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W H O T e c h n i c a l R e p o r t S e r i e s

981

Forty-seventh report

WHO Expert Committeeon Specificationsfor PharmaceuticalPreparations

Te Expert Committee on Specifcations or PharmaceuticalPreparations works towards clear, independent and practicalstandards and guidelines or the quality assurance o medicines. Standards are developed by the Committee through

worldwide consultation and an international consensus-building process. Te ollowing new guidelines were adoptedand recommended or use: Release procedure or InternationalChemical Reerence Substances; WHO guidelines on quality risk management; WHO guidelines on variations to aprequalifed product; and the Collaborative procedure betweenthe World Health Organization Prequalifcation o MedicinesProgramme and national medicines regulatory authoritiesin the assessment and accelerated national registration o WHO-prequalifed pharmaceutical products.

WH O E x p e r t C ommi t t e e on

S p e c i f c a t i on s or P h a r m a c e u t i c a l P r e p a r a t i on s

9 8 1

WH O T e c h ni c a l R e p o r t S e r i e s

8/22/2019 informe 47 TRS981


Te World Health Organization was established in 1948 as a sp ecialized agency o theUnited Nations serving as the directing and coordinating authority or internationalhealth matters and public health. One o WHO's constitutional unctions is toprovide objective and reliable inormation and advice in the eld o human health, aresponsibility that it ulls in part through its extensive programme o publications.

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For urther inormation, please contact WHO Press, World Health Organization; 1211Geneva 27, Switzerland; www.who.int/bookorders; tel.: +41 22 791 3264; ax: +41 22791 4857; e-mail: [email protected].

Te International Pharmacopoeia, ourth edition.Volume 1: general notices; monographs or pharmaceutical substances (A–O)Volume 2: monographs or pharmaceutical substances (P–Z); monographs or dosageorms and radiopharmaceutical preparations; methods o analysis; reagents.2006 (1500 pages), also available on CD-ROM and onlineFirst supplement: general notices; monographs or pharmaceutical substances;monographs or dosage orms; general and specic monographs; methods o analysis;International Chemical Reerence Substances; International Inrared ReerenceSpectra; reagents, test solutions and volumetric solutions.2008 (309 pages), also available on CD-ROM and onlineSecond supplement: general notices; monographs or pharmaceutical substances andradiopharmaceuticals; monographs or dosage orms; general and specic monographs;

methods o analysis; International Chemical Reerence Substances; InternationalInrared Reerence Spectra; reagents, test solutions and volumetric solutions.2011 (CD-ROM and online)

Basic tests or drugs: pharmaceutical substances, medicinal plant materials anddosage orms1998 (94 pages)

Basic tests or pharmaceutical dosage orms1991 (134 pages)

Quality Assurance o Pharmaceuticals: a compendium o guidelines and relatedmaterialsUpdated, comprehensive edition, 2011 (CD-ROM and online)Also available on: WHO training modules on GMP. A resource and study pack ortrainers, 2007 (CD-ROM).

WHO Expert Committee on Specifcations or Pharmaceutical PreparationsForty-sixth report.WHO echnical Report Series, No. 970, 2012 (235 pages)

International Nonproprietary Names (INN) or pharmaceutical substancesCumulative List No. 142011 (available on CD-ROM only)

Te Selection and Use o Essential MedicinesReport o the WHO Expert Committee (including the 17th WHO Model List o Essential Medicines and the 3rd WHO Model List o Essential Medicines or Children)WHO echnical Report Series, No. 965, 2011 (263 pages)

WHO Expert Committee on Biological StandardizationFify-seventh report.WHO echnical Report Series, No. 964, 2012 (228 pages)

SELECTED WHO PUBLICATIONS OF RELATED INTEREST

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(tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected];

order online: http://www.who.int/bookorders)

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WHO Expert Committeeon Specificationsfor PharmaceuticalPreparations

W H T e c h n i c a l R e p o r t S e r i e s

9

his report contains the collective views of an international group of experts and

does not necessarily represent the decisions or the stated policy o the World Health Organization

Forty-seventh report

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© World Health Organization 2013

All rights reserved. Publications o the World Health Organization are available on the WHO

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Design: WHO/WHP (Sophie Guetaneh Aguettant)

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Printed in Italy

WHO Library Cataloguing-in-Publication Data

Forty-seventh report o the WHO Expert Committee on specifcations or pharmaceutical

preparations.

(WHO technical report series ; no. 981)

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 120981 6 (NLM classifcation: QV 771)

ISSN 0512-3054

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iii

Contents

WHO Expert Committee on Specifcations or Pharmaceutical Preparations vi

1. Introduction 1

2. General policy 2

2.1 Cross-cutting pharmaceutical quality assurance issues 2

2.2 International collaboration 2

2.2.1 Collaboration with international organizations and agencies 2

2.2.2 Pharmacopoeial Discussion Group 3

2.2.3 International Conerence on Harmonisation 3

2.2.4 International Conerence o Drug Regulatory Authorities4

2.2.5 World Health Assembly resolution on new Member States' mechanism on

substandard/spurious/alsely-labelled/alsifed/countereit medicines 4

3. Quality control – specifcations and tests 5

3.1 The International Pharmacopoeia 5

3.1.1 Fourth Edition update 5

3.1.2 Annotated work plan 5

3.2 Specifcations or medicines, including children's medicines 5

3.2.1 Medicines or human immunodefciency virus and related conditions 5

3.2.2 Antituberculosis medicines 6

3.2.3 Antimalarial medicines 63.2.4 Anti-inectives 8

3.2.5 Other medicines 9

3.3 Harmonized texts 10

3.3.1 Revision o monograph on General method 5.5 Dissolution test or solid

oral dosage orms 10

3.4 Preace, general notices and supplementary inormation sections o

The International Pharmacopoeia 10

3.4.1 Proposal or revision o monograph on capsules 10

3.4.2 Proposal or revision o general monographs: parenteral preparations 11

3.4.3 Proposal or revision o 5.1 Uniormity o content or single-dosepreparations 11

3.4.4 Proposal or revision o high-perormance liquid chromatography 12

3.4.5 General method or the supplementary inormation section o the Fourth

Edition o The International Pharmacopoeia: Resistance to crushing o tablets 12


Edition o The International Pharmacopoeia: Measurement o consistency by

penetrometry 12


Edition o The International Pharmacopoeia: Sotening time determination

o lipophilic suppositories 13

3.4.8 Bacterial endotoxin 13

4. Quality control – International Reerence Materials (International

Chemical Reerence Substances and Inrared Reerence Spectra) 14

4.1 Update on International Chemical Reerence Substances 14

4.1.1 Overview 14

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4.1.2 Report on activities o the host organization related to International

Chemical Reerence Substances 14

4.1.3 Adoption o established International Chemical Reerence Substances 154.1.4 Supplementary inormation section o The International Pharmacopoeia:

4. Reerence substances and reerence spectra 16

4.1.5 New release procedure or International Chemical Reerence Substances 16

4.1.6 Policy on naming International Chemical Reerence Substances in

The International Pharmacopoeia 17

4.1.7 Proposal to reduce analytical testing o high-purity candidate material 17

5. Quality control – national laboratories 19

5.1 External Quality Assurance Assessment Scheme 19

5.1.1 Overview 19

5.1.2 Final report o Procedure 4 19

5.1.3 Preliminary report o Procedure 5 and additional inormation with regard to

possible sources o error 19

5.1.4 Proposal or Phase 6 19

6. Quality assurance – good manuacturing practices 21

6.1 Updates o WHO GMP texts 21

6.2 Training materials 21

7. Quality assurance – new approaches 22

7.1 Quality risk management22

7.2 Pharmacopoeial harmonization 22

7.3 Screening technologies 24

7.4 Survey on laboratories report 24

8. Quality assurance – distribution and trade o pharmaceuticals 25

8.1 Revision o model quality assurance system or procurement agencies 25

8.2 Assessment tool based on the model quality assurance system 25

8.3 Monitoring and surveillance o national supply chain 25

8.4 Proposal or revision o good trade and distribution practices 26

9. Prequalifcation o priority essential medicines including active

pharmaceutical ingredients 28

9.1 Update on the Prequalifcation o Medicines Programme managed by WHO 28

10. Prequalifcation o active pharmaceutical ingredients 29

10.1 Update on the prequalifcation o active pharmaceutical ingredients 29

11. Prequalifcation o quality control laboratories 30

11.1 Update on the prequalifcation o quality control laboratories 30

11.2 Update on WHO quality monitoring projects 30

12. Regulatory guidance 3112.1 Extemporaneous dispensing and administration o medicines to children 31

12.2 Guidance on variations to a prequalifed product 32

12.3 Collaborative procedure between the WHO Prequalifcation o Medicines

Programme and national medicine regulatory authorities in the assessment and

accelerated registration o national WHO-prequalifed pharmaceutical products 32

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12.4 Proposal or a procedure on sampling and market surveillance survey 33

12.5 Comparator products 33

12.6 Biowaiver 34

13. Nomenclature, terminology and databases 35

13.1 Quality assurance terminology 35

13.2 International Nonproprietary Names or pharmaceutical substances 35

14. Miscellaneous 36

14.1 Quality assurance o pharmaceuticals: a compendium o guidelines and

related materials 36

14.2 Strategy 36

15. Summary and recommendations 37

Acknowledgements 44

Annex 1

Release procedure or International Chemical Reerence Substances 59

Annex 2

WHO guidelines on quality risk management 61

Annex 3

WHO guidelines on variations to a prequalifed product 93

Annex 4

Collaborative procedure between the World Health Organization Prequalifcation

o Medicines Programme and national medicines regulatory authorities

in the assessment and accelerated national registration o WHO-prequalifed

pharmaceutical products 155

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W H O T e c h n i c a l R e p o r t S e r i e s , N o . 9

8 1 , 2 0 1 3

WHO Expert Committee on Specifcations or Pharmaceutical Preparations Forty-seventh report

WHO Expert Committee on Specifcations

or Pharmaceutical PreparationsAmsterdam, 9–12 October 2012

Members

Professor S.A. Bawazir, Head of Drug Sector and Vice-President, Saudi Food and Drug

Authority, Riyadh, Saudi Arabia (Chairperson)

Professor T.G. Dekker, Research Institute for Industrial Pharmacy, North-West University,

Potchefstroom, South Africa

Ms N.M. Guerrero Rivas, Quality Assurance, Laboratory, Instituto Especializado de Análisis,Ciudad Universitaria Octavio Méndez Pereira, Panamá, Republic of Panama

(Co‑Chairperson)

Professor J. Hoogmartens, Leuven, Belgium

Professor S. Jin, Chief Expert for Pharmaceutical Products, National Institutes for Food and

Drug Control, Beijing, People's Republic of China (Rapporteur )

Professor H.G. Kristensen, Vedbaek, Denmark

Ms G.N. Mahlangu, Director-General, Medicines Control Authority of Zimbabwe, Harare,Zimbabwe

Ms C. Munyimba-Yeta, Director, Inspectorate and Licensing, Pharmaceutical Regulatory

Authority, Lusaka, Zambia (Rapporteur )

Ms L. Slamet, Deputy for Therapeutic Products, Narcotics, Psychotropic and Addictive

Substance Control, National Agency of Drug and Food Control, Jakarta Pusat,

Indonesia1

Temporary advisersProfessor J.B. Dressman, Director, Institute of Pharmaceutical Technology, Johann

Wolfgang Goethe-University, Frankfurt am Main, Germany1

Ms M.Y. Low, Director, Pharmaceutical Division, Applied Sciences Group, Health Sciences

Authority, Singapore

Professor A.J. Nunn, Formby, Liverpool, England

Mrs L. Paleshnuik, Arnprior, Ontario, Canada

Dr S. Parra, Manager, Generic Drug Quality Division 1, Bureau of Pharmaceutical Sciences, Therapeutic Products Directorate, Health Canada, Ottawa, Ontario, Canada

1 Unable to attend.

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WHO Expert Committee on Specifcations or Pharmaceutical Preparations

Ms M.-L. Rabouhans, Chiswick, London, England

Dr J.-L. Robert, Head o Department, Service du Contrôle des Médicaments, LaboratoireNational de Santé, Luxembourg

Dr A.J. van Zyl, Sea Point, South Arica

Representation rom United Nations ofces2

United Nations Children's Fund (UNICEF)

Dr P.S. Jakobsen, Quality Assurance Specialist, UNICEF Supply Division, Copenhagen,

Denmark

Representation rom specialized agencies and related organizations3

The Global Fund to Fight AIDS, Tuberculosis and Malaria

Ms J. Daviaud, Quality Assurance Specialist, Grant Management Support, Geneva,

Switzerland

Representation rom intergovernmental organizations4

Council of Europe

Dr A. Lodi, Head o Laboratory Department, European Directorate or the Quality o Medicines & HealthCare, Strasbourg, France

Representation rom nongovernmental organizations5

International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)

Dr G.L. France, Vice Chair, Regulatory Policy and Technical Standards (RPTS), IFPMA, and

Region Head, Quality Europe, Novartis Consumer Health Services SA, Novartis Group:

Quality Systems & Standards, Switzerland

Dr R. Horder, Abbott, England.International Generic Pharmaceutical Alliance (IGPA)

Dr N. Cappuccino, Chie Executive Ofcer, Pharmaceutical Intellectual Resource Services

LLC, Lambertville, NJ, USA

2 Unable to attend: United Nations Development Programme, New York, NY, USA.3 Unable to attend: International Atomic Energy Agency, Vienna, Austria; United Nations Industrial

Development Organization, Vienna, Austria; World Intellectual Property Organization, Geneva, Switzerland;

The World Bank, Washington, DC, USA; World Customs Organization, Brussels, Belgium; World TradeOrganization, Geneva, Switzerland.

4 Unable to attend: European Commission, Brussels, Belgium; European Medicines Agency, London,England.

5 Unable to attend: Commonwealth Pharmacists Association, London, England; European Chemical IndustryCouncil, Brussels, Belgium.

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8 1 , 2 0 1 3


6 Unable to attend: Farmacopea Argentina, Buenos Aires, Argentina; Farmacopéia Brasileria, Santa Maria RS,Brazil.

International Pharmaceutical Excipients Council (IPEC)

Dr E. Krämer, Good distribution practices (GDP) Committee Chair, IPEC Europe, Brussels,

Belgium

International Pharmaceutical Federation (FIP)

Dr L. Besançon, The Hague, Netherlands

International Society for Pharmaceutical Engineering (ISPE)

Dr G.L. France, Region Head, Quality Europe, Novartis Consumer Health Services SA,

Novartis Group: Quality Systems & Standards, Switzerland

World Self‑Medication Industry (WSMI)

Dr R. Torano, Quality Executive, Pharmacopoeial Intelligence and Advocacy, GlaxoSmithKline,England

Observer

Pharmaceutical Inspection Co‑operation Scheme (PIC/S)

Dr A. Hayes, Geneva, Switzerland

Pharmacopoeias6

British Pharmacopoeia CommissionMrs M. Vallender, Editor-in-Chief, BP and Laboratory Services, London, England

Pharmacopoeia of the People's Republic of China

Dr P. Wang, Deputy Secretary-General, Beijing, People's Republic of China

Indonesian Pharmacopoeia Commission

Dr A. Zaini, Director for Standardization of Drug and Food Control, National Agency of

Therapeutic Products and Household Healthcare, Percetakan, Indonesia

Committee of the Japanese Pharmacopoeia

Dr T. Kawanishi, Deputy Director General, National Institute of Health Sciences, Tokyo,Japan

Pharmacopoeia of the Republic of Korea

Dr I. Kim, Director, Pharmaceutical Standardization and Research Division, National Institute

of Food and Drug Safety Evaluation (NIFDS), Korea Food and Drug Administration

(KFDA), Chungbuk, Republic of Korea;

Dr H.-S. Kim, Deputy Director, Pharmaceutical Standardization Division, National Institute

of Food and Drug Safety Evaluation (NIFDS), Korea Food and Drug Administration

(KFDA), Chungbuk, Republic of Korea

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State Pharmacopoeia of the Russian Federation

Dr A. Mironov, General Director, Federal State Budgetary Institution Scientic Centre

or Expert Evaluation o Medicinal Products (FSBI SCEMP); Dr I.V. Sakaeva, DeputyGeneral Director, FSBI SCEMP; Dr E.I. Sakanjan, Director, Centre o Pharmacopoeia and

International Cooperation, FSBI SCEMP; Dr O.N. Gubareva, Deputy Head, Department

o International Cooperation, FSBI SCEMP; Dr R.A. Lavrenchuk, Research Fellow,

Department o State Pharmacopoeia and Pharmacopoeia Analysis, FSBI SCEMP,

Pharmacopoeia Committee, Ministry o Health, Moscow, Russian Federation

Pharmacopoeia of Ukraine

Proessor O. Gryzodub, Director, Ukrainian Scientic Pharmacopoeial Centre or Quality

o Medicines, Pharmacopoeia o Ukraine, Kharkov, Ukraine;

Dr M. Dmitriieva, Senior Research Ofcer, Head o the PTS Group, Ukrainian Scientic

Pharmacopoeial Centre or Quality o Medicines, Pharmacopoeia o Ukraine, Kharkov,

Ukraine

United States Pharmacopeia

Dr Karen Russo, Vice President, Small Molecules, Documentary Standards Division,

Rockville, MD, USA

Representation rom WHO regional ofces7

WHO Secretariat

Health Systems and Services (HSS)8

Dr C.F. Etienne, Assistant Director-General

Essential Medicines and Health Products (HSS/EMP)

Mr C. de Joncheere, Director, Essential Medicines and Health Products (EMP)

Quality Assurance and Safety: Medicines (EMP/QSM)

Dr L. Rägo, Coordinator, Quality Assurance and Saety: Medicines (QSM)

Dr S. Kopp, Manager, Medicines Quality Assurance Programme, QSM (Secretary )

Dr H. Schmidt, QSM

Blood Products and Related Biologicals, QSM8

Medicines Regulatory Support Programme (MRS), QSM

Dr A. Prat

7 Unable to attend: Regional Ofce or Arica, Brazzaville, Congo; Regional Ofce or the Americas, PanAmerican Health Organization, Washington, DC, USA; Regional Ofce or the Eastern Mediterranean, Cairo,Egypt; Regional Ofce or Europe, Copenhagen, Denmark; Regional Ofce or South-East Asia, New Delhi,India; Regional Ofce or the Western Pacic, Manila, Philippines.

8 Unable to attend.

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8 1 , 2 0 1 3


9 Unable to attend.

International Nonproprietary Names Programme (INN), QSM

Dr R.G. Balocco, Manager

Prequalifcation Programme, QSM

Dr J. Sabartova

Dr M. Smid

Medicines Access and Rational Use (EMP/MAR)9

Traditional Medicine (Health Policy, Development and Services (HDS)/TRM) 9

Quality, Saety and Standards (Immunization, Vaccines and Biologicals (IVB)/QSS)9

Mr David Bramley (report writer)

Special acknowledgement and appreciation is given to Dr J.A. Molzon, Associate Director

for International Programs, Center for Drug Evaluation and Research, US Food and Drug

Administration, Silver Spring, MD, USA, who attended as observer in her function as

member of the WHO Expert Advisory Panel on the International Pharmacopoeia and

Pharmaceutical Preparations.

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Declarations of interest

Members o the WHO Expert Committee on Specications or Pharmaceutical Preparationsand temporary advisers reported the ollowing:

Proessor S. Bawazir, Proessor T. Dekker, Ms N. Guerrero Rivas, Proessor J. Hoogmartens,

Proessor S. Jin, Ms M.Y. Low, Ms C. Munyimba-Yeta, Dr L. Paleshnuik, Ms M.-L. Rabouhans

and Dr J.-L. Robert reported no conficts o interest.

Proessor H.G. Kristensen reported that he and his wie, a ormer employee o Novo

Nordisk, hold investment interests in the company. Proessor Kristensen has provided

an expert opinion and testimony as an independent expert in patent cases regarding

the ormulation and processing o medicines. The declaration did not confict with thesubjects o the meeting.

Ms G.N. Mahlangu reported that she would receive an out-o-pocket allowance rom the

Medicines Control Authority o Zimbabwe in accordance with the travel allowances

schedule or sponsored travel.

Dr S. Parra reported that she is a ull-time employee o a governmental organization

(Canadian Ministry o Health) and, as such, is a civil servant receiving remuneration

rom a regulatory agency. Dr Parra works or the department that approves new

medicines or the Canadian market. As an employee o Health Canada she representsher organization in international orums and was present in sessions on topics relevant

to her work (i.e. evaluation o the quality part o drug applications) as a stakeholder.

Proessor A.J. Nunn reported that he took part in discussions o the paediatric hospital

pharmacy practice or Rosemont Pharmaceuticals, or which he personally received

payment in 2012. His research unit received a research grant in 2011 o £250 000 rom

the United Kingdom National Institute or Health Research; a research grant “GRIP”

WP5 rom EU FP7 or the current year o €6 million (part-consortium); and personal

conerence costs in 2011 rom the European Paediatric Formulations Initiative. He is a

member o the European Medicines Agency (EMA) Paediatric Committee (PDCO) and

PDCO Formulation Working Party, considering ormulation development or paediatric

investigation parties and or guidelines (2010–2014). Proessor Nunn was not present

in any Expert Committee session during which individual products were discussed.

Dr A.J. van Zyl reported that he received the ees or the current year or consulting or the

United States Pharmacopeia (USP), the Global Fund, and pharmaceutical companies.

He has provided an expert opinion on good manuacturing practices (GMP) in an

arbitration case or Norton Rose, Cape Town, South Arica, rom August 2011 to date.

The declarations o interest were presented to the Expert Committee or inormation.

There were no comments rom Committee members or temporary advisers.

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1

1. Introduction

Te WHO Expert Committee on Specifcations or Pharmaceutical Preparationsmet in Amsterdam rom 9 to 12 October 2012. Mr C. de Joncheere, Director o the Department o Essential Medicines and Health Products (EMP) at the WorldHealth Organization (WHO) opened the meeting. On behal o the Director-General o WHO, Mr de Joncheere welcomed the participants to the orty-seventhmeeting o the Expert Committee. He reminded the members o the ExpertCommittee o the importance o the Expert Committee system to the work o WHO. Te work o the Expert Committee on Specifcations or PharmaceuticalPreparations had provided considerable support, among others, to the WHOPrequalifcation o Medicines Programme (PQP) to the extent that the work o that Programme depended on the Expert Committee. He thanked the memberso the Committee or their service to the Organization and its Member States.

Dr L. Rägo, Coordinator o the Quality Assurance and Saety: Medicines(QSM) team added his welcome to that o Mr de Joncheere. He reiterated the

value o the contributions to WHO's work made by experts around the world.Such assistance helped WHO to keep abreast o changes in the environment. Henoted that or the third time it had been planned to hold an open session during

the meeting o the Expert Committee to respond to the interest in the quality o medicines previously demonstrated by Member States during the World HealthAssembly. However, as no Member States had confrmed that they would attend,the open session was not to be held on this occasion.

Te meeting elected Proessor S.A. Bawazir as Chairperson, Ms N.M.Guerrero Rivas as Co-Chairperson, and Proessor S. Jin and Ms C. Munyimba-Yeta as Rapporteurs.

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2. General policy

2.1 Cross-cutting pharmaceutical quality assurance issuesTe Secretary to the Expert Committee gave a short overview o the generalprinciples and working procedures o this Committee. She reminded the memberso the Expert Committee that this was one o WHO’s oldest Expert Committeesand that its work and its reports had long been seen as very signifcant or theOrganization. She presented the report o the orty-sixth meeting o the ExpertCommittee o October 2011, which had been published during the year. She notedrecent activities o the Expert Committees on Biological Standardization and on

the Selection and Use o Essential Medicines, and mentioned recent publicationson herbal and complementary medicines.

2.2 International collaboration2.2.1 Collaboration with international organizations and agencies

The Global Fund to Fight AIDS, Tuberculosis and Malaria

Te work o the Global Fund to Fight AIDS, uberculosis and Malaria (GFAM)was summarized or members o the Expert Committee. GFAM has so ar

unded antiretroviral (ARV) treatment or 3.6 million people, treatment or 9.3million people newly diagnosed with inectious tuberculosis, 260 million malariamedicine treatments and has distributed 270 million insecticide-treated bednets.It was noted that there was a continuing need to balance the internationalstandards o GFAM with the standards and requirements o individual countries.Procurement is done according to model quality assurance system (MQAS)principles and according to national and international laws. Te Global Fundhas a strict selection process, defned in its quality assurance policy, so quality standards must be assured either by WHO/PQP or by a stringent regulatory

authority. When no products meet these standards, products reviewed by anExpert Review Panel (ERP) can be considered, but only under strict conditions.Countries are requested to monitor quality throughout the supply chain.

Te Global Fund's ERP (hosted by EMP/QSM) reviews the dossiers o products. So ar the ERP has perormed a risk–beneft assessment o 58 dossierson ARVs, o which 29 (50%) were successul; 291 dossiers on antituberculosismedicines, o which 96 (33%) were successul, and 68 dossiers on antimalarials,o which 22 (32%) were successul.

QSM's support to the Global Fund is provided through the prequalifcation

programmes or medicines and quality control laboratories (QCLs), QSMtechnical expertise, the monographs (on ARVs, artemisinin combination therapy (AC), antituberculosis and anti-inective medicines) o Te International Pharmacopoeia, and through the development and updating o quality assuranceguidelines.

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General policy

3

Te Expert Committee thanked the Global Fund or its report andexpressed appreciation or its strong commitment to ensuring the highest quality

standards during the procurement and supply process.

United Nations Children's Fund

Te United Nations Children's Fund (UNICEF) is present in some 170 countries.Its Supply Division, located in Copenhagen, Denmark, procures supplies,including medicines, or UNICEF and partners. UNICEF country oces do notcarry out procurement o medicines themselves. Ninety per cent o UNICEFsupplies are or Arica and Asia.

UNICEF prequalication o medicines applies to both suppliers andproducts. UNICEF carries out good manuacturing practices (GMP) inspectionsitsel mainly to check compliance with WHO GMP guidelines. Around 100 GMPinspections were carried out in 2007–2012, and 19 companies ailed the inspection.

Virtually all pharmaceutical products supplied by UNICEF are on theWHO Model List o Essential Medicines. Vaccines, human immunodeciency

virus (HIV), antimalarial and antituberculosis medicines must be prequalied by WHO and listed on the WHO Prequalication web site.

Te Expert Committee thanked UNICEF or its report and expressed

appreciation or its strong commitment to ensuring the highest quality standardsduring the procurement and supply process.

2.2.2 Pharmacopoeial Discussion Group

Te Expert Committee received a report on the Pharmacopoeial DiscussionGroup (PDG), o which WHO is an observer. At present, 28 o the 35 generalchapters and 43 o the 62 excipient monographs o the current work programmehave been harmonized. Representatives o the three pharmacopoeias that make

up the PDG discussed ways to improve and speed up the harmonization processand proposed a number o options. est procedures concerning excipientadulteration were also discussed. Te Expert Committee took note o the report.

2.2.3 International Conference on Harmonisation

Te International Conerence on Harmonisation o echnical Requirementsor Registration o Pharmaceuticals or Human Use (ICH) is reviewing its work and making plans or the uture. Te ICH Steering Committee has agreedto set up a quality brainstorming group, working chiefy by teleconerence, to

advise ICH parties. Current plans include revision o guidelines, such as thoseon specications, and it is expected to proactively review which new guidelinesmay be needed in the uture. ICH has plans to develop training on its guidelines,both within the ICH regions and outside. Te ollowing topics are currently being pursued in the area o quality: Q3D (residual metals); M7 (genotoxic

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impurities); and a question and answer (Q&A) document on Q7 (GMP or activepharmaceutical ingredients (APIs)).

Te Expert Committee expressed its thanks or the report.

2.2.4 International Conerence o Drug Regulatory Authorities

Te International Conerence o Drug Regulatory Authorities (ICDRA) providesmedicines regulatory authorities o WHO Member States with a orum to meetand discuss ways to strengthen collaboration. Te ICDRAs have been instrumentalin guiding regulatory authorities, WHO and interested stakeholders and indetermining priorities or action in the national and international regulation o

medicines, vaccines, biomedicines and herbals.Te programme o the 15th ICDRA, scheduled or 23–26 October 2012

in allinn, Estonia, was outlined or the Expert Committee. Te Committee'sattention was also drawn to a pre-conerence meeting on “Te quality o medicinesin a globalized world: ocus on active pharmaceutical ingredients” organized

jointly by the State Agency o Medicines o Estonia, the European Directorate orthe Quality o Medicines & HealthCare (EDQM) and WHO.

Te Expert Committee noted the programme or both the conerenceand the pre-conerence meeting.

2.2.5 World Health Assembly resolution on new MemberStates' mechanism on substandard/spurious/alsely-labelled/alsifed/countereit medical products

Te Secretary to the Expert Committee described the creation o a new MemberStates' mechanism on substandard/spurious/alsely-labelled/alsied/countereit(SSFFC) medical products. Tis mechanism was agreed upon at the Sixty-hWorld Health Assembly in 2012 ollowing the recommendation o a working

group o Member States on SSFFC medical products which met twice in 2011.Te mechanism, which is set to meet at least once each year, is open torepresentation by all WHO Member States and, where applicable, by regionaleconomic integration organizations. Te goal o the mechanism is “to protectpublic health and promote access to afordable, sae, ecacious and quality medical products, promote, through efective collaboration among MemberStates and the Secretariat, the prevention and control o substandard/spurious/alsely-labelled/alsied/countereit medical products and associated activities”.Te rst meeting o this new mechanism would discuss the structure, governance

and a work plan in November 2012 in Argentina.It was recognized that the Expert Committee might have a role in

supporting the mechanism.

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3. Quality control – specifcations and tests

3.1 The International Pharmacopoeia3.1.1 Fourth Edition update

Te Expert Committee was inormed that the Tird Supplement to the FourthEdition would be published as a CD-ROM. Te Expert Committee urged therapid publication and placing o adopted monographs on the WHO web site.

3.1.2 Annotated work plan

Te annotated work plan or 2011, which remained valid, was presented to the

Expert Committee. Members commented on the work plan and noted it.

3.2 Specifcations or medicines, including children's medicines3.2.1 Medicines or human immunodefciency virus and related conditions

Abacavir sulfate

Te Expert Committee discussed a proposal or revision o the monograph onabacavir sulate. Following discussion at the consultation on specications ormedicines and quality control laboratory issues in May 2012, a draf o the revisedmonograph had been sent out or comments, which had been consolidated by the secretariat. It was proposed to revise the solubility o abacavir sulate rom“reely soluble in water” to “soluble in water”. Te Expert Committee notedthat solubility is not a specication but is included or inormation. Te ExpertCommittee endorsed the monograph, subject to the amendments proposed.

Abacavir oral solution

Following notication rom collaborating quality laboratories, manuacturers

and assessment specialists, o plans to revise the requirement or the pH test in thepublished monograph on abacavir oral solution, a draf revision was circulated orcomments in July 2012. Te Expert Committee discussed the proposed revision,which involved an extension o the pH range, in light o the comments receivedand endorsed the change. Te Expert Committee adopted the monograph,subject to the amendments proposed.

Nevirapine monographs

Te Expert Committee discussed proposals or correction o the monographs on

nevirapine, nevirapine oral suspension and nevirapine tablets. It was noted thatthe nomenclature would ollow the new policy on naming International ChemicalReerence Substances (ICRS) (see 4.1.6). Copies o the current monographs werecirculated showing the proposed changes. Te Expert Committee adopted themonographs, subject to the amendments proposed.

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Tenofovir disoproxil fumarate

Following the adoption o the monograph on tenoovir disoproxil umarate inOctober 2009, the secretariat was inormed by users about diculties encounteredwith the specic optical rotation test. Te collaborating laboratory which wasassigned the development o the monograph investigated the issue, and new acceptance limits or this test were proposed. A draf revision o the monographwas discussed at the consultation in May 2012, ollowing which a urther drafo the monograph was sent out or public consultation. Te comments receivedwere subsequently consolidated and the draf was revised accordingly.

Te Expert Committee discussed the revised draf. Te monograph wasadopted subject to the changes proposed.

