radiation. In addition,
some products, such as certain live and adjuvanted vaccines (for example,
bacille CalmetteGurin (BCG) or cholera), may not be sterilized by filtration
processes. For these axenic products, processing should be conducted aseptically
to minimize the introduction of contaminants from the point where a potential
contamination cannot be removed from the manufacturing process. Relevant
WHO documents should be consulted on the validation of specific manufacturing
steps such as virus removal or inactivation (21). Robust environmental controls
and monitoring and, wherever feasible, in situ cleaning and sterilization systems,
together with the use of closed systems can significantly reduce the risk of
accidental contamination and cross-contamination.
Control usually involves biological analytical techniques, which typically
have a greater variability than physicochemical determinations. The combination
of variability in starting materials and the potential for subtle changes during
the manufacturing process of biological products also requires an emphasis
on production consistency. This is of particular concern because of the need
to link consistency to original clinical trials documenting the products safety
and efficacy. A robust manufacturing process is therefore crucial and in-process
controls take on a particular importance in the manufacture of biological active
substances and medicinal products.
Because of the risks inherent in producing and manipulating pathogenic
and transmissible microorganisms during the production and testing of
biological materials, GMP should prioritize the safety of the recipient to whom
the biological product is administered, the safety of personnel during operation
and the protection of the environment.
Biosafety considerations should follow national guidelines and (if
applicable and available) international guidelines. In most countries, the
regulation of GMP and biosafety are governed by different institutions. In the
context of manufacturing pathogenic biological products of Biosafety Risk Group
3 and 4, close collaboration between such institutions is especially required to
assure that both product contamination and environmental contamination levels
are controlled within acceptable limits. Specific recommendations regarding
containment are outlined below in section 10.
123
5. Pharmaceutical quality system and

quality risk management
Biological products, like any pharmaceutical product, should be manufactured
in accordance with the requirements of a pharmaceutical quality system (PQS)
based on a life-cycle approach as defined in WHO good manufacturing practices
for pharmaceutical products: main principles (2). This approach facilitates
innovation and continual improvement, and also strengthens the link between
pharmaceutical development and manufacturing activities.
QRM principles should be used to develop the control strategy across
all manufacturing and control stages including materials sourcing and
storage, personnel and materials flow, manufacture and packaging, quality
control, quality assurance, storage and distribution activities, as described in
relevant WHO guidelines (14) and other documents (22). Due to the inherent
variability of biological processes and starting materials, ongoing trend analysis
and periodic review are particularly important elements of PQS. Thus, special
attention should be paid to starting material controls, change control, trend
analysis and deviation management in order to ensure production consistency.
Monitoring systems should be designed so as to provide early detection of any
unwanted or unanticipated factors that may affect the quality, safety and efficacy
of the product. The effectiveness of the control strategy in monitoring, reducing
and managing such risks should be regularly reviewed and the systems updated
as required taking into account scientific and technical progress.
6. Personnel
6.1 Personnel responsible for production and control should have an
adequate background in relevant scientific disciplines such as microbiology,
biology, biometry, chemistry, medicine, pharmacy, pharmacology, virology,

immunology, biotechnology and veterinary medicine, together with
sufficient practical experience to enable them to perform their duties.
6.2 The health status of personnel should be taken into consideration as
part of ensuring product safety. Where necessary, personnel engaged
in production, maintenance, testing and animal care (and inspections)
should be vaccinated with appropriate specific vaccines and have regular
health checks. Any changes in the health status of personnel which could
adversely affect the quality of the product should preclude their working
in the production area, and appropriate records kept. The scope and
frequency of health monitoring should be commensurate with the risk to
the product and personnel.
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Annex 3
6.3 Training in cleaning and disinfection procedures, hygiene and microbiology

should emphasize the risk of microbial and adventitious contamination and
the nature of the target microorganisms and growth media routinely used.
6.4 Where required to minimize the opportunity for cross-contamination,
restrictions on the movement of all personnel (including quality control,
maintenance and cleaning staff) should be defined on the basis of QRM
principles. In general, all personnel including those not routinely involved
in the production operation (such as management, engineering staff and
validation staff or auditors) should not pass from areas with exposure to
live microorganisms, genetically modified microorganisms, animal tissue,
toxins, venoms or animals to areas where other products (inactivated or
sterile) or different organisms are handled. If such passage is unavoidable
during a working day, then contamination control measures (for example,
clearly defined decontamination measures such as a complete change of
appropriate clothing and shoes, and showering if applicable) should be
followed by all personnel visiting any such production area unless otherwise
justified on the basis of QRM.
6.5 Because the risks are difficult to manage, personnel working in an animal
facility should be restricted from entering production areas where potential
risks of cross-contamination exist.
6.6 Staff assigned to the production of BCG products should not work with
other infectious agents. In particular, they should not work with virulent
strains of Mycobacterium tuberculosis, nor should they be exposed to a
known risk of tuberculosis infection (23). Additionally, they should
be carefully monitored, with regular health checks that screen for
tuberculosisinfection.
6.7 If personnel working in BCG manufacturing and in animal quarters need
to be reassigned to other manufacturing units they should not be allowed
into such units until they pass their health check.
7. Starting materials
7.1 The source, origin and suitability of active substances, starting materials
(for example, cryo-protectants and feeder cells), buffers and media (for
example, reagents, growth media, serum, enzymes, cytokines, growth
factors and amino acids) and other components of the finished product
should be clearly defined and controlled according to the principles set out
in WHO guidance on GMP for pharmaceutical products (2).
125
7.2 Manufacturers should retain information describing the source and quality
of the biological materials used for at least 1 year after the expiry date
of the finished products and according to local regulations concerning
biological products. It has been found that documents retained for longer
periods may provide useful information related to adverse events following
immunization (AEFIs) and other investigations.
7.3 All starting material suppliers (that is, manufacturers) should be initially
qualified on the basis of documented criteria and a risk-based approach.
Regular assessments of their status should also be carried out. Particular
attention should be given to the identification and monitoring of any
variability that may affect biological processes. When starting materials
are sourced from brokers who could increase the risk of contamination
by performing repackaging operations under GMP (2, 4) they should be
carefully qualified; an audit may form part of such qualification, as needed.
7.4 An identity test, or equivalent, should be performed on each batch of
received starting materials prior to release. The number of containers
sampled should be justified on the basis of QRM principles and in agreement
with all applicable guidelines (2). The identification of all starting materials
should be in compliance with the requirements appropriate to the stage
of manufacture. The level of testing should be commensurate with the
qualification level of the supplier and the nature of the materials used. In the
case of starting material used to manufacture active substances the number
of samples taken should be based on statistically recognized criteria and
QRM principles (2). However, for starting materials and intermediates used
in the formulation of finished product each container should be sampled
for identity testing in accordance with the main principles of GMP for
pharmaceutical products unless reduced testing has been validated.
7.5 The sampling process should not adversely affect the quality of the
product. Incoming starting materials should be sampled under appropriate

conditions in order to prevent contamination and cross-contamination.
7.6 Where justified (such as the special case of sterile starting materials) it
may be acceptable to reduce the risk of contamination by not performing
sampling at the time of receipt but to perform the testing later on samples
taken at the time of use. In such cases, release of the finished product is
conditional upon satisfactory results of these tests.
7.7 Where the necessary tests for approving starting materials take a
significantly long time, it may be permissible by exception to process
starting materials before the test results are available. The use of these
materials should be clearly justified in a documented manner, and the risks
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should be understood and assessed under the principles of QRM. In such

cases, release of the finished product is conditional upon satisfactory results
from the tests. It must be ensured that this is not standard practice and
occurs only with justification of the risk taken.
7.8 The risk of contamination of starting materials during their passage
along the supply chain should be assessed, with particular emphasis on
adventitious agents such as those causing TSEs (24). Other materials
that come into direct contact with manufacturing equipment and/or
with potential product contact surfaces (such as filter media, growth
media during aseptic process simulations and lubricants) should also be
controlled. A quality risk assessment should be performed to evaluate the
potential for adventitious agents in biological starting materials.
7.9 Where required, the sterilization of starting materials should be carried
out by heat whenever possible. Where necessary, other appropriate
validated methods may also be used for this purpose (such as irradiation
and filtration).
7.10 The controls required for ensuring the quality of sterile starting materials
and of the aseptic manufacturing process should be based on the principles
and guidance contained in the current WHO good manufacturing practices
for sterile pharmaceutical products (3).
7.11 The transport of critical materials, reference materials, active substances,
human tissues and cells to the manufacturing site should be controlled
as part of a written quality agreement between the responsible parties if
they are different commercial entities. Manufacturing sites should have
documentary evidence of adherence to the specified storage and transport
conditions, including cold chain requirements, if required. The required
traceability starting at tissue establishments through to the recipient(s),
and including the traceability of materials in contact with the cells or tissues
should be ensured, maintained and documented.
8. Seed lots and cell banks

8.1 The recommendations set out in WHO good manufacturing practices for
active pharmaceutical ingredients (4) should be followed specifically
section 18 on specific guidance for active pharmaceutical ingredients
manufactured by cell culture/fermentation.
8.2 Where human or animal cells are used as feeder cells in the manufacturing
process, appropriate controls over their sourcing, testing, transport and
storage should be in place.
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8.3 In order to prevent the unwanted drift of genetic properties which

might result from repeated subcultures or multiple generations, the
production of biological products obtained by microbial culture, cell
culture or propagation in embryos and animals should be based on a
system of master and working seed lots and/or cell banks; which is the
beginning of the manufacturing process of certain biological products (for
example,vaccines).
8.4 The number of generations (expressed as passages or doublings) between
the seed lot or cell bank and the finished product, defined as maximum,
should be consistent with the marketing authorization dossier and should
not be exceeded.
8.5 Cell-based medicinal products are often generated from a cell stock
obtained from a limited number of passages. In contrast with the two-
tier system of MCBs and WCBs, the number of production runs from a
cell stock is limited by the number of aliquots obtained after expansion
and does not cover the entire life-cycle of the product. Cell stock changes
should be covered by a validation protocol and communicated to the NRA,
as applicable.
8.6 Establishment and handling of the MCBs and WCBs should be performed
under conditions which are demonstrably appropriate. These should
include an appropriately controlled environment to protect the seed lot and
the cell bank, and the personnel handling them. To establish the minimum
requirements for clean room grade and environmental monitoring in the
case of vaccines see the WHO Environmental monitoring of clean rooms
in vaccine manufacturing facilities: points to consider for manufacturers of
human vaccines (25). During the establishment of the seed lot and cell
bank, no other living or infectious material (such as viruses, cell lines or
microbial strains) should be handled simultaneously in the same area or by

the same persons, as set out in current WHO Recommendations (26).
8.7 Quarantine and release procedures for master and working cell banks/seed
lots should be followed, including adequate characterization and testing for
contaminants. Initially, full characterization testing of the MCB should be
done, including genetic identification. A new MCB (from a previous initial
clone, MCB or WCB) should be subjected to the same established testing as
the original MCB, unless otherwise justified. Thereafter, the viability, purity
and other stability-indicating attributes of seed lots and cell banks should
be checked regularly according to justified criteria. Evidence of the stability
and recovery of the seed lots and banks should be documented and records
should be kept in a manner that permits trend evaluation.
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8.8 Each storage container should be adequately sealed, clearly labelled and
kept at an appropriate temperature. A stock inventory should be kept. The
storage temperature should be recorded continuously and, where applicable,
the liquid nitrogen level should be monitored. Any deviation from the set
limits, and any corrective and preventive action taken, should be recorded.
Temperature deviations should be detected as early as possible (for example,
through the use of an alarm system for temperature and nitrogen levels).
8.9 Seed lots and cell banks should be stored and used in such a way as to
minimize the risks of contamination or alteration (for example, stored
in qualified ultra-low temperature freezers or liquid nitrogen storage
containers). Control measures for the storage of different seeds and/or
cells in the same area or equipment should prevent mix-up and should
take into account the infectious nature of the materials in order to prevent
cross-contamination.
8.10 MSLs, MCBs, and preferably also WSLs and WCBs, should be stored in
two or more controlled separate sites in order to minimize the risk of
total loss due to natural disaster, equipment malfunction or human error.
A contingency plan should be in place.
8.11 The storage and handling conditions for the cell or seed banks should
be defined. Access should be controlled and restricted to authorized
personnel, and appropriate access records maintained. Records of location,
identity and inventory of individual containers should also be kept. Once
containers are removed from the seed lot/cell bank management system
they should not be returned to stock.
9. Premises and equipment

9.1 In general, preparations containing live microorganisms or live viruses
should not be manufactured and containers should not be filled in areas
used for the processing of other pharmaceutical products. However, if the
manufacturer can demonstrate and validate effective containment and
decontamination of the live microorganisms and viruses then the use of
multi-product facilities may be justifiable. In such cases, measures such as
campaign production, closed systems and/or disposable systems should be
considered and should be based on QRM principles (see sections 10 and
13 below on containment and campaign production respectively).
9.2 Documented QRM should be carried out for every additional product
in a biological manufacturing multi-product facility, which may include
a potency and toxicological evaluation based on cross-contamination
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risks. Other factors to be taken into account include facility/equipment

design and use, personnel and material flows, microbiological controls,
physicochemical characteristics of the active substance, process
characteristics, cleaning processes and analytical capabilities relative to
the relevant limits established from product evaluation. The outcome
of the QRM process should be the basis for determining the necessity
for premises and equipment to be dedicated to a particular product
or product family, and the extent to which this should be the case. This
may include dedicating specific product-contact parts. The NRA should
approve the use of a manufacturing facility for the production of multiple
products on case-to-case basis.
9.3 Killed vaccines, antisera and other biological products including those
made by rDNA techniques, toxoids and bacterial extracts may, following
inactivation, be manufactured on the same premises provided that
adequate decontamination and cleaning measures are implemented on
the basis of QRM.
9.4 Cleaning and sanitization should take into account the fact that processes
often include the handling of growth media and other growth-promoting
agents. Validation studies should be carried out to ensure the effectiveness of
cleaning, sanitization and disinfection, including elimination of residues
of used agents. Environmental and personnel safety precautions should be
taken during the cleaning and sanitization processes. The use of cleaning
and sanitizing agents should not pose any major risk to the performance
of equipment.
The use of closed systems to improve asepsis and containment
should be considered where practicable. Where open systems are utilized
during processing (for example, during addition of growth supplements,
media, buffers and gases, and during sampling and aseptic manipulations
during the handling of live cells such as in cell-therapy products) control

measures should be put in place to prevent contamination, mix-up
and cross-contamination. Logical and unidirectional flows of personnel,
materials and processes, and the use of clean-in-place and sterilize-in-place
systems, should be considered wherever possible. Where sterile single-use
systems such as bags and connectors are utilized, they should be qualified
with respect to suitability, extractables, leachables and integrity.
9.5 Because of the variability of biological products, and of the corresponding
manufacturing processes, approved starting materials that have to be
measured or weighed for the production process (such as growth media,
solutions and buffers) may be kept in small stocks in the production area
for a specified period of time according to defined criteria such as for
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the duration of manufacture of the batch or of the campaign. Appropriate

storage conditions and controls should be maintained during such
temporary storage. These materials should not be returned to the general
stock. Materials used to formulate buffers, growth media and so on
should be weighed and made into a solution in a contained area using
local protection (such as a classified weighing booth) and outside the
aseptic processing areas in order to minimize particulate contamination
of the latter.
9.6 In manufacturing facilities, the mix-up of entry and exit of personnel
should be avoided through the use of separate changing rooms or through
procedural controls where Biosafety Risk Group 3 or 4 organisms are
handled (20).
10. Containment
10.1 Airborne dissemination of live microorganisms and viruses used for the
production process, including those from personnel, should be avoided.
10.2 Adequate precautions should be taken to avoid contamination of the
drainage system with dangerous effluents. Drainage systems should be
designed in such a way that effluents can be effectively neutralized or
decontaminated to minimize the risk of cross-contamination. Specific and
validated decontamination systems should be considered for effluents
when infectious and/or potentially infectious materials are used for
production. Local regulations should be complied with in order to
minimize the risk of contamination of the external environment according
to the risk associated with the biohazardous nature of waste materials.
10.3 Dedicated production areas should be used for the handling of live cells
capable of persistence in the manufacturing environment, for pathogenic
organisms of Biosafety Risk Group 3 or 4 and/or for spore-forming
organisms until the inactivation process is accomplished and verified. For
Bacillus anthracis, Clostridium tetani and Clostridium botulinum strictly
dedicated facilities should be utilized for each individual product.
Up-to-date information on these and other high-risk or special agents
should be sought from major information resources (27). Where campaign
manufacture of spore-forming organisms occurs in a facility or suite of
facilities only one product should be processed at any one time.
Use of any pathogenic organism above Biosafety Risk Group 3
may be permitted by the NRA according to the biohazard classification
of the organism, the risk assessment of the biological product and its
emergency demand.
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10.4 Production of BCG-related product should take place in a dedicated

area and by means of dedicated equipment and utilities (such as heating,
ventilation and air conditioning (HVAC) systems) in order to minimize
the hazard of cross-contamination.
10.5 Specific containment requirements apply to poliomyelitis vaccine in
accordance with the WHO global action plan to minimize poliovirus
facility-associated risk (28) and with WHO Guidelines for the safe
production and quality control of inactivated poliomyelitis vaccine
manufactured from wild polioviruses (29). The measures and procedures
necessary for containment (that is, for protecting the environment and
ensuring the safety of the operator) should not conflict with those for
ensuring product quality.
10.6 Air-handling systems should be designed, constructed and maintained to
minimize the risk of cross-contamination between different manufacturing
areas as required. The need for dedicated air-handling units or single-
pass systems should be based on QRM principles, taking into account the
biohazard classification and containment requirements of the relevant
organism, and process and equipment risks. In the case of Biosafety Risk
Group 3 organisms, air should not be recirculated to any other area in the
facility and should be exhausted through high-efficiency particulate air
(HEPA) filters that are regularly checked for performance. A dedicated
non-recirculating ventilation system and HEPA-filtering of exhaust air are
required when handling Biosafety Risk Group 4 organisms (27).
10.7 Primary containment equipment should be designed and initially qualified
for integrity in order to ensure that the escape of biological agents and/
or material into the immediate working area and outside environment is
prevented. Thereafter, in line with relevant guidelines and QRM principles,
periodical tests should be performed to ensure that the equipment is in

proper working condition.
10.8 Activities associated with the handling of live biological agents (such
as centrifugation and blending of products which can lead to aerosol
formation) should be contained in such a way as to prevent contamination
of other products or the egress of live agents into the working and/or
outside environment. The viability of such organisms and their biohazard
classification should be taken into consideration as part of the management
of such risks.
Accidental spillages, especially of live organisms, must be dealt
with quickly and safely. Validated decontamination measures should be
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available for each organism or groups of related organisms. Where different

strains of a single bacteria species or very similar viruses are involved,
the decontamination process may be validated with one representative
strain, unless the strains vary significantly in their resistance to the
decontaminating agent(s) used.
10.9 Areas where Biosafety Risk Group 3 or 4 organisms are handled should
always have a negative air pressure relative to the environment. This will
ensure the containment of the organism in unlikely events such as failure
of the door interlock. Air-lock doors should be interlocked to prevent
them being opened simultaneously. Differential pressure alarms should be
present wherever required, and should be validated and monitored.
10.10 Air-vent filters should be hydrophobic and subject to integrity testing at

intervals determined by a QRM approach.
10.11 Where the filtration of exhaust air is necessary, the safe changing of filters
should be ensured or bag-in-bag-out housings should be employed. Once
removed, filters should be decontaminated and properly destroyed. In
addition to HEPA filtration other inactivation technologies such as heat
inactivation and steam scavenging may be considered for exhaust air to
ensure effective inactivation of pathogenic organisms of Biosafety Risk
Group 3 and/or 4.
11. Clean rooms

11.1 The WHO good manufacturing practices for sterile pharmaceutical
products (3) defines and establishes the required class/grade of clean
areas for the manufacture of sterile products according to the operations
performed, including final aseptic fill. Additionally, in order to address the
specific manufacturing processes involved in the production of biological
products, and particularly vaccines, the WHO Environmental monitoring
of clean rooms in vaccine manufacturing facilities: points to consider for
manufacturers of human vaccines (25) guidance document may be used
to develop the environmental classification requirements for biological
manufacturing processes.
As part of the control strategy, the degree of environmental control
of particulate and microbial contamination of the production premises
should be adapted to the intermediate or finished product, and also to the
production step, taking into account the potential level of contamination of
the starting materials and the risks to the finished product.
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11.2 The environmental monitoring programme should be supplemented with

methods to detect the presence of the specific microorganisms used for
production (for example, recombinant yeast and toxin- or polysaccharide-
producing bacteria). The environmental monitoring programme may also
include detection of the produced organisms and adventitious agents of
production organisms, especially when campaign manufacture is applied
on the basis of QRM principles.
12. Production
12.1 Since cultivation conditions, media and reagents are designed to promote
the growth of cells or microbial organisms, typically in an axenic state,
particular attention should be paid to the control strategy for ensuring that
effective steps are in place for preventing or minimizing the occurrence of
unwanted bioburden, endotoxins, viruses of animal and human origin, and
associated metabolites.
12.2 The QRM process should be the basis for implementing the technical and
organizational measures required to control the risks of contamination
and cross-contamination. These could include, though are not limited to:
carrying out processing and filling in segregated areas;
containing material transfer by means of an airlock and appropriate
type of pass box with validated transfer procedures, clothing change
and effective washing and decontamination of equipment;
recirculation of only treated (HEPA-filtered) air;
acquiring knowledge of the key characteristics (for example,
pathogenicity, detectability, persistence and susceptibility to
inactivation) of all cells, organisms and any adventitious agents within

the same facility;
when considering the acceptability of concurrent work in cases
where production is characterized by multiple small batches from
different starting materials (for example, cell-based products) taking
into account factors such as the health status of donors and the
risk of total loss of a product from or for specific patients during
development of the cross-contamination control strategy;
preventing the risk of live organisms and spores entering non-related
areas or equipment by addressing all potential routes of cross-
contamination (for example, through the HVAC system) through
the use of single-use components and closed systems;
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conducting environmental monitoring specific to the microorganism

being manufactured in adjacent areas while paying attention to
cross-contamination risks arising from the use of certain monitoring
equipment (such as that used for airborne particle monitoring) in
areas handling live and/or spore-forming organisms;
using campaign-based production (see section 13 below).
12.3 When applicable, the inoculum preparation area should be designed so as
to effectively control the risk of contamination, and should be equipped
with a biosafety hood for primary containment.
12.4 If possible, growth media should be sterilized in situ by heat or in-line
microbial-retentive filters. Additionally, in-line microbial-retentive filters
should be used for the routine addition of gases, media, acids, alkalis and
so on to fermenters or bioreactors.
12.5 Data from continuous monitoring of certain production processes (such
as fermentation) should form part of the batch record. Where continuous
culture is used, special consideration should be given to parameters such
as temperature, pH, pO2 , CO2 and the rate of feed or carbon source with
respect to growth of cells.
12.6 In cases where a viral inactivation or removal process is performed,
measures should be taken (for example, in relation to facility layout,
unidirectional flow and equipment) to avoid the risk of recontamination
of treated products by non-treated products.
12.7 A wide variety of equipment and components (for example, resins,
matrices and cassettes) are used for purification purposes. QRM principles
should be applied to devise the control strategy regarding such equipment
and associated components when used in campaign manufacture and
in multi-product facilities. The reuse of components at different stages
of processing of one product is discouraged but, if performed, should
be validated. Acceptance criteria, operating conditions, regeneration
methods, lifespan and sanitization or sterilization methods, cleaning
process, and hold time between the use of reused components should be
defined and validated. The reuse of components for different products is
not acceptable.
12.8 Where adverse donor (human or animal) health information becomes
available after procurement and/or processing, and this information relates
to product quality, then appropriate measures should be taken including
product recall, if applicable.
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12.9 Antibiotics may be used during the early stages of production to help
prevent inadvertent microbial contamination or to reduce the bioburden
of living tissues and cells. In this case, the use of antibiotics should be
well justified, and they should be cleared from the manufacturing process
at the stage specified in the marketing authorization. Acceptable residual
levels should be defined and validated. Penicillin and other beta-lactam
antibiotics should not be used at any stage of the process.
12.10 A procedure should be in place to address equipment and/or accessories
failure (such as air vent filter failure) which should include a product impact
review. If such failures are discovered following batch release the NRA
should be notified and the need for a batch recall should be considered.
13. Campaign production

13.1 The decision to use a facility or filling line for campaign manufacture
should be justified in a documented manner and should be based on a
systematic risk approach for each product (or strain) taking into account
the containment requirements and the risk of cross-contamination to
the next product. Campaign changeover procedures, including sensitive
techniques used for the determination of residues, should be validated
and proper cleaning acceptance criteria should be defined on a toxicology
basis of product residues from the last campaign, as applicable. Equipment
assigned to continued production or to campaign production of successive
batches of the same intermediate product should be cleaned at appropriate
validated intervals to prevent build-up and carry-over of contaminants
(such as product degradants or objectionable levels of microorganisms).
13.2 For downstream operations of certain products (for example, pertussis
or diphtheria vaccines) campaign production may be acceptable if well
justified. For finishing operations (formulation and filling) the need

for dedicated facilities or the use of campaigns in the same facility will
depend on the specific characteristics of the biological product, on the
characteristics of the other products (including any non-biological
products), on the filling technologies used (such as single-use closed
systems) and on local NRA regulations. Labelling and packaging
operations can be carried out in a multi-product facility.
13.3 Campaign changeover involves intensive decontamination/sterilization
(if required) and cleaning of the equipment and manufacturing area.
Decontamination/sterilization (if required) and cleaning should include
all equipment and accessories used during production, as well as the
facility itself. The following recommendations should be considered:
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waste should be removed from the manufacturing area or sent to the

bio-waste system in a safe manner;
materials should be transferred by a validated procedure;
the Quality Unit should confirm area clearance by inspection, and
review the campaign changeover data (including monitoring results)
prior to releasing the area for the next product.
13.4 When required, the corresponding diluent for the product can be filled in
the same facility in line with the defined campaign production strategy
for finished product.
13.5 When campaign-based manufacturing is considered, the facility layout
and the design of the premises and equipment should permit effective
cleaning and decontamination/sterilization (if required) based on QRM
principles and validated procedures following the production campaign.
In addition, consideration may need to be given at the design stage of
facility layout to the possible need for fumigation.
14. Labelling
14.1 The information provided on the inner label (also called the container
label) and on the outer label (on the packaging) should be readable and
legible, and the content approved by the NRA.
14.2 Minimal key information should be printed on the inner label, and
additional information should be provided on the outer label (for example,
carton) and/or product leaflet.
14.3 The suitability of labels for low and ultra-low storage temperatures should
be verified, if applicable. The label should remain properly attached to the
container under different storage conditions during the shelf-life of the
product. The label and its adhesive should have no adverse effect on the
quality of the product caused by leaching, migration and/or other means.
15. Validation
15.1 Biological processes, handling of live materials and using campaign-based
production, if applicable, are the major aspects of biological product
manufacturing which require process and cleaning validation. The
validation of such processes given the typical variability of biological
products, the possible use of harmful and toxic materials and the need
for inactivation processes plays an important role in demonstrating
production consistency and in proving that the critical process parameters
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and product attributes are controlled. Where available, WHO guidance

documents should be consulted on the validation of specific manufacturing
methods (for example, virus removal or inactivation (21)).
15.2 A QRM approach should be used to determine the scope and extent
ofvalidation.
15.3 All critical biological processes (including inoculation, multiplication,
fermentation, cell disruption, inactivation, purification, virus removal,
removal of toxic and harmful additives, filtration, formulation and aseptic
filling) are subject, as applicable, to process validation. Manufacturing
control parameters to be validated may include specific addition sequences,
mixing speeds, time and temperature controls, limits of light exposure
and containment.
15.4 After initial process validation studies have been finalized and routine
production has begun, critical processes should be subject to monitoring
and trending with the objective of assuring consistency and detecting any
unexpected variability. The monitoring strategy should be defined, taking
into consideration factors such as the inherent variability, complexity of
quality attributes and heterogeneity of biological products. A system or
systems for detecting unplanned departures from the process as designed
should be in place to ensure that the process remains in a state of control.
Collection and evaluation of information and data on the performance of
the process will allow for detection of undesired process variability and
will determine whether action should be taken to prevent, anticipate and/or
correct problems so that the process remains under control.
15.5 Cleaning validation should be performed in order to confirm the
effectiveness of cleaning procedures designed to remove biological
substances, growth media, process reagents, cleaning agents, inactivation

agents and so on. Careful consideration should be given to cleaning
validation when campaign-based production is practised.
15.6 Critical processes for inactivation or elimination of potentially harmful
microorganisms of Biosafety Risk Group 2 or above, including genetically
modified ones, are subject to validation.
15.7 Process revalidation may be triggered by a process change as part
of the change-control system. In addition, because of the variability of
processes, products and methods, process revalidation may be conducted
at predetermined regular intervals according to risk considerations.
Adetailed review of all changes, trends and deviations occurring within a
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defined time period for example, 1 year, based on the regular product
quality review (PQR) may indicate a need for process revalidation.
15.8 The integrity and specified hold times of containers used to store
intermediate products should be validated unless such intermediate
products are freshly prepared and used immediately.
16. Quality control

16.1 As part of quality control sampling and testing procedures for biological
materials and products, special consideration should be given to the
nature of the materials being sampled (for example, the need to avoid
contamination, ensure biocontainment and/or cold chain requirements)
in order to ensure that the testing carried out is representative.
16.2 Samples for post-release use typically fall into one of two categories
reference samples or retention samples for the purposes of analytical
testing and identification respectively. For finished products the reference
and retention samples will in many instances be presented identically
as fully packaged units. In such circumstances, reference and retention
samples may be regarded as interchangeable.
Reference samples of biological starting materials should be
retained under the recommended storage conditions for at least 1 year
beyond the expiry date of the corresponding finished product. Reference
samples of other starting materials (other than solvents, gases and
water) as well as intermediates for which critical parameters cannot be
tested in the final product should be retained for at least 2 years after
the release of the product if their stability allows for this storage period.
Certain startingmaterials such as components of growth media need not
necessarily be retained.
Retention samples of a finished product should be stored in their
final packaging at the recommended storage conditions for at least 1 year
after the expiry date.
16.3 For cell-based products, microbiological tests (for example, sterility tests
or purity checks) should be conducted on cultures of cells or cell banks
free of antibiotics and other inhibitory substances in order to provide
evidence of the absence of bacterial and fungal contamination, and to be
able to detect fastidious organisms where appropriate. Where antibiotics
are used, they should be removed by filtration at the time of testing.
16.4 The traceability, proper use and storage of reference standards should
be ensured, defined and recorded. The stability of reference standards
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should be monitored, and their performance trended. The WHO

Recommendations for the preparation, characterization and establishment
of international and other biological reference standards (30) should
befollowed.
16.5 All stability studies including real-time/real-condition stability, accelerated
stability and stress testing should be carried out according to relevant
WHO and other guidelines (31) or other recognized documents. Trend
analysis of the test results from the stability monitoring programme should
assure the early detection of any process or assay drift, and this information
should be part of the PQR of biological products.
16.6 For products where ongoing stability monitoring would normally require
testing using animals, and no appropriate alternative or validated
techniques are available, the frequency of testing may take into account a
risk-based approach. The principle of bracketing and matrix designs may
be applied if scientifically justified in the stability protocol.
16.7 All analytical methods used in the quality control and in-process control
of biological products should be well characterized, validated and
documented to a satisfactory standard in order to yield reliable results.
The fundamental parameters of this validation include linearity, accuracy,
precision, selectivity/specificity, sensitivity and reproducibility (3235).
16.8 For test methods described in relevant pharmacopoeial monographs,
qualification of the laboratory test equipment and personnel should be
performed. In addition, repeat precision and comparability precision should
be shown in the case of animal tests. Repeatability and reproducibility
should also be demonstrated by reviewing retrospective test data.
In addition to the common parameters typically used for validating
assays (such as accuracy and precision) additional measurements (for
example, of the performance of references, critical reagents and/or cell

lines) should be considered during the validation of bioassays based on
the biological nature of the assay and reagents used.
17. Documentation (batch processing records)

17.1 In general, the processing records of regular production batches should
provide a complete account of the manufacturing activities of each
batch of biological product showing that it has been produced, tested and
dispensed into containers in accordance with the approved procedures.
In the case of vaccines, a batch processing record and a summary
protocol should be prepared for each batch for the purpose of lot release
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by the NRA. The information included in the summary protocol should

follow the WHO Guidelines for independent lot release of vaccines by
regulatory authorities (36). The summary protocol and all associated
records should be of a type approved by the NRA.
17.2 Manufacturing batch records should be retained for at least 1 year after
the expiry date of the batch of the biological product and should be readily
retrievable for inspection by the NRA. It has been found that documents
retained for longer periods may provide useful information related to
AEFI and other investigations.
17.3 Starting materials may require additional documentation on source,
origin, supply chain, method of manufacture and controls applied in order
to ensure an appropriate level of control, including of microbiological
quality if applicable.
17.4 Some product types may require a specific definition of what materials
constitute a batch particularly somatic cells in the context of ATMPs.
For autologous and donor-matched situations, the manufactured product
should be viewed as a batch.
18. Use of animals

18.1 A wide range of animals is used for the manufacture or quality control
of biological products. Special considerations are required when animal
facilities are present at a manufacturing site.
18.2 The presence of live animals in the production area should be avoided
unless otherwise justified. Embryonated eggs are allowed in the production
area, if applicable. If the extraction of tissues or organs from animals is
required then particular care should be taken to prevent contamination
of the production area (for example, appropriate disinfection procedures
should be undertaken).
18.3 Areas used for performing tests involving animals or microorganisms
should be well separated from premises used for the manufacturing of
products and should have completely separate ventilation systems and
separate staff. The separation of different animal species before and
during testing should be considered, as should the necessary animal
acclimatization process, as part of the test requirements.
18.4 In addition to monitoring compliance with TSE regulations (24) other
adventitious agents that are of concern (including those causing zoonotic
diseases and diseases in source animals) should also be monitored and
141
recorded in line with specialist advice on establishing such programmes.

Instances of ill health occurring in the source/donor animals should be
investigated with respect to their suitability, and the suitability of in-contact
animals, for continued use (for example, in manufacture, as sources of
starting materials, and for quality control and safety testing). Decisions
should be documented.
18.5 A look-back procedure should be in place in relation to the decision-
making process used to evaluate the continued suitability of the biological
active substance or finished product in which animal-sourced starting
materials have been used or incorporated. This decision-making process
may include the retesting of reference samples from previous collections
from the same donor animal (where applicable) to establish the last
negative donation. The withdrawal period of therapeutic agents used to
treat source/donor animals should be documented and should be taken
into account when considering the removal of those animals from the
programme for defined periods.
18.6 Particular care should be taken to prevent and monitor infections in
source/donor animals. Measures taken should cover aspects such as
sourcing, facilities, husbandry, biosafety procedures, testing regimes,
control of bedding and feed materials, 100% fresh air supply, appropriate
design of the HVAC system, water supply and appropriate temperature
and humidity conditions for the species being handled. This is of special
relevance to SPF animals where pharmacopoeial monograph requirements
should be met. Housing and health monitoring should also be defined for
other categories of animals (for example, healthy flocks or herds).
18.7 For products manufactured from transgenic animals, traceability should
be maintained in the creation of such animals from the source animals.
Note should be taken of national requirements for animal quarters, care

and quarantine.
18.8 For different animal species and lines, key criteria should be defined,
monitored and recorded. These may include the age, sex, weight and health
status of the animals.
18.9 Animals, biological agents and tests carried out should be appropriately
identified to prevent any risk of mix-up and to control all identified hazards.
18.10 The facility layout should ensure a unidirectional and segregated flow of
healthy animals, inoculated animals and waste-decontamination areas.
Personnel and visitors should also follow a defined flow in order to avoid
cross-contamination.
142
Annex 3
19. Authors and acknowledgements

The scientific basis for the revision of these WHO Guidelines was discussed at
a working group meeting held in Bangkok, Thailand, 1013 September 2007
and attended by: Dr M.M.F. Ahmed, Center for Control of Biologicals and
Vaccines, Egypt; Dr H. Alitamsar, PT Bio Farma, Indonesia; Mr P. Angtrakool,
Ministry of Public Health, Thailand; Dr D. Buckley, Consultant, Monash,
Australia; Dr M. Dennehy, The Biovac Institute, South Africa; Ms X. Dong,
Beijing Tiantan Biological Products Co. Ltd, China; Dr H.J.M. van de Donk,
Consultant, Den Haag, Netherlands; Dr M. Gheisarzardeh, Ministry of Health
and Medical Education, the Islamic Republic of Iran; Dr H.T. Hong, National
Institute for Control of Vaccine and Biologicals, Viet Nam; Mrs W. Jariyapan,
WHO Regional Office for South-East Asia, India; Mr M. Javadekar, Serum
Institute of India Ltd, India; DrD. Jiang, State Food and Drug Administration,
China; Mrs T. Jivapaisarnpong, Ministry of Public Health, Thailand; Dr A.
Khadem, Pasteur Institute of Iran, the Islamic Republic of Iran; Professor S.
Khomvilai, Thai Red Cross Society, Thailand; Dr K-H. Kim, Korean Food and
Drug Administration, Republic of Korea; DrKustantinah, National Agency of
Drug and Food Control, Indonesia; Professor C.K. Lee, Advisor to the Korean
Food and Drug Administration, Republic of Korea; Mrs J. Li, Sinovac Biotech
Co. Ltd, China; V.G. Maqueda, Biologist, Buenos Aires, Argentina; Dr K-I.
Min, Korean Food and Drug Administration, Republic of Korea; Mr I. Rees,
Medicines and Healthcare Products Regulatory Agency, the United Kingdom;
Dr C.H. Sia, Health Sciences Authority, Singapore; Dr M. Suhardono, PT Bio
Farma, Indonesia; Ms J. Teo, Centre for Drug Administration, Singapore; Ms P.S.
Thanaphollert, Ministry of Public Health, Thailand; Mr S. Thirapakpoomanunt,
Ministry of Public Health, Thailand; Ms A.R.T. Utami, National Agency of
Drug and Food Control, Indonesia; Dr D.T.H. Van, Institute for Vaccine and
Biologicals, Viet Nam; Mr B. Wibisono, National Agency of Drug and Food
Control, Indonesia; Mr J. Yang, Kunming Institute of Medical Biology, China;
Mr Y. Yu, Kunming Institute of Medical Biology, China; and Dr I. Knezevic
and Dr S. Lambert, World Health Organization, Switzerland and a WHO
drafting group meeting held in Geneva, Switzerland, 3031 October 2013 and
attended by: Mr R. Acs, Central Drugs Standard Control Organisation, India;
Mr M. Eisenhawer, WHO Regional Office for South-East Asia, India; Dr S.
Fakhrzadeh, Ministry of Health and Medical Education, the Islamic Republic
of Iran; V.G. Maqueda, Biologist, Buenos Aires, Argentina; Mrs K. Porkaew,
Ministry of Public Health, Thailand; Dr S.O. Rumiano, Consultant, Buenos
Aires, Argentina; Dr Y. Wang, National Institutes for Food and Drug Control,
China; Mr B. Wibisono, National Agency of Drug and Food Control, Indonesia;
and Dr A. Chawla, Dr A.R. Khadem, DrI. Knezevic, Dr S. Kopp and Dr D. Lei,
World Health Organization, Switzerland.
143
Based upon the principles defined in the above working group and
drafting group meetings the first draft of these Guidelines was prepared by Mr R.
Acs, Central Drugs Standard Control Organisation, India; Dr B. Yez Chamizo,
Centro para el Control Estatal de Medicamentos, Equipos y Dispositivos Mdicos,
Cuba; Dr S. Fakhrzadeh, Ministry of Health and Medical Education, the Islamic
Republic of Iran; Mrs K. Porkaew, Ministry of Public Health, Thailand; Dr S.O.
Rumiano, Consultant, Buenos Aires, Argentina; Dr Y. Wang, National Institutes
for Food and Drug Control, China; Mr B. Wibisono, National Agency of Drug
and Food Control, Indonesia; Mr M. Eisenhawer, WHO Regional Office for
South-East Asia, India; Dr A. Chawla, Consultant, Greater Noida, India; Dr A.R.
Khadem, World Health Organization, Switzerland; V.G. Maqueda, Biologist,
Buenos Aires, Argentina; and Dr D. Lei, World Health Organization, Switzerland.
A second draft was then prepared by V.G. Maqueda, Biologist, Buenos
Aires, Argentina; Dr B. Yez Chamizo, Centro para el Control Estatal de
Medicamentos, Equipos y Dispositivos Mdicos, Cuba; Dr S. Fakhrzadeh,
Ministry of Health and Medical Education, the Islamic Republic of Iran;
DrS.O. Rumiano, Consultant, Buenos Aires, Argentina; Dr Y. Wang, National
Institutes for Food and Drug Control, China; Mr B. Wibisono, National Agency
of Drug and Food Control, Indonesia; Mr M. Eisenhawer, WHO Regional
Office for South-East Asia, India; Dr A. Chawla, Consultant, Greater Noida,
India; and Dr A.R. Khadem and Dr D. Lei, World Health Organization,
Switzerland following a consultation held in Tunis, Tunisia, 2224 July 2014
and attended by: Dr H. Baiao, National Authority for Medicines and Health
Products, Portugal; MrsR. Bose, Ministry of Health and Family Welfare, India;
Mr C. Cabral, Butantan Institute, Brazil; Dr R. Chaplinsky, GSK Vaccines,
Belgium; Dr A. Chawla, Consultant, Greater Noida, India; Mr M. Diagne,
Direction de la Pharmacie et des Laboratoires, Senegal; Mr M. Eisenhawer,
WHO Regional Office for South-East Asia, India; Dr S. Fakhrzadeh, Ministry
of Health and Medical Education, the Islamic Republic of Iran; Mrs R. Frikha,
Directorate of Pharmacy Inspection, Tunisia; Dr M. Gershman, Pfizer, the USA;

Ms A.R. Cornelio Geyer, Agncia Nacional de Vigilncia Sanitria, Brazil; DrE.
Griffiths, Consultant, Kingston-upon-Thames, the United Kingdom; Dr N.
Harjee, Consultant, Ontario, Canada; Ms D.T.M. Hang, Ministry of Health,
Viet Nam; Dr H. Langar, WHO Regional Office for the Eastern Mediterranean,
Egypt; Dr P. Lauer, Sanofi Pasteur, France; DrC.K. Lee, Korea Food and Drug
Administration, Republic of Korea; Dr H. Leng, Medicines Regulatory Authority,
South Africa; Dr M.G. Lopez Santos, Comisin Federal para la Proteccin contra
Riesgos Sanitarios, Mexico; V.G. Maqueda, Biologist, Buenos Aires, Argentina;
Dr A. Mihaylova, Bulgarian Drug Agency, Bulgaria; Dr J. Miteva, Bulgarian
Drug Agency, Bulgaria; Dr S. Pagliusi, DCVMN International, Switzerland;
DrV.A. Pessanha, Oswaldo Cruz Foundation, Brazil; Mrs K. Porkaew, Ministry
of Public Health, Thailand; Dr S. Ramanan, Amgen, the USA; Dr P. Rampignon,
144
Annex 3
GSK Vaccines, Belgium; Dr D. Rebeski, The Biovac Institute, South Africa;

Dr M. Refaat, Central Administration for Pharmaceutical Affairs, Egypt;
DrS.O. Rumiano, Consultant, Buenos Aires, Argentina; Dr A.L. Salvati, Agenzia
Italiana del Farmaco, Italy; Dr J. Shin, WHO Regional Office for the Western
Pacific, Philippines; Dr W. Stevens, Health Canada, Canada; Dr I. Susanti, PT
Bio Farma, Indonesia; Ms C.S. Takata, Butantan Institute, Brazil; Dr S. Uddin,
Directorate General of Drug Administration, Bangladesh; Dr Y. Wang, National
Institutes for Food and Drug Control, China; Mr B. Wibisono, National Agency
of Drug and Food Control, Indonesia; and Dr A.K. Broojerdi, Dr D. Lei, Dr I.
Streipa-Nauman and Dr D.J. Wood, World Health Organization, Switzerland.
The document WHO/BS/2015.2253, incorporating comments received
from regulators and industry following public consultation on the WHO
Biologicals website, was prepared by V.G. Maqueda, Biologist, Buenos Aires,
Argentina; Dr B. Yez Chamizo, Centro para el Control Estatal de Medicamentos,
Equipos y Dispositivos Mdicos, Cuba; Dr S. Fakhrzadeh, Ministry of Health and
Medical Education, the Islamic Republic of Iran; Dr S.O. Rumiano, Consultant,
Buenos Aires, Argentina; Dr Y. Wang, National Institutes for Food and Drug
Control, China; Dr A. Chawla, Consultant, Greater Noida, India; Dr M. Refaat,
Central Administration for Pharmaceutical Affairs, Egypt; Dr A. Khadem, Pasteur
Institute of Iran, the Islamic Republic of Iran; and Dr M. Chafai, Dr D. Lei, Dr D.
Mubangizi and Dr I.R. Thrussell, World Health Organization, Switzerland.
Further changes were subsequently made to document WHO/BS/
2015.2253 by the WHO Expert Committee on Biological Standardization.
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Annex 4
Guidance on good manufacturing practices: inspection
report
Background
The need for revision of the Guidance on good manufacturing practices: inspection
report (World Health Organization (WHO) Technical Report Series, No.908,
Annex 6, 2003) was brought to the attention of the WHO Expert Committee
on Specifications for Pharmaceutical Preparations. The intent of this update
is to bring it in line with the current format used by the Prequalification
Team (PQT) for its inspections and the formats currently used internationally
in national and regional inspectorates. In addition, the concepts of risk
management, as, for example, included in the WHO guidelines on quality risk
management (WHO Technical Report Series, No.986, Annex 6, 2014), have
been taken into consideration.
1 Introduction 150
2. Scope 150
3. Glossary 150
4. General principles 151
Appendix 1 Guidance on good manufacturing practices: inspection report 155
Appendix 2 Example of a risk category assessment of the site depending on level of
compliance and inspection frequency 164
149
1. Introduction
1.1 This guidance describes general principles and a recommended format for
inspection reports for use by organizations performing pharmaceutical
inspections. It aims to support convergence of practices in drawing up
inspection reports so as to facilitate cooperation and information sharing.
2. Scope
2.1 These guidelines apply to reports on inspections of active pharmaceutical
ingredients (APIs) and finished pharmaceutical products (FPPs). A separate
template may be used for inspections of contract research organizations
and quality control laboratories.
3. Glossary
correction. A correction is any action that is taken to eliminate a
nonconformity. However, corrections do not address causes. When applied
to products, corrections can include reworking products, reprocessing them,
regrading them, assigning them to a different use, or simply destroying them.
corrective action. Corrective actions are steps that are taken to eliminate
the causes of existing nonconformities in order to prevent recurrence. The
corrective action process tries to make sure that existing nonconformities and
potentially undesirable situations do not happen again. While corrective actions
prevent recurrence, preventive actions prevent occurrence. Both types of actions
are intended to prevent nonconformities.
corrective and preventive action. A system for implementing corrective
actions and preventive actions resulting from an investigation of complaints,

product rejections, non-conformances, recalls, deviations, audits, regulatory
inspections and findings, and trends from process performance and product
quality monitoring.
deficiency. Non-fulfilment of a requirement. In this sense this term can
be used interchangeably with nonconformity.
inspection observation. An inspection observation is a finding or
a statement of fact made during an inspection and substantiated by objective
evidence. Such findings may be positive or negative. Positive observations
should take the form of a description of the processes that the firm is carrying
out particularly well and that may be considered examples of particularly
good practice. Negative observations are findings of non-compliance with
requirements.
150
Annex 4
nonconformity. Nonconformity refers to a failure to comply with

requirements. A requirement is a need, expectation or obligation. It can be
stated or implied by an organization, its customers or other interested parties.
There are many types of requirements. These include quality requirements,
customer requirements, management requirements, product requirements,
process requirements and legal requirements. Whenever an organization fails to
meet one of these requirements, a nonconformity occurs.
preventive action. Preventive actions are steps that are taken to
remove the causes of potential nonconformities or potential situations that
areundesirable.
4. General principles
4.1 When a site at which pharmaceutical products are manufactured is
inspected, the inspector(s) responsible should draw up a report. The
inspection report should include the items shown in the proposed model
inspection report (Appendix1), adapted as appropriate, according to
the national or regional settings and to the scope and purpose of the
inspection. Where relevant the appropriate system of good manufacturing
practices (GMP) or the nationally appropriate legal basis for GMP, should
be indicated.
4.2 The purpose of an inspection report is to provide a factual and objective
record of the inspection that includes what was done, the inspection
observations or findings (positive and negative) for each activity inspected,
as communicated to the company before the end of the inspection, and a
conclusion that is applicable at the time that the report is written. Positive
findings may include praise for noteworthy efforts in areas that are seen
as excellent examples of implementation of the requirements of the
guidelines. They could also be conveyed when the company has shown
significant improvement in certain areas compared to the findings from
previous inspections. Noteworthy efforts do not require any action. Their
inclusion in the inspection report is done to highlight areas of strength
for future tracking of improvements or areas of decline and to show the
organization what areas it can feel proud of.
4.3 The report should be prepared in a timely manner after an inspection,
with the participation of all members of the inspection team under the
coordination of the lead inspector. The report should be reviewed in
accordance with the quality system of the inspectorate.
4.4 The inspection report should, as appropriate, be written in the third person,
passive voice and the past tense.
151
Example: Cleaning logs for rooms and equipment were maintained

in all areas of the factory.
4.5 All the observations that are considered as deficiencies/noncompliances
should be listed under Part 3 of the report. Each observation included
in an inspection report should be referenced to the relevant GMP text,
WHO guidelines or conditions or commitments under the marketing
authorization. An observation that cannot be reasonably referenced should
not be listed as a deficiency.
4.6 The non-compliance statement should include the requirement (R),
evidence (E) and deficiency (D).
Example: (R) The relevant cleaning records and source data should
be kept in cleaning validation reports; (E) the source of three
samples taken for recovery testing during the process equipment
validation was not traceable; (D) cleaning validation reports did
not include sufficient data.
4.7 Deficiencies/noncompliance statements should distinguish whether the
defect lies in the system itself or in a failure to comply with the system.
For instance, when cleaning is found to be suboptimal, it is important to
know whether the standard operating procedures (SOPs) are inadequate
or lacking, or whether adequate written procedures exist but are not being
followed by personnel.
4.8 Where more than one deficiency relates to the same basic quality system
failure, the deficiencies should be grouped and listed as a single observation,
under a heading that reflects the basic system failure.
4.9 Deficiencies should be reported with a focus on risk to patient health and/
or need for corrective and preventive action (CAPA).

4.10 The report should not include comments that could be construed as
proposed specific solutions to issues raised. Recommendations should
relate to recommended regulatory action as appropriate.
4.11 Each deficiency should be classified as critical, major or other, according to
the following definitions, which may be adapted according to the national
or regional legal context.
4.11.1 A critical deficiency may be defined as an observation that has produced,
or may result in a significant risk of producing, a product that is harmful
to the user.
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Annex 4
4.11.2 A major deficiency may be defined as a non-critical observation that:
a) has produced or may produce a product that does not comply with
its marketing authorization and/or prequalification application
(including variations);
b) indicates a major deviation from the GMP guide;
c) indicates a failure to carry out satisfactory procedures for release
ofbatches;
d) indicates a failure of the person responsible for quality assurance/
quality control to fulfil his or her duties;
e) consists of several other deficiencies, none of which on its own may
be major, but which together may represent a major deficiency and
should be explained and reported as such.
4.11.3 A deficiency may be classified as other if it cannot be classified as either

critical or major, but indicates a departure from GMP. A deficiency
may be other either because it is judged as minor or because there is
insufficient information to classify it as major or critical.
4.11.4 Classification of a deficiency is based on the assessed risk level and

may vary depending on the nature of the products manufactured, e.g.
in some circumstances an example of an other deficiency may be
categorized as major.
4.11.5 A deficiency that was reported at a previous inspection and was not
corrected may be reported with a higher classification.
4.11.6 One-off minor lapses or less significant issues are usually not formally
reported, but are brought to the attention of the manufacturer during
the inspection.
4.11.7 The status of compliance with WHO GMP guidelines should be

determined by the nature and number of deficiencies:
a) When there are other deficiencies only:
i. the site is considered to be operating at an acceptable level

ofGMP compliance,
ii. the manufacturer is expected to provide CAPAs,
iii. CAPAs are evaluated and followed up during the next
routineinspection.
153
b) When there are other and a few major deficiencies (e.g. < 6 1):
i. the site is compliant with GMP after assessing the CAPAs,
ii. CAPAs for all deficiencies to include actions implemented
and/or planned, timelines and documented evidence of
completion, as appropriate,
iii. CAPAs are evaluated on paper and may or may not include
anon-site, follow-up inspection.
c) When there are critical or several major deficiencies (e.g. 6):
i. the site is considered to be operating at an unacceptable level
of compliance with GMP guidelines,
ii. another inspection will normally be required,
iii. administrative and/or legal enforcement actions are applied as
necessary.
4.12 The next date for inspection of the site should be determined depending
on the level of compliance and risk category as defined under national
or regional procedures. Appendix 2 provides an example of how the next
inspection date may be determined. Other approaches may be used.
4.13 The report shall be signed by all inspection team members, but may be
signed by the lead inspector after consultation with and on behalf of the
inspection team, and reviewed in accordance with the quality system of
the inspectorate.
The number six is related to the six systems to be inspected, as listed in Appendix 1.
1
154
Annex 4
Appendix 1
Guidance on good manufacturing practices: inspection
report
Model inspection report
Part 1 General information

Manufacturer details
Company Name of manufacturer
information Corporate address of manufacturer (including telephone,
fax, email and 24-hour telephone numbers)
Contact person, telephone number and email address
Inspected site Address of inspected manufacturing site if different from
that given above (including global positioning system
(GPS) coordinates
in World Geodetic System (WGS) 84: latitude and longitude
expressed in decimal degrees, taken at the main entrance
of the site; data universal numbering system (D-U-N-S)
number: NNNNNNNNN, where each N represents a number
from 09, if available) and specific production blocks or
workshops inspected if the whole site was not inspected
Site number (e.g. unit number, site master file number or
number allocated by the responsible authority)
Manufacturing licence number (if applicable)
Key personnel
Summary of activities For example, manufacture of active pharmaceutical
performed at the site ingredient(s) (APIs), manufacture of finished
pharmaceutical products (FPPs), intermediates or bulk
packaging, laboratory testing, batch release, distribution
and importer activities
Inspection details
Date(s) of
inspection(s)
Type of inspection For example, initial, routine, follow-up, special
Inspector(s) Name(s) and agency affiliations of lead inspector,
inspector(s), accompanying experts and observers
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Table continued
Competent regulatory For foreign inspections, state whether the national
authority regulatory authority (NRA) of the country where the
inspection took place was informed and whether it took
part in the inspection
GMP guidelines List the relevant guidelines stating the title of the
used for assessing guidelines, the title of the publication and web address
compliance where the guidelines can be accessed, for example:
1. WHO good manufacturing practices for pharmaceutical
products: main principles. In: WHO Expert Committee on
Specifications for Pharmaceutical Preparations: forty-
eighth report. Geneva: World Health Organization; 2014:
Annex 2 (WHO Technical Report Series, No. 986;
http://www.who.int/entity/medicines/areas/quality_
safety/quality_assurance/TRS986annex2.pdf?ua=1)
Introduction
Brief summary of Description of main activities (including, e.g. FPP(s) or
the manufacturing API(s) manufactured and their reference/registration/active
activities pharmaceutical ingredient master file (APIMF)/drug master
file (DMF)/certificate of suitability to the monographs
of the European Pharmacopoeia (CEP) numbers, as
appropriate); other manufacturing activities carried out
on the site (e.g. manufacture of cosmetics, research and
development); use of outside scientific, analytical or other
technical assistance in manufacture and quality control
Brief description of the quality management system of the
firm responsible for manufacture. Reference can be made
to a site master file if one is available
History Previous inspection date and history of regulatory agency

inspections
Summary of past inspections; observations on CAPA from
previous inspection
Major change since previous inspection and planned
future changes
GMP-related recalls from the market of any product in the
past two years
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Annex 4
Table continued
Brief report of inspection activities undertaken
Scope and limitations For example, blocks inspected, areas of interest, focus
ofinspection
Out-of-scope: areas, activities or product lines not inspected
Restrictions: constraints noted in inspecting specific areas
Areas inspected For example, dosage form(s) included in the inspection
Key persons met Names and job titles
Part 2 Brief summary of the findings and recommendations

(where applicable)
This part of the report is arranged based on the WHO
Guidance for good manufacturing practices: main
principles. It may also be arranged according to six
inspection systems, namely:
1. pharmaceutical quality system,
2. production system,
3. facilities and equipment system,
4. laboratory control system,
5. materials system,
6. packaging and labelling system.The observations
made during the inspection that are considered to
be non-compliant with GMP should be listed. Where
positive observations are included in the report, a clear
distinction should be made between positive and non-
compliant.
Non-compliant observations can be classified, e.g. as
critical, major and other if the Member State concerned has
defined these terms
The date by which corrective action and completion are
requested in accordance with the policy of the NRA should
be given.
1. Pharmaceutical Describe the pharmaceutical quality system (PQS) in
quality system place and how well the elements are institutionalized and
implemented, including the quality risk management
(QRM) and product quality review (PQR)
157
Table continued
(where applicable)
2. Good manufacturing Briefly describe how the elements of GMP are
practices for implemented
pharmaceutical
products
3. Sanitation and Describe procedures and records relating to sanitation and
hygiene hygiene for personnel, premises, equipment, production
materials, cleaning materials and others that could become
a source of contamination
4. Qualification and Describe policies, procedures, records and any other
validation evidence for qualification and validation and how the
validation status is monitored and maintained
5. Complaints Describe procedures, responsibilities and records for
handling complaints, including extension of investigation
to other batches, possibility of counterfeits, trending and
consideration for recall and notification of competent
authorities
6. Product recalls Describe the existence of a recall procedure and evidence
of its effectiveness; provisions for notification of customers
and competent authorities and segregation of recalled
products
7. Contract production, Describe how contractors are evaluated, how compliance
analysis and other with marketing authorization is ensured, existence of
activities comprehensive contracts and clarity of responsibilities
andlimits
8. Self-inspection, a) Self-inspection:
quality audits and describe the procedures and items for self-inspection
suppliers audits and and quality audits; constitution of self-inspection
approval team(s); frequency of self-inspection; existence of self-
inspection schedules and report; system for monitoring
follow-up actions.
b) Suppliers audits and approval:
describe procedures for evaluation and approval of
suppliers including applications of risk management
principles, especially determining the need and
frequency for on-site audits.
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Annex 4
Table continued
(where applicable)
9. Personnel Describe availability of adequate numbers of sufficiently
qualified and experienced personnel, clarity of
their responsibilities, limits and reporting hierarchy.
Qualifications, experience and responsibilities of key
personnel (head of production, head(s) of the quality
unit(s), authorized person) and procedures for delegation
of their responsibilities
10. Training Describe comprehensiveness of procedures and records
for induction, specialized and continuing training and
evaluation of its effectiveness; coverage of GMP and
concepts of quality assurance during training; training of
visitors and evaluation consultants and contract staff
11. Personal hygiene Describe system in place for initial and regular health
examination of staff appropriate to their responsibilities.
Measures and facilities to impart, maintain and monitor
knowledge of a high level of personal hygiene. Measures
to ensure personnel do not become a source of
contamination to the product, including hand-washing
and gowning. Appropriate restriction of smoking, eating,
drinking, chewing and related materials from production,
laboratory and storage areas
12. Premises Description of the appropriateness of the location,
design, construction and maintenance of premises to
minimize errors, avoid cross-contamination, permit
effective cleaning and maintenance; measures for dust
control; specific measures for ancillary areas, storage areas,
weighing areas, production areas and quality control
areas; measures for appropriate segregation and restricted
access; provisions for appropriate lighting, effective
ventilation and air-control to prevent contamination and
cross-contamination, as well as control of temperature and,
where necessary, humidity
13. Equipment Describe the adequacy of the numbers, type, location,
design and construction, and maintenance of equipment
to minimize errors, avoid cross-contamination, permit
effective cleaning and maintenance; use, cleaning and
maintenance procedures, records and logs; calibration of
balances and other measuring instruments; status labelling
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Table continued
(where applicable)
14. Materials Describe measures in place to select, store, approve and
use materials (including water) of appropriate quality and
how these measures cover starting materials, packaging
materials, intermediate and bulk products, finished
products, reagents, culture media and reference standards.
Describe also the measures for the handling and control of
rejected, recovered, reprocessed and reworked materials;
recalled products; returned goods; and waste materials
15. Documentation Describe the comprehensiveness and adequacy of the
documentation system in place (labels; specifications
and testing procedures, starting, packaging materials,
intermediate, bulk products and finished products; master
formulas; packaging instructions; batch processing
and packaging records; standard operating procedures
(SOPs) and records) and how principles of good
documentation and data management (attributable,
legible, contemporaneous, original, accurate (ALCOA)) are
institutionalized, implemented and maintained
16. Good practices in Describe procedures, facilities and controls in place for
production production (processing and packaging); prevention
of risk of mix-up, cross-contamination and bacterial
contamination during production
17. Good practices in Describe the extent of the organizational and functional
quality control independence of the quality control function and the
adequacy of its resourcing.
Describe the procedures, facilities, organization and
documentation in place which ensure that the necessary
and relevant tests are actually carried out and that

materials are not released for use, nor products released
for sale or supply, until their quality has been judged to be
compliant with the requirements.
Describe the procedures for the control of starting
materials and intermediate, bulk and finished products;
test requirements; procedures and responsibilities for
batch record review; procedures, records and facilities for
initial and ongoing stability studies; policy, procedures,
facilities and records for retention samples.
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Annex 4
Table continued
(where applicable)
Samples taken (if applicable)
Assessment of the site (if applicable)
master file
Annexes attached
Part 3 List of deficiencies

List of deficiencies Deficiencies should be listed by category with reference
to the relevant section(s) of GMP guidelines. This may be
presented in a tabular format, giving references to the
relevant GMP requirement:
Deficiencies References
1. Critical 1.1
1.2
2. Major 2.1
2.2
3. Other 3.1
3.2
Part 4 Outcome
Initial conclusion Statement regarding the GMP status, including information
on any restrictions in scope.
The following guidance may be used to determine the
outcome of the inspection based on the nature and
number of deficiencies observed:
other deficiencies only: operating at an acceptable level
of compliance with GMP guidelines;
other and a few (e.g. < 6) major deficiencies: decision
on level of compliance to be made after receipt and
evaluation of CAPAs;
any critical or several (e.g. 6) major deficiencies:
operating at an unacceptable level of compliance with
GMP guidelines.
161
Part 5 List of GMP guidelines referenced in the inspection

References List of GMP guidelines referred to in the inspection, for example:
1. WHO good manufacturing practices for pharmaceutical products:
main principles. In: WHO Expert Committee on Specifications for
Pharmaceutical Preparations: forty-eighth report. Geneva: World
Health Organization; 2014: Annex 2
(WHO Technical Report Series, No. 986; http://www.who.int/
medicines/publications/pharmprep/en/index.html)
2. WHO good manufacturing practices for sterile pharmaceutical
products. In: WHO Expert Committee on Specifications for
Pharmaceutical Preparations: forty-fifth report. Geneva: World
3. WHO good manufacturing practices for active pharmaceutical
ingredients. In: WHO Expert Committee on Specifications for
Pharmaceutical Preparations: forty-fourth report. Geneva: World
4. WHO good manufacturing practices: water for pharmaceutical
use. In: WHO Expert Committee on Specifications for
Pharmaceutical Preparations: forty-sixth report. Geneva: World
5. WHO guidelines on good manufacturing practices for heating,
ventilation and air-conditioning systems for non-sterile
pharmaceutical dosage forms. In: WHO Expert Committee on
Specifications for Pharmaceutical Preparations: forty-fifth report.

Geneva: World Health Organization; 2011: Annex 5
6. General guidelines for the establishment maintenance and
distribution of chemical reference substances. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations:
forty-first report. Geneva: World Health Organization; 2011:
Annex3
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Annex 4
Part 6 Assessment of company response, final conclusion, risk

rating and next due date
Brief narrative on
the adequacy of the
companys response to
issues to be addressed
Final conclusion Final statement of GMP compliance, including information
on any restrictions in scope
Risk rating following For example, low (L), medium (M), high (H), critical (C)
the inspection
Date next inspection The inspectorate may decide to include this information for
due (for planning internal use only
purposes)
Name(s) (all inspectors
or lead inspector)
Signature(s) (all
inspectors or lead
inspector)
Date
163
Appendix 2
Example of a risk category assessment of the site
depending on level of compliance and inspection frequency
GMP compliance rating and related inspection frequency

(in months)
Risk category
ofthe site Acceptable
Unacceptable
Good Satisfactory Basic
Critical (C) 24 18 12 Determine on a
casebycase basis
High (H) 30 20 15 Determine on a
casebycase basis
Medium (M) 36 24 18 Determine on a
casebycase basis
Low (L) 48 36 24 Determine on a
casebycase basis
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Annex 5
Guidance on good data and record management practices
Background
During an informal consultation on inspection, good manufacturing practices
and risk management guidance in medicines manufacturing held by the
World Health Organization (WHO) in Geneva in April 2014, a proposal for
new guidance on good data management was discussed and its development
recommended. The participants included national inspectors and specialists
in the various agenda topics, as well as staff of the Prequalification Team
(PQT)Inspections.
The WHO Expert Committee on Specifications for Pharmaceutical
Preparations received feedback from this informal consultation during its
forty-ninth meeting in October 2014. A concept paper was received from PQT
Inspections describing the proposed structure of a new guidance document,
which was discussed in detail. The concept paper consolidated existing normative
principles and gave some illustrative examples of their implementation. In
the Appendix to the concept paper, extracts from existing good practices and
guidance documents were combined to illustrate the current relevant guidance
on assuring the reliability of data and related GXP (good (anything) practice)
matters. In view of the increasing number of observations made during
inspections that relate to data management practices, the Committee endorsed
the proposal.
Following this endorsement, a draft document was prepared by
members of PQTInspection and a drafting group, including national inspectors.
This draft was discussed at a consultation on data management, bioequivalence,
good manufacturing practices and medicines inspection held from 29 June to
1July 2015.
A revised draft document was subsequently prepared by the authors in
collaboration with the drafting group, based on the feedback received during
this consultation, and the subsequent WHO workshop on data management.
Collaboration is being sought with other organizations towards future
convergence in this area.
165
1. Introduction 167
2. Aims and objectives of this guidance 169
3. Glossary 169
4. Principles 173
5. Quality risk management to ensure good data management 177
6. Management governance and quality audits 178
7. Contracted organizations, suppliers and service providers 180
8. Training in good data and record management 182
9. Good documentation practices 182
10. Designing and validating systems to assure data quality
and reliability 183
11. Managing data and records throughout the data life cycle 186
12. Addressing data reliability issues 189
References and further reading 190
Appendix 1 Expectations and examples of special risk management considerations
for the implementation of ALCOA (-plus) principles in paper-based and
electronic systems 192
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Annex 5
1. Introduction
1.1 Medicines regulatory systems worldwide have always depended upon the
knowledge of organizations that develop, manufacture and package, test,
distribute and monitor pharmaceutical products. Implicit in the assessment
and review process is trust between the regulator and the regulated that
the information submitted in dossiers and used in day-to-day decision-
making is comprehensive, complete and reliable. The data on which
these decisions are based should therefore be complete as well as being
attributable, legible, contemporaneous, original and accurate, commonly
referred to as ALCOA.
1.2 These basic ALCOA principles and the related good practice expectations
that assure data reliability are not new and much high- and mid-level
normative guidance already exists. However, in recent years, the number of
observations made regarding good data and record management practices
(GDRP) during inspections of good manufacturing practice (GMP) (1),
good clinical practice (GCP) and good laboratory practice (GLP) has been
increasing. The reasons for the increasing concern of health authorities
regarding data reliability are undoubtedly multifactorial and include
increased regulatory awareness and concern regarding gaps between
industry choices and appropriate and modern control strategies.
1.3 Contributing factors include failures by organizations to apply robust
systems that inhibit data risks, to improve the detection of situations where
data reliability may be compromised, and/or to investigate and address
root causes when failures do arise. For example, organizations subject to
medical product good practice requirements have been using validated
computerized systems for many decades but many fail to adequately review
and manage original electronic records and instead often only review and
manage incomplete and/or inappropriate printouts. These observations
highlight the need for industry to modernize control strategies and apply
modern quality risk management (QRM) and sound scientific principles to
current business models (such as outsourcing and globalization) as well as
technologies currently in use (such as computerized systems).
1.4 Examples of controls that may require development and strengthening to
ensure good data management strategies include, but are not limited to:
a QRM approach that effectively assures patient safety and product
quality and validity of data by ensuring that management aligns
expectations with actual process capabilities. Management should
take responsibility for good data management by first setting realistic
and achievable expectations for the true and current capabilities of
167
a process, a method, an environment, personnel, or technologies,

among others;
monitoring of processes and allocation of the necessary resources by
management to ensure and enhance infrastructure, as required (for
example, to continuously improve processes and methods, to ensure
adequate design and maintenance of buildings, facilities, equipment
and systems; to ensure adequate reliable power and water supplies;
to provide necessary training for personnel; and to allocate the
necessary resources to the oversight of contract sites and suppliers
to ensure adequate quality standards are met). Active engagement of
management in this manner remediates and reduces pressures and
possible sources of error that may increase data integrity risks;
adoption of a quality culture within the company that encourages
personnel to be transparent about failures so that management
has an accurate understanding of risks and can then provide the
necessary resources to achieve expectations and meet data quality
standards: a reporting mechanism independent of management
hierarchy should be provided for;
mapping of data processes and application of modern QRM and
sound scientific principles throughout the data life cycle;
ensuring that all site personnel are kept up to date about the
application of good documentation practices (GDocP) to ensure
that the GXP principles of ALCOA are understood and applied
to electronic data in the same manner that has historically been
applied to paper records;
implementation and confirmation during validation of computerized
systems and subsequent change control, that all necessary controls
for GDocP for electronic data are in place and that the probability of
the occurrence of errors in the data is minimized;
training of personnel who use computerized systems and review

electronic data in basic understanding of how computerized systems
work and how to efficiently review the electronic data, which
includes metadata and audit trails;
definition and management of appropriate roles and responsibilities
for quality agreements and contracts entered into by contract
givers and contract acceptors, including the need for risk-based
monitoring of data generated and managed by the contract acceptor
on behalf of the contract giver;
modernization of quality assurance inspection techniques and
gathering of quality metrics to efficiently and effectively identify
risks and opportunities to improve data processes.
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Annex 5
2. Aims and objectives of this guidance

2.1 This guidance consolidates existing normative principles and gives
detailed illustrative implementation guidance to bridge the gaps in
current guidance. Additionally, it gives explanations as to what these high-
level requirements mean in practice and what should be demonstrably
implemented to achieve compliance.
2.2 These guidelines highlight, and in some instances clarify, the application
of data management procedures. The focus is on those principles that are
implicit in existing WHO guidelines and that if not robustly implemented
can impact on data reliability and completeness and undermine the
robustness of decision-making based upon those data. Illustrative
examples are provided as to how these principles may be applied to
current technologies and business models. These guidelines do not define
all expected controls for assuring data reliability and this guidance should
be considered in conjunction with existing WHO guidelines and other
related international references.
2.3 This guidance is of an evolutionary, illustrative nature and will therefore be
subject to periodic review based upon experience with its implementation
and usefulness, as well as the feedback provided by the stakeholders,
including national regulatory authorities (NRAs).
3. Glossary
ALCOA. A commonly used acronym for attributable, legible,
contemporaneous, original and accurate.
ALCOA-plus. A commonly used acronym for attributable, legible,
contemporaneous, original and accurate, which puts additional emphasis on
the attributes of being complete, consistent, enduring and available implicit
basic ALCOA principles.
archival. Archiving is the process of protecting records from the
possibility of being further altered or deleted, and storing these records
under the control of independent data management personnel throughout
the required retention period. Archived records should include, for example,
associated metadata and electronic signatures.
archivist. An independent individual designated in good laboratory
practice (GLP) who has been authorized by management to be responsible
for the management of the archive, i.e. for the operations and procedures for
archiving. GLP requires a designated archivist (i.e. an individual); however, in
169
other GXPs the roles and responsibilities of the archivist are normally fulfilled
by several designated personnel or groups of personnel (e.g. both quality
assurance document control personnel and information technology (IT) system
administrators) without there being one single person assigned responsibility for
control as is required in GLP.
It is recognized that in certain circumstances it may be necessary for the
archivist to delegate specific archiving tasks, for example, the management of
electronic data, to specific IT personnel. Tasks, duties and responsibilities should
be specified and detailed in standard operating procedures. The responsibilities
of the archivist and the staff to whom archival tasks are delegated include
for both paper and electronic data ensuring that access to the archive is
controlled, ensuring that the orderly storage and retrieval of records and
materials is facilitated by a system of indexing, and ensuring that movement
of records and materials into and out of the archives is properly controlled and
documented. These procedures and records should be periodically reviewed by
an independent auditor.
audit trail. The audit trail is a form of metadata that contains information
associated with actions that relate to the creation, modification or deletion of
GXP records. An audit trail provides for secure recording of life-cycle details
such as creation, additions, deletions or alterations of information in a record,
either paper or electronic, without obscuring or overwriting the original record.
An audit trail facilitates the reconstruction of the history of such events relating
to the record regardless of its medium, including the who, what, when and why
of the action.
For example, in a paper record, an audit trail of a change would be
documented via a single-line cross-out that allows the original entry to remain
legible and documents the initials of the person making the change, the date
of the change and the reason for the change, as required to substantiate and
justify the change. In electronic records, secure, computer-generated, time-
stamped audit trails should allow for reconstruction of the course of events
relating to the creation, modification and deletion of electronic data. Computer-
generated audit trails should retain the original entry and document the user
identification, the time/date stamp of the action, as well as the reason for the
change, as required to substantiate and justify the action. Computer-generated
audit trails may include discrete event logs, history files, database queries or
reports or other mechanisms that display events related to the computerized
system, specific electronic records or specific data contained within the record.
backup. A backup means a copy of one or more electronic files created
asan alternative in case the original data or system are lost or become unusable
(for example, in the event of a system crash or corruption of a disk). It is
important to note that backup differs from archival in that back-up copies of
electronic records are typically only temporarily stored for the purposes of
170
Annex 5
disaster recovery and may be periodically overwritten. Such temporary back-up

copies should not be relied upon as an archival mechanism.
computerized system. A computerized system collectively controls the
performance of one or more automated processes and/or functions. It includes
computer hardware, software, peripheral devices, networks and documentation,
e.g. manuals and standard operating procedures, as well as the personnel
interfacing with the hardware and software, e.g. users and information technology
support personnel.
control strategy. A planned set of controls, derived from current
protocol, test article or product and process understanding, which assures
protocol compliance, process performance, product quality and data reliability,
as applicable. The controls should include appropriate parameters and quality
attributes related to study subjects, test systems, product materials and
components, technologies and equipment, facilities, operating conditions,
specifications and the associated methods and frequency of monitoring
andcontrol.
corrective and preventive action (CAPA, also sometimes called
corrective action/preventive action) refers to the actions taken to improve an
organization's processes and to eliminate causes of non-conformities or other
undesirable situations. CAPA is a concept common across the GXPs (good
laboratory practices, good clinical practices and good manufacturing practices),
and numerous International Organization for Standardization business standards.
The process focuses on the systematic investigation of the root causes of
identified problems or identified risks in an attempt to prevent their recurrence
(for corrective action) or to prevent occurrence (for preventive action).
data. Data means all original records and true copies of original records,
including source data and metadata and all subsequent transformations and
reports of these data, which are generated or recorded at the time of the GXP
activity and allow full and complete reconstruction and evaluation of the GXP
activity. Data should be accurately recorded by permanent means at the time
of the activity. Data may be contained in paper records (such as worksheets
and logbooks), electronic records and audit trails, photographs, microfilm
or microfiche, audio- or video-files or any other media whereby information
related to GXP activities is recorded.
data governance. The totality of arrangements to ensure that data,
irrespective of the format in which they are generated, are recorded, processed,
retained and used to ensure a complete, consistent and accurate record
throughout the data life cycle.
data integrity. Data integrity is the degree to which data are complete,
consistent, accurate, trustworthy and reliable and that these characteristics of the
data are maintained throughout the data life cycle. The data should be collected
and maintained in a secure manner, such that they are attributable, legible,
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contemporaneously recorded, original or a true copy and accurate. Assuring data

integrity requires appropriate quality and risk management systems, including
adherence to sound scientific principles and good documentation practices.
data life cycle. All phases of the process by which data are created,
recorded, processed, reviewed, analysed and reported, transferred, stored and
retrieved and monitored until retirement and disposal. There should be a
planned approach to assessing, monitoring and managing the data and the risks
to those data in a manner commensurate with potential impact on patient
safety, product quality and/or the reliability of the decisions made throughout
all phases of the data life cycle.
dynamic record format. Records in dynamic format, such as electronic
records, that allow for an interactive relationship between the user and the
record content. For example, electronic records in database formats allow the
user to track, trend and query data; chromatography records maintained as
electronic records allow the user (with proper access permissions) to reprocess
the data and expand the baseline to view the integration more clearly.
fully-electronic approach. This term refers to use of a computerized
system in which the original electronic records are electronically signed.
good data and record management practices. The totality of organized
measures that should be in place to collectively and individually ensure
that data and records are secure, attributable, legible, traceable, permanent,
contemporaneously recorded, original and accurate and that if not robustly
implemented can impact on data reliability and completeness and undermine
the robustness of decision-making based upon those data records.
good documentation practices. In the context of these guidelines, good
documentation practices are those measures that collectively and individually
ensure documentation, whether paper or electronic, is secure, attributable, legible,
traceable, permanent, contemporaneously recorded, original and accurate.
GXP. Acronym for the group of good practice guides governing the
preclinical, clinical, manufacturing, testing, storage, distribution and post-market

activities for regulated pharmaceuticals, biologicals and medical devices, such as
good laboratory practices, good clinical practices, good manufacturing practices,
good pharmacovigilance practices and good distribution practices.
hybrid approach. This refers to the use of a computerized system in
which there is a combination of original electronic records and paper records
that comprise the total record set that should be reviewed and retained. An
example of a hybrid approach is where laboratory analysts use computerized
instrument systems that create original electronic records and then print a
summary of the results. The hybrid approach requires a secure link between all
record types, including paper and electronic, throughout the records retention
period. Where hybrid approaches are used, appropriate controls for electronic
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documents, such as templates, forms and master documents, that may be

printed, should be available.
metadata. Metadata are data about data that provide the contextual
information required to understand those data. These include structural
and descriptive metadata. Such data describe the structure, data elements,
interrelationships and other characteristics of data. They also permit data to
be attributable to an individual. Metadata necessary to evaluate the meaning
of data should be securely linked to the data and subject to adequate review.
For example, in weighing, the number 8 is meaningless without metadata, i.e. the
unit, mg. Other examples of metadata include the time/date stamp of an activity,
the operator identification (ID) of the person who performed an activity, the
instrument ID used, processing parameters, sequence files, audit trails and other
data required to understand data and reconstruct activities.
quality metrics. Quality metrics are objective measures used by
management and other interested parties to monitor the overall state of quality
of a GXP organization, activity or process or study conduct, as applicable. They
include measures to assess the effective functioning of quality system controls
and of the performance, quality and safety of medicinal products and reliability
of data.
quality risk management. A systematic process for the assessment,
control, communication and review of risks to the quality of the pharmaceutical
product throughout the product life cycle.
senior management. Person(s) who direct and control a company or site
at the highest levels with the authority and responsibility to mobilize resources
within the company or site.
static record format. A static record format, such as a paper or pdf
record, is one that is fixed and allows little or no interaction between the user
and the record content. For example, once printed or converted to static pdfs,
chromatography records lose the capability of being reprocessed or enabling
more detailed viewing of baselines.
true copy. A true copy is a copy of an original recording of data that
has been verified and certified to confirm it is an exact and complete copy that
preserves the entire content and meaning of the original record, including, in
the case of electronic data, all essential metadata and the original record format
as appropriate.
4. Principles
4.1 GDRP are critical elements of the pharmaceutical quality system and a
systematic approach should be implemented to provide a high level of
assurance that throughout the product life cycle, all GXP records and data
are complete and reliable.
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4.2 The data governance programme should include policies and governance
procedures that address the general principles listed below for a good data
management programme. These principles are clarified with additional
detail in the sections below.
4.3 Applicability to both paper and electronic data. The requirements for
GDRP that assure robust control of data validity apply equally to paper
and electronic data. Organizations subject to GXP should be fully aware
that reverting from automated or computerized to manual or paper-based
systems does not in itself remove the need for robust management controls.
4.4 Applicability to contract givers and contract acceptors. The principles of
these guidelines apply to contract givers and contract acceptors. Contract
givers are ultimately responsible for the robustness of all decisions made on
the basis of GXP data, including those made on the basis of data provided
to them by contract acceptors. Contract givers should therefore perform
risk-based, due diligence to assure themselves that contract acceptors have
in place appropriate programmes to ensure the veracity, completeness and
reliability of the data provided.
4.5 Good documentation practices. To achieve robust decisions, the
supporting data set needs to be reliable and complete. GDocP should be
followed in order to ensure all records, both paper and electronic, allow
the full reconstruction and traceability of GXP activities.
4.6 Management governance. To establish a robust and sustainable good data
management system it is important that senior management ensure that
appropriate data management governance programmes are in place (for
details see Section 6).
Elements of effective management governance should include:
application of modern QRM principles and good data management

principles that assure the validity, completeness and reliability of data;
application of appropriate quality metrics;
assurance that personnel are not subject to commercial, political,
financial and other organizational pressures or incentives that may
adversely affect the quality and integrity of their work;
allocation of adequate human and technical resources such that the
workload, work hours and pressures on those responsible for data
generation and record keeping do not increase errors;
ensure staff are aware of the importance of their role in ensuring
data integrity and the relationship of these activities to assuring
product quality and protecting patient safety.
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4.7 Quality culture. Management, with the support of the quality unit, should
establish and maintain a working environment that minimizes the risk
of non-compliant records and erroneous records and data. An essential
element of the quality culture is the transparent and open reporting
of deviations, errors, omissions and aberrant results at all levels of the
organization, irrespective of hierarchy. Steps should be taken to prevent,
and to detect and correct weaknesses in systems and procedures that may
lead to data errors so as to continually improve the robustness of scientific
decision-making within the organization. Senior management should
actively discourage any management practices that might reasonably be
expected to inhibit the active and complete reporting of such issues, for
example, hierarchical constraints and blame cultures.
4.8 Quality risk management and sound scientific principles. Robust decision-
making requires appropriate quality and risk management systems, and
adherence to sound scientific and statistical principles, which must be
based upon reliable data. For example, the scientific principle of being an
objective, unbiased observer regarding the outcome of a sample analysis
requires that suspect results be investigated and rejected from the reported
results only if they are clearly attributable to an identified cause. Adhering
to good data and record-keeping principles requires that any rejected
results be recorded, together with a documented justification for their
rejection, and that this documentation is subject to review andretention.
4.9 Data life cycle management. Continual improvement of products to
ensure and enhance their safety, efficacy and quality requires a data
governance approach to ensure management of data integrity risks
throughout all phases of the process by which data are created, recorded,
processed, transmitted, reviewed, reported, archived and retrieved and
this management process is subject to regular review. To ensure that the
organization, assimilation and analysis of data into information facilitates
evidence-based and reliable decision-making, data governance should
address data ownership and accountability for data process(es) and risk
management of the data life cycle.
4.10 To ensure that the organization, assimilation and analysis of data into a
format or structure that facilitates evidence-based and reliable decision-
making, data governance should address data ownership and accountability
for data process(es) and risk management of the data life cycle.
4.11 Design of record-keeping methodologies and systems. Record-keeping
methodologies and systems, whether paper or electronic, should be
designed in a way that encourages compliance with the principles of
dataintegrity.
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4.12 Examples include, but are not restricted to:

restricting the ability to change any clock used for recording timed
events, for example, system clocks in electronic systems and
process instrumentation;
ensuring controlled forms used for recording GXP data (e.g. paper
batch records, paper case report forms and laboratory worksheets)
are accessible at the locations where an activity is taking place, at the
time that the activity is taking place, so that ad hoc data recording
and later transcription is not necessary;
controlling the issuance of blank paper templates for data recording
of GXP activities so that all printed forms can be reconciled and
accounted for;
restricting user access rights to automated systems to prevent (or
audit trail) data amendments;
ensuring automated data capture or printers are attached and
connected to equipment, such as balances, to ensure independent
and timely recording of the data;
ensuring proximity of printers to sites of relevant activities;
ensuring ease of access to locations of sampling points (e.g. sampling
points for water systems) to allow easy and efficient performance of
sampling by the operators and therefore minimizing the temptation
to take shortcuts or falsify samples;
ensuring access to original electronic data for staff performing data
checking activities.
4.13 Data and record media should be durable. For paper records, the ink
should be indelible. Temperature-sensitive or photosensitive inks and
other erasable inks should not be used. Paper should also not be
temperature-sensitive, photosensitive or easily oxidizable. If this is not
feasible or limited (as may be the case in printouts from legacy printers
of balance and other instruments in quality control laboratories), then
true or certified copies should be available until this equipment is retired
or replaced.
4.14 Maintenance of record-keeping systems. The systems implemented and
maintained for both paper and electronic record-keeping should take
account of scientific and technical progress. Systems, procedures and
methodology used to record and store data should be periodically reviewed
for effectiveness and updated as necessary.
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5. Quality risk management to ensure

good data management
5.1 All organizations performing work subject to GXP are required by
applicable existing WHO guidance to establish, implement and maintain
an appropriate quality management system, the elements of which should
be documented in their prescribed format, such as a quality manual or
other appropriate documentation. The quality manual, or equivalent
documentation, should include a quality policy statement of managements
commitment to an effective quality management system and to good
professional practice. These policies should include a code of ethics and
code of proper conduct to assure the reliability and completeness of data,
including mechanisms for staff to report any quality and compliance
questions or concerns to management.
5.2 Within the quality management system, the organization should establish
the appropriate infrastructure, organizational structure, written policies
and procedures, processes and systems to both prevent and detect
situations that may impact on data integrity and, in turn, the risk-based
and scientific robustness of decisions based upon those data.
5.3 QRM is an essential component of an effective data and record validity
programme. The effort and resources assigned to data and record
management should be commensurate with the risk to product quality. The
risk-based approach to record and data management should ensure that
adequate resources are allocated and that control strategies for the assurance
of the integrity of GXP data are commensurate with their potential impact
on product quality and patient safety and related decision-making.
5.4 Strategies that promote good practices and prevent record and data
integrity issues from occurring are preferred and are likely to be the most
effective and cost-effective. For example, access controls that allow only
people with the appropriate authorization to alter a master processing
formula will reduce the probability of invalid and aberrant data being
generated. Such preventive measures, when effectively implemented, also
reduce the amount of monitoring required to detect uncontrolled change.
5.5 Record and data integrity risks should be assessed, mitigated,
communicated and reviewed throughout the data life cycle in accordance
with the principles of QRM. Examples of approaches that may enhance
data reliability are given in these guidelines but should be viewed as
recommendations. Other approaches may be justified and shown to be
equally effective in achieving satisfactory control of risk. Organizations
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should therefore design appropriate tools and strategies for the management
of data integrity risks based upon their own GXP activities, technologies
and processes.
5.6 A data management programme developed and implemented upon the
basis of sound QRM principles is expected to leverage existing technologies
to their full potential. This in turn will streamline data processes in a
manner that not only improves data management but also the business
process efficiency and effectiveness, thereby reducing costs and facilitating
continual improvement.
6. Management governance and quality audits

6.1 Assuring robust data integrity begins with management, which has
the overall responsibility for the technical operations and provision
of resources to ensure the required quality of GXP operations. Senior
management has the ultimate responsibility for ensuring that an effective
quality system is in place to achieve the quality objectives, and that
staff roles, responsibilities and authorities, including those required for
effective data governance programmes, are defined, communicated and
implemented throughout the organization. Leadership is essential to
establish and maintain a company-wide commitment to data reliability as
an essential element of the quality system.
6.2 The building blocks of behaviours, procedural/policy considerations
and basic technical controls together form the foundation of good data
governance, upon which future revisions can be built. For example, a
good data governance programme requires the necessary management
arrangements to ensure personnel are not subject to commercial,
political, financial and other pressures or conflicts of interest that may

adversely affect the quality of their work and integrity of their data.
Management should also make staff aware of the relevance of data
integrity and the importance of their role in protecting the safety of
patients and the reputation of their organization for quality products
and services.
6.3 Management should create a work environment in which staff are
encouraged to communicate failures and mistakes, including data reliability
issues, so that corrective and preventive actions can be taken and the
quality of an organizations products and services enhanced. This includes
ensuring adequate information flow between staff at all levels. Senior
management should actively discourage any management practices that
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might reasonably be expected to inhibit the active and complete reporting

of such issues, for example, hierarchical constraints and blame cultures.
6.4 Management reviews and regular reporting of quality metrics facilitate
meeting these objectives. This requires designation of a quality manager
who has direct access to the highest level of management and can directly
communicate risks, so that senior management is made aware of any issues
and can allocate resources to address them. To fulfil this role the quality
unit should conduct and report to management formal, documented risk
reviews of the key performance indicators of the quality management
system. These should include metrics related to data integrity that will help
identify opportunities for improvement. For example:
tracking and trending of invalid and aberrant data may reveal
unforeseen variability in processes and procedures previously
believed to be robust, opportunities to enhance analytical procedures
and their validation, validation of processes, training of personnel
or sourcing of raw materials and components;
adequate review of audit trails, including those reviewed as part of
key decision-making steps (e.g. GMP batch release, issuance of a GLP
study report or approval of case report forms), may reveal incorrect
processing of data, help prevent incorrect results from being reported
and identify the need for additional training of personnel;
routine audits and/or self-inspections of computerized systems may
reveal gaps in security controls that inadvertently allow personnel
to access and potentially alter time/date stamps. Such findings
help raise awareness among management of the need to allocate
resources to improve validation controls for computerized systems;
monitoring of contract acceptors and tracking and trending of
associated quality metrics for these sites help to identify risks that
may indicate the need for more active engagement and allocation
of additional resources by the contract giver to ensure quality
standards are met.
6.5 Quality audits of suppliers, self-inspections and risk reviews should
identify and inform management of opportunities to improve foundational
systems and processes that have an impact on data reliability. Allocation
of resources by management to these improvements of systems and
processes may efficiently reduce data integrity risks. For example,
identifying and addressing technical difficulties with the equipment used
to perform multiple GXP operations may greatly improve the reliability
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of data for all of these operations. Another example relates to identifying

conflicts of interests affecting security. Allocating independent technical
support personnel to perform system administration for computerized
systems, including managing security, backup and archival, reduces
potential conflicts of interest and may greatly streamline and improve data
management efficiency.
6.6 All GXP records held by the GXP organization are subject to inspection
by the responsible health authorities. This includes original electronic data
and metadata, such as audit trails maintained in computerized systems.
Management of both contract givers and contract acceptors should
ensure that adequate resources are available and that procedures for
computerized systems are available for inspection. System administrator
personnel should be available to readily retrieve requested records and
facilitate inspections.
7. Contracted organizations, suppliers

and service providers
7.1 The increasing outsourcing of GXP work to contracted organizations, e.g.
contract research organizations, suppliers and other service providers,
emphasizes the need to establish and robustly maintain defined roles
and responsibilities to assure complete and accurate data and records
throughout these relationships. The responsibilities of the contract giver
and acceptor, should comprehensively address the processes of both
parties that should be followed to ensure data integrity. These details
should be included in the contract described in the WHO GXPs relevant
to the outsourced work performed or the services provided.
7.2 The organization that outsources work has the responsibility for
the integrity of all results reported, including those furnished by any
subcontracting organization or service provider. These responsibilities
extend to any providers of relevant computing services. When outsourcing
databases and software provision, the contract giver should ensure that
any subcontractors have been agreed upon and are included in the quality
agreement with the contract accepter, and are appropriately qualified and
trained in GRDP. Their activities should be monitored on a regular basis
at intervals determined through risk assessment. This also applies to
cloudbased service providers.
7.3 To fulfil this responsibility, in addition to having their own governance
systems, outsourcing organizations should verify the adequacy of the
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governance systems of the contract acceptor, through an audit or other

suitable means. This should include the adequacy of the contract acceptors
controls over suppliers and a list of significant authorized third parties
working for the contract acceptor.
7.4 The personnel who evaluate and periodically assess the competence of a
contracted organization or service provider should have the appropriate
background, qualifications, experience and training to assess data integrity
governance systems and to detect validity issues. The nature and frequency
of the evaluation of the contract acceptor and the approach to ongoing
monitoring of their work should be based upon documented assessment
of risk. This assessment should include an assessment of relevant data
processes and their risks.
7.5 The expected data integrity control strategies should be included in
quality agreements and in written contract and technical arrangements,
as appropriate and applicable, between the contract giver and the contract
acceptor. These should include provisions for the contract giver to have
access to all data held by the contracted organization that are relevant
to the contract givers product or service as well as all relevant quality
systems records. This should include ensuring access by the contract
giver to electronic records, including audit trails, held in the contracted
organizations computerized systems as well as any printed reports and
other relevant paper or electronic records.
7.6 Where data and document retention is contracted to a third party,
particular attention should be paid to understanding the ownership and
retrieval of data held under this arrangement. The physical location where
the data are held, and the impact of any laws applicable to that geographical
location, should also be considered. Agreements and contracts should
establish mutually agreed consequences if the contract acceptor denies,
refuses or limits the contract givers access to their records held by the
contract acceptor. The agreements and contracts should also contain
provisions for actions to be taken in the event of business closure or
bankruptcy of the third party to ensure that access is maintained and the
data can be transferred before the cessation of all business activities.
7.7 When outsourcing databases, the contract giver should ensure that if
subcontractors are used, in particular cloud-based service providers, they
are included in the quality agreement and are appropriately qualified and
trained in GRDP. Their activities should be monitored on a regular basis
at intervals determined through riskassessment.
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8. Training in good data and record management

8.1 Personnel should be trained in data integrity policies and agree to
abide by them. Management should ensure that personnel are trained
to understand and distinguish between proper and improper conduct,
including deliberate falsification, and should be made aware of the
potential consequences.
8.2 In addition, key personnel, including managers, supervisors and quality

unit personnel, should be trained in measures to prevent and detect data
issues. This may require specific training in evaluating the configuration
settings and reviewing electronic data and metadata, such as audit trails,
for individual computerized systems used in the generation, processing
and reporting of data. For example, the quality unit should learn how to
evaluate configuration settings that may intentionally or unintentionally
allow data to be overwritten or obscured through the use of hidden fields
or data annotation tools. Supervisors responsible for reviewing electronic
data should learn which audit trails in the system track significant data
changes and how these might be most efficiently accessed as part of
theirreview.
8.3 Management should also ensure that, at the time of hire and periodically
afterwards, as needed, all personnel are trained in procedures to
ensure GDocP for both paper and electronic records. The quality unit
should include checks for adherence to GDocP for both paper records
and electronic records in their day-to-day work, system and facility
auditsandself-inspections and report any opportunities for improvement
to management.
9. Good documentation practices

9.1 The basic building blocks of good GXP data are to follow GDocP and
then to manage risks to the accuracy, completeness, consistency and
reliability of the data throughout their entire period of usefulness that
is, throughout the data life cycle.
Personnel should follow GDocP for both paper records and
electronic records in order to assure data integrity. These principles
require that documentation has the characteristics of being attributable,
legible, contemporaneously recorded, original and accurate (sometimes
referred to as ALCOA). These essential characteristics apply equally for
both paper and electronic records.
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9.2 Attributable. Attributable means information is captured in the record so

that it is uniquely identified as executed by the originator of the data (e.g.
a person or a computer system).
9.3 Legible, traceable and permanent. The terms legible and traceable and
permanent refer to the requirements that data are readable, understandable,
and allow a clear picture of the sequencing of steps or events in the record
so that all GXP activities conducted can be fully reconstructed by the
people reviewing these records at any point during the records retention
period set by the applicable GXP.
9.4 Contemporaneous. Contemporaneous data are data recorded at the time
they are generated or observed.
9.5 Original. Original data include the first or source capture of data or
information and all subsequent data required to fully reconstruct the
conduct of the GXP activity. The GXP requirements for original data
include the following:
original data should be reviewed;
original data and/or true and verified copies that preserve the
content and meaning of the original data should be retained;
as such, original records should be complete, enduring and readily
retrievable and readable throughout the records retention period.
9.6 Accurate. The term accurate means data are correct, truthful, complete,
valid and reliable.
9.7 Implicit in the above-listed requirements for ALCOA are that the records
should be complete, consistent, enduring and available (to emphasize
these requirements, this is sometimes referred to as ALCOA-plus).
9.8 Further guidance to aid understanding as to how these requirements
apply in each case and the special risk considerations that may need to be
taken into account during implementation are provided in Appendix 1.
10. Designing and validating systems to

assure data quality and reliability
10.1 Record-keeping methodologies and systems, whether paper or electronic,
should be designed in a way that encourages compliance and assures data
quality and reliability. All requirements and controls necessary to ensure
GDRP should be adhered to for both paper and electronic records.
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Validation to assure good documentation

practices for electronic data
10.2 To assure the integrity of electronic data, computerized systems should be
validated at a level appropriate for their use and application. Validation
should address the necessary controls to ensure the integrity of data,
including original electronic data and any printouts or PDF reports from
the system. In particular, the approach should ensure that GDocP will
be implemented and that data integrity risks will be properly managed
throughout the data life cycle.
10.3 The Supplementary guidelines on good manufacturing practices:
validation (WHO Technical Report Series, No. 937, 2006, Annex 4 (24) 1
provide a more comprehensive presentation of validation considerations.
The key aspects of validation that help assure GDocP for electronic data
include, but are not limited to, the following.
10.4 User involvement. Users should be adequately involved in validation
activities to define critical data and data life cycle controls that assure
dataintegrity.
Examples of activities to engage users may include: prototyping,
user specification of critical data so that risk-based controls can be
applied, user involvement in testing to facilitate user acceptance and
knowledge of system features, and others.
10.5 Configuration and design controls. The validation activities should ensure
configuration settings and design controls for GDocP are enabled and
managed across the computing environment (including both the software
application and operating systems environments).
Activities include, but are not limited to:
documenting configuration specifications for commercial off-the-

shelf systems as well as user-developed systems, as applicable;
restricting security configuration settings for system administrators
to independent personnel, where technically feasible;
disabling configuration settings that allow overwriting and
reprocessing of data without traceability;
restricting access to time/date stamps.
Currently under review.