3.2.2 Antituberculosis medicines

Cycloserine

Following a request rom a user o Te International Pharmacopoeia, it hadbeen proposed to change the system suitability criterion o the test or relatedsubstances in the monograph on cycloserine. A revision o the monograph wassent out or public consultation and urther proposals or changes were received.

Te Expert Committee reviewed the proposals or the revision o

the monograph on cycloserine and adopted the monograph, subject to theamendments proposed.

Cycloserine capsules

As in the case o the cycloserine monograph, it was proposed to change thesystem suitability criterion o the test or related substances in the monographon cycloserine capsules ollowing a request rom a user o Te International Pharmacopoeia. A revision o the monograph was sent out or public consultation

and urther proposals or changes were received.Te Expert Committee reviewed the proposals or the revision o themonographs on cycloserine capsules and adopted the monograph, subject to theamendments proposed.

3.2.3 Antimalarial medicines

Artesunate

Te revision o the monograph on artesunate had been adopted by the ExpertCommittee in 2011 and included the correction o inormation related to the

stereochemistry o artesunate impurity A (artenimol). Further to the changesalready agreed, it was proposed to align the conditions or identity tests C and Dto the test descriptions given in the document New basic tests for antimalarials.

Te Expert Committee adopted the monograph, subject to theamendments proposed.

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Artesunate tablets

A user o Te International Pharmacopoeia had reported a problem with the

chromatography described in the dissolution testing o artesunate tablets. A

collaborating centre investigated the issue, advised corrections to the monograph

and recommended aligning the conditions or identity tests C and D to the test

descriptions given in the document New basic tests for antimalarials.Te Expert Committee adopted the monograph subject to the

amendments proposed.

Artesunate for injection

In view o the proposed changes to the monographs on artesunate and artesunate

tablets, it was also proposed to change the monograph on artesunate or injection

accordingly.Te Expert Committee discussed the revised monograph, and adopted

the monograph subject to the amendments proposed.

Artemisinin

In October 2011 the Expert Committee adopted the document Recommendations

for quality requirements when artemisinin is used as a starting material inthe production of antimalarial active pharmaceutical ingredients, including a

specication or artemisinin used as a starting material. Te Committee urtheradvised that the monograph on artemisinin in Te International Pharmacopoeia

should be aligned with the new specication o artemisinin used as a starting

material. Consequently a draf revision o the monograph on artemisinin was

discussed at the consultation in May 2012 and circulated or public consultation

in August 2012.

Te Expert Committee reviewed the proposed draf o the monograph.Te monograph was adopted subject to the amendments proposed. It was

noted that certain proposed changes would require that the same changes

should be made to the specication on artemisinin used as a starting material.Te Expert Committee thereore requested the secretariat to make the changes

to the specication on artemisinin as a starting material, provided they areconrmed by one o the WHO collaborating centres, and to publish the revisedRecommendations for quality requirements when artemisinin is used as a starting

material in the production of antimalarial active pharmaceutical ingredients as an

annex to the report o the current meeting.1

1 During the compilation of the report it was unfortunately revealed that further investigations would benecessary.

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Artemisinin tablets and artemisinin capsules

Te International Pharmacopoeia contains monographs on artemisinin tabletsand artemisinin capsules. However, according to WHO guidelines or the

treatment o malaria, artemisinin and its derivatives should no longer be used as

monotherapy since xed-dose combination ormulations are recommended. It

was thereore proposed to suppress the monographs on artemisinin tablets and

artemisinin capsules.

Te Expert Committee agreed that the monographs were no longer

in line with WHO policy and they should not appear in uture editions o Te

International Pharmacopoeia. Te secretariat was asked to nd a means to

suppress the monographs, i.e. by removing them rom the current edition o TeInternational Pharmacopoeia and by explaining why this action has been taken.

Mefoquine hydrochloride

Following the Expert Committee's adoption o the monograph on meoquine

tablets in October 2010, a revision o the monograph on meoquine API was

begun. A draf text or revision was discussed by the Expert Committee in October

2011 and at the consultation in May 2012. Te draf was subsequently revised

in light o comments made during the consultation and was then circulated orpublic consultation in July–August 2012.

Te Expert Committee adopted the monograph, subject to the

amendments proposed.

3.2.4 Anti-infectives

Cloxacillin

A user o Te International Pharmacopoeia had reported that the specied limit

or bacterial endotoxins in the monograph on cloxacillin sodium or sterileuse was high compared to the limit specied in other pharmacopoeias. Tis

was discussed with selected experts and, in consequence, the monograph was

corrected to bring it in line with the limits specied in other pharmacopoeias.

Te Expert Committee noted the amendment.

Fluconazole

A proposed draf o the monograph on uconazole was rst discussed at the

consultation in May 2012. Te draf monograph was then sent out or publicconsultation. Comments received were consolidated by the secretariat, and the

monograph was urther revised in light o the comments received.

Te Expert Committee reviewed the draf, noted progress in the

development o the monograph, and proposed urther amendments.

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Fluconazole capsules

A proposed draf o the monograph on uconazole capsules was discussed at theconsultation in May 2012. Te draf monograph was then circulated or publicconsultation. Comments received were consolidated by the secretariat, and themonograph was urther revised in light o the comments received.

Te Expert Committee reviewed the draf. Afer noting progress in thedevelopment o the monograph, the Expert Committee proposed a number o urther changes.

Fluconazole for injection

A proposed draf o the monograph on uconazole or injection was discussedat the consultation in May 2012. Te draf monograph was then circulated orpublic consultation. Comments received were consolidated by the secretariat,and the monograph was urther revised in light o the comments received.

Te Expert Committee reviewed the draf. Progress in the developmento the monograph was noted and the Expert Committee proposed a number o urther changes.

Pyrantel oral suspension

A draf proposal or the monograph on pyrantel oral suspension was discussedby the Expert Committee in October 2011 and at the consultation in May 2012. Following the consultation, the draf revision was circulated or publicconsultation and comments received were subsequently consolidated by thesecretariat.

Te Expert Committee adopted the monograph subject to theamendments proposed.

Sulfamethoxazole and trimethoprim intravenous infusion and oral suspension

Te draf monographs on sulamethoxazole and trimethoprim intravenousinusion and oral suspension, which had been proposed or inclusion in TeInternational Pharmacopoeia, were discussed at the consultation in May 2012and circulated or public consultation in the same month. Revised drafs o thetwo documents were circulated widely or urther comment in August 2012.Comments subsequently received were consolidated by the secretariat.

Te Expert Committee noted progress in the development o themonographs and proposed a number o changes.

3.2.5 Other medicines

Levornorgestrel and ethinylestradiol tablets

A draf proposal or the monograph on levonorgestrel and ethinylestradiol tabletswas circulated or public consultation in February 2012 and comments received

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were collated by the secretariat prior to discussion at the consultation in May 2012, where it was proposed to align the conditions or the dissolution testing

to the respective test described in the monograph on levonorgestrel tablets. Tecollaborating centre investigated the possibility and subsequently revised theproposal.

Te Expert Committee adopted the monograph, subject to theamendments proposed.

Zinc acetate and zinc gluconate

Draf proposals or the monographs on zinc acetate and zinc gluconate were

rst discussed at the consultation in May 2012. Te documents were sent out orpublic consultation in August 2012 and were subsequently revised taking intoaccount the comments received.

It was agreed that limits to microbial contamination should be includedin the monograph on zinc gluconate.

Te Expert Committee adopted the monographs on zinc acetate and zincgluconate subject to the amendments proposed.

3.3 Harmonized texts3.3.1 Revision of monograph on General method 5.5

Dissolution test for solid oral dosage forms

In October 2010 the Expert Committee recommended revision o the dissolutiontest or solid oral dosage orms. Following discussion o a draf with commentsby the Expert Committee in October 2011 and at the consultation in May 2012,a revised draf was circulated or public consultation in July 2012. Commentsreceived were collated by the secretariat or consideration by the ExpertCommittee.

Te Expert Committee noted that the text was based on the internationally harmonized texts developed by the PDG. It was developed in line with the styleand requirements used in Te International Pharmacopoeia, and the chapter on“est conditions and dissolution media” was added to the original PDG text.

In its review o the draf text, the Expert Committee made a numbero urther proposals or change. Te monograph was adopted subject toimplementation o the amendments proposed.

3.4

Preface, general notices and supplementary informationsections of The International Pharmacopoeia3.4.1 Proposal for revision of monograph on capsules

Te draf o a revised monograph on capsules was considered in May 2012 atthe Consultation on specications or medicines and quality control laboratory

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issues and was subsequently mailed out or public consultation. Te commentsreceived were collated by the secretariat or submission to the Expert Committee.

It had been noted that the requirements o the monograph did notnecessarily apply to preparations that were intended or any use other than by oral administration. It was pointed out that such non-oral preparations, orexample, vaginal or rectal capsules, might require a special ormulation, methodo manuacture, or orm o presentation appropriate to their particular use. Starchcapsules (ofen known as cachets) are also not included in the monograph.

Te Expert Committee adopted the text as proposed.

3.4.2

Proposal for revision of general monographs: parenteral preparationsFollowing discussion at the May 2012 consultation, the draf general monographon parenteral preparations was circulated or public consultation. Te commentsreceived were then collated by the secretariat in August and September 2012 inpreparation or consideration by the Expert Committee.

Te proposed revisions o this general monograph were part o the review o general monographs endorsed by the Expert Committee at its orty-secondmeeting. Account was taken o recently adopted revised texts or 3.2 est orsterility, 3.4 est or bacterial endotoxins, 5.6 Extractable volume and 5.7 est

or particulate contamination.One o the major changes proposed in the revision was the required

compliance o all parenteral preparations with tests or bacterial endotoxins(or, where justied, pyrogens). Consequently, a review o the individualmonographs or injections is necessary, with the addition o a test and limitor bacterial endotoxins to each monograph that currently does not includesuch a requirement. It was noted that the requirements o the monographdid not necessarily apply to human blood and products derived rom humanblood, to immunological preparations, to peritoneal dialysis solutions or toradiopharmaceutical preparations.

Te Expert Committee proposed a number o changes to the draf andadopted the monograph subject to the amendments proposed.

3.4.3 Proposal for revision of 5.1 Uniformity of content for single-dose preparations

Te preliminary draf o the revision o the chapter o Te International Pharmacopoeia on uniormity o content or single-dose preparations was

discussed at the consultation in May 2012. It was subsequently circulated orpublic consultation. Comments received were collated by the secretariat prior tothe meeting o the Expert Committee.

Te Expert Committee noted that it was proposed to revise the text tobring it in line with the draf proposal or revision o the general monograph on

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parenteral preparations. Te Expert Committee adopted the text subject to theamendments proposed.

3.4.4 Proposal for revision of high-performance liquid chromatography

A preliminary draf o the revision o the document on high-perormanceliquid chromatography (HPLC) was reviewed at the consultation in May 2012.Te document was then sent out or public consultation in July 2012 and thecomments received were subsequently collated by the secretariat. It was pointedout that it was proposed to revise the chapter o Te International Pharmacopoeia on HPLC to include, among other additions, a description o the dwell volume

and the peak-to-valley ratio.Te Expert Committee adopted the text, subject to the amendmentsproposed.

3.4.5 General method for the supplementary informationsection of the Fourth Edition of The International Pharmacopoeia: Resistance to crushing of tablets

At its meeting in October 2007 the Expert Committee recommended that ageneral method text on the resistance to crushing o tablets should be includedin the supplementary inormation section o Te International Pharmacopoeia.Subsequently, at the Committee's meeting in October 2009, a revision o the generalmonograph on tablets was adopted in which, in the section on “Manuacturing”,reerence is made to a general method or resistance to crushing o tablets.

Te draf text on resistance to crushing o tablets, which is based on thetext in the European Pharmacopoeia, was discussed at the May 2012 consultationand was subsequently circulated or public consultation, with comments receivedbeing collated in September and October 2012. Tis test is intended to determine,

under dened conditions, the resistance to crushing o tablets, measured by the orce needed to disrupt them by crushing. It was noted that the EuropeanPharmacopoeia had granted permission or the text to be reproduced in TeInternational Pharmacopoeia.


3.4.6 General method for the supplementary information sectionof the Fourth Edition of The International Pharmacopoeia:Measurement of consistency by penetrometry

In October 2007 the Expert Committee recommended that a general methodtext on the measurement o consistency by penetrometry should be included inthe supplementary inormation section o Te International Pharmacopoeia. Apreliminary draf text was discussed at the May 2012 consultation. Followingthat discussion, a urther draf was circulated or public consultation, and the

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comments received were collated by the secretariat. Tis test is intended tomeasure, under determined and validated conditions, the penetration o an

object with a specied shape and size into the product to be examined.Te dra text on the measurement o consistency is based on the text

in the European Pharmacopoeia, rom which permission had been granted toreproduce the text in Te International Pharmacopoeia.


3.4.7 General method for the supplementary information sectionof the Fourth Edition of The International Pharmacopoeia:

Softening time determination of lipophilic suppositoriesIn October 2007 the Expert Committee recommended that a general methodtext on the determination o soening time o lipophilic suppositories shouldbe included in the supplementary inormation section o Te International Pharmacopoeia. A preliminary dra text was discussed at the consultationin May 2012. Following the consultation a revised text was sent out or publicconsultation and the comments received were collated by the secretariat prior tothe meeting o the Expert Committee.

Te test is intended to determine, under dened conditions, the time that

elapses beore a suppository maintained in water soens to the extent that it nolonger ofers resistance when a dened weight is applied. Te proposed text isbased on the text in the European Pharmacopoeia rom which permission hadbeen received to reproduce the text in Te International Pharmacopoeia.


3.4.8 Bacterial endotoxin

Te Expert Committee was inormed that the establishment o a primary reerence

standard or endotoxin would be considered by the WHO Expert Committee orBiological Standardization.

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4. Quality control – International Reference

Materials (International Chemical ReferenceSubstances and Infrared Reference Spectra)

4.1 Update on International Chemical Reference Substances4.1.1 Overview

International Chemical Reerence Substances (ICRS) are reerence substances thatare used as primary standards in physical and chemical tests that are describedin Te International Pharmacopoeia, and or establishing ocial secondary

standards. Te standards are ocially adopted by the Expert Committee.

4.1.2 Report on activities of the host organization related toInternational Chemical Reference Substances

In 2010 the European Directorate or the Quality o Medicines & HealthCare(EDQM) o the Council o Europe took over responsibility or establishing,preparing, storing and distributing WHO ICRS. Te Expert Committee receiveda report rom EDQM regarding this work, as o 31 March 2012. EDQM reportedthat initial challenges in taking over existing stock o ICRS rom Apoteket, whichwas a ormer WHO collaborating centre responsible or the distribution o theICRS, had now been overcome. A good and productive working relationshipbetween EDQM and the staf o Te International Pharmacopoeia was reported.

In 2011, EDQM distributed a total o 876 ICRS, with 61% o the totalnumber o items being sold within the WHO European Region. Eight studiesto establish new ICRS were carried out, and ve new ICRS were provisionally adopted or proposed or adoption. One study was perormed to establish a new International Inrared Reerence Spectrum (IIRS) or proguanyl hydrochloride.

Monitoring or continued tness or purpose was carried out on 19 ICRS.EDQM noted the importance o veriying the easibility and availability o the envisaged International Chemical Reerence Substance as the monographis being established. Further, it was pointed out that inormation in terms o chemical composition and structure o the impurities intended to become ICRSshould be systematically included in Te International Pharmacopoeia.

Te Expert Committee thanked EDQM or its work and took note o the report.

Te secretariat inormed the Expert Committee that EDQM announced

in 2012 that it could not carry out any production o ICRS involving compoundingo diferent materials into one ICRS. In addition, EDQM stated that it wasnot in a position to establish ICRS that are not mentioned in Te International Pharmacopoeia, although they may be mentioned in other WHO quality assurancedocuments.

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EDQM explained that, while it would honour the terms o its contractwith WHO, it could not commit to expanding its responsibility to include the

development o ICRS not explicitly covered by that agreement.Te Expert Committee expressed concern at the possible lack o

compound reerence materials. It was suggested that manuacturers and nationalpharmacopoeias may be able to assist. Te Expert Committee requested thesecretariat to react to the new situation by approaching national pharmacopoeiasto assess what assistance they might provide.

4.1.3 Adoption of established International Chemical Reference Substances

Since the meeting o the Expert Committee in October 2011, EDQM hadestablished several ICRS and one IIRS. Following a decision o the ExpertCommittee in 2010, the secretariat had already provisionally released some o these ICRS or distribution. Tese were:

■ pyrimethamine ICRS;

■ erythromycin ethylsuccinate ICRS;

■ niridazole ICRS;

■ ciprooxacin ICRS;

■ azobenzene melting-point ICRS.

Te decisions to release the substances were taken in consultationwith WHO collaborating centres and national control laboratories. Te ExpertCommittee adopted these ICRS as proposed.

Some reerence substances had not been provisionally released, namely:

■ atenolol ICRS;

■ dacarbazine ICRS;

■ phenobarbital ICRS;

■ spironolactone ICRS.

Tis was because the establishment reports were received too late to beassessed beore the meeting o the Expert Committee. Tese ICRS were adopted,subject to conrmation by the relevant experts.

In the case o artemisinin the secretariat concluded that it was not possibleto assign a single content to the candidate material that would be suitable orboth assay methods described in Te International Pharmacopoeia. Te matter

was discussed with selected experts and it was decided to revise the monographon artemisinin.

With regard to pentamidine isetionate, it was ound during the revisiono the report that the IR spectrum o the candidate material was diferentrom the IR spectra published in the British Pharmacopoeia and in the Indian

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Pharmacopoeia. In agreement with selected experts, the secretariat decided topostpone the provisional release o pentamidine isetionate ICRS 1.

Te Expert Committee adopted the ICRS subject to clarication o thediferences and to conrmation that the recorded IR spectrum corresponds topentamidine isetionate.

In addition, EDQM had established the IIRS on proguanil hydrochloride.Te Expert Committee took note o this action.

4.1.4 Supplementary information section of The International Pharmacopoeia: 4. Reference substances and reference spectra

Te document on reerence substances and reerence spectra was initially submitted to the consultation in May 2012. Te dra was circulated orcomment in June 2012 and the comments were collated in August 2012. Tedocument describes principles to be applied during the establishment and useo ICRS in order to guarantee that the reerence substances are suitable ortheir intended purpose. Te document is not applicable to WHO InternationalBiological Reerence Preparations. Te proposed chapter would be part o thesupplementary inormation section o Te International Pharmacopoeia, whichprovides the user with texts or guidance and inormation, and will not constitute

part o the standards.

4.1.5 New release procedure for International Chemical Reference Substances

At its orty-h meeting, the Expert Committee agreed on a new releaseprocedure or ICRS.1 On the basis o this procedure, case-reports issued by EDQMaer analytical testing o candidate material were reviewed by the secretariatwith assistance rom collaborating laboratories. I the testing was perormedaccording to the General guidelines for the establishment, maintenance and

distribution of chemical reference substances and the candidate material was oundsuitable, the secretariat, in collaboration with the collaborating laboratories,released the ICRS provisionally. In accordance with the rules, the case-reportswere subsequently submitted to the Expert Committee at its next meetingor nal adoption. Aer provisional release, EDQM begins the distribution o these ICRS.

Tis process expedited the release o ICRS and enabled WHO toreact more quickly to urgent demands or reerence substances. However, theprocedure did not clearly allocate the accountability or the release o ICRS to a

single person or body. Te Expert Committee discussed the issue and agreed onthe ollowing amendment to the new procedure:

1 See Annex 1, WHO Technical Report Series, No. 961, 2011.

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Afer testing o candidate material, the custodian centre or ICRS

will submit analytical case-reports to a newly established ExpertCommittee subgroup on ICRS, which should consist o threeexperts and a representative o the secretariat. Te subgroup willdecide on the suitability o the reerence substance and adopt theICRS on behal o the Expert Committee. During the ollowingmeeting o the Expert Committee, the subgroup will report on thenewly released ICRS.

A revised procedure appears as Annex 1 to this report.

Te Expert Committee approved the nomination o Proessor Dekker,Proessor Hoogmartens and Proessor Jin as members o the subgroup on ICRS.Each subgroup member should nominate one other expert rom their respectivecollaborating centres as a back-up.

4.1.6 Policy on naming International Chemical ReferenceSubstances in The International Pharmacopoeia

Following a discussion on the policy or naming ICRS in Te International Pharmacopoeia, the Expert Committee adopted a proposal to use the ollowingnomenclature or reerence standards in new monographs:

■ or standards on active pharmaceutical ingredients: [INNM name]RS;

■ or standards on impurities: [INN name o respective API] impurity [A, B, C or …] RS;

■ or standards or mixture o standards used or system suitability tests or peak identication, as intended: [INN name] or system

suitability RS; ■ [INN name] or peak identication RS;

■ or substances used to calibrate melting-point instruments: [INNname] Melting Point RS.

Te Expert Committee adopted the new proposal as a step towardsa systematic way o expressing the names or ICRS in uture and recognizedthat the certicate o analysis accompanying the ICRS would include urtherinormation on the precise nature o the substance.

4.1.7 Proposal to reduce analytical testing of high-purity candidate material

Te Expert Committee reviewed a proposal to reduce collaborative testing o high-purity candidate material or ICRS used or assay and established using themass-balance approach. Assays o ICRS established by mass balance are usually

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established in collaborative trials, where not only EDQM, but also several othercollaborating laboratories, analyse the proposed substance following a common

protocol that describes the procedures to be employed. Te results obtained areused to assign a content value to the reference standards.

o conserve resources in the participating laboratories, it was proposednot to run collaborative trials for candidate material of high purity (at least 99.5%)and to use solely analytical data obtained in a single laboratory to characterizethe ICRS. It was noted that the proposal did not apply to reference materialsestablished with approaches other than mass balance (i.e. melting-point standards),where a collaborative study would be carried out in any case.

Te Expert Committee adopted the proposal.

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5. Quality control – national laboratories

5.1 External Quality Assurance Assessment Scheme5.1.1 Overview

Te External Quality Assurance Assessment Scheme (EQAAS) is a programmeor the external evaluation o quality control management systems in chemicalcontrol laboratories. It uses interlaboratory comparisons to determine theperormance o participating laboratories in carrying out specifc tests ormeasurements. Te scheme supplements laboratories' internal quality assuranceprocedures by providing an external measure or their testing capabilities.

Te current Phase 5 o the EQAAS will end in March 2013. Tesubsequent Phase 6 will be scheduled rom 1 April 2013 to 30 March 2016. TeExpert Committee noted that unding was being sought or the continuation o this service.

5.1.2 Final report of Procedure 4

Procedure 4 o Phase 5 o the EQAAS was related to pH and weight per millilitre.Forty-two o 53 laboratories (79%) rom all six WHO regions reported satisactory

results or the two determinations requested.Te Expert Committee noted the report and endorsed ollow-up actionby the secretariat with the laboratories.

5.1.3 Preliminary report of Procedure 5 and additionalinformation with regard to possible sources of error

Procedure 5 o Phase 5 o the EQAAS is concerned with assay by liquidchromatography. Forty-seven participant laboratories submitted their results orthis study. Te raw data rom the study were reported to the Expert Committee.Again some 80% o the laboratories reported satisactory results.

wo urther tests remain to be completed in Phase 5.Te Expert Committee noted the report and endorsed ollow-up action

by the secretariat with the laboratories, or the investigation o the results thatwere unsatisactory and on corrective measures or the uture.

5.1.4 Proposal for Phase 6

During Phase 6 o the EQAAS, it was proposed to perorm profciency tests on

the ollowing samples using the indicated techniques:

■ assay by titration;

■ determination o specifc optical rotation;

■ assay by HPLC;

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■ dissolution test (paddle apparatus, UV-Vis absorptionspectrophotometry);

■ water determination by Karl Fischer titration;

■ related substances by HPLC.

Te Expert Committee reviewed the proposal and adopted the testtechniques for Phase 6.

Tere was also a discussion on the possibility of using the opportunity of testing for monitoring quality of the products on the respective national marketsin cases where the laboratories met the required standards of performance. Tis,

however, would be outside the scope of the EQAAS.

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6. Quality assurance – good manufacturing practices

6.1 Updates of WHO GMP textsIn 2011 the Expert Committee approved updates to three GMP texts. Tesecretariat reported that no proposals for updating of GMP materials had beenreceived since then. It was noted, however, that a number of European Union (EU)and United States Food and Drug Administration (US-FDA) GMP guidelineshad been recently updated.

Te Expert Committee requested the secretariat to make a proposal onhow to revise the WHO guidelines in light of these trends in other new guidelines.

6.2 Training materialsTe process for the revision of the WHO training modules was approved by the Expert Committee in October 2011 to bring them in line with the updatedguidelines. Each slide of the modules was therefore checked for correctness inrelation to the various revised GMP texts. All basic training modules had beenrevised and updated and were being reviewed. Major changes were made to theGMP training modules, e.g. for the module on quality management, to include

risk assessment and other new factors. Te Expert Committee was informedthat there was currently no training material on microbiology laboratories andhazardous materials as these GMP texts had only been developed in recent years.A number of other training modules were still under revision. It was noted thatall WHO GMP guidelines are to be provided on a CD-ROM.

Te Expert Committee expressed its gratitude for the update.

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7. Quality assurance – new approaches

7.1 Quality risk managementTe rst dra points or guidelines on this topic were initially prepared in 2010

and widely circulated or comments. Te Expert Committee commented on the

dras in 2010 and 2011. Numerous comments were received during the global

consultation phases. During the inormal consultation on WHO quality risk

management and quality guidelines held on 28–30 June 2011, it was suggested

that the principles included in these guidelines could be more concise to enable a

timely initial implementation. Full implementation o the quality risk management

(QRM) system and the application o the related tools would necessitate a longertime rame. Te QRM approach was considered by all experts to be a crucial

element o quality assurance in the uture.

Subsequent to the meeting o the Expert Committee in October 2011, the

document on QRM was completely restructured on the basis o the numerous

comments made and advice received beore and during the consultation. Te

aim o the guidelines is to assist the development and implementation o efective

QRM, covering activities such as research and development, sourcing o materials,

manuacturing, packaging, testing, storage and distribution.Te Expert Committee reviewed the document and the most recent

proposals or revisions based on eedback and comments received in response to a

urther round o global consultation. Members o the Committee made proposals

or a number o amendments. Te Expert Committee adopted the revision o the

guidelines, subject to implementation o the changes approved (Annex 2).

7.2 Pharmacopoeial harmonization

At the International meeting o world pharmacopoeias held on 28 February to 1 March 2012, the 23 pharmacopoeias present committed to urther eforts

towards pharmacopoeias harmonization. Te participants acknowledged that

the harmonization o standards would be essential to global public health in the

uture. Pharmacopoeial harmonization was also a plenary topic at the two-day

public conerence organized by the International Pharmaceutical Federation

(FIP) and WHO in Amsterdam in October 2012.

International meeting of world pharmacopoeiasWHO maintains an Index of pharmacopoeias and had organized a meeting

inviting all world pharmacopoeias included therein, rom 28 February to 2 March

2012. wenty-three pharmacopoeias attended the meeting to discuss challenges

and issues. Tey committed to working urther towards harmonization and to

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strengthening WHO's role when developing global standards or the production

and testing o medicines. It was recognized that the harmonization o standards

has become increasingly important or public health or a number o reasons, oneo the most important being to combat alsied and substandard medicines.

Te meeting had called or greater collaborative work and sharing o

inormation between world pharmacopoeias. An important recommendation was

to develop good pharmacopoeial practices, and a draing group was established

to take this project orward. Te role o Te International Pharmacopoeia

was appreciated. Furthermore, it was agreed to hold a public conerence o

pharmacopoeias in October 2012 in connection with the FIP Centennial Congress,

inviting all stakeholders and users to discuss uture approaches.

WHO–International Pharmaceutical Federation Conference

Te two-day public conerence on “International world o pharmacopoeias. Now

and in uture”, jointly organized by WHO and FIP was held in Amsterdam on

7–8 October 2012. Te conerence addressed pharmacopoeial harmonization

opportunities or collaboration and good pharmacopoeial practice, as well as the

way orward or pharmacopoeias in a changing environment. Workshops were

held on impurities, residues and on challenges in developing herbal medicinesmonographs and applying them in practice.

Discussion

Te Expert Committee expressed its appreciation or this joint efort between

WHO and FIP, and thanked FIP or its continued collaboration.

Te Expert Committee urged more requent communication between

the pharmacopoeias and stressed the need to produce a high-level document

reecting those principles and elements considered by pharmacopoeias to be

important. It was noted that harmonization o approaches would help to expand

access to medicines in developing countries and that consistency between

pharmacopoeias would be a help to the pharmaceutical industry. When each

country had its own specications or medicines, this made it very expensive or

manuacturers to tailor their exports to comply with each country's requirements.

Te Expert Committee agreed to WHO's coordination o pharmacopoeial

harmonization activities, and supported urther work with the global

pharmacopoeias to develop good pharmacopoeial practices as a basis or uture

harmonization and collaboration. Tis would be coordinated by the secretariatwhich would contact the pharmacopoeias or proposals regarding the scope and

important elements to be included in the uture good pharmacopoeial practices.

As this good practice developed, it would be communicated according to the

usual consultation process.

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7.3 Screening technologies

Te Expert Committee was brieed on new developments regarding analyticalscreening technologies. It was reported that some alsied medicines wouldproduce wrong results, as they may have been deliberately prepared to producealse-positive results. In addition, WHO increasingly receives requests romcountries or assistance in dealing with cases o suspect medicines causing serioushealth problems to patients.

Te Expert Committee expressed concern at this growing issue.Members discussed possible causes and solutions, although they recognized thatthe most efective analytical and orensic solutions were likely to be expensive.

In particular, it was stressed that WHO could not efectively nd a solutionwithout collaboration with stakeholders, such as manuacturers and regulatory authorities. Te secretariat was requested to review the trends o new laboratory technologies and to report back to the Expert Committee.

7.4 Survey on laboratories reportA survey was initiated among WHO collaborating centres and those participatingin the EQAAS, being mainly national quality control laboratories (QCLs), to

determine the number o QCLs that were involved in testing suspect samplesand how they deal with such samples. Te data are still being analysed but will beprovided to the Expert Committee when they become available.

Te Expert Committee welcomed this initiative and noted the report.

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8. Quality assurance – distribution and

trade of pharmaceuticals8.1 Revision of model quality assurance

system for procurement agenciesTe model quality assurance system (MQAS) or procurement agencies wasadopted by the Expert Committee in October 2005, since when it has beenused by many organizations. At a GFAM–WHO joint stakeholders meeting inAugust 2011, WHO and GFAM identied the need or revision o the MQASand the need or an assessment tool or procurement agencies. Te MQAS

was reviewed and a proposal or revision initiated; and an assessment tool wasdeveloped with major procurement organizations and agencies. Both activitiesollowed a consultative process. During this process, it was noted that not all theprocurement organizations used the system.

wo inormal meetings were organized by GFAM in 2012 to review progress in both the MQAS and the proposed new assessment tool. Te revisedMQAS and the proposed assessment tool were then circulated or commentin August 2012 by WHO ollowing the usual Expert Committee consultation

process. Comments were collated and the draf revised MQAS and the commentswere presented to the Expert Committee or consideration.Te Expert Committee considered the comments and proposed a number

o amendments to the draf. Te Expert Committee endorsed the proposal or arevision o the MQAS, and noted progress made to date.

8.2 Assessment tool based on the modelquality assurance system

In August 2011, WHO and GFAM identied the need or a new assessment toolor procurement agencies in conjunction with the revision o the MQAS. Teproposed assessment tool was based on the MQAS. A draf o the proposed toolwas prepared during 2012 and was circulated or comment. Te draf was beingtested in a pilot process rom August to December 2012, afer which it would beurther reviewed and revised according to the experience gained.

Te Expert Committee endorsed the proposal to develop a new assessmenttool based on the MQAS, thanked the GFAM or nancing the initiative, andnoted progress made to date. It was requested that the assessment tool should be

published as an appendix to the MQAS.