1
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For systems to be used in clinical trials, configuration and

design controls should be in place to protect the blinding of the trial,
for example, by restricting access to randomization data that may be
stored electronically.
10.6 Data life cycle. Validation should include assessing risk and developing
quality risk mitigation strategies for the data life cycle, including controls
to prevent and detect risks throughout the steps of:
data generation and capture;
data transmission;
data processing;
data review;
data reporting, including handling of invalid and atypical data;
data retention and retrieval;
data disposal.
Activities might include, but are not limited to:
determining the risk-based approach to reviewing electronic data
and audit trails based upon process understanding and knowledge
of potential impact on products and patients;
writing SOPs defining review of original electronic records and
including meaningful metadata such as audit trails and review of
any associated printouts or PDF records;
documenting the system architecture and data flow, including the
flow of electronic data and all associated metadata, from the point of
creation through archival and retrieval;
ensuring that the relationships between data and metadata are
maintained intact throughout the data life cycle.
10.7 SOPs and training. The validation activities should ensure that adequate
training and procedures are developed prior to release of the system for
GXP use. These should address:
computerized systems administration;
computerized systems use;
review of electronic data and meaningful metadata, such as audit
trails, including training that may be required in system features that
enable users to efficiently and effectively process data and review
electronic data and metadata.
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10.8 Other validation controls to ensure good data management for both
electronic data and associated paper data should be implemented as
deemed appropriate for the system type and its intended use.
11. Managing data and records

throughout the data life cycle
11.1 Data processes should be designed to adequately mitigate and control and
continuously review the data integrity risks associated with the steps of
acquiring, processing, reviewing and reporting data, as well as the physical
flow of the data and associated metadata during this process through
storage and retrieval.
11.2 QRM of the data life cycle requires understanding the science and
technology of the data process and their inherent limitations. Good data
process design, based upon process understanding and the application of
sound scientific principles, including QRM, would be expected to increase
the assurance of data integrity and to result in an effective and efficient
business process.
11.3 Data integrity risks are likely to occur and to be highest when data processes
or specific data process steps are inconsistent, subjective, open to bias,
unsecured, unnecessarily complex or redundant, duplicated, undefined,
not well understood, hybrid, based upon unproven assumptions and/or
donot adhere to GDRP.
11.4 Good data process design should consider, for each step of the data process,
ensuring and enhancing controls, whenever possible, so that each step is:
consistent;
objective, independent and secure;
simple and streamlined;

well-defined and understood;
automated;
scientifically and statistically sound;
properly documented according to GDRP.
Examples of considerations for each phase of the data life cycle
are provided below.
11.5 Data collection and recording. All data collection and recording should
be performed following GDRP and should apply risk-based controls to
protect and verify critical data.
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11.6 Example consideration.

Data entries, such as the sample identification for laboratory tests or the
recording of source data for inclusion of a patient in a clinical trial, should
be verified by a second person or entered through technical means such
as barcoding, as appropriate for the intended use of these data. Additional
controls may include locking critical data entries after the data are verified
and review of audit trails for critical data to detect if they have been altered.
11.7 Data processing. To ensure data integrity, data processing should be done
in an objective manner, free from bias, using validated/qualified or verified
protocols, processes, methods, systems, equipment and according to
approved procedures and training programmes.
11.8 Example considerations.
GXP organizations should take precautions to discourage testing or
processing data towards a desired outcome. For example:
to minimize potential bias and ensure consistent data processing,
test methods should have established sample acquisition and
processing parameters, established in default version-controlled
electronic acquisition and processing method files, as appropriate.
Changes to these default parameters may be necessary during
sample processing, but these changes should be documented (who,
what, when?) and justified (why?);
system suitability runs should include only established standards or
reference materials of known concentration to provide an appropriate
comparator for the potential variability of the instrument. If a sample
(e.g. a well-characterized secondary standard) is used for system
suitability or a trial run, written procedures should be established
and followed and the results included in the data review process.
The article under test should not be used for trial run purposes or to
evaluate suitability of the system;
clinical and safety studies should be designed to prevent and detect
statistical bias that may occur through improper selection of data to
be included in statistical calculations.
11.9 Data review and reporting. Data should be reviewed and, where
appropriate, evaluated statistically after completion of the process to
determine whether outcomes are consistent and compliant with established
standards. The evaluation should take into consideration all data,
including atypical, suspect or rejected data, together with the reported
data. This includes a review of the original paper and electronic records.
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11.10 For example, during self-inspection, some key questions to ask are: Am I
collecting all my data? Am I considering all my data? If I have excluded
some data from my decision-making process, what is the justification
for doing so, and are all the data retained, including both rejected and
reported data?
11.11 The approach to reviewing specific record content, such as critical data
fields and metadata such as cross-outs on paper records and audit trails
in electronic records, should meet all applicable regulatory requirements
and be risk-based.
11.12 Whenever out-of-trend or atypical results are obtained they should be

investigated. This includes investigating and determining corrective
and preventive actions for invalid runs, failures, repeats and other
atypical data. All data should be included in the dataset unless there is a
documented scientific explanation for their exclusion.
11.13 During the data life cycle, data should be subject to continuous
monitoring, as appropriate, to enhance process understanding and
facilitate knowledge management and informed decision-making.
11.14 Example considerations

To ensure that the entire set of data is considered in the reported data, the
review of original electronic data should include checks of all locations
where data may have been stored, including locations where voided,
deleted, invalid or rejected data may have been stored.
11.15 Data retention and retrieval. Retention of paper and electronic records
is discussed in the section above, including measures for backup and
archival of electronic data and metadata.
11.16 Example consideration
1) Data folders on some stand-alone systems may not include all audit
trails or other metadata needed to reconstruct all activities. Other
metadata may be found in other electronic folders or in operating
system logs. When archiving electronic data, it is important to
ensure that associated metadata are archived with the relevant
data set or securely traceable to the data set through appropriate
documentation. The ability to successfully retrieve from the archives
the entire data set, including metadata, should be verified.
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2) Only validated systems are used for storage of data; however, the
media used for the storage of data do not have an indefinite lifespan.
Consideration must be given to the longevity of media and the
environment in which they are stored. Examples include the fading
of microfilm records, the decreasing readability of the coatings of
optical media such as compact disks (CDs) and digital versatile/
video disks (DVDs), and the fact that these media may become
brittle. Similarly, historical data stored on magnetic media will also
become unreadable over time as a result of deterioration.
12. Addressing data reliability issues

12.1 When issues with data validity and reliability are discovered, it is important
that their potential impact on patient safety and product quality and on
the reliability of information used for decision-making and applications
is examined as a top priority. Health authorities should be notified if the
investigation identifies material impact on patients, products, reported
information or on application dossiers.
12.2 The investigation should ensure that copies of all data are secured in a
timely manner to permit a thorough review of the event and all potentially
related processes.
12.3 The people involved should be interviewed to better understand the
nature of the failure and how it occurred and what might have been done
to prevent and detect the issue sooner. This should include discussions
with the people involved in data integrity issues, as well as supervisory
personnel, quality assurance and management staff.
12.4 The investigation should not be limited to the specific issue identified but
should also consider potential impact on previous decisions based upon
the data and systems now found to be unreliable. In addition, it is vital that
the deeper, underlying root cause(s) of the issue be considered, including
potential management pressures and incentives, for example, a lack of
adequate resources.
12.5 Corrective and preventive actions taken should not only address
the identified issue, but also previous decisions and datasets that are
impacted, as well as deeper, underlying root causes, including the need
for realignment of management expectations and allocation of additional
resources to prevent risks from recurring in the future.
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References and further reading

References
1. WHO good manufacturing practices for pharmaceutical products: main principles. In: WHO
Expert Committee on Specifications for Pharmaceutical Preparations: forty-eighth report.
Geneva: World Health Organization; 2014: Annex 2 (WHO Technical Report Series, No. 986), also
available on CD-ROM and online.
2. Supplementary guidelines on good manufacturing practice: validation. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations: fortieth report. Geneva: World
3. Supplementary guidelines on good manufacturing practice: validation. Qualification of systems
and equipment. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations:
fortieth report. Geneva: World Health Organization; 2006: Annex 4, Appendix 6 (WHO Technical
Report Series, No. 937).
4. Supplementary guidelines on good manufacturing practices: validation. Validation of
computerized systems. In: WHO Expert Committee on Specifications for Pharmaceutical
Preparations: fortieth report. Geneva: World Health Organization; 2006: Annex 4, Appendix 5
(WHO Technical Report Series, No. 937).
Further reading
Computerised systems. In: The rules governing medicinal products in the European Union. Volume4:
Good manufacturing practice (GMP) guidelines: Annex 11. Brussels: European Commission (http://
ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-4/pdfs-en/anx11en.pdf).
Good automated manufacturing practice (GAMP) good practice guide: electronic data archiving.
Tampa (FL): International Society for Pharmaceutical Engineering (ISPE); 2007.
Good automated manufacturing practice GAMP good practice guide: A risk-based approach to GxP
compliant laboratory computerized systems, 2nd edition. Tampa (FL): International Society for
Pharmaceutical Engineering (ISPE); 2012.
MHRA GMP data integrity definitions and guidance for industry. London: Medicines and Healthcare
Products Regulatory Agency; March 2015 (https://www.gov.uk/government/uploads/system/uploads/
attachment_data/file/412735/Data_integrity_definitions_and_guidance_v2.pdf).
OECD series on principles of good laboratory practice (GLP) and compliance monitoring. Paris:
Organisation for Economic Co-operation and Development (http://www.oecd.org/chemicalsafety/
testing/oecdseriesonprinciplesofgoodlaboratorypracticeglpandcompliancemonitoring.htm).
Official Medicines Control Laboratories Network of the Council of Europe: Quality assurance documents:
PA/PH/OMCL (08) 69 3R Validation of computerised systems core document (https://www.edqm.
eu/sites/default/files/medias/fichiers/Validation_of_Computerised_Systems_Core_Document.pdf )
and its annexes:
PA/PH/OMCL (08) 87 2R Annex 1: Validation of computerised calculation systems: example
of validation of in-house software
(https://www.edqm.eu/sites/default/files/medias/fichiers/NEW_Annex_1_Validation_of_
computerised_calculation.pdf).
PA/PH/OMCL (08) 88 R Annex 2: Validation of databases (DB), laboratory information
management systems (LIMS) and electronic laboratory notebooks (ELN)
Databases_DB_Laboratory_.pdf).
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Annex 5
PA/PH/OMCL (08) 89 R Annex 3: Validation of computers as part of test equipment

computers_as_part_of_tes.pdf).
Title 21 Code of Federal Regulations (21 CFR Part 11): Electronic records; electronic signatures. US Food
and Drug Administration. The current status of 21 CFR Part 11 Guidance is located under Regulations
and Guidance at: http://www.fda.gov/cder/gmp/index.htm see background: http://www.fda.gov/
OHRMS/DOCKETS/98fr/03-4312.pdf.
PIC/S guide to good manufacturing practice for medicinal products annexes: Annex 11 Computerised
systems. Geneva: Pharmaceutical Inspection Co-operation Scheme.
PIC/S PI 011-3 Good practices for computerised systems in regulated GxP environments. Geneva:
Pharmaceutical Inspection Co-operation Scheme.
WHO good manufacturing practices for active pharmaceutical ingredients. In: WHO Expert Committee
Organization; 2010: Annex 2 (WHO Technical Report Series, No. 957).
WHO good practices for pharmaceutical quality control laboratories. In: WHO Expert Committee
191
Appendix 1
Expectations and examples of special risk management
considerations for the implementation of ALCOA (-plus)
principles in paper-based and electronic systems
Organizations should follow good documentation practices (GDocP) in order
to assure the accuracy, completeness, consistency and reliability of the records
and data throughout their entire period of usefulness that is, throughout
the data life cycle. The principles require that documentation should have the
characteristics of being attributable, legible, contemporaneously recorded,
original and accurate (sometimes referred to as ALCOA).
The tables in this appendix provide further guidance on the
implementation of the general ALCOA requirements for both paper and
electronic records and systems. In addition, examples of special risk management
considerations as well as several illustrative examples are provided of how these
measures are typically implemented.
These illustrative examples are provided to aid understanding of the
concepts and of how successful risk-based implementation might be achieved.
These examples should not be taken as setting new normative requirements.
Attributable. Attributable means information is captured in the record so that
it is uniquely identified as having been executed by the originator of the data
(e.g. a person or computer system).
Attributable
Expectations for paper records Expectations for electronic records

Attribution of actions in paper Attribution of actions in electronic records should
records should occur, as occur, as appropriate, through the useof:
appropriate, through the use of: unique user logons that link the user to actions
initials; that create, modify or delete data;
full handwritten signature; unique electronic signatures (can be either
personal seal; biometric or non-biometric);
date and, when necessary, time. an audit trail that should capture user
identification (ID) and date and time stamps;
signatures, which must be securely and
permanently linked to the record being signed.
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Special risk management considerations for controls to ensure

that actions and records are attributed to a unique individual
For legally-binding signatures, there should be a verifiable, secure
link between the unique, identifiable (actual) person signing and
the signature event. Signatures should be permanently linked to the
record being signed. Systems which use one application for signing
a document and another to store the document being signed should
ensure that the two remain linked to ensure that the attribution is
not broken.
Signatures and personal seals should be executed at the time of
review or performance of the event or action being recorded.
Use of a personal seal to sign documents requires additional risk
management controls, such as handwritten dates and procedures that
require storage of the seal in a secure location with access limited
only to the assigned individual, or equipped with other means of
preventing potential misuse.
Use of stored digital images of a persons handwritten signature
to sign a document is not acceptable. This practice compromises
confidence in the authenticity of these signatures when these stored
images are not maintained in a secure location, access to which
is limited only to the assigned individual, or equipped with other
means of preventing potential misuse, and instead are placed in
documents and emails where they can be easily copied and reused
by others. Legally binding, handwritten signatures should be dated at
the time of signing and electronic signatures should include the time/
date stamp of signing to record the contemporaneous nature of the
signing event.
The use of hybrid systems is discouraged, but where legacy systems
are awaiting replacement, mitigating controls should be in place.
The use of shared and generic logon credentials should be avoided
to ensure that actions documented in electronic records can be
attributed to a unique individual. This would apply to the software
application level and all applicable network environments where
personnel may perform actions (e.g. workstation and server
operating systems). Where such technical controls are not available
or feasible, for example, in legacy electronic systems or where
logon would terminate an application or stop the process running,
combinations of paper and electronic records should be used to meet
the requirements to attribute actions to the individuals concerned.
In such cases, original records generated during the course of GXP
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activities must be complete and must be maintained throughout

the records retention period in a manner that allows the full
reconstruction of the GXP activities.
A hybrid approach might exceptionally be used to sign electronic
records when the system lacks features for electronic signatures,
provided adequate security can be maintained. The hybrid approach
is likely to be more burdensome than a fully-electronic approach;
therefore, utilizing electronic signatures, whenever available, is
recommended. For example, the execution and attribution of an
electronic record by attachment of a handwritten signature may
be performed through a simple means that would create a single-
page controlled form associated with the written procedures for
system use and data review. The document should list the electronic
dataset reviewed and any metadata subject to review, and would
provide fields for the author, reviewer and/or approver of the
dataset to insert a handwritten signature. This paper record with
the handwritten signatures should then be securely and traceably
linked to the electronic dataset, either through procedural means,
such as use of detailed archives indexes, or technical means, such as
embedding a true-copy scanned image of the signature page into the
electronic dataset.
Replacement of hybrid systems should be a priority.
The use of a scribe to record an activity on behalf of another
operator should be considered only on an exceptional basis and
should only take place where:
the act of recording places the product or activity at risk, e.g.
documenting line interventions by aseptic area operators;
to accommodate cultural differences or mitigate staff literacy/
language limitations, for instance, where an activity is performed

by an operator, but witnessed and recorded by a supervisor or
officer.
In both situations, the supervisory recording should be contemporaneous
with the task being performed and should identify both the person performing
the observed task and the person completing the record. The person performing
the observed task should countersign the record wherever possible, although
it is accepted that this countersigning step will be retrospective. The process
for supervisory (scribe) documentation completion should be described in
an approved procedure which should also specify the activities to which the
process applies.
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Legible, traceable and permanent

The terms legible, traceable and permanent refer to the requirements that data
are readable, understandable and allow a clear picture of the sequencing of
steps or events in the record so that all GXP activities conducted can be fully
reconstructed by people reviewing these records at any point during the records
retention period set by the applicable GXP.
Legible, traceable, permanent

Legible, traceable and permanent Legible, traceable and permanent controls
controls for paper records include, but for electronic records include, but are not
are not limited to: limited to:
use of permanent, indelible ink; designing and configuring computer
no use of pencil or erasures; systems and writing standard operating
procedures (SOPs), as required, that
use of single-line cross-outs to record
enforce the saving of electronic data
changes with name, date and reason
at the time of the activity and before
recorded (i.e. the paper equivalent to
proceeding to the next step of the
the audit trail);
sequence of events (e.g. controls that
no use of opaque correction fluid or prohibit generation and processing and
otherwise obscuring the record; deletion of data in temporary memory
controlled issuance of bound, and that instead enforce the committing
paginated notebooks with sequentially of the data at the time of the activity to
numbered pages (i.e. thatallow durable memory before moving to the
detection of missing or skipped pages); next step in the sequence);
controlled issuance of sequentially use of secure, time-stamped audit trails
numbered copies of blank forms that independently record operator
(i.e. that allow all issued forms to be actions and attribute actions to the
accounted for); logged-on individual;
archival of paper records by configuration settings that restrict
independent, designated personnel in access to enhanced security permissions
secure and controlled paper archives (such as the system administrator role
(archivist is the term used for these that can be used to potentially turn off
personnel in quality control, good the audit trails or enable overwriting
laboratory practices (GLP) and good and deletion of data), only to persons
clinical practices (GCP) settings. independent of those responsible for
In good manufacturing practices the content of the electronic records;
(GMP) settings this role is normally configuration settings and SOPs, as
designated to specific individual(s) in required, to disable and prohibit the
the quality assurance unit); ability to overwrite data, including
prohibiting overwriting of preliminary
and intermediate processing of data;
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Table continued
Legible, traceable, permanent
preservation of paper/ink that strictly controlled configuration and use
fades over time where their use is of data annotation tools in a manner
unavoidable. that prevents data in displays and
printouts from being obscured;
validated backup of electronic records
toensure disaster recovery;
validated archival of electronic records
by independent, designated archivist(s)
in secure and controlled electronic
archives.
Special risk management considerations for legible,

traceable and permanent recording of GXP data
When computerized systems are used to generate electronic data, it
should be possible to associate all changes to data with the people
who make those changes, and those changes should be time-
stamped and a reason for the change recorded where applicable. This
traceability of user actions should be documented via computer-
generated audit trails or in other metadata fields or system features
that meet these requirements.
Users should not be able to amend or switch off the audit trails or
alternative means of providing traceability of user actions.
The need for the implementation of appropriate audit trail
functionality should be considered for all new computerized systems.

Where an existing computerized system lacks computer-generated
audit trails, personnel may use alternative means such as procedurally-
controlled use of logbooks, change control, record version control
or other combinations of paper and electronic records to meet GXP
regulatory expectations for traceability to document the what, who,
when and why of an action. Procedural controls should include
written procedures, training programmes, review of records and
audits and self-inspections of the governing process(es).
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When archival of electronic records is used, the archiving process

should be done in a controlled manner to preserve the integrity
of the records. Electronic archives should be validated, secured
and maintained in a state of control throughout the data life cycle.
Electronic records archived manually or automatically should be
stored in secure and controlled electronic archives, accessible only by
independent, designated archivists or by their approved delegates.
Appropriate separation of duties should be established so that

business process owners, or other users who may have a conflict of
interest, are not granted enhanced security access permissions at
any system level (e.g. operating system, application and database).
Further, highly privileged system administrator accounts should
be reserved for designated technical personnel, e.g. information
technology (IT) personnel, who are fully independent of the
personnel responsible for the content of the records, as these types
of accounts may include the ability to change settings to overwrite,
rename, delete, move data, change time/date settings, disable audit
trails and perform other system maintenance functions that turn off
the good data and record management practices (GDRP) controls
for legible and traceable electronic data. Where it is not feasible to
assign these independent security roles, other control strategies
should be used to reduce data validity risks.
To avoid conflicts of interest, these enhanced system access

permissions should only be granted to personnel with system
maintenance roles (e.g. IT, metrology, records control,
engineering), that are fully independent of the personnel
responsible for the content of the records (e.g. laboratory
analysts, laboratory management, clinical investigators, study
directors, production operators and production management).
Where these independent security role assignments are not
feasible, other control strategies should be used to reduce data
validity risks.
It is particularly important that individuals with enhanced access permissions

understand the impact of any changes they make using these privileges. Personnel
with enhanced access should therefore also be trained in data integrity principles.
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Contemporaneous
Contemporaneous data are data recorded at the time they are generated
orobserved.
Contemporaneous
Contemporaneous recording of actions Contemporaneous recording of actions
in paper records should occur, as in electronic records should occur, as
appropriate, through use of: appropriate, through use of:
written procedures, and training and configuration settings, SOPs and
review and audit and self-inspection controls that ensure that data recorded
controls that ensure personnel record in temporary memory are committed
data entries and information at the to durable media upon completion
time of the activity directly in official of the step or event and before
controlled documents (e.g. laboratory proceeding to the next step or event
notebooks, batch records, case in order to ensure the permanent
reportforms); recording of the step or event at the
procedures requiring that activities time it is conducted;
be recorded in paper records with the secure system time/date stamps that
date of the activity (and time as well, cannot be altered by personnel;
ifit is a time-sensitive activity); procedures and maintenance
good document design, which programmes that ensure time/date
encourages good practice: documents stamps are synchronized across the
should be appropriately designed GXP operations;
and the availability of blank forms/ controls that allow for the
documents in which the activities are determination of the timing of one
recorded should be ensured; activity relative to another (e.g. time
recording of the date and time of zone controls);
activities using synchronized time availability of the system to the user at

sources (facility and computerized the time of the activity.
system clocks) which cannot be
changed by unauthorized personnel.
Where possible, data and time
recording of manual activities
(e.g. weighing) should be done
automatically.
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Special risk management considerations for

contemporaneous recording of GXP data
Training programmes in GDocP should emphasize that it is

unacceptable to record data first in unofficial documentation (e.g. on
a scrap of paper) and later transfer the data to official documentation
(e.g. the laboratory notebook). Instead, original data should be
recorded directly in official records, such as approved analytical
worksheets, immediately at the time of the GXP activity.
Training programmes should emphasize that it is unacceptable to
backdate or forward date a record. Instead the date recorded should
be the actual date of the data entry. Late entries should be indicated as
such with both the date of the activity and the date of the entry being
recorded. If a person makes mistakes on a paper document he or she
should make single-line corrections, sign and date them, provide
reasons for the changes and retain this record in the record set.
If users of stand-alone computerized systems are provided with full
administrator rights to the workstation operating systems on which
the original electronic records are stored, this may inappropriately
grant permission to users to rename, copy or delete files stored
on the local system and to change the time/date stamp. For this
reason, validation of the stand-alone computerized system should
ensure proper security restrictions to protect time/date settings
and ensure data integrity in all computing environments, including
the workstation operating system, the software application and any
other applicable network environments.
Original
Original data include the first or source capture of data or information and all
subsequent data required to fully reconstruct the conduct of the GXP activity.
The GXP requirements for original data include the following:
original data should be reviewed;
original data and/or true and verified copies that preserve the
content and meaning of the original data should be retained;
as such, original records should be complete, enduring and readily
retrievable and readable throughout the records retention period.
Examples of original data include original electronic data and metadata in
stand-alone computerized laboratory instrument systems (e.g. ultraviolet/visible
spectrophotometry (UV/Vis), Fourier transform infrared spectroscopy (FT-IR),
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electrocardiogram (ECG), liquid chromatography-tandem mass spectrometry

(LC/MS/MS) and haematology and chemistry analysers), original electronic data
and metadata in automated production systems (e.g. automated filter integrity
testers, supervisory control and data acquisition (SCADA) and distributed
control system (DCS)), original electronic data and metadata in network database
systems (e.g. laboratory information management system (LIMS), enterprise
resource planning (ERP), manufacturing execution systems (MES), electronic
case report form/electronic data capture (eCRF/EDC), toxicology databases, and
deviation and corrective and preventive action (CAPA) databases), handwritten
sample preparation information in paper notebooks, printed recordings of
balance readings, electronic health records and paper batch records.
Review of original records

Controls for review of original paper Controls for review of original electronic
records include, but are not limited to: records include, but are not limited to:
written procedures and training and written procedures and training and
review and audit and self-inspection review and audit and inspection
controls to ensure that personnel controls that ensure personnel conduct
conduct an adequate review and an adequate review and approval of
approval of original paper records, original electronic records, including
including those used to record human readable source records of
the contemporaneous capture of electronic data;
information; data review procedures describing
data review procedures describing review of original electronic data
review of relevant metadata. For and relevant metadata. For example,
example, written procedures for review written procedures for review should
should require that personnel evaluate require that personnel evaluate
changes made to original information changes made to original information

on paper records (such as changes in electronic records (such as changes
documented in cross-out or data documented in audit trails or history
correction) to ensure these changes fields or found in other meaningful
are appropriately documented, and metadata) to ensure these changes
justified with substantiating evidence are appropriately documented and
and investigated when required; justified with substantiating evidence
and investigated when required;
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Table continued
Review of original records
documentation of data review. For documentation of data review. For
paper records this is typically signified electronic records, this is typically
by signing the paper records that have signified by electronically signing
been reviewed. Where record approval the electronic data set that has been
is a separate process this should also be reviewed and approved. Written
similarly signed. Written procedures for procedures for data review should
data review should clarify the meaning clarify the meaning of the review and
of the review and approval signatures approval signatures to ensure that
to ensure that the people concerned the personnel concerned understand
understand their responsibility as their responsibility as reviewers and
reviewers and approvers to assure the approvers to assure the integrity,
integrity, accuracy, consistency and accuracy, consistency and compliance
compliance with established standards with established standards of the
of the paper records subject to review electronic data and metadata subject
and approval; to review and approval;
a procedure describing the actions a procedure describing the actions
to be taken if data review identifies to be taken if data review identifies
an error or omission. This procedure an error or omission. This procedure
should enable data corrections or should enable data corrections or
clarifications to be made in a GXP- clarifications to be made in a GXP-
compliant manner, providing visibility compliant manner, providing visibility
of the original record and audit-trailed of the original record and audit trailed
traceability of the correction, using traceability of the correction, using
ALCOA principles. ALCOA principles.
Special risk management considerations for review of original records

Data integrity risks may occur when people choose to rely solely
upon paper printouts or PDF reports from computerized systems
without meeting applicable regulatory expectations for original
records. Original records should be reviewed this includes
electronic records. If the reviewer only reviews the subset of data
provided as a printout or PDF, risks may go undetected and harm
may occur.
Although original records should be reviewed, and all personnel
involved are fully accountable for the integrity and reliability of the
subsequent decisions made based upon original records, a risk-
based review of the content of original records is recommended.
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Systems typically include many metadata fields and audit trails. It is

expected that during validation of the system the organization will
establish based upon a documented and justified risk assessment
the frequency, roles and responsibilities, and the approach used
to review the various types of meaningful metadata, such as audit
trails. For example, under some circumstances, an organization may
justify periodic review of audit trails that track system maintenance
activities, whereas audit trails that track changes to critical GXP
data with a direct impact on patient safety or product quality would
be expected to be reviewed each and every time the associated data
set is being reviewed and approved and prior to decision-making.
Certain aspects of defining the audit trail review process (e.g.
frequency) may be initiated during validation and then adjusted
over time during the system life cycle, based upon risk reviews and
to ensure continual improvement.
A risk-based approach to reviewing data requires process
understanding and knowledge of the key quality risks in the given
process that may impact patients, products, compliance and the
overall accuracy, consistency and reliability of GXP decision-making.
When original records are electronic, a risk-based approach to
reviewing original electronic data also requires an understanding of
the computerized system, the data and metadata, and the data flows.
When determining a risk-based approach to reviewing audit trails
in GXP computerized systems, it is important to note that some
software developers may design mechanisms for tracking user actions
related to the most critical GXP data using metadata features and
may not have named these audit trails but may instead have used
the naming convention audit trail to track other computer system
and file maintenance activities. For example, changes to scientific
data may sometimes be most readily viewed by running various

database queries or by viewing metadata fields labelled history
files or by review of designed and validated system reports, and the
files designated by the software developer as audit trails alone may
be of limited value for an effective review. The risk-based review
of electronic data and metadata, such as audit trails, requires an
understanding of the system and the scientific process governing the
data life cycle so that the meaningful metadata are subject to review,
regardless of the naming conventions used by the software developer.
Systems may be designed to facilitate audit trail review by various
means; for example, the system design may permit audit trails to
be reviewed as a list of relevant data or by a validated exception
reporting process.
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Written procedures for data review should define the frequency, roles
and responsibilities and approach to review of meaningful metadata,
such as audit trails. These procedures should also describe how
aberrant data are to be handled if found during the review. Personnel
who conduct such reviews should have adequate and appropriate
training in the review process as well as in the software systems
containing the data subject to review. The organization should make
the necessary provisions for personnel reviewing the data to access
the system(s) containing the electronic data and metadata.
Quality assurance should also review a sample of relevant audit trails,
raw data and metadata as part of self-inspection to ensure ongoing
compliance with the data governance policy and procedures.
Any significant variation from expected outcomes should be fully
recorded and investigated.
In the hybrid approach, which is not the preferred approach, paper
printouts of original electronic records from computerized systems
may be useful as summary reports if the requirements for original
electronic records are also met. To rely upon these printed summaries
of results for future decision-making, a second person would have to
review the original electronic data and any relevant metadata such
as audit trails, to verify that the printed summary is representative
of all results. This verification would then be documented and the
printout could be used for subsequent decision-making.
The GXP organization may choose a fully electronic approach to
allow more efficient, streamlined record review and record retention.
This would require authenticated and secure electronic signatures
to be implemented for signing records where required. This, in turn,
would require preservation of the original electronic records, or
true copy, as well as the necessary software and hardware or other
suitable reader equipment to view the records during the records
retention period.
System design and the manner of data capture can significantly
influence the ease with which data consistency can be assured. For
example, and where applicable, the use of programmed edit checks
or features such as drop-down lists, check boxes or branching of
questions or data fields based on entries are useful in improving
data consistency.
Data and their metadata should be maintained in such a way that
they are available for review by authorized individuals, and in a
format that is suitable for review for as long as the data retention
requirements apply. It is desirable that the data should be maintained
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and available in the original system in which they were generated

for the longest possible period of time. When the original system is
retired or decommissioned, migration of the data to other systems or
other means of preserving the data should be used in a manner that
preserves the context and meaning of the data, allowing the relevant
steps to be reconstructed. Checks of accessibility to archived data,
irrespective of format, and including relevant metadata, should be
undertaken to confirm that the data are enduring, and continue to
be available, readable and understandable by a human being.
Retention of original records or true copies

Controls for retention of original paper Controls for retention of original electronic
records or true copies of original paper records or true copies of original electronic
records include, but are not limited to: records include, but are not limited to:
controlled and secure storage areas, routine back-up copies of original
including archives, for paper records; electronic records stored in another
a designated paper archivist(s) who location as a safeguard in case of disaster
is independent of GXP operations is that causes loss of the original electronic
required by GLP guidelines; in other records;
GXPs the roles and responsibilities controlled and secure storage areas,
for archiving GXP records should be including archives, for electronic records;
defined and monitored (and should a designated electronic archivist(s) such
normally be the responsibility of as is required in GLP guidelines who is
the quality assurance function or independent of GXP operations (the
an independent documentation designated personnel should be suitably
controlunit); qualified and have relevant experience
indexing of records to permit ready and appropriate training to perform
retrieval; their duties);
periodic tests at appropriate intervals indexing of records to permit ready

based upon risk assessment, to verify retrieval;
the ability to retrieve archived paper or periodic tests to verify the ability to
static format records; retrieve archived electronic data from
the provision of suitable reader storage locations. The ability to retrieve
equipment when required, such as archived electronic data from storage
microfiche or microfilm readers if locations should be tested during the
original paper records are copied as validation of the electronic archive.
true copies to microfilm or microfiche After validation the ability to retrieve
for archiving; archived electronic data from the
storage locations should be periodically
reconfirmed, including retrieval from
third-party storage;
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Table continued
Retention of original records or true copies
written procedures, training, review the provision of suitable reader
and audit, and self-inspection of equipment, such as software, operating
processes defining conversion, as systems and virtualized environments,
needed, of an original paper record to view the archived electronic data
totrue copy should include the when required;
following steps: written procedures, training, review and
a copy/copies is/are made of the audit and self-inspection of processes
original paper record(s), preserving defining conversion, as needed, of
the original record format, the static original electronic records to true copy
format, as required (e.g. photocopy, to include the following steps:
scan), a copy/copies is/are made of
the copy/copies need to be the original electronic data set,
compared with the original record(s) preserving the original record format,
to determine if the copy preserves the dynamic format, as required (e.g.
the entire content and meaning of archival copy of the entire set of
the original record, that metadata are electronic data and metadata made
included, that no data are missing using a validated back-up process),
in the copy. The way that the record a second person verifier or technical
format is preserved is important for verification process (such as use of
record meaning if the copy is to meet technical hash) to confirm successful
the requirements of a true copy of backup) whereby a comparison is
the original paper record(s), made of the electronic archival copy
the verifier documents the with the original electronic data set
verification in a manner securely to confirm the copy preserves the
linked to the copy/copies indicating entire content and meaning of the
it is a true copy, or provides original record (i.e. all of the data
equivalent certification. and metadata are included, no data
are missing in the copy, any dynamic
record format that is important for
record meaning and interpretation
is preserved and the file was not
corrupted during the execution of the
validated back-up process),
if the copy meets the requirements
as a true copy of the original, then
the verifier or technical verification
process should document the
verification in a manner that is
securely linked to the copy/copies,
certifying that it is a true copy.
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Special risk management considerations for retention

of original records and/or true copies
Data and document retention arrangements should ensure the
protection of records from deliberate or inadvertent alteration or loss.
Secure controls should be in place to ensure the data integrity of the
record throughout the retention period. Archival processes should be
defined in written procedures and validated where appropriate.
Data collected or recorded (manually and/or by recording
instruments or computerized systems) during a process or procedure
should show that all the defined and required steps have been taken
and that the quantity and quality of the output are as expected, and
should enable the complete history of the process or material to be
traced and be retained in a comprehensible and accessible form. That
is, original records and/or true copies should be complete, consistent
and enduring.
A true copy of original records may be retained in lieu of the
original records only if the copy has been compared to the original
records and verified to contain the entire content and meaning of
the original records, including applicable metadata and audit trails.
If true copies of original paper records are made by scanning the
original paper and conversion to an electronic image, such as PDF,
then additional measures to protect the electronic image from
further alteration are required (e.g. storage in a secure network
location with access limited to electronic archivist personnel only,
and measures taken to control potential use of annotation tools or
other means of preventing further alteration of the copy).
Consideration should be given to preservation where necessary of
the full content and meaning of original hand-signed paper records,

especially when the handwritten signature is an important aspect of
the overall integrity and reliability of the record and in accordance
with the value of the record over time. For example, in a clinical
trial it may be important to preserve original hand-signed informed
consent records throughout the useful life of this record as an
essential aspect of the trial and related application integrity.
True copies of electronic records should preserve the dynamic
format of the original electronic data as this is essential to
preserving the meaning of the original electronic data, e.g. if the old
software or equipment is retired. For example, the original dynamic
electronic spectral files created by instruments such as FT-IR, UV/
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Vis, chromatography systems and others can be reprocessed, but a

pdf or printout is fixed or static and the ability to expand baselines,
view the full spectrum, reprocess and interact dynamically with the
data set would be lost in the PDF or printout. As another example,
preserving the dynamic format of clinical study data captured in
an eCRF system allows searching and querying of data, whereas
a pdf of the eCRF data, even if it includes a PDF of audit trails,
would lose this aspect of the content and meaning of the original
eCRF data. Clinical investigators should have access to original
records throughout the study and records retention period in a
manner that preserves the full content and meaning of the source
information. It may be decided to maintain complete copies of
electronic data as well as PDF/printed summaries of these electronic
data in the archives to mitigate risks of a complete loss of ability to
readily view the data should the software and hardware be retired.
However, under these circumstances, especially for data that
support critical decision-making, even if PDF/printed summaries
are maintained, the complete copies of electronic data should
continue to be maintained throughout the records retention period
to allow for investigations that may be necessary under unexpected
circumstances, such as application integrity investigations.
Preserving the original electronic data in electronic form is also
important because data in dynamic format facilitate usability of the
data for subsequent processes. For example, having temperature
logger data maintained electronically facilitates subsequent tracking
and trending and monitoring of temperatures in statistical process
control charts.
In addition to the option of creating true copies of original electronic
data as verified back-up copies that are then secured in electronic
archives, another option for creating a true copy of original
electronic data would be to migrate the original electronic data from
one system to another and to verify and document that the validated
data migration process preserved the entire content, including
all meaningful metadata, as well as the meaning of the original
electronic data.
Electronic signature information should be retained as part of the
original electronic record. This should remain linked to the record
and be readable throughout the retention period, regardless of the
system used for archiving the records.
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Accurate
The term accurate means data are correct, truthful, complete, valid and reliable.
For both paper and electronic records, achieving the goal of accurate
data requires adequate procedures, processes, systems and controls that comprise
the quality management system. The quality management system should be
appropriate to the scope of its activities and risk-based.
Controls that assure the accuracy of data in paper records and electronic
records include, but are not limited to:
qualification, calibration and maintenance of equipment, such as

balances and pH meters, that generate printouts;
validation of computerized systems that generate, process, maintain,
distribute or archive electronic records;
systems must be validated to ensure their integrity while transmitting
between/among computerized systems;
validation of analytical methods;
validation of production processes;
review of GXP records;
investigation of deviations and doubtful and out-of-specifications
results; and
many other risk management controls within the quality
management system.
Examples of these controls applied to the data life cycle are provided
below.
Special risk management considerations for assuring accurate GXP records

The entry of critical data into a computer by an authorized person

(e.g. entry of a master processing formula) requires an additional
check on the accuracy of the data entered manually. This check
may be done by independent verification and release for use by a
second authorized person or by validated electronic means. For
example, to detect and manage risks associated with critical data,
procedures would require verification by a second person, such as
a member of the quality unit staff, of: calculation formulas entered
into spreadsheets; master data entered into LIMS such as fields for
specification ranges used to flag out-of-specification values on the
certificate of analysis; and other critical master data, as appropriate.
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In addition, once verified, these critical data fields would be locked

to prevent further modification, when feasible and appropriate, and
only modified through a formal change control process.
The validity of the data capture process is fundamental to ensuring
that high-quality data are produced.
Where used, standard dictionaries and thesauruses, tables (e.g. units
and scales) should be controlled.
The process of data transfer between systems should be validated.
The migration of data into and export from systems requires specific
planned testing and control.
Time may not be critical for all activities. When the activity is time-
critical, printed records should display the time/date stamp.
For example: To ensure the accuracy of sample weights recorded on a paper

printout from the balance, the balance would be appropriately calibrated before
use and properly maintained. In addition, synchronizing and locking the
metadata settings on the balance for the time/date settings would ensure accurate
recordings of time/date on the balance printout.
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Good trade and distribution practices for pharmaceutical
starting materials
Introduction 212
1. Quality management 213
2. Organization and personnel 214
3. Premises 215
4. Procurement, warehousing and storage 216
5. Equipment 218
6. Documentation 219
7. Repackaging and relabelling 220
8. Complaints 223
9. Recalls 223
10. Returned goods 224
11. Handling of non-conforming materials 224
12. Dispatch and transport 225
13. Contract activities 226
References 226
211
Introduction
Good manufacturing practices for active pharmaceutical ingredients were
published in 2000 by The International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human Use
(ICH), in ICH Q7 (1). Section 17 of this ICH text includes guidelines for agents,
brokers, traders, distributors, repackers and relabellers. This section was written
based on the outcome of the World Health Organization (WHO) investigation
into deaths resulting from the intentional relabelling of industrial grade
ethylene glycol as pharmaceutical grade material. This material was subsequently
formulated into a paediatric medicine that caused many deaths. Section 17 of this
good manufacturing practice (GMP) guide for active pharmaceutical ingredients
(APIs) applies to any party other than the original manufacturer which may trade
and/or take possession, repack, relabel, manipulate, distribute or store an API or
API intermediate. The scope of ICH Q7 does not include excipients.
Following a number of incidents involving diethylene glycol and a World
Health Assembly resolution (WHA52.19), WHO published the Good trade and
distribution practices for pharmaceutical starting materials in 2004 (2). At the time
of publication of these guidelines, WHO had not yet adopted the text from ICH
Q7 as GMP for APIs. The WHO guidance for excipients (3), published in 1999,
did not cover trade and distribution practices for excipients.
In 2010, WHO published Good manufacturing practices for active
pharmaceutical ingredients (4), which reflect the text from ICH Q7 and include
Section 17 of that document, to replace the existing WHO GMP for APIs.1
The WHO Expert Committee on Specifications for Pharmaceutical
Preparations discussed the revision of the Good trade and distribution practices
for pharmaceutical starting materials at several meetings. The scope of this
WHO guidance on Good trade and distribution practices for pharmaceutical
starting materials is applicable to any ingredient that is used in the manufacture
of a medicinal product, including APIs, excipients and any others.

Note: Material deriving from non-pharmaceutical grades, such as food, industrial
or technical grades, should not be designated as pharmaceutical grade when it is
not produced under the required manufacturing conditions and quality system.
For finished pharmaceutical products (FPPs), details can be found in the WHO
good distribution practices for pharmaceutical products (5).
It is important to note that any party that engages in repackaging or blending of an API is considered to
1
be a manufacturer and must submit appropriate registration documents for such manufacturing. He or
she must also comply with the GMP for APIs as stated in WHO Technical Report Series, No. 957, Annex 2,
2010 (4).
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1. Quality management
1.1 Within an organization, quality assurance serves as a management tool. In
contractual situations, quality assurance also serves to generate confidence
in the supplier. There should be a documented quality policy describing
the overall intentions and direction of the distributor regarding quality,
which should be formally expressed and authorized by management. The
quality policy should clearly indicate that the distributor implements and
maintains good trade and distribution practices (GTDP) as described in
these guidelines, within the organization and its services.
1.2 Quality management should include:
an appropriate infrastructure or quality system, encompassing the
organizational structure, procedures, processes and resources. The
size, structure and complexity of the distributor and its activities
should be taken into consideration when developing or modifying
the quality system;
an independent quality unit (or designee), which is responsible for
all quality-related matters;
an appropriate quality risk management (QRM) system to enable a
systematic process for the assessment, control, communication and
review of risks to the quality of the product. The extent of application
of the QRM system should reflect the operations performed;
a validation/qualification system to ensure that the resulting product
is capable of meeting the requirements for the specified application;
systematic actions necessary to ensure adequate confidence that a
material (or service) and relevant documentation will satisfy given
requirements for quality the totality of these actions is termed
quality assurance;
a clear documented procedure for selecting, approving, disqualifying
and re-approving suppliers of pharmaceutical starting materials
andservices;
a robust deviation management and change control programme
designed to ensure that quality is continually assessed and
maintained: these should include a customer notification where
appropriate;
a system ensuring traceability of products and associated
documentation throughout the entire supply chain.
1.3 The system should cover for example, but not be limited to, the quality
assurance principles in these guidelines.
213
1.4 All parties involved in the manufacture and supply chain must exercise
responsibility to ensure the quality and safety of the materials and
products, and that they are fit for their intended use in accordance with
their specifications.
1.5 The responsibilities placed on any one individual should not be so

extensive as to present any risk to quality. In the event of a supplier
having a limited number of staff, some duties may be delegated or
contracted out to designated persons who are appropriately qualified.
There should, however, be no gaps or unexplained overlaps related to the
application of GTDP for pharmaceutical starting materials as described
in theseguidelines.
1.6 Where electronic commerce (e-commerce) is used, defined procedures

and adequate systems should be in place to ensure confidence in the
quality of the material and its traceability.
1.7 Authorized release procedures should be in place to ensure that when

material is released for its intended purpose, it is of an appropriate quality,
meets its specifications and is sourced from approved suppliers.
1.8 Implementation of QRM principles using appropriate tools such as

hazard analysis and critical control point (HACCP); inspection and
certification of compliance with an appropriate quality system such as
applicable International Organization for Standardization (ISO) series,
and recognition of compliance with national and/or regional standards by
external bodies is recommended. However, this should not be seen as a
substitute for the implementation of these guidelines or for conforming,
for example, to pharmaceutical GMP and good storage practices (GSP)
requirements, as applicable.
1.9 A system should be in place for the performance of regular internal audits
with the aim of continuous improvement. The findings of the audit and
any corrective and preventive actions taken, including verification of their
effectiveness, should be documented and brought to the attention of the
responsible management.
2. Organization and personnel

2.1 There should be an adequate organizational structure and a sufficient
number of personnel should be employed to carry out all the tasks for
which the supplier is responsible.
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2.2 Individual responsibilities should be clearly defined, understood by

the individuals concerned and recorded in writing (as job descriptions
or in a contract). Certain activities, such as supervision of performance
of activities in accordance with local legislation, may require special
attention. Personnel should be suitably qualified, trained and authorized
to undertake their duties and responsibilities.
2.3 All personnel should be aware of the principles of the appropriate
guidelines, including but not limited to GTDP.
2.4 Personnel should receive initial and continuing training relevant to their
tasks. Training should be provided by qualified trainers in accordance with
a training programme. The effectiveness of training should be verified
where appropriate. Training records should be maintained. All personnel
should be motivated to support the establishment and maintenance of
quality standards.
2.5 Personnel dealing with hazardous materials (such as highly active, toxic,
infectious or sensitizing materials) should be given specific training and
should be provided with the necessary protective equipment. Documented
policies and procedures for the use of personal protective equipment
should be followed to decrease exposure of workers working directly with
products and those in the immediate environment.
2.6 Personnel who may be exposed to materials from open containers should
maintain good hygiene, have no open wounds and should wear appropriate
protective garments, gloves, masks and goggles.
3. Premises
3.1 Premises, including laboratory facilities, must be located, designed,
constructed, adapted and maintained to suit the operations to be carried
out. Their layout and design must aim to minimize the risk of errors and
permit effective cleaning and maintenance in order to avoid contamination,
cross-contamination, mix ups, build-up of dust, dirt or waste and, in
general, any adverse effect on the quality of materials.
3.2 Measures should be in place to prevent unauthorized persons from
entering the premises.
3.3 Premises should be designed, equipped and maintained so as to afford
maximum protection against the entry of insects, rodents or other animals.
A pest control programme should be implemented and maintained. Its
effectiveness should be monitored.
215
3.4 Suitable supporting facilities and utilities (such as air control, ventilation
and lighting) should be in place and appropriate to the activities performed,
in order to avoid contamination, cross-contamination and degradation of
the material. Utilities that could affect product quality should be identified
and monitored.
3.5 If sampling of pharmaceutical starting materials is performed, the sampling
area should be separate and in a controlled environment. Sampling should
only be performed in a storage area if it can be conducted in such a way
that there is no risk of contamination or cross-contamination. Adequate
cleaning procedures should be in place for the sampling areas.
4. Procurement, warehousing and storage

Note: GSP are applicable in all circumstances in which, and in all areas where,
materials are stored.
4.1 Materials should be purchased from approved suppliers in accordance with
mutually agreed formal specifications.
4.2 Actions should be taken to minimize the risk of falsified or non-conforming
materials entering the supply chain.
4.3 There should be authorized procedures describing the activities relating
to the receipt, storage and distribution of materials. Steps should be taken
to ensure and document that the arriving consignment is correct and
that the products originate from approved suppliers. Deliveries should
be examined to check that containers have not been damaged, altered or
tampered with, and that closures and security seals are intact.
4.4 Storage areas should have sufficient capacity to allow orderly storage of
the various categories of materials.

4.5 Receipt and dispatch bays should be equipped with the means to protect
materials from adverse environmental conditions. Reception areas should
be designed and equipped to allow containers of incoming materials to
be cleaned before storage if appropriate. Upon receipt, material should be
segregated until released by the quality unit.
4.6 Segregated areas should be provided for the storage of received,
quarantined, rejected, recalled and returned material, including materials
with damaged packaging. Any system replacing physical segregation, such
as electronic segregation based on a computerized system, should provide
equivalent security and should be appropriately qualified and validated.
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Annex 6
4.7 The storage areas should be kept clean and dry.

4.8 Segregated areas and materials should be appropriately identified.
4.9 The required storage conditions, as specified for the material, should be
maintained within acceptable limits at all times during storage. Appropriate
checks to confirm that required shipping conditions have been met should
be conducted as soon as possible after receipt.
The product should be transferred to appropriate storage facilities
immediately after checks to be made in the goods receiving area have
beenconducted.
4.10 Where special storage conditions are required (e.g. particular temperature,
humidity or protection from light) these should be provided, monitored
and recorded as appropriate.
4.11 Highly active materials, narcotics, other dangerous drugs and substances
presenting special risks of abuse, fire or explosion should be stored in safe,
dedicated and secure areas. In addition and where applicable, international
conventions and national legislation are to be adhered to.
4.12 Special attention should be given to the design, use, cleaning and
maintenance of all equipment for bulk handling and storage, such as tanks
and silos.
4.13 Products should be packed in such a way as to avoid breakage,
contamination, tampering or theft. The packing should be adequate to
maintain the quality of the product during transport. If special shipping
conditions have to be met they should be defined, provided and controlled.
The containers in which products are shipped should be sealed and should
clearly indicate the authenticity of the product and its supplier.
4.14 Spillages should be cleaned up as soon as possible to prevent possible
crosscontamination and hazard.
4.15 Provision should be made for the proper and safe storage of waste
materials awaiting disposal. Toxic substances and flammable materials
should be stored in suitably designed, separate, closed containers in
enclosed areas, taking into account the relevant national legislation.
4.16 A default system should be in place to ensure that those materials due to
expire first are sold or distributed first (earliest expiry/first out). Where no
expiry dates are specified for the materials, the first in/first out principle
should be applied.
217
4.17 A process should be in place to ensure that materials that have reached
their expiry or retest date should be withdrawn immediately from saleable
stock. Materials with a retest date should be retested according to the
appropriate specifications. Materials with an expiry date should not be
retested or used after that date.
4.18 Stock inventory should be checked regularly, at least for quantity, overall
condition and retesting or expiration dates. Any discrepancies should
beinvestigated.
4.19 Controls should be in place to ensure that the correct product is picked,
packed and distributed. The material should have an appropriate remaining
shelf life. All batch numbers should be recorded.
4.20 Storage areas should be clean and free from accumulated waste and from
vermin. A written sanitation programme should be available, indicating the
frequency of cleaning and the methods to be used to clean the premises
and storage areas.
5. Equipment
5.1 Equipment must be located, designed, constructed, adapted, qualified,
used, cleaned and maintained to suit the operations to be carried out.
Its layout, design and use should aim to minimize the risk of errors
and permit effective cleaning and maintenance so as to avoid cross-
contamination, build-up of dust or dirt and any adverse effect on the
quality ofmaterials.
5.2 Defective equipment should not be used and should either be removed or
labelled as defective. Equipment should be disposed of in such a way as to
prevent any misuse.

5.3 The status of the equipment should be readily identifiable.
5.4 Fixed pipework should be clearly labelled to indicate the contents and,
where applicable, the direction of flow.
5.5 All services, piping and devices should be adequately marked and special
attention paid to the provision of non-interchangeable connections or
adaptors for dangerous gases, liquids and other materials.
5.6 Balances and other measuring equipment of an appropriate range and
precision should be available and should be calibrated in accordance with
a suitable schedule.
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5.7 Dedicated equipment should be used where appropriate when handling

and/or processing pharmaceutical starting materials. Where non-dedicated
equipment is used cleaning validation should be performed.
5.8 Closed equipment should be used when possible. If open equipment is
used, suitable measures should be taken to prevent contamination.
5.9 Procedures should be in place for the operation and maintenance of
equipment. Lubricants and other materials used on surfaces that come into
direct contact with the materials should be of the appropriate grade, e.g.
food-grade oil, and should not alter the quality of the materials.
5.10 Washing and cleaning equipment should be chosen and used such that it
cannot be a source of contamination.
6. Documentation
6.1 Documents, in particular instructions and procedures relating to any
activity that might have an impact on the quality of materials, should
be designed, completed, reviewed and distributed with care. Documents
should be completed, approved, signed and dated by appropriate authorized
persons and should not be changed without authorization. Specifications
for materials, including packaging materials, should be available, reviewed
and revised on a regular basis.
6.2 Documents should have unambiguous contents: their title, nature and
purpose should be clearly stated. They should be laid out in an orderly
manner and be easy to check.
6.3 Certificates of analysis (COAs) issued by the original manufacturer should
be provided. If additional testing is done, all COAs should be provided.
COAs should document product traceability back to the
manufacturer by naming the original manufacturer and the manufacturing
site. COAs should indicate which results were obtained by testing the
original material and which results came from skip-lot testing or other
testing and should specify the organization responsible for issuing the COA.
6.4 Before any material is sold or distributed, the supplier should ensure
that the COAs and results are available and that the results meet the
required specifications.
6.5 The original manufacturer and the intermediaries handling the material
should always be traceable and transparent; and this information should
be made available to authorities and end-users, downstream and upstream,
when requested.
219
6.6 Depending upon risk assessment, and in accordance with the national
requirements, quality agreements should form the basis of the relationship
for all parties involved in the supply chain. The agreements should include
mechanisms to allow transfer of information, e.g. quality or regulatory
information and change control.
6.7 Labels applied to containers should be clear, unambiguous, permanently
fixed and should be printed in the companys agreed format. The
information on the label should be indelible.
6.8 Each container should be identified by labelling bearing at least the
following information:
the name of the pharmaceutical starting material (including grade
and reference to pharmacopoeias where relevant);
if applicable, the International Nonproprietary Name (INN);
the amount (weight or volume);
the batch number assigned by the original manufacturer or the
batch number assigned by the repacker, if the material has been
repacked and relabelled;
the retest date or expiry date (where applicable);
the storage conditions;
handling precautions, where necessary;
identification of the original manufacturing site;
name and contact details of the supplier.
6.9 Relevant storage and handling information and safety data sheets should
be available.
6.10 Records should be kept and must be readily available upon request in
accordance with GMP and GSP (6).
7. Repackaging and relabelling

7.1 Operations, such as combining into a homogeneous batch, repackaging
and/or relabelling, are manufacturing processes and are not recommended.
In circumstances where they are to be conducted, their performance
should be in compliance with GMP.
Note: It is important to note that any party who engages in repackaging or blending
of an API is considered to be a manufacturer and must submit appropriate
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Annex 6
registration documents for such manufacturing. They must also comply with the
GMP for APIs as set out in WHO Technical Report Series, No. 957, Annex 2,
2010 (4).
7.2 Special attention should be given to the following points:
prevention of contamination, cross-contamination and mix ups;
appropriate environmental conditions for dispensing, packaging
and sampling;
security of stocks of labels, line clearance checks, online inspections,
destruction of excess batch-printed labels and label reconciliation;
good sanitation and hygiene practices;
maintaining batch integrity (mixing of different batches of the same
solid material should normally not be done);
as part of batch records, all labels that were removed from the
original container during operations, and a sample of the new label,
should be kept;
if more than one batch of labels is used in one operation, samples of
each batch should be kept;
maintaining product identity, integrity and traceability.
7.3 Upon receipt, packaging materials should be placed in quarantine and
should not be used prior to release. There should be procedures for the
inspection, approval and release of the packaging materials.
7.4 When different batches of a material from the same original manufacturing
site are received by a distributor and combined into a homogeneous batch,
the conformity of each batch with its specification should be confirmed
before it is added.
7.5 Only materials from the same manufacturing site, received by a distributor
and conforming to the same specifications, can be mixed. If different
batches of the same material are mixed to form a homogeneous batch
it should be defined as a new batch, tested and supplied with a batch
certificate of analysis. In such cases the customer should be informed that
the material supplied is a mixture of manufacturers batches.
7.6 In all cases, traceability back to the manufacturer should be documented
by identifying the original manufacturer of the specific batch of the
material and its manufacturing site.
7.7 If batches are combined or mixed, the oldest batch should determine the
expiry or retest date assigned to the combined or mixed batch.
221
7.8 If the integrity and quality of the batch is maintained during repackaging
and relabelling, then the original COA of the original manufacturer should
be provided.
If retesting is done, both the original and the new COA should be
provided as long as the batch integrity is maintained. The batch referred to
on the new COA should be traceable to the original COA.
7.9 Repackaging of materials should be carried out using approved packaging
materials for which the quality and suitability have been established as
being equal to or better than those of the original container.
7.10 The reuse of containers should be discouraged unless they have been
cleaned using a validated procedure. Recycled containers should not be
used unless there is evidence that the quality of the material packed in
them will not be adversely affected.
7.11 Materials should be repackaged only if efficient environmental control
exists to ensure that there is no possibility of contamination, cross-
contamination, degradation, physicochemical changes and/or mix ups.
The quality of air supplied to the area should be suitable for the activities
performed, e.g. there should be efficient filtration.
7.12 Suitable procedures should be followed to ensure proper label control.
7.13 Containers of repackaged material and relabelled containers should bear
both the name of the original manufacturing site and the name of the
distributor/repacker.
7.14 Procedures should be in place to ensure maintenance of the identity
and quality of the material by appropriate means, both before and after
repackaging operations.
7.15 Each batch of repackaged material should be tested to ensure that the
material conforms to documented specifications.
7.16 There should be a procedure to ensure that appropriate repackaging
documentation, in addition to the test results, is evaluated prior to release
of the repackaged material.
7.17 Sampling, analytical testing and batch release procedures should be in
accordance with GMP.
7.18 Only official pharmacopoeial methods or validated analytical test methods
should be used for the analysis. Where alternatives to the test methods
specified in a monograph are used to provide test results, those alternative
methods should be demonstrated to be suitable and equivalent.
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7.19 Out-of-specification test results should be investigated and documented.
7.20 Samples of pharmaceutical starting materials in appropriate quantities

should be kept for at least one year after the expiry or retest date, or for
three years after distribution is complete.
7.21 The repacker and relabeller should ensure that the stability of the material
is not adversely affected by the repackaging or relabelling. Stability studies
to justify assigned expiration or retest dates should be conducted if the
pharmaceutical starting material is repackaged in a container different
from that used by the original manufacturer. It is recognized that some
excipients may not need additional stability studies.
8. Complaints
8.1 All complaints and other information concerning potentially defective
materials must be carefully reviewed according to written procedures
that describe the action to be taken and specify the criteria on which a
decision to recall a product should be based. Records of complaints should
be retained and evaluated for trends at defined intervals.
8.2 Any complaint concerning a material defect should be recorded and

thoroughly investigated to identify the origin or reason for the complaint
(e.g. the repackaging procedure or the original manufacturing process).
Corrective and preventive actions should be taken where appropriate,
andrecorded.
8.3 If a defect in a pharmaceutical starting material is discovered or suspected,

consideration should be given to whether other batches should be checked.
8.4 Where necessary, appropriate follow-up action, possibly including a recall,

should be taken after investigation and evaluation of the complaint.
8.5 The manufacturer and customers should be informed if action is needed

following possible faulty manufacturing, packaging, deterioration or any
other serious quality problems with a pharmaceutical starting material.
9. Recalls
9.1 There should be a system for recalling promptly and effectively from the
market, materials known or suspected to be defective.
9.2 The original manufacturer should be informed in the event of a recall.

223
9.3 There should be detailed written procedures for the organization of

any recall activity. These procedure(s) should be regularly reviewed
andupdated.
9.4 All recalled materials should be stored in a secure area while their fate
isdecided.
9.5 In the event of serious or potentially life-threatening situations, all
customers and competent authorities in all countries to which a given
material may have been distributed should be promptly informed of any
intention to recall the material.
9.6 All records should be readily available to the designated person(s)
responsible for recalls. These records should contain sufficient information
on materials supplied to customers (including exported materials).
9.7 The effectiveness of the arrangements for recalls should be evaluated at
regular intervals.
10. Returned goods

10.1 Goods returned to the supplier should be appropriately identified and
quarantined. The conditions under which returned goods have been
stored and shipped should be evaluated to determine the quality of the
returned goods.
10.2 The quality unit or designee should decide on the disposition of the
returned goods following a formal and documented investigation process.
Corrective and preventive actions should be taken where appropriate.
11. Handling of non-conforming materials

11.1 Non-conforming materials should be handled in accordance with a
procedure that will prevent their introduction or reintroduction into the
market. Records covering all activities, including destruction, disposal,
return and reclassification, should be maintained.
11.2 An investigation should be performed to establish whether any other
batches are also affected. Corrective and preventive measures should be
taken where necessary.
11.3 The disposition of the material, including downgrading to other suitable
purposes, should be documented.
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11.4 Non-conforming materials should never be blended with materials that

do comply with specifications.
12. Dispatch and transport

12.1 Materials should be loaded, unloaded and transported in a manner that
will ensure the maintenance of controlled conditions where applicable (e.g.
temperature, protection from the environment). The transport process
should not adversely affect the materials. Any carrier used for transport
should be approved according to a written procedure unless the carrier has
been selected by the customer.
12.2 Requirements for special transport and/or storage conditions should
be stated on the label and/or in the transport documentation. If the
pharmaceutical starting material is intended to be transferred outside the
control of the manufacturers materials management system, the name
and address of the manufacturer, quality of contents, special transport
conditions and any special legal requirements should also be included on
the label and/or in the transport documentation.
12.3 The supplier of the materials should ensure that the contract acceptor for
transportation of the materials is aware of and provides the appropriate
storage and transport conditions, e.g. through audits.
12.4 Procedures should be in place to ensure proper cleaning and prevention of
cross-contamination when liquids (tanks) and bulk or packed materials
are transported.
12.5 The bulk transport of pharmaceutical starting materials requires numerous
precautions to avoid contamination and cross-contamination. The best
practice is to use dedicated equipment, tanks or containers.
12.6 Packaging materials and transportation containers should be suitable to
prevent damage to the pharmaceutical starting materials during transport.
12.7 For bulk transport, validated cleaning procedures should be used between
loadings, and a list of restricted previous cargoes must be supplied to the
transport companies.
12.8 Steps should be taken to prevent unauthorized access to the materials
being transported.
12.9 General international requirements regarding safety aspects (e.g. prevention
of explosion and of contamination of the environment) should be observed.
225
13. Contract activities

13.1 Any activity performed, as referenced in the GMP and GTDP guidelines,
delegated to another party, should be agreed upon in a written contract.
13.2 The contract giver should evaluate the proposed contract acceptors
compliance with GTDP before entering into an agreement.
13.3 All contract acceptors should comply with the requirements in these
guidelines. Special consideration should be given to the prevention of
cross-contamination and to maintaining traceability.
13.4 There should be a written and approved contract or formal agreement
between the contract giver and contract acceptor that addresses and
defines in detail the responsibilities with respect to GTDP and which
party is responsible for which quality measures.
13.5 Subcontracting may be permissible under certain conditions, subject to
approval by the contract giver, especially for activities such as sampling,
analysis, repacking and relabelling.
References
1. ICH harmonised tripartite guideline: Good manufacturing practice guide for active pharmaceutical
ingredients Q7. Geneva: International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use; 2000.
2. Good trade and distribution practices for pharmaceutical starting materials. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations: thirty-eighth report. Geneva:
World Health Organization; 2004: Annex 2 (WHO Technical Report Series, No. 917).
3. Good manufacturing practice: supplementary guidelines for the manufacture of pharmaceutical
excipients. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: thirty-
fifth report. Geneva: World Health Organization; 1999: Annex 5 (WHO Technical Report Series,
No.885).
4. Good manufacturing practices for active pharmaceutical ingredients. In: WHO Expert Committee
5. WHO good distribution practices for pharmaceutical products. In: WHO Expert Committee
6. Guide to good storage practices for pharmaceuticals. In: WHO Expert Committee on Specifications
for Pharmaceutical Preparations: thirty-seventh report. Geneva: World Health Organization;
2003: Annex 9 (WHO Technical Report Series, No. 908).
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Guidelines on the conduct of surveys of the quality
ofmedicines
1. Introduction 228
2. Glossary 229
3. Objectives of the survey and initial planning 229
4. Survey management and time frame 233
5. Methodology 236
5.1 Selection of areas to be sampled 236
5.2 Selection of medicines to be surveyed 236
5.3 Selection of sample collection sites 238
5.3.1 Types of sample collection sites 238
5.3.2 Sampling designs 239
5.3.2.1 Convenience sampling 239
5.3.2.2 Simple random sampling 240
5.3.2.3 Stratified random sampling 240
5.3.2.4 Lot quality assurance sampling 241
5.3.2.5 Sentinel site monitoring 242
5.4 Sampling plans 242
5.4.1 Number of dosage units to be collected 243
5.5 Sample collection 244
5.5.1 Overt sampling versus mystery-shopper approach 244
5.5.2 Instructions to sample collectors 246
5.6 Storage and transportation of samples 248
5.7 Testing 249
5.7.1 Testing laboratory 249
5.7.2 Tests to be conducted 250
5.7.3 Test methods and specifications 252
5.7.4 Receipt and testing of samples by a testing laboratory 253
6. Data management and publication 254
References 255
Appendix 1 Example of a sample collection form 257
Appendix 2 Content of the analytical test report/certificate of analysis 259
Appendix 3 Outline of the content of a survey report 261
227
1. Introduction
Good quality medicines are essential for efficient disease management. To
ensure that good quality medicines are available to patients in their countries,
national medicines regulatory authorities (NMRAs) can apply various regulatory
instruments. These are:
authorization/registration for marketing following the assessment
of product documentation, inspection to ascertain manufacturers
compliance with the principles of good manufacturing practices
(GMP) and approval of product information;
post-marketing surveillance activities, including maintenance
of products authorization and/or registration through
variations or renewals, regular inspections of manufacturers,
wholesalers, distributors and retailers, quality control testing and
pharmacovigilance;
implementation of regulatory actions in the event of any quality
problem being found.
Quality surveys may serve as a source of information about the quality
of medicines available to patients and are an important part of regulatory
systems in all countries, whether they are strong or weak. However, it has to be
borne in mind that quality surveys that rely only on laboratory testing cannot
offer complete assurance that medicines are safe and effective as formulated.
Quality surveys can be organized by NMRAs, international organizations,
procurement agents, nongovernmental organizations (NGOs) or academic and
research groups.
If properly collected, interpreted and used relevant data are vital for
the planning of effective interventions to improve the quality of medicines.
Surveys give snapshots of the medicine quality situation; however, the accuracy,
reliability and interpretation of the data obtained depend on the survey design,
organization of sample collection and available resources. Medicine quality
surveys are costly and limitations on resources may restrict the number of
samples collected, parameters tested, techniques to be used for analysis or
number of staff available to conduct the survey and analysis. Therefore it is
important to optimize use of resources by focusing on those medicines and
parameters that pose a higher risk to patients and apply risk analysis during
planning of the survey. Also cooperation with partners, joint organization of
surveys in several countries, and sharing testing capacities, experience and
information can enhance the effectiveness of quality surveys.
These guidelines outline the steps to consider when preparing and
conducting a survey of medicines quality. They provide recommendations
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and examples of various methodological approaches with a discussion of their

advantages and disadvantages, and suggestions on preparation of reports on the
results obtained from such surveys.
2. Glossary
pharmaceutical outlet. Any point (licensed or unlicensed) of sale or
provision of medicines for individual patients or other medicine providers.
sample collected in a quality survey. A product in a given presentation
(identified by its name, content of active pharmaceutical ingredient(s) (API(s)),
dosage form, strength, batch number, production date (if known), expiration
date, collection date and name of manufacturer or labelled registration holder)
collected at the specific sample collection site. It means that the same product
characterized by the same name, content of APIs, dosage form, strength, batch,
and from the same manufacturer collected in two different sites represents two
samples. Each sample should consist of the number of dosage units (e.g. tablets,
capsules, ampoules, vials or bottles) required by the sampling plan.
sampling plan. A plan that contains detailed identification of sites where
samples will be collected, medicines to be sampled, minimum number of dosage
units to be collected per sample, number of samples to be collected per medicine
and total number of samples to be collected in the area for which the sampling
plan is prepared. It also contains detailed instructions for sample collectors.
3. Objectives of the survey and initial planning

In general, quality surveys are organized to assess the quality of medicines
provided to patients and generate the data that can help to formulate strategies
and plans to ensure provision of good quality medicines. They may be organized
to confirm that patients are receiving satisfactory medicines and give reassurance
that the regulatory system is functional, or when there is a suspicion that patients
are not receiving satisfactory medicines. Detailed objectives must be set at the
start of planning since all the activities and requirements of the survey should be
derived from its objectives. The objectives of a quality survey should reflect the
reasons why the survey is being conducted and should be formulated in a way
that enables identification of medicines for the survey, sites of sample collection,
surveyed areas, regions or countries, and tests to be conducted. Clearly defined
objectives are essential for setting the conditions for sampling and testing, which
should be described in detail in the survey protocol.
229
There is a wide range of possible objectives, a few examples of which are

given below:
to evaluate the quality of selected medicines available in the market,
in selected areas, regions or countries, at various levels of the
distribution/supply chain with the aim of assessing the exposure of
patients to poor-quality medicines and proposing appropriate actions;
to evaluate the quality of specific medicines used in the treatment
programme;
to compare the quality of domestically produced and imported
medicines in order to recommend appropriate regulatory actions
and adjust pharmaceutical policy in the country concerned;
to identify possible causes of inferior quality of specific productsto
which patients are exposed and to propose possible strategies
and implementation plans to address the problems identified by
thesurvey;
to test the quality of selected medicines in order to support the
NMRA in identification of manufacturers that are not in compliance
with quality standards and regulatory measures;
to find out if, within a selected category of medicines, any spurious/
falsely labelled/falsified/counterfeit (SFFC) products have penetrated
the market in selected areas, regions or countries, what the possible
health impacts may be for patients, and to propose possible strategies
and implementation plans to prevent harm to patients.
To ensure that a survey provides the necessary information it is essential,
in addition to a primary objective, to set appropriate and relevant questions to
be addressed in the survey. Some examples of such questions include:
What proportion of sampled medicines fails quality testing?
What proportions of sampled medicines fail quality testing at different

levels of the regulated distribution chain and in the informal market?
What proportions of medicines sampled from different
geographical regions fail quality testing?
What proportions of sampled domestically produced and imported
medicines fail quality testing?
Which specific quality tests do the selected medicines fail?
Are any of the deficiencies critical, i.e. could they substantially
affect treatment efficiency and/or cause harm to patients?
Are there treatment failures related to a specific disease, which can
be associated with low-quality medicines?
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What is the registration status of the sampled products and

whatproportions of registered and unregistered products fail
quality testing?
What are the supply chains by which poor-quality medicines are
distributed and what are the market segments they serve?
Are there any indicators of poor storage and distribution conditions
that influence quality of sampled medicines?
Are there poor-quality medicines in the selected area, e.g. at the
border checkpoint?
What is the proportion of poor-quality medicines being sold and/
or the proportion of pharmaceutical outlets selling poor-quality
medicines in a particular area?
Does the proportion of poor-quality medicines or the proportion
of pharmaceutical outlets selling poor-quality medicines exceed a
predetermined level?
Has there been a change in the quality of a medicine or medicine
category, or in an area (in the case of repeated random surveys with
consistent design)?
Setting reasonable objectives and an appropriate design for a survey
needs initial planning. Some examples of questions that should be considered in
the planning phase are given below.
What is already known about the quality and risk of inferior quality
of the target medicines?
The information may be available from the scientific literature, alerts
on medicines quality, or a search of published studies (e.g. in PubMed
or Google Scholar). When an NMRA is involved in the survey
it is important to gather information from inspectors, assessors,
laboratory and pharmacovigilance experts and to design the survey
in cooperation with such a multidisciplinary team. Discussions with
pharmacists and other health-care professionals may also help to
prioritize surveys.
What is the distribution/supply system of the target medicines?
Distribution/supply chains vary between countries and even within
a country they may be different for different categories of medicines.
In order to design the survey properly it is important to understand
how the target medicines are supplied in the surveyed area and how
they reach patients. Knowledge of the distribution/supply chain of
the target medicines enables risk-based selection of the sampling
231
sites that best serve the survey objectives. Complex supply chains
pose a higher risk of quality deterioration and should be prioritized
in market surveillance activities. Information on distribution/supply
chains should be available to NMRAs, ministries of health, provincial
health departments and health centres or other governmental
organizations. In the public domain, some information can be found
on the World Health Organization (WHO) Essential Medicines and
Health Products Department website (http://www.who.int/medicines/
areas/coordination/partnerscoordination/en/). Several international
NGOs are mapping pharmaceutical outlets in various areas and
publishing the information on their websites, e.g. Population
Services International (PSI) (http://www.psi.org/) or, specifically for
antimalarials, ACTWatch (http://www.actwatch.info/). If the survey
is intended to focus on unlicensed outlets, an initial investigation
may be necessary to identify and map the relevant locations.
What health-seeking behaviour is associated with the target medicines?
For some surveys it may also be important to understand where
different categories of patients tend to buy their medicines and what
kind of product they buy. In many countries the medicines market
is heavily segmented with different markets for people with different
spending power and different ethnicity. For example, the wealthier
people may go to pharmacies or private clinics, whereas the poorest
go to grocery shops or street peddlers, and people in the middle-
income category may go to hospitals. There will also be brands of
the same product sold at different prices aimed at different market
segments. If such information is needed, an initial pre-survey
should be performed.
What is the overall volume of use of the target medicines?

The higher the volumes of a particular medicine used the bigger the
impact the inferior-quality medicine will have on patients. Therefore
medicines with high consumption volumes should be prioritized
in market surveillance activities. It may be difficult to obtain data
on consumption volumes in some countries but estimates based on
distribution volumes or information from various disease control
programmes can be used.
What registered medicines are available in the surveyed area?
It may be useful for the evaluation of survey results to have available
lists of registered medicines in the surveyed countries. These lists
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can often be obtained from NMRAs or ministries of health and

sometimes may be published on their websites. Additionally, most
countries make available unregistered medicines under certain
conditions, e.g. specific medicines may be used in public health
programmes or donated.
What brands of the target medicines are available in the surveyed
area or in the selected outlets?
If the objective of the survey is to obtain an overall impression of
the quality of medicines available on the market, samples produced
by as many manufacturers as possible should be collected and it
may be necessary to visit several sampling sites. Often, it is very
difficult to know in advance how many brands of a specific medicine
(containing the same API in the same dosage form) are sold in a
particular market or what their market share is. A pilot study asking
for a product list at the selling points may help in collecting the data
needed to better plan the survey.
For correct understanding and proper interpretation of the results and
conclusions of the survey, its limitations should always be stated and explained.
4. Survey management and time frame

Ideally, the authorities (ministry of health and/or NMRA) of target countries
should be involved and should agree with the survey plan before it is implemented.
The responsibilities and tasks of the people who have key roles in the survey
organization (e.g. principal survey coordinator and the local coordinators in
individual areas or countries) should be identified at the beginning and should
include those with the responsibility for monitoring the conduct of the survey,
performing analysis, processing results and preparing the final report. Lines and
means of communication should be agreed in advance.
The primary aim of a medicines quality survey is to reduce harm to
patients and enforce medicines quality standards. Surveys are organized for
market surveillance or to generate new scientific knowledge. Normally they
do not require ethical approval; however, such approval may be needed for an
epidemiological survey. As the requirements for ethical clearance vary between
countries, the regulations on ethical approval in the target countries should be
verified before planning a specific survey.
It is recommended that before sample collection starts, a meeting with
local coordinators is organized to explain and discuss the project and the survey
protocol, and to provide detailed instructions to ensure survey consistency.
233
After data analysis and before publication of the report it is useful to hold a
meeting with appropriate stakeholders to discuss the results, conclusions and
actions needed.
Timing of sample collection is important since seasonal changes in
environmental conditions may have an influence on the quality of the medicine
collected. It is possible that falsified antimalarials are more common during the
malaria season, or that access to outlets in rural areas may be impeded in
therainy season, for example as a result of floods or landslides.
Issues such as the use of the results and their public availability should be
clearly understood by the responsible authorities and all parties involved in the
survey from the beginning. Relevant regulatory measures in individual countries
lie within the responsibility of the NMRA, when applicable in collaboration
with the police or other enforcement bodies (with respect to falsified medicines
or criminal negligence). Therefore, if an NMRA does not organize the survey
directly, it should be provided with the results before their publication to be
able to investigate in line with the regulatory practice and legislation with the
relevant manufacturer and, if appropriate, adopt necessary regulatory measures.
A publication plan including authorship of any papers to be submitted
for peer-reviewed publication and a distribution list of those to whom the report
will be disseminated should be agreed at the beginning of the survey. A policy
should be adopted concerning public release of data that might be considered
confidential. The default position should be to distribute the data as widely and
openly as possible.
The survey protocol should include the plan of survey activities and
the personnel responsible for the completion of the different steps within the
estimated time frames (Table A7.1). It is important to plan the financial resources
expected for the whole survey before it commences.
Table A7.1
Example plan of survey activities
Activity Time frame Responsible

person
Selection of areas/regions/countries and
medicines to be surveyed
Preparation of survey protocol
Agreement with authority/authorities in
surveyed country/countries
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Table A7.1 continued

Activity Time frame Responsible
person
Seeking ethical clearance for an
epidemiological survey
Selection of testing laboratory/laboratories
Finalization of testing protocol in agreement
with testing laboratory/laboratories
Meeting held with local coordinators
from the target areas to discuss the
surveyprotocol
Preparation of detailed sampling plans
Preparation and pilot test of data collection
instructions and procedures, if needed
Training and supervision of personnel
collecting samples
Collection of samples and transport to
testing laboratory/laboratories in a manner
that assures sample chain of custody and
maintaining samples in a state of control, to
preclude compromising the samples during
shipment or transfer to the laboratory
Database of information on collected
samples (including scanned pictures or
photographs of the dosage form, label and
package leaflet)
Testing of samples
Compilation of results
Data analysis
Report drafting
Meeting with appropriate stakeholders to
discuss the results and the actions needed
Report finalization
Distribution and publication of the results
235
5. Methodology
All surveys should be conducted according to a predefined survey protocol.
Inadequate instructions on the protocol or noncompliance with the protocol, e.g.
insufficient sample size, incorrect sampling and/or testing, may lead to inaccurate
results and policy recommendations. Careful consideration of the methodology
and ethical issues should guide the survey preparation and the people involved
should comply with the instructions and with appropriate ethical standards.
In principle, in addition to the background and explanation of the survey
objectives and limitations, the survey protocol should contain information on
the following.
5.1 Selection of areas to be sampled

A number of different geographical areas should be sampled unless the objectives
expressly justify targeting only one area. Samples should be collected in various
locations, as situations in rural and suburban areas often differ. Depending on
the survey objectives, the following variables may be considered when selecting
areas to be surveyed:
population density;
incidence or prevalence of the disease for which the target medicines
are indicated;
level of risk of poor-quality medicines, e.g. the risk may be higher
along trade routes across country borders, in areas where poor-
quality medicines have been previously found, areas where formal
health services are limited, and in areas where the NMRA has few or
no resources to monitor the distribution of medicines;
degree of urbanization;
income level of the population in the target area;
areas with complex distribution systems;

areas with outlets selling predominantly unregistered and/or illegal
medicines.
Sampling several countries according to the same survey protocol gives a
broader picture of the quality of medicines in the region and enables comparisons
between countries to be made.
Selection of the sampled areas should be explained and justified.
5.2 Selection of medicines to be surveyed

The category of medicines to be surveyed may be characterized in various
ways, e.g. according to their content of APIs, therapeutic group classification,
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formulation, the specific programme under which they are supplied, or the
manufacturer or distributor declared on the label. If collection of commonly used
products is required, a pre-survey investigation of treatment-seeking behaviour
may be necessary. Collaborating with other actors, such as national disease
control programmes, may help to identify products commonly used.
Selection of medicines is driven by the survey objectives and public health
considerations. The potential public health impact of poor-quality medicines
should be a key guide for selection. To optimize use of available resources the
survey should focus on medicines posing most risk to patients, e.g. where
the therapeutic index is narrow, substandard quality could lead to a significant
change in the health outcome, or certain categories may be particularly
vulnerable to counterfeiting. To estimate risks posed by individual medicines
an analysis should be performed. Aspects to consider may include:
probability of occurrence of a quality problem, taking into account:
complexity of manufacture,
stability of the medicine risk of quality deterioration under
local conditions of storage, distribution and use,
compliance of manufacturers of the target medicines with GMP
principles,
complexity of distribution chain for the target medicines and
likelihood of non-compliance with good distribution practices
(GDP) principles and approved storage conditions during
distribution and storage;
exposure of patients to the medicine and seriousness of potential
health impairment, considering:
extent of exposed population number of patients and length
oftreatment, and volumes used,
vulnerability of target population susceptibility of treated
population to the undesired effects of the medicine,
complexity of the dosage form in relation to the route
ofadministration,
therapeutic properties and risk, such as safety margins and risk
of side effects, risk of therapeutic failure, acute versus chronic
exposure, and risk of development of resistance.
Instructions should be provided to sample collectors with regard to the
dosage forms and strengths of the selected medicines to be collected. Unless
the objectives of the survey require a focus on a particular brand or brands,
instructions should be given to the collectors on how to select samples if several
brands are available at the sample collection site.
237
The number of medicines that should be selected for the survey depends
on available resources (both financial and human) and care should be taken to
keep the survey manageable.
5.3 Selection of sample collection sites

5.3.1 Types of sample collection sites
Types of pharmaceutical outlets vary greatly both within and between countries
and may be classified according to the countries medicine legislation. To allow
comparison between regions and/or countries, outlets can be classed as:
public (government);
formal (licensed), i.e. registered private for profit and private not for
profit (nongovernmental organizations (NGOs));
informal (unlicensed).
Another way to classify sample collection sites is according to their level
in the supply chain:
Level 1 points of entry to the market, e.g. warehouses of importers
or manufacturers, central medical stores, NGO central stores,
procurement centres or other facilities supplied directly within
various programmes, central wholesalers and/or distributors;
Level 2 wholesalers and/or distributors, pharmacies and other
regulated retailers, dispensing facilities, hospitals, health centres,
sub-health centres, district hospitals, clinics, polyclinics, cabinets,
treatment centres, health posts and community health workers;
Level 3 informal outlets selling medicines outside the approved
distribution system, e.g. kiosks, street vendors, grocery shops, drug
stores and itinerant sellers;
Level 4: virtual outlets, e.g. sales of medicines via the Internet.

Sampling should usually be performed in both the public and private
sectors as well as in the informal market, i.e. both licensed and unlicensed
outlets should be included. Types of sites for sample collection should be
selected in the way that will best serve the survey objectives and the selection
should be explained.
Quality of samples collected in the supply chain close to the point of
sale to patients (Levels 2 and 3) may be influenced by distribution and storage
conditions. However, these samples will be the closest in terms of quality to the
medicines that patients actually take. When a medicine at Level 2 or 3 is found
to be substandard, possibly due to degradation, subsequent sampling of that
medicine at Level 1 may identify the source of the problem in the supply chain.
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Samples collected at points of entry to the market (Level 1) should be less

affected by the conditions they may encounter during in-country distribution,
but are relatively distant from the actual quality of medicines that patients
will have access to and take. Sampling at this point in the supply chain has the
advantage of determining the quality of products as supplied by manufacturers
and allowing quality issues to be detected before the products reach patients.
Corrective actions may be more easily taken if the results are quickly available.
Once the types of sample collection sites have been selected, the areas,
regions or countries to be sampled need to be mapped and the sites where
samples will actually be collected during the survey should be identified (by
address and facility type). Good local knowledge of the distribution and supply
chain structure for the target medicines and information on where patients
obtain medicines is needed. Cooperation with NMRAs and relevant disease
control programmes in this respect is crucial. If the survey objectives require
collection of samples offered by itinerant sellers, it may not be possible to map
their territory and a pre-survey investigation, e.g. in households, may be
needed. Another option would be to include a list of the outlets where itinerant
vendors buy their medicines.
5.3.2 Sampling designs

Various designs can be used for selection of sample collection sites. The choice
depends on the objectives of the survey, the risks and consequences of inherent
decision errors and biases, and available resources.
5.3.2.1 Convenience sampling

Convenience sampling is a non-probability sampling technique based on the
judgement of the survey organizer. The sites, however, should not be selected
just because of their convenient accessibility and proximity. There should be
defined rules guiding the selection so as to best reflect the survey objectives.
Whenever convenience sampling is used, it is necessary to report how the
sites were identified and which types and what proportion of the outlets
theselection represents.
Convenience samples are simple and do not necessarily need complete
lists of outlets in defined areas, which may be difficult to obtain especially for
unlicensed or mobile outlets. However, they are inherently prone to biases that
have to be considered when interpreting the survey outcomes. Such surveys are
predominantly used for selection of sample collection sites, e.g. by NMRAs for
market surveillance. To utilize resources in the most efficient way NMRAs focus
on outlets where the risk of poor-quality medicines being found is high. When
selecting such sites the risk analysis should take into account, for example, how
medicines are distributed to the site, transport conditions, storage conditions
239
and handling of products at the site, and experience of the NMRA with the
distribution chain and sites.
The results of convenience sampling cannot be generalized to other
areas, even within the same country, or reliably interpreted over time. However,
such surveys may provide the evidence necessary to support regulatory actions
or to signal a quality problem. If convenience sampling does indicate a medicine
quality problem, further investigation or regulatory actions can be initiated. If
a wider picture is needed, subsequent surveys using probability sampling can
be designed. If convenience surveys do not reveal a problem one should bear
in mind that this may be a false-negative result. It is important to explain the
limitations of this technique in reports and scientific papers.
Despite its limitations, convenience sampling is most suitable for NMRAs
to identify high-risk areas for further regulatory actions.
Examples of convenience sampling include some surveys conducted in
Africa (1, 2) and South East Asia (3, 4).
5.3.2.2 Simple random sampling

Random sampling is a probability sampling technique that, if the sample size is
sufficient, will give reliable estimates (with confidence intervals) of the prevalence
of outlets selling poor-quality medicines. Formulas for calculation of sample size
for random sampling can be found in the literature (5, 6). The disadvantages of
random sampling are the large sample sizes needed, the necessity for complete
lists of the locations of the target outlets and the additional costs in terms of
labour and time. In addition, it is important to recognize that a random survey
will only produce reliable and useful information if the list of outlets and actual
within-outlet sampling is consistent with the primary aims of the survey. For
example, a random survey of the quality of a medicine in the private sector, when
most patients obtain this medicine in the public sector would not be useful, nor
would a random survey using overt shoppers for a medicine which the outlet staff
know should not be sold to patients. Comparisons with subsequent estimates

using this same sampling design should, however, be valid and will allow the
evaluation of interventions.
5.3.2.3 Stratified random sampling

Stratified sampling is a probability sampling technique wherein the researcher
divides the entire group of subjects to be investigated (e.g. outlets) into
different subgroups (layers or strata), then randomly selects the final subjects
proportionally from the different subgroups. Stratified sampling can be used
to adjust for potential differences, e.g. sales volume, type of customers, or
geographical, trade and socioeconomic variables (such as rural versus urban,
private versus public outlets and one geographical area versus another) may
240
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beconsidered. Stratification requires adjustment of the sample size calculation.