8.3 Monitoring and surveillance of national supply chainWHO has recently initiated a project ocusing specically on building globalcapacity or surveillance and monitoring o SSFFC medicines; the project

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responds to the act that the problem o SSFFC medicines has continued to grow in complexity, scale and geographical extent.

Te project's long-term objective is to signicantly improve the quantity,quality and analysis o data on the incidence o SSFFC medicines – throughbuilding on existing systems and by creation o a global surveillance andmonitoring system – to provide stakeholders with a sound basis on which tobuild and collaborate on strategies or radically reducing the incidence o SSFFCmedicines and protecting supply chains.

Moreover, the increased quality o data and detailed inormation willenable more ecient inormation exchange between countries and acilitate

regulatory action to protect patients and consumers.Te project aims to create a sustainable surveillance and monitoringsystem or collecting, disseminating and analysing inormation on SSFFCmedicines, based upon analysis o experience with existing systems such as therapid alert system (RAS) in the WHO Western Pacic Region, and refecting atleast the requirements o the project participants, but ideally the requirementso all stakeholders. It will collect best practices or reporting o cases o SSFFCmedicines, and will acilitate common understanding and unication o theminimum standards needed or individual case-reports. In addition it is intended

to help national medicines regulatory authorities (NMRAs) to identiy SSFFCmedicines that have entered or that threaten to enter their country's supply chain. Data and case-reports relating to SSFFC medicines will be collected romNMRAs, to generate sound and reliable evidence o where incidence o suchmedicines is most serious. Te aim is to promote sharing o inormation andexpertise between NMRAs, in order to stimulate action (including alerts andregulatory action to protect patients and consumers), and closer collaboration, tominimize the negative impact o SSFFC medicines.

Te project is currently in the pilot phase testing a new inormation

technology (I) platorm and reporting processes developed over the past twoyears. At present 10 countries are participating actively in the pilot study. Oncethe system is up and running other countries will be able to join.

Te Expert Committee valued the new project on market surveillanceand noted the report.

8.4 Proposal for revision of good trade and distribution practicesTe WHO guide on Good trade and distribution practices for pharmaceutical

starting materials was published in 2003. In 2006, the International PharmaceuticalExcipients Council (IPEC) – an industry association comprising excipientmanuacturers, excipient distributors and their pharmaceutical customers –published its GDP Guide for pharmaceutical excipients, which was ully alignedwith the WHO document. Since the publication o these guidelines, a number o

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new developments and concepts, including, or example, risk management, haveinuenced good distribution practices (GDP) principles and processes. It was

noted that a number o recent incidents have created awareness o the need orurther improvement o the present guidelines.

Te IPEC Federation presented an update on its activities concerninggood trade and distribution practices. Te IPEC Federation proposed a revisionand update o the WHO good trade and distribution practices (GDP) guide andofered its support in providing a proposal. Tis could be developed by the IPECFederation member groups by the end o 2012. It was noted that any dra o the WHO GDP guide would be circulated or review using WHO’s wide globalconsultation process and would be submitted to the WHO Expert Committeeor consideration or adoption. Following adoption, the IPEC Federation wouldthen update its own guide in line with that o WHO.

Te Expert Committee discussed the need or revising and updating theWHO GDP guide and endorsed the proposal.

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9. Prequalifcation o priority essential medicines

including active pharmaceutical ingredients9.1 Update on the Prequalifcation o Medicines

Programme managed by WHOPQP was launched in 2001 at WHO headquarters in partnership with the JointUnited Nations Programme on HIV/AIDS (UNAIDS), UNICEF and the UnitedNations Population Fund (UNFPA), and with support rom the World Bank. PQPis thus a United Nations Programme administered by WHO. Te Programme'socus was originally the evaluation o medicines or treating HIV/AIDS, malaria

and tuberculosis, but products in other therapeutic categories are now alsoevaluated. Since October 2010 PQP has started to prequaliy APIs.

Most prequalifed fnished pharmaceutical products are generics, butare not exclusively so. Te prequalifcation procedure begins with an invitationor expressions o interest. It was noted that there have been ewer submissionsin the area o tuberculosis than or other diseases covered by this Programme.Tirty-fve products (34 o them generic) were prequalifed during 2011. Sixty-eight dossiers were received and 46 were accepted or evaluation. Nearly 1000

assessment reports were produced and more than 500 variations to prequalifedproducts were assessed.It was noted that the norms and standards developed and approved

through the Expert Committee underpin all o PQP's activities. Te ExpertCommittee expressed its gratitude or the report and or the work o PQP.

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10. Prequalifcation o active pharmaceutical ingredients

10.1 Update on the prequalifcation o activepharmaceutical ingredients

Te prequalifcation o APIs began in October 2010 as a pilot project intendedto identiy APIs that are o good quality and are manuactured in compliancewith GMP. In 2011 PQP prequalifed its frst APIs (six or antimalarials and twoor antituberculosis medicines). Manuacturers are invited to apply on the basiso their products. Te list o prequalifed APIs is published on the WHO website and a document confrming prequalifcation o the API is supplied to the

manuacturer. NMRAs may also request urther inormation on a particular API.As o October 2012, 62 applications or the prequalifcation o APIs had beenreceived and 23 had been prequalifed and published on the web site.

Te Expert Committee expressed appreciation or the report.

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11. Prequalifcation o quality control laboratories

11.1 Update on the prequalifcation o quality control laboratoriesTe prequalication procedure or quality control laboratories (QCLs) wasoriginally established in 2004 or Arica only and has since expanded globally.Any QCL (whether public or private) may now participate in the programme.Participation is voluntary and 55 laboratories have asked to participate since 2004(73% being national QCLs). Te Expert Committee heard that 24 laboratories arecurrently prequalied, with at least one in each WHO region. Te programmealso includes capacity-building, with training and technical assistance provided

or national QCLs in developing countries.An inormal network o QCLs, which have been prequalied, have

submitted an application or prequalication or have actively participated inprequalication testing projects or other activities, is currently being set up incooperation with a WHO collaborating centre in South Arica. Te objectivesare to support the quality o laboratory testing within the network, to acilitatereliable testing o medicines procured by United Nations agencies, and to acilitateinormation exchange, networking and work-sharing.

Te benets to QCLs o prequalication include the possibility to provide

testing services to United Nations agencies and other organizations, the recognitionthat comes o being listed as a WHO-prequalied laboratory, the learning processo improving laboratory standards, and the possibility o being assisted by WHOexpert consultants and o participating in WHO-organized training. Te ExpertCommittee heard that countries appreciate having prequalied laboratories intheir own region or the convenience and speed o service that these laboratoriesprovide.

Te Expert Committee expressed its appreciation or the report.

11.2 Update on WHO quality monitoring projectsPQP organizes quality monitoring o medicines projects to monitor the quality o prequalied products and o medicines procured by United Nations agencies.It was noted that this contributes to the quality control o medicines in MemberStates and to capacity-building through cooperation with NMRAs. Te ExpertCommittee heard that, in response to a complaint o poor quality, a survey o thequality o antimalarials supplied within phase 1 o the Afordable Medicines Facility malaria project (AMFm), which is managed by GFAM, is being conducted. Te

evaluation will cover both the product itsel and the storage conditions.Te Expert Committee expressed its appreciation or the report.

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12. Regulatory guidance

12.1 Extemporaneous dispensing andadministration of medicines to children

In October 2011 the Expert Committee adopted a document on points to considerin the pharmaceutical ormulations or paediatric medicines. A revised versiono the document was prepared and circulated or public consultation in August2012. Te comments received were subsequently collated by the secretariat. Inconnection with this new guidance document, a second one on Provision by health-care proessionals o patient-specifc preparations or children that are not

available as authorized products – points to consider , was discussed.Tis guidance document had been previously discussed during the

meeting o the WHO Expert Committee on the Selection and Use o EssentialMedicines which took place in Accra, Ghana on 21–25 March 2011.

Both Committees had, despite certain reservations regarding the riskso inappropriate preparations and the risks o diverting eforts aimed at thedevelopment o age-appropriate dosage orms or children, recommended urtherdeveloping such guidance aer a careul review and wide consultation in order tomeet the current need or advice. Te project continued, with the assistance rom

specialists, as a joint WHO–FIP endeavour.In the course o urther development and consultation on this document,

the working group suggested taking a more general approach; ofering adviceto more than just one group, i.e. those concerned with paediatric patients, andtackling special populations, including, or example, paediatric patients togetherwith geriatric patients in one document. Te updated version o the workingdocument was newly entitled FIP–WHO technical guidelines: considerations onthe provision by health-care proessionals o patient-specifc enteral compounding or special populations (or example, paediatric and geriatric patients) when no suitable

authorized products are available, and the content was adjusted accordingly.Te Expert Committee expressed concern at the efort to address both

paediatric and geriatric ormulations in one document. In attempting to includeormulations or the two patient groups, it was elt that the document had becomemore technical and had lost some o its initial ocus on access to medicines orchildren, when no registered nished product or children exists on the market.

Te Expert Committee requested that the document should be reocusedon compounding o paediatric ormulations, and should then be circulated inits revised orm or public consultation prior to being considered at the next

meeting o the Expert Committee.Te secretariat was requested to liaise with the authors to review the

documents and to consider all comments made by the Expert Committee overthe course o the preparation o this document, and to post the dra on the WHOweb site or public review.

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12.2 Guidance on variations to a prequalifed product

In October 2011, the Expert Committee adopted new generic quality guidelines,published as Annex 4 o WHO echnical Report Series, No. 970, under the titleWHO Guidelines on submission o documentation or a multisource (generic) fnished pharmaceutical product or the WHO Prequalifcation o MedicinesProgramme: quality part . Te Expert Committee at that time also proposedthat subsequently a new general document on variations guidelines should beconsidered, which would be in line with these newly adopted guidelines. Te new document was mailed out or public consultation in May 2012 and the commentsreceived were subsequently collated by the secretariat. A revised version was then

mailed out or urther comment in August 2012.Te revised document Guidance on variations to a prequalifed product

retains the basic structure and unction o the previous variations guidelines buthas been completely updated and expanded to bring it in line with the principleso the new generic quality guidelines.

Te Expert Committee adopted the document (Annex 3). It was noted,however, that the adopted document was intended or use specically in regard toPQP and the development o a similar general guidance document on variationswas recommended.

12.3 Collaborative procedure between the WHO Prequalifcationo Medicines Programme and national medicine regulatoryauthorities in the assessment and accelerated registrationo national WHO-prequalifed pharmaceutical products

Te Expert Committee reviewed the draf o a collaborative procedure betweenthe PQP and NMRAs or the assessment and accelerated national registration

o WHO-prequalied pharmaceutical products. PQP had been approached by anumber o NMRAs seeking assistance with national registration o prequaliedproducts, which in some cases took a long time, delaying the availability o medicines to patients.

Te aim o the proposed procedure was to accelerate national registration(marketing authorization) o WHO-prequalied medicines in countries withparticipating NMRAs, and to assist NMRAs to ocus their regulatory resourceson the country-specic aspects o national registration decision-making.

Given scarce regulatory resources in countries which are recipients o

WHO-prequalied medicines, it was elt that NMRAs in these countries may benet rom inormation on the outcomes o assessments and inspections already organized when they assess prequalied medicinal products. With the agreemento prequalication holders, PQP would be prepared – under conditions describedin the collaborative procedure – to share ull assessment and inspection reports

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with interested NMRAs. NMRAs would retain their prerogative to makesovereign decisions on registration, and the collaborative procedure would not

interere with national legislation, decision-making processes or regulatory ees.Te principles or the procedure had initially been discussed and agreed

at a meeting o the heads o medicines regulatory authorities o East Arica inFebruary 2009. A document describing the procedure had subsequently beendiscussed at a series o meetings with regulators, manuacturers and expertsbeore being discussed at the consultation in May 2012. Te document had alsobeen reviewed by the WHO Legal Counsel.

Te Expert Committee discussed the draf document describing thecollaborative procedure and made a number o proposals or amendments. Tedocument was adopted subject to the amendments proposed (Annex 4).

12.4 Proposal for a procedure on samplingand market surveillance survey

Following the recommendation made by the WHO Expert Committee onSpecications or Pharmaceutical Preparations at its orty-sixth meeting inOctober 2011, to continue the development o sampling procedures based on thenumerous examples obtained rom many countries as eedback to the secretariat's

communications, internal discussions took place to propose new guidanceon sampling and market surveillance surveys. A proposal or a procedure onsampling and market surveillance was subsequently drafed and sent out orcomment in September 2012 and the comments received prior to the meeting o the Expert Committee in October 2012 were collated by the secretariat.

Te proposal was based on an existing survey protocol developed by the WHO Prequalication Laboratory Programme, which had been extensively involved in the establishment o survey protocols or major studies or antimalarialand antituberculosis medicines. Te proposal included an annotated survey protocol, survey orms, a testing protocol and listed the content o a typicalanalytical test report.

Te Expert Committee noted that the document would be o particularimportance in monitoring and post-marketing surveillance, and agreed that itshould be urther developed as a general document providing advice on samplingor various groups o medicines. Te Expert Committee also noted the needor separate, specic guidance in relation to spurious/alsely-labelled/alsied/countereit (SFFC) medical products.

12.5 Comparator productsA comparator product is a pharmaceutical product with which the multisourceproduct is intended to be interchangeable in clinical practice. In 1999 the ExpertCommittee adopted a document on comparator products. Tis contained a list

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o international comparator pharmaceutical products or the equivalence testingand assessment o interchangeable multisource (generic) products and included

a decision-tree or use in identiying comparator pharmaceutical products.Te list was intended to serve as an inormation tool or medicines regulatory authorities and manuacturers o pharmaceuticals, although it was not intendedto be binding on those responsible or choosing a reerence product. At that timethe Expert Committee noted that the list and the guidance provided would needto be updated periodically.

A revision o the comparator list is in progress. Te aim is to have a list o suitable comparators o acceptable quality that is harmonized with the PQP listand which contains products that are easily accessible.

Te Expert Committee expressed its thanks or the continuing work oncomparator products,

12.6 Biowaiver

Te term “biowaiver” is applied to a regulatory medicines approval processwhen the dossier is approved on the basis o evidence o equivalence other thanthrough in vivo equivalence testing. A series o monographs have been publishedthat contain essentially literature reviews, gathering and organizing relevant data

that should be taken into consideration in deciding whether a biowaiver couldbe recommended or a new ormulation o a specic API. Further work on thesebiowaiver reviews has been done by FIP. Some 40–50 reviews o APIs have beenpublished. Tese scientic reviews provide the basis upon which to update therelated annex (WHO echnical Report Series, No. 937, 2006, Annex 8), publishedtogether with the Multisource (generic) pharmaceuticals: guidelines on registrationrequirements to establish interchangeability (WHO echnical Report Series,No. 937, 2006, Annex 7).

Te Expert Committee noted the situation and thanked FIP or itswork in this area. Te Committee encouraged continuing eforts to update thisannex in collaboration with the WHO collaborating centre, to circulate thedra or comments and to present the dra revision to the next meeting o theExpert Committee.

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13. Nomenclature, terminology and databases

13.1 Quality assurance terminologyTe WHO web site provides access to a database o terms and denitions, whichalso indicates the WHO guidelines in which these terms and denitions appear.In October 2011 the Expert Committee created a subgroup to review the list o terms and denitions to ensure its standardization and potentially to reduce thenumber o denitions or each term. Work in this area is ongoing.

13.2 International Nonproprietary Names

for pharmaceutical substancesTe Expert Committee received an update on the WHO Programme orInternational Nonproprietary Names (INN) or pharmaceutical substances andreceived the strategic plan o the INN Programme or 2011–2016.

It was noted that the number o INN had increased signicantly in thepast two years. Te latest cumulative list o INN (Cumulative List 14), containingsome 8500 INN, was published by WHO in January 2012. A review o the lengtho time required or acceptance o an INN showed that the average is 11.9 months,

with 86% o INN being accepted aer one or two rounds o discussion. New stems and pre-stems have also been published.A notable increase has been seen in the number o biological INN and

this trend is expected to continue. Te Expert Committee also noted that thepossible need or a nomenclature scheme or cell therapies is under discussion.

In response to a number o requests to use the INN in databases alsoor commercial products, the Programme has developed a web service – namedINN Global Data Hub – to ofer INN data access to INN stakeholders. Te INNGlobal Data Hub is a soware system designed to support machine-to-machine

interaction over the network. Te MedNet web site was demonstrated, showingthe number o users worldwide.

Te Expert Committee noted the report on the work o the INNProgramme.

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14. Miscellaneous

14.1 Quality assurance of pharmaceuticals: a compendiumof guidelines and related materials

Te Expert Committee was informed that a CD-ROM had been producedcontaining a compendium of all current WHO guidelines and related materialson quality assurance.

14.2 StrategyAll areas of WHO had been requested to prepare strategies that would guidetheir future activities. Members of the Expert Committee were invited to proposeelements that could be included in the future strategy of QSM.

opics raised included:

■ biosimilars, which relate both to biologicals and pharmaceuticalpreparations, through increased liaison and collaboration with theExpert Committee on Biological Standardization;

■ increased collaboration between pharmacopoeias and

harmonization; ■ increased availability of international expertise to national

laboratories (in particular in view of the increased need to identify SFFC drugs);

■ facilitation of training for NMRAs;

■ prioritization, especially to retain and maintain the current coreactivities in this area.

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15. Summary and recommendations

Te WHO Expert Committee on Specifcations or Pharmaceutical Preparationsadvises the Director-General o WHO in the area o quality assurance o medicines. Te Expert Committee provides recommendations and guidance orthe purpose o assuring the quality o medicines throughout their entire lie-cycle,i.e. rom their initial development through to their fnal distribution to patients.

Since its creation in 1947, this Expert Committee has given independentexpert advice in the orm o practical recommendations, clearly defned standards,and international guidelines or quality medicines. Te recommendations,standards and guidelines adopted by the Committee are developed through a

broad international consensus-building process.At its orty-seventh meeting rom 9 to 12 October 2012, the Expert

Committee addressed a range o issues. Tese included the United NationsPrequalifcation Programme which is managed by WHO, the prequalifcationo quality control laboratories, WHO's External Quality Assurance AssessmentScheme, a revision o the Organization's model quality assurance system, guidanceon making paediatric ormulations available and a revision o WHO’s guidanceon good trade and distribution practices.

Te Expert Committee reviewed specifcations and tests or a number

o antiretroviral, antimalarial, anti-inective and other medicines, adoptingthose that it judged to be suitable or inclusion as monographs in TeInternational Pharmacopoeia. General texts and supplementary inormationsections o Te International Pharmacopoeia were also reviewed and wereadopted where appropriate. In addition, arrangements or the quality control o international reerence materials were discussed and a number o ICRS and oneIIRS were adopted.

Te work o this Committee in urthering access to high-quality medicines relates to a number o other WHO committees and United Nations

bodies, as well as to national and regional authorities and procurement agenciesand to the pharmaceutical industry. Tus, the Committee's discussion includedissues that are being addressed by the WHO Expert Committee on BiologicalStandardization, and the Expert Committee on the Selection and Use o EssentialMedicines and its subcommittee on Medicines or Children. Committeemembers considered reports rom the Global Fund to Fight AIDS, uberculosisand Malaria and rom the United Nations Children's Fund, as well as discussinga variety o elements o regulatory guidance and a proposed revision to WHO'sadvice on GMP. raining on GMP was discussed and advice was given on quality

risk management.Te Expert Committee noted considerable collaboration with other

bodies – particularly the FIP, with which WHO had jointly organized recentconerences, and the International Conerence o Drug Regulatory Authorities.In addition, ollowing WHO's convening o a meeting o pharmacopoeias in

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early 2012, the Committee encouraged urther collaboration between the world'spharmacopoeias leading to harmonization o their work.

A ull list o the decisions and recommendations made by the ExpertCommittee at its orty-seventh meeting is given below.

Te ollowing new guidelines were adopted and recommended or use:

■ Release procedure or International Chemical Reerence Substances(Annex 1)

■ WHO guidelines on quality risk management (Annex 2)

■ WHO guidelines on variations to a prequalied product (Annex 3)

■ Collaborative procedure between the World Health OrganizationPrequalication o Medicines Programme and national medicinesregulatory authorities in the assessment and accelerated national

registration o WHO-prequalied pharmaceutical products(Annex 4)

For inclusion in The International Pharmacopoeia

Te ollowing monographs were adopted:

■ for antiretroviral medicines

– abacavir sulate

– abacavir oral solution

– nevirapine

– nevirapine oral suspension

– nevirapine tablets

– tenoovir disoproxil umarate

■ for antimalarial medicines

– artesunate

– artesunate tablets

– artesunate or injection

– artemisinin

– mefoquine hydrochloride ■ for antituberculosis medicines

– cycloserine

– cycloserine capsules

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39

■ for anti-infectives

– cloxacillin sodium – pyrantel oral suspension

■ for other medicines

– levonorgestrel and ethinylestradiol tablets

– zinc acetate

– zinc gluconate

■ suppression of monographs

– artemisinin tablets

– artemisinin capsules

■ for harmonized general texts

– dissolution test or solid oral dosage orms (based on PDG text)

■ general policy topics and general revision issues for:

– capsules

– parenteral preparations

– uniormity o content or single-dose preparations

– high-perormance liquid chromatography

■ supplementary information section:

– resistance to crushing o tablets

– measurement o consistency by penetrometry

– sofening time determination o lipophilic suppositories.

■ Te Committee adopted the following new ICRS:

– atenolol ICRS;

– azobenzene melting point ICRS;

– ciprooxacin ICRS;

– dacarbazine ICRS;

– erythromycin ethylsuccinate ICRS;

– niridazole ICRS;

– phenobarbital ICRS;

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– pyrimethamine ICRS;

– spironolactone ICRS;

■ the following International Infrared Reference Spectrum (IIRS) for:

– proguanil hydrochloride IIRS;

■ and new policies on ICRS for:

– naming ICRS in Te International Pharmacopoeia;

– analytical testing o high purity candidate material.

Te ollowing recommendations were made in the various quality assurance-related areas. Progress on the suggested actions should be reported tothe Expert Committee on Specications or Pharmaceutical Preparations at itsnext meeting.

Collaboration with and among pharmacopoeias

■ Te Expert Committee expressed recognition and support or WHO'sinitiative to work closely with other pharmacopoeias.

■ It endorsed the development o good pharmacopoeial practicesunder the aegis o WHO and the Expert Committee on Specicationsor Pharmaceutical Preparations in collaboration with the worldpharmacopoeias.

The International Pharmacopoeia

■ Continue development o specications or APIs, medicines, general

methods and texts and general supplementary inormation inaccordance with the work plan and as decided at this meeting.

■ Continue the eforts at international collaboration in relation to therevision and inclusion o specic monographs and general methods.

■ Continue the preparatory work or a subsequent supplement to TeInternational Pharmacopoeia, or towards a h edition, especially inelectronic orm (CD-ROM and online).

International Chemical Reference Substances (ICRS)

■ Continue promoting the use o International Chemical ReerenceSubstances (ICRS) through various activities, including a promotionalofer to national authorities.

■ Continue the eforts to urther enhance the development o new ICRS.

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41

■ In response to the concern expressed by the Expert Committee atthe possible lack o candidate material or reerence substances it was

suggested that manuacturers and national pharmacopoeias may beable to assist. Te Expert Committee requested the secretariat to reactto the new situation by approaching national pharmacopoeias toassess what assistance could be provided.

External Quality Assurance Assessment Scheme (EQAAS)

■ Continue the External Quality Assurance Assessment Scheme(EQAAS) or pharmaceutical quality control laboratories, Phase 5,

onwards. ■ Continuation o the scheme with Phase 6, as unds allow.

Quality control laboratories

■ Continue the survey on quality control laboratories perorminganalysis o suspect spurious/alsely-labelled/alsifed/countereit(SFFC) medicines and report back on the outcome.

Good manufacturing practices (GMP) and manufacture

■ Continue to ollow up on the revision process or GMP or biologicalsundertaken under the aegis o the Expert Committee on BiologicalStandardization.

■ Study the need or an update o the GMP general principles to covernew developments globally.

■ Continue the review o the revised GMP training modules with a

view to making them publicly available as soon as possible.

WHO model quality assurance system for procurement agencies

In close collaboration with the Global Fund:

■ Continue the process o revision o the model quality assurancesystem or procurement agencies.

■ Continue the development o an assessment tool or procurementagencies.

Update of good trade and distribution practices (GTDP)

■ Continue the process o revision o GDP in collaboration withpartner organizations specialized in this feld.

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Guidelines on submission o documentation or a multisource(generic) fnished pharmaceutical product

■ Develop a new general document or the quality part based on

the specifc guidance developed or the WHO Prequalifcation o

Medicines Programme.

■ Develop a new general document or the variations based on the

specifc guidance developed or the WHO Prequalifcation o

Medicines Programme.

Provision by health-care proessionals o patient-specifc preparations orchildren that are not available as authorized products: points to consider

■ Further develop these “points to consider” jointly with FIP as

a practice guidance document or compounding, ocusing on

paediatrics.

Update on biowaiver and comparator products

■ Provide an update o the list o possible biowaivers and comparator

products ollowing review by the members o the Expert Committee

to replace the version o 2002.

Sampling procedures or monitoring o market situations

■ Continue development o sampling procedures based on the

numerous examples obtained rom many countries as eedback to

the secretariat's communications.

Screening technologies procedures or monitoring o market situations

■ Review the trends in new technologies or screening suspect

samples.

Quality assurance terminology

■ Continue the work on the preerred terms included in the current

quality assurance terminology database based on the analysis

prepared by the secretariat, with a group o experts, or which a

consultation had already started.

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43

Index of pharmacopoeias

■ Consult with representatives o the individual world pharmacopeiasincluded in the Index of pharmacopoeias in order to complete and

validate the inormation therein.

WHO databases

■ Maintain the International Nonproprietary Names (INN) databaseand continue to make it available on the web site.

■ Maintain the Quality Assurance database and continue to make itavailable on the web site.

■ Continue the work o the terminology subgroup to urther review the list o terms and denitions covered by this Expert Committee.

Financial situation analysis

In view o the number o important tasks ahead, the Expert Committeeemphasized the need or continued unding to the Medicines Quality AssuranceProgramme and the need to reach out to programmes and organizations thatuse the international guidelines and standards developed by this Committee, asthese were almost exclusively supported by the Prequalication o MedicinesProgramme. Te Expert Committee was concerned that the number o staf working in this area was not sucient to perorm the tasks required.

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Acknowledgements

Special acknowledgement was made by the Committee to Mrs W. Bonny, Mr C.de Joncheere, Ms M. Gaspard, Mr D. Jasovský, Dr S. Kopp, Ms C. Mendy, Dr H.Schmidt and to Dr L. Rägo, Quality Assurance and Saety: Medicines, EssentialMedicines and Health Products, WHO, Geneva, Switzerland, and to Mr D. Bramley,Prangins, Switzerland, who were instrumental in the preparation and proceedingso the meeting.

echnical guidance included in this report has been produced with thefnancial assistance o the European Union, the Bill & Melinda Gates Foundationand UNIAID.

Te Committee also acknowledged with thanks the valuable contributionsmade to its work by the ollowing agencies, institutions, organizations,pharmacopoeias, WHO collaborating centres, WHO programmes and persons:

Active Pharmaceutical Ingredients Committee, European ChemicalIndustry Council, Brussels, Belgium; Danish Medicines Agency, Copenhagen,Denmark; European Association o Pharmaceutical Full-line Wholesalers,Groupement International de la Répartition Pharmaceutique, Brussels, Belgium;European Commission, Brussels, Belgium; European Directorate or the Quality

o Medicines and HealthCare, Council o Europe, Strasbourg, France; EuropeanFederation o Pharmaceutical Industries and Associations, Brussels, Belgium;European Medicines Agency, London, England; Te Global Fund to FightAIDS, uberculosis and Malaria, Vernier, Switzerland; Healthcare DistributionManagement Association, Arlington, VA, USA; Indian Drug Manuacturers'Association, Mumbai, India; International Federation o PharmaceuticalManuacturers and Associations, Geneva, Switzerland; International GenericPharmaceutical Alliance, Brussels, Belgium; International PharmaceuticalExcipients Council Europe, Brussels, Belgium; International Pharmaceutical

Federation, Te Hague, Netherlands; International Society or PharmaceuticalEngineering, ampa, Florida, USA; Pharmaceutical Inspection Co-operationScheme, Geneva, Switzerland; Pharmaceutical Research and Manuacturers o America, Washington, DC, USA; Swissmedic, Swiss Agency or TerapeuticProducts, Berne, Switzerland; Terapeutic Goods Administration, Woden,AC, Australia; United Nations Children’s Fund, Supply Division, Copenhagen,Denmark; United Nations Children's Fund, New York, USA; United NationsDevelopment Programme, New York, USA; Te World Bank, Washington, DC,USA; World Intellectual Property Organization, Geneva, Switzerland; World

Sel-Medication Industry, Ferney-Voltaire, France.Laboratoire National de Contrôle des Produits Pharmaceutiques, Chéraga,

Alger, Algeria; Instituto Nacional de Medicamentos, Buenos Aires, Argentina;Expert Analytic Laboratory, Centre o Drug and Medical echnology Expertise,Yerevan, Armenia; Laboratoire national de contrôle de qualité des médicaments

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45

et consommables médicaux, Cotonou, Benin; Agency or Medicinal Productsand Medical Devices, Control Laboratory, Sarajevo, Bosnia and Herzegovina;

Instituto Nacional de Controle de Qualidade em Saúde, Rio de Janeiro, Brazil;Laboratoire National de Santé Publique, Ouagadougou, Burkina Faso; NationalProduct Quality Control Centre, Ministry o Health, Phnom Penh, Cambodia;Laboratoire National de Contrôle de Qualité des Médicaments et d’Expertise,Yaoundé, Cameroon; Departamento de Control Nacional, Unidad de Controlde Calidad de Medicamentos comercializados, Institutu de Salud Pública,Santiago de Chile, Chile; National Institutes or Food and Drug Control, Beijing,People’s Republic o China; Medicamentos y Productos Biológicos del INVIMA,Bogotá, Colombia; Laboratorio de Análisis y Asesoría Farmacéutica, Facultadde Farmacia, Universidad de Costa Rica, San José, Costa Rica; Laboratoriode Normas y Calidad de Medicamentos, Caja Costarricense de Seguro Social,Universidad de Costa Rica, Alajuela, Costa Rica; Laboratoire National de la SantéPublique, Abidjan, Côte d'Ivoire; Ocina Sanitaria Panamericana, OPS/OMS,La Habana, Cuba; National Organization or Drug Control and Research, Cairo,Egypt; Drug Quality Control and Toxicology Laboratory, Drug Administrationand Control Authority, Addis Ababa, Ethiopia; Centrale Humanitaire Médico-Pharmaceutique, Clermont-Ferrand, France; Food and Drugs Board, Quality

Control Laboratory, Accra, Ghana; Laboratoire national de contrôle de qualitédes medicaments, Conakry, Guinea; Laboratory or Quality Evaluation andControl, National Institute o Pharmacy, Budapest, Hungary; Central DrugsLaboratory, Kolkata, India; Provincial Drug and Food Quality Control Laboratory,Yogyakarta, Indonesia; Food and Drugs Control Laboratories, Ministry o Healthand Medical Education, Tehran, Iran (Islamic Republic o); Caribbean RegionalDrug Testing Laboratory, Kingston, Jamaica; Mission or Essential Drugs andSupplies, Nairobi, Kenya; National Quality Control Laboratory or Drugs andMedical Devices, Nairobi, Kenya; Food and Drug Quality Control Center,

Ministry o Health, Vientiane, Lao People's Democratic Republic; Laboratoire deContrôle de Qualité des Médicaments, Agence du Médicament de Madagascar,Antananarivo, Madagascar; Centre or Quality Control, National PharmaceuticalControl Bureau, Petaling Jaya, Selangor, Malaysia; Laboratoire National de laSanté du Mali, Bamako, Mali; Laboratoire National de Contrôle des Médicaments,Rabat, Morocco; Quality Surveillance Laboratory, Windhoek, Namibia; NationalMedicines Laboratory, Department o Drug Administration, Kathmandu, Nepal;Laboratoire National de Santé Publique et d'Expertise, Niamey, Niger; CentralQuality Control Laboratory, Directorate General o Pharmaceutical Afairs and

Drug Control, Ministry o Health, Muscat, Oman; Drug Control and TraditionalMedicine Division, National Institute o Health, Islamabad, Pakistan; InstitutoEspecializado de Análisis, Universidad de Panamá, Panama; Centro Nacionalde Control de Calidad, Instituto Nacional de Salud, Lima, Peru; Bureau o Foodand Drugs, Department o Health, Muntinlupa City, Philippines; Laboratory or

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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; LaboratoireNational de Contrôle des Médicaments, Dakar Etoile, Senegal; PharmaceuticalDivision, Applied Sciences Group, Health Sciences Authority, Singapore; Centrefor 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 AssuranceLaboratory, 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, TeSchool of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar-es-Salaam, United Republic of anzania; anzania Food and Drug Authority,Dar-es-Salaam, United Republic of anzania; Bureau of Drug and Narcotic,Department of Medical Sciences, Ministry of Public Health, Nonthaburi,Tailand; Laboratoire National de Contrôle des Médicaments, unis, unisia;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, Comisión Para El Control de Calidadde Medicamentos, Montevideo, Uruguay; Instituto Nacional de Higiene “RafaelRangel”, Caracas, Venezuela; National Institute of Drug Quality Control, Hanoi,Viet Nam; Medicines Control Authority, Control Laboratory of Zimbabwe,Harare, Zimbabwe.

Farmacopea Argentina, Instituto Nacional de Medicamentos, CiudadAutónoma de Buenos Aires, Buenos Aires, Argentina; Farmacopeia Brasileira,Brasileira, Brazil; British Pharmacopoeia, London, England; Chinese

Pharmacopoeia, Beijing, People's Republic of China; Croatian Pharmacopoeia,Zagreb, Croatia; Czech Pharmacopoeia, Prague, Czech Republic; EuropeanPharmacopoeia, European Directorate for the Quality of Medicines andHealthCare, Council of Europe, Strasbourg, France; Finnish MedicinesAgency, Helsinki, Finland; Pharmacopée française, Agence nationale desécurité du médicament et des produits de santé, Saint-Denis, France; GermanPharmacopoeia, Bonn, Germany; Hungarian Pharmacopoeia, Budapest, Hungary;Indian Pharmacopoeia, Raj Nagar, Ghaziabad, India; Indonesian Pharmacopoeia,Jakarta, Indonesia; Iranian Pharmacopoeia, ehran, Iran (Islamic Republic of);

Japanese Pharmacopoeia, okyo, Japan; Kazakhstan Pharmacopoeia, Almaty,Kazakhstan; Korean Pharmacopoeia, Cheongwon-gun, Chungcheongbuk-do,Republic of Korea; Mexican Pharmacopoeia, México DF, Mexico; PortuguesePharmacopoeia, Lisbon, Portugal; Russian Pharmacopoeia, Moscow, RussianFederation; Serbian Pharmacopoeia, Belgrade, Serbia; Spanish Pharmacopoeia,

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Acknowledgements

47

Madrid, Spain; Swedish Pharmacopoeia, Uppsala, Sweden; Swiss Pharmacopoeia,Berne, Switzerland; Ukrainian Pharmacopoeia, Kharkov, Ukraine; United States

Pharmacopeia, Rockville, MD, USA; Vietnamese Pharmacopoeia, Hanoi, Viet Nam.WHO Centre Collaborateur pour la Conormité des Médicaments,

Laboratoire national de Contrôle des Produits Pharmaceutiques, Alger, Algeria;WHO Collaborating Centre or Drug Quality Assurance, Terapeutic GoodsAdministration Laboratories, Woden, AC, Australia; WHO CollaboratingCentre or Drug Quality Assurance, National Institutes or Food and DrugControl, Beijing, People’s Republic o China; WHO Collaborating Centre orResearch on Bioequivalence esting o Medicines, Frankurt am Main, Germany;WHO Collaborating Centre or Drug Inormation and Quality Assurance,National Institute o Pharmacy, Budapest, Hungary; WHO Collaborating Centreor Quality Assurance o Essential Drugs, Central Drugs Laboratory, Calcutta,India; WHO Collaborating Centre or Regulatory Control o Pharmaceuticals,National Pharmaceutical Control Bureau, Jalan University, Ministry o Health,Petaling Jaya, Malaysia; WHO Collaborating Centre or Medicines Quality Assurance, Pharmaceutical Laboratory, Centre or Analytical Science, HealthSciences Authority, Singapore; WHO Collaborating Centre or Quality Assuranceo Medicines, North-West University, Potchestroom, South Arica; WHO

Collaborating Centre or Quality Assurance o Essential Drugs, Bureau o Drugand Narcotic, Department o Medical Sciences, Ministry o Public Health,Nonthaburi, Tailand.

Anti-Countereiting Medicines Programme, WHO, Geneva, Switzerland;Blood Products and Related Biologicals Programme, WHO, Geneva, Switzerland;Global Malaria Programme, WHO, Geneva, Switzerland; HIV/AIDS Programme,WHO, Geneva, Switzerland; International Nonproprietary Names Programme,WHO, Geneva, Switzerland; Medicines Access and Rational Use, WHO,Geneva, Switzerland; Medicines Regulatory Support Programme, WHO,

Geneva, Switzerland; Oce o the Legal Counsel, WHO, Geneva, Switzerland;Prequalication o Medicines Programme, WHO, Geneva, Switzerland; Quality,Assurance and Saety: Medicines, WHO, Geneva, Switzerland; Quality, Saety and Standards, WHO, Geneva, Switzerland; raditional and Complementary Medicine, WHO, Geneva, Switzerland; WHO Regional Oce or Arica, Brazzaville,Congo; WHO Regional Oce or the Americas/Pan American Health Organization,Washington, DC, USA; WHO Regional Oce or the Eastern Mediterranean, Cairo,Egypt; WHO Regional Oce or Europe, Copenhagen, Denmark; WHO RegionalOce or South-East Asia, New Delhi, India; WHO Regional Oce or the Western

Pacic, Manila, Philippines.Mrs . Abdul Sattar, Acting Director General, Directorate General o

Pharmaceutical Afairs and Drug Control, Ministry o Health, Muscat, Oman;Dr F. Abiodun, Benin City, Nigeria; Dr E. Adams, Laboratorium voorFarmaceutische Chemie en Analyse van Geneesmiddelen, Leuven, Belgium;

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Dr M. Adarkwah-Yiadom, Standard Ocer, Ghana Standards Board, Drugs,Cosmetics and Forensic Laboratory esting Division, Accra, Ghana; Proessor I.

Addae-Mensah, University o Ghana, Legon, Ghana; Dr K. Agravat, Regulatory Afairs, Unimark Remedies Limited, Ahmedabad, India; Ms R. Ahmad, Centreor Product Registration, National Pharmaceutical Control Bureau, Ministry o Health, Petaling Jaya, Malaysia; Mrs S. Ahmed Jafar, Directorate General o Pharmaceutical Afairs and Drug Control, Ministry o Health, Muscat, Oman;AMGEN Inc., Engineering, West Greenwich, RI, USA; Dr C. Anquez raxler,European Sel-Medication Industry, Brussels, Belgium; Dr H. Arentsen,Regulatory Intelligence and Policy Specialist, Regulatory Development Strategy,H. Lundbeck A/S, Copenhagen-Valby, Denmark; Astellas Pharma Europe BV,Leiderdorp, the Netherlands; Dr C. Athlan, Quality Reviewer, Swissmedic,Berne, Switzerland; Dr A. Ba, Directeur, Qualité et Développement, CentraleHumanitaire Medico-Pharmaceutique, Clermont-Ferrand, France; Mr N. Banerjee,Cipa Limited, Goa, India; Dr H. Batista, US Food and Drug Administration,Silver Spring, MD, USA; Mr B. Baudrand, OECI, Paris, France; Dr O.P. Baula,Deputy Director, State Pharmacological Center, Ministry o Health, Kiev,Ukraine; Proessor S.A. Bawazir, Head o Drug Sector and Vice-President orDrug Afairs, Saudi Food and Drug Authority, Riyadh, Saudi Arabia; Dr M.G.

Beatrice, Vice President, Corporate Regulatory and Quality Science, Abbott,Abbott Park, IL, USA; Dr .L. Bedane, Drug Administration and Control, AddisAbaba, Ethiopia; Ms .J. Bell, WHO Focal Point, US Food and DrugAdministration, Silver Spring, MD, USA; Dr I.B.G. Bernstein, Director, Pharmacy Afairs, Oce o the Commissioner/Oce o Policy, US Food and DrugAdministration, Silver Spring, MD, USA; Dr L. Besançon, Manager, Scienticand Proessional Afairs, International Pharmaceutical Federation, Te Hague,the Netherlands; Dr R.P. Best, President and CEO, International Society orPharmaceutical Engineering, ampa, FL, USA; Dr A. Bevilacqua, US

Pharmacopeia, Bedord, MA, USA; Dr L. Bigger, Regulatory and ScienticAfairs, International Federation o Pharmaceutical Manuacturers Associations,Geneva, Switzerland; Dr J. Bishop III, Review Management Staf, Oce o theDirector, Center or Biologics Evaluation and Research/FDA, Rockville, MD,USA; Dr L. Bonthuys, Pretoria, South Arica; Mr M.H. Boon, Deputy Director,Overseas Audit Unit – Audit Branch, Audit & Licensing Division, Health ProductsRegulation Group, Singapore; Proessor R. Boudet-Dalbin, Faculté de Pharmacie,Laboratoire de Chimie Térapeutique, Paris, France; Dr S.K. Branch, ActingGroup Manager, Special Populations Group, Medicines and Healthcare Products

Regulatory Agency, London, England; Dr E. Brendel, Bayer HealthCare AG,Elbereld, Germany; Dr M. Brits, Deputy Director, WHO Collaborating Centreor the Quality Assurance o Medicines, North-West University, PotchestroomCampus, Potchestroom, South Arica; Mr C. Brown, Inspections Enorcementand Standards Division, Medicines and Healthcare Products Regulatory Agency,

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London, England; Dr W. Bukachi, Project Coordinator, International Afairs, USPharmacopeia, Rockville, MD, USA; Ms A. Bukirwa, National (Food and) Drug

Authority, Kampala, Uganda; Bureau o Drug and Narcotic, Department o Medical Sciences, Ministry o Public Health, Nonthaburi, Tailand; Dr F. Burnett,Managing Director, Pharmaceutical Procurement Service, Organization o Eastern Caribbean States, Casties, St Lucia; Dr W. Cabri, Research andDevelopment, Director, Chemistry and Analytical Development, Sigma-tauIndustrie Farmaceutiche Riunite SpA, Pomezia, Italy; Dr. D. Calam, Wiltshire,England; Dr N. Cappuccino, Lambertville, NJ, USA; Dr A. Castro, Regulatory Afairs Director and Senior Pharmacist, Roche Servicios SA, Heredia, Costa Rica;Dr D. Catsoulacos, Scientic Administrator, Manuacturing and Quality Compliance, Compliance and Inspection, European Medicines Agency, London,England; Mr J.-M. Caudron, Braine-le-Château, Belgium; Mr P. Cenizo, SouthernArican Pharmaceutical Regulatory Afairs Association (SAPRAA), Randburg,South Arica; Mr X. Chan, Project Manager, International PharmaceuticalFederation, Te Hague, the Netherlands; Dr B. Chapart, Pharma Review Manager,Global Analytical Development, Sano-Aventis Pharma, Anthony, France;Ms Cheah Nuan Ping, Director, Cosmetics & Cigarette esting Laboratory,Pharmaceutical Division, Applied Sciences Group, Health Sciences Authority,

Singapore; Dr X. Chen, Director, Division o Drug Distribution Supervision,State Food and Drug Administration, Beijing, People's Republic o China;Proessor Y. Cherrah, Faculté de Médecine et Pharmacie, Rabat, Morocco;Dr Y.H. Choi, Scientic Ocer, Korea Food & Drug Administration, Cheongwon-gun, Chungbuk, Republic o Korea; Cipla Limited, Mumbai, India; Ms I. Clamou,Assistant Manager, Scientic,echnical and Regulatory Afairs, EuropeanFederation o Pharmaceutical Industries and Associations, Brussels, Belgium;Dr M. Cooke, Senior Manager, Global Quality, Operations, AstraZeneca,Maccleseld, Cheshire, England; Dr C. Cra, Member, United States

Pharmacopeia International Health Expert Committee, Rockville, MD, USA;Dr R.L. Dana, Senior Vice President, Regulatory Afairs and Parenteral DrugAssociation raining and Research Institute, Parenteral Drug Association,Bethesda, MD, USA; Mr M.M. Das, Barisha, Kolkata, India; Dr J. Daviaud, SeniorPharmaceutical QA Ocer, Pharmaceutical Procurement Unit, Global Fund toFight AIDS, uberculosis and Malaria, Geneva, Switzerland; Dr V. Davoust,Quality & Regulatory Policy, Pharmaceutical Sciences, Pzer Global Research & Development, Paris, France; Proessor . Dekker, Research Institute or IndustrialPharmacy, North-West University, Potchestroom, South Arica; Dr M. Derecque-

Pois, Director General, European Association o Pharmaceutical Full-lineWholesalers, Brussels, Belgium; Proessor J.B. Dressman, Institut ürPharmazeutische echnologie, Biozentrum, Johann Wolgang Goethe-Universität,Frankurt am Main, Germany; Dr A.. Ducca, Senior Director, Regulatory Afairs, Healthcare Distribution Management Association, Arlington, VA, USA;

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Dr .D. Dufy, Lowden International, unstall, Richmond, N. Yorks, England;Dr S. Durand-Stamatiadis, Director, Inormation and Communication, World

Sel-Medication Industry, Ferney-Voltaire, France; Dr P. Ellis, Director, ExternalAdvocacy, Quality Centre o Excellence, GlaxoSmithKline, Brentord, Middlesex,England; European Compliance Academy Foundation, Heidelberg, Germany;European Medicines Agency, London, England; Fedearma, Ciudad, Guatemala;F. Hofman-La Roche Ltd, Basel, Switzerland; Dr A. Falodun, Department o Pharmaceutical Chemistry, Faculty o Pharmacy, University o Benin, Benin City,Nigeria; Federal Ministry o Health, Bonn, Germany; Dr E. Feer, Member,United States Pharmacopeia International Health Expert Committee, Rockville,MD, USA; Dr R. Fendt, Head, Global Regulatory & GMP Compliance Pharma,Care Chemicals Division, BASF, Limburgerho, Germany; Mr A. Ferreira doNascimento, Agência Nacional de Vigilância, Brasília, Brazil; Mr M. FitzGerald,European Association o Pharmaceutical Full-line Wholesalers, Brussels,Belgium; Dr A. Flueckiger, Head, Corporate Health Protection, Corporate Saety,Health & Environmental Protection, F. Hofmann-La Roche, Basel, Switzerland;Dr G.L. France, Head, Q&A Compliance, EU Region, Novartis Consumer HealthServices SA, Nyon, Switzerland; Mr . Fujino, Director, International Afairs,Japan Generic Medicines Association, okyo, Japan; Miss Y. Gao, Project

Manager, Chinese Pharmacopoeia Commission, Beijing, People’s Republic o China; Dr M. Garvin, Senior Director, Scientic and Regulatory Afairs,Pharmaceutical Research and Manuacturers o America, Washington, DC, USA;Dr X. Ge, Senior Analytical Scientist, Pharmaceutical Laboratory, PharmaceuticalDivision, Applied Sciences Group, Health Sciences Authority, Singapore; Dr L.Gibril, Compliance Coordinator, Novartis Pharma SAE, Amiria, Cairo, Egypt;Dr F. Giorgi, Research and Development, Analytical Development Manager,Sigma-tau Industrie Farmaceutiche Riunite SpA, Pomezia, Italy; Dr L. Girard,Head, Global Pharmacopoeial Afairs, Novartis Group Quality, Quality Systems

and Standards, Basel, Switzerland; GlaxoSmithKline, Brentord, Middlesex,England; GlaxoSmithKline Biologicals SA, Wavre, Belgium; GlaxoSmithKline,Sales raining Centre, Research riangle Park, NC, USA; Ms J. Gouws,Department o Health, Medicines Control Council, Pretoria, South Arica; Dr M.Goverde, QC Expert Microbiology, Novartis Pharma AG, Basel, Switzerland;Ms R.Govithavatangaphong, Director, Bureau o Drug and Narcotics, Departmento Medical Sciences, Ministry o Public Health, Nonthaburi, Tailand; Dr J.Grande, Manager, Regulatory Afairs, McNeil Consumer Healthcare, Markham,England; Dr A. Gray, Senior Lecturer, Department o Terapeutics and Medicines

Management and Consultant Pharmacist, Centre or the AIDS Programme o Research in South Arica (CAPRISA), Nelson R Mandela School o Medicine,University o KwaZulu-Natal, Congella, South Arica; Dr M. Guazzaroni Jacobs,Director, Quality and Regulatory Policy, Pzer Inc., New York, NY, USA; Ms N.M.Guerrero Rivas, Instituto Especializado de Análisis, Estaeta Universitaria,

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Panamá, Panama; Guilin Pharmaceutical Company Ltd, Guilin, People's Republico China; Dr R. Guinet, Agence nationale de sécurité du médicament et des

produits de santé, Saint-Denis, France; Proessor R. Guy, Proessor o Pharmaceutical Sciences, Department o Pharmacy & Pharmacology, University o Bath, Claverton Down, Bath, England; Dr N. Habib, Director General o Medical Supplies, Ministry o Health, Oman; Dr N. Hamilton, Industrial Quality and Compliance, Industrial Afairs, Sano Aventis, West Malling, Kent, England;Dr S. Harada, International Afairs Division, Minister's Secretariat, Ministry o Health, Labour and Welare, Tokyo, Japan; Dr A. Hawwa, Lecturer in Pharmacy (Medicines in Children), Medical Biology Centre, Queen's University Belast,Belast, Northern Ireland; Dr M. Hayes-Bachmeyer, Technical Regulatory Afairs,Pharmaceuticals Division, F. Hofmann-la Roche, Basel, Switzerland; Mr Y.Hebron, Tanzania Food and Drugs Authority, Dar-es-Salaam, United Republic o Tanzania; Dr G.W. Heddell, Director, Inspection Enorcement & StandardsDivision, Medicines and Healthcare Products Regulatory Agency, London,England; Dr D. Hege-Voelksen, Swissmedic, Berne, Switzerland; Ms J. Hiep, QAPharmacist and Auditor, Adcock Ingram, Bryanston, South Arica; Ms M.Hirschhorn, Head, Quality and Chemistry Sector, Comisión para el Control deCalidad de Medicamentos (Drug and Control Commission), Montevideo,

Uruguay; Proessor J. Hoogmartens, Leuven, Belgium; Dr K. Hoppu, Director,Poison Inormation Centre, Helsinki University Central Hospital, Helsinki,Finland; Dr R. Horder, Abbott, Maidencombe, England; Dr H. Hoseh, Head o Registration Unit, Drug Directorate, Jordan Food and Drug Administration,Jordan; Dr X. Hou, Chemical & Materials, Singapore; Dr N. Ibrahim, NationalPharmaceutical Control Bureau, Ministry o Health, Jalan University, PetalingJaya, Indonesia; Indian Drug Manuacturers' Association, Worli, Mumbai, India;Dr J. Isasi Rocas, Pharmaceutical Chemist, Lima, Peru; Proessor R. Jachowicz,Head, Department o Pharmaceutical Technology and Biopharmaceutics,

Jagiellonian University Medical College, Faculty o Pharmacy, Kraków, Poland;Ms M. Kira, Consultant, Non-Governmental Organizations and Industry Relations Section, Department o External Relations, World Intellectual Property Organization, Geneva, Switzerland; Dr R. Jähnke, Global Pharma Health Funde.V., Frankurt, Germany; Dr M. James, GlaxoSmithKline, Brentord, Middlesex,England; Dr A. Janssen, Manager, Regulatory Afairs, DMV Fonterra Excipients,FrieslandCampina Ingredients Innovation, Goch, Germany; Proessor S. Jin,Chie Expert or Pharmaceutical Products, National Institutes or Food and DrugControl, Beijing, People's Republic o China; Dr P. Jones, Director, Analytical

Control, Pharmaceutical Sciences, Pzer Global R&D, Sandwich, England;Dr Y. Juillet, Consultant, Paris, France; Mr D. Jünemann, Teaching Assistant;Institut ür Pharmazeutische Technologie, Biozentrum, Johann WolgangGoethe-Universität, Frankurt am Main, Germany; Ms A. Junttonen, SeniorPharmaceutical Inspector, National Agency or Medicines, Helsinki, Finland;

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Dr M. Kaplan, Director, Institute or Standardization and Control o Pharmaceuticals, Jerusalem, Israel; Dr M. Karga-Hinds, Director, Barbados Drug

Service, Christchurch, Barbados; Dr A.M. Kaukonen, National Agency orMedicines, Helsinki, Finland; Ms H. Kavale, Cipla, Mumbai, India; Dr .Kawanishi, Deputy Director General, National Institute o Health Sciences,okyo, Japan; Dr S. Keitel, Director, European Directorate or the Quality o Medicines and Healthcare, Strasbourg, France; Dr K. Keller, Director andProessor, Federal Ministry o Health, Bonn, Germany; Dr M. Keller, Inspector,Division o Certicates and Licencing, Swissmedic, Berne, Switzerland; Dr L.Kerr, Scientic Operations Adviser, Oce o Laboratories and Scientic Services,Terapeutic Goods Administration, Woden, AC, Australia; Dr M. Khan,Director, Federal Research Center Lie Sciences, US Food and DrugAdministration, Silver Spring, MD, USA; Proessor K. Kimura, Drug Managementand Policy, Institute o Medical, Pharmaceutical and Health Sciences, KanazawaUniversity, Kanazawa-city, Japan; Dr H. Köszegi-Szalai, Head, Department orQuality Assessment and Control, National Institute o Pharmacy, Budapest,Hungary; Dr A. Kovacs, Secretariat, Pharmaceutical Inspection Co-operationScheme, Geneva, Switzerland; Ms S. Kox, Senior Director Scientic Afairs,European Generic Medicines Association, Brussels, Belgium; Dr P. Kozarewicz,

Scientic Administrator, Quality o Medicines Sector, Human Unit Pre-Authorization, European Medicines Agency, London, England; Dr A. Krauss,Principal Chemist, Oce o Laboratories and Scientic Services, TerapeuticGoods Administration, Woden, AC, Australia; Proessor H.G. Kristensen,Vedbaek, Denmark; Mr A. Kuperman, Industry Pharmacist, Strasbourg, France;Proessor S. Läer, Institut ür Klinische Pharmazie und Pharmakotherapie,Heinrich-Heine-Universität, Düsseldor, Germany; Dr J.-M. Legrand,GlaxoSmithKline Biologicals, Wavre, Belgium; Dr Li H., Head, ChemicalProducts Division, Chinese Pharmacopoeia Commission, Beijing, People’s

Republic o China; Dr A. Lodi, Head, Laboratory Department, EuropeanDirectorate or the Quality o Medicines and HealthCare, Strasbourg, France;Mr M. Lok, Head o Oce, Oce o Manuacturing Quality, Terapeutic GoodsAdministration, Woden, AC, Australia; Ms M.Y. Low, Director, PharmaceuticalDivision, Applied Sciences Group, Health Sciences Authority, Singapore; Dr J.C.Lyda, Senior Director, Regulatory Afairs, Parenteral Drug Association Europe,Glienicke/ Berlin, Germany; Mr D. Mader, Compliance Auditor, GlaxoSmithKline,Cape own, South Arica; Ms G.N. Mahlangu, Director General, MedicinesControl Authority o Zimbabwe, Harare, Zimbabwe; Mangalam Drugs and

Organics Limited, Mumbai, India; Dr M. Mantri, Bicholim, Goa, India; Dr B.Matthews, Alcon, Hemel Hempstead, Herts, England; Dr Y. Matthews, Regulatory Operations Executive, GE Healthcare, Amersham, Bucks, England; Dr G. McGurk,Executive Inspector, Irish Medicines Board, Dublin, Ireland; Dr A. Mechkovski,Moscow, Russian Federation; Medicines and Healthcare Products Regulatory

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Agency, Inspection & Standards Division, London, England; Dr M. Mehmandoust,Agence nationale de sécurité du médicament et des produits de santé, Saint-

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Division, Pharmaceutical and Medical Devices Agency, Tokyo, Japan; Dr O.Morin, Regulatory and Scientic Afairs, International Federation o Pharmaceutical Manuacturers Associations, Geneva, Switzerland; Dr J.M.Morris, Irish Medicines Board, Dublin, Ireland; Mr T. Moser, Galenica, Berne,Switzerland; Dr A.E. Muhairwe, Executive Secretary and Registrar, NationalDrug Authority, Kampala, Uganda; Dr. S. Mülbach, Director, Senior Regulatory Counsellor, Vior Pharma, Glattbrugg, Switzerland; Ms C. Munyimba-Yeta,Director, Inspectorate and Licensing, Pharmaceutical Regulatory Authority,Lusaka, Zambia; Ms N. Nan, Chie Pharmacist, National Institutes or Food and

Drug Control, Beijing, People’s Republic o China; Miss X. Nan, Project Ocer,China Center or Pharmaceutical International Exchange, Beijing, People’sRepublic o China; Dr E. Narciandi, Head, Technology Transer Department,Center or Genetic Engineering & Biotechnology, La Havana, Cuba; NationalAgency o Drug and Food Control, Jakarta Pusat, Indonesia; National Authority o Medicines and Health Products (INFARMED), Directorate or the Evaluationo Medicinal Products, Lisbon, Portugal; National Institute o Drug Quality Control o Vietnam, Hanoi, Viet Nam; Dr R. Neri, Sano, Antony, France; Dr E.Nickličková, Inspector, State Institute or Drug Control, Prague, Czech Republic;

Proessor A. Nicolas, Radiopharmacien, Expert analyse, Pharmacie, HôpitalBrabois Adultes, Vandoeuvre, France; Dr H.K. Nielsen, Technical Specialist,Essential Medicines, Medicines and Nutrition Centre, UNICEF Supply Division,Copenhagen, Denmark; Dr K. Nodop, Inspections, European Medicines Agency,London, England; Novartis Group, Novartis Campus, Basel, Switzerland;

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Proessor A. Nunn, Formby, Liverpool, England; Dr A. Ojoo, United NationsChildren's Fund, Copenhagen, Denmark; Mr S. O'Neill, Managing Director, Te

Compliance Group, Dublin, Ireland; Dr L. Oresic, Head, Quality AssuranceDepartment, Croatian Agency or Medicinal Products and Medical Devices,Zagreb, Croatia; Dr P.B. Orhii, Director-General, National Agency or Food andDrug Administration and Control, Abuja, Nigeria; Dr N. Orphanos, InternationalPrograms Division, Bureau o Policy, Science, and International Programs,Terapeutic Products Directorate, Health Products & Food Branch, HealthCanada, Ottawa, Canada; Proessor .L. Paál, Director-General, National Instituteo Pharmacy, Budapest, Hungary; Dr P.R. Pabrai, New Delhi, India; Mrs L.Paleshnuik, President, LP Inc., Amprior, Ontario, Canada; Dr S. Parra, Manager,Generic Drugs Quality Division 1, Bureau o Pharmaceutical Sciences,Terapeutic Products Directorate, Health Canada, Ottawa, Canada; Dr Passek,Federal Ministry o Health, Bonn, Germany; Dr D.B. Patel, Secretary-General,Indian Drug Manuacturers' Association, Mumbai, India; Proessor S. Patnala,Proessor, Pharmaceutical Analysis and Coordinator, University InstrumentationFacility, KLE University, Belgaum, India; Mr C. Perrin, Pharmacist, InternationalUnion Against uberculosis and Lung Disease, Paris, France; Dr M. Phadke,Senior Manager, Analytical Research, Ipca Laboratories, Mumbai, India;

Pharmaceutical Inspection Co-operation Scheme, Geneva, Switzerland; Dr B.Phillips, Medicines and Healthcare Products Regulatory Agency, London,England; Dr B. Pimentel, European Chemical Industry Council, Brussels,Belgium; Polychromix, Inc., Wilmington, MA, USA; Dr A. Pontén-Engelhardt,Head o Stability Management, Global Quality, Operations, AstraZeneca,Södertälje, Sweden; Ms A. Poompanich, Bangkok, Tailand; Dr R. Prabhu,Regulatory Afairs Department, Cipla, Mumbai, India; Dr R.P. Prasad, Director,Department o Drug Administration, Kathmandu, Nepal; Ms S.J. Putter, Walmer,Port Elizabeth, South Arica; Ms M.-L. Rabouhans, Chiswick, London, England;

Dr A. Rajan, Director, Celogen Liescience & echnologies, Mumbai, India;Mr .L. Rauber, Specialist in Health Surveillance, Agência Nacional de VigilânciaSanitária Agency, Brasilia, Brazil; Mr N. Raw, Inspection, Emorcement andStandards Division, Medicines and Healthcare Products Regulatory Agency,London, England; Dr J.-L. Robert, Service du Contrôle des Médicaments,Laboratoire National de Santé, Luxembourg; Dr S. Rönninger, Global Quality Manager, F. Hofmann-La Roche, Basel, Switzerland; Dr N. Ruangrittinon,Bureau o Drug and Narcotic Department o Medical Sciences, Ministry o PublicHealth, Nonthaburi, Tailand; Dr K.A. Russo, Vice President, Small Molecules,

United States Pharmacopeia, Rockville, MD, USA; Dr A.P. Sam, Merck, theNetherlands; Dr C. Sánchez, CECMED, Havana, Cuba; Dr L.M. Santos, ScienticLiaison – International Health, Te United States Pharmacopeia, Rockville, MD,USA; Dr . Sasaki, Pharmaceutical and Medical Devices Agency, okyo, Japan;Dr J. Satanarayana, Matrix Laboratories, Secunderabad, India; Dr B. Schmauser,

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Bundesinstitut ür Arzneimittel und Medizinprodukte, Bonn, Germany; Dr A.Schuchmann, Brazil; Dr A. Seiter, Member, United States Pharmacopeia

International Health Expert Committee, Rockville, MD, USA; Ms K. Semp,eaching Assistant, Institut ür Pharmazeutische echnologie, Biozentrum,Johann Wolgang Goethe-Universität, Frankurt am Main, Germany; Dr U. Shah,Formulation Research Fellow, Cheshire, Merseyside & North Wales LRN,Medicines or Children Research Network, Royal Liverpool Children's NHSrust, Liverpool, England; Dr R. Shaikh, Pakistan; Dr P.D. Sheth, Vice-President,International Pharmaceutical Federation, New Delhi, India; Ms R. Shimonovitz,Head o Inspectorates, Institute or Standardization and Control o Pharmaceuticals, Ministry o Health, Israel; Dr P.G. Shrotriya, Ambli, Ahmedabad,India; Dr M. Sigonda, Director-General, anzania Food and Drugs Authority,Dar-es-Salaam, United Republic o anzania; Dr G.N. Singh, Secretary-cum-Scientic Director, Government o India, Central Indian PharmacopoeiaLaboratory, Ministry o Health and Family Welare, Ghaziabad, India; Dr S.Singh, Proessor and Head, Department o Pharmaceutical Analysis, NationalInstitute o Pharmaceutical Education and Research, Nagar, Punjab, India; Ms K.Sinivuo, Senior Researcher and Secretary, National Agency or Medicines,Helsinki, Finland; Dr L. Slamet, Director, Drug Control, General Directorate o

Drug and Food Control, Jakarta, Indonesia; Mr D. Smith, Principal Scientist, SSI,Guateng, South Arica; Dr C. Sokhan, Deputy Director, Department o Drug andFood, Phnom Penh, Cambodia; Dr A. Spreitzhoer, AGES PharmMed, Vienna,Austria; Dr K. Srinivas, rimulgherry, Secunderabad, India; State Regulatory Agency or Medical Activities, Ministry o Labour, Health and Social Afairs,bilisi, Georgia; Dr J.A. Steichen, Manager, Regulatory and Quality ComplianceServices, Sas Solutions, LLC, Indianapolis, IN, USA; Dr Y. Stewart, Scientic,echnical and Regulatory Afairs, European Federation o PharmaceuticalIndustries and Associations, Brussels, Belgium; Dr L. Stoppa, Agenzia Italiana del