Sampling that is proportional to the number of outlets will be more efficient than
simple random sampling. It is important that the randomization procedure is
done using formal random number tables or statistical software. This technique
has been used in a stratified random survey in Lao Peoples Democratic
Republic(7). Other examples of random surveys come from Nigeria (8) and the
United Republic of Tanzania (9).
5.3.2.4 Lot quality assurance sampling

An alternative approach to formal random sampling that is simpler and less
expensive, and needs smaller sample sizes, is lot quality assurance sampling
(LQAS). This technique can be used to determine whether the prevalence of
outlets selling poor-quality medicines exceeds a certain threshold.
LQAS is designed to find out whether a lot of goods meets the desired
specifications without having to inspect the entire lot. Thus, the sample size
in LQAS is defined as the number of outlets or medicines (goods) that are
selected for each site or region (lot) and the only outcome is that the site or
region is acceptable or unacceptable. Setting the level of risk taken by not
inspecting each and every item enables the researcher to accept or reject an
entire lot after inspecting a randomly selected sample of items. Therefore the
sample size in LQAS is based on defined threshold values that classify good
and bad outcomes and the probability of error that the researchers are willing
to tolerate.
Acceptable probabilities of error must be specified, i.e. the risk of
accepting a bad lot (consumer risk) and the risk of not accepting a good
lot (provider risk). These risks are commonly referred to as Type I (alpha) and
Type II (beta) errors, respectively. The former is often set to 0.05. This means
that if the null hypothesis (that the site has fewer outlets selling poor-quality
medicines than the specified value) is true, there is a 5% chance that a site
with an unacceptable proportion of outlets selling poor-quality medicines will
be accepted or go undetected. In general, Type I risk is set lower than the
TypeII risk.
Once the threshold values and probabilities of error have been
considered, a sample size and decision value can be obtained. The decision value
is the number of outlets selling poor-quality medicines that need to be found
before an area is considered unacceptable. LQAS still requires random sampling
and preparation of complete lists of the locations of the outlets, and has the
disadvantage that it does not estimate an exact prevalence. The advantage is that
it requires relatively smaller sample sizes. Sampling can stop once the number
of outlets selling poor-quality medicine is exceeded, greatly reducing sampling
time and costs.
241
As LQAS will only provide a binary result, formal random sampling may
be required to examine longitudinal changes in the prevalence of poor-quality
medicines accurately. It can also be useful as a way to monitor the situation
when the exact prevalence of poor-quality medicines is known.
There has been almost no discussion as to what proportion of outlets
selling poor-quality medicines should be regarded as unacceptable. Ideally there
should be zero-tolerance for outlets selling poor-quality medicines, as even a
1% prevalence of such medicines for potentially fatal diseases, such as malaria,
tuberculosis and HIV, is disastrous for individual patients.
Examples of this approach are described in several publications (10, 11).
Sampling procedures and tables for lot acceptance by parties who receive goods
manufactured by others can be found in the international standards, e.g. ANSI/
ASQ Z1.4 and Z1.9 or ISO 2859 and ISO 3951 series.1
5.3.2.5 Sentinel site monitoring

Sentinel site monitoring involves following the quality of medicines in a particular
locality over time. There are no common rules as to whether these sites should be
chosen on the basis of potentially important variables such as rural versus urban
and private versus public outlets, or as to sampling design (i.e. convenience or
random samples or LQAS). The power of this methodology resides in allowing
longitudinal changes to be followed in one place, but data from fixed sentinel site
monitoring should be interpreted with caution. Sentinel site monitoring suffers
from the disadvantage that shop owners may soon realize that they are being
sampled, change their behaviour accordingly and thus cease to be representative.
Examples of this approach include the survey in the Mekong region (12).
5.4 Sampling plans

Sampling plans should be prepared for each area, region or country involved
in the survey and should be in compliance with requirements identified in the

survey protocol. They should specify the:
individual sites where collectors should collect samples (by facility
type and address, possibly including global positioning system
(GPS) coordinates);
medicines to be sampled (by APIs, dosage form, strength, and, if
needed, also by package size);
http://asq.org/knowledge-center/Z14.Z19/index.html;
1
http://www.iso.org/iso/home/store/catalogue_tc/catalogue_detail.htm?csnumber=39991;
http://www.iso.org/iso/home/store/catalogue_tc/catalogue_detail.htm?csnumber=57490.
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minimum number of dosage units to be collected per sample;

number of samples to be collected per medicine;
total number of samples to be collected in the relevant area, region
or country.
Sampling plans should also contain detailed instructions for collectors.
Examples of sampling plans for surveys organized by WHO can be found in the
published survey reports.2
5.4.1 Number of dosage units to be collected

The number of dosage units that should be collected per sample depends on the
survey objectives, surveyed medicines, tests to be conducted, testing methods
to be employed and available resources. To protect the integrity of the samples
and avoid quality deterioration before testing, dosage units should normally not
be taken out of the original primary and secondary packaging, and only intact
and unopened packages should be collected. Sampling plans usually define the
minimum number of dosage units to be collected per sample. The appropriate
number of packages is collected in relation to the available package size.
In surveys aiming to provide evidence to support regulatory actions,
which are often organized by NMRAs or with their participation, pharmacopoeial
tests performed in compliance with pharmacopoeial procedures are commonly
used. In such surveys the principles of good practices for pharmaceutical quality
control laboratories (13) should be followed and the number of dosage units per
sample should allow:
the planned tests to be conducted;
investigation and confirmatory testing of samples found to be
outof-specification (OOS);
sufficient retention samples to be used in case of dispute.
To fulfil these requirements, suitably large numbers of dosage units per
sample should be collected (e.g. 100 tablets, 40 injection solution ampoules
or powder for injection vials, depending on the medicine and the requested
tests), which may be difficult to obtain from some outlets. Requests for such
large quantities of products may also suggest to the outlet owner that the
buyer is not an ordinary shopper, in cases where the survey objectives require
a mystery-shopper approach. The minimum number of dosage units of each
selected medicine to be collected should be agreed with the testing laboratory.
World Health Organization Prequalification of Medicines Programme. Quality Monitoring (http://www.

2
who.int/prequal/).
243
Theadvantage of surveys using pharmacopoeial procedures is the possibility to

apply quality acceptance criteria as defined in pharmacopoeias. The disadvantage
is that the rather time- and resource-intensive laboratory testing leads to fewer
samples that can be included in the survey.
Other types of surveys include quality screening surveys using basic,
simple tests, non-destructive techniques (such as Raman and infrared (IR)
spectroscopy) or unofficial testing methods (i.e. non-pharmacopoeial or not
approved by the NMRA during the registration process) to assess the identity
of the API and estimate its content. Such surveys cannot be used as a basis
for regulatory actions but may prompt further investigations with appropriate
protocols. The advantage is that only a few dosage units need to be collected per
sample, a higher number of samples can be collected and the mystery-shopper
approach can be used, if needed. The disadvantage is that when testing only a few
individual dosage units, the usual pharmacopoeial quality acceptance criteria
are difficult to apply, e.g. when estimating the content of the API by testing only
a few individual tablets, pharmacopoeial criteria for the assay cannot be used.
Testing of individual dosage units to assess the content of API raises the
question of how many dosage units, within a specific medicine sample, need
to be analysed. The variability of individual units can be very high, especially
within a sample of poor-quality medicine. Various statistical approaches to
representative medicine sampling, especially for forensic analysis purposes, have
been described. These are published, e.g. by the United Nations (UN) Office
on Drugs and Crime (14), Scientific Working Group for the Analysis of Seized
Drugs (15), European Network of Forensic Sciences Institutes,3 and in other
publications (16).
Sampling procedures to ensure that representative samples are taken by
authorities, procurement agencies, manufacturers or customers, for acceptance
of consignments, batch release testing, in-process controls, special controls,
inspection for customs clearance, deterioration and adulteration, or for obtaining
a retention sample are described in the WHO guidelines for sampling of

pharmaceutical products and related materials (17).
5.5 Sample collection

5.5.1 Overt sampling versus mystery-shopper approach
The decision on who should collect samples will depend on the survey objectives,
the regulatory status of the target medicines and what is known about the
knowledge and attitude of the sellers (i.e. whether they know that the outlet
Calculator for qualitative sampling of seized drugs (http://www.enfsi.eu/documents/enfsi-dwg-calculator-

3
qualitative-sampling-seized-drugs-2012).
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Annex 7
is selling poor-quality medicines and understand the health, legal and ethical
implications). If outlet staff are anxious to avoid poor-quality medicines and are
informed about the survey objectives, overt sampling with feedback would allow
more data to be collected on poor-quality medicines and their risk factors and
lead to a direct improvement in the medicine supply. Overt sampling may be the
only possible method in some circumstances, such as when collecting samples
at locations where people are seen first by clinicians, or in the public sector.
However, many outlets in countries with weak medicines regulation sell
expired or unregistered medicines, which may make outlet staff suspicious and
anxious about investigations. If the seller knows or is concerned that his or her
stock contains illegal or poor-quality medicines and that the buyer is potentially
linked to the NMRA, this may influence which medicines are offered. An
additional concern is that in many resource-poor countries the medicine market
is heavily segmented with different markets for people with different spending
power and ethnicity. Even within a single outlet there will often be several
different brands of the same medicine at different prices aimed at different
market segments. In such cases a covert, mystery-shopper approach may be
appropriate (18). The identity and purpose of the buyer should not be generally
known by the outlet being evaluated. Sampling should usually be performed
by nationals of the country concerned although there may be some situations,
such as suspicion that migrant workers may take inferior medicines, where this
would not be applicable. It may not be safe for people living in the same wider
community to act as purchasers. In contrast, in some remote rural locations,
it would be difficult for someone who is not local to request medicines as this
would cause suspicion. The safety of those acting as mystery shoppers should be
considered, a risk assessment performed and instructions appropriate to local
conditions need to be developed.
The mystery shopper mimics a normal shopper from the community
in which the outlet is located and should dress, speak and behave appropriately
for that community. Shoppers should use a standard scenario, e.g. pretending
to be a visitor from another part of the country who needs some medicines for
a specified disease, for a specific reason and for a stereotypical patient. Mystery
shoppers should be prepared to explain the real purpose of their visit to protect
themselves if their identity is revealed.
After leaving the survey site the mystery shopper should record details
of each purchase. Price, name of the provider and/or outlet, and an estimation
of temperature at the site should be documented as well as the conditions of
the purchase, e.g. how many people were in the outlet, how long the purchase
took, the nature of the interaction between the mystery shopper and outlet
staff, whether it was easy to convince the provider to sell medicines, and any
other information needed to meet the survey objectives. All medicines collected
245
should be properly identified and stored, e.g. in a plastic bag labelled with the
name of the outlet.
The mystery shopper should brief the local coordinator for the surveyed
area upon his or her return from each outlet. The local coordinator should
transcribe the reported interaction together with a translation if appropriate.
Translations should use a meaning-based method, rather than a literal or
interpretative approach. The original text with translation should be double-
checked for accuracy by other members of the team and kept.
Examples of overt sampling include some surveys in Asia (19, 20) and
an example using the mystery-shopper approach can be found in the report of a
survey conducted in Lao Peoples Democratic Republic (7).
5.5.2 Instructions to sample collectors

The local coordinator for each area, region or country will arrange for training
of collectors to familiarize them with the project, survey protocol, sampling plan
and instructions for collection of samples. Staff from the NMRA and different
national disease control programmes may provide a useful insight into the
survey planning. Instructions and procedures for data collection should be
well understood by the collectors (translated into the language of the collectors,
pilot-tested and revised, if needed). The following principles should be stated in
detailed instructions for collectors.
The minimum number of dosage units per sample and number of

batches to be collected from each collection site for each selected
medicine as indicated in the sampling plan should be adhered to.
The target medicines, their dosage forms, strengths and package
sizes should be defined. As outlets may have more than one
brand of a particular medicine available, instructions should be
provided on how to decide which to choose if a selection has

to be made. It should be taken into consideration that mystery
shoppers requesting a very specific brand or product may alert
sellers. However, such an approach may be required if evidence
suggests that only one brand of an essential medicine is affected by
falsification or substandard production. It may be useful to consider
using a specific written prescription for a number of items including
the target medicine. This can reduce the suspicion that might be
raised by a verbal request. Using the written prescription format
may also enable the quality of dispensing, labelling directions and
counselling to bestudied.
All units of one sample should have the same batch number.
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Annex 7
The medicine samples should not be taken out of the original primary
and secondary packaging (although removal from large secondary
packs is appropriate). Containers such as bottles and vials should
not be opened. Where medicines are sold without package leaflets,
or in unlabelled plastic bags coming from large-sized boxes (locally
repacked), or as individual dosage forms, this should be recorded.
Ideally, samples collected should have at least six months remaining
before expiry to allow sufficient time for chemical analysis.
However, the frequency of expired medicines is also an important
outcome measure and any expired medicine found in the outlet
should be recorded.
The medicine labels and package leaflets should not be removed
ordamaged.
Each sample should be recorded separately using the sample
collection form (for an example see Appendix 1). Whenever the
required information is not available this should be noted in the
appropriate space on the sample collection form; any observed
abnormalities should also be recorded.
Each sample should be identified by a unique sample code, defined
on the sample collection form and specified on all original packages
belonging to the respective sample. It should be written legibly
and should not obscure the basic product information. The sample
collection form and all packages belonging to one sample should be
kept together (e.g. blisters inserted in a dedicated zip-lock plastic
bag or an envelope marked with the appropriate sample code and
trade name of the product). For large surveys, barcode systems may
be helpful to reduce errors.
When overt sampling is used, manufacturers batch certificates of
analysis should be collected with the samples, if available, and kept
with the sample collection form.
Storage conditions at the site (temperature, humidity, access of light
and any other observations) should be described in the sample
collection form. When overt sampling is used collectors can measure
the temperature if it is not controlled at the site. Mystery shoppers
can estimate and record the temperature.
Samples should be collected and kept under controlled conditions
in line with the product label requirements. The cold chain has to be
maintained, where required. Samples should be kept protected from
light, excessive moisture or dryness. Safety measures against theft
should be taken; medicine boxes should be kept in a locked area.
247
The period within which samples should be collected and the deadline
for sending the last sample to the testing laboratory should be clearly indicated
and adhered to.
Normally samples of collected medicines should be paid for by collectors.
The cost of collected samples needs to be taken into account when determining
the numbers of samples to be collected. In some countries, NMRA inspectors
have legal power to collect samples from the market without reimbursement.
Collectors should be mindful of the stock of sampled products held
in outlets, and of the potential difficulties of replenishing sampled medicines
through the supply chain, so as not to jeopardize the availability of these
medicines to patients. If there is a risk of product shortage after sampling,
replacement of the sampled amount should be arranged immediately after the
survey or, less desirably, collection of that particular product from that outlet
should be omitted.
For surveys seeking to determine the proportion of poor-quality
medicines sold to patients, data on product-specific sales volumes from the
outlets may be necessary. These data can be collected after sampling, especially
when the mystery-shopper approach is used, and sellers should be informed
about the survey. This approach requires the support of the NMRA as data on
sales volumes are better collected by inspectors or by officers of the authority.
5.6 Storage and transportation of samples

Storage and transportation of the samples to the testing laboratory should
be done according to the requirements set out in paragraph 2.3 of WHO
Guidelines for sampling of pharmaceutical products and related materials (17).
Transportation should be as quick and direct as possible so as not to jeopardize
the quality of the collected samples.
The samples should be kept in their original packaging and stored
under the conditions specified on the label; freezing should be

avoided and, where required, the cold chain should be maintained.
For transport, all samples should be packaged adequately and
transported in such a way as to avoid breakage and contamination.
Any residual space in the container should be filled with a
suitablematerial.
For temperature-sensitive medicines, temperature data loggers
may be included within shipments to document maintenance of an
appropriate temperature during prolonged transit.
A covering letter, copies of sample collection forms and, if available,
copies of the manufacturers batch certificate of analysis should
accompany the samples.
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Where collectors do not transport samples directly to the testing

laboratory, samples, with the accompanying documents, should be
sent by a courier service. The documentation with each shipment
should clearly indicate that the samples are being sent for laboratory
testing purposes only, will not be used on humans or animals, have
no commercial value and will not be placed on the market. If the
country where the laboratory is located requires permission for
importation of samples, the laboratory or NMRA of that country
may be able to assist to avoid long clearance procedures. The staff
of the testing laboratory should be informed of the shipment and
provided with the tracking number assigned by the courier service
to enable them to follow the shipment and arrange collection as
soon as possible.
Copies of sample collection forms and, if available, copies of
manufacturers batch certificates of analysis should also be sent
to the principal survey coordinator or the person preparing the
surveyreport.
5.7 Testing
5.7.1 Testing laboratory
It is important that only quality control laboratories with demonstrated capability
to produce reliable test results are used in quality surveys. Therefore laboratories
for testing should be carefully selected and should meet the following criteria:
the laboratory works in compliance with WHO Good practices for
pharmaceutical quality control laboratories (13), is preferably a WHO
prequalified 4 laboratory or is a laboratory where other evidence of
equivalent working standards is available;
the laboratory is capable and competent to perform the tests
required by the testing protocol;
the laboratory should have sufficient capacity and should agree to
test the required number of samples within the specified period for
the cost specified according to the available budget.
The choice of the testing laboratory or laboratories should be explained
in the survey protocol, reports and publications. One or more laboratories may
be used for testing the samples collected during the survey. If several laboratories
are testing collected samples, samples should be divided in such a way that all
The list of WHO-prequalified laboratories can be found at www.who.int/prequal.

4
249
samples containing the same APIs are assigned for testing to the same laboratory.
Many countries do not have a fully functioning quality control laboratory and
should consider making arrangements with a laboratory abroad. The appropriate
arrangements with the laboratory have to be made in advance.
Within the usual selection procedure and the resulting agreement the
following should be clearly specified in addition to the usual elements of such
agreements (such as deadlines and financial arrangements):
medicines and numbers of samples to be tested, tests to be
conducted and specifications to be used, according to the testing
protocol. If more than one testing laboratory is selected, a specific
testing protocol should be prepared for each laboratory;
responsibilities of the laboratory during the survey as specified in
section 5.7.4;
confidentiality declaration made by the laboratory;
acceptance of a possible audit of the laboratory, access to records
and retained samples.
Following conclusion of the agreement(s), the principal survey
coordinator should inform the local coordinators in the areas, regions or
countries participating in the survey about the following:
name and address of the laboratory or laboratories;
the contact person(s) in the laboratory; and
medicines assigned for testing to the particular laboratory.
The laboratory normally starts testing only when all the samples
containing the same API in the same dosage form have been received. Therefore
it is important to set and adhere to the deadline for sending samples to the
testing laboratory.
5.7.2 Tests to be conducted

Laboratory testing of all collected samples should be performed according to
the testing protocol, which is a part of the survey protocol, and should be agreed
with the testing laboratory or laboratories. Depending on the survey objectives,
target medicines and available resources, the tests to be done on samples
collected in the survey may include:
verifying the identity;
performing complete pharmacopoeial or analogous testing;
performing special or specific tests.
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If testing is expected to provide a full picture of the quality of target

medicines, it should be performed according to a pharmacopoeial or analogous
monograph and the following tests are, in principle, included:
appearance, visual inspection;
identity;
assay for APIs declared on the label;
test for related substances;
for solid dosage forms dissolution or disintegration, uniformity
of dosage units (by mass or content), fineness of dispersion, for
dispersible tablets;
for liquid dosage forms pH value and volume in containers or
extractable volume;
for parenteral products sterility and bacterial endotoxins tests.
Inclusion of tests for uniformity of content for single-dose dosage forms,
or for sterility and bacterial endotoxins, which are costly and time consuming,
and necessitate the collection of more dosage units, should be considered
in relation to the target medicines and available resources. It is impossible to
achieve 100% certainty about sterility of the product through testing only and
inspections and enforcement of compliance with GMP principles may be more
efficient tools for verification in some cases.
The packaging of each collected sample, labelling and package leaflets
should be inspected visually for any signs of being an SFFC product. The World
Health Professionals Association has published a checklist that may be used for
this purpose (21). Laboratory analysis is not always successful in identifying
falsified or substandard medicines and any suspicious product that is identified
should be further examined in cooperation with the NMRA in the country of
collection and the manufacturer declared on the label of the suspicious sample
(for guidance on conducting such investigations see the WHO guidelines5).
Information on labels and in package leaflets can also be checked
for quality and completeness of essential information, and compliance with
requirements and approved product information in the country of collection can
be verified. However, when more than one country is involved in the survey, it
should be kept in mind that requirements for information to be provided on
medicines labels and package leaflets may differ between countries.
Testing of suspect substandard/spurious/falsely-labelled/falsified/counterfeit medicines (QAS/15.634)

5
(draft in preparation).
251
Screening methods do not provide a full picture of the quality of

medicines and may be more likely to underestimate non-compliant findings
than laboratory testing methods (1). However, they do enable testing of a
large number of samples in the field, e.g. to search for SFFC medicines. It is
recommended that outcomes of screening are verified by laboratory testing, at
least for a random selection of those samples that pass screening and for all
those that fail.
5.7.3 Test methods and specifications

Test methods and specifications should be selected in the way that will best serve
the survey objectives. In general, when samples from different manufacturers
are collected in a quality survey, all samples containing the same APIs in the
same dosage form are tested using the same method and specification to enable
comparison of samples from different manufacturers. This specification is then
used to decide on compliance or non-compliance of tested samples for the
purposes of the survey. It should be noted that individual manufacturers may
use different specifications and different methods for testing of their products
and those specifications and methods may be approved by regulatory authorities
in the countries concerned. Non-compliance with the specification selected
for the survey does not therefore necessarily imply non-compliance with the
specifications approved in the country but it indicates to the respective NMRA
the need to look at the product and conditions of regulatory approval more
closely and discuss these with the manufacturer or registration holder.
Wherever appropriate, pharmacopoeial methods and specifications
should be used. A national pharmacopoeia may be applicable if a survey is
organized in one country. If several countries are involved, widely accepted
pharmacopoeias (such as the British Pharmacopoeia, European Pharmacopoeia,
The International Pharmacopoeia or the United States Pharmacopeia) may be
appropriate. In spite of efforts to harmonize pharmacopoeias there are still many
differences between them. When a monograph for the particular medicine being
tested is available in more than one pharmacopoeia the ability of the different
methods and specifications to reveal quality problems should be considered and
the monograph selected accordingly. Suitability of test methods for the intended
use should be appropriately verified.
If no monograph for the target medicine exists in a pharmacopoeia or
the existing monographs do not cover the desired tests, a validated method
ofthe laboratory should be used.
When samples from one manufacturer only are tested in a survey,
that manufacturers methods and specifications can be used, if available to the
testing laboratory. The performance of such methods under the conditions of
the testing laboratory should be verified.
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If samples suspected of being an SFFC product are tested, pharmacopoeial

methods may not be sufficient and further examination should be conducted
(for guidance on such investigations see WHO guidelines6).
Once the tests to be performed and the methods and specifications to
be used have been selected, the testing protocol should be finalized. For each of
the target medicines the protocol should contain the list of tests to be conducted,
reference to methods to be used and specifications to be employed. Examples
of testing protocols used for surveys organized by WHO can be found in the
published survey reports.7
5.7.4 Receipt and testing of samples by a testing laboratory

When samples are received, the testing laboratory should:
inspect each sample to ensure that the labelling is in conformity
with the information provided in the sample collection form
or test request; an electronic databank (e.g. scanned pictures or
photographs of the medicines, e.g. of the tablets, packaging and
package leaflet) is recommended;
store the samples according to the conditions set out on the product
labels, including compliance with any cold chain requirements;
conduct quality testing in line with the testing protocol and in
compliance with WHO Good practices for pharmaceutical quality
control laboratories (13), including appropriate verification of test
methods, investigation and documentation of each OOS result
according to the laboratory standard operating procedure. If the
OOS result is confirmed, it should be reported without delay to the
principal survey coordinator who should receive both the results
and the investigation report;
prepare complete analytical test reports and certificates of analysis
containing the information listed in Appendix 2. The principal
survey coordinator should define the format of the outcome (e.g.
separately for each sample or as a tabulated report);
keep document(s) received with the samples, records of testing
of each sample including all raw data, and retention samples
according to the requirements defined by the principal survey
6
Testing of suspect substandard/spurious/falsely-labelled/falsified/counterfeit medicines (QAS/15.634)
(draft in preparation).
7
For details of the various studies carried out using the protocol referred to, see:
http://apps.who.int/prequal/
253
coordinator (e.g. for at least six months if the sample complied

with the specifications, or for at least one year or until the expiry
date (whichever is longer) if it did not comply) and archive data
according to the agreed conditions.
6. Data management and publication

To allow proper interpretation, the data obtained during collection and testing
of samples should be summarized and appropriately organized in a database
(using Excel sheets or software for epidemiological studies), linking each sample
with all the data gathered and ensuring consistency and security. Suitable
precautions should be taken to avoid errors. For analysis of large sets of data,
statistical software may be used. If relevant, personal identification of individuals
who participated in the survey (e.g. buyers and sellers) should be entered in the
database using codes only.
The NMRAs of countries involved in the survey should be informed
immediately about confirmed OOS results. NMRAs should carry out their
investigations with the involvement of the relevant manufacturer, registration
holder or other party (e.g. procurement organizations). It should be kept in mind
that if the testing methods and specifications approved during the registration
process differ from those used in the survey, it may be necessary to retest the
product concerned using the approved manufacturers method, where available.
Appropriate measures should be taken to ensure the accuracy of the results.
Once survey results have been compiled, evaluated and summarized they
should be shared with the NMRAs involved as they may provide information
on medicine quality problems that will alert NMRAs and manufacturers.
Before publication of the results, it is useful to hold a meeting with appropriate
stakeholders to discuss the results and the actions needed. The WHO Rapid
Alert System should be informed when results are considered to constitute a
public health emergency.

A detailed survey report should be prepared that includes all test results
on the collected samples together with their interpretation. An example outline
for the survey report content is provided in Appendix 3. Recommendations for
items to be addressed in the reports of medicines quality surveys can also be
found in the published literature (22).
The report should be published as widely and openly as possible. The
conclusions and wording should be prepared with caution so as not to cause
embarrassment or panic. The risk that patients will stop taking genuine
medicines and that the public will lose faith in medicines or the health-care
system should be reduced by careful wording. Also any potential harm that
might be caused to manufacturers, suppliers or outlets should be considered to
avoid any legal actions.
254
Annex 7
References
1. Survey of the quality of selected antimalarial medicines circulating in six countries of sub-Saharan
Africa. Geneva: World Health Organization; 2011 (http://www.who.int/prequal/info_applicants/
qclabs/monitoring_documents/WHO_QAMSA_report.pdf, accessed 25 November 2015).
2. United States Pharmacopeia Drug Quality and Information Program. Survey of the quality of
selected antimalarial medicines circulating in Madagascar, Senegal, and Uganda November
2009. Rockville (MD): The United States Pharmacopeial Convention; 2010 (http://www.usp.org/
worldwide/dqi/resources/technicalReports, accessed 25 November 2015).
3. Newton P, Proux S, Green M, Smithuis F, Rozendaal J, Prakongpan S, et al. Fake artesunate in
Southeast Asia. Lancet. 2001;357(9272):194850.
4. Dondorp AM, Newton PN, Mayxay M, Van Damme W, Smithuis FM, Yeung S, et al. Fake antimalarials
in Southeast Asia are a major impediment to malaria control: multinational cross-sectional survey
on the prevalence of fake antimalarials. Trop Med Int Health. 2004; 9(12):12416.
5. Cochran WG. Sampling techniques, second edition. New York: John Wiley and Sons; 1963.
6. Yamane T. Statistics: an introductory analysis, second edition. New York: Harper and Row; 1967.
7. Sengaloundeth S, Green MD, Fernndez FM, Manolin O, Phommavong K, Insixiengmay V. A
stratified random survey of the proportion of poor-quality oral artesunate sold at medicine
outlets in the Lao PDR implications for therapeutic failure and drug resistance. Malar J.
2009;8:172. doi: 10.1186/1475-2875-8-172.
8. Onwujekwe O, Kaur H, Dike N, Shu E, Uzochukwu B, Hanson K, et al. Quality of anti-malarial drugs
provided by public and private healthcare providers in south-east Nigeria. Malar J. 2009;8:22. doi:
10.1186/1475-2875-8-22.
9. Kaur H, Goodman C, Thompson E, Thompson KA, Masanja I, Kachur SP, et al. A nationwide survey
of the quality of antimalarials in retail outlets in Tanzania. PLoS One. 2008;3(10):e3403.
10. Khojah HMJ, Pallos H, Yoshida N, Akazawa M, Tsuboi H, Kazuko K. The quality of medicines in
community pharmacies in Riyadh, Saudi Arabia. A lot quality assurance sampling (LQAS)-based
survey. Pharmacol Pharm. 2013;4(7):5119. doi: 10.4236/pp. 2013.47074.
11. Lemeshow S, Taber S. Lot quality assurance sampling: single- and double-sampling plans. World
Health Stat Q. 1991;44(3):11532.
12. Phanouvong S. Mekong Malaria Initiative. Antimalarial drug quality monitoring and evaluation.
Indicators. Rockville (MD): United States Pharmacopeia Drug Quality and Information Program;
2004 (http://pdf.usaid.gov/pdf_docs/pnadh147.pdf, accessed 25 November 2015).
13. Good practices for pharmaceutical quality control laboratories. In: WHO Expert Committee
Organization; 2010: Annex 1 (WHO Technical Report Series, No. 957 (http://www.who.int/prequal/
info_general/documents/TRS957/GPCL_TRS957_Annex1.pdf, accessed 25 November 2015).
14. United Nations Office on Drugs and Crime. Guidelines on representative drug sampling for use
by national drug analysis laboratories. New York: United Nations; 2009 (http://www.unodc.org/
documents/scientific/Drug_Sampling.pdf, accessed 25 November 2015).
15. Scientific working group for the analysis of seized drugs (SWGDRUG). Recommendations. United
States Department of Justice Drug Enforcement Administration; 2011 (http://www.swgdrug.org/
Documents/SWGDRUG%20Recommendations%206.pdf, accessed 25 November 2015).
16. Hoffman CG, Frank RS, Hinkley SW. Representative sampling of drug seizures in multiple
containers. ASTM International. 1991;36(2).
255
17. WHO guidelines for sampling of pharmaceutical products and related materials. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations: thirty-ninth report. Geneva: World
18. Madden JM, Quick JD, Ross-Degnan D, Kafle KK. Undercover careseekers: Simulated clients in the
study of health provider behavior in developing countries. Soc Sci Med. 1997;45(10):146582.
19. ACTwatch. Outlet survey. Kingdom of Cambodia. 2011 Survey Report. Washington (DC): Population
Services International; 2011 (http://www.actwatch.info/sites/default/files/content/outlet-reports/
ACTwatch%20Cambodia%20OS%20Endline_2011.pdf, accessed 25 November 2015).
20. Survey of the quality of anti-tuberculosis medicines circulating in selected newly independent
states of the former Soviet Union. Geneva: World Health Organization; 2011 (http://www.who.
int/prequal/info_applicants/qclabs/monitoring_documents/TBQuality-Survey_Nov2011.pdf,
accessed 25 November 2015).
21. Be aware. Tool for visual inspection of medicines. Ferney Voltaire: World Health Professions
Alliance (http://www.whpa.org/Toolkit_BeAware_Inspection.pdf, accessed 25 November 2015).
22. Newton PN, Lee SJ, Goodman C, Fernndez FM, Yeung S, Phanouvong S, et al. Guidelines for field
surveys of the quality of medicines: A proposal. PLoS Med. 2009;6(3):02520257.
256
Annex 7
Appendix 1
Example of a sample collection form1
SURVEY TITLE
Area/region/country: Sample code:
(Area/region/country code/medicine abbreviation/
sequence number/sampling date dd/mm/yy)2
Name of location/place where sample was taken:
Address (with telephone, fax number and email address, GPS coordinates, if
applicable):
Organization and names of people who collected the sample:

1.
2.
Product name of the sample:
Name of active pharmaceutical ingredient(s) (INN) with strength:
Dosage form (tablet, injection, powder for injection, etc.):

Package size, type and packaging material of the container:
Batch/lot number:
Date of manufacture: Expiry date:
Regulatory status in the country, registration number if applicable:
Name and address of the manufacturer:
The sample collection form should always be kept with the collected sample.
1
Area/region/country code: e.g. for countries, the two-letter code is used for the Internet country top-
2
level domains; medicines abbreviations to be established; sample code system can be extended to be
appropriate for a collection system in a particular area, region or country.
257
Quantity collected (number of tablets/ampoules/vials and number of packages):
Initial first page:

Product name: Sample code:
Date the batch was received at the location:
Storage and climatic conditions at sampling site:
Conditions controlled? Yes No
Temperature and humidity in the place where the sample was stored at the
time of sample collection:
Comments on suitability of premises where products are stored, abnormalities,

remarks or observations that may be considered relevant, if any:
Date:
Signature of person(s) taking Signature of representative of the

samples facility where sample was taken
(only for overt sampling, optional)
1.
2.
Note: Samples collected must remain in their original primary and secondary
packaging, intact and unopened.
258
Annex 7
Appendix 2
Content of the analytical test report/certificate of analysis
Name and address of the laboratory performing the sample testing
Name and address of the originator of the request for testing
Number/code of the analytical test report/certificate of analysis
Sample reference number assigned by the laboratory and sample
code assigned at the time of sampling (specified in the sample
collection form and packages belonging to one sample)
Date on which the sample was received
Name of the area, region or country where the sample was collected
Sample product name (trade name as it appears on the label), dosage
form, APIs, strength, package size (e.g. number of tablets in one
blister and number of blisters in the secondary packaging, volume in
one ampoule and number of ampoules in secondary packaging)
Description of the sample (describing both the product and the
primary and secondary packaging, type and packaging material of
primary container); if there is any sign of unsatisfactory handling
during transportation, this should be mentioned
Batch number of the sample, expiry date and, if available, date
ofmanufacture
Number of units received for the sample
Name and full address of the manufacturer (as specified on the label
or in the package leaflet)
Reference to the specifications used for testing the sample, including
the limits
If a reference substance was used for quantitative determination, this
substance should be specified (e.g. The International Pharmacopoeia,
British Pharmacopoeia or United States Pharmacopeia reference
substance or working standard)
Results of all the tests performed; for the evaluation and
interpretation of results it is useful to request numerical results
wherever possible, any observation made during testing, and the
following details:
for content uniformity, all results for individual units,
for dissolution test, results for all tablets tested,
259
for assay, results of each individual sample preparation (usually

3 sample preparations), the average and the relative standard
deviation; in the case of an OOS result followed by retesting, also
the investigation report and results of retesting
Conclusion as to whether or not the sample complies with the
specifications set for the survey
Date on which the test was completed
Signature of the head of the laboratory or authorized person
260
Annex 7
Appendix 3
Outline of the content of a survey report
Glossary and abbreviations

Executive summary
1. Introduction
1.1 Background
1.2 Objectives of the survey
2. Methodology
2.1 Survey period
2.2 Selection of medicines for sampling and testing
2.3 Selection of areas, regions or countries
2.4 Sampling design and selection of sample collection sites
2.5 Sample collection and transportation
2.6 Testing laboratories
2.7 Quality tests performed and test methods and specifications used
2.8 Definition of compliance of samples with standards
3. Results
3.1 Overview of samples collected
3.1.1 Medicines
3.1.2 Manufacturers and batches
3.1.3 Sites of sample collection
3.1.4 Storage and transportation conditions
3.2 Registration status of sampled products
3.3 Compliance with specifications
3.3.1 Overall results
3.3.2 Results of specific quality tests for individual products
4. Discussion
4.1 Testing methods and data quality
4.2 Limitations of methodology
4.3 Interpretation of the results
4.4 Recommendations
5. Conclusions
6. Other information (conflict of interests, funding)
References
Attachments Detailed test results tabled for individual samples
261
Annex 8
Collaborative procedure between the World Health
Organization (WHO) Prequalification Team and national
regulatory authorities in the assessment and accelerated
national registration of WHO-prequalified pharmaceutical
products and vaccines
1. Definitions 264
2. Background information 265
3. Principles of collaboration 267
4. Steps in the collaboration for national registration of a
pharmaceutical product or a vaccine 274
5. Collaboration mechanisms for post-prequalification and/or
post-registration variations 279
6. Withdrawals, suspensions or delistingsof prequalified
pharmaceutical productsorvaccines and national deregistrations 280
References 281
Appendix 1 National regulatory authority participation agreement and undertaking
for national regulatory authority focalpoint(s) 282
Appendix 2 Consent of WHO prequalification holder for WHO to share information
with the national regulatory authority confidentially under the Procedure 292
Appendix 3 Expression of interest to national regulatory authority (NRA) in the
assessment and accelerated national registration, acceptance by NRA and
notification of Procedure outcomes 295
Appendix 4 Report on post-registration actions in respect of a product registered
under the Procedure 303
263
1. Definitions
Collaborative procedure (Procedure)1
Procedure for collaboration between the World Health Organization (WHO)
Prequalification Team (WHO/PQT) and interested national regulatory authorities
(NRAs) in the assessment and accelerated national registration of WHO-
prequalified pharmaceutical products and vaccines.
Participating authorities or participating NRAs

NRAs that voluntarily agree to implement this collaborative procedure and
accept the task of processing applications for registration of WHO-prequalified
pharmaceutical products and vaccines in accordance with the terms of the
Procedure. A list of participating authorities is posted on the WHO/PQT
website (for pharmaceutical products at http://www.who.int/prequal/, and
for vaccines at http://www.who.int/immunization_standards/vaccine_quality/
expedited_review/en/).
Pharmaceutical product
Any substance or combination of substances marketed or manufactured to be
marketed for treating or preventing disease in human beings, or with a view
to making a medical diagnosis in human beings, or to restoring, correcting or
modifying physiological functions in human beings.
Vaccine
A vaccine is a biological preparation that improves immunity to a particular
disease. A vaccine typically contains an agent that resembles a disease-
causing microorganism and is often made from weakened or killed forms of
the microbe, its toxins, one of its surface proteins or genetically-engineered

material. The agent stimulates the bodys immune system to recognize the
agent as foreign, destroy it and remember it, so that the immune system
can more easily recognize and destroy any of these microorganisms that it
laterencounters.
Collaborative procedure between the World Health Organization (WHO) Prequalification of Medicines
1
Programme and national medicines regulatory authorities in the assessment and accelerated national
registration of WHO-prequalified pharmaceutical products appeared as Annex 4 (WHO Technical Report
Series, No. 981, 2013).
264
Annex 8
2. Background information
National assessment of applications for registration of pharmaceutical products
and vaccines (marketing authorization) is the key regulatory process that enables
NRAs to evaluate and monitor the quality, safety and efficacy of pharmaceutical
products and vaccines. For most countries the approach to registration of
pharmaceutical products and vaccines is a combination of two components:
the NRAs own assessment of application documentation combined
with verification of compliance with relevant good practices by
inspections (mostly focusing on good manufacturing practices
(GMP) and inspections of manufacturing sites) and testing of
product characteristics when applicable;
consideration by the NRA of decisions and outcomes of assessments
and inspections made by NRAs in other countries, and for vaccines
also official batch release by the national control laboratory
performing the oversight of the vaccines.
Consideration of the outcomes of assessments and inspections by
authorities, whose regulatory decisions are based on acceptable standards,
substantially contributes to savings in regulatory resources and improvements
in the quality of regulatory decisions, while retaining the prerogative of NRAs
to conclude their assessment by sovereign decisions, which reflect their own
judgement of the benefitrisk balance as it relates to their specific country
situation and the legislation in place. Taking into consideration the regulatory
decisions of other NRAs requires setting up a system that will permit:
identification of reference authorities whose regulatory decisions
are based on acceptable standards and identification of documents
associated with such regulatory decisions, which are relevant to
the regulatory environment in the country wishing to rely on
suchdecisions;
assurance that the product for which the decision has been taken by
the reference NRA is the same (see section 3.2) as the product being
assessed or, if it is not the same, that a clear understanding exists of
the differences between the products subjected to assessment in the
two regulatory environments;
efficient use of available scientific expertise and human and financial
resources to decide, with reasonable certainty, on the benefitrisk
profile of an evaluated product when used in a given country;
the choice by each NRA of the approaches that will make best use of
the resources, workload and competence of individual NRAs.
265
Approaches could range from completely independent data reviews and

inspections to adoption of regulatory decisions of reference authorities without
any further scientific review. A pragmatic approach is to verify whether the
product submitted for registration is the same (see section 3.2) as the product
already prequalified and assess only those areas which relate to use of the product
in the country concerned and where failure to comply with regulatory standards
could pose health risks (e.g. stability data). In the other areas, the outcomes of
reference authorities may be adopted.
To enhance timely access to prequalified products in countries, to ensure
that the product in countries is the same as the one which is prequalified and
to provide a model for regulatory information exchange among countries, this
Procedure has been developed based on the above-mentioned considerations.
In line with the Procedure for prequalification of pharmaceutical products (1) and
the Procedure for assessing the acceptability in principle of vaccines for purchase
by United Nations agencies (2) it aims to provide a convenient tool for NRAs
wishing to enhance their premarketing evaluation and registration system by
taking advantage of the scientific assessment work conducted by WHO/PQT.
For pharmaceutical products the present procedure is complementary to the
WHO/PQT collaborative procedure with NRAs in inspection activities (http://
www.who.int/prequal, Inspections).
The collaborative procedure was first piloted in June 2012 and is
currently in use for pharmaceutical products (http://www.who.int/prequal,
Collaborative Registration). For vaccines another procedure for expedited
review of imported prequalified vaccines for use in national immunization
programmes was published in 2007 and has been implemented for national
registrations since 2010. However, this procedure did not include collaborative
arrangements with the NRAs. In 2010 WHO/PQT piloted an expedited
registration procedure that involved sharing of the WHO/PQT assessment
reports with the NRAs.
Enhanced collaboration and information exchange between NRAs

and WHO/PQT benefits all partners. Subject to the agreement of the WHO
prequalification (PQ) holders concerned, NRAs have access to assessment
outcomes that are not in the public domain and that have been prepared in
conformity with the WHO recommended standards on which the Procedure for
prequalification of pharmaceutical products (1) and the Procedure for assessing
the acceptability in principle of vaccines for purchase by United Nations agencies
(2) are based. Such reports and relevant WHO documents help NRAs to make
their decisions and also assist in training national regulatory staff. At the same
time, feedback from NRAs on the information and documentation received
from WHO/PQT under the Procedure allows WHO/PQT to improve its work
and ensures that the outcomes of its assessments are relevant to NRAs. As a
consequence patients and vaccinees benefit from this collaboration by gaining
266
Annex 8
faster access to pharmaceutical products and vaccines that have been found
acceptable in principle for procurement by United Nations (UN) agencies.
The collaborative registration procedure can be of particular relevance when
implemented for pharmaceutical products and vaccines in emergency situations.
Depending on available resources, participating authorities have the
opportunity to participate in the assessment process and in inspections organized
by WHO/PQT.
This collaborative procedure also benefits manufacturers of prequalified
pharmaceutical products and vaccines through faster and better harmonized
regulatory approvals in participating countries. This Procedure, when combined
with the WHO/PQT collaborative procedure with NRAs in inspection activities,
alleviates the burden of additional national inspections on manufacturers.
3. Principles of collaboration
3.1 This collaborative procedure is applicable to:
pharmaceutical products that have been assessed and inspected by
WHO/PQT in line with the procedures and standards available at
www.who.int/prequal (Information for applicants) and have been
found to be acceptable in principle for procurement by UN agencies
as listed in the List of WHO prequalified medicines, available at www.
who.int/prequal. The Procedure is not applicable to pharmaceutical
products that have been listed as prequalified on the basis of
approval by stringent regulatory authorities (SRAs).2 For such
products the principal part of the assessment has been performed
by SRAs and WHO/PQT is not in possession of assessment and
inspection reports that can be shared;
vaccines that have been assessed and inspected by WHO/PQT in
line with the procedures and standards available at http://www.
who.int/immunization_standards/vaccine_quality/pq_system/en/
and have been found to be acceptable in principle for procurement
by UN agencies as listed in the List of WHO prequalified vaccines,
available at http://www.who.int/immunization_standards/vaccine_
quality/PQ_vaccine_list_en/en/. This Procedure is applicable to
Products listed as prequalified according to the procedure described in the Guidelines on submission
2
of documentation for prequalification of finished pharmaceutical products approved by stringent

regulatory authorities. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations:
forty-eighth report. Geneva: World Health Organization; 2014: Annex 5 (WHO Technical Report Series,
No. 986).
267
vaccines that successfully passed either the standard or streamlined

prequalification process: http://www.who.int/immunization_
standards/vaccine_quality/pq_revision2010/en/).
Although the Procedure mostly serves to accelerate the assessment and
registration of prequalified multisource (generic) pharmaceutical products it is
applicable to vaccines and any pharmaceutical product for which the safety and
efficacy has been documented to WHO/PQT by the submission of preclinical
and clinical data.
The Procedure has three major stakeholders: WHO/PQT, interested
NRAs and those WHO PQ holders or applicants 3 who agree that this Procedure
is used for applications for national registration of their WHO-prequalified
product submitted to an NRA.
3.2 WHO/PQT and participating authorities receive applications for the same
pharmaceutical product or vaccine. Within the context of this Procedure,
the same pharmaceutical product or same vaccine is characterized by:
the same product dossier; 4
the same manufacturing chain, processes, control of materials and
finished product, and in the case of vaccines also by the same batch
release scheme;
the same active ingredient and finished product specifications;
the same essential elements of product information for
pharmaceutical products,5 in the case of vaccines by the same
product information, packaging presentation and labelling.
3
If the applicant for national registration is not the same as the WHO PQ holder, the WHO PQ holder must
confirm to the NRA and WHO/PQT by an authorization letter (as per the template annexed to Appendix 3,
Part A) that the applicant is acting for, or pursuant to rights derived from, the WHO PQ holder and that
the WHO PQ holder agrees with the application of the procedure in the country concerned.
4
Submission of dossiers in common technical document (CTD) format as required by WHO/PQT is
considered a standard. In exceptional situations data can be organized differently in line with specific
national or WHO requirements; however, the technical data included in the dossier must be the
same. There may be country-specific differences in administrative data, or if required by NRAs under
exceptional circumstances, additional technical data can be provided (e.g. bioequivalence with a
country-specific comparator).
5
The essential elements of product information include in particular the indications, contraindications,
posology (dosing), special warnings and precautions for use, adverse reactions, storage conditions,
primary packaging and shelf life. Differences in brand name, the name of applicant or WHO PQ holder,
language, format and degree of detail of the product information, labelling of internal and external
packaging, among others, are not considered essential for the purposes of this Procedure. The language
of the product information may be different as long as the information content is the same as that
approved by WHO/PQT.
268
Annex 8
3.3 WHO/PQT, with the agreement of the WHO PQ holder, shares the full
outcome of prequalification assessments, inspections and, if relevant, also
results of laboratory testing, including final assessment and inspection
reports, with participating authorities, under appropriate obligations of
confidentiality and restrictions on use (see below).
As regards sharing the outcomes of assessments, inspections and
results of laboratory testing, only data owned by the WHO PQ holder and
WHO are shared. Sharing of any other data (e.g. related to a closed part of
the Active pharmaceutical ingredient master file) is subject to additional
agreement of the data owners concerned.
3.4 For the purpose of this collaborative procedure, participating authorities
accept the product documentation and reports in the format in which
they are routinely prepared by WHO in accordance with the Procedure
for prequalification of pharmaceutical products (1) and the Procedure for
assessing the acceptability in principle of vaccines for purchase by United
Nations agencies (2). It should be noted, however, that participating
authorities may require applicants to comply with specific requirements
for local regulatory review. Each participating authority should make such
specific requirements public.
3.5 Fees to be paid by the applicants to participating authorities continue
to follow standard national procedures. Similarly, the submission by
manufacturers of samples for laboratory testing if required continues
to follow standard procedures as defined in national legislation and/
or as defined by NRAs. Participating authorities are advised to refrain
from preregistration laboratory testing. Results from the laboratory
testing organized in the course of prequalification assessment or
inspections will be included in the information package available to each
participating authority.
3.6 Consistent with the terms of Appendix 1, Part A and Appendix 3, Part B,
each participating authority commits itself:
to treat any information and documentation provided to it by WHO/
PQT pursuant to this Procedure as confidential in accordance
with the terms of Appendix 1, Part A, and to allow access to such
information and documentation only to persons 6
This includes the focal point(s) and all other persons in the NRA who have access to any information and
6
documentation provided by WHO/PQT.