Farmaco, Rome, Italy; Dr R.W. Stringham, Scientic Director, Drug Access eam,Clinton Health Access Initiative, Boston, MA, USA; Dr N. Sullivan, Director,Sensapharm, Sunderland, England; Mr Philip Sumner, Pzer Global Engineering,USA; Dr S. Sur, Kiev, Ukraine; Dr E. Swanepoel, Head, Operations, ResearchInstitute or Industrial Pharmacy, North-West University, Potchestroom, SouthArica; Proessor M. Sznitowska, Department o Pharmaceutical echnology,Medical University o Gdansk, Gdansk, Poland; Dr D. eitz, Manager, Bristol-Myers Squibb Company, New Brunswick, NJ, USA; eva API Division, Petahiqva, Israel; Dr N. Tao, National Institute o Drug Quality Control, Hanoi, Viet

Nam; Dr B.B. Tapa, Chie Drug Administrator, Department o DrugAdministration, Ministry o Health and Population, Kathmandu, Nepal; Dr R.orano, Pharmacopoeial echnical Expert, GlaxoSmithKline, Co. Durham,England; Ms M. reebamroong, Senior Pharmacist, Drug Quality and Saety,Department o Medical Sciences, Bureau o Drug and Narcotic, Ministry o

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Public Health, Nonthaburi, Tailand; Mr R. ribe, Holder, AC, Australia;Associate Proessor rinh Van Lau, Director, National Institute o Drug Quality

Control, Hanoi, Viet Nam; Proessor u Guoshi, National Institute or the Controlo Pharmaceutical and Biological Products, Ministry o Public Health, Beijing,People’s Republic o China; Dr C. uleu, Senior Lecturer and Deputy Director,Department o Pharmaceutics and Centre or Paediatric Pharmacy Research,School o Pharmacy, University o London, London, England; Dr Richard urner,British Pharmacopoeia Commission, Medicines and Healthcare ProductsRegulatory Agency, London, England; United States o America Food and DrugAdministration, Center or Drug Evaluation and Research, Silver Spring, MD,USA; United States o America Food and Drug Administration, Oce o PediatricTerapeutics, Oce o the Commissioner, Rockville, MD, USA; Ms E. Uramis,GMP Advisor, Ocina Central Polo Cientíco, La Havana, Cuba; Dr A.R..Utami, National Agency or Drugs and Food Control, Jakarta Pusat, Indonesia;Mrs M. Vallender, Editor-in-Chie, British Pharmacopoeia CommissionSecretariat, London, England; Mr M. van Bruggen, EU Liaison – Regulatory Intelligence, F. Hofmann-La Roche, Basel, Switzerland; Mr F. Vandendriessche,Merck, Sharp and Dohme Europe, Brussels, Belgium; Dr J.E. van Oudtshoorn,Pretoria, South Arica; Dr A.J. van Zyl, Cape own, South Arica; Mr A. Vezali

Montai, Specialist in Regulation and GMP, Agência Nacional de Vigilância,Brasília, Brazil; Mrs L. Vignoli, Regulatory Afairs, Pharmaceuticals andCosmetics, Roquette Cie, Lestren, France; Dr O. del Rosario Villalva Rojas,Executive Director, Quality Control Laboratories, National Quality ControlCenter, National Institute o Health, Lima, Peru; Mr L. Viornery, Agence nationalede sécurité du médicament et des produits de santé, Saint Denis, France; Dr L.Virgili, USA; Mr Wang Ju, Deputy Commissioner, Dalian Food and DrugAdministration, Dalian, Liaoning, People's Republic o China; Mr P. Wang,Deputy Secretary-General, Chinese Pharmacopoeia Commission, Beijing,

People’s Republic o China; Dr G. Wang'ang'a, Head, Microbiological and MedicalDevices Units, National Quality Control Laboratory, Nairobi, Kenya; Dr A. Ward,Regulatory Afairs, Avecia Vaccines, Billingham, England; Dr D. Waters, ActingScientic Operations Advisor, Oce o Laboratories and Scientic Services,Terapeutic Goods Administration, Woden, AC, Australia; Dr W. Watson,Associate Manager, CMC Regulatory Afairs, Gilead Sciences International,Cambridge, England; Dr D.E. Webber, Director-General, World Sel-MedicationIndustry, Ferney-Voltaire, France; Proessor W. Wieniawski, Polish PharmaceuticalSociety, Warsaw, Poland; Dr S. Wolgang, US Food and Drug Administration,

Silver Spring, MD, USA; Mr E. Wondemagegnehu Biwota, Addis Ababa, Ethiopia;World Sel-Medication Industry, Ferney-Voltaire, France; Dr B. Wright, GroupManager, GMP/GDP, North East Region, Medicines Inspectorate, Medicines andHealthcare Products Regulatory Agency, York, England; Ms X. Wu, Counsellor,Intellectual Property Division, World rade Organization, Geneva, Switzerland;

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Proessor Z.-Y. Yang, Guangzhou Municipal Institute or Drug Control,Guangzhou, People’s Republic o China; Proessor Z.-Y. Yang, Member, United

States Pharmacopeia International Health Expert Committee, Rockville, MD,USA; Dr D. Yi, Scientist, US Pharmacopeia, Rockville, MD, USA; Dr H. Yusuu,National Agency or Food and Drug Administration and Control, Abuja, Nigeria;Dr M. Zahn, Keltern, Germany; Dr H. Zhang, GMP Department Head, Centeror Certifcation & Evaluation, Shanghai Food and Drug Administration,Shanghai, People's Republic o China; Dr T. Zimmer, CD Saety, Quality & Environmental Protection, Boehringer Ingelheim, Ingelheim, Germany; Dr N.Zvolinska, Deputy Director, Pharmaceutical Department, State PharmacologicalCentre, Ministry o Health, Kiev, Ukraine; Mrs M. Zweygarth, Consultant,Geneva, Switzerland.

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Annex 1

Release procedure for International Chemical ReferenceSubstances

BackgroundDuring its orty-fh meeting in 2010 the Expert Committee on Specicationsor Pharmaceutical Preparations agreed on a release procedure or International

Chemical Reerence Substances (ICRS) (1). Based on this procedure case-reportsissued by the custodian centre or ICRS afer analytical testing o candidatematerial were reviewed by the Secretariat with assistance rom collaboratinglaboratories. I the testing was perormed according to the General guidelines for the establishment, maintenance and distribution of chemical reference substances (2)and the candidate material was ound suitable, the Secretariat, in cooperation withthe collaborating laboratories, released the ICRS provisionally. In accordance withthe rules, the case-reports were subsequently submitted to the Expert Committeeon Specications or Pharmaceutical Preparations during its subsequent meeting,

or nal adoption. Afer provisional release the custodian centre or ICRS startedthe distribution o the ICRS.Tis process expedited the release o ICRS and enabled WHO to react

more quickly to urgent demands or ICRS. However, the procedure did notclearly allocate the accountability or the release o ICRS to a single time, personor body. Tereore, the Expert Committee members adopted the ollowing new procedure (Figure 1).

Figure 1New procedure for the adoption of ICRS

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W H O T e c h n i c a l R e p o r t S e r i e s N o . 9

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New release procedure

Afer testing o candidate material, the custodian centre or ICRS will submitanalytical case-reports to a newly established ICRS Board, which consists o three experts and a representative o the Secretariat. Te Board will decide onthe suitability o the reerence substance on behal o the Expert Committee andadopt the ICRS, i ound to be suitable or the intended use. In case the Boardhas queries or considers during its in-depth review that there is a need oradditional inormation and/or studies, the Secretariat will contact the custodiancentre accordingly. Te eedback will in turn be submitted to the Board or itsconsideration and nal decision.

During the subsequent meeting o the Expert Committee its memberswill be inormed about newly adopted ICRS.

References

1. Release procedure of International Chemical Reference Substances. In: WHO Expert Committee

on Specifcations or Pharmaceutical Preparations. Forty-fth report . Geneva, World Health

Organization, 2011, Annex 1 (WHO Technical Report Series, No. 961).

2. General guidelines for the establishment, maintenance and distribution of chemical reference

substances. In: WHO Expert Committee on Specifcations or Pharmaceutical Preparations. Forty-frst report . Geneva, World Health Organization, 2001, Annex 3 (WHO Technical Report Series, No. 943).

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Annex 2

WHO guidelines on quality risk management

1. Introduction 62

1.1 Background and scope 621.2 Principles o quality risk management 64

2. Glossary 67

3. Quality risk management process 70

3.1 Initiating a QRM process 703.2 Personnel involved in QRM 703.3 Knowledge o the product and process 713.4 Risk assessment 713.5 Risk control 723.6 Risk review 733.7 Verifcation o QRM process and methodologies 74

3.8 Risk communication and documentation 75

4. QRM application for pharmaceuticals 76

4.1 Training and education 764.2 Responsibilities 764.3 QRM application during product development 774.4 QRM application during validation and qualifcation 784.5 QRM application during commercial manuacturing 79

4.5.1 QRM integration with key quality system elements 794.5.2 QRM application in product manuacturing operations 80

5. QRM considerations for medicines regulatory authorities 815.1 Introduction 815.2 QRM application to inspection strategy 82

5.2.1 Risk management in inspections 825.2.2 Inspection planning and conduct 825.2.3 Corrective action and preventive action review, and scheduling o

routine inspections 835.2.4 Complaint handling and investigation 83

5.3 Inspection o QRM at a manuacturing site 835.4 QRM applied to dossier review (assessment) 85

6. Risk management tools 87

References 91

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1. Introduction

1.1 Background and scopeIn most countries compliance with good manuacturing practices (GMP)(1, 2) (including validation), medicines regulatory activities and inspections,together with supply chain controls throughout the product lie-cycle, providegood assurance that risks are largely controlled. However, where control isless efective, patients may be put at risk through the production o medicineso inadequate quality. Te assessment o individual risks related to specicproducts and starting materials and the recognition o hazards at specic stages

o production or distribution should permit regulatory authorities to improvecontrol o medicines by increasing the efectiveness o their activities within thelimits o the available resources. Quality risk management (QRM) is a processthat is relevant to all countries and should provide a rationale to understand risk and mitigate it through appropriate and robust controls.

Te aim o these guidelines is to assist the development andimplementation o efective QRM, covering activities such as research anddevelopment, sourcing o materials, manuacturing, packaging, testing, storageand distribution. In the past, hazard analysis and critical control point (HACCP)

methodology, traditionally a ood saety management system but subsequently applied to other industries, has been the basis o WHO risk management guidanceto the pharmaceutical industry (3).

More recently international guidance has emerged (2, 4–7 ) that is o specic relevance to the pharmaceutical industry and which addresses theull scope o pharmaceutical industry QRM more efectively than HACCPprinciples, including how to structure regulatory lings using a risk-basedapproach. Consequently, these WHO guidelines have been developed as anupdate on WHO's advice to the pharmaceutical industry, taking account o this

new guidance.o protect patients in terms o quality, saety and ecacy o medicines,

international medicines regulatory authorities (MRAs) are recommendingpharmaceutical manuacturers to adopt a risk-based approach to the lie-cycleo a pharmaceutical product. Some MRAs require the adoption o a risk-basedapproach or specic areas in the lie-cycle o a pharmaceutical product, e.g.environmental monitoring in sterile products manuacture. Te level o QRMactivity and the density o associated documentation will evolve as the productprogresses rom early development through to routine production.

QRM is the overall and continuing process o appropriately managingrisks to product quality throughout the product's lie-cycle in order to optimizeits benet–risk balance. It is a systematic process or the assessment, control,communication and review o risks to the quality o the medicinal product. It canbe applied both proactively and retrospectively.

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While the choice o the tools to support the QRM approach is optionaland may vary, the tools chosen need to be appropriate or the intended use.

In return or using this approach, there are potential opportunitiesor both MRAs and pharmaceutical manuacturers (8) as summarized in theollowing sections.

■ Quality risk management (QRM) principles can be applied to bothMRAs and pharmaceutical manuacturers:

– MRAs: systematic and structured planning o reviews andinspections that are risk-based. Te submission review andinspection programmes can also operate in a coordinated andsynergistic manner.

– Manuacturers: design, development, manuacture anddistribution, i.e. the lie-cycle o a pharmaceutical product. QRMshould be an integral element o the pharmaceutical quality system (QS).

■ Science-based decision-making can be embedded into QRMprocesses:

– MRAs: decisions regarding review, inspection or inspectionrequency should consider product risk and GMP complianceo the manuacturer. Te MRA accepts residual risks throughunderstanding the QRM decisions involved.

– Manuacturers: quality decisions and ling commitments canbe based on a science-based understanding o the process andQRM (when using the quality by design approach, and otherapproaches where appropriate). Its efective application shouldofer manuacturers greater reedom to decide how to comply with the principles o GMP and this, thereore, should encourageinnovation.

Te control strategy or the process ocuses on critical quality attributesand critical process parameters.

■ Resources can be ocused on risks to patients:

– MRAs: QRM can be used to determine the best allocation o inspection resources, both in terms o product types and orspecic areas o ocus or a given inspection. Tis enables the mostecient and efective scrutiny o the most signicant health risks.Tose manuacturers with poor histories o GMP compliance canalso be more closely and requently evaluated by on-site inspectionthan those manuacturers with better records.

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– Manuacturers: evaluation o quality risk through science-baseddecisions can be linked ultimately to protection o the patient by

ensuring the quality, saety and ecacy o the product. A corporateculture is supported to produce cost-efective medicines, withoutcompromising quality, while maintaining the ocus on the patientas a primary stakeholder in all activities.

■ Restrictive and unnecessary practices can be avoided:

– MRAs: regulatory scrutiny should consider the level o risk topatients. Improvement and innovation by manuacturers should

be encouraged. – Manuacturers: instead o having systems designed to inhibit

change and minimize business risk, changes can be managedwithin a company's quality management system. Innovation andthe adoption o the latest scientic advances in manuacturing andtechnology are supported. Unnecessary testing can be eliminated,or example, with real-time release testing.

■ Communication and transparency are acilitated:

– MRAs: acilitate dialogue with pharmaceutical manuacturersand communicate clearly to the industry and the public how the inspection programme may be adjusted based on the risk topatients. Inormation-sharing between MRAs will contribute to abetter risk management approach globally.

– Manuacturers: matrix team approach, stakeholders are keptinormed through science-based decisions. Tis builds a cultureo trust and a “one-team” mindset with a ocus on the product

and the patient.

Tese guidelines will align with the general ramework described in othercurrent international guidance on this subject.

1.2 Principles of quality risk managementIt is not always appropriate nor always necessary to use a ormal risk managementprocess (using recognized tools and/or internal procedures, e.g. standardoperating procedures (SOPs)). Te use o an inormal risk management process(using empirical tools or internal procedures) can also be considered acceptable.

Te two primary principles o QRM are that:

■ Te evaluation o the risk to quality should be based on scienticknowledge and ultimately linked to the protection o the patient.

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■ Te level o efort, ormality and documentation o the QRMprocess should be commensurate with the level o risk.

In addition to the two principles above, the ollowing principles are alsopart o the QRM methodology:

■ When applied, processes using QRM methodologies should bedynamic, iterative and responsive to change.

■ Te capability or continual improvement should be embedded in theQRM process.

Tis guidance describes the WHO approach to QRM, using the conceptsdescribed in ICH Q9 (6) and illustrated in Figure 1. Te emphasis on eachcomponent o the ramework might difer rom case to case but a robust processwill incorporate consideration o all the elements at a level o detail that iscommensurate with the specic risk.

Figure 1

Overview of a typical quality risk management process

Reproduced from reference 5: ICH Q9: Quality Risk Management.

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Decision points are not shown in the diagram above because decisions

can occur at any point in the process. Te decision might be:

■ to return to the previous step and seek urther inormation;

■ to adjust the risk models; or even

■ to terminate the risk management process based upon inormation

that supports such a decision.

Te approach described in these guidelines may be used to:

■ systematically analyse products and processes to ensure that the best

scientic rationale is in place to improve the probability o success;

■ identiy important knowledge gaps associated with processes that

need to be understood to properly identiy risks;

■ provide the communication process that will best interace with all

relevant parties involved in the QRM activities;

■ acilitate the transer o process knowledge and product development

history to ease product progression throughout its lie-cycle and to

supplement already available knowledge about the product; ■ enable the pharmaceutical industry to adopt a risk-based approach

to development as described in regulatory guidance (4–6 ). Te

QRM outputs will potentially serve as reerence documents to

support product development and control strategy discussions in

regulatory lings.

Early in development, the purpose o the QRM process may be to

acquire sucient product and process knowledge to assess risks associated

with ormulation development o the nished pharmaceutical product (FPP)according to the quality target product prole (QPP). In recognizing risks and

knowledge gaps, the QRM process plays a signicant role in proactively enabling

the prioritization and mitigation o risks. Te objective is to develop the FPP

through maximizing product and process knowledge and risk mitigation.

As FPP development progresses, in addition to supporting that

development, the purpose o the QRM process is to determine and manage

risks to bioavailability, saety, ecacy and product quality. QRM in development

should diferentiate process parameters and quality attributes rom critical processparameters (CPPs) and critical quality attributes (CQAs), thereby contributing to

dening and rening the control strategy.

Te long process o product development is inevitably complex and

requires the continual exchange o data, decisions and updates both internally

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within companies and, where required, with external stakeholders, such as MRAs.

A crucial aspect o product development and QRM is the maintenance o an

efective and secure knowledge management and documentation system. Sucha system must acilitate transparent communication and the highlighting o key

issues to stakeholders and must also include a well-structured archive. Clearly,

the ability to organize diverse data and inormation efectively and then retrieve

it as required or updating and urther evaluation, e.g. or the purposes o process

validation, would be hugely benecial.

Finally, it should be noted that QRM activities are ocused on the product/

process development and product manuacturing, ultimately to ensure a robust,

sae and efective FPP.

2. Glossary

Te denitions given below apply to the terms used in these guidelines. Tey may

have diferent meanings in other contexts.

control strategy

A planned set o controls, derived rom current product and process understanding

that assures process perormance and product quality. Te controls can include

parameters and attributes related to active pharmaceutical ingredients (APIs)

and nished pharmaceutical product (FPP) materials and components, acility

and equipment operating conditions, in-process controls, nished product

specications, and the associated methods and requency o monitoring and

control.

critical quality attribute (CQA)

A physical, chemical, biological or microbiological property or characteristic thatshould be within an appropriate limit, range, or distribution to ensure the desired

product quality.

ailure mode

Diferent ways that a process or subprocess can ail to provide the anticipated

result.

ailure mode, eects and criticality analysis (FMECA)

A systematic method o identiying and preventing product and process problems.

fnished pharmaceutical product (FPP)

A nished dosage orm o a pharmaceutical product that has undergone all stages

o manuacture, including packaging in its nal container and labelling.

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ormal experimental design

A structured, organized method or determining the relationship between actorsafecting a process and the output o that process. Also known as “design o experiments”.

occurrence

Probability o negative events within a xed time rame.

pharmaceutical product

Any material or product intended or human or veterinary use presented in itsnished dosage orm or as a starting material or use in such a dosage orm, that

is subject to control by pharmaceutical legislation in the exporting state and/orthe importing state.

pharmaceutical product target profle (PPTP)

A denition o the target properties o the FPP, including dosage orm andstrength(s), route o administration and relevant drug release and pharmacokineticrequirements.

planned risk assessment

An assessment that is conducted in advance o an activity, either beore any work is conducted or beore urther work is conducted. Tis enables quality to be builtinto activities and risk to be reduced, e.g. design o high containment acilities ormanuacture o cytotoxic products.

process robustness

Ability o a process to tolerate variability o materials and changes o the processand equipment without negative impact on quality.

qualifcation

Te action o proving and documenting that any premises, systems and equipmentare properly installed and/or work correctly and lead to the expected results.Qualication is oen a part (the initial stage) o validation, but the individualqualication steps alone do not constitute process validation.

quality critical process parameter

A process parameter which could have an impact on the critical quality attribute.

quality risk management

A systematic process or the assessment, control communication, and review o risks to the quality o the pharmaceutical product across the product lie-cycle.

risk

Combination o the probability o occurrence o harm and severity o the harm.

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risk analysis

Te estimation o the risk associated with the identied hazards.

risk assessment

A systematic process o organizing inormation to support a risk decision to bemade within a risk management process. It consists o the identication o hazardsand the evaluation o risk associated with exposure to those hazards.

risk control

Te sharing o inormation about risk and risk management between the decision-maker and other stakeholders.

risk evaluation

Te comparison o the estimated risk to given risk criteria using a quantitativeor qualitative scale to determine the signicance o the risk.

risk identifcation

Te systematic use o inormation to identiy potential sources o harm (hazards)reerring to the risk question or problem description.

risk priority number (RPN)A numeric assessment o risk assigned to a process, or steps in a process, as parto ailure mode efects analysis (FMEA). Each ailure mode gets a numeric scorethat quanties likelihood o occurrence, likelihood o detection and severity o impact. Te product o these three scores is the RPN or that ailure mode.RPN = severity rating × occurrence rating × detection rating.

risk review

Review or monitoring o output or results o the risk management processconsidering (i appropriate) new knowledge and experience about the risk.

stakeholder

Any individual, group or organization that can afect, be afected by, or perceiveitsel to be afected by a risk. Primary stakeholders are the patient, health-careproessional, MRAs and the pharmaceutical industry.

unplanned risk assessment

An assessment that is conducted to assess the impact o a situation that hasalready occurred, e.g. impact o a deviation rom normal ways o working.

validation

Te documented act o proving that any procedure, process, equipment, material,activity or system actually leads to the expected results.

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verifcation

Te application o methods, procedures, tests and other evaluations, in addition tomonitoring, to determine compliance with the quality risk management activities.

3. Quality risk management process

3.1 Initiating a QRM processQRM activities should be perormed using systematic processes designed tocoordinate, acilitate and improve science-based decision-making with respectto risk. Te possible steps to be taken in initiating and planning a QRM process

might include the ollowing (5):

■ dene the problem and/or risk question, including pertinentassumptions identiying the potential or risk;

■ assemble background inormation and/or data on the potentialhazard, harm or human health impact relevant to the risk assessment;

■ identiy a leader and the necessary resources;

■ speciy a timeline, the deliverables, and an appropriate level o

decision-making or the risk management process.Internal SOPs should dene steps, stakeholders, roles and responsibilities

(governance and management responsibilities).

3.2 Personnel involved in QRMTe implementing party, i.e. the pharmaceutical manuacturer or regulatory authority, should assure that personnel with appropriate product-specicknowledge and expertise are available to ensure efective planning and

completion o QRM activities. Tis may be best accomplished by assembling amultidisciplinary team according to the guidance provided in section 4.2.Te personnel appointed should be able to:

■ conduct a risk analysis;

■ identiy and analyse potential risks;

■ evaluate risks and determine which ones should be controlled andwhich ones can be accepted;

■ recommend and implement adequate risk control measures;

■ devise procedures or risk review, monitoring and verication;

■ consider the impact o risk ndings on related or similar productsand/or processes.

QRM activities should be dened and documented.

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3.3 Knowledge of the product and process

QRM should be based on knowledge o the product or processes concerned,according to the stage o the product lie-cycle.A ow diagram may be helpul, covering all operations and controls in

the process under evaluation. When applying QRM to a given operation, thesteps preceding and ollowing that operation should also be considered. A block-type diagram may be suciently descriptive. Amendments to the ow diagrammay be made where appropriate, and should be documented.

3.4 Risk assessmentWhen risk assessment is conducted, saety and ecacy need to be considered inaddition to the quality concerns.

During the assessment all the risks that may reasonably be expected tooccur when conducting the activity under evaluation should be listed. Tis is

usually done when the risk assessment is made or the rst time, i.e. initiated,when there is a change or a concern and may also be applied to existing processes.An analysis should be conducted to identiy which risks it is essential to eliminateor to reduce to acceptable levels.

A thorough risk assessment is required to ensure efective risk control.Risk assessment should review the materials, operations, equipment, storage,distribution and intended use o the product. ypically a list o the potentialrisks (biological, chemical and physical) which may be introduced, increased orcontrolled in each area should be drawn up. In the risk assessment the ollowing

basic questions should be addressed:

■ What might go wrong?

■ What is the nature o possible risks?

■ What is the probability o their occurrence and how easy is it to

detect them?

■ What are the consequences (the severity)?

It should then be decided which o the potential risks should be addressedby the QRM activities and what control measures, i any, should be taken oreach risk. I a risk has been identied at a step where control is necessary orsaety, and no control measure exists at that step or at any other, the product or

process should be modied at that step, or at an earlier or later stage, to includesuch a control measure. More than one control measure may be required tocontrol a specic risk and more than one risk may be controlled by a speciedcontrol measure.

Options or risk assessment methodologies are described in section 5.

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Risk assessment can be aided by the use o a decision-tree, whichacilitates a logical approach. Te way that a decision-tree is used will depend

on the operation concerned, e.g. production, packaging, reprocessing, storage ordistribution. Te best use o QRM tools is discussed urther in section 5.

Normally, potential risks in relation to the ollowing should be considered:

■ materials and ingredients;

■ physical characteristics and composition o the product;

■ processing procedures;

■ microbial limits, where applicable;

■ premises; ■ equipment;

■ packaging;

■ sanitation and hygiene;

■ personnel (human error);

■ utilities;

■ supply chain.

Te output o a risk assessment is either a quantitative estimate o risk (numeric probability) or a qualitative description o a range o risk (e.g. high/medium/low) and may be related to a risk matrix (see section 5). Te scoringsystem and trigger points or mitigating action are subjective so the rationale orscore categorization should be dened in as much detail as possible. I the scoreand trigger action are supported by actual evidence it should be more obviouswhat mitigating action is required – the mitigating action is as important as thescore assigned. Proessional judgement should be used in interpreting the actualevidence but must be subject to justication.

Records o risk assessments should be maintained.Te expectation o QRM is to assess risks to the product quality and to

the patient and then manage these risks so that they are kept at an acceptablelevel. It is appropriate or companies to assess their control systems so as toimplement the appropriate controls to ensure product quality and patient saety.An important principle in QRM is to design risks out o the process or eliminatesuch risks prospectively, whenever practical and easible. Risk assessment andmitigation to achieve cost savings, but which could be to the detriment o thewell-being o the patient, is an unacceptable practice (9).

3.5 Risk control

Risk control is a decision-making activity designed to reduce and/or accept risks.It usually occurs afer risk assessment, and at a undamental level its purpose is toreduce the risk to an acceptable level.

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During risk control activities the ollowing key questions should be asked:

■ What can be done to reduce or eliminate risks? ■ What is the appropriate balance between benefts, risks and resources?

■ Are new risks introduced as a result o the identifed risks beingcontrolled?

Risk control can include:

■ not proceeding with the risky activity;

■ taking the risk;

■ removing the risk source;

■ changing the likelihood o the risk;

■ changing the consequences o the risk;

■ sharing the risk with another party (e.g. contractor);

■ retaining the risk by inormed decision.

Risk control activities usually involve identiying controls and measures

which may reduce or control the risk associated with a ailure mode or negativeevent. Risk control activities can serve to determine critical process parametersor certain controls, how they will be monitored, and the level o qualifcationand validation, i any, which may be required or such controls.

I risk assessments are conducted and risk controls are employed they should be documented. I the risk assessment is conducted or an ongoing activity it should be subject to periodic review and the requency o review should beappropriate or the nature o the activity.

Based on the criticality or level o risk, specifc corrective actions should

be developed to prevent recurrence o instances where there have been deviationsrom established risk control measures, especially or high risks. Tese actionsshould ensure that the risk is brought under control as soon as possible in

compliance with the established deviation handling procedures.

Specifc corrective actions should be developed in advance or each

identifed risk, including what is to be done when a deviation occurs and who is

responsible or implementing the corrective actions. A record should be kept andmaintained o the actions taken.

3.6 Risk review

Appropriate systems should be in place to ensure that the output o the QRM

process is periodically monitored and reviewed, as appropriate, to assess new

inormation that may impact on the original QRM decision. Examples o such

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changes include changes to control systems, changes to equipment and processes,changes in suppliers or contractors and organizational restructuring.

Monitoring is the scheduled measurement or observation o a specic risk control measure relative to its acceptance limits. Monitoring should be recorded.

All records and documents associated with risk review should be signed

and dated by the person(s) carrying out the review and by a responsible ocial(s)o the quality unit o the company.

3.7 Verifcation o QRM process and methodologiesOnce in production, the QRM documentation can be integrated into the quality

system and used to provide input into the product process.Te established QRM process and methodologies need to be veried.

Verication and auditing methods, procedures and tests, including randomsampling and analysis, can be used to determine whether the QRM process is

working appropriately. Te requency o verication should be sucient to

conrm the proper unctioning o the QRM process.

Verication activities include:

■ review o the QRM process and its records;

■ review o deviations and product dispositions (management control);

■ conrmation that identied risks are being kept under control.

Initial verication o the planned QRM activities is necessary to determine

whether they are scientically and technically sound, that all risks have been

identied and that, i the QRM activities are properly completed, the risks will be

efectively controlled.Inormation reviewed to veriy the QRM process should include:

■ expert advice and scientic studies;

■ in-plant observations, measurements and evaluations.

Subsequent verications should be perormed and documented by a

QRM team or an independent expert, as needed. For example, verications may

be conducted when there is an unexplained system ailure, when a signicantchange in product, process or packaging occurs or new risks are recognized.

Where possible, verication should include actions to conrm the ecacy o all

elements o the QRM activities.In addition, a comprehensive review o the QRM process and specic

instances o QRM application by an independent third party may be useul.Tis would include a technical evaluation o the risk analysis and each element

o the QRM process and its application as well as an on-site review o all ow

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diagrams and appropriate records o the operation o the QRM activity. Such a

comprehensive verication is independent o other verication procedures and

should be perormed to ensure that the QRM process is resulting in the controlo the risks. I the results o the comprehensive verication identiy deciencies,

the QRM process should be modied as necessary.

Individuals doing verication should have appropriate technical expertise

to perorm this unction.

3.8 Risk communication and documentation

Communication o the QRM process should include key stakeholders. Engaging

the key stakeholders in both the data collection process or the risk assessmentand the decision-making or risk control will ensure their commitment and

support or the QRM. Te output o the QRM process and associated risk

analysis justiying the approach taken should be documented and endorsed by

the organization’s quality unit and management. Additionally, this inormation

should be communicated to stakeholders to keep them inormed and to ensure

their support.

Tere should be a report or every risk assessment, but the level o efort,

ormality and documentation necessary will be commensurate with the level o risk (2).

Regarding conclusions o a risk assessment, the mitigation controls

should minimize the likelihood o risk to patient saety to an acceptable level o

assurance, on the understanding that no risk whatsoever is unlikely in reality.

Te degree o risk tolerated very much depends on the circumstances, the

proximity to the patient and other controls that might ollow in response to the

process being assessed beore the product reaches the patient (2). It is expected

that risk mitigation plans will be developed and implemented wherever any

risk to patient saety is posed. Companies should take the holistic view and be

mindul that critical issues oen arise where multiple ailures in systems occur

together, so mitigation plans should be suciently robust to cover this scenario.

Inspectors will assess whether risk assessments underrate the likelihood o

occurrence and the consequences o overrating detection such that the patient

risk is underestimated. Te actual evidence behind statements should be robust

to challenge by inspectors.

All risk assessments perormed by an organization should be documented.

Te documentation should list and track all key risks as perceived by theorganization and summarize how the risks have been mitigated. Tere should

be a clear reerence to risk assessments and a list o risk assessments conducted

should be maintained. A management process should be in place to review QRM

– this may be incorporated into the quality management review process.

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4. QRM application for pharmaceuticals

4.1 Training and educationraining o relevant personnel in industry, MRAs and universities in QRMprinciples and applications is essential or its efective implementation. Industry employees should understand what QRM is, possess the skills necessary toapply it properly, and have access to appropriate resources to enable the efective

practice o the QRM principles.In developing the training programme to support QRM activities,

working instructions and procedures should be drawn up which clariy the

strategy and dene the tasks o all personnel involved in these activities. Specictraining should be provided as required to enhance awareness. Staf with the

responsibility or managing and reviewing risks should receive ormal training

in the relevant procedures.

Cooperation between producers, traders and responsible authorities is vital. Opportunities should be provided or the joint training o industrial staf

and MRAs to encourage and maintain a continuous dialogue and create a climate

o understanding in the practical application o QRM.

Te success o QRM depends on the education and training o management and employees to understand the importance o QRM in producing

and supplying sae pharmaceuticals.

4.2 Responsibilities

Successul application o QRM is dependent on a clear understanding o responsibilities by all personnel involved in the QRM activities. It is recommended

that a cross-unctional matrix o assigned responsibilities and accountabilities is

drawn up and shared with all relevant personnel.

Te pharmaceutical manuacturer should ensure that appropriate

knowledge and expertise are available or the efective planning and completion

o QRM activities. QRM activities are usually, but not always, undertaken by a

matrix o interdisciplinary teams. When teams are ormed they should includeexperts rom the appropriate areas (e.g. quality unit, product development,

engineering, regulatory afairs, production operations, statistics, clinical, and

others, such as sales, marketing or legal, as applicable), in addition to individuals

who are knowledgeable about the QRM process.

In this respect it is acceptable or external consultants to participate in theQRM matrix team where they can provide specic expertise or knowledge. Teir

role should be justiable and clearly dened and the resultant accountability

must be understood. A technical agreement or other equivalent document with

the consultant may be appropriate where a GMP responsibility is assumed.

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Similarly, contract staf may become involved in leading or participatingin risk assessments, e.g. a contract authorized person. Te extent o their

involvement and responsibility and accountability must be documented ina technical agreement or other equivalent document between the individual

concerned and the pharmaceutical company. Regarding the authorized personit is important that a company’s internal procedures are clear on where the

responsibility lies or nal approval o risk acceptance documents.

Efective matrix team leadership is required to take responsibility or

coordinating QRM across various unctions and departments o the organization

and to ensure that the QRM activities are adequately dened, planned, resourced,

deployed and reviewed. Te leader and team will need to identiy criticalresources required to implement the QRM activities, and also speciy a timeline,

deliverables and appropriate levels o decision-making or the QRM process.

4.3 QRM application during product development

Te application o QRM procedures evolves through the various stages in thedevelopment o a product.

Te rst QRM exercise should be perormed once the QPP is dened

and preormulation work on the candidate medicine is complete. At this stage o aproject there may be signicant gaps in knowledge. Tereore, it will be important

to apply risk tools that are appropriate or such a situation. Tese might include:

■ cause and efect diagrams (also known as Ishikawa or Fishbone

diagrams);

■ owcharts (e.g. input-process-output (IPO));

■ decision-trees;

■ ault-tree analysis;■ relationship matrices.

As the product progresses to later stage o development, a more detailedanalysis o the risks associated with both the active pharmaceutical ingredient

(API) and the FPP should be considered. Risks would cover concerns associated

with stability, bioavailability and patient saety including any challenges to these

areas resulting rom the manuacturing process (including, or example, API

orm conversion under certain conditions o processing).

As product knowledge advances, more detailed QRM exercises can beconsidered, concentrating on areas considered to present higher priority risk.

As the product's critical quality attributes (CQAs) become dened, the potential

risks arising rom each input material (API, excipients, any device or pack

components) and each secondary product unit operation can be investigated.

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Eventually, or the developed FPP, the increasingly comprehensive risk

assessment will support a thorough understanding o the product and will enable

all key variables to be identied, understood and controlled.

4.4 QRM application during validation and qualifcation

In keeping with the principles o QRM, these guidelines recommend that

process validation embraces the product lie-cycle concept already mentioned.

Accordingly, process validation activities should involve the generation and

evaluation o data throughout the process, rom development to ull-scale

production, which will provide a science-based assurance o consistent delivery

o quality product in the production operation (9–10).

It is important to emphasize that the building o scientic assurance

begins early in development. It is obtained through rational design o experiments

and robust evaluation o data during product and process development through

to the commercial production phase, by which time the API and FPP CQAs are

well understood and controlled. In this scenario, validation or (perhaps more

appropriately termed) conormance batches serve to reinorce the science- or

risk-based decisions that have been made as product development has advanced

and should demonstrate good control o all critical sources o variability that havebeen identied. Any unplanned variations within a batch or between batches

should be evaluated employing suitable statistical tools, e.g. trend analysis, to

check on process control.

A potential advantage o this approach is that there can be exibility in

the number o validation or conormance batches required or regulatory scrutiny

prior to approval. Te traditional number o batches required or validation has

been three but, with QRM embedded in a product's development process, the

number o conormance batches needed depends on the depth o knowledgeabout the process. For very low-volume products, e.g. orphan drugs, this may

preclude the need to manuacture multiple batches. It would be benecial or

decisions o this nature regarding conormance batches to have an efective

company–MRA dialogue to agree on requirements or a regulatory submission.

When applicable, the principles o QRM should also be applied or

qualication activities.

QRM principles can be used to determine the scope o qualication. Tey

can also be used to determine the optimal schedule or maintenance, monitoring,calibration and requalication.

Manuacturers should have sucient knowledge o the process and

product to ensure that by the time the product is commercialized, processes are

optimized and risks are minimized.

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4.5 QRM application during commercial manufacturing

In general, implementing QRM should not obviate a manuacturer’s obligationto comply with regulatory expectations (e.g. regulatory requirements, regulatory lings and inspection commitments). All QRM activities should be structuredin a way that allows responsibility or risk assessment and actions at appropriatelevels o the hierarchy within the organization. Special ocus can be put on the risk assessment and risk control during the lie-cycle o a product, and may include:

■ product quality risks;

■ adverse impact on patient health resulting rom product quality

deects; ■ interruption o product supply to patients;

■ GMP and regulatory compliance risks;

■ multisite risks;

■ multiproduct risks;

■ new acility and changes to existing acility, e.g. start-ups, new commercial manuacturing processes, technology transers andproduct discontinuation.

Aer completion o the risk assessment and risk control activities, theoutcomes should be summarized and appropriately communicated. Te resultsmay be documented in a new or existing report or they may be included aspart o another document approved by appropriate decision-makers (e.g. siteor unctional management, system owner, or quality unit). A risk review isimportant i new risks or changes to existing risk levels are identied as a resulto planned or unplanned events such as routine operation, changes, complaints,product returns, discrepancies or deviations, data monitoring, trends, inspections

or audits, or changes in regulatory environment. Risk review may also includeevaluation o, or example:

■ efectiveness o risk control activities and actions;

■ changes in observed risk levels or existing controls.

In principal, areas o ocus when implementing QRM in commercialmanuacturing include a system ocus, a process ocus and a product ocus.

4.5.1 QRM integration with key quality system elementsEfective QRM can acilitate the decision on “What to do?” and, thereore,support better and more inormed decisions. QRM should be integrated intoexisting quality system elements and related business processes and documentedappropriately.

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Accordingly, the use o QRM can be benecial across a broad spectrumo operations, e.g.:

■ integrated quality management:

– documentation

– training and education

– quality deects

– auditing and inspection

– change management and change control (includes equipment,

acilities, utilities, control and IT systems) – continual improvement and corrective and preventive actions(CAPA);

■ acilities, equipment and utilities:

– design

– qualication

– maintenance and decommissioning o acility or equipment

– hygiene aspects– cleaning o equipment and environmental control

– calibration and preventive maintenance

– computer systems and computer-controlled equipment;

■ supplier, materials and contract service management:

– assessment and evaluation o suppliers and contract manuacturers

– starting material

– use o materials

– storage

– logistics and distribution conditions;

■ technology transer:

– rom development to manuacturing

– during commercial manuacturing between sites

– rom commercial manuacturing to product discontinuation.

4.5.2 QRM application in product manufacturing operations

Efective QRM can acilitate the “How to do it?” and, thereore, ensure that theproducts will meet acceptable standards or saety, quality, and compliance.

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Among others, QRM methodology can support the ollowing actions toassess and control quality risks:

■ production:

– manuacturing process risks

– validation

– in-process sampling and testing controls

– production planning

– deviation and investigation management

– change management;

■ laboratory control and stability studies:

– out-o-specifcation results

– retest period and expiry date

– method transers;

■ packaging and labelling:

– design o packages – selection o container-closure system

– label controls;

■ storage, transport and distribution:

– e.g. cold chain.

5. QRM considerations for medicinesregulatory authorities

5.1 Introduction

A key principle o these guidelines is that all MRAs, manuacturing sites indeveloping countries and API manuacturers should demonstrate, whereverappropriate, application o QRM throughout the product lie-cycle ordevelopment and manuacturing acilities. Inspectors will review this QRMsystem as part o the quality systems section o the inspection (along with

complaints, recalls, deviations, product quality reviews and others).Equally, it is recommended that QRM be applied by the MRAs (or

examples see (2, 8)) themselves (reviewers and inspectorates) as there are clearbenefts o a QRM-based review and inspection plan. For example, inspectorscan allocate time and resources commensurate with the perceived signifcance o

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risk in any given situation and can be pragmatic regarding the level o scrutiny and degree o ormality required.

5.2 QRM application to inspection strategy5.2.1 Risk management in inspections

Te inspection section or unit o an MRA should operate within a written,implemented quality management system (11). SOPs should be ollowed oractivities including (but not limited to) inspection planning, review o correctiveand preventive actions aer inspections and complaint handling and investigation.Where appropriate, the procedures and activities during inspection should be in

line with the principles o QRM.Te unit should have a risk management plan that describes the

philosophy, approach, procedures and implementation o risk management. Terisk management plan should be reviewed and updated on a continuous basis, orat least annually, and should cover all types o inspections (including GMP, goodclinical practices (GCP), good laboratory practices (GLP)) and other activities.

Appropriate risk assessment tools should be used in the process, andthe risk assessment or a site to be inspected should be documented on a risk

assessment worksheet. Records should be maintained.A metric system should be used or risk ratings, e.g. on a scale rom 1 to 3.

5.2.2 Inspection planning and conduct

Te requency and scope o inspections should be determined based on risk assessment that covers product risk and patient risk.

Risk rating should normally be done only or sites that have beenpreviously inspected. Te risk assessment worksheet should be completed aerevery inspection. Inspection o a site that has not been inspected previously

may be waived only in cases where a recognition procedure exists betweenregulatory inspection units, and where, in addition, appropriate evidence o GXPcompliance is available which indicates that there is no risk or an acceptably low risk to products and patients.

Various actors should be considered in the risk assessment exercise, andthese actors may be diferent or the diferent types o GXP inspections. Risk actors to be considered depend on the type o inspection, and may include:

■ outcome o inspection by another regulatory authority;

■ outcome o the previous inspection;

■ complexity o the site (e.g. buildings, utilities);

■ complexity o the product (e.g. sterile, non-sterile);

■ type o product (e.g. biological, low-dose);

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■ complaints and recalls;

■ signifcance o changes (e.g. equipment, key personnel);

■ results o product testing;

■ risk to the patient;

■ complex route o synthesis (API);

■ polymorphism (API);

■ biopharmaceutical classifcation o the product;

■ innovative or emerging technology.

Te number o inspectors and number o days required or the inspection,as well as the scope o the inspection, should be determined based on the risk rating o the site inspection.

Inspection reports should contain fndings and observations. Departuresrom GXP should be classifed where appropriate, as “critical”, “major” or “minor”.

Te unit should have an SOP that describes the classifcation process.Classifcation should be based on risk assessment. Te level o risk assignedshould be in accordance with the nature o the observation as well as the numbero occurrences.

5.2.3 Corrective action and preventive action review,and scheduling of routine inspections

CAPA should be requested rom a site, ollowing an inspection. Te CAPAsshould address the observations included in an inspection report. Based on theoutcome o the inspection and the acceptability o the CAPA, the risk rating o the site should be reviewed and recorded.

Inspection requency should be defned based on the risk rating. For

example, the requency can be defned as every 6, 12, 18 or 24 months. (Note: Temaximum time interval should be no more than every 36 months.)

5.2.4 Complaint handling and investigation

Handling and investigation o quality complaints should be done in accordancewith a written SOP. Te scope and depth o the investigation (including whether adesk review or on-site inspection will be done) should be based on risk assessment.

5.3 Inspection of QRM at a manufacturing siteNote: During inspections, inspectors should assess whether a manuacturerhas appropriate skills and scientifc knowledge, as well as product and processknowledge, or the QRM procedure being inspected. Tis is also relevant where acompany has made use o contracted parties.

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Te company's QRM procedure should be appropriately detailed and

should be integrated into the company’s quality management system. It should

cover at least the ollowing areas:

■ It should speciy the general approach to both planned and unplanned

risk assessment, including scope, responsibilities, controls, approvals,

management systems, applicability and exclusions.

■ Personnel should have appropriate qualications, experience and

training. Teir responsibilities with regard to QRM should be clearly

dened.

■ Senior management should be involved in the identication andimplementation o QRM principles within the company.

■ Te risk management procedure(s) or each area o application

should be clearly dened.

■ Quality assurance principles should be applied to QRM-related

documentation, e.g. review, approval, implementation and archiving.

QRM policies and procedures should be clear and the workow should

be systematic and conducted in a logical order.

■ Te procedure or risk management should be implemented.

■ Manuacturers should identiy signicant risks and consider all the

relevant data rom reliable sources.

■ Te level o efort and resources used in risk assessment should be

appropriate to the importance o the identied problem.

■ Critical issues should be addressed with appropriate urgency and

ormality. ■ Tere should be a logical selection o tools or risk assessment.

■ Risk acceptance criteria should be appropriate.

■ Risk assessments should not underrate the severity, nor overrate

detection o occurrences resulting in underestimating patient risk.

■ Te risk acceptance criteria should be appropriate or the specic

situation in question.

■ Risk controls should be efective. ■ Te company should have a review programme to measure the

efectiveness o the measures taken.

■ Risk-based decision(s) should be science-based and concordant with

the predened acceptance criteria.

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All documentation related to the QRM activities should be completed

within a reasonable period and should be accessible. Risk assessments perormed

should be reviewed when appropriate, and additional controls implementedwhen required.

Personnel should be trained and assessed in the principles o QRM.

Where appropriate, a team o members o personnel should participate in the

QRM processes.

5.4 QRM applied to dossier review (assessment)

Te assessment processes o national medicines regulatory authorities (NMRAs)

rely on QRM principles in the management o resources (time and assessors), aswell as in the management o product-related risk actors. Ecient management

o resources minimizes the risk that limited resources are not used to their best

efect, and ultimately ensures that important products are made available in a

timely manner. Key actors to be considered include the prioritization o dossiers,

the screening process, identication o the specic risk actors inherent to a given

dossier or dosage orm, and allocation o resources to the various sections o

a dossier or a given product. In addition, product-related risk actors must be

managed throughout the lie-cycle o the product, or example, through efectivecommunication between assessors and inspectors, and by establishing systems

or dealing with the products aer approval.

Te allocation o priority to dossiers should take into account the

therapeutic needs o the regional population (e.g. disease occurrence, the need

or paediatric ormulations, combination products, or experience with innovative

or emerging technology) and the availability o medicines on the market.

Prioritization should be a dynamic process to enable it to accommodate emerging

issues such as pandemics. Other considerations related to prioritization based on

medical need may include xed-dose combinations versus single-ingredient or

co-packaged products, extended release products versus products administered

as two or three daily doses, second-line versus rst-line products, exible dosage

orms such as dispersible tablets and variable dose products such as oral liquids.

Te screening process examines the completeness o a dossier. Screening

ensures that only those dossiers that meet minimum standards or completeness

can enter into the ull assessment process. Insucient screening processes allow

lower quality dossiers to be accepted or review, thus signicantly increasing

assessment time.Identication o dossier-related and product-related risk actors allows

or the allocation o appropriate resources to specic dossiers. Possible risk

actors include: the experience and track record o the manuacturer, narrow

therapeutic range products, sterile versus non-sterile APIs and products;

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API-related considerations such as use o semi-synthetic and ermentationproducts, complex routes o synthesis, polymorphism, isomerism and potential

genotoxic impurities; and product-related considerations such as the use o novel excipients, the complexity o the ormulation, single-ingredient versusxed-dose combinations, and special delivery systems (e.g. modied release,transdermal products, and inhalation products). Once risk actors have beenidentied, resources should be allocated to minimize risk. For example, assessorswith expertise related to the product-related risk identied should be assigned toassess the dossier whenever possible. When resources allow, the assessors may be organized according to specialization, assigning assessors to various product

categories (e.g. generic products, sterile products, solid oral dosage orms, orspecial delivery systems). Tis can acilitate the development o expertise inkey areas and promote consistency o review, as well as ensuring that productsrequiring specialized knowledge are identied and assessed by those with theappropriate expertise. Where a high level o risk is identied or a dossier, themore experienced assessors need at least to be available on a consultation basis.

Te risk level associated with a dossier may change during the courseo assessment. For example, rejection o the bioequivalence study will result inadditional time required to conduct and assess additional studies and associated

additional quality inormation. In such a scenario the risk relates both to the useo additional resources and to an increased risk that the overall product quality may be poor.

Allocation o resources to various aspects or sections o the dossier is animportant QRM consideration, in order to ensure that the resources used arecommensurate with the risk level. An understanding o the relative criticality o dossier sections or aspects is necessary or ecient use o resources. All aspects o the dossier are important to achieve overall quality, saety and ecacy; however

some areas are inherently more critical rom a risk perspective and warrantmore attention in the assessment process. Examples include the clinical reviews,bioavailability reviews, API synthesis, specications and stability studies, FPPmanuacturing details, pharmaceutical development studies including biowaiver

justication, process validation, specications and stability studies. An exampleapplicable to most simple solid oral products is that more time should be allocatedto the review o manuacturing steps prior to packaging than to reviewing thepackaging process.

During the assessment process there should be a standard procedure

or communicating to the inspectors those issues identied which may requireconsideration during inspection. Aer approval o a product, QRM principlesshould be applied to evaluate the impact o proposed variations or changes. Clearguidelines that outline possible post-approval changes and assign an associatedrisk level are an efective means to achieve this.

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6. Risk management tools

A variety o tools can be used or the purposes o QRM, either alone or incombination. It is important to note that no single tool or combination o tools

is applicable to every situation in which a QRM procedure is used. Examples

o tools are listed in regulatory guidance (6 , 8); neither list is exhaustive. Te

important criterion or acceptability is that the tool or tools are used efectively to

support the key attributes o a good risk assessment.

Te Product Quality Research Institute (PQRI) Manuacturing echnology

Committee (MC) has produced a summary (9) o common risk management

principles and best practices, several working tools to oster consistency inthe use o ICH Q9 (5) in day-to-day risk management decision-making, and a

series o examples o risk management applications currently in use by major

pharmaceutical rms. Tey have also produced very helpul risk tool training

modules or risk ranking and ltering, ailure modes efects analysis (FMEA)

(12–15), hazard operability analysis (HAZOP) (16 ) and HACCP (3).

One aspect worth highlighting is the development o a risk matrix to

acilitate categorization o risks identied during the risk assessment phase. In

order to prioritize a risk, it is essential to agree upon its signicance. Te risk associated with any situation or event can be represented as the impact o that

event multiplied by the probability o its occurrence; in other words: how likely is

it to happen? and how severe would it be i it did happen? Impact and probability

can each be classied, e.g. into 5 levels (1–5) or with a weighting towards the

higher probability and impact ratings (e.g. 1, 3, 5, 7, 10, etc.), so that a grid or

matrix can be constructed (able 1).

Table 1

An example of a probability versus impact matrix

Impact

Probability Negligible Marginal Moderate Critical Catastrophic

Almost certain 5 10 15 20 25

Likely 4 8 12 16 20

Possible 3 6 9 12 15

Unlikely 2 4 6 8 10

Rare 1 2 3 4 5

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Te shading in the table represents an example o how the risk values(sometimes called composite risk indices or risk index values) can be assigned a

high, medium or low status. Te denition or each status should be predeterminedin the QRM process afer consideration o the specic consequences or theprocess undergoing risk assessment. Tese consequences can be split accordingto the probability and impact scores, as exemplied in able 2.

Table 2

Example of a consequences table for probability and impact

Score Probability Example Score Impact Consequence

1 Rare •Seenevery

10–30 years

1 Negligible •Noregulatoryissue

•Noeectonandnot

noticeable by patient

2 Unlikely •Seenevery

5–10 years

2 Marginal •MayrequireMRA

notifcation

•Decisiontorelease

product not

compromised

3 Possible •Seenevery

1–5 years

3 Moderate •MRAinspection

may identiy a

major concern but

deciencyquite

easily resolved

•Limitedproduct

recall possible

4 Likely •Seento

occur morethan once a

year

4 Critical •MRAinspectionmay

conclude seriousnon-compliance

•Likelyproductrecall

rom one or more

markets

5 Almost

certain

•Seenseveral

times a year

5 Catastrophic •Enforcementaction

by MRA such as

consent decree,

product seizure

•GlobalproductrecallMRA, Medicines regulatory authority.

Source: Based on reerence 9. This table has been amended, but was originally produced within the

context o the Product Quality Research Institute (PQRI), 2107 Wilson Blvd, Suite 700, Arlington, Virginia

22201-3042,USA;website:http://www.pqri.org/index.asp.PQRIhaskindlyagreedtotheuseofits

material.

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Tis table is a very basic example and would need to be customized orthe specic process in question to enable a better and more practical denition o

the consequence categories. It should be cautioned that the value o a risk matrixrelies very heavily upon input inormation and should only be used by staf witha good understanding o the embedded judgements and, as such, the resolutiono the low, medium or high categorization.

As a summary o the common, well-recognized QRM tool optionsavailable or the purposes o these guidelines, able 3 has been based on theone rom the Product Quality Research Institute Manuacturing echnology Committee (PQRI-MC) report (9). Te list is not comprehensive but it doesinclude some o the more requently used approaches.

Table 3

Examples of common risk management tools

Risk management tool Description, attributes Potential applications

Tools

Diagramanalysis• Flowcharts• Check sheets• Process mapping•Cause/eectdiagrams

•Simpletechniquesthatare commonly used to

gather and organizedata, structure risk management processesand acilitate decision-making

• Compilation o observations, trends or

other empirical inormationto support a variety o less complex deviations,complaints, deaults orother circumstances

Risk ranking andltering

• Method to compare andrank risks

• Typically involvesevaluation o multiplediversequantitativeand

qualitativefactorsforeachrisk, and weighting actorsand risk score

• Prioritizing operatingareas or sites or audit orassessment

• Useul or situations whenthe risks and underlying

consequencesarediverseand difcult to compareusing a single tool

Fault-tree analysis • Method used to identiy allroot causes o an assumedailure or problem

• Used to evaluate systemor subsystem ailures oneat a time, but can combinemultiple causes o ailure

by identiying causal chains• Relies heavily on ull

process understanding toidentiy causal actors

• Investigate productcomplaints

•Evaluatedeviations

continues

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Tools

Hazard operability

analysis (HAZOP)

• Tool assumes that risk

events are caused by

deviations rom the design

and operating intentions

•Uses a systematic

techniquetohelpidentify

potential deviations rom

normal use or design

intentions

•Access manuacturing

processes, suppliers,

facilitiesandequipment

•Commonly used to

evaluate process saety

hazards

Hazard analysis and

critical control point

(HACCP)

•Identiy and implement

process controls that

consistently and

eectivelypreventhazard

conditions rom occurring

•Bottom-up approach that

considers how to prevent

hazards rom occurring

and/or propagating

•Emphasizesstrengthof

preventive controls rather

than ability to detect

•Better or preventive

applications than reactive

•Valuable precursor or

complement to process

validation

•Assessment o the

efcacy o critical controlpoints and the ability to

consistently execute them

or any process

Failuremodeseects

analysis(FMEA)

•Assumes comprehensive

understanding o the

process and that CPPs

have been dened prior to

initiating the assessment.

Tool ensures that CPPs will

be met.

•Assesses potential ailure

modes or processes, and

theprobableeecton

outcomes and/or product

perormance

•Once ailure modes are

known, risk reductionactions can be applied to

eliminate, reduce or control

potential ailures

•Evaluateequipment

and acilities; analyse a

manuacturing process

to identiy high risk steps

and/or critical parameters

Table 3 continued

continues

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Tools

Failuremodeseects

analysis(FMEA)

•Highly dependent upon

strong understanding of

product, process and/or

facility under evaluation

•Output is a relative “risk

score” for each failure

mode

Source: Based on reference9. This table has been amended, but was originally produced within the

context of the Product Quality Research Institute (PQRI), 2107 Wilson Blvd, Suite 700, Arlington, Virginia

22201-3042,USA;website:http://www.pqri.org/index.asp.PQRIhaskindlyagreedtotheuseofits

material.

References

1. Quality assurance of pharmaceuticals. A compendium of guidelines and related materials. Vol. 2, 2nd

updated ed. Good manufacturing practices and inspection. Geneva, World Health Organization,

2007; Quality assurance of pharmaceuticals. A compendium of guidelines and related materials.World Health Organization, 2011 (CD-ROM) (http://www.who.int/medicines/areas/quality_saety/

quality_assurance/guidelines/en/index.html).

2. EudraLex The rules governing medicinal products in the European Union, Vol. 4. Good manufacturing

practice (GMP) guidelines (http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm).

3. Application o hazard analysis and critical control point (HACCP) methodology to pharmaceuticals.

In: Quality assurance of pharmaceuticals. A compendium of guidelines and related materials. Vol. 2,

2nd updated ed. Good manufacturing practices and inspection. Geneva, World Health Organization,

2007; Quality assurance of pharmaceuticals. A compendium of guidelines and related materials .

World Health Organization, 2011 (CD-ROM) (http://www.who.int/medicines/areas/quality_saety/

quality_assurance/guidelines/en/index.html).

4. ICH harmonised tripartite guideline. ICH Q8(R2): Pharmaceutical development. August 2008

(http://www.ich.org).

5. ICH harmonised tripartite guideline. ICH Q9: Quality risk management 9 November 2005

IFPMA; Quality Risk Management ICH Q9 Briefng pack, July 2006, ICH-webpage publishing; ICH

harmonised Q8/9/10 Questions & Answers, November 2010; ICH harmonised Q8/9/10 Training

material, November 2010, ICH-webpage publishing; ICH harmonised points to consider or ICH

Q8/Q9/Q10 implementation, 6 December 2011 (FIP, AM and IFPMA) (http://www.ich.org).

6. Guidance for industry: PAT – A framework for innovative pharmaceutical development,

manufacturing and quality assurance. US Food and Drug Administration, Center or Drug

Evaluation and Research (FDA CDER), September 2004 (http://www.da.gov/Drugs/deault.htm).

7. Pharmaceutical cGMPs for the 21st century – A risk-based approach. US Food and Drug

Administration, Center or Drug Evaluation and Research (FDA CDER), September 2004 (http://

www.da.gov/Drugs/deault.htm).

8. Medicines and Healthcare Products Regulatory Agency. MHRA guidance: GMP-QRM – Frequently

Table 3 continued

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asked questions (http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/

GoodManufacturingPractice/FAQ/QualityRiskManagement/index.htm).

9. Frank T et al. Quality risk management principles and industry case studies (December 2008)sponsored by the Product Quality Research Institute Manufacturing Technology Committee

(PQRI-MTC) (http://www.pqri.org).

10. Boedecker B. GMP Inspectorate of Hannover, Germany. EU GMP requirements – quality systems.

Presentation Ankara, Turkey Ministry of Health, 20–21 October 2009.

11. WHO guidelines on quality system requirements for national good manufacturing practice

inspectorates. In: WHO Expert Committee on Specications or Pharmaceutical Preparations. Thirty-

sixth Report . Geneva, World Health Organization, 2002 (WHO Technical Report Series, No. 902),

Annex 8 (http://www.who.int/medicines/areas/quality_safety/quality_assurance/inspections/en/

index.html).

12. US Department of Health and Human Services Food and Drug Administration Center for Drug

Evaluation and Research (CDER)/Center for Biologics Evaluation and Research (CBER)/Center

for Veterinary Medicine (CVM) guidance or industry – process validation: general principles

and practices. Silver Spring, MD, IFPMA, 2011 (http://www.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf).

13. Stamatis DH. Failure mode and efect analysis. FMEA from theory to execution, 2nd ed. Milwaukee,

American Society for Quality, Quality Press, 2003.

14. Guidelines or ailure modes and efects analysis (FMEA) or medical devices. Ontario, Canada,

Dyadem Press, 2003.

15. McDermott R et al. The basics o FMEA. Portland, OR, Productivity, 1996.16. IEC 61882 - Hazard operability analysis (HAZOP). Geneva, International Electrotechnical

Commission, Headquarters (IEC 61882 Ed.1, b:2001).

Further readingFDA's new process validation guidance – A detailed analysis. European Compliance Academy, November

2008 (http://www.gmp-compliance.org/eca_news_1402_5699,6013.html).

Validation of analytical procedures used in the examination of pharmaceutical materials. In: WHO

Expert Committee on Specications or Pharmaceutical Preparations. Thirty-second report . Geneva, World

Health Organization, 1992 (WHO Technical Report Series, No. 823), Annex 5 (http://who.int/medicines/

publications/pharmprep/en/index.html).

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Annex 3

WHO guidelines on variations to a prequalifed product

Introduction 96

1. Background 97

1.1 Objectives 971.2 Scope and application 98

2. Guidance or implementation 99

2.1 Reporting types 992.1.1 Notifcations 1002.1.2 Minor variation (Vmin) 1012.1.3 Major variation (Vmaj) 1012.1.4 New applications and extension applications 1012.1.5 Labelling inormation 101

2.2 Conditions to be ulflled 101

2.3 Documentation required 102

3. Glossary 102

4. Administrative changes 104

1. Change in the name and/or corporate address o the supplier o the FPP 1042. Change in the name or address o a manuacturer o an API that is not a supplier

o a prequalifed API or that is not supported by a CEP 1053. Change in the name and/or address o a manuacturer o the FPP 1054. Deletion o a manuacturing site or manuacturer 105

5. Changes to a CEP or to a confrmation o API-prequalifcationdocument 106

5. Submission o a new or updated CEP or an API or starting material or

intermediate used in the manuacturing process o the API 1066. Submission o a new or updated confrmation o API-prequalifcation document 1077. Submission o a new or updated transmissible spongiorm encephalopathy

(TSE) CEP or an excipient or API (addition or replacement) 108

6. Quality changes 108

3.2. S Drug substance (or API) 108

3.2. S.2 Manuacture 1088. Replacement or addition o a new manuacturing site or manuacturer o an API 1089. Change or addition o a manuacturing block or unit at a currently accepted site

o API manuacture 11210. Change in the manuacturing process o the API 11211. Change in the in-process tests or limits applied during the manuacture o the API 114

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12. Change in batch size o the API or intermediate 11613. Change to the specications or analytical procedures applied to materials used

in the manuacture o the API (e.g. raw materials, starting materials, reactionintermediates, solvents, reagents, catalysts) 117

3.2. S.4 Control of the API by the API manufacturer 11814. Changes to the test parameters, acceptance criteria, or analytical procedures

o the API manuacturer that do not require a change to the FPP manuacturer's

API specications 118

3.2. S.4 Control of the API by the FPP manufacturer 11915. Change to the test parameters or acceptance criteria o the API specications

o the FPP manuacturer 11916. Change to the analytical procedures used to control the API by the FPP

manuacturer 121

3.2. S.6 Container-closure system 12317. Change in the immediate packaging (primary and unctional secondary

components) or the storage and shipment o the API 12318. Change in the specications o the immediate packaging or the storage and

shipment o the API 12419. Change to an analytical procedure on the immediate packaging o the API 125

3.2. S.7 Stability 12620. Change in the retest period or shel-lie o the API 12621. Change in the labelled storage conditions o the API 126

3.2. P Drug product (or FPP) 127

3.2. P.1 Description and composition of the FPP 12722. Change in the composition o a solution dosage orm 12723. Change in the colouring system or the avouring system currently used in

the FPP 12824. Change in weight o tablet coatings or capsule shells 13025. Change in the composition o an immediate-release solid oral dosage orm 13026. Change or addition o imprints, embossing or other markings, including

replacement or addition o inks used or product markings and change inscoring conguration 132

27. Change in dimensions without change in qualitative or quantitativecomposition and mean mass 133

3.2. P.3 Manufacture 13428. Addition or replacement o a manuacturing site or part or all o the

manuacturing process or an FPP 13429. Replacement or addition o a site involving batch control testing 13630. Change in the batch size o the FPP 13631. Change in the manuacturing process o the FPP 13832. Change to in-process tests or limits applied during the manuacture o the FPP

or intermediate 139

3.2. P.4 Control of excipients 14033. Change in source o an excipient rom a TSE risk to a material o vegetable or

synthetic origin 14034. Change in the specications or analytical procedures or an excipient 14135. Change in specications o an excipient to comply with an ofcially recognized

pharmacopoeia 141

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3.2. P.5 Control of FPP 14236. Change in the standard claimed or the FPP rom an in-house to an ocially

recognized pharmacopoeial standard 14237. Change in the specications o the FPP involving test parameters and

acceptance criteria 14338. Change in the analytical procedures or the FPP 144

3.2. P.7 Container-closure system 14539. Replacement or addition o a primary packaging type 14540. Change in the package size 14641. Change in the shape or dimensions o the container or closure 14742. Change in qualitative and/or quantitative composition o the immediate

packaging material 147

43. Change in the specications o the immediate packaging 14844. Change to an analytical procedure on the immediate packaging 14945. Change in any part o the (primary) packaging material not in contact with

the FPP ormulation (e.g. colour o ip-of caps, colour code rings on ampoules,

or change o needle shield) 15046. Change to an administration or measuring device that is not an integral part o

the primary packaging (excluding spacer devices or metered dose inhalers) 150

3.2. P.8 Stability 15147. Change in the shel-lie o the FPP (as packaged or sale) 15148. Change in the in-use period o the FPP (ater rst opening or ater reconstitution

or dilution) 15149. Change in the labelled storage conditions o the nished pharmaceutical product

(as packaged or sale), the product during the in-use period or the product ater

reconstitution or dilution 152

Appendix 1. Examples o changes that make a new application or extension application

necessary 153

Appendix 2. Changes to excipients 154

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Introduction

Te variation guidelines have been completely updated and expanded, bringingthem into line with the principles o the new generic quality guidelines, WHOGuidelines on submission o documentation or a multisource (generic) fnished pharmaceutical product or the WHO Prequalifcation o Medicines Programme:quality part .