269
who have a need to know for the purpose of the assessment and
accelerated registration of the product in question in the country
and any post-registration processes that may be required,
who are bound by confidentiality undertakings in respect of such
information and documentation which are no less stringent than
those reproduced in Appendix 1, Part A;
to issue its national regulatory decision on registration of a given

prequalified product (whether positive or negative) within 90
calendar days 7 of regulatory time.8 If the applicant takes a long
time to complete missing parts of the documentation without any
justification, to provide additional data or to respond to other
queries raised by NRAs, or if the applicant fails to provide the NRA
with necessary information and cooperation, the NRA is entitled
to terminate the Procedure and switch to the normal registration
process. Such termination is communicated to the applicant and to
WHO/PQT using Appendix 3, Part C.
These commitments are provided by each participating authority
to WHO/PQT in writing by entering into the agreement for participation
in this Procedure as reproduced in Appendix 1, Part A and are reconfirmed
for each pharmaceutical product or vaccine for which collaboration is
sought (see Appendix 3, Part B).
Each participating NRA nominates a maximum of three focal
points and specifies their areas of responsibility (inspections, assessment
of pharmaceutical products, assessment of vaccines). These focal points
will access the restricted-access website through which WHO/PQT will
communicate all confidential information and documentation. Upon
7
Participating authorities should issue their national regulatory decisions at the earliest opportunity after
being given access to the confidential information and documentation on a given prequalified product.
Although a time limit of 90 days of regulatory time is defined in the Procedure, the decision should
normally be taken within 60 days. This deadline can be extended to a maximum of 90 days if predefined
dates of technical or decision-making meetings do not allow a participating authority to issue its decision
within 60 days. If a participating authority does not issue its decision within 90 days of regulatory time
and does not communicate valid reasons for the delay to WHO/PQT, WHO/PQT can follow up with the
head of the NRA to clarify the situation. The timeline should be reduced as much as possible to facilitate
access to products needed in case of emergency situations.
8
Regulatory time starts after a valid application for the registration according to the Procedure has been
received and access to the confidential information has been granted (whichever is the later) and
continues until the date of decision on registration. The regulatory time does not include the time granted
to the applicant to complete missing parts of the documentation, provide additional data or respond to
queries raised by NRAs.
270
Annex 8
justified request of an NRA to WHO/PQT, the number of focal points can

be increased.
Focal points designated by the NRA must sign the undertaking
reproduced in Appendix 1, Part B before they will be granted access to
the restricted-access website. Any change in designated focal points must
be communicated to WHO/PQT in writing without delay and must be
accompanied by an undertaking (Appendix 1, Part B) signed by the new
focal point(s).
3.7 The decision whether or not to register a given product in a particular
country remains the prerogative and responsibility of each participating
authority. Accordingly a participating authority may come to a different
conclusion from that reached by WHO/PQT or can decide to discontinue
the Procedure for a specific product. Within 30 calendar days of having
taken its decision, the participating authority reports this decision to
WHO/PQT, together with the dates of submission and registration
and, if applicable, any deviations from the WHO/PQTs decision on
prequalification and the reasons for such deviations 9 and/or any decision
to discontinue the Procedure for a specific product. It does so through the
restricted-access website by completing the form in Part C of Appendix 3
or providing the same information in another format. The NRA provides a
copy of the completed form or the information to the applicant.
3.8 Participation by WHO PQ holders/applicants is voluntary, through the
submission to a participating NRA of the expression of interest reproduced
in Part A of Appendix 3. For each product such participation will be subject
to the WHO PQ holder/applicant accepting the terms of this Procedure,
including the confidential exchange of information and documentation
between WHO/PQT and the NRA (see Appendix 2).
The WHO PQ holder/applicant can cease participation in this
Procedure at any time provided that he or she informs WHO/PQT and
the participating NRAs in writing of his or her decision. In such a case
the NRA shall cease all use of the information disclosed to it for the
respective product(s) as per the terms of the participation agreement (see
Appendix1).
This refers to a decision not to approve the registration of a WHO-prequalified product and to a decision
9
to approve the registration, but with deviations in indications, contraindications, posology (dosing),
special warnings and precautions for use, adverse drug reactions, storage conditions and shelf life. For
pharmaceutical products differences in brand name, name of applicant or WHO PQ holder, format of
product information, level of detail of product information, labelling of internal and external packaging
and language of product information are not considered to be deviations from the PQ conclusions.
271
3.9 The requirements and procedures in case of a variation (as defined in WHO
guidelines (3)) may differ between NRAs and WHO/PQT. The present
collaborative procedure includes a variation procedure (see section 5)
which is aimed at promoting consistency between variations accepted by
WHO/PQT and variations accepted by participating authorities. There
could be situations in which a manufacturer of a WHO-prequalified
product submits a variation application to a participating authority and
not to WHO/PQT or vice versa. In such a case the conditions of the
national registration, which were initially harmonized with the WHO
PQ decision, may become essentially different through the product life
cycle. In such a case a product registered and procured in a participating
country would no longer be the same as the WHO-prequalified product
because the specifications, manufacturing sites and/or other essential
parameters would no longer be the ones accepted by WHO/PQT. The
WHO PQ holders/applicants and NRAs are expected to inform WHO/
PQT of the differences and the reasons for them, if, due to inconsistencies
in variations, the nationally-registered product is no longer the same as the
WHO-prequalified product.
As a result, applicants are required to submit to participating
authorities without delay, at the latest 30 calendar days after acceptance of
the variation by WHO/PQT, those variations which are subject to national
regulatory requirements. WHO/PQT will inform the NRAs that have
registered individual prequalified products, through the restricted-access
website, about variations to the prequalification status of such products
if and when regulatory action is deemed to be justified. Participating
authorities are encouraged to follow the outcomes of the WHO variation
procedures for nationally-approved WHO-prequalified products.
If a national variation procedure results in the nationally-
registered product being no longer the same (see section 3.2) as the
WHO-prequalified product, or in the event that a variation of a WHO-
prequalified product is not followed by the same variation of the nationally
registered product (in the case that the particular variation is subject to
national regulatory requirements), the participating authority informs
WHO/PQT of the situation by submitting the form in Appendix 4, clearly
specifying the deviations. The deadline for informing WHO/PQT is 30
days after the NRA has been informed by WHO/PQT about variation
outcome. The variation approved by WHO/PQT will be considered by
WHO/PQT as accepted by the NRA on a non-objection basis 30 days
after information-sharing, unless and until the NRA informs WHO/PQT
otherwise. Other participating NRAs, which have registered the WHO-
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Annex 8
prequalified product in question pursuant to this Procedure, will be

made aware of such deviations through the restricted-access website. In
addition, if the fact that a WHO-prequalified product has been registered
in a particular country pursuant to this Procedure has been made public,
any subsequent deviations should also be made public.
3.10 If a prequalified product is withdrawn by the WHO PQ holder, or is

suspended or delisted by WHO/PQT, WHO/PQT will inform each
participating authority that has approved, or is in the process of reviewing
the product pursuant to this Procedure, of the withdrawal, suspension or
delisting and the reasons for taking this action, through the restricted-
access website and subject to the obligations of confidentiality contained
in Appendix 1, Part A. Similarly, when an NRA deregisters or suspends
the registration of a prequalified pharmaceutical product or vaccine for
any reason, it will inform WHO/PQT of this decision and of its reasons
through the restricted-access website. Other participating NRAs which
have registered the WHO-prequalified product in question pursuant
to this Procedure will be made aware of such national deregistration
or suspension through the restricted-access website. In addition, if the
fact that a WHO-prequalified product has been registered in a country
pursuant to this Procedure has been made public, any subsequent
deregistration or suspension should also be made public by posting on the
WHO/PQT website.
3.11 Participation in this Procedure does not exempt applicants for national
registration and holders of national registration from the respective
national regulatory requirements. Participating authorities retain the
right to assess submitted data and organize site inspections to the
extent they deem appropriate. WHO encourages NRAs not to perform
repetitive assessment of thoroughly assessed data, but rather to focus
on data verification so that they can be assured that the same product
is submitted for registration as is prequalified. It is highly recommended
not to reinspect the sites that have already been inspected by WHO/PQT
inspection teams or by NRAs recognized by WHO as stringent and as
functional with respect to inspections of vaccine manufacturing sites.
3.12 Sharing of information related to the Procedure between WHO/PQT,

WHO PQ holders/applicants and NRAs is governed by Appendices 1, 2,
3 and 4. Completed Appendices 1 and 2 must be submitted to WHO/PQT
without any change in their content. Provision of Appendices 3 and 4 can
be substituted by provision of the same information by other means.
273
4. Steps in the collaboration for national registration

of a pharmaceutical product or a vaccine
4.1 The applicant submits the product dossier for a WHO-prequalified
pharmaceutical product or a vaccine to a participating NRA. The technical
part of the dossier is updated to reflect the data as approved by WHO/PQT
during the initial prequalification procedure, and consecutive variation
procedures and requalification (where applicable). The applicant must
provide the participating authority with:
an application dossier complying with established national
requirements, including the same technical information as that
approved by WHO/PQT. To the extent that national regulatory
requirements allow, the technical part of the dossier will be identical
to the current version of the WHO/PQT dossier.10 In specific cases
the NRA may prefer a dossier which is abbreviated in line with
national requirements;
an expression of interest reproduced in Part A of Appendix 3;
data and samples according to country-specific requirements;
any fees that may be payable to the NRA pursuant to national
requirements.
Wherever possible, to minimize the workload of the NRA and
facilitate the process, applicants should ensure that they express their
interest in using the Procedure (Appendix 3, Part A) to the NRA and to
WHO/PQT before submitting a national application for registration. If
acceptable to NRAs, not only should the technical content of the dossiers
be the same, but also the format in which data are presented should closely
follow the format in which dossiers are submitted to WHO/PQT, i.e.the
common technical document (CTD) format. In the case of vaccines

theproduct summary file format may be also applicable.
In situations where the applicant wishes to apply the Procedure
to an application which is already pending within the NRA, the applicant
should first update the dossier to ensure that the technical part of the
information is the same as that approved by WHO/PQT.
In the case of vaccines that are prequalified by the Streamlined procedure for vaccines with marketing
10
authorization/licensing granted by eligible NRAs (as defined in the Procedure for assessing the
acceptability, in principle, of vaccines, for purchase by United Nations agencies. In: WHO Expert Committee
on Biological Standardization: sixty-first report. Geneva: World Health Organization; 2013: Annex 6 (WHO
Technical Report Series, No. 978)) the submitted data should reflect essential data submitted to the NRA
that granted the authorization/licence and additional documents as provided to WHO.
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Annex 8
4.2 For each application under this Procedure, WHO/PQT is informed by

the WHO PQ holder/applicant about the submission to the participating
NRA by providing a completed copy of Appendix 3, Part A. The WHO
PQ holder provides WHO at this time with its written consent for WHO/
PQT to provide the product-related information in compliance with
the applicable confidentiality requirements to the NRA of the country
concerned (see Appendix 2).
4.3 The participating NRA informs WHO/PQT and the respective applicant of
each application which it accepts or declines to include in this Procedure
(Appendix 3, Part B). It is for the individual NRAs to decide whether to
apply the Procedure for individual submissions. The Procedure applies
only to applications that the NRA has accepted as complete.
4.4 Within 30 calendar days of receipt of the WHO PQ holders consent,
WHO/PQT shares the most recent product-related information and
assessment, inspection and laboratory-testing outcomes through the
restricted-access website with the participating authority. This information
is subject to the obligations of confidentiality and restrictions on use
and may include assessment report(s), variation assessment report(s) if
applicable, inspection report(s) of the most recent inspection(s), the letter
of prequalification or requalification and results of laboratory testing,
if applicable. At the request of the participating authority, WHO/PQT
provides explanations and/or more detailed information. If NRAs have
significant concerns or questions which would preclude the registration
of the prequalified pharmaceutical product or vaccine in their country,
questions may be sent to WHO/PQT, preferably within 60 calendar days
from the first day of the regulatory time. WHO/PQT will facilitate the
problem resolution in cooperation with relevant parties.
4.5 After receiving the information and documentation from WHO/PQT, the
participating authority undertakes an accelerated assessment of the product
in question. For each application, the participating authority is required to
issue the relevant national decision within 90 calendar days of regulatory
time.11 Within 30 days of having taken its decision the participating
authority reports this decision, together with an indication of the dates of
submission, registration and, if applicable, the length of the non-regulatory
time. The participating authority also reports any deviations from the
WHO PQ conclusion and the reasons for such deviations, or, if a decision
See footnote 7.
11
275
has been made to discontinue the Procedure for a product, the reasons for
such discontinuation, to WHO/PQT through the restricted-access website.
This report is provided to WHO/PQT using Part C of Appendix 3 and is
copied to the applicant. WHO/PQT lists pharmaceutical products and
vaccines registered according to this Procedure by participating NRAs on
its public website. The steps in the collaboration for national registration of
a pharmaceutical product or vaccine are summarized in Figure A8.1.
Figure A8.1
Flowchart showing the principal steps of the collaborative procedure
The NRA confirms to WHO/PQT its interest in participating in the Procedure and
nominates focal point(s) for access to the restricted-access website. The NRA
completes signs and submits to WHO/PQT the agreement reproduced in Appendix1,
Part A. The focal point(s) who are nominated to access the restricted-access website
complete and submit the undertaking reproduced in Appendix 1, Part B, to WHO/PQT.
Appendix 1, Part A and Appendix 1, Part B
WHO/PQT lists the participating NRAs on its public website.
Registration process
The applicant submits the application for national registration of the WHO-
prequalified pharmaceutical product or vaccine to the participating authority and
informs the authority of its interest in following the Procedure by completing the
expression of interest reproduced in Appendix 3, Part A. If the applicant for national
registration is not the same as the WHO PQ holder, the WHO PQ holder confirms
to the NRA and WHO/PQT by an authorization letter (as per the form annexed to
Appendix 3, Part A) that the applicant is acting for, or pursuant to rights derived
from, the WHO PQ holder and that the PQ holder agrees with the application of the
Procedure in the country concerned.
Appendix 3, Part A
276
Annex 8
Figure A8.1 continued
The WHO PQ holder/applicant informs WHO/PQT about the submission of its

application to the NRA(s) (by providing a copy of completed Appendix 3, Part A) and,
for each product and country, provides WHO/PQT with its written consent to share
the product-related information and documentation, under confidential cover, with
the participating authority. The WHO PQ holder completes and signs the consent
form reproduced in Appendix 2 and submits it to WHO/PQT.
Appendix 2
The participating authority informs WHO/PQT and the applicant of its consent to apply
the Procedure to the application for registration of the product, on the understanding
that the application is accepted as complete, or of its refusal by completing and
signing Part B of Appendix 3.
Appendix 3, Part B
Within 30 calendar days of receipt of the WHO PQ holders consent, WHO/PQT provides
the participating authority with product-related information and documentation,
and provides additional explanations, if requested, through the restricted-access
website, and subject to the obligations of confidentiality and restrictions on use in
place between WHO/PQT and the NRA.
The participating authority uses the product-related information and documentation

provided by WHO/PQT and by the applicant, at its discretion, to come to its conclusion
about national registration and makes its decision on the registration within 90
calendar days of regulatory time.12
Within 30 calendar days of having taken its decision, the participating authority
informs WHO/PQT and the applicant of this decision, together with an indication of the
dates of submission and registration and, if applicable, any deviations from the WHO
PQ conclusions and the reasons for such deviations, through the restricted-access
website. This report is provided to WHO/PQT by completing Part C of Appendix 3.
Appendix 3, Part C
See footnote7.
12
277
WHO/PQT lists pharmaceutical products registered by participating NRAs according

to this Procedure on its public website
Post-registration processes
The WHO PQ holder/applicant submits to participating authorities at the latest

30 calendar days after acceptance of the variation by WHO/PQT those variations
which are subject to national regulatory requirements. If regulatory action is
deemed to be justified, WHO/PQT promptly provides the participating authorities
concerned, through the restricted-access website, and subject to the above-
mentioned obligations of confidentiality and restrictions on use, with outcomes
of its variation assessment and relevant post-prequalification inspection, and any
related information it considers relevant. If a national variation procedure results in
the nationally-registered product being no longer the same (see section 3.2) as the
WHO-prequalified product, or in the event that a variation of a WHO-prequalified
product is not followed by the same variation of the nationally-registered product,
the participating authority informs WHO of the situation within 30 calendar days of
obtaining access to the information and documentation provided by WHO/PQT, by
submitting the form reproduced in Appendix 4, clearly specifying the deviations.
Other participating NRAs that have registered the WHO-prequalified product in
question pursuant to this Procedure will be made aware of such deviations through
the restricted-access website.
Appendix 4
WHO/PQT informs the participating authority, through the restricted-access website,

and subject to the above-mentioned obligations of confidentiality and restrictions
on use, about withdrawals, suspensions or delistings of prequalified pharmaceutical
products or vaccines. The participating authority informs WHO/PQT, through the

restricted-access website, of national de-registration or suspension (for any reason) of
a prequalified pharmaceutical product or vaccine and the reasons for doing so. Other
participating NRAs which have registered the WHO-prequalified product in question
pursuant to this Procedure will be made aware of such national de-registration or
suspension, through the restricted-access website.
Appendix 4
278
Annex 8
WHO/PQT removes a product from the list published in line with this procedure:
if the nationally-registered product is no longer the same (see
section3.2) as the WHO-prequalified product, or
if the NRA deregisters a WHO-prequalified product, or
if WHO/PQT delists a WHO-prequalified product.
WHO/PQT will also publish the reasons for the removal from the list.
5. Collaboration mechanisms for post-prequalification

and/or post-registration variations
5.1 Those post-prequalification variations submitted to WHO/PQT, which are
subject to national regulatory requirements, are expected to be submitted
to any relevant participating authorities without delay at the latest 30
calendar days after acceptance of the variation by WHO/PQT. Submission
of variations to NRAs should respect national regulatory requirements.
Applicants for national variations should inform participating authorities
that the same application for a variation is being processed by WHO/PQT.
5.2 WHO/PQT promptly shares the outcomes of variation assessment and
of related post-prequalification inspection (if applicable), through the
restricted-access website, and subject to the above-mentioned obligations
of confidentiality and restrictions on use, with the relevant participating
authorities, in all cases in which a variation (including notification
according to WHO/PQTs variation procedures (3)) requires regulatory
action (e.g. where product quality, safety, efficacy or patient information
materials are concerned).
Within 30 days of obtaining access to the information and
documentation from WHO/PQT, each participating authority informs
WHO/PQT through the restricted-access website if and to what extent
a variation of a WHO-prequalified product is not followed by the
same accepted variation of the nationally-registered product and, as a
consequence, the nationally-registered product is no longer the same (see
section 3.2) as the WHO-prequalified product. The variation approved by
WHO/PQT will be considered by WHO/PQT as accepted by the NRA on
a non-objection basis 30 days after information-sharing, unless and until
the NRA informs WHO/PQT otherwise.
5.3 If a national variation procedure occurs independently of a variation
submitted to WHO/PQT and results in the nationally-registered product
279
being no longer the same (see section 3.2) as the WHO-prequalified

product, the participating authority informs WHO/PQT within 30 days
about the subject and outcome of this national variation procedure.
5.4 Deviations under 5.2 and 5.3 above may include change of source of active
ingredients or starting materials, manufacturing sites, manufacturing
process, product specifications, testing methods, storage conditions, shelf
life, packaging material, indications, contraindications, posology (dosing),
special warnings and precautions for use, adverse reactions and other
changes specified in WHO/PQT guidelines (3). Differences in brand name,
name of applicant or WHO PQ holder, format of product information,
level of detail of product information, labelling of internal and external
packaging and language of product information are not considered
to be deviations from the conclusions during the prequalification of
pharmaceutical products. For vaccines, such changes must be reported
to WHO/PQT, which provides its opinion on the extent to which the
difference represents deviation from conclusions during prequalification.
5.5 If a national variation procedure results in the nationally-registered
product being no longer the same (see section 3.2) as the WHO-
prequalified product, or if a variation of the WHO-prequalified product
is not followed by a variation of the nationally-registered product and,
as a consequence, the nationally-registered product is no longer the
same, the WHO PQ holder will inform WHO/PQT of the differences and
theirreasons.
5.6 WHO/PQT removes a product from the list published in line with this
Procedure if the nationally-registered product is no longer the same
(seesection 3.2) as the WHO-prequalified product.
6. Withdrawals, suspensions or delistingsof

prequalified pharmaceutical productsorvaccines
and national deregistrations
6.1 If a WHO-prequalified product is withdrawn by the WHO PQ holder,
or if a product is suspended or delisted by WHO/PQT, WHO/PQT will
promptly, through the restricted-access website, and subject to the above-
mentioned obligations of confidentiality and restrictions on use, inform
relevant participating authorities accordingly, providing the reasons
whenever needed.
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Annex 8
6.2 In the case that a participating NRA deregisters or suspends the

registration of a prequalified pharmaceutical product or vaccine for any
reason, the participating authority informs WHO/PQT of the decision
(together with an indication of the reasons), through the restricted-access
website. The information should be provided promptly whenever there are
concerns about product quality, safety or efficacy and in all other cases
within 30days. A participating authority is encouraged to consult WHO/
PQT before adopting a decision about deregistration or suspension of
registration of a WHO-prequalified product.
6.3 In the case that a WHO-prequalified product is deregistered at the national
level, or in the case that WHO/PQT delists a prequalified product, WHO/
PQT adjusts the information about this product on its website accordingly.
References
1. Procedure for prequalification of pharmaceutical products. In: WHO Expert Committee on
Specifications for Pharmaceutical Preparations: forty-fifth report. Geneva: World Health
2. Procedure for assessing the acceptability, in principle, of vaccines, for purchase by United
Nations agencies. In: WHO Expert Committee on Biological Standardization: sixty-first report.
Geneva: World Health Organization; 2013: Annex 6 (WHO Technical Report Series, No. 978).
3. For pharmaceutical products: WHO guidelines on variations to a prequalified product. In: WHO
Expert Committee on Specifications for Pharmaceutical Preparations: forty-seventh report.
Geneva: World Health Organization; 2013: Annex 3 (WHO Technical Report Series, No. 981), (and
any updates thereto).
For vaccines: http://www.who.int/immunization_standards/vaccine_quality/variations_pq_
vaccine/en/ (and any updates thereto).
281
Appendix 1
National regulatory authority participation agreement
and undertaking for national regulatory authority
focalpoint(s)
Appendix 1, Part A
Agreement to participate in the collaborative procedure between the World
Health Organization (WHO) Prequalification Team (WHO/PQT) and national
regulatory authorities (NRAs) in the assessment and accelerated national
registration of WHO-prequalified pharmaceutical products and vaccines
Details of NRA
Name of NRA: (the NRA)
Postal address:
Country: (the Country)

Telephone number (please include codes):
Email (please indicate contact details as appropriate for inclusion in the list of
participating NRAs maintained on the WHO website):
Scope of agreement
Applicants for national registration of a particular WHO-prequalified
pharmaceutical product or vaccine (hereafter referred to as Applicants) may
express their interest to the NRA in the assessment and accelerated registration
of this product (the Product) in the Country under the Collaborative

Procedure between WHO/PQT and NRAs in the assessment and accelerated
national registration of WHO-prequalified pharmaceutical products or vaccines
(hereafter referred to as the Procedure).1
Subject to the NRA agreeing to conduct such assessment and consider
such accelerated registration of the Product under the Procedure (by submitting
If the applicant for national registration is not the same as the WHO prequalification (PQ) holder, the
1
WHO PQ holder must confirm to the NRA and to WHO/PQT by an authorization letter (as per the
template annexed to Appendix 3, Part A) that the applicant is acting for, or pursuant to rights derived
from, the WHO PQ holder, and that the WHO PQ holder agrees with the application of the Procedure in
the country concerned.
282
Annex 8
the form reproduced in Part B of Appendix 3 attached to the Procedure to

WHO/PQT through the restricted-acce ss website), the NRA hereby confirms
for each such Product that it will adhere to, and collaborate with the WHO/PQT
and the Applicant for registration of the Product in accordance with the terms
of the Procedure.
Confidentiality of information
Any information and documentation relating to the Product and provided
by WHO/PQT to the NRA under the Procedure may include but shall not
necessarily be limited to:
the full WHO/PQT assessment and inspection outcomes (reports)
and if relevant, also results of laboratory testing;
information and documentation on variations (as defined in WHO
guidelines 2), as well as information and documentation on any actions
\taken by WHO/PQT or NRAs post-prequalification of the Product;
all such data, reports, information and documentation being
hereinafter referred to as the Information.
As regards sharing the outcomes of assessments, inspections and
laboratory testing, only data owned by the WHO PQ holder and WHO/PQT
are shared. Sharing of any other data is subject to additional agreement of the
data owners concerned.
WHO/PQT agrees to make such information available to the NRA
through a restricted-access website exclusively for the purpose of the assessment
and accelerated registration of the Product in the Country and any post-
registration processes that may be required, in accordance with and subject to the
terms of the Procedure (the Purpose). The NRA agrees to treat any Information
provided by WHO/PQT as aforesaid as strictly confidential and proprietary to
WHO/PQT, the WHO PQ holder/Applicant and/or parties collaborating with
WHO/PQT and/or the WHO PQ holder/Applicant. In this regard, the NRA
agrees to use such Information only for the Purpose and to make no other
use thereof. Thus, the NRA undertakes to maintain the Information received
from WHO/PQT in strict confidence, and to take all reasonable measures to
ensurethat:
For pharmaceutical products: WHO guidelines on variations to a prequalified product. In: WHO Expert
2
Committee on Specifications for Pharmaceutical Preparations: forty-seventh report. Geneva: World Health
Organization; 2013: Annex 3 (WHO Technical Report Series, No. 981), (and any updates thereto).
For vaccines: http://www.who.int/immunization_standards/vaccine_quality/variations_pq_vaccine/en/
(and any updates thereto).
283
the Information received from WHO/PQT shall not be used for any
purpose other than the Purpose;
the Information shall only be disclosed to persons who have a need
to know for the aforesaid Purpose and are bound by confidentiality
undertakings in respect of such information and documentation
which are no less stringent than those contained herein.
The NRA warrants and represents that it has adequate procedures in

place to ensure compliance with its aforesaid obligations.
The obligations of confidentiality and restrictions on use contained
herein shall not cease on completion of the Purpose.
The obligations of confidentiality and restrictions on use contained
herein shall not apply to any part of the Information which the NRA is clearly
able to demonstrate:
was in the public domain or the subject of public knowledge

at thetime of disclosure by WHO/PQT to the NRA under the
Procedure; or
becomes part of the public domain or the subject of public
knowledge through no fault of the NRA; or
is required to be disclosed by law, provided that the NRA shall in
such event immediately notify WHO/PQT and the Applicant in
writing of such obligation and shall provide adequate opportunity
to WHO/PQT and/or the Applicant to object to such disclosure or
request confidential treatment thereof (provided always, however,
that nothing contained herein shall be construed as a waiver of
the privileges and immunities enjoyed by WHO/PQT and/or as
submitting WHO/PQT to any national court jurisdiction).
Upon completion of the Purpose, the NRA shall cease all use and make
no further use of the Information disclosed to it under the Procedure, and shall
promptly destroy all of the Information received from WHO/PQT which is in
tangible or other form, except that the NRA may retain copies of the Information
in accordance with its established archival procedures, subject always, however,
to the above-mentioned obligations of confidentiality and restrictions on use.
The Purpose for each product shall be deemed completed as soon as:
the WHO PQ holder/Applicant discontinues participation in the

Procedure for the particular product;
284
Annex 8
the Product is deregistered by the NRA and/or delisted by

WHO/PQT.
The access right of the NRAs focal point(s) to the restricted-access

website will cease automatically upon the NRA ceasing to participate in the
Procedure. If and as soon as an NRA focal point is replaced by a new focal
point or ceases to be an employee of the NRA, such focal points access to the
restricted-access website shall automatically terminate.
The NRA agrees that it has no right in or to the Information and that
nothing contained herein shall be construed, by implication or otherwise, as the
grant of a licence to the NRA to use the Information other than for the Purpose.
Timelines
In respect of each Product that the NRA agrees to assess and consider for
accelerated registration under the Procedure, the NRA undertakes to abide by
the terms of the Procedure, including but not limited to the following timelines
for processing each application:
within 90 calendar days of regulatory time 3 after obtaining access

(through the restricted access website) to:
the data submitted to WHO/PQT for prequalification of the
Product and owned by the WHO PQ holder,
the full WHO/PQT assessment and inspection outcomes (reports),
the NRA undertakes to take a decision on the national registration
of the Product;
within 30 working days of the NRAs decision on national registration

of the Product, the NRA undertakes to inform WHO/PQT of this
decision and of any deviations from WHO conclusions during
prequalification (with an indication of the reasons for such
deviations) by completing and submitting the form attached as
Appendix 3, Part C to the Procedure to WHO/PQT through the
restricted-access website;
Regulatory time starts after a valid application for the registration according to the Procedure has been
3
received and access to the confidential information has been granted (whichever is the later) and
continues until the date of decision on registration. The regulatory time does not include the time
granted to the applicant to complete missing parts of the documentation, provide additional data or
respond to queries raised by NRAs.
285
if a national variation procedure results in the nationally-registered

product being no longer the same 4 as the WHO-prequalified
product, or if and to the extent a variation of a WHO-prequalified
product is not followed by a variation of the nationally-registered
product and as a consequence, the nationally-registered product
is no longer the same as the WHO-prequalified product, the
NRA undertakes to inform WHO/PQT thereof (together with an
indication of the reasons for such deviations) within 30 days of the
conclusion of the national variation procedure or within 30 days
of having received access to the information and documentation
provided by WHO/PQT, as the case may be (i.e. by completing and
submitting the form attached to the Procedure as Appendix 4 to
WHO/PQT through the restricted-access website); 5
the NRA undertakes to inform WHO/PQT in the case that the
NRA deregisters or suspends the registration of the Product in the
Country, by completing and submitting the form attached to the
Procedure as an Appendix 4, to WHO/PQT through the restricted-
access website, and to do so promptly if this decision is based
on quality, safety or efficacy concerns, and within 30 days if this
decision is based on other reasons.
Focal points for access to restricted-access website

The NRA has designated the person(s) listed below to act as focal point(s) for
access to WHO/PQTs restricted-access website. The undertaking(s) completed
and signed by the focal point(s) is (are) attached hereto as an Appendix to
thisagreement.
Any change in designated focal points must be communicated to
WHO/PQT without delay in writing and will be subject to the new focal point
having signed and submitted to WHO/PQT the undertaking reproduced in
Appendix 1, Part B to the Procedure. The NRA also undertakes to inform

WHO/PQT if and as soon as a designated focal point ceases to be an employee
of the NRA.
4
Within the context of this Procedure, the same pharmaceutical product/same vaccine is characterized by
the same product dossier; the same manufacturing chain, processes and control of materials and finished
product, in the case of vaccines also by the same batch release scheme; the same active ingredient and
finished product specifications; and the same essential elements of product information for pharmaceutical
products, in the case of vaccines by the same product information, packaging presentation and labelling.
5
If the fact that a WHO-prequalified product has been registered in a country pursuant to this Procedure has
been made public, any subsequent deviations should also be made public.
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Focal point for inspections

If applicable, this should be the same focal point as for the WHO/PQT Collaborative
Procedure with NRAs in inspection activities (http://who.int/prequal, Inspections).
The same person should be designated for inspections of pharmaceutical products
and vaccines.
1.
Mr/Ms/Dr
First name (and initials):
Surname/family name:
Title in NRA:
Email:
Telephone:
A signed Undertaking is attached.
Focal point(s) for dossier assessment

For dossier assessment, different persons can be nominated for pharmaceutical
products and vaccines. The same person may be nominated to be the focal point
for inspections and dossier assessment. If additional person(s) are nominated for
dossier assessment, please complete the details below.
2.
Mr/Ms/Dr as a focal point for dossier assessment of
pharmaceutical products only
pharmaceutical products and vaccines
Title in NRA:
Email:
Telephone:
A signed Undertaking is attached
3.
Mr/Ms/Dr as a focal point for dossier assessment of vaccines
Title in NRA:
287
Email:
Telephone:
A signed Undertaking is attached
Miscellaneous
The NRA agrees that WHO/PQT may list its name on the WHO/PQT website
as a participant in the Procedure. Except as provided hereinbefore, neither
party shall, without the prior written consent of the other party, refer to the
relationship of the parties under this Agreement and/or to the relationship of the
other party to the Product, the Information and/or the Purpose, in any statement
or material of an advertising or promotional nature.
This Agreement shall not be modified except by mutual agreement of
WHO and the NRA in writing. The NRA furthermore undertakes to promptly
inform WHO/PQT of any circumstances or change in circumstances that may
affect the implementation of this Agreement.
The parties shall use their best efforts to settle amicably any dispute
relating to the interpretation or execution of this Agreement. In the event of
failure of the latter, the dispute shall be settled by arbitration. The arbitration
shall be conducted in accordance with the modalities to be agreed upon by the
parties or in the absence of agreement, with the UNCITRAL Arbitration Rules
in effect on the date of this Agreement. The parties shall accept the arbitral
award as final.
It is agreed furthermore that nothing contained in this Agreement shall
be construed as a waiver of any of the privileges and immunities enjoyed by
WHO under national and international law, and/or as submitting WHO to any
national court jurisdiction.
Agreed and accepted for pharmaceutical products and vaccines.
For the NRA

Signature:
Name:
Title:
Place and date:
Attachments:
Signed Undertaking(s) of NRA focal point(s) (Appendix 1, Part B)
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Annex 8
Appendix 1, Part B
Undertaking for NRA focal point(s)
The undersigned:
Mr/Ms/Dr
Title in NRA:
Name of NRA: (the NRA)
Country: (the Country)
Email:
Telephone:
Applicants for national registration of WHO-prequalified pharmaceutical

products or vaccines (hereafter referred to as Applicants) may express their
interest to the national regulatory authority (NRA) in the assessment and
accelerated national registration of such products under the Collaborative
Procedure between the World Health Organization (WHO) Prequalification
Team (WHO/PQT) and national regulatory authorities in the assessment and
and vaccines (hereafter referred to as the Procedure).6
Subject to the NRA agreeing to conduct such assessment and
consider such accelerated registration of a WHO-prequalified product under
the Procedure, WHO/PQT will communicate confidential Information (as
hereinafter defined) relating to each such product to the NRA, and the NRA
will communicate outcomes of the national registration procedure and post-
registration actions in respect of such products to WHO/PQT, through a
restricted-access website, which can be accessed only by the focal points
designated by the NRA, including the undersigned. For the purpose of accessing
the restricted-access website and downloading Information and uploading
reports in accordance with and subject to the terms of the Procedure, WHO/
PQT will provide the undersigned with a secret access code. The undersigned
undertakes to treat this access code as strictly confidential and not to disclose
it to any other person whatsoever. The undersigned furthermore undertakes
If the applicant for national registration is not the same as the WHO PQ holder, the WHO PQ holder
6
must confirm to the NRA and to WHO/PQT by an authorization letter (as per the template annexed to
Appendix 3, Part A) that the applicant is acting for, or pursuant to rights derived from, the WHO PQ
holder, and that the PQ holder agrees with the application of the Procedure in the country concerned.
289
to take all precautionary measures that may be needed to prevent any other
person whatsoever from obtaining the aforesaid secret access code and from
accessing the restricted-access website (i.e. except for the other designated focal
points who have signed this Undertaking).
Information as aforesaid means any information and documentation
relating to a WHO-prequalified product to be provided by WHO/PQT to the
NRA under the Procedure, including but not necessarily limited to:
the full WHO/PQT assessment and inspection outcomes (reports)
and if relevant, also results of laboratory testing;
information and documentation on subsequent variations (as defined
in WHO guidelines 7), as well as information and documentation on
any actions taken by WHO/PQT or NRAs post-prequalification of
the Product.
As regards sharing the outcomes of assessments, inspections and results
of laboratory testing, only data owned by the WHO PQ holder and WHO/PQT
are shared. Sharing of any other data is subject to additional agreement of the
data owners concerned.
The undersigned confirms that:
1. the NRA has bound him or her to obligations of confidentiality
and restrictions on use no less stringent than those contained in
Appendix 1, Part A to the Procedure; and that
2. the aforesaid obligations of confidentiality and restrictions on use
shall not cease on completion of the assessment and accelerated
registration of any product in the Country, nor on completion
of any post-registration processes that may be required, nor on
the undersigned ceasing to be an employee of (or ceasing to have
another relationship with) the NRA.
The undersigned shall automatically cease having the right to access the
restricted-access website when the NRA designates a new focal point to replace
the undersigned or when the undersigned ceases to be an employee of the NRA.
This Undertaking shall not be modified except by mutual agreement of
WHO and the undersigned in writing. The undersigned furthermore undertakes
7
Committee on Specifications for Pharmaceutical Preparations: forty-seventh report. Geneva: World

Health Organization; 2013: Annex 3 (WHO Technical Report Series, No. 981), (and any updates thereto).
290
Annex 8
to promptly inform WHO/PQT of any circumstances or change in circumstances

that may affect the implementation of this Undertaking.
The parties shall use their best efforts to settle amicably any dispute
relating to the interpretation or execution of this Undertaking. In the event of
failure of the latter the dispute shall be settled by arbitration. The arbitration
shall be conducted in accordance with the modalities to be agreed upon by the
parties or in the absence of agreement, with the UNCITRAL Arbitration Rules
in effect on the date of this Undertaking. The parties shall accept the arbitral
award as final.
It is agreed furthermore that nothing contained in this Undertaking
shall be construed as a waiver of any of the privileges and immunities enjoyed
by WHO under national and international law, and/or as submitting WHO to
any national court jurisdiction.
Agreed and accepted by the undersigned:

Signature:
Name:
Title in NRA:
Place and date:
291
Appendix 2
Consent of WHO prequalification holder for WHO to
share information with the national regulatory authority
confidentially under the Procedure
Reference is made to the attached expression of interest in the assessment and
accelerated national registration under the Procedure of the following World
Health Organization (WHO) prequalified pharmaceutical product or vaccine
(hereafter referred to as the Product) in [country].1
pharmaceutical product
vaccine
WHO prequalification details:

WHO prequalification (PQ) reference number:
Date of prequalification (dd/mm/yyyy):
Date of requalification (if applicable):
WHO PQ holder:2
Application details:
Name of entity: (the Applicant)
Street:
City and country:
Email:
Telephone:
The WHO PQ holder hereby consents to the WHO Prequalification Team

(WHO/PQT) providing the following information and documentation to the
national regulatory authority (NRA) of [country]
Please complete a separate copy of this Annex for each country.

1
If the applicant for national registration is not the same as the WHO PQ holder, the WHO PQ holder
2
must confirm to the NRA and to WHO/PQT by an authorization letter (as per the template annexed to
Appendix 3, Part A) that the applicant is acting for, or pursuant to rights derived from, the WHO PQ
holder, and that the PQ holder agrees with the application of the Procedure in the country concerned.
292
Annex 8
(the NRA) for the assessment and accelerated registration of the Product in the
country under the Procedure and to freely discuss the same with the aforesaid
NRA for this purpose:
the full WHO/PQT assessment and inspection outcomes (reports),

results of laboratory testing and, if relevant, also assessment and
inspections reports of other regulatory bodies, provided that these
bodies gave their written consent to the use of such reports for the
purpose of the Procedure;
information and documentation on subsequent variations
(as defined in WHO guidelines 3), as well as information and
documentation on any actions taken by WHO/PQT post-
prequalification of the Product;
all such data, reports, information and documentation being
hereinafter referred to as the Information.
As regards sharing the outcomes of assessments and inspections, only

data owned by the WHO PQ holder and WHO/PQT are shared. Sharing of any
other data is subject to additional agreement of the data owners concerned.4
Such consent is subject to the NRA having entered into an agreement
with WHO/PQT as per Part A of Appendix 1 to the Procedure and having
agreed to conduct the assessment and consider the accelerated registration of the
Product under the Procedure, by having submitted the form reproduced in Part
B of Appendix 3 to the Procedure to WHO/PQT.
The WHO PQ holder/Applicant commits to submit post-prequalification
variations to WHO/PQT and any relevant participating authorities respecting
national regulatory requirements. Variations should be submitted to participating
authorities at the latest 30 calendar days after acceptance of the variation by
WHO/PQT. Participating authorities should be informed about the fact that the
same application for a variation is being processed by WHO/PQT. If a national
variation procedure results in the nationally-registered product being no longer
3
4
In the case that certain data submitted to WHO/PQT by the WHO PQ holder in relation to PQ of the
Product are not in his/her ownership, the WHO PQ holder specifies such data in an annex to this
declaration of consent.
293
the same 5 as the WHO-prequalified product, or if a variation of the WHO-

prequalified product is not followed by a variation of the nationally-registered
product and, as a consequence, the nationally-registered product is no longer the
same, the WHO PQ holder/Applicant will inform WHO/PQT of the differences
and their reasons.
For the WHO PQ holder

Signature:
Name:
Title:
Place:
Date (dd/mm/yyyy):
Within the context of this Procedure, the same pharmaceutical product/same vaccine is characterized
5
by the same product dossier; the same manufacturing chain, processes and control of materials and
finished product, and in the case of vaccines also by the same batch release scheme; the same active
ingredient and finished product specifications; as well as the same essential elements of product
information for pharmaceutical products, and, in the case of vaccines, by the same product information,
packaging presentation and labelling.
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Annex 8
Appendix 3
Expression of interest to national regulatory authority
(NRA) in the assessment and accelerated national
registration, acceptance by NRA and notification of
Procedure outcomes
Appendix 3, Part A
Expression of interest to the national regulatory authorities (NRAs) in the
assessment and accelerated national registration of a World Health Organization
(WHO)-prequalified pharmaceutical product or vaccine
In line with the Procedure, the undersigned Applicant1 expresses its interest
in the application of the above-mentioned Procedure by the NRA of
[country] (the NRA) in respect of the following
submission for national registration:
pharmaceutical product
vaccine
Street:
City and country:
Email:
Telephone:
Date of application (dd/mm/yyyy):
Product name in national system (if known):
National reference number (if known):
If the applicant for national registration is not the same as the WHO prequalification (PQ) holder, the
1
WHO PQ holder must confirm to the NRA and to WHO/Prequalification Team (PQT) by an authorization
letter (as per the template annexed to Appendix 3, Part A) that the applicant is acting for, or pursuant
to rights derived from, the WHO PQ holder, and that the PQ holder agrees with the application of the
Procedure in the country concerned.
295
Product details for pharmaceutical products:

Active pharmaceutical ingredient(s) (API(s)) (international nonproprietary
name (INN)):
Dosage form and strength:

Packaging:
Manufacturing site(s), including block(s)/unit(s), if appropriate:
Product details for vaccines:

Name of vaccine:
Composition:
Packaging:

WHO PQ reference number:
WHO PQ holder:
The Applicant confirms that the information and documentation provided

in support of the above-mentioned submission for national registration is
true and correct, that the product submitted for national registration is the
same 2 as the WHO-prequalified product and that the technical information
in the registration dossier is the same 3 as that approved by WHO/PQT during

theinitial prequalification procedure, and consecutive variation procedures and
2
Within the context of this Procedure, the same pharmaceutical product/same vaccine is characterized by
the same product dossier; the same manufacturing chain, processes and control of materials and finished
product, and in the case of vaccines also by the same batch release scheme; the same active ingredient
and finished product specifications; as well as the same essential elements of product information for
pharmaceutical products, and, in the case of vaccines, by the same product information, packaging
presentation and labelling.
3
Only the technical data included in the dossier must be the same. There may be country-specific
differences in administrative data, or if required by NRAs under exceptional circumstances, additional
technical data can be provided (e.g. bioequivalence with a country-specific comparator).
296
Annex 8
requalification (where applicable). Minor differences 4 from the information

submitted to WHO/PQT are the following:
Subject to the NRA agreeing to conduct the assessment and consider the
accelerated registration of the Product under the Procedure, the Applicant:
1. undertakes to adhere to, and collaborate with the NRA and WHO/
PQT in accordance with the terms of the Procedure; and
2. will authorize WHO/PQT 5 to provide the NRA confidential access
to the following information and documentation and to freely
discuss the same with the aforesaid NRA for the above-mentioned
Purpose:
the full WHO/PQT assessment and inspection outcomes
(reports), results of laboratory testing and if relevant, also
assessment and inspections reports of other regulatory bodies,
provided that these bodies gave their written consent to the use
of such reports for the purpose of the Procedure,
information and documentation on subsequent variations
(as defined in WHO guidelines 6), as well as information and
documentation on any actions taken by WHO/PQT post-
prequalification of the Product.
As regards sharing the outcomes of assessments and inspections, only

data owned by the WHO PQ holder and WHO are shared. Sharing of any other
data is subject to additional agreement of the data owners concerned.
4
As defined in section 3.2 of the Procedure, in the case of pharmaceutical products, examples of minor
differences which are not considered essential may include differences in administrative information,
brand name, name of applicant (provided that the applicant is acting for, and has the authority to
represent the WHO PQ holder), format of product information, level of detail of product information,
labelling of internal and external packaging and language of product information.
5
If the applicant for national registration is not the same as the WHO PQ holder, then the authorization to
WHO/PQT must be provided by the WHO PQ holder or their legal representative.
6
297
3. authorizes the NRA to freely share and discuss all registration-

related and Product-related information provided by the Applicant
to the NRA, with WHO/PQT, subject to the obligations of
confidentiality and restrictions on use as contained in the NRAs
participation agreement and focal points undertakings.
The application for national registration was submitted before the Applicant
decided to apply the Procedure to the Product and therefore at the time
of submission the registration dossier did not respect conditions of the
Procedure. Steps taken to update the submission to the NRA to make the
dossier the same as required by the Procedure are listed and referenced in
the attached letter.
The Applicant is not the WHO PQ holder. An authorization letter from the
WHO PQ holder is attached.
For the Applicant

Signature:
Name:
Title:
Place:
Date (dd/mm/yyyy):
Template for authorization letter

[To be provided if the applicant is not the WHO PQ holder. Please provide a
separate letter for each NRA concerned, with a copy to WHO/PQT.]
This is to confirm that (name of applicant) seeking

registration for prequalified product number (WHO PQ

number) in (name of country) under the WHO collaborative
procedure for accelerated registration of WHO-prequalified products, is acting
for, or pursuant to rights derived from (name of WHO
PQ holder) and that (name of WHO PQ holder) agrees with the
application of the Procedure in the country concerned.
For (name of WHO PQ holder):

Signature:
Name:
Title:
Date:
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Annex 8
Appendix 3, Part B
Decision on acceptance by the NRA to apply the Procedure to a specified WHO-
prequalified product and request for access to product-specific information and
documentation
Please complete all fields marked *. For other fields, if there have been changes
to the details as completed in Part A, please complete the relevant fields below.
Where fields below are left blank, the data in Part A are considered to be valid.
Street:
City and country:
Email:
Telephone:
*Date of receipt of submission (dd/mm/yyyy):
Product name in national system (if known):
*National reference number:

Active pharmaceutical ingredient(s) (API(s)) (international nonproprietary
name (INN)):

Packaging:
Manufacturing site(s), including block(s)/unit(s) if appropriate:

Name of vaccine:
Composition:
Packaging:
299

*WHO PQ reference number:
WHO PQ holder:
Please complete either section A or section B below:

Section A
The NRA agrees to conduct the assessment and the accelerated registration
of the above-mentioned product (the Product) under the Procedure and
requests access to product-specific information, in accordance with and
subject to the terms of the Procedure and the Agreement between WHO/
PQT and the NRA dated / / (dd/mm/yyyy).
Section B
The NRA has decided not to apply the Procedure to the above-mentioned
Product for the following reasons:
*For the NRA of (indicate country)

Signature:
Name:
Title:
Place:
*Date (dd/mm/yyyy):
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Annex 8
Appendix 3, Part C
Notification of outcomes of national registration procedure by the NRA
Product and application details as completed in Parts A and B above apply.
Please complete either section A or section B below:

Section A
Registration has been granted under the terms of the Procedure, and the
above-mentioned product (the Product) is identified as follows in the
national medicines register:
Name of the Product:

National registration number:
Date of registration (dd/mm/yyyy):
Non-regulatory time (days):
Product details (if different from those specified in Parts A and B):
API(s) (INN):
Packaging:

Name of vaccine:
Composition:
Packaging:
Registration holder (if different from the Applicant as specified in

Parts A and B):
Name of entity:
Street:
City and country:
301
Email:
Telephone:
Are the national registration conclusions different from prequalification

outcomes? 7 (yes/no)
If you answered yes to the above question, please specify:
Deviation Reason
Please specify whether registration is subject to specific commitments, the

registration is provisional or conditional, use of the Product is limited by
specific prescribing restrictions, or additional clinical trials or additional data
are required:
Section B
Please complete as appropriate:
The application for registration of the Product was rejected for the following
reasons:
The collaborative procedure was discontinued for this application for the
following reasons:
For the NRA

Signature:
Name:
Title:
Place:
Date (dd/mm/yyyy):
This refers to deviations in indications, contraindications, posology (dosing), special warnings and
7
precautions for use, adverse drug reactions, storage conditions and shelf life. For pharmaceutical products
differences in brand name, name of applicant/PQ holder, format of product information, level of detail of
product information, labelling of internal and external packaging and language of product information
are not considered to be a deviation from the PQ conclusions.
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Appendix 4
Report on post-registration actions in respect of a product
registered under the Procedure
Variation of the national registration resulting in the national registration
conditions being inconsistent with the WHO/PQT prequalification conclusions
Deregistration or suspension of the registration of the product
Product details:
Product name in national system: (the Product)
National registration number:
Date of registration (dd/mm/yyyy):

WHO PQ reference number:
WHO PQ holder:
The national variation procedure has resulted in the nationally-registered

Product being no longer the same1 as the WHO-prequalified product.
Deviation Reason
Within the context of this Procedure, the same pharmaceutical product/same vaccine is characterized
1
by the same product dossier; the same manufacturing chain, processes and control of materials and
finished product, and in the case of vaccines also by the same batch release scheme; the same active
ingredient and finished product specifications; as well as the same essential elements of product
information for pharmaceutical products, and, in the case of vaccines, by the same product information,
packaging presentation and labelling.
303
The variation notified to the NRA by WHO/PQT has not been followed
by a variation of the nationally-registered Product and, as a consequence,
the nationally-registered product is no longer the same1 as the WHO-
prequalified product.
Deviation Reason
The Product has been deregistered or the registration of the Product has
been suspended.
Deregistration: (yes/no)
suspension of registration: (yes/no)
Effective date: / / (dd/mm/yyyy)
Reasons:
For the NRA

Signature:
Name:
Title:
Place:
Date (dd/mm/yyyy):
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Annex 9
Guidance for organizations performing in vivo
bioequivalence studies
Background
During an informal consultation held in 2014, and at the forty-ninth meeting
of the World Health Organization (WHO) Expert Committee on Specifications
for Pharmaceutical Preparations, discussion took place regarding the possible
revision of the guidance for organizations performing in vivo bioequivalence
studies (WHO Technical Report Series, No.937, Annex 9, 2006). The WHO
Expert Committee on Specifications for Pharmaceutical Preparations agreed that
in light of the new developments a draft for revision would be prepared.
These new guidelines take into consideration the revision of the
multisource guidelines, as well as the creation of new guidance on good data
management. The revision will also take into account the experience accumulated
in the area of assessing and inspecting bioequivalence (BE) studies since 2006.
In areas where the same problems are repeatedly identified by inspectors, the
new guidelines provide clarifications, and supplementary details have been
added on bioanalysis. The guidelines also put increased emphasis on subject
safety and data integrity.
Based on the first working document:1 this second version incorporates
the numerous comments and the feedback received from the public consultation,
the WHO Prequalification Team (PQT) and from the Consultation on data
management, bioequivalence, GMP and medicines inspection held in 2015.
WHO/PQT was set up in 2001 to assure that medicinal products supplied
for procurement meet WHO norms and standards with respect to quality, safety
and efficacy (http://www.who.int/prequal/). Specifically, there is a requirement
that the submitted product dossier with all its necessary contents is assessed
and found acceptable, and that the manufacturing sites for the finished
pharmaceutical product (FPP), as well as the active pharmaceutical ingredient
(API), are inspected and found to comply with WHO good manufacturing
practices (GMP). Since products submitted to WHO/PQT are usually multisource
(generic) products, therapeutic equivalence is generally demonstrated by
performing a BE study, for example in a contract research organization (also
known as a clinical research organization) (CRO). For prequalification of such
http://www.who.int/medicines/areas/quality_safety/quality_assurance/BE-invivo-studies-guidance-
1
QAS15-622_21052015.pdf?ua=1.
305
a product it is vital that, in addition to the above-mentioned requirements, the

CRO used by the sponsor for BE studies complies with WHO good clinical
practices (GCP) and considers relevant elements from WHO good laboratory
practices (GLP) and good practices for quality control (QC) laboratories to
ensure integrity and traceability of data. In addition, if local legal provisions
exist, CROs should be licensed by the respective national medicines authority.
Where required by national regulations, BE studies should be authorized by the
national regulatory authority. Those involved in the conduct and analysis of BE
studies on products to be submitted for prequalification therefore need to ensure
that they comply with the relevant WHO norms and standards so that they can
be prepared for any inspections by WHO.
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Annex 9
Introduction 309
1. Scope 309
2. Glossary 310
A. GENERAL SECTION 314
3. Organization and management 314
4. Computer systems 316
General 316
Hardware 316
Software 317
Networks 318
Data management 318
5. Quality management 319
6. Archive facilities 321
7. Premises 321
8. Personnel 323
B. CLINICAL SECTION 324
9. Clinical phase 324
10. Clinical laboratory 325
11. Ethics 326
11.1 Independent ethics committee 326
11.2 Informed consent 326
12. Monitoring 327
13. Investigators 328
14. Receiving, storage and handling of investigational products 329
15. Case report forms 332
16. Volunteers and recruitment methods 333
17. Food and fluids 335
18. Safety, adverse events and adverse event reporting 335
C. BIOANALYTICAL SECTION 336
19. Method development 336
20. Method validation 336
21. Sample collection, storage and handling of biological material 337
22. Analysis of study samples 337
307
23. Data processing and documentation 339

24. Good laboratory practices 340
D. PHARMACOKINETIC, STATISTICAL CALCULATIONS AND
REPORTING SECTION 341
25. Pharmacokinetic and statistical calculations 341
26. Study report 342
References 342
Appendix 1 Example list of standard operating procedures at a contract research
organization 344
308
Annex 9
Introduction
Multisource pharmaceutical products need to conform to the same standards
of quality, efficacy and safety as the originators (comparator) product.
Specifically, the multisource product should be therapeutically equivalent and
interchangeable with the comparator product. Testing the BE between a product
and a suitable comparator (pharmaceutically equivalent or a pharmaceutical
alternative) in a pharmacokinetic study with a limited number of subjects is
one way of demonstrating therapeutic equivalence without having to perform
a clinical trial involving many patients. In such a pharmacokinetic study any
statement about the safety and efficacy of the test product will be a prediction
based on measurement of systemic concentrations, assuming that essentially
similar plasma concentrations of the active pharmaceutical ingredient (API)
and/or of its metabolite will result in essentially similar concentrations at the
site of action and therefore an essentially similar therapeutic outcome. The BE
study thus provides indirect evidence of the efficacy and safety of a multisource
pharmaceutical product. Often this will be the only evidence that the product
is safe and efficacious. It is therefore crucial that the BE study is performed in
an appropriate manner. Several guidance documents stress the importance of
onsite inspections to verify compliance with standards of GCP (13).
1. Scope
The objective of this document is to provide guidance to organizations that
are involved in the conduct and analysis of in vivo BE studies. This guidance
supersedes the version published in the WHO Technical Report Series, No. 937,
2006 (4).
BE studies should be performed in compliance with the general
regulatory requirements and good practices recommendations as specified in
the WHO BE guidelines (5), GCP (1) and GLP (2) guidelines. It is acknowledged
that GLP formally apply only to nonclinical safety studies. However the WHO
BE guidelines require that the validation of bioanalytical methods and the
analysis of BE study samples be performed following the principles of GLP.
This does not imply that the laboratory in charge of the bioanalytical part of the
study should be monitored as part of a national GLP compliance programme.
These guidelines provide advice on the conduct of BE studies and the
bioanalysis of study samples. Particular consideration is given to premises,
equipment, organization and management. Recommended documents, standard
operating procedures (SOPs) and records are listed in Appendix 1, but this is
309
not to be considered an exhaustive list other documents may be necessary

depending on each individual CROs functional and compliance needs.
These guidelines provide information on:
organization and management;
study protocols;
clinical phase of a study;
bioanalytical phase of a study;
pharmacokinetic and statistical analysis;
study report;
quality management system.
This document does not replace the above-mentioned GCP or GLP
guidelines. It is therefore not a stand-alone document.
2. Glossary
The definitions given below apply to the terms used in this guidance. They
may have different meanings in other contexts. Unless otherwise stated, the
definitions are reproduced from Guidelines for good clinical practice for trials on
pharmaceutical products (1).
adverse event. Any untoward medical occurrence in a clinical trial
subject administered a pharmaceutical product; it does not necessarily have a
causal relationship with the treatment.
audit of a trial. A systematic examination, carried out independently of
those directly involved in the trial, to determine whether the conduct of a trial
complies with the agreed protocol and whether the data reported are consistent
with the records on site, e.g. whether data reported or recorded in the case-report
forms are consonant with those found in hospital files and other original records.
bioequivalence. Two pharmaceutical products are bioequivalent if they
are pharmaceutically equivalent or pharmaceutical alternatives, and their
bioavailabilities, in terms of rate (C max and t max) and extent of absorption (area
under the curve), after administration of the same molar dose under the same
conditions, are similar to such a degree that their effects can be expected to be
essentially the same.
calibration curve samples (or calibration standards). A matrix to which
a known amount of analyte has been added or spiked. Calibration standards are
used to construct calibration curves.
case-report form. A document that is used to record data on each trial
subject during the course of the trial, as defined by the protocol. The data should
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be collected by procedures which guarantee preservation, retention and retrieval

of information and allow easy access for verification, audit and inspection.
comparator product (or reference product). The comparator product is
a pharmaceutical product with which the multisource product is intended to be
interchangeable in clinical practice. The comparator product will normally be the
innovator product for which efficacy, safety and quality have been established.
If the innovator product is no longer marketed in the jurisdiction, the selection
principle as described in Guidance on the selection of comparator pharmaceutical
products for equivalence assessment of interchangeable multisource (generic)
products (5) should be used to identify a suitable alternative comparator product.
contract. A document, dated and signed by the investigator, institution
and sponsor, that sets out any agreements on financial matters and delegation/
distribution of responsibilities. The protocol may also serve as a contract when it
contains such information and is signed. Contracts can also be signed with other
parties such as vendors supplying services to the contract research organization.
contract research organization (CRO). A scientific organization
(commercial, academic or other) to which a sponsor may transfer some of its
tasks and obligations. Any such transfer should be defined in writing.
In the context of this guidance document, bioequivalence studies are
often contracted by the sponsor to a CRO, which will perform some of the tasks
of the sponsor, but which will also perform the trial. The investigator (clinical
part of the study) and the study director (bioanalytical part of the study) are then
employees of the CRO.
To facilitate reading, the term CRO is used throughout this
document to designate any organization performing the trial, even though it is
acknowledged that part or all of the study may be performed in-house by the
sponsor itself or at a hospital.
ethics committee (6). An independent body (a review board or
a committee, institutional, regional or national), constituted of medical
professionals and non-medical members, whose responsibility is to verify
that the safety, integrity and human rights of the subjects participating in
a particular trial are protected and to consider the general ethics of the trial,
thereby providing public reassurance. Ethics committees should be constituted
and operated so that their tasks can be executed free from bias and from any
influence of those who are conducting the trial.
final report. A comprehensive description of the trial after its completion
including a description of experimental methods (including statistical methods)
and materials, a presentation and evaluation of the results, statistical analysis and
acritical, ethical, statistical and clinical appraisal.
good clinical practice. A standard for clinical studies which encompasses
the design, conduct, monitoring, termination, audit, analysis, reporting and
documentation of the studies and which ensures that the studies are scientifically
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and ethically sound and that the clinical properties of the pharmaceutical
product (diagnostic, therapeutic or prophylactic) under investigation are
properly documented.
good laboratory practice. A quality system concerned with the
organizational process and the conditions under which nonclinical health and
environmental safety studies are planned, performed, monitored, recorded,
archived and reported.
informed consent. A subjects voluntary confirmation of willingness
to participate in a particular trial and the documentation thereof. This consent
should be sought only after all appropriate information has been given about the
trial, including an explanation of its status as research, its objectives, potential
benefits, risks and inconveniences, alternative treatment that may be available,
and of the subjects rights and responsibilities in accordance with the current
revision of the Declaration of Helsinki.
inspection. An officially conducted examination (i.e. review of
the conduct of the trial, including quality assurance, personnel involved,
any delegation of authority and audit) by relevant authorities at the site of
investigation and/or at the site of the sponsor in order to verify adherence to
good clinical practices and good laboratory practices as set out in this document.
internal standard. Test compound(s) (e.g. a structurally similar analogue
or stable isotope-labelled compound) added to calibration standards, quality
control samples and study samples at a known and constant concentration to
correct for experimental variability during sample preparation and analysis.
investigational labelling. Labelling developed specifically for products
involved in a clinical trial.
investigational product (or study product). Any pharmaceutical product
(see definition) or placebo being tested or used as a reference in a clinical trial.
investigator. A person responsible for the trial and for the rights, health
and welfare of the subjects in the trial. The investigator should have qualifications
and competence in accordance with local laws and regulations as evidenced by

up-to-date curriculum vitae and other credentials. Decisions relating to, and
the provision of, medical or dental care must always be the responsibility of a
clinically competent person legally allowed to practise medicine or dentistry.
lower limit of quantification. The lower limit of quantification of an
individual analytical procedure is the lowest amount of analyte in a sample that
can be quantitatively determined with predefined precision and accuracy.
metadata. Metadata are data that describe the attributes of other data,
and provide context and meaning. Typically, these are data that describe the
structure, data elements, interrelationships and other characteristics of data.
They also permit data to be attributable to an individual. Examples of metadata
are the audit trails provided by certain types of software.
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monitor. A person appointed by, and responsible to, the sponsor or

contract research organization for the monitoring and reporting of progress of
the trial and for verification of data.
pharmaceutical product. Any substance or combination of substances
which has a therapeutic, prophylactic or diagnostic use, or is intended to
modify physiological functions, and is presented in a dosage form suitable for
administration to humans.
principal investigator. The investigator serving as coordinator for
certain kinds of clinical trials, e.g. multicentre trials.
Note: principle investigator also has a specific, but different meaning
in good laboratory practices, which is seldom used in bioequivalence studies.
To avoid any misunderstanding, the term principal investigator will only be
used in this guidance document with its good clinical practices meaning.
protocol. A document that states the background, rationale and
objectives of the trial and describes its design, methodology and organization,
including statistical considerations, and the conditions under which it is to
be performed and managed. The protocol should be dated and signed by the
investigator, the institution involved and the sponsor. It can also function as
acontract.
quality assurance relating to clinical trials. Systems and quality control
procedures that are established to ensure that the trial is performed and the data
are generated in compliance with good clinical practices and good laboratory
practices. These include procedures to be followed which apply to ethical and
professional conduct, standard operating procedures, reporting, and professional
qualifications or skills of personnel.
quality control samples. A spiked sample used to monitor the
performance of a bioanalytical method and to assess the integrity and validity
ofthe results of the unknown samples analysed in an individual batch.
raw data. All records or certified copies of original observations, clinical
findings or other activities in a clinical trial necessary for the reconstruction
and evaluation of the trial. Such material includes laboratory notes, memoranda,
calculations and documents, as well as all records of data from automated
instruments or exact, verified copies, e.g. in the form of photocopies or
microfiches. Raw data can also include photographic negatives, microfilm,
magnetic media (e.g. computer diskettes) and optical media (CD-ROMs).
serious adverse event. An event that is associated with death, admission
to hospital, prolongation of a hospital stay, persistent or significant disability or
incapacity, or is otherwise life-threatening in connection with a clinical trial.
sponsor. An individual, a company, an institution or an organization that
takes responsibility for the initiation, management and/or financing of a clinical
trial. When an investigator initiates and takes full responsibility for a trial, the
investigator then also assumes the role of the sponsor.
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standard operating procedures. Standard, detailed, written instructions

for the management of clinical trials. They provide a general framework
enabling the efficient implementation and performance of all the functions and
activities for a particular trial as described in this document.
study director. According to the Organisation for Economic Co-
operation and Development principles of good laboratory practice: the
individual responsible for the overall conduct of the nonclinical health and
environmental safety study. In a bioequivalence study the individual responsible
for the conduct of the bioanalytical part of the study.
study product. see investigational product.
test product. Any pharmaceutical product (see definition) or placebo
being tested against the reference in a clinical trial. In a bioequivalence study,
this is the multisource product being tested against the comparator product.
trial subject. An individual who participates in a clinical trial, either as
a recipient of the pharmaceutical product under investigation or as a control.
The individual may be:
a healthy person who volunteers to participate in a trial;
a person with a condition unrelated to the use of the investigational
product;
a person (usually a patient) whose condition is relevant to the use
of the investigational product.
upper limit of quantification. The upper limit of quantification of an
individual analytical procedure is the highest amount of analyte in a sample
which can be quantitatively determined with predefined precision and accuracy.
validation. Action of proving and documenting, in accordance with
the principles of good clinical practices and good laboratory practices, that
any procedure, process, equipment (including the software or hardware used),
material, activity or system actually and consistently leads to the expected results.
verification of data. The procedures carried out to ensure that the data
contained in the final report match original observations. These procedures may
apply to raw data, data in case-report forms (in hard copy or electronic form),
computer printouts and statistical analysis and tables.
A. GENERAL SECTION
3. Organization and management
Note: the acronym CRO is used throughout this document to refer not only
to a contract research organization, but also to any organization involved in the
conduct of in vivo BE studies or in the analysis of samples or of data from such
in vivo BE studies
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3.1 Where national requirements exist as to the legal status of a CRO these
have to be complied with. This also applies to the research unit which is a
subsidiary of the manufacturer.
3.2 The CRO should have an organization chart depicting key positions and
the names of responsible persons. The organization chart should be dated,
authorized and kept up to date.
3.3 There should be job descriptions for all personnel, including a description
of their responsibilities. Every job description should be signed and dated
by the staff member to whom it applies.
3.4 There should be a list of signatures of the authorized personnel performing
tasks during each study.
3.5 For the bioanalytical part of the trial, the principles of GLP clearly establish
the responsibilities of the test facility management. For the clinical part
ofthe trial, the CRO management should be aware that as the investigator
is an employee of the CRO, some of the responsibilities usually assigned to
the investigator would in a similar way reside with the CRO management.
At a minimum, the CRO management should:
ensure that the principles of GCP and GLP, as appropriate, are
complied with in the CRO;
ensure that a sufficient number of qualified personnel, appropriate
facilities, equipment and materials are available for the timely and
proper conduct of the study;
ensure the maintenance of a record of the qualifications, training,
experience and job description for each professional and
technicalindividual;
ensure that personnel clearly understand the functions they are to
perform and, where necessary, provide training for these functions;
ensure that appropriate and technically valid SOPs are established
and followed, and approve all original and revised SOPs and ensure
the maintenance of a historical file of all SOPs;
ensure that there is a quality assurance (QA) programme with
designated personnel and assure that the QA responsibility is being
performed in accordance with the principles of GLP and GCP,
asappropriate;
ensure that an individual is identified as responsible for the
management of the archive(s), and ensure that the documents
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transferred to the archives are kept under adequate conditions for

the appropriate duration;
ensure that supplies meet requirements appropriate to their use in a
study;
establish procedures to ensure that computerized systems are
suitable for their intended purpose, and are validated, operated and
maintained in accordance with the principles of GCP and GLP,
asappropriate.
4. Computer systems
Note: this section highlights only some of the requirements for computer
systems that are specific to BE studies. Organizations involved in BE studies
should ensure that the relevant principles of the following guidelines are
appropriately followed:
GAMP 5: A risk-based approach to compliant GxP computerized
systems (7);
Good practices for computerised systems in regulated GXP
environments, PIC/S guidance (8);
US Food and Drug Administration (FDA) Guidance for industry:
part 11 (9);
EU guidelines for good manufacturing practice and medicinal products
for human and veterinary use Annex 11, Computerised systems (10);
WHO Guidance on good data and record management practices (11).
General
4.1 Computer systems should be qualified and validated (hardware, software,
networks, data storage systems and interfaces (710). Qualification is the

planning, carrying out and recording of tests on equipment and systems
which form part of the validated process, to demonstrate that the
equipment or system will perform as intended.
Hardware
4.2 There should be a sufficient number of computers to enable personnel
to perform data entry and data handling, required calculations and
compilation of reports.
4.3 Computers should have sufficient capacity and memory for the
intendeduse.
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Software
4.4 There should be access control to the trial-related information entered
and stored in computers. The method of access control should be specified
(e.g. password protection) and a list of people who have access to the
database should be maintained. Secure and unique, individual-specific
identifiers and passwords should be used.
4.5 The software programs used to perform key steps detailed in these
guidelines should be suitable and validated for the intended use. Whether
standard, off-the-shelf software is purchased or bespoke software is
developed, developer, vendor and/or service provider qualification and/or
validation certificates may be provided but it is the users responsibility to
ensure that the software is validated for its intended use and that it was
developed in a controlled manner in accordance with a QA system.
4.6 Formal qualification and validation should generally be carried out by the
developer. Performance qualification should take account of the specific
users requirements, of regulatory/guideline requirements for BE studies,
of the operating environment in which it will be used, and of how it will
be used by an organizations staff in the context of a study. Quality risk
management should be applied when deciding which components need
to be validated. All phases of their life cycle should be considered. For
example, when a CRO decommissions the software in use for high-
performance liquid chromatography (HPLC) and mass spectrometric
(MS) analysis (e.g. HPLC-MS/MS), it should ensure that the data collected
by the system using this software remain fully readable. This could be
done, for instance, by having the old software installed on a workstation
for inspection and/or verification purposes only.
4.7 There should be SOPs in place for usage of each software program that is
used to perform activities of a BE study.
4.8 There should be a system in place for the implementation of regular
updates to key software programs (e.g. those used for control and data
processing of chromatographic and MS systems) whenever required,
following an appropriate risk assessment on the potential impact that it
could have on current data and on qualification or validation status.
4.9 Software programs used, frequency of virus testing, storage of data and the
procedure for backups and long-term archiving of all relevant electronic
data should be specified in writing. The frequency of backups and archiving
should be specified. If back-up data are periodically rewritten as part of
the back-up procedure, the data from the backups should be archived
regularly, preferably before rewriting is done.
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4.10 The programs used should be able to provide the required quality and
management information, reliably and accurately. Programs necessary
for data management include word processing, data entry, databases,
graphics, pharmacokinetics and statistical programs. Self-designed software
programs must be suitable and validated for their intended use.
4.11 Since data for BE studies are often transferred electronically between
organizations involved in the studies, verification that the software used by
each organization is compatible with the others and that there is no impact
on the data so-transferred, should be conducted prior to commencing key
study-related tasks.
4.12 These requirements apply to all systems used in clinical BE studies,
e.g. subject database, electronic case report forms, electrocardiogram
(ECG) recording software, HPLC-MS/MS software, software used for
pharmacokinetic analysis, for statistical analysis and any other relevant
system.
Networks
4.13 Networks, including the full client/server architecture and interfaces such
as laboratory information management systems, when used, should be
appropriately designed, qualified, managed and controlled.
4.14 Access to each component of the system by the different users at any given
organization involved in the studies, should be appropriately defined,
controlled and documented.
4.15 There should be a documented inventory of all computerized systems on
the network, with a clear identification of those which are GXP regulated.
Any changes to the network, including the temporary addition or removal
of systems from the network, should be documented.
Data management
4.16 Data entry includes transfer of the data from case report forms (CRFs),
analytical data and any other data relevant to the reliability and integrity of
a study, to the computerized system.
4.17 Data entry procedures should be designed to prevent errors. The data
entry process should be specified in the SOP.
4.18 Data validation methodology (proofreading, double data entry, electronic
logical control) should be specified in writing and performed.
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4.19 Changes to data entered in the database should be made by authorized

persons only. Changes should be specified and documented.
4.20 Electronic data should be backed up at regular intervals. The reliability
and completeness of these backups should be verified data should not be
selected, rather all data should be comprehensively backed up.
4.21 All of the raw electronic data must be kept. This includes:
all metadata associated with a computerized system and the
equipment associated with it (which includes the audit trails for
integration, for results, projects and for the entire instrument);
validation data and metadata in the form of their source
electronicfiles.
PDF copies are not sufficient on their own, unless it can be
demonstrated that these are the raw data and that no alteration was
possible after they weregenerated.
4.22 All electronic records obtained from HPLC and MS analysis (e.g. HPLC-
MS/MS) are required to be retained, maintained and backed up. It should
be ensured that backup data are exact and complete and that they are secure
against alteration, inadvertent erasures or loss. The printed paper copy of
the chromatogram would not be considered a true, exact and complete
copy of all the electronic raw data used to create that chromatogram.
Printed chromatograms do not generally include, for example, the sample
sequence, instrument method, processing method, integration settings or
the full audit trail, all of which were used to create the chromatogram or are
associated with its validity. Therefore there should be a greater emphasis on
conservation of electronic data than paper data, as paper data are usually
not considered the true source data, except, for instance, in the case of
paper logbooks where the original record was handwritten.
4.23 If data are transformed during processing steps (such as in the example
of re-integration of chromatographic data), it should always be possible to
compare the original data with the processed data.
5. Quality management
5.1 The CRO should have appropriate QA and QC systems with written SOPs
to ensure that trials are conducted and data are generated, documented
and reported in compliance with the protocol, GCP, GLP, GMP and the
applicable regulatory requirements.
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5.2 QA personnel should be independent of the work they are quality

assuring, including:
conducting or monitoring of the trial;
conducting bioanalysis;
performing reporting and pharmacokinetic and statistical analyses.
As a consequence, QA personnel should not be directly involved
in trial-related activities, and an in-process audit by QA personnel does
not replace oversight by another person when required.
5.3 The QA unit should be responsible for:
verifying all activities undertaken during the study;
ensuring that the quality management systems, are followed,
reviewed and updated;
determining that the protocol and SOPs are made available to study
personnel and are being followed;
checking all the study data for reliability and traceability;
planning and performing self-inspections (internal audits) at regular
and defined intervals in accordance with an SOP, and following up
on any corrective action as required, to determine if all studies are
conducted in accordance with GCP and GLP;
ensuring that contract facilities adhere to GCP and, if applicable, to
GLP: this would include auditing of such facilities, and following up
on any corrective action required;
verifying that the trial report accurately and completely reflects the
data from the study and the methods and procedures followed;
promptly reporting audit findings in writing to management, to the
investigator and to the study director, as applicable.

5.4 The CRO should allow the sponsor to monitor the studies and to perform
audits of the clinical and analytical study and sites and should provide
suitable office space for these activities.
5.5 Both in-process and retrospective QA verifications (e.g. in bioanalysis,
as the samples and standards are being prepared and tested) should
beperformed.
5.6 The quality management system should include root cause analysis,
tracking for trends, ensuring all aspects of data integrity and the
implementation of appropriate corrective and preventive action (CAPA).
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6. Archive facilities
6.1 The CRO should have sufficient and appropriately secure storage space,
which should be fireproof, relative humidity-controlled and pest-controlled,
for archiving of the trial-related documentation. Archives should also be
protected from flooding.
6.2 An SOP should be in place for archiving.
6.3 Access to archive storage areas should be controlled and restricted to
authorized personnel.
6.4 Records of document access and return should be maintained.
6.5 The length of time for which study documentation, including raw data, is
kept in the archive should be defined in the SOP and may vary depending
on country requirements. This period should be specified in the contract
between the sponsor and the CRO, which should include provisions for
financing of the archiving.
6.6 All data, including both paper and electronic versions, should be easy to
retrieve and traceable.
7. Premises
7.1 The facilities should be kept clean and should have adequate lighting,
ventilation and, if required, environmental control. Floors, walls and
working bench surfaces should be easy to clean and to decontaminate.
7.2 Clinical trials must be carried out under conditions that ensure adequate
safety for the subjects. The site selected should be appropriate to the
potential risk involved.
7.3 The CRO should have sufficient space to accommodate the personnel
and activities required to perform the studies. The trial site must have
adequate facilities, including laboratories, and equipment. The facilities
used for the clinical phase of the study, including areas listed in paragraph
9.6, should be well organized in order to carry out the activities in a
logical order.
7.4 Entry to the facility should be restricted and controlled. There should be
alarm systems to detect the exit of subjects from clinical facilities, or the
doors should be locked (but only if emergency evacuation can still be
ensured). Any entry to and exit from the facility should be recorded.
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7.5 Sites where clinical activities take place should include a pharmacy where
investigational products should be stored under appropriate conditions
with entry and exit restricted by access control. Appropriate entry/exit
records of each visit to the pharmacy should be maintained.
7.6 Utilities such as water, air, gas and electricity should be adequate, stable
and uninterrupted.
7.7 Access to telephone, email and facsimile facilities should be available to
ensure proper communication. The CRO should have the necessary office
equipment (printer, copy machine) to perform the required activities.
7.8 Laboratory premises should be designed to suit the operations to be
carried out in them. Sufficient space should be provided to avoid mix-ups,
contamination and cross-contamination. Adequate storage space suitable
for samples, standards, solvents, reagents and records should be available.
7.9 Laboratory premises should be designed to provide adequate protection
to all employees and authorized external personnel, including inspectors
or auditors, by ensuring their safety while handling or working in the
presence of chemicals and biological samples. Inappropriate working
conditions can have a negative impact on the quality of the work performed
and of the data generated.
The general rules for safe working in accordance with national
regulations and SOPs normally include the following requirements.
Safety data sheets should be available to staff before testing is
carried out. Staff working in the laboratory should be familiar with
and knowledgeable about the material safety data sheets for the
chemicals and solvents that they are handling.
Smoking, eating and drinking in the laboratory should be prohibited.
Staff should know how to use the firefighting equipment, including

fire extinguishers, fire blankets and gas masks.
Staff should wear laboratory coats or other protective clothing,
including eye protection.
Appropriate care should be taken when handling, for example,
highly potent, infectious or volatile substances.
Highly toxic and/or genotoxic samples should be handled in a
specially designed facility to avoid the risk of contamination.
All containers of chemicals should be fully labelled and include
prominent warnings (e.g. poison, flammable or radioactive)
whenever appropriate.
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Adequate insulation and spark-proofing should be provided for

electrical wiring and equipment, including refrigerators.
Rules on safe handling of cylinders of compressed gases should
be observed and staff should be familiar with the relevant colour
identification codes.
Staff should be aware of the need to avoid working alone in
thelaboratory.
First-aid materials should be provided and staff instructed in first-
aid techniques, emergency care and the use of antidotes.
Containers containing volatile organic solvents, such as mobile
phases or liquid/liquid extraction solvents should be closed with an
appropriate seal.
Volatile organic chemicals should be handled under certified
fume-hoods or air extractors and safety and eye showers should be
available in the laboratory.
7.10 Premises should have suitable systems in place to dispose of waste, to
treat fumes and to protect the environment in conformance with local or
national regulations.
8. Personnel
8.1 There should be a sufficient number of medical, paramedical, technical and
clerical staff with the appropriate qualifications, training and experience
to support the trial and to be able to respond effectively to all reasonably
foreseeable emergencies. The number of members of staff required
depends on the number and complexity of the trials performed by the CRO.
At all stages of the trial, including at night, there should be a sufficient
number of appropriately qualified and trained personnel to ensure that the
rights, safety and well-being of the subjects are safeguarded, and to care for
the subjects in emergency situations.
8.2 The delegation of significant trial-related duties should be documented
inwriting.
8.3 Contract workers may be employed to perform certain activities. All
contract workers who have access to the clinical or bioanalytical areas
or who are performing trial-related activities should be provided with
adequate information, training and job descriptions. Their contracts
should be signed before beginning their work.
8.4 Current curricula vitae and training records should be kept for full-time
and contract workers.
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8.5 The personnel responsible for the planning and conduct of the study
should have appropriate qualifications and sufficient knowledge and
experience in the relevant field. They should receive the study-specific
information and training required for the performance of their work.
8.6 Records of training and assessment of knowledge of GCP, GLP and any
other relevant area or technique should be maintained.
8.7 There should be adequate measures in place to protect personnel from
accidental infection (e.g. from accidental needle pricks) while obtaining
blood samples from subjects or while handling samples that are derived
from blood products (e.g. plasma and its extracts) or while handling or
disposing of infectious waste.
B. CLINICAL SECTION
9. Clinical phase
Note: As in vivo BE trials are considered as clinical trials, specifically as a PhaseI
study, the general requirements and recommendations of GCP apply to all BE
trials. Clinical trials must be carried out under conditions that ensure adequate
safety of the subjects. The clinical phase of the study can be performed on the
premises of a CRO or by contracting suitable premises in a hospital.
9.1 A CRO should have rooms meeting the requirements listed in the
sectionsbelow.
9.2 There should be sufficient space to accommodate the study subjects.
9.3 Where appropriate, beds should be available for the subjects. The
necessity for beds and for overnight stays depends on the type of trial
and investigational product and should be specified in the trial protocol.
Overnight stays are usually required for the night prior to dosing to
ensure adequately controlled conditions and that there is no intake of
food or medication within the number of hours that is specified in the
trial protocol.
9.4 Systems should be in place in the accommodation facilities so that subjects
can alert CRO staff in case of need.
9.5 Facilities for changing and storing clothes and for washing and toilet
purposes should be clean, well ordered, easily accessible and appropriate
for the number of users. Lockable toilets should be alarmed and doors
should be designed to ensure that they can be opened from the outside
should there be a medical emergency.
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9.6 The study site should have rooms or areas, as appropriate, for the following:
subjects registration and screening;
obtaining informed consent of individual subjects without
compromising privacy;
subjects housing;
subjects recreation;
pharmaceutical operations (restricted access room, e.g. for storage,
repacking, dispensing, documentation) (see also section 14);
administration of the investigational products and sample collection;
sample processing (e.g. plasma separation) and storage (freezer);
controlled access storage of study materials, medication and
documentation including CRFs;
preparation of standardized meals and a dining hall;
proper care of subjects who require emergency or other medical
care, with emergency or first-aid equipment and appropriate
medication for use in emergencies;
archiving.
9.7 Provisions should be made for the urgent transportation of subjects to a
hospital or clinic equipped for their emergency care, if required.
9.8 Access to key documents, such as the randomization list, should be
restricted to specific personnel, such as the pharmacist in charge of the
study. Such documents should be password-secured (if electronic) or kept
under lock and key (if in the form of a hard copy) and their distribution
9.9 Equipment used should be appropriately calibrated at predefined intervals.
9.10 The adequate function and performance of emergency-use equipment
(e.g. defibrillators) should be verified at appropriate intervals.
10. Clinical laboratory

10.1 A suitable clinical laboratory should be used for analysing samples.
Whenever possible this should be an accredited laboratory.
10.2 Haematological tests, urine analysis and other tests should be performed
during the clinical trial as specified in the study protocol.
10.3 Sample labelling, receipt, storage and chain of custody should ensure full
traceability and sample integrity (9).
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10.4 The CRO should receive information about the analytical methods used
in the laboratory, a dated list of laboratory normal ranges and, if available,
the accreditation certificate of the laboratory. These should be available for
inspection by regulatory authorities upon request.
10.5 The laboratory should provide the CRO with current and signed curricula
vitae of the responsible individuals.
10.6 Individual reports should be created by the laboratory for each subject
and should be included in the CRFs. Source or raw data for all tests
performed should be archived by the laboratory in electronic or paper
formats, depending on their source and the laboratorys storage capacity.
Electronic formats are preferred.
10.7 Data integrity requirements apply to all tests related to the study (11).
For instance, raw data should be adequately protected from modification
ordeletion.
11. Ethics
11.1 Independent ethics committee
Trials must be approved by an independent ethics committee (IEC) (or
equivalent) before any study is conducted, according to WHO operational
guidelines for ethics committees that review biomedical research (6), and to
the legislation in force. This Committee must be independent from the
sponsor, the investigator and the CRO. Detailed minutes should be kept
of the discussions, recommendations and decisions of the IEC meetings.
The IEC should be given sufficient time for reviewing protocols, informed
consent forms (ICFs) and related documentation.
11.2 Informed consent

The following points should be borne in mind in relation to informed
consent.
Information for study participants should be given to them
in a language and at a level of complexity appropriate to their
understanding, both orally and in writing.
Informed consent must always be given by the subject and
documented in writing before the start of any trial-related activities,
in accordance with GCP. If informed consent is also recorded by
video, this recording should be retained in accordance with local
legal requirements.
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The information must make clear that participation is voluntary

and that the subject has the right to withdraw from the study on his
or her own initiative at any time, without having to give a reason
(compensation should be paid pro rata temporis). If subjects who
withdraw from the study offer their reasons for doing so, those
reasons should be included in the study records.
The subject must have access to information about insurance and
other procedures for compensation or treatment should he or she be
injured or disabled by participating in the trial or during screening.
The volunteers or subjects should be given the opportunity to discuss
with a physician their concerns regarding potential side effects
or reactions from the use of the investigational products before
participating in the trial. They should also be given the opportunity
and sufficient time to discuss their concerns about participating
in the trial with individuals outside the CRO, such as friends and
family members, if they wish.
If the ICF is available in several languages (e.g. in English and
in the local language, or in several vernacular languages) care
should be taken to ensure that all versions of the form contain the
sameinformation.
12. Monitoring
Note: monitoring is an essential activity to ensure the quality of the clinical trial.
12.1 The monitor should be appropriately qualified (see section 8: Personnel).
The main responsibility of the monitor for a BE study is to ensure that
the study is conducted in accordance with the protocol, GCP, GLP and
applicable ethical and regulatory requirements. This includes verification
of the use of correct procedures for completion of CRFs and verification of
the accuracy of data obtained.
12.2 The sponsor can delegate the monitoring function to the CRO. In such
cases the CRO should be able to arrange for the monitoring of the trial
according to regulatory requirements. In this situation, attention should
be paid to the independence of the monitoring function to avoid conflicts
of interest and pressure on the monitors. The monitoring reports should
always be provided to the sponsor.
12.3 A risk-based approach to monitoring can be considered. However, a pre-
and post-study visit, as well as a monitoring visit during the conduct of the
trial, are usually performed. The monitor should prepare a written report
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after each site visit and communicate any issues to the CRO and to the
sponsor as quickly as possible, even while the study is being conducted,
if possible, to enable prompt corrective action. Such communications and
corrective actions should be documented.
12.4 When the monitoring is delegated to the CRO, SOPs should be available
todescribe:
the designation of monitors, who should be independent from the
personnel performing the trial;
procedures for the monitoring visit;
the extent of source data verification, including with regard to
accountability of the investigational products and adherence to
theprotocol.
The extent of the monitoring, including the number of visits to be
performed, should be agreed with the sponsor.
12.5 Separate SOPs (with checklists for the monitor) for the initiation visit,
routine monitoring visits and a closing visit are recommended.
12.6 Appropriate entry/exit records of each monitoring visit should be
maintained.
13. Investigators
13.1 The principal investigator (PI) should have the overall responsibility for
the clinical conduct of the study, including clinical aspects of study design,
administration of the products under investigation, contacts with local
authorities and the ethics committee and for signing the protocol and the
final study report.

13.2 The investigator(s) should have appropriate qualifications, be suitably
trained and have experience in the conduct of BE studies (the legal status of
persons authorized to act as investigators differs between countries) and at
least one investigator must be legally allowed to practise medicine.
13.3 The medically-qualified investigator should be responsible for the integrity,
health and welfare of the subjects during the trial and for the accurate
documentation of all trial-related clinical data.
13.4 The CRO is responsible for selecting investigator(s). If the investigators
are not permanent employees of the CRO, external investigators should be
contracted and adequately trained.
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14. Receiving, storage and handling of

investigational products
14.1 CROs should record all the information concerning the receipt, storage,
handling and accountability of investigational products at every stage of
the trial. CROs must keep records of information about the shipment,
delivery, receipt, description, storage (including storage conditions),
dispensing, administration, reconciliation, return and/or destruction of
any remaining pharmaceutical products. Details of the pharmaceutical
product used should include dosage form and strength, lot number, expiry
date and any other coding that identifies the specific characteristics of the
product tested.
14.2 A suitably qualified person within the CRO or a local pharmacy or hospital
pharmacy should assume responsibility for storage, delivery, return and
keeping records of the investigational products.
14.3 Pharmaceutical products should be stored under appropriate conditions
as specified in the official product information provided by the sponsor.
14.4 All study medication should be kept in a securely locked area accessible
only to authorized personnel.
14.5 Randomization should be performed in accordance with an SOP and
records should be maintained, including the randomization list and seed,
if applicable. The randomization list should normally be accessible only to
the person who generates it, a dispensing pharmacist and the statistician,
and should not be circulated or made available to other staff members via
any medium. A system should be in place to allow the PI or delegated staff
to access the randomization list in case of emergency.
14.6 Labelling should be performed in accordance with the following
requirements.
The printing step should be done in a manner that reduces potential
risks of mislabelling and in accordance with an SOP.
Each label should include the following information:
name of the sponsor,
a statement reading for clinical trial use only,
trial reference number or study number,
batch number,
subject identification number (to whom the product is destined
to be given),
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study period,
active ingredient and dosage,
the storage conditions,
expiry date (month/year) or retest date,
identification of the product (i.e. test or reference).
Compliance of all labels with the randomization list should be
verified once they have been printed and prior to labelling of the
containers.
Labels should be pasted onto the container, not on the lid, to ensure
that the information is not lost once the lid is removed.
The system used for labelling and documenting the administration
of the product should make it possible to verify that each subject did
receive the product dispensed for him or her, for instance, by using
labels with a tear-off portion. In this case, labels should be designed
in such a way that two identical labels are pasted onto the container
and the second label can be easily cut or detached and pasted onto
the CRF at the time of dosing (e.g. two labels printed side by side,
with only one that is actually pasted onto the container and another
that remains attached but unpasted. Using two independent labels
one stuck on the container, one kept loose should be avoided
owing to the risk of mix-ups).
The empty containers should be labelled separately for the test and
the reference investigational products and should remain adequately
segregated in a secure area under lock and key to avoid the risk of
any potential mix-ups, until the dispensing stage.
Label reconciliation should be performed.
Appropriate, detailed records should be maintained for each of the
above steps.
14.7 Dispensing and packaging should be performed in accordance with the
following requirements.
The surface on which the product will be handled should be
thoroughly cleaned before bringing bottles of the product into
the area. Any product containers (full or empty), lone dosage
formulations, labelling materials, contaminants, dirt and debris
should be removed from the area.
A second person should verify that the surface area (otherwise
referred to as the line) is indeed clear and clean before bringing in
and opening containers of the product.
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Test and reference products should be handled using an appropriate

instrument, such as a spatula or spoon, as opposed to gloved hands.
Tablets should be distributed into each container in accordance with
the randomization list for the comparator or for the test product as
appropriate. The two products should never be handled at the same
time. This also applies to the labelled containers.
Records should be made of this step in a manner similar to that
used for manufacturing batch records, as described in WHO GMP
guidelines, i.e. each and every step should be recorded sequentially
in detail.
The surface upon which the product is handled and its surroundings
should be cleared and cleaned immediately before and after
initiating the dispensing of the next product. It is important to note
that this also applies to different products used in the same study.
Investigational product accountability and dispensing records
should be maintained at all times. Each activity should be
documented at the time it is performed. This includes:
records of doses dispensed and returned or destroyed,
records of cleaning and clearance of the area before dispensing,
record of verification of adequate cleaning and clearance of
thearea,
record of verification by a second person of each step.
Any factors that could affect the integrity of the data relating to
investigational medicinal products and comparators should be recorded,
monitored and controlled.
For further guidance on labelling and dispensing, please refer to
the WHO good manufacturing practices: supplementary guidelines for the
manufacture of investigational pharmaceutical products for clinical trials in
humans (12).
14.8 Dosing should meet the following requirements.
Dosing should be performed in accordance with an SOP.
Dosing should be performed under the supervision of the
investigator or of a qualified staff member to whom this task has
been explicitly delegated in writing.
Whenever possible, just prior to dosing, a check should be
performed to ensure that vial contents match the information on
the label.
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The exact time of dosing should be documented.