Te guidelines1 retain the basic structure and unction o the previous variation guidelines, and have been expanded to include the classifcation o additional post-approval/post-prequalifcation changes and to establish the levelo risk inherent to each change.2 Although the general requirements have not

signifcantly changed, the additional details help the reader to classiy changesthat may occur related to all the major sections o a quality dossier, to understandthe considerations necessary to assess the risk o each change, and to determinethe documentation required to support the change.

In some cases, changes that previously were considered major changesby deault are now classifed minor variations or notifcations, and some minor

variations have been reclassifed as notifcations. In addition, or some categoriesthat previously required acceptance o the change prior to implementation, theapplicant can now implement the change immediately upon notifcation.

Te change categories are organized according to the structure o thecommon technical document (CD). Te specifc CD sections associated withindividual data requirements have been identifed in order to assist in the fling o documentation (reproduced with corresponding numbers in bold). Presentationcorresponds to section 1.4 in Annex 4 o WHO echnical Report Series, No. 970.3

Changes are classifed as major only in those instances where the levelo risk is considered to be high and it is deemed necessary to provide the WHOPrequalifcation o Medicines Programme (WHO/PQP) with adequate time

or an assessment o the supporting documentation. Particular circumstancesare identifed where lower reporting requirements (annual notifcation (AN),immediate notifcation (IN) or minor variation (Vmin)) are possible. In all caseswhere notifcation to WHO/PQP or acceptance by WHO/PQP is required prior

1 Guidance on variations to a prequalifed product dossier. In: WHO Expert Committee on Specifcations or Pharmaceutical Preparations. Forty‑frst report . Geneva, World Health Organization, 2007 (WHO TechnicalReport Series, No. 943), Annex 6.

2 WHO Guidelines on quality risk management. In: WHO Expert Committee on Specifcations or Pharmaceutical Preparations. Forty‑seventh report . Geneva, World Health Organization, 2013 (WHO

Technical Report Series, No. 981), Annex 2.3 Guidelines on submission o documentation or a multisource (generic) fnished pharmaceutical product

or the WHO Prequalifcation o Medicines Programme: quality part. In: WHO Expert Committee onSpecifcations or Pharmaceutical Preparations. Forty‑sixth report . Geneva, World Health Organization, 2012(WHO Technical Report Series, No. 970), Annex 4.

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to implementation, assessment timelines will be published in order to providepredictable and reasonable timerames.

In addition, the guidelines assist in understanding the possibleconsequences o the listed changes, and may be useul as a risk management toolto promote or enhance best practices within organizations.

A companion Question and Answer document is in preparation to assistin interpretation o the guidelines. Tis document will address many o thequestions raised during the guidelines circulation process.

1. Background

Tis guidance document is technically and structurally inspired by the EuropeanUnion Institutions and Bodies Commission's Guideline on the details o the

various categories o variations to the terms o marketing authorizations ormedicinal products or human use and veterinary medicinal products. It isintended to provide supportive inormation on how to present an application toimplement a change to a product.

Tis guidance supersedes the guidance published in 2007.4

An applicant is responsible or the saety, ecacy and quality o a product

throughout its lie-cycle. Tereore, the applicant is required to make changes to thedetails o the product in order to accommodate technical and scientic progress,or to improve or introduce additional saeguards or the prequalied product.Such changes, whether administrative or substantive, are reerred to as variationsand may be subject to acceptance by WHO/PQP prior to implementation.

echnical requirements or the diferent types o variations are set out inthese guidelines in order to acilitate the submission o appropriate documentationby applicants and their assessment by WHO/PQP and to ensure that variations tothe medicinal product do not result in health concerns.

Te procedure or submitting variations is not within the scope o theseguidelines. Advice on the procedure or submitting a variation and current review timelines are set out on the WHO/PQP web site which may be updated rom timeto time. Applicants are advised to consult inormation on the web site wheneverthey are considering the submission o a variation application.

1.1 ObjectivesTese guidelines are intended to:

■ assist applicants with the classication o changes made to thequality part o a prequalied nished pharmaceutical product (FPP);

4 See footnote 1.

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■ provide guidance on the technical and other general datarequirements to support changes to the quality attributes o the active

pharmaceutical ingredient (API) or FPP.

1.2 Scope and applicationTese guidelines apply to applicants intending to make changes to the quality sections o product dossiers or an API or an FPP. Tis guidance should be readin conjunction with the WHO Guidelines on submission o documentation or amultisource (generic) fnished pharmaceutical product or the WHO Prequalifcationo Medicines Programme: quality part 5 as well as other related WHO guidelines.

Tis guidance document is applicable only to APIs and excipientsmanuactured by chemical synthesis or semi-synthetic processes and FPPscontaining such APIs and excipients. APIs produced by ermentation and APIso biological, biotechnological or herbal origin are treated as special cases. Teapplicant is requested to contact WHO/PQP regarding planned variations tosuch products.

Te notication requirements or API-related changes difer dependingon the manner in which inormation on the API was submitted in the FPPapplication, namely, use o a prequalied API, use o a European Pharmacopoeia

Certicate o Suitability (CEP), use o the API master le (APIMF) procedure, oras provided in ull within the dossier.

Te conditions and documentation stipulated in this guidance or API-related variations ocus primarily on those FPPs that relied upon the provisiono ull API inormation within the FPP dossier. In general FPPs that rely uponthe APIMF procedure have reduced reporting requirements because the APImanuacturers themselves have notied the relevant API-related change directly to WHO/PQP. Similarly, when an FPP relies upon a CEP or a prequalied API,FPP applicants are required to notiy WHO/PQP only when the associated CEP

or Conrmation o API Prequalication document has been revised.Guidance or API manuacturers on the technical and procedural

requirements or changes to prequalied APIs and to APIs supported by theAPIMF procedure is available on the Prequalication web site. Regardless o whether the API-related change is notied primarily by the API manuacturer(API prequalication (API-PQ) procedure, APIMF procedure or CEP), or theFPP manuacturer (ull API inormation in dossier) the technical requirementsare in principle the same as those stipulated in these guidelines.

Whenever FPPs have been prequalied on the basis o approval by a

stringent regulatory authority (SRA) (innovator products or generic products),subsequent applications or variations should be approved by the same SRA and

5 See footnote 3.

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WHO/PQP should be notied o the approval o the changes. Applicants are

advised to reer to the Letter o Prequalication.

When a variation leads to a revision o the summary o productcharacteristics (SmPC), the patient inormation leafet (PIL), labelling and

packaging leafet and updated product inormation should be submitted as part

o the application.

For variations that require generation o stability data on the API or FPP,

the stability studies required, including commitment batches, should always be

continued to cover the currently accepted retest or shel-lie period. WHO/PQP

should be inormed immediately i any problems with the stability o APIs or

FPPs occur during storage, e.g. i ound to be outside specications or potentially outside specications.

Applicants should be aware that some variations may require the

submission o additional consequential variations, including where the variation

states, “no variation is required, such changes are handled as amendments to

the APIMF by the APIMF holder”. Tereore, or any given change the applicant

should consider whether one or more variations may be required to be submitted.

I changes to the dossier only concern editorial changes, such changes

need not be submitted as a separate variation, but can be included as a noticationtogether with a subsequent variation concerning that part o the dossier. In

such a case, a declaration should be provided that the contents o the associated

sections o the dossier have not been changed by the editorial changes beyond the

substance o the variation submitted.

2. Guidance for implementation

2.1 Reporting types

Te denitions outlined in the ollowing reporting types are intended to provide

guidance with respect to the classication o quality-related changes. Specic

examples o changes are provided in these guidelines. However, it should be noted

that a change not covered by these guidelines, should be considered as a major

change by deault. Whenever the applicant is unclear about the classication o a

particular change, WHO/PQP should be contacted. It remains the responsibility

o the applicant to submit relevant documentation to justiy that the change will

not have a negative impact on the quality o the product.

Individual changes normally require the submission o separate variations.

Grouping o variations is acceptable only under the ollowing circumstances:

■ when variations are consequential to each other, e.g. introduction o a

new impurity specication that requires a new analytical procedure;

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■ when the same change afects multiple FPPs, e.g. addition o a new API manuacturing site or multiple FPPs;

■ when all the changes are annual notication.

For the purposes o classication, an application involving two or moretypes o variations will be considered as the highest risk type, e.g. a variationgrouping both a minor change and a major change will be classied as a majorchange.

Applicants are also advised to exercise caution whenever several changesto the same FPP are envisaged. Although each o the individual changes may be classied as a particular reporting type, classication within a higher risk category may be warranted as a result o the composite efect o these changes. Inall such cases, applicants are advised to contact WHO/PQP prior to submissiono the variation application to obtain guidance on classiying such changes.

2.1.1 Notifcations

Notications are changes that could have minimal or no adverse efects onthe overall saety, ecacy and quality o the FPP. Such notications do notrequire prior acceptance, but must be notied to WHO/PQP immediately aer

implementation (immediate notication (IN)), or within 12 months ollowingimplementation (annual notication (AN)) o the change.

It should be highlighted that an IN or AN may be rejected in speciccircumstances with the consequence that the applicant must cease to apply thealready implemented variation.

Annual notifcation (AN)

Applicants must satisy themselves that they meet all o the prescribed conditions

or the change. Te change should be summarized as part o the notication butthe indicated documentation is not required to be submitted. Te documentationindicated or ANs should be available on request or at the time o inspection.ANs should be submitted to WHO/PQP within 12 months o implementationo the changes. For convenience applicants may group several AN changes as asingle submission.

Immediate notifcation (IN)

Applicants must satisy themselves that they meet all o the prescribed conditions

or the change and submit all required documentation with the noticationapplication. Such changes can be implemented immediately at the time o submission and they can be considered accepted i an objection is not issued by WHO/PQP within 30 calendar days o the date o acknowledgement o receipto the application.

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2.1.2 Minor variation (Vmin)

Minor variations are changes that may have minor efects on the overall saety,ecacy and quality o the FPP. Applicants must satisy themselves that they meet all o the prescribed conditions or the change and submit all requireddocumentation with the variation application.

Such variations can be implemented i no objection letter has been issuedwithin a time period indicated on the WHO/PQP web site. Should questionsarise during the specied period, the change can only be implemented on receipto a letter o acceptance rom WHO/PQP.

2.1.3

Major variation (Vmaj)Major variations are changes that could have major efects on the overall saety,ecacy and quality o the FPP. Te documentation required or the changesincluded in this reporting type should be submitted. Prior acceptance by WHO/PQP is required beore the changes can be implemented. A letter o acceptance will be issued or all major variations i and when the variation isconsidered acceptable.

2.1.4 New applications and extension applications

Certain changes are so undamental that they alter the terms o the accepteddossier and consequently cannot be considered as changes. In these cases a new dossier must be submitted. Examples o such changes are listed in Appendix 1.

2.1.5 Labelling inormation

For any change to labelling inormation (SmPC, PIL, labels) not covered by the variation categories described in this document, WHO/PQP must be notied andsubmission o the revised labelling inormation is expected as per the guidance

on the WHO/PQP web site.

2.2 Conditions to be ulflledFor each variation, attempts have been made to identiy particular circumstanceswhere lower reporting requirements (IN, AN or Vmin) are possible. A changethat does not meet all o the conditions stipulated or these specic circumstancesis considered to be a Vmaj.

In some circumstances Vmaj categories have been specically stated ora given variation. Tis has been done to indicate to applicants what documents

should be provided. Tis is or inormational purposes only. Te list o documentation is not intended to be comprehensive and urther documentationmay be required. For all changes it remains the responsibility o the applicant toprovide all necessary documents to demonstrate that the change does not have anegative efect on the saety, ecacy or quality o the FPP.

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2.3 Documentation required

Examples o variations are organized according to the structure o the CD. Foreach variation, certain documents have been identied as supporting data and areorganized according to CD structure. Regardless o the documents specied,applicants should ensure that they have provided all relevant inormation tosupport the variation.

Where applicable, the ollowing should be included in the application:

■ a variation application orm (a template can be downloaded romthe web site). All sections o this orm should be completed and the

document signed. Electronic versions o the application orm, both asa Word document and a scanned signed PDF, should be provided inaddition to the printed version;

■ an updated quality inormation summary (QIS) (i applicable);

■ replacement o the relevant sections o the dossier as per CD ormat;

■ copies o SmPC, PIL and labels, i relevant.

It should be noted that WHO/PQP reserves the right to request urtherinormation not explicitly described in these guidelines.

Te QIS provides a summary o the key quality inormation rom theproduct dossier. For FPPs that have an agreed-upon QIS, the QIS should berevised and submitted (in Word ormat only) with every variation application.Any revised sections within the QIS should be highlighted. I there is no changeto the QIS as a result o the variation, a statement should be made in the coveringletter to this efect.

Alternative approaches to the principles and practices described in thisdocument may be acceptable provided they are supported by adequate scientic

justication. It is also important to note that WHO/PQP may request inormationor material, or dene conditions not specically described in this guidance, inorder to adequately assess the saety, ecacy and quality o an FPP.

3. Glossary

Te denitions provided below apply to the terms used in this guidance. Tey may have diferent meanings in other contexts and documents.

active pharmaceutical ingredient (API)A substance used in the FPP, intended to urnish pharmacological activity orto otherwise have direct efect in the diagnosis, cure, mitigation, treatment orprevention o disease, or to have direct efect in restoring, correcting or modiyingphysiological unctions in human beings.

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active pharmaceutical ingredient (API) starting material

A raw material, intermediate, or an API that is used in the production o an APIand that is incorporated as a signicant structural ragment into the structureo the API. An API starting material can be an article o commerce, a materialpurchased rom one or more suppliers under contract or commercial agreement,or produced in-house.

applicant

For the purposes o this document, the term applicant reers to any person orentity who has participated in the procedure or prequalication o FPPs by submission o the required documentation on a product that has been listed afer

evaluation as prequalied.

biobatch

Te batch used to establish bioequivalence or similarity to the comparatorproduct as determined in bioequivalence or biowaiver studies, respectively.

nal intermediate

Te last reaction intermediate in the synthetic pathway that undergoes synthetictransormation to the API or the crude API. Purication is not considered to be

a synthetic transormation.

nished pharmaceutical product (FPP)

A nished dosage orm o a pharmaceutical product which has undergone allstages o manuacture including packaging in its nal container and labelling.

in-process control

Check perormed during manuacture to monitor or to adjust the process inorder to ensure that the nal product conorms to its specications.

manuacturer

A company that carries out operations such as production, packaging, repackaging,labelling and re-labelling o pharmaceuticals.

ofcially recognized pharmacopoeia (or compendium)

Tose pharmacopoeias recognized in the WHO/PQP (i.e. Te International Pharmacopoeia (Ph. Int.), the European Pharmacopoeia (Ph. Eur.), the BritishPharmacopoeia (BP), the Japanese Pharmacopoeia (JP) and the United StatesPharmacopeia (USP)).

pilot-scale batch

A batch o an API or FPP manuactured by a procedure ully representative o and simulating that to be applied to a ull production-scale batch. For example,or solid oral dosage orms, a pilot scale is generally, at a minimum, one-tenth

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6 Procedure or prequalifcation o pharmaceutical products. In: WHO Expert Committee on Specifcations or Pharmaceutical Preparations. Forty‑third report . Geneva, World Health Organization, 2009 (WHO TechnicalReport Series, No. 953), Annex 3.

that o a ull production scale or 100 000 tablets or capsules, whichever is thelarger, unless otherwise adequately justifed.6

production batch

A batch o an API or FPP manuactured at production scale by using productionequipment in a production acility as specifed in the application.

stringent regulatory authority (SRA)

A stringent regulatory authority is:

■ the medicines regulatory authority in a country which is: (a) amember o the International Conerence on Harmonisation (ICH)(European Union (EU), Japan and the United States o America); or(b) an ICH Observer, being the European Free Trade Association(EFTA) as represented by SwissMedic and Health Canada (as may beupdated rom time to time); or (c) a regulatory authority associatedwith an ICH member through a legally-binding, mutual recognitionagreement including Australia, Iceland, Liechtenstein and Norway (asmay be updated rom time to time);

■ only in relation to good manuacturing practices (GMP)

inspections: a medicines regulatory authority that is a member o thePharmaceutical Inspection Co-operation Scheme (PIC/S) as specifedat http://www.picscheme.org

4. Administrative changes

Description o change Conditions to

be ulflled

Documentation

required

Reporting

type

1 Change in the name and/or corporate address o thesupplier o the FPP.

1 1 IN

Conditions to be ulflled

1. Conrmation that the supplier o the product remains the same legal entity.

Documentation required

1. A ormal document rom a relevant ofcial body (e.g. the national medicinesregulatory authority (NMRA)) in which the new name and/or address is mentioned.

continues

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Description o change Conditions tobe ulflled

Documentationrequired

Reportingtype

2 Change in the name oraddress o a manuacturer o an API that is not a supplierofaprequaliedAPIorthatisnotsupportedbyaCEP.

1 1–2 IN


1. No change in the location o the manuacturing site and in the manuacturing

operations.


1. A ormal document rom a relevant ofcial body (e.g. NMRA) in which the new nameand/or address is mentioned.

2. An updated Letter o Access in case o change in the name o the holder o the APIMF.


be ulflled

Documentation

required

Reporting

type

3 Change in the name and/oraddress o a manuacturer o the FPP.

1 1 IN


1. No change in the location o the manuacturing site and in the manuacturingoperations.


1. Copy o the modied manuacturing authorization or a ormal document rom arelevant ofcial body (e.g. NMRA) in which the new name and/or address is mentioned.


be ulflled

Documentation

required

Reporting

type

4 Deletionofamanufacturingsiteormanufacturerinvolving:

4a production o the API startingmaterial

1 1 AN

4b production or testing o the

API intermediate or API

1–2 1 IN

4c production, packaging ortesting o the intermediateor FPP

1–2 1 IN

Table continued

continues

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Conditions to be ulflled1. At least one other site continues to perorm the same unction(s) as the site(s)

intended to be deleted.

2. The deletion o the site is not a result o critical defciencies in manuacturing.


1. Clear identifcation o the manuacturing, packaging and/or testing site to be deleted,

in the letter accompanying the application.

5. Changes to a CEP or to a confrmationo API-prequalifcation document


be ulflled

Documentation

required

Reporting

type

5 SubmissionofaneworupdatedCEPforanAPIorstartingmaterialor

intermediate used in the manuacturing process o the API:

5a.1 rom a currently accepted

manuacturer

1–5 1–5 AN

5a.2 1–4 1–6 IN

5a.3 1, 3–4 1–6 Vmin

5b.1 rom a new manuacturer 1–4 1–6 IN

5b.2 1, 3– 4 1–6 Vmin

Conditions to be ulflled1. No change in the FPP release and shel-lie specifcations.

2.Unchanged(excludingtightening)additional(toPh.Eur.)specicationsforany

impurities including organic, inorganic and genotoxic impurities and residual

solvents, with the exception o residual solvents when the limits stipulated comply

withICHrequirements.

3. The manuacturing process o the API, starting material or intermediate does not

include the use o materials o human or animal origin or which an assessment o

viralsafetydataisrequired.

4. For low solubility APIs the polymorph is the same, and whenever particle size iscritical(includinglowsolubilityAPIs)thereisnosignicantdierenceinparticle

size distribution, compared to the API lot used in the preparation o the biobatch.

5.NorevisionoftheFPPmanufacturer'sAPIspecicationsisrequired.

Table continued

continues

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Documentation required1.Copyofthecurrent(updated)CEP,includinganyannexesandadeclarationof

accessfortheCEPtobedulylledoutbytheCEPholderonbehalfoftheFPP

manufacturerorapplicanttotheWHO/PQPwhoreferstotheCEP.

2. A written commitment that the applicant will inorm WHO/PQP in the event that the

CEPiswithdrawnandanacknowledgementthatwithdrawaloftheCEPwillrequire

additionalconsiderationoftheAPIdatarequirementstosupporttheproduct

dossier.

3. Replacement o the relevant pages o the dossier with the revised inormation or

theCEPsubmissionoptionstipulatedundersection3.2.SoftheWHOGuidelines

on submission o documentation or a multisource (generic) fnished pharmaceutical

product or the WHO Prequalifcation o Medicines Programme: quality part .

4. (S.2.5) For sterile APIs, data on the sterilization process o the API, including

validation data.

5.(P.8.2)InthecaseofthesubmissionofaCEPforanAPI,ifthequalitycharacteristics

o the API are changed in such a way that it may impact the stability o the FPP,

a commitment to put under stability one batch o the FPP o at least pilot-scale,

and to continue the study throughout the currently accepted shel-lie and to

immediately report any out-o-specifcation results to WHO/PQP.

6. (S.4.1) Copy o FPP manuacturer’s revised API specifcations.


be ulflled

Documentation

required

Reporting

type

6 SubmissionofaneworupdatedconrmationofAPI-prequalication

document

6a.1 rom a currently accepted

manuacturer

1–3 1–3, 5 AN

6a.2 1–2 1–5 Vmin

6b.1 rom a new manuacturer 1–3 1–3, 5 IN

6b.2 1–2 1–5 Vmin


1. No change in the FPP release and shel-lie specifcations.

2. For low solubility APIs the API polymorph is the same, and whenever particle size is

critical(includinglowsolubilityAPIs)thereisnosignicantdierenceinparticlesize

distribution, compared to the API lot used in the preparation o the biobatch.

3.ThereisnodierenceinimpurityproleoftheproposedAPItobesupplied,including organic, inorganic, genotoxic impurities and residual solvents, compared

to that o the API currently supplied. The proposed API manuacturer's specifcations

donotrequiretherevisionoftheFPPmanufacturer'sAPIspecications.

Table continued

continues

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Table continued

Documentation required1. Copy o the current (updated) confrmation o API-PQ document. The API

manuacturer should duly fll out the authorization box with the name o theapplicant or FPP manuacturer seeking to use the document.

2. Replacement o the relevant pages o the dossier with the revised inormation

or the API-PQ procedure submission option (Option 1: confrmation o API Prequalifcation document ) stipulated under section 3.2.S. o the WHO Guidelineson submission o documentation or a multisource (generic) fnished pharmaceutical product or the WHO Prequalifcation o Medicines Programme: quality part .

3. (S.2.5) For sterile APIs, data on the sterilization process o the API, including validation.

4. (S.4.1) Copy o FPP manuacturer's revised API specifcations.5.(P.8.2)IfthequalitycharacteristicsoftheAPIarechangedinsuchawaythatitmay

impact the stability o the FPP, a commitment to put under stability one batch o

at least pilot-scale o the FPP and to continue the study throughout the currently

accepted shel-lie and to immediately report any out-o-specifcation results to

WHO/PQP.


be ulflled

Documentation

required

Reporting

type

7 Submission o a new orupdated transmissiblespongiorm encephalopathy(TSE)CEPforanexcipientorAPI (addition or replacement)

None 1 AN


None


1.Copyofthecurrent(updated)TSECEP.

6. Quality changes

3.2. S Drug substance (or API)3.2. S.2 Manufacture

Description o change Conditions tobe ulflled Documentationrequired Reportingtype

8 Replacement or addition o a new manuacturing site or manuacturer o anAPI involving:

continues

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Reportingtype

8a.1 API testing only 1, 2, 4 1, 3–4 IN

8a.2 2, 4 1, 3–4 Vmin

8b.1 production o API starting

material

3–4 Novariationisrequired;

such changes are handled as

amendments to the APIMF by

the APIMF holder.

8b.2 4–5 1–2, 12 IN

8b.3 None 1,2,5, 7–8,12, 13 Vmaj

8c.1 production o API

intermediate




the APIMF holder.

8c.2 4, 6 1–2, 12 IN

8c.3 None 1, 2, 5, 7–8, 12, 13 Vmaj

8d.1 production o API (APIMF

procedure)

3, 7–9 1, 2, 6, 8 IN

8d.2 3, 7, 9 1, 2, 6–8 Vmin

8e.1 production o API (ull

dossier)

1, 9–11 1–2, 4, 8–9 IN

8e.2 None 1, 2, 4, 5, 7–8,

10–11, 13

Vmaj


1. The API is non-sterile.

2. The transer o analytical methods has been successully undertaken.

3. The new site is supported by an APIMF that is currently accepted through the

APIMF procedure and the FPP manuacturer holds a valid Letter o Access.

4. No change in the FPP manuacturer's API specifcations.

5. The impurity profle o the API starting material is essentially the same as other

acceptedsources.Theintroductionofthenewsupplierdoesnotrequirethe

revision o the API manuacturer's API starting material specifcations. The route o

synthesis is verifed as identical to that already accepted.

6. Specifcations (including in-process, methods o analysis o all materials), methodo manuacture and detailed route o synthesis are verifed as identical to those

alreadyaccepted.Theintroductionofthenewsupplierdoesnotrequirethe

revision o the API manuacturer's API intermediate specifcations.

Table continued

continues

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Table continued

Conditions to be ulflled7. No change in the FPP release and end-o-shel-lie specications.

8. NodierenceinimpurityproleoftheproposedAPItobesupplied,includingorganic, inorganic and genotoxic impurities and residual solvents. The proposedAPImanufacturer’sspecicationsdonotrequiretherevisionoftheFPPmanuacturer’s API specications.

9. For low-solubility APIs the API polymorph is the same, and whenever particle sizeiscritical(includinglow-solubilityAPIs)thereisnosignicantdierenceinparticlesize distribution, compared to the API lot used in the preparation o the biobatch.

10. Specications (including in-process controls, methods o analysis o all

materials), method o manuacture (including batch size) and detailed route o synthesis are veried as identical to those already accepted (such situations aregenerally limited to additional sites by the same manuacturer or a new contractmanufacturingsitewithevidenceofanacceptableandsimilarqualitysystemtothat o the main manuacturer).

11. Where materials o human or animal origin are used in the process, themanufacturerdoesnotuseanynewsupplierforwhichassessmentisrequiredo viral saety or o compliance with the current WHO Guidelines on transmissiblespongiorm encephalopathies in relation to biological and pharmaceutical products(www.who.int/biologicals)orEMA'sNote or guidance on minimizing the risk o

transmitting animal spongiorm encephalopathy agents via human and veterinary medicinal products (www.emea.europa.eu/ema) orequivalentguidelinesoftheICHregion and associated countries.


1. (S.2.1) Name, address, and responsibility o the proposed site or acility involvedin manuacture or testing (including block(s) and unit(s)). A valid testingauthorizationoracerticateofGMPcompliance,ifapplicable.

2. (S.2.2) A side-by-side comparison o the manuacturing fowcharts or productiono the API, intermediate, or API starting material (as applicable) at the parent and

proposedsitesandatabulatedsummaryofthedierences.3. (S.4.3) Copies or summaries o validation reports or method transer reports, which

demonstrateequivalenceofanalyticalprocedurestobeusedattheproposedtesting site.

4. (S.4.4)Descriptionofthebatches,copiesofcerticatesofanalysisandbatchanalysis data (in a comparative tabular ormat) or at least two (minimum pilot-scale) batches o the API rom the currently accepted and proposed manuacturersand/or sites.

5. Relevantsectionsof(S)documentationinfullmentofrequirementsforfullinormation provided in the dossier under section 3.2.S o the WHO Guidelines on

submission o documentation or a multisource (generic) fnished pharmaceutical product or the WHO Prequalifcation o Medicines Programme: quality part .7

continues

7 See footnote 3.

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Table continued

Documentation required6. The open part o the new APIMF (with a Letter o Access provided in Module 1)

anddocumentationinfullmentofrequirementsfortheAPIMFoptionunder

section 3.2.S o the WHO Guidelines on submission o documentation or a

multisource (generic) fnished pharmaceutical product or the WHO Prequalifcation o

Medicines Programme: quality part .8

7. (P.8.2)IfthequalitycharacteristicsoftheAPIarechangedinsuchawaythatit

may impact the stability o the FPP, a commitment to put under stability one

production-scale batch o the FPP and to continue the study throughout the

currently accepted shel-lie and to immediately report any out o specifcation

results to WHO/PQP.

8. (S.4.1) A copy o the FPP manuacturer's API specifcations.

9. (S.2)AdeclarationfromthesupplieroftheprequaliedFPPthattherouteof

synthesis,materials,qualitycontrolproceduresandspecicationsoftheAPIand

key (ultimate) intermediate in the manuacturing process o the API (i applicable)

are the same as those already accepted.

10.AdiscussionoftheimpactofthenewAPIonthesafety,ecacyandqualityofthe

FPP.

11.ForlowsolubilityAPIswherepolymorphicformisdierentorwheneverparticlesizeiscritical(includinglow-solubilityAPIs)wherethereisasignicantdierence

in particle size distribution compared to the lot used in the biobatch, evidence

thatthedierencesdonotimpactthequalityandbioavailabilityoftheFPP.

12. Certifcates o analysis or at least one batch o API starting material or

intermediate (as applicable) issued by the new supplier and by the API

manuacturer. Comparative batch analysis o fnal API manuactured using API

starting material or intermediate (as applicable) rom the new source and rom

a previously accepted source. For an alternative source o plant-derived starting

material, control o pesticide residues must be established. This can either be in

the orm o an attestation rom the starting material supplier that no pesticides

are used during the growth o the plant material, or by providing the results o

pesticide screening rom one batch o the starting material.

13. An analysis o the impact o the change in supplier with respect to the need or API

stability studies and a commitment to conduct such studies i necessary.

8 See footnote 3.

continues

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8 1 , 2 0 1 3


Table continued



Reportingtype

9a change or addition o a

manuacturing block or unit

at a currently accepted site

o API manuacture




the APIMF holder.