To ensure that the subject has swallowed the product, a mouth check
should be performed by looking under the tongue, under the lips,
in the corners of the mouth and between gums and cheeks, using
a tongue depressor or a spatula and a penlight, in the case of solid
oral dosage forms. For other dosage forms, verification of adequate
administration should be performed by other suitable means. This
If more than one dosage unit is administered, this should be
clearlydocumented.
Dosing can be documented directly in the CRFs. If re-transcribed
in the case of report forms from other documents, the original
documents should be retained.
Investigational product reconciliation after dosing should be verified
by a second responsible person.
14.9 The investigator should follow the protocol requirements, the

randomization scheme and, where required, blinding. The investigator
should ensure that the use of the investigational product is documented
insuch a way as to ensure appropriate dosage.
14.10 Samples of the product in the original container should be retained for
possible confirmatory testing in the future for a period of at least one
year after the expiry date of the newest product (test or reference) or in
compliance with the applicable national requirements or international
recommendations, as appropriate. Sample retention should be defined
and described in an SOP and be specified in the contract between the
sponsor and the CRO. Dispensed products that were not administered
should also be retained.
15. Case report forms

15.1 CRFs should be used to record data on each subject during the course of
the trial.
15.2 The CRO should have a procedure for designing CRFs if the sponsor
requests the CRO to do so. The use of a standardized format or template
is recommended. This should be adapted for each study protocol in
accordance with the requirements for that particular study. The CRF
should be reviewed against other trial documentation, such as the protocol
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and trial database, to ensure that appropriate information and data are
captured and that the CRF is consistent with other trial documentation.
15.3 The data to be collected on each volunteer should be specified in the
trial protocol. Any data to be recorded directly on the CRF (i.e. no prior
written or electronic record of data), and to be considered to be source
data, should be identified in the protocol.
15.4 CRFs should reflect the actual results obtained during the study and allow
easy access for verification, audit and inspection of the data.
15.5 Appropriate procedures should be established and followed to document
the investigators certification of the accuracy of CRFs. Any errors or
omissions should be clarified with the investigator, corrected, dated and
signed and explained on the CRF.
15.6 Copies of the clinical laboratory reports and all ECGs should be included
with the CRFs for each subject and should be submitted together with
the dossier, if applicable, in accordance with the requirements of the
regulatory authority to which the dossier is submitted.
16. Volunteers and recruitment methods

Note: The selection of subjects should be performed sufficiently far in advance
to ensure that a sufficient number of subjects will be available for the study. The
last-minute selection of additional subjects may result in noncompliance with
the inclusion and exclusion criteria, possibly compromising the safety of the
subjects and the integrity of the trial data. The use of a generic screening process
to select a pool of subjects that can be enrolled in any BE study conducted at the
CRO (unless the protocol foresees specific inclusion or exclusion criteria) can
help to achieve this goal.
16.1 Procedures for the recruitment of volunteers should be available and
should include a description of the potential methods that can be used by
the CRO for this purpose. A database should be maintained on volunteers,
to avoid cross-participation and to specify a minimum time that should
elapse between a volunteers participation in one study and the next.
Access to the database should be password controlled in order to secure
confidential information on volunteers or subjects.
16.2 Identification of volunteers and subjects should be ensured by reliable
means. If a biometric system is used, this system should be periodically
validated, as well as after any change made to the validated system that
could affect its function.
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16.3 The informed consent of potential subjects should be obtained for any
screening procedures required to determine eligibility for the study in
addition to informed consent for participation in the research portion of
the study.
16.4 Criteria for subject selection (inclusion and exclusion criteria) and
screening procedures should be described in the clinical trial protocol.
16.5 The results of subject screening and of trial participation should be

recorded in a validated database maintained by the CRO. If a regional or
national volunteer database exists, then this should be checked to find
out whether any of the subjects have participated in a previous trial and
participation data should be uploaded to this central repository to prevent
over-volunteering. Access to the database should be password controlled
in order to secure confidential subject information.
16.6 Ideally the CROs database should record and allow the users to query:
contact details;
sex;
status: e.g. eligible, disqualified, not eligible, quarantined, and the
reason for this status if applicable;
date and place of last study participation, if applicable/if known;
date of last screening;
a unique code assigned to the subject which will never change;
outcome of last trial: e.g. completed, randomized but not dosed,
withdrawn for personal reasons, withdrawn for medical reasons.
These data should be backed up daily and be available for review

at any time.
16.7 Medical records should be generated for each subject and should include
information obtained during each screening visit and from each study
in which the subject has participated, which could be relevant for the
inclusion and follow-up of the subject in subsequent trials. Access to
previous medical records for individual subjects should be available and
a consistency check conducted where trial-specific medical records are
generated. This is important to ensure that safety issues can be assessed
before a subjects enrolment in a study.
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17. Food and fluids

17.1 As meals can significantly affect absorption of active pharmaceutical
ingredients, fasting and meals should be standardized and adequately
controlled and scheduled during the study days. The CRO should be
able to arrange for standardized meals, snacks and drinks for the study
subjects as described in the clinical trial protocol.
17.2 Records should be maintained of the timing, duration and amount of food
and fluids consumed. Prior to samples being obtained from ambulatory
subjects, they should be asked about their food and drink consumption, if
the protocol contains specific requirements.
17.3 Standardized meals should be designed by a dietitian with appropriate

qualifications, training and experience. If such services are contracted
out, a formal contract with terms of reference should be available.
18. Safety, adverse events and adverse event reporting

18.1 Appropriate study planning includes adequate evaluation of risk to
the subjects. The study should be planned, organized, performed and
monitored so that the safety profile will be acceptable, including to
thevolunteers.
18.2 First-aid equipment and appropriate rescue medication should be

available and ready for emergency use at the study site where there
should be adequate facilities for the proper care of subjects who require
emergency or other medical treatment. Any treatment given to a subject
should be documented and included in the CRF and in the supporting
documentation, as necessary.
18.3 A medical doctor should be responsible for medical decisions in the

case of adverse events and for notifying the relevant health authorities,
the sponsor and, when applicable, the ethics committee, without delay
in the case of serious adverse events. Appropriate timelines should be
respected in accordance with national regulations.
18.4 The CRO should have appropriate adverse event registration and reporting
forms, which should be provided to the investigator; these forms can be
part of the CRF. If required the sponsors forms may be used.
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C. BIOANALYTICAL SECTION
Note: The measurement of analyte concentrations (API or metabolites) may be
performed by the same CRO as conducted the clinical study, or this work may
be contracted to another laboratory or CRO.
19. Method development

19.1 The bioanalytical laboratory should provide a detailed description of
how a bioanalytical method was developed. The laboratory should keep
a copy of any publications used in developing the bioanalytical method.
The modifications and adaptations to the published method made by the
laboratory should be documented.
19.2 Selection of the internal standard should be justifiable by sound scientific
principles. In general, the chemical and physical properties of the
internal standard should be as close to those of the analyte as possible.
Both stable isotope-labelled and non-isotope-labelled internal standards
are acceptable, although the use of a stable isotope-labelled internal
standard is recommended when MS methods are used. The selection of
a stable isotope-labelled internal standard should take into consideration
factors such as the isotope labelling positions in order to limit the risk of
exchange reactions.
19.3 The procedure for method development should ensure that methods are
created in a manner that will minimize any potential human error.
20. Method validation

The most up-to-date guidelines available from stringent regulatory authorities
(SRAs) on the topic of bioanalytical method validation should be followed.

20.1 Validation requirements for the analytical method should be described
in the protocol. There should be separate SOPs for analytical method
validation.
20.2 Data to support the stability of the samples under the stated conditions
and period of storage should be available, preferably before the start of
the study.
20.3 Method validation should be performed with at least one run that is
comparable in length to those that are expected to be used for analysis
ofsamples.
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21. Sample collection, storage and

handling of biological material
21.1 The specification of the samples (serum, plasma or urine), sampling
method, volume and number of samples should be stated in the clinical
trial protocol and in the information provided to the volunteers.
21.2 There should be documented procedures for the collection, preparation,
transport or shipping and storage of samples.
21.3 Any specific lighting conditions foreseen by the protocol or other
documents should be complied with. This should be documented.
21.4 Actual sampling times and deviations from the prespecified sampling
times should be recorded. Deviations should be noted in the study
report and should be taken into consideration when calculating the
pharmacokinetic parameters.
21.5 Labelling of collected samples should be clear to ensure correct
identification and traceability of each sample.
21.6 The conditions for the storage of samples depend on the analyte. However,
all storage conditions (e.g. freezer temperature) should be specified in
the study protocol, controlled, monitored and recorded throughout the
storage period and during transportation. Procedures should be in place
to ensure maintenance of sample integrity in case of system failures.
21.7 Records of the storage and retrieval of samples should be maintained.
21.8 It is recommended to keep duplicate or back-up samples, and to store and
ship them separately.
21.9 The duration of storage of bioanalytical samples should be specified in
the contract between the sponsor and the CRO.
21.10 Local requirements for the handling and destruction of any remaining
biological materials should be complied with.
22. Analysis of study samples

The most up-to-date guidelines from SRAs on the topic of bioanalytical method
validation should be followed. Additionally:
22.1 The results of the method validation should be available before the
initiation of study sample analysis, with the possible exception of the
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evaluation of the long-term stability of the analyte in matrix. However,

these results should be available before the study report is issued and
should be submitted with the validation report in the application.
22.2 Each analytical run should include calibration curve (CC) standards,
QC samples and subject samples processed simultaneously. The exact
sequence of processing should be documented. All samples collected
from a given subject during all trial periods should be analysed in the
same run unless scientifically justified (e.g. where the limited stability of
samples necessitates the analysis of period one samples before period two
is conducted).
22.3 Equipment with an adequate capacity should be used to enable all samples
in a run to be processed simultaneously, rather than splitting the samples
into several extraction batches. However, if using several extraction batches
within a single analytical run cannot be avoided, each batch should include
QC samples. The acceptance criteria for the analytical run should be
defined in an SOP first for the full run, then if the run is acceptable, for
each individual extraction batch.
22.4 Every effort should be made during method development to avoid carry-
over effects. If carry-over cannot be avoided, procedures should be
implemented to limit its influence, for instance, by inserting wash samples
into runs after samples with a high concentration.
22.5 With regard to the use of blank plasma in the preparation of CCs and QCs:
the number of freezethaw cycles and the duration of storage that a
given blank plasma sample can be submitted to should be limited as
much as possible to ensure that there is no degradation and/or any
change of its properties. Freezing blank plasma in small volumes
should be considered to help limit the number of freezethaw cycles

for any given blank plasma sample;
the anticoagulant that was used for the blank plasma should be
documented. It should match the anticoagulant that was used in
study samples, in nature and in proportion.
22.6 With regard to incurred sample reanalysis:
incurred sample reanalysis should be performed in line with the
European Medicines Agency (EMA) Guidelines on bioanalytical
method validation (13);
large differences between results may indicate analytical issues and
should be investigated.
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23. Data processing and documentation

23.1 Integration settings should be science-based and fully justifiable. Smoothing
should be kept low enough not to mask possible interferences and changes
in peak geometry.
23.2 The different iterations used to obtain a CC should be saved if a given CC
fails, it is not acceptable to exclude CCs which meet acceptance criteria or,
similarly, to include CC standards that do not meet criteria, just to make
the calibration or the QC standards pass. The source data should contain
the original, first evaluation of runs (containing all calibration samples). If
several calibration samples are excluded sequentially, the CC obtained at
each step should be retained to document that the criteria for excluding the
next sample were met. If electronic raw data are used it is acceptable to save
only the final calibration if it is possible to revert to the initial calibration
during an inspection. The process and criteria for acceptance and exclusion
of CC standards should be described in an SOP.
23.3 If the first or last calibration sample is rejected, the calibration range
should be truncated, i.e. the second calibration sample becomes the lower
limit of quantification (LLOQ) in that run (or the penultimate calibration
sample becomes the upper limit of quantification (ULOQ). Samples with
a concentration below the revised LLOQ (or above the revised ULOQ)
should be reanalysed. Alternatively, the whole run may be repeated, but
this is not the preferred option.
23.4 Internal standard variation should be trended and used as part of the
verifications of result validity. Significant changes in internal standard
response could signal an analytical problem that requires an investigation
and/or sample reanalysis. Significant differences between the internal
standard results of CC standards or QC standards versus samples could
also signal problems affecting the reliability of the results.
23.5 Full audit trails should be activated at all times and on all analytical
instruments in a given facility, before, during and after the method
validation and the study of interest.
23.6 All original analytical raw data (e.g. calculations, chromatograms and their
associated audit trails) should be documented in a manner that will ensure
traceability with respect to the sample number, equipment used, date
andtime of analysis and the name(s) of the technician(s). If several audit
trail files are generated, all should be retained (e.g. results table audit trail,
project audit trail and instrument audit trail).
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23.7 Each data point should be traceable to a specific sample, including

sample number, time of collection of the sample, time of centrifugation,
if applicable, time when the sample was placed in the freezer and time of
sample analysis, to be able to determine whether any aberrant results might
have been caused by sample mishandling.
24. Good laboratory practices

24.1 Although most GLP guidelines (2) apply formally only to nonclinical
safety studies, general principles of GLP should also be followed during
the bioanalytical part of BE studies.
24.2 Analysis should be performed in a laboratory with established QA

systems(14).
24.3 Key sample storage systems or other areas requiring environmental

controls should be adequately qualified, calibrated and maintained. There
should be an alarm system or an adequate monitoring system to control
the temperature of the critical stage areas and key sample storage systems,
such as freezers. If there is an automatic alarm system it has to be tested
regularly to check its functionality. The daily monitoring and all the alarm
checks should be documented. There should be a system in place to ensure
that timely and appropriate action is taken following an alarm.
24.4 For the purposes of qualification and requalification, the temperature-

mapping of the freezers and refrigerators should be run for between 24
and 72 hours, or more if justified. Remapping should be done after any
significant modifications to the storage units.
24.5 Appropriate repairs and/or transfer of samples to other equivalent storage

units should be considered whenever an analysis of temperature monitoring
records shows unexplained variability outside normal operating limits.
24.6 Balances, other measuring devices and equipment and instruments used
during the conduct of a trial should be periodically calibrated and verified
before use. They should be fit for their intended purpose.
24.7 There should be SOPs for the operation, use, calibration, checks and
preventive maintenance of equipment. Records should be maintained.
Items of equipment used during the course of the trial should be
identified to enable verification that they have been appropriately qualified
andcalibrated.
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24.8 Chemicals, reference substances, reagents, solvents and solutions should

be labelled to indicate identity, purity, concentration (if appropriate),
expiry date and specific storage instructions. Information concerning
source, preparation date and stability should be available.
D. PHARMACOKINETIC, STATISTICAL
CALCULATIONS AND REPORTING SECTION
25. Pharmacokinetic and statistical calculations
25.1 The statistical model underlying any primary BE analysis should be stated
in the protocol and/or a statistical analysis plan. It should be made clear
which factors are fixed and which are random and whether the model is a
mixed effects model, a normal linear model, or another type. If the methods
of statistical analysis are amended following approval of the protocol then
this should be documented in a protocol amendment and should also be
reported in the clinical study report together with the reason for change.
25.2 Calculations should be made by suitably qualified personnel (see section 8:
Personnel).
25.3 The means of performing pharmacokinetic and statistical calculations
(both software and scripts) should be specified in the study protocol and/
or a pharmacokinetic analysis plan and a statistical analysis plan. Data
analysis should conform to these requirements. This should include the
manner in which area under the curve from time zero to infinity (AUC inf )
isderived (i.e. how the points used for extrapolation are selected).
25.4 Calculations should be made using validated software and scripts. Software
and scripts should be validated or qualified using an SOP, ideally with
datasets of varying complexity and with the alpha level(s) actually in use.
Self-designed software should be demonstrated as suitable for intended use.
For guidance on the use of computerized systems (see section 4: Computer
systems) (8).
25.5 Data values input should be double-checked by a second qualified person
in accordance with an SOP.
25.6 A database of trial records should be maintained and should ideally be
locked as soon as possible after completion of the study. Once it is locked
the study can be unblinded and statistical analysis performed. The dates of
locking and statistical analysis should be documented and mentioned in
the study report, and the process should be defined in a suitable procedure.
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26. Study report

26.1 The clinical study report should accurately reflect all the study procedures
and results.
26.2 The clinical study report should be well written and presented. All
deviations from the protocol in the performance of the study should
bereported.
26.3 There should be no discrepancies between the results stated in the report
and the actual original (raw) data.
26.4 The report should comply with regulatory requirements as applicable and
be presented in a standard format.
26.5 The study report should include a report on the bioanalytical part of
the trial, including a description of the bioanalytical method used and the
report of the validation of this method.
26.6 The clinical study report should be approved by the investigator and
sponsor. The bioanalytical report should be approved by the study director.
26.7 The report should be approved (signed and dated) by the responsible
personnel.
26.8 All monitoring and audit reports should be available before release of the
final study report.
References
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Committee on Selection and Use of Essential Medicines: sixth report. Geneva: World Health
Organization; 1995: Annex 3 (WHO Technical Report Series, No. 850), pp. 97137.
2. WHO handbook on good laboratory practice: Quality practices for regulated non-clinical research
and development. Geneva: World Health Organization; 2009.
3. OECD series on principles of good laboratory practice and compliance monitoring, number 1:
OECD principles on good laboratory practice (as revised in 1997). Paris: Organisation for Economic
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Expert Committee on Selection and Use of Essential Medicines: fortieth report. Geneva: World
5. Guidance on the selection of comparator pharmaceutical products for equivalence assessment
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Annex8 (WHO Technical Report Series, No. 992).
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6. WHO Operational guidelines for ethics committees that review biomedical research. Geneva:
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Engineering (ISPE); 2009.
8. Good practices for computerised systems in regulated GXP environments, PIC/S Guidance.
Geneva: Pharmaceutical Inspection Convention Pharmaceutical Inspection Co-operation Scheme;
2007 (PI 0113, 25).
9. Guidance for industry: part 11, electronic records; electronic signatures scope and application.
US Food and Drug Administration; 2003 (http://www.fda.gov/downloads/RegulatoryInformation/
Guidances/ucm125125.pdf, accessed 27 February 2016).
10. EU guidelines for good manufacturing practice and medicinal products for human and veterinary
use. Annex 11, Computerised systems. Brussels: European Commission (SANCO/C8/AM/sl/
ares(2010)1064599).
11. Guidance on good data and record management practices. In: WHO Expert Committee on
Specifications for Pharmaceutical Preparations: fiftieth report. Geneva: World Health Organization;
2016: Annex 5 (WHO Technical Report Series, No. 996).
12. WHO good manufacturing practices: supplementary guidelines for the manufacture of
investigational pharmaceutical products for clinical trials in humans. In: WHO Expert Committee
on Specifications for Pharmaceutical Preparations: thirty-fourth report. Geneva: World Health
13. Guidelines on bioanalytical method validation. London: Committee for Medicinal Products for
Human Use (CHMP); 2012 (EMEA/CHMP/EWP/192217/2009 Rev.1 Corr.*).
14. Reflection paper for laboratories that perform the analysis or evaluation of clinical trial samples.
London: European Medicines Agency; 2012 (EMA/INS/GCP/532137/2010).
343
Appendix 1
Example list of standard operating procedures at a
contract research organization
The following is an example list of the standard operating procedures (SOPs)
that should be used at contract research organizations (CROs). This list is
not exhaustive as additional procedures may be necessary depending on the
functional and compliance requirements at the facility concerned.
All of the documents at the CRO related to a bioequivalence (BE) clinical
trial should be controlled (e.g. version date, date approved, etc.) documents.
This control is easier if the documents are in the SOP format or are appended
to SOPs.
SOPs should be in place at least for all the critical and major operations
in the BE/clinical trial.
Number and name of SOP

1. Conduct of BE study
2. Archiving and retrieval of documents related to a BE study
3. Quality assurance of a BE study; audits of clinical and bioanalytical part of
the study and the study report
4. Study files
5. Preparation and review of the protocol for the study
6. Amendment to the protocol for the study
7. Protocol deviations/violation recording and reporting
8. Sponsor/CRO quality assurance agreement on conducting the BE study
9. Process for approval of study by ethical committee

10. Bioavailability (BA)/BE report
11. Study report
12. Written informed consent
13. Obtaining written informed consent for screening from study volunteers
14. Allocation of identification numbers to volunteers at various stages in
BEstudy
15. Investigators brochure
16. Case report form (CRF)
17. Preparation of CRF, review and completion
344
Annex 9
18. Data collection and CRF completion

19. Adverse/serious adverse event monitoring, recording and reporting
20. Organizational chart for the study
21. Training of personnel
22. Responsibilities of the members of the research team
23. Monitoring of the study by the sponsor
24. Conduct of pre-study meeting.
25. Study start-up
26. Subject management
27. SOP on mobilization of individuals for registration in volunteer bank
28. Eligibility criteria for registration and registration of individuals in
volunteer bank
29. Handling of subject withdrawal
30. Allocation of identification numbers to volunteers at various stages in
thebiostudy
31. Screening of volunteers enrolled for the study
32. Collection of urine samples from subjects for detection of drugs of abuse
and transportation of samples to pathology laboratory
33. Custodian duties
34. Payments to research subjects for BE studies
35. Procedures for entry into and exit from clinical unit
36. Handling of subject check-in and check-out
37. Housekeeping at clinical unit
38. Planning, preparation, evaluation and service of standardized meals for
bio-studies
39. Distribution of meals to study subjects
40. Operation and maintenance of nurse call system
41. Administration of oral solid dosage form of the investigational product to
human subjects during BE study
42. Cannulation of study subjects
43. Collection of blood samples from study subjects
44. Identification of biological samples
45. Recording of vital signs of subjects
46. Operation and verification of fire alarm system
47. Administration of oxygen to subject from medical oxygen cylinder
345
48. Emergency care of subjects during BA/BE study

49. Availability of ambulance during BA/BE study
50. Centrifugation and separation of blood samples
51. Storage of plasma and serum samples
52. Segregation of bio-samples
53. Transfer of plasma and serum samples to bioanalytical laboratory
54. Procedures for washing glassware
55. Recording temperature and relative humidity of rooms
56. Instructions on operation and maintenance procedures for all the
equipment in the clinical unit
57. Numbering the equipment and logbooks for use in the clinical unit
58. Control of access to pharmacy
59. Pharmacy area requirements
60. Authorization related to investigational product storage, dispensing and
retrieval from storage for BE study
61. Investigational product receipt, return and accountability documentation
62. Investigational product receipt and return procedures
63. Storage of investigational products in the pharmacy
64. Line clearance before and after dispensing
65. Documentation of line clearance and dispensing; packaging records and
release of dispensed products
66. Retention of samples of investigational products
67. Disposal of archived investigational products
68. Disposal of biological materials
69. Procedures for bioanalytical laboratory (SOPs for the different items of
equipment, analytical methods, reagent preparation)

70. Out-of-specification in the laboratory
71. Acceptance criteria for analytical runs: acceptance of calibration curves,
acceptance of the runs based on quality control samples results
72. Chromatographic acceptance criteria and chromatogram integration
73. Sample re-assay
74. Pharmacokinetic data from bioanalytical data
75. Procedure for statistical analysis in a BE study
346
Annex 10
WHO general guidance on variations to multisource
pharmaceutical products
1. Introduction 348
2. Scope 348
3. Glossary 349
4. General considerations 351
5. Reporting categories for quality changes 352
5.1 Notifications 353
5.2 Minor variations 353
5.3 Major variations 353
6. New applications 354
7. Considerations for changes in product information and labelling 354
8. Procedures 355
8.1 General 355
8.2 Presubmission meetings 355
8.3 Proposed documentation for minor variations 355
8.4 Proposed documentation for variations requiring prior approval 356
8.5 Review procedures 357
References 357
347
1. Introduction
A marketing authorization (MA) holder or applicant is responsible for the
quality, safety and efficacy (QSE) of a finished pharmaceutical product (FPP)
that is placed on the market, throughout its life cycle. After the FPP has been
authorized for marketing, the manufacturer will often wish to make changes
(variations) for a number of reasons, for example, to respond to technical
and scientific progress, to improve the quality of the FPP, to apply updates to
the retest period for the active pharmaceutical ingredient (API) or shelf life
of the FPP, to meet market requirements such as for scale-up or additional
manufacturing sites, or to update product information (e.g. the information on
adverse reactions). Such changes, regardless of their nature, are referred to as
variations and may require the approval of the national medicines regulatory
authority (NMRA) prior to implementation.
NMRAs and MA holders should recognize that:
any change to the manufacture of the API or the FPP may impact
the QSE of that FPP;
any change to the information associated with the FPP (i.e. product
labelling information) may have an impact on the safe and effective
use of that FPP.
This document is intended to serve as a guide for establishing national
requirements for the regulation of post-approval changes. The proposed
categories of changes and reporting procedures are provided in these guidelines.
It is possible that modification of these principles may be justified in light of
riskbenefit and legal considerations specific to each NMRA.
2. Scope
This document provides guidance for NMRAs on the regulation of variations to

the original MA dossier or MA for an authorized multisource pharmaceutical
product on:
procedures and criteria for the appropriate categorization and

reporting of changes; and
how NMRAs can establish regulatory procedures for the post-
approval variations to an authorized FPP.
These guidelines can be used by NMRAs with respect to changes to the

quality sections of product dossiers and should be read in conjunction with the
348
Annex 10
Guidelines on submission of documentation for a multisource (generic) finished

product: quality part (1) as well as other related WHO guidelines or applicable
national guidelines. These guidelines are intended to provide an overview of
the principles that NMRAs should consider when establishing pharmaceutical
product variation procedures. Specific guidance on data requirements or risk
categorization of a particular change cannot be provided since the approach
taken by a specific NMRA is intrinsically linked to the regulatory framework
and resources available to that NMRA. Nonetheless, illustrative examples of the
data required to enable NMRAs to evaluate the impact of the variation on QSE
are provided in detail in the Guidelines on variations to a prequalified product (2)
or other national guidelines.
These guidelines are applicable only to APIs manufactured by chemical
synthesis or semisynthetic processes and FPPs containing such APIs. APIs
produced by fermentation and APIs of biological, biotechnological or herbal
origin fall outside the scope of these guidelines. For vaccines, NMRAs may
refer to the WHO Guidelines for procedures and data requirements for changes to
approved vaccines (3).
3. Glossary
The definitions provided below apply to the terms used in this guidance. They
may have different meanings in other contexts and documents.
active pharmaceutical ingredient. Any substance or mixture of
substances intended to be used in the manufacture of a pharmaceutical dosage
form, and that, when so used, becomes an active ingredient of that pharmaceutical
dosage form. Such substances are intended to furnish pharmacological activity
or other direct effect in the diagnosis, cure, mitigation, treatment or prevention
of disease, or to affect the structure and function of the body.
active pharmaceutical ingredient starting material. A raw material,
intermediate or an active pharmaceutical ingredient (API) that is used in the
production of an API and that is incorporated as a significant structural fragment
into the structure of the API. An API starting material can be an article of
commerce, a material purchased from one or more suppliers under contract or
commercial agreement or produced in-house.
biobatch. The batch used to establish bioequivalence or similarity to
the comparator product as determined in bioequivalence or biowaiver studies,
respectively.
finished pharmaceutical product. A finished dosage form of a
pharmaceutical product which has undergone all stages of manufacture
including packaging in its final container and labelling.
349
in-process control. Check performed during manufacture to monitor

or to adjust the process in order to ensure that the final product conforms to
itsspecifications.
manufacturer. A company that carries out operations such as production,
packaging, repackaging, labelling and relabelling of pharmaceuticals.
marketing authorization holder. For the purposes of this document,
the term marketing authorization holder refers to any person or entity that
holds the legal responsibility for the product on the market by submission of
the required documentation on a product that has been listed after evaluation as
registered or approved.
multisource (generic) pharmaceutical product. Pharmaceutically
equivalent or pharmaceutically alternative products that may or may not be
therapeutically equivalent. Multisource pharmaceutical products that are
therapeutically equivalent are interchangeable.
officially recognized pharmacopoeia (or compendium). Those
pharmacopoeias recognized by the national regulatory agencies (e.g. national
pharmacopoeia (if applicable), the British Pharmacopoeia, the European
Pharmacopoeia, The International Pharmacopoeia, the Japanese Pharmacopoeia
and the United States Pharmacopeia).
pilot-scale batch. A batch of an active pharmaceutical ingredient
or finished pharmaceutical product manufactured by a procedure fully
representative of and simulating that to be applied to a full production-scale
batch. For example, for solid oral dosage forms, a pilot scale is generally, at
a minimum, one-tenth that of a full production scale or 100000 tablets or
capsules, whichever is the larger, unless otherwise adequately justified.
production batch. A batch of an active pharmaceutical ingredient or
finished pharmaceutical product manufactured at production scale by using
production equipment in a production facility as specified in the application.
register. A list of all the pharmaceutical products authorized for
marketing in a particular country. The medicines regulatory authority of the

country in question maintains the register.
registered medicinal products. Pharmaceutical products that have a
marketing authorization.
validation. The demonstration, with documentary evidence, that any
procedure, process, equipment, material, activity or system leads to the
expected results.
variation. A change to any aspect of a pharmaceutical product,
including but not limited to, the change of use of a starting material, a change
to formulation, method and site of manufacture, specifications for the finished
product and ingredients, container and container labelling and product
information.
350
Annex 10
4. General considerations
For any change, the MA holder must consider the potential impact upon the
QSE of the FPP. As part of this consideration the MA holder should decide if
the information in the original MA needs to be supplemented and whether
this requires an official submission to the responsible NMRA or a change in
the application dossier, based on the recommendations in these guidelines.
Prior to implementing the variation, the MA holder should assess the effects
of the variation and demonstrate through appropriate studies the absence of
a significant negative effect of the change on the QSE of the FPP. MA holders
should be aware that some variations generate subsequent changes that might
require the submission of additional consequential variations. Therefore, for any
given variation, the MA holder should consider whether it is better to submit
more than one variation. In general no variation should be implemented without
the approval of the NMRA unless exempted in the national guidelines.
Even well-resourced agencies find it difficult to evaluate all the
pharmaceutical changes that are made to all products. This has resulted in a
shift towards increased self-assessment of changes by the MA holder. Therefore
it is necessary to define those changes that can be made without the NMRAs
prior approval (self-assessable changes) and those that require prior approval
based on an understanding of the risk and how best to manage this risk. NMRAs
may also establish an intermediate category of changes that do not require prior
approval but must be notified (notifiable changes) and may or may not be
subject to assessment.
MA holders are expected to evaluate the specific change that they are
planning to make in the context of their particular circumstances to determine
the impact on product QSE. In an application to vary the MA, the MA holder
advises the NMRA of an intended change and submits appropriate supportive
data. To encourage MA holders to give prior notice regarding such changes,
submissions for variations should be processed as quickly as possible. The NMRA
should consider publication of the timelines for processing the variations.
Implementation of these guidelines should not affect supply of and
access to medicines. Therefore NMRAs are strongly encouraged to establish
requirements that are commensurate with public health priorities and their own
regulatory capacity and resources. Communication of proposed procedures and
requirements to the pharmaceutical industry should also be ensured so that they
can adequately plan for the implementation of any new guidance.
Regional NMRA associations or networks could serve as forums
for sharing information and exchanging experience on technical issues and
regulatory decisions. Use of such networks would expand the capacity of
individual NMRAs through work sharing and recognition of the decisions
351
ofother NMRAs in the network and convergence of regulatory requirements,

thus avoiding unnecessary repetition of evaluations of the same variation by
multiple NMRAs.
In these guidelines, descriptions of the reporting categories are discussed
in section 5; proposed recommendations on the regulatory procedures for the
reporting of changes to the NMRAs are discussed in section 8.
5. Reporting categories for quality changes

In order to enhance predictability, guidelines on the data requirements and
conditions for the various categories of variations should be established and
regularly updated in light of scientific and technical progress, taking into account
the impact of the variation on the product QSE and how to manage this risk.
In addition to considering the impact of the change on a products
QSE, NMRAs may also modify the risk classification of a change through the
introduction of prerequisites that must be met by the MA holder. In this way a
change nominally identified as high-risk may be categorized across several risk
categories depending on the conditions applied. Generally speaking the greater
the number and specificity of the prerequisites the greater the possibility that the
change can be self-assessed by the MA holder.
An additional consideration for NMRAs when designing their variation
procedure is the determination of the default risk-category of changes not
described in their variation guidance. For example, if an unspecified change
defaults to a major variation, then effort should be focused on describing the
conditions and data requirements for circumstances where the change might be
considered as a lower risk category. In contrast, if a change defaults to a minor
variation, then the conditions and data requirements of major changes and low-
risk changes must be clearly defined.
The definitions outlined in the following reporting categories are
intended to provide examples of change classification strategies that may be

adopted by NMRAs for quality-related changes. Examples of specific variations
data and conditions requirements can be found in the WHO guidelines on
variations to a prequalified product (2) or other national regulatory guidelines
that NMRAs may consult or reference; attention should be given to the default
risk category underpinning the specific guidance.
NMRAs should also issue statements that whenever the MA holder is
unclear about the categorization of a particular variation, the respective NMRA
should be contacted.
Variations may be categorized into major variation, minor variation and
notification. NMRAs may decide to have fewer categories or more categories
depending on their national requirements.
352
Annex 10
5.1 Notifications
Notifications can be made for changes to the product that may have no potential
or a minimal potential to have a negative impact on the QSE. The MA holder
may implement such variations without prior approval by the NMRA. The
NMRA may require the MA holder to submit these variations as immediate
notifications (i.e. within a specific time frame after implementation) or as
annual notifications.
5.2 Minor variations

Minor variations are changes to the product that may have a potential to
have a moderate or negative impact on the QSE. Therefore such changes
must be submitted to the NMRA with all required documentation prior to
implementation. The MA holder may implement the change if no objection
letter has been issued within a time period specified by the NMRA.
5.3 Major variations

Major variations are changes to the product that may have a significant potential
to have a negative impact on the QSE. A major variation should be reviewed and
approved by the NMRA prior to implementation of the change.
Individual changes normally require the submission of separate
variations, but to increase efficiency NMRAs may accept grouping of variations
under specific circumstances, for example:
when variations are consequential to each other, e.g. introduction
of a new impurity specification that requires a new analytical
procedure;
when the same change affects multiple FPPs from the same
MAholder, e.g. addition of a new API manufacturing site for
multiple FPPs;
when all the changes are annual notifications;
when variations are related to a common technical topic, for example
drug master file updates or changes to the analytical procedures and
specifications to comply with pharmacopoeias.
MA holders and NMRAs should exercise caution whenever several
changes to the same FPP are envisaged. Although each of the individual changes
may be classified in a particular category, classification within a higher-risk
category may be warranted as a result of the composite effect of these changes.
In all such cases, it is recommended that MA holders are able to contact the
NMRA prior to submission of the variation application to obtain guidance on
classifying such changes.
353
If changes to the dossier only concern editorial changes, such changes

typically need not be submitted as a separate variation but can be included as
a notification together with a subsequent variation concerning that part of the
dossier. In such a case a declaration should be provided indicating that the
contents of the associated sections of the dossier have not been altered by the
editorial changes beyond the substance of the variation submitted.
The timeline and implementation of the variation are subject to the
NMRAs specific provisions and should be made publicly available.
6. New applications
Certain changes are so fundamental that they alter the terms of the accepted
dossier and consequently cannot be considered as variations. In these cases
submission of a new dossier should be considered, in line with applicable
national requirements for applications for MA.
Examples of such changes are:
change of the API to a different API;
inclusion of an additional API in a multicomponent product;
removal of one API from a multicomponent product;
change in the dose and/or strength of one or more APIs;
change from an immediate-release product to an extended- or
delayed-release dosage form or vice versa;
change from a liquid to a powder for reconstitution or vice versa;
changes in the route of administration.
7. Considerations for changes in product

information and labelling
For any change to product information1 (summary of product characteristics

(SmPC), patient information leaflet (PIL) and/or labels) the NMRA should be
notified and submission of the revised product information and/or labelling is
expected as per country-specific requirements.
When a variation leads to a revision of the SmPC, the PIL and/or labelling,
the updated information should be submitted as part of the variation. NMRAs
may request the MA holder to submit a side-by-side tabular comparison of the
current and proposed changes.
Different regions and countries use different terminology for product information. In this document,
1
package insert, the PIL and label are used to refer to product information.
354
Annex 10
Note that a change in the recommendations for use for a multisource

product, such as indications or patient population would result in the product no
longer being interchangeable with the comparator product. Therefore the NMRAs
may need to take this into consideration prior to approval of such changes.
8. Procedures
8.1 General
NMRAs should establish procedures and criteria for adequate oversight of
variations to authorized products. These should include written instructions
regarding the submission procedures and timelines with action dates, to
be consulted by MA holders when they prepare applications for variations.
Depending on the category of the variation, different timelines may be applicable.
Regulation of post-approval variations is part of the whole regulatory
framework, which includes among other aspects, MA, good manufacturing
practices (GMP) inspection and post-marketing surveillance. Different branches
of the NMRA often perform these activities. It is essential that these different
branches interact and exchange information effectively and that the roles and
responsibilities of each branch are clearly defined, particularly when they operate
as separate entities. When multiple branches are involved in the evaluation of
a variation a formal decision-making process should be in place to discuss, for
instance, whether a change may require a GMP inspection or may be reviewed
during the next routine inspection. Procedures should also be established so
that the outcomes of inspections are verified or taken into account prior to the
approval of variations. Good coordination and communication are pivotal.
8.2 Presubmission meetings

NMRAs should establish procedures to allow MA holders the opportunity to
obtain advice prior to submitting variations. MA holders should be encouraged
to contact the NMRA regarding plans for future changes and proposed filing
dates for changes to authorized products to aid NMRAs in the planning and
allocation of review resources.
8.3 Proposed documentation for minor variations

Where applicable the following basic information may be included as part of
the description of the variation in the immediate notification, or the annual
notification where prior approval is not required:
a covering letter (including a list of changes, describing each in
sufficient detail to allow for a quick assessment as to whether the
appropriate reporting category has been used);
355
an application form;
a list of subsections of the current dossier affected by the change(s);
a list and description of each change, reason for change(s) and
the date each change was implemented (each change should be
described in sufficient detail to allow for a quick assessment as to
whether the appropriate reporting category has been used);
the relevant summary of data from studies and tests performed to
assess the effects of each variation on product quality, including
(where applicable) a list of cross- references to the change control
and change validation protocols and standard operating procedures
(SOPs) that were used to assess or demonstrate the effect of
thevariation;
copies of the updated subsections of the original dossier.
The description should also include:
the name(s) of one or more FPP(s) affected or involved in the
change (e.g. different label strengths/product presentations);
reference to any previously approved variations, if the change
affected multiple products.
Executed batch records, SOPs and data from studies and tests performed
to assess the effects of each change should be kept on file and made available to
the NMRA upon request (e.g. during an inspection).
In the case of annual notifications, which represents the lowest risk
category, it may be permissible not to request any summary data if the
acceptability of the change can be determined without them.
Proposed documentation for variations

8.4
requiring prior approval
Where applicable the following basic information may be included in the
application for variations requiring prior approval:
a covering letter (including a list of changes describing each in
sufficient detail to allow for a quick assessment as to whether the
appropriate reporting category has been used);
an application form;
a list of subsections of the original dossier affected by the change(s);
a document summarizing the current and proposed condition(s)
and the reason(s) for the change(s);
356
Annex 10
where relevant, a side-by-side comparison of the currently approved

and the proposed information;
replacement of the relevant subsections of the dossier in accordance
with the acceptable dossier format for the NMRAs concerned, with
the proposed changes clearly annotated;
copies of the SmPC, PIL and labels, if relevant;
the relevant summary of data from studies and tests performed to
assess the effects of each variation on product quality, including
(where applicable) a list of cross-references to change control and
change validation protocols and SOPs that were used to assess or
demonstrate the effect of the variation;
registration status and date of the proposed change(s) in other
countries and/or agencies that have already approved the variation(s),
especially the country of origin and the reference agencies.
8.5 Review procedures

Taking into account the national situation, the capacity of the NMRA and
regional harmonization initiatives, the NMRA should adopt a risk-based review
strategy for assessment, concentrating most effort on those changes considered
to carry the greatest risk. A key factor in reducing workload is to ensure that
the variation documentation requirements permit rapid assessment of changes.
Moreover, the NMRA may consider whether it will:
rely on decisions made by other national authorities;
rely on assessment reports prepared by other national authorities;
prepare its own full assessment reports;
use some combination of these approaches.
If the decision of another NMRA is adopted, it is nevertheless essential
for certain minimum information to be available. Where the NMRA has granted
MA based on a reference NMRA or WHO prequalification it is recommended
that any post-approval variations of such products should have prior approval
from the initial reference NMRA or WHO prequalification (4, 5), as appropriate.
References
1. Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical
product: quality part. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations:
forty-eighth report. Geneva: World Health Organization; 2014: Annex 6 (WHO Technical Report
Series, No. 986).
357
2. Guidelines on variations to a prequalified product. In: WHO Expert Committee on Specifications

for Pharmaceutical Preparations: forty-seventh report. Geneva: World Health Organization; 2013:
Annex 3 (WHO Technical Report Series, No. 981).
3. Guidelines for procedures and data requirements for changes to approved vaccines. In: WHO
Expert Committee on Biological Standardization: sixty-fifth report. Geneva: World Health
Organization; 2015: Annex 4 (Technical Report Series, No. 993).
4. Guidelines on submission of documentation for prequalification of finished pharmaceutical
products approved by stringent regulatory authorities. In: WHO Expert Committee on
Specifications for Pharmaceutical Preparations: forty-eighth report. Geneva: World Health
5. Collaborative procedure between the World Health Organization Prequalification Team and
national regulatory authorities in the assessment and accelerated national registration of WHO-
prequalified pharmaceutical products and vaccines. In: WHO Expert Committee on Specifications
for Pharmaceutical Preparations: fiftieth report. Geneva: World Health Organization; 2016:
Annex8 (WHO Technical Report Series, No. 996).
358
SELECTED WHO PUBLICATIONS OF RELATED INTEREST
The International Pharmacopoeia, fifth edition.

2015 (CD-ROM and online)
The World Health Organization (WHO) was established in 1948 as a specialized Quality Assurance of Pharmaceuticals: a compendium of guidelines and related
agency of the United Nations serving as the directing and coordinating authority materials
for international health matters and public health. One of WHOs constitutional Updated, comprehensive edition, 2015 (CD-ROM and online)
functions is to provide objective and reliable information and advice in the field of WHO Expert Committee on Specifications for Pharmaceutical Preparations
human health, a responsibility that it fulfils in part through its extensive programme Forty-ninth report.
of publications. WHO Technical Report Series, No. 992, 2015 (210 pages)
The Organization seeks through its publications to support national health strategies International Nonproprietary Names (INN) for pharmaceutical substances
and address the most pressing public health concerns of populations around the world. Cumulative List No. 16
To respond to the needs of Member States at all levels of development, WHO publishes 2015 (available on CD-ROM only)
practical manuals, handbooks and training material for specific categories of health The selection and use of essential medicines
workers; internationally applicable guidelines and standards; reviews and analyses of Report of the WHO Expert Committee (the 19th WHO Model List of Essential
health policies, programmes and research; and state-of-the-art consensus reports that Medicines and including the 5th WHO Model List of Essential Medicines for Children).
offer technical advice and recommendations for decision-makers. These books are WHO Technical Report Series, No. 994, 2015 (546 pages)
closely tied to the Organizations priority activities, encompassing disease prevention
and control, the development of equitable health systems based on primary health Biological Standardization
care, and health promotion for individuals and communities. Progress towards better Report of the WHO Expert Committee on Biological Standardization
health for all also demands the global dissemination and exchange of information WHO Technical Report Series, No. 993, 2015 (262 pages)
that draws on the knowledge and experience of all WHOs member countries and the
collaboration of world leaders in public health and the biomedical sciences.
To ensure the widest possible availability of authoritative information and guidance on

health matters, WHO secures the broad international distribution of its publications
and encourages their translation and adaptation. By helping to promote and protect
health and prevent and control disease throughout the world, WHOs books contribute
to achieving the Organizations principal objective the attainment by all people of
the highest possible level of health.
The WHO Technical Report Series makes available the findings of various international
groups of experts that provide WHO with the latest scientific and technical advice on
a broad range of medical and public health subjects. Members of such expert groups
serve without remuneration in their personal capacities rather than as representatives
of governments or other bodies; their views do not necessarily reflect the decisions or
the stated policy of WHO.
An annual subscription to this series, comprising about four to six such reports, costs
CHF 150.00/US$ 180.00 (CHF 105.00/US$ 126.00 in developing countries). For further
information, please contact: WHO Press, World Health Organization, 20 Avenue
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email:[email protected]; order on line: http://www.who.int/bookorders).
Further information on these and other WHO publications can be obtained from
WHO Press, World Health Organization, 1211 Geneva 27, Switzerland
http://www.who.int/bookorders
tel.: +41 22 791 3264; fax: +41 22 791 4857; email: [email protected]
996
996

The Expert Committee on Specifications for Pharmaceutical
Preparations works towards clear, independent and practical

standards and guidelines for the quality assurance of
medicines. Standards are developed by the Committee through
worldwide consultation and an international consensus-
building process. The following new guidelines were adopted
and recommended for use. Good pharmacopoeial practices;
FIP-WHO technical guidelines: points to consider in the
on Specifications
preparations that are not available as authorized products; for Pharmaceutical
Preparations
Guidance on good manufacturing practices for biological
products; Guidance on good manufacturing practices:
inspection report, including Appendix 1: Model inspection
report; Guidance on good data and record management
practices; Good trade and distribution practices for starting
materials; Guidelines on the conduct of surveys of the
quality ofmedicines; Collaborative procedure between
the World Health Organization (WHO) prequalification
Fiftieth report
team and national regulatory authorities in the assessment
and accelerated national registration of WHO-prequalified
pharmaceutical products and vaccines; Guidance for
organizations performing in vivo bioequivalence studies;
and World Health Organization (WHO) general guidance on
variations to multisource pharmaceutical products.
WHO Technical Report Series

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What guidelines were adopted by WHO Expert Committee on Specifications for Pharmaceutical Preparations?

What guidelines were adopted by WHO Expert Committee on Specifications for Pharmaceutical Preparations?

What are WHO's constitutional functions?

What are WHO's constitutional functions?

996

WHO Expert Committee on Specifications for Pharmaceutical Preparations

WHO Expert Committee

The International Pharmacopoeia, fifth edition.

To ensure the widest possible availability of authoritative information and guidance on

WHO Expert Committee

This report contains the views of an international group of experts, and

World Health Organization 2016

13. Summary and recommendations 42

WHO Expert Committee on Specifications

Agency (ANVISA), Brasilia, Brazil

Dr Alfredo Garca Arieta, Head of Service on Pharmacokinetics and Generic Medicines,

Representation from United Nations offices3

Representation from specialized agencies and related organizations4

Representation from intergovernmental organizations5

European Medicines Agency (EMA)

Representation from nongovernmental organizations6

Representation from WHO Regional Offices10

Mr D. Mubangizi, Group Lead, Inspections

Global TB Programme (GTB)

Many of the Expert Committee Members have extensive governmental

Pharmaceutical Preparations maintains The International Pharmacopoeia and

Steering Committee and adopted by the Committee in 2014. A further

Expert Committee on Biological Standardization (ECBS)

2.2 International collaboration

UNICEF applies the WHO model quality assurance system for

Pharmacopoeial Discussion Group (PDG)

Model regulatory framework for medical devices

Trade names of stationary phases

3.1.2 Workplan 20152016

programmes and other partners. For future monograph elaboration, priority

Monographs proposed for elaboration or suppression

abacavir, efavirenz and lamivudine tablets

artenimol and piperaquine phosphate dispersible tablets

The Committee endorsed the workplan as presented.

3.2 Specifications for medicines, including childrens

on screening technology, sampling and specifications for medicines in April 2015

Magnesium sulfate and magnesium sulfate injection

Misoprostol, misoprostol dispersion and misoprostol tablets

Norethisterone and norethisterone tablets

3.2.2 Antimalarial medicines

3.2.3 Antituberculosis medicines

3.2.4 Medicines for tropical diseases

3.2.5 Medicines for chronic diseases and for mental health

Carbamazepine, carbamazepine tablets, carbamazepine

3.2.6 Other anti-infective medicines

Flucytosine and flucytosine intravenous infusion

3.2.7 Other medicines

Levomethorphan limit test for dextromethorphan-containing finished products

be completed in October 2015.

written report received from IAEA to the Committee.

3.3 General policy

secondary standards derived from them and established by another

gentamicin sulfate (ICRS0319)

Replacement of mercuric acetate