9b 1, 3–5 1–4 IN


1. The API is non-sterile.2. The API manuacturing block or unit is currently accepted through the APIMF

procedure.

3.Thesamequalitysystemcoverscurrentlyacceptedandproposedunitsorblocks.

4. For low-solubility APIs, there is no change in the polymorphic orm and whenever

particle size is critical (including low solubility APIs) there is no signifcant change to

the particle size distribution compared to the API lot used in the preparation o the

biobatch.

5.Nochangeintherouteofsynthesis,qualitycontrolproceduresandspecicationsof

the API and key (ultimate) intermediate in the manuacturing process o the API (i

applicable).Minorchangesintheequipmentareacceptable.


1.(S.2)AdeclarationfromthesupplieroftheFPPthattherouteofsynthesis,quality

control procedures and specifcations o the API and key (ultimate) intermediate in

the manuacturing process o the API (i applicable) are the same as those already

accepted.

2. (S.2.1) Name, address, and responsibility o the proposed production site or acility

involved in manuacturing and/or testing (including block(s) and unit(s)). A valid

manufacturingand/ortestingauthorizationandacerticateofGMPcompliance,if

available.

3.(S.4.4)Descriptionofthebatches,copiesofcerticatesofanalysisandbatchanalysis

data (in a comparative tabular ormat) or at least two (minimum pilot-scale)

batches o the API rom the currently accepted and proposed units or blocks.

4.(S.2.2)AsummaryofdierencesbetweenmanufactureandcontroloftheAPIatthe

currently accepted and proposed units or blocks, i applicable.


be ulflled

Documentation

required

Reporting

type

10a change in the


o the API

1–3, 9 1–2, 8 AN

10b.1 1–2, 4, 6–9 3–4, 11–12 IN

continues

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113

Table continued

continues



Reportingtype

10b.2 change in the


o the API

1–2, 4, 6–8, 10 3–4, 11–12 Vmin

10c 1–2, 4–7 3–4, 11–12 Vmin

10d None 2–14 Vmaj


1. No change in the physical state (e.g. crystalline, amorphous) o the API.

2. For low solubility APIs, there is no change in the polymorphic orm and wheneverparticle size is critical (including low solubility APIs) there is no signicant change

in the particle size distribution compared to that o the API lot used in the

preparation o the biobatch.

3. The API manuacturing site is currently accepted through the APIMF procedure.

4. Where materials o human or animal origin are used in the process, the

manuacturer does not use any new process or which assessment o viral saety

dataorTSEriskassessmentisrequired.

5. No change in the route o synthesis (i.e. intermediates remain the same) and there

are no new reagents, catalysts or solvents used in the process.

6. Nochangeinqualitativeandquantitativeimpurityproleorinphysicochemical

properties o the API.

7. ThechangedoesnotaectthesterilizationproceduresofasterileAPI.

8. The change involves only steps beore the nal intermediate.

9. Thechangedoesnotrequirerevisionofthestartingmaterial,intermediateorAPI

specications.

10.ThechangedoesnotrequirerevisionoftheAPIspecications.

Documentation required1. A copy o the APIMF amendment acceptance letter.

2. (P.8.2)IfthequalitycharacteristicsoftheAPIarechangedinawaythatmayimpact

the stability o the FPP, a commitment to put under stability one production-scale

batch o the FPP and to continue the study throughout the currently accepted

shel-lie and to immediately report any out o specication results to WHO/PQP.

3. (S.2.2) A side-by-side comparison o the current process and the new process.

4. (S.2.2) A fow diagram o the proposed synthetic process(es) and a brie narrative

description o the proposed manuacturing process(es).

5. (S.2.3)Informationonthequalityandcontrolsofthematerials(e.g.rawmaterials,

starting materials, solvents, reagents, catalysts) used in the manuacture o the

proposed API, where applicable.

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Documentation required6. (S.2.3)EitheraTSECEPforanynewsourceofmaterialor,whereapplicable,

documented evidence that the specifc source o the material that carries a risk o TSEhaspreviouslybeenassessedbythecompetentauthorityandshowntocomplywith the current WHO guidelines on transmissible spongiform encephalopathies inrelation to biological and pharmaceutical products (www.who.int/biologicals) orEMA’sNote for guidance on minimizing the risk of transmitting animal spongiformencephalopathy agents via human and veterinary medicinal products (www.emea.europa.eu/ema)orequivalentguidelinesoftheICHregionandassociatedcountries.

7. (S.2.4) Inormation on controls o critical steps and intermediates, where applicable.8. (S.2.5)Evidenceofprocessvalidationand/orevaluationstudiesforsterilization,ifapplicable.

9. (S.3.1)Evidenceforelucidationofstructure,whereapplicable.10. (S.3.2) Inormation on impurities.11. (S.4.1) A copy o currently accepted specifcations o API (and starting material and

intermediate, i applicable).12.(S.4.4)Descriptionofthebatches,certicatesofanalysisorbatchanalysisreport,

and summary o results, in a comparative tabular ormat, or at least two batches(minimum pilot-scale) manuactured according to the current and proposed

processes.13. (S.7.1) Results o two batches o at least pilot-scale with a minimum o three monthso accelerated (and intermediate as appropriate) and three months o long-termtesting o the proposed API.

14. For low-solubility APIs where the polymorphic orm has changed or wheneverparticle size is critical (including low-solubility APIs) where there is dissimilar particlesize distribution compared to the lot used in the biobatch, evidence that thedierencesdonotimpactthequalityandbioavailabilityoftheFPP.


be ulflled

Documentation

required

Reporting

type

11 Change in the in-process tests or limits applied during the manuacture o the API:

11a any change in the


controls

1 Novariationisrequired;such changes are handled asamendments to the APIMF bythe APIMF holder

11b tightening o in-processlimits

2–4 1 AN

11c addition o a new in-

process test and limit

2, 5 1–5 AN

Table continued

continues

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115

Table continued

continues



Reportingtype

11d addition or replacement

o an in-process test as

a result o a saety or

qualityissue

None 1–5, 7, 8–10 Vmin

11e.1 deletion o an in-process

test

2, 6–7 1–3, 6 AN

11e.2 None 1–3, 7–10 Vmaj

11 relaxation o thein-process test limits

None 1–3, 5, 7–10 Vmaj


1. API manuacturing site is currently accepted through the APIMF procedure.

2. The change is not necessitated by unexpected events arising during manuacturee.g.anewunqualiedimpurityorachangeintotalimpuritylimits.

3. The change is within the range o currently accepted limits.

4. The analytical procedure remains the same, or changes to the analytical procedureare minor.

5. Anynewanalyticalproceduredoesnotconcernanovelnon-standardtechniqueorastandardtechniqueusedinanovelway.

6. Theaectedparameterisnon-signicant.

7. ThechangedoesnotaectthesterilizationproceduresofasterileAPI.


1. A comparison o the currently accepted and the proposed in-process tests.

2. (S.2.2) Flow diagram o the proposed synthetic process(es) and a brie narrativedescription o the proposed manuacturing process(es).

3. (S.2.4) Inormation on the controls perormed at critical steps o the manuacturingprocess and on intermediates o the proposed API.

4. Detailsofanynewnon-pharmacopoeialanalyticalmethodandvalidationdatawhere relevant.

5. Justifcation or the new in-process test and/or limits.

6. Justifcation and/or risk-assessment showing that the parameter is non-signifcant.

7. (S.2.5)Evidenceofprocessvalidationand/orevaluationstudiesforsterilization,where applicable.

8. (S.3.2) Inormation on impurities, i applicable.

9. (S.4.1) Copy o currently accepted specifcations o API (and intermediates, i

applicable).10.(S.4.4)Descriptionofthebatches,certicatesofanalysisorbatchanalysisreport

and summary o results, in a comparative tabular ormat, or at least two batches(minimum pilot-scale) or all specifcation parameters.

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Table continued



Reportingtype

12 Change in batch size o the API or intermediate involving:

12a up to 10-old compared

to the currently accepted

batch size

1–2, 4, 6 1, 3–4 AN

12b.1 downscaling 1–4 1, 3–4 AN

12b.2 1–3 1–4 IN

12c any change in scale

(APIMF procedure)

5 1–2, 4–5 AN

12d more than 10-old

increase compared to the

currently accepted batch

size

1–2, 4, 6 1, 3–4 Vmin

Conditions to be ulflled1. No changes to the manuacturing process other than those necessitated by

changesinscale(e.g.useofadierentsizeofequipment).

2.Thechangedoesnotaectthereproducibilityoftheprocess.

3. The change is not necessitated by unexpected events arising during manuacture or

due to stability concerns.

4. The change does not concern a sterile API.

5. The API manuacturing site and batch size is currently accepted through the APIMF

procedure.

6. The proposed batch size increase is relative to either the originally accepted batchsize,orthebatchsizeacceptedthroughasubsequentmajororminorvariation.


1. (S2.2) A brie narrative description o the manuacturing process.

2. (S.2.5) Where applicable, evidence o process validation and/or evaluation studies

or sterilization.

3. (S.4.1) Copy o the currently accepted specifcations o the API (and o the

intermediate, i applicable).

4. (S.4.4) Batch analysis data (in tabular ormat) issued by the FPP manuacturer ora minimum o two batches each o the currently accepted batch size and the

proposed batch size.

5. A copy o the APIMF amendment acceptance letter.

continues

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117

Table continued



Reportingtype

13 Change to the specifcations or analytical procedures applied to materials used

in the manuacture o the API (e.g. raw materials, starting materials, reaction

intermediates, solvents, reagents, catalysts) involving:

13a any change 1 Novariationisrequired;



the APIMF holder

13b tightening o the

specifcation limits

2–4 1–3 AN

13c minor change to an

analytical procedure

5–7 2–3 AN

13d addition o a new

specifcation parameter

and a correspondinganalytical procedure where

necessary

2, 7–9 1–3 AN

13e deletion o a specifcation

parameter or deletion o

an analytical procedure

2, 10 1–4 AN

13 addition or replacement o

a specifcation parameter

as a result o a saety orqualityissue

None 1–3, 5 Vmin

13g relaxation o the currently

accepted specifcation

limits or solvents,

reagents, catalysts and raw

materials

4, 7, 9–10 1, 3–4 IN

13h relaxation o the

currently acceptedspecifcation limits or

API starting materials and

intermediates

None 1–3, 5 Vmaj

continues

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8 1 , 2 0 1 3


Table continued

Conditions to be ulflled1. API manuacturing site is currently accepted through the APIMF procedure.

2. The change is not necessitated by ailure to meet specifcations resulting rom

unexpected events arising during manuacture, or because o stability concerns.

3. Any change is within the range o currently accepted limits.

4. The analytical procedure remains the same.

5. Themethodofanalysisisbasedonthesameanalyticaltechniqueorprinciple(e.g.

changes to the analytical procedure are within allowable adjustments, to column

length and other parameters, but do not include variations beyond the acceptable

rangesoradierenttypeofcolumnandmethod).

6. Appropriate validation studies have been perormed in accordance with the

relevant guidelines and show that the updated analytical procedure is at least

equivalenttotheformeranalyticalprocedure.

7. No change to the total impurity limits; no new impurities are detected.

8. Anynewanalyticalproceduredoesnotconcernanovelnon-standardtechnique

orastandardtechniqueusedinanovelway.

9. The change does not concern a genotoxic impurity.

10.Theaectedparameterisnon-signicantorthealternativeanalyticalprocedure

has been previously accepted.


1. Comparative table o currently accepted and proposed specifcations.

2. (S.2.3)Informationonthequalityandcontrolsofthematerials(e.g.rawmaterials,

starting materials, solvents, reagents, catalysts) used in the manuacture o the

proposed API, where applicable.

3. (S.2.4) Inormation on intermediates, where applicable.

4. Justifcation and/or risk assessment showing that the parameter is non-signifcant.

5. (S.3.2) Inormation on impurities, where applicable.

3.2. S.4 Control of the API by the API manufacturer


be ulflled

Documentation

required

Reporting

type

14 Changes to the test parameters, acceptance criteria, or analytical procedures o

theAPImanufacturerthatdonotrequireachangetotheFPPmanufacturer's

API specifcations involving:

14a a. API supported throughthe APIMF procedure.

1–2 Novariationisrequired;such changes are handled as

amendments to the associated

APIMF

continues

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119

Table continued

continues



Reportingtype

14b b. API not supported

through the APIMF

procedure.

2 1–4 IN


1. The revised test parameters, acceptance criteria, or analytical procedures have been

submitted as amendments to the associated APIMF and accepted.

2. The API manuacturer has provided the relevant documentation to the FPP

manuacturer. The FPP manuacturer has considered the API manuacturer'srevisionsanddeterminedthatnoconsequentialrevisionstotheFPPmanufacturer's

APItestparameters,acceptancecriteria,oranalyticalproceduresarerequiredto

ensurethatadequatecontroloftheAPIismaintained.


1. (S.4.1) Copy o the current and proposed API specications dated and signed by the

API manuacturer.

2. (S.4.2) Copies or summaries o analytical procedures, i new analytical proceduresare used.

3. (S.4.3) Copies or summaries o validation reports or new or revised analyticalprocedures, i applicable.

4.JusticationastowhythechangedoesnotaecttheFPPmanufacturer's

specications.

3.2. S.4 Control of the API by the FPP manufacturer


be ulflled

Documentation

required

Reporting

type

15 Change to the test parameters or acceptance criteria o the API specications

o the FPP manuacturer involving:

15a updating a test

parameter or acceptance

criterion controlled in

compliance with an

ofcially recognized

pharmacopoeial

monograph as a resulto an update to this

monograph to which the

API is controlled.

11 1–5 AN

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Table continued

continues



Reportingtype

15b.1 deletion o a test

parameter1–2 1, 6 AN

15b.2 10 1, 6, 8 IN

15b.3 None 1, 6 Vmaj

15c.1 addition o a test

parameter1, 4–8 1–6 AN

15c.2 1, 5–6, 10 1–6, 8 IN

15c.3 1, 5–6 1–6 Vmin

15c.4 None 1–7 Vmaj

15d.1 replacement o a test

parameter1, 5–8 1–6 IN

15d.2 5, 7, 10 1–6, 8 Vmin

15d.3 None 1–7 Vmaj

15e.1 tightening o an

acceptance criterion

1, 3, 9 1, 6 AN

15.1 relaxation o anacceptance criterion

1, 5–9 1, 6 IN

15.2 5, 7, 10 1, 6, 8 Vmin

15.3 None 1, 6–7 Vmaj




2. The deleted test has been demonstrated to be redundant with respect to theremaining tests.

3. The change is within the range o currently accepted acceptance criteria.

4. Anynewanalyticalproceduredoesnotconcernanovel,non-standardtechnique

orastandardtechniqueusedinanovelway.

5. For insoluble APIs there is no change in the polymorphic orm and wheneverparticle size is critical (including low-solubility APIs) there is no change in particle

size distribution acceptance criteria.

6. No additional impurity ound over the ICH identifcation threshold.

7. The change does not concern sterility testing.

8. The change does not involve the control o a genotoxic impurity.

9. The associated analytical procedure remains the same.10. The change has resulted rom a revision o the API manuacturer’s specifcations

and is accepted as part o an APIMF amendment.

11.NochangeisrequiredinFPPreleaseandshelf-lifespecications.

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121

Documentation required1. (S.4.1) A copy o the proposed API specications (o the FPP manuacturer) dated

and signed by authorized personnel and a comparative table o currently acceptedand proposed specications. In addition, i the change has resulted rom a revisionto the API manuacturer's specications, a copy o the API specications (o the APImanuacturer) dated and signed by authorized personnel and a comparative tableo currently accepted and proposed specications.

2. (S.4.2) Copies or summaries o analytical procedures, i new analytical proceduresare used.

3. (S.4.3) Copies or summaries o validation or verication reports issued by the FPP

manuacturer, i new analytical procedures are used.4. (S.4.3) Where an in-house analytical procedure is used and a pharmacopoeialstandardisclaimed,resultsofanequivalencestudybetweenthein-houseandpharmacopoeial methods.

5. (S.4.4)Descriptionofthebatches,certicatesofanalysisorbatchanalysisreport,and summary o results in tabular ormat, or at least one batch i new tests and/oranalytical methods are implemented.

6. (S.4.5) Justication o the proposed API specications (e.g. test parameters,acceptance criteria, or analytical procedures).

7. (P.2) Where changes have occurred to the particle size criteria o an insoluble API or

whereverparticlesizeiscritical,evidenceisprovidedthatthechangesdonotaectthe in vitro release properties and bioavailability o the FPP. In general, it is sufcientto provide multipoint comparative dissolution proles (in three media covering thephysiological range (pH 1.2 or (0.1N HCl), 4.5 and 6.8) without suractant) or onebatch o FPP manuactured using API that meets the proposed criteria; one batch o FPP manuactured using API that meets the currently accepted criteria; and data ontheFPPbatchusedintheregistrationbioequivalencestudy.However,iftheroutinedissolution medium contains a suractant, the applicant should contact WHO/PQPor advice. For changes to the polymorph o an insoluble API the applicant shouldcontact WHO/PQP or advice beore embarking upon any investigation.

8. Copy o the APIMF amendment acceptance letter.


be ulflled

Documentation

required

Reporting

type

16 Change to the analytical procedures used to control the API by the FPPmanuacturer involving:

16a change in an analyticalprocedure as a resulto a revision to the

ofcially recognizedpharmacopoeialmonograph to which theAPI is controlled.

None 1–3 AN

continues

Table continued

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8 1 , 2 0 1 3


16b change rom a currentlyaccepted in-house

analytical procedure to


in an ofcially recognized

pharmacopoeia or rom

the analytical procedure in

one ofcially recognized

pharmacopoeia to an

analytical procedure in

another ofcial recognizedpharmacopoeia

None 1–4 IN

16c.1 addition o an analytical

procedure

1–3 1–3 AN

16c.2 3, 8 1–3, 5 AN

16c.3 8 1–3, 5 Vmin

16c.4 None 1–3 Vmaj

16d.1 modication or

replacement o ananalytical procedure

1–6 1–4 AN

16d.2 2–3, 5–6, 8 1–5 AN

16d.3 1–3, 5–6 1–4 Vmin

16d.4 5–6, 8 1–5 Vmin

16d.5 None 1–4 Vmaj

16e.1 deletion o an analytical

procedure

6–7 1, 6 AN

16e.2 6, 8 1, 5, 6 IN

16e.3 None 1, 6 Vmaj


1.Anynewanalyticalproceduredoesnotconcernanovel,non-standardtechniqueor

astandardtechniqueusedinanovelway.

2. The change is not necessitated by ailure to meet specications resulting rom


3. No new impurities have been detected as a result o the use o the new analytical

method.

4.Themethodofanalysisisbasedonthesameanalyticaltechniqueorprinciple(e.g.changes to the analytical procedure are within allowable adjustments to column


rangesoradierenttypeofcolumnandmethod),andnonewimpuritiesaredetected.

Table continued

continues

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123

Conditions to be ulflled5. Comparative studies are available demonstrating that the proposed analytical

procedureisatleastequivalenttothecurrentlyacceptedanalyticalprocedure.


7.Thedeletedanalyticalprocedureisanalternativemethodandisequivalenttoa

currently accepted method.

8. The new or modifed analytical method is identical to that used by the API

manuacturer and has been accepted as part o an amendment to the associated

APIMF.


1. (S.4.1) Copy o the proposed API specifcations dated and signed by authorized

personnel and a comparative table o currently accepted and proposed specifcations.

2. (S.4.2) Copies or summaries o analytical procedures i new or signifcantly modifed

analytical procedures are used.

3. (S.4.3) Copies or summaries o validation or verifcation reports issued by the FPP

manuacturer i new or signifcantly modifed analytical procedures are used.

4. (S.4.4) Comparative analytical results demonstrating that the proposed analytical

proceduresareatleastequivalenttotheacceptedanalyticalprocedures.

5. A copy o the APIMF acceptance letter.

6. (S.4.5) Justifcation or the deletion o the analytical procedure, with supporting data.

3.2. S.6 Container-closure system


be ulflled

Documentation

required

Reporting

type

17a Change in the immediatepackaging (primary and

unctional secondary

components) or the storage

and shipment o the API

3, 4 1–2, 4 AN17b 1–2, 4 2–3 IN

17c 4 1–3 Vmin


1. Results demonstrate that the proposed primary packaging type is at least

equivalenttothecurrentlyacceptedprimarypackagingtypewithrespecttoits

relevant properties (e.g. including results o transportation or interaction studies,

and moisture permeability among others).2. The change does not concern a sterile API.

3. The change has previously been accepted through the APIMF procedure.

4. The change is not the result o stability issues.

Table continued

continues

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8 1 , 2 0 1 3


Documentation required1.(S.2.5)Evidenceofprocessvalidationand/orevaluationstudiesforsterilizationifdierentfromthecurrentprocess.

2. (S.6) Inormation on the proposed primary packaging (e.g. description andspecifcations) and data in ulfllment o condition 1.

3.(S.7.1)Resultsof(oracommitmenttostudyinthecaseofdemonstratedequivalentor more protective packaging) a minimum o 3 months o accelerated (andintermediate, as appropriate) and 3 months o long-term testing o the API in theproposed primary packaging type.

4. A copy o the APIMF amendment acceptance letter.


be ulflled

Documentation

required

Reporting

type

18 Change in the specifcations o the immediate packaging or the storage and

shipment o the API involving:

18a tightening o specifcation

limits

1–2 1 AN

18b addition o a testparameter

2–3 1–3 AN

18c deletion o a non-critical

parameter

2 1, 4 AN

18d any change (APIMF

procedure)

4 Novariationisrequired;



APIMF

Conditions to be ulflled1. The change is within the range o currently accepted limits.

2. The change is not necessitated by ailure to meet specifcations resulting romunexpected events arising during manuacture, or because o stability concerns.

3.Anynewanalyticalproceduredoesnotconcernanovel,non-standardtechniqueorastandardtechniqueusedinanovelway.



1. (S.4.5) Comparative table o currently accepted and proposed specifcations,

justifcation o the proposed specifcations.2.(S.4.2)Detailsofmethodandsummaryofvalidationofnewanalyticalprocedure.

3. (S.6) Certifcate o analysis or one batch.

4. Justifcation to demonstrate that the parameter is not critical.

Table continued

continues

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125



Reportingtype

19 Change to an analytical procedure on the immediate packaging o the API

involving:

19a minor change to an


1–3 1 AN

19b other changes to an


including additionor replacement o an


2–4 1 AN

19c deletion o an analytical

procedure

5 2 AN

19d any change (APIMF

procedure)

6 Novariationisrequired;



APIMF


1.Themethodofanalysisisbasedonthesameanalyticaltechniqueorprinciple(e.g.

changes to the analytical procedure are within allowable adjustments to column



2. Appropriate (re)validation studies have been perormed in accordance with the

relevant guidelines.

3.Comparativestudiesindicatethenewanalyticalproceduretobeatleastequivalent

to the currently accepted procedure.







1. (S.6) Comparative validation results demonstrating that the currently accepted and

proposedproceduresareatleastequivalent.2. Justifcation or deletion o the analytical procedure.

Table continued

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8 1 , 2 0 1 3


3.2. S.7 Stability


be ulflled

Documentation

required

Reporting

type

20 Change in the retest period or shel-lie o the API involving:

20a any change (APIMF

procedure)

4 4 IN

20b reduction 3 1–2 IN

20c extension 1–2 1–3 Vmin


1. No change to the primary packaging in direct contact with the API or to the

recommended condition o storage.

2. Stability data were generated in accordance with the currently accepted stability

protocol.


because o stability concerns.

4. The revised retest period has previously been accepted through the APIMF

procedure.


1. (S.7.1) Proposed retest period or shel-lie, summary o stability testing according to

currently accepted protocol and test results.

2. (S.7.2) Updated post-acceptance stability protocol and stability commitment and

justifcation o change, when applicable.

3. (S.7.3) Stability data to support the change.



be ulflled

Documentation

required

Reporting

type

21 Change in the labelled storage conditions o the API involving:

21a any change in storage

conditions (APIMF

procedure)

1 1 IN

21b any change in storage

conditions

2 2 Vmin


1. The revised storage conditions have previously been accepted through the APIMF

procedure.

continues

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127

Conditions to be ulflled2. The change is not necessitated by ailure to meet specifcations resulting rom




2. (S.7.1) Stability and/or compatibility test results to support the change to the

storage conditions.

3.2. P Drug product (or FPP)3.2. P.1 Description and composition of the FPP


be ulflled

Documentation

required

Reporting

type

22a Change in the composition

o a solution dosage orm

1–6 2, 4, 7, 9–10 IN

22b None 1–10 Vmaj

Conditions to be ulflled1. Theaectedexcipient(s)does/donotfunctiontoaectthesolubilityand/orthe

absorption o the API.

2. Theaectedexcipient(s)does/donotfunctionasapreservativeorpreservative

enhancer.

3. Nochangeinthespecicationsoftheaectedexcipient(s)ortheFPP.

4. No change in the physical characteristics o the FPP (e.g. viscosity, osmolality, pH).

5. The change does not concern a sterile FPP.

6. Theexcipientsarequalitativelythesame.Thechangeintheamount(or

concentration) o each excipient is within ±10% o the amount (or concentration)ofeachexcipientintheoriginallyprequaliedproduct.


1. Supporting clinical or comparative bioavailability data or justifcation or not

submittinganewbioequivalencestudyaccordingtothecurrentWHOguidelines

onbioequivalence.

2. (P.1)DescriptionandcompositionoftheFPP.

3. (P.2)Discussiononthecomponentsoftheproposedproduct(e.g.choiceof

excipients, compatibility o API and excipients, suitability studies on the packaging

system or the changed product).4. (P.3) Batch ormula, description o manuacturing process and process controls,

controls o critical steps and intermediates, process validation protocol and/or

evaluation.

Table continued

continues

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8 1 , 2 0 1 3


Table continued

continues

5. (P.4) Control o excipients, i new excipients are proposed.6. (P.4.5)Ifapplicable,eitheraCEPforanynewcomponentofanimalorigin

susceptibletoTSEriskor,whereapplicable,documentedevidencethatthespecic

sourceoftheTSEriskmaterialhasbeenpreviouslyassessedbyanNMRAintheICH

region or associated countries and shown to comply with the scope o the current

guidelines in the countries o the ICH region or associated countries. The ollowing

inormation should be included or each such material: name o manuacturer,

species and tissues rom which the material is derived, country o origin o the

source animals, and use o the material.

7. (P.5) Copies o FPP release and shel-lie specications and certicates o analysis

or a minimum o two pilot- or production-scale batches. I applicable, datato demonstrate that the new excipient does not interere with the analytical

procedures or the FPP.

8. (P.8.1) Results o stability testing generated on at least two pilot- or production-

scale batches with a minimum o 3 months o accelerated (and intermediate, as

appropriate) and 3 months o long-term testing.

9. (P.8.2) Updated post-acceptance stability protocol and stability commitment to

place the rst production-scale batch o each strength o the proposed product

into the long-term stability programme (bracketing and matrixing or multiple

strengths and packaging components could be applied, i scientically justied).

10. (R.1) Copies o relevant pages o blank master production documents with changes

highlighted, as well as relevant pages o the executed production document

or one batch and conrmation that there are no changes to the production

documents other than those highlighted.


be ulflled

Documentation

required

Reporting

type

23 Change in the colouring system or the favouring system currently used in the

FPP involving:

23a reduction or increase o

one or more components

o the colouring or the

favouring system

1–3, 6 1, 4, 6–7 AN

23b deletion, addition or

replacement o one or more

components o the colouring

or the favouring system

1–6 1–7 IN


1. No change in the unctional characteristics o the pharmaceutical orm e.g.disintegration time or dissolution prole.

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129

Conditions to be ulflled2. Any minor adjustment to the ormulation to maintain the total weight is made using

an excipient which currently makes up a major part o the FPP ormulation.

3. Specifcations or the FPP are updated only with respect to appearance, odour and/or taste or i relevant, deletion or addition o a test or identifcation.

4. Any new component must comply with section 3.2.P.4 o the WHO Guidelines onsubmission o documentation or a multisource (generic) fnished pharmaceutical product or the WHO Prequalifcation o Medicines Programme: quality part .9

5. Any new component does not include the use o materials o human or animaloriginforwhichassessmentofviralsafetydataisrequired,orisincompliancewith

the current WHO Guidelines on transmissible spongiorm encephalopathies in relationto biological and pharmaceutical products(www.who.int/biologicals)orEMA'sNoteor guidance on minimizing the risk o transmitting animal spongiorm encephalopathy agents via human and veterinary medicinal products (www.emea.europa.eu/ema) or anequivalentguidefromtheICHregionandassociatedcountries.

6.Whereapplicable,thechangedoesnotaectthedierentiationbetweenstrengthsandforpaediatricformulationsitdoesnotrequiresubmissionofresultsoftasteacceptability studies.


1. Sample o the FPP.2.(P.2)DiscussiononthecomponentsoftheFPP(e.g.compatibilityofAPIand

qualitativecompositionofthecolouringoravouringsystemifpurchasedasamixture, with specifcations, i relevant).

3.(P.4.5)EitheraCEPforanynewcomponentofanimaloriginsusceptibletoTSEriskor,whereapplicable,documentedevidencethatthespecicsourceoftheTSEriskmaterialhas been previously assessed by an NMRA in the ICH region or associated countries andshown to comply with the scope o the current guidelines in the countries o the ICHregion or associated countries. The ollowing inormation should be included or eachsuch material: name o manuacturer, species and tissues rom which the material is

derived, country o origin o the source animals, and use o the material.4. (P.5) Copies o revised FPP release and shel-lie specifcations and certifcates o analysis or a minimum o two pilot- or production-scale batches.

5. (P.5.3) I applicable, data to demonstrate that the new excipient does not intererewith the analytical procedures or the FPP.

6. (P.8.1) Results o stability testing generated on at least two pilot- or production-scale batches with a minimum o 3 months o accelerated (and intermediate, asappropriate) and 3 months o long-term testing.

7. (R.1) Copies o relevant sections o blank master production documents with changeshighlighted as well as relevant pages o the executed production documents or

one batch and confrmation that there are no changes to the production documentsother than those highlighted.

Table continued

continues

9 See footnote 3.

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8 1 , 2 0 1 3




Reportingtype

24 Change in weight o tablet coatings or capsule shells involving:

24a immediate-release oral FPPs 1–3 2–5 AN

24b gastro-resistant, modifed

or prolonged release FPPs

None 1–5 Vmaj


1. Multipoint in vitro dissolution profles o the proposed version o the product

(determined in the routine release medium on at least two batches o pilot- orproduction-scale), are similar to the dissolution profles o the biobatch.

2. Coating is not a critical actor or the release mechanism.

3. Specifcations or the FPP are updated only with respect to weight and dimensions,i applicable.


1.JusticationfornotsubmittinganewbioequivalencestudyaccordingtothecurrentWHOguidelinesonbioequivalence(Proposal to waive in vivo bioequivalencerequirements for WHO Model List of Essential Medicines immediate-release, solid oral

dosage forms, WHO Technical Report Series, No. 937, 2006, Annex 8).2. (P.2) Comparative multipoint in vitro dissolution profles in the routine release

medium (or media), on at least two batches o pilot- or production-scale o theproposed product versus the biobatch.

3. (P.5) Copies o revised FPP release and shel-lie specifcations and certifcates o analysis or a minimum o one pilot- or production-scale batch.

4. (P.8.1) Results o stability testing generated on at least one pilot- or production-scale batch with a minimum o 3 months o accelerated (and intermediate, asappropriate) and 3 months o long-term testing.

5. (R.1) Copies o relevant sections o blank master production documents with

changes highlighted as well as relevant pages o the executed productiondocuments or one batch and confrmation that there are no changes to theproduction documents other than those highlighted.


be ulflled

Documentation

required

Reporting

type

25 Change in the composition o an immediate-release solid oral dosage orm

including:

25a.1 replacement o asingle excipient with a

comparable excipient at

a similar concentration

1–5 1–10 Vmin

25a.2 None 1–10 Vmaj

Table continued

continues

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131



Reportingtype

25b.1 quantitativechangesin

excipients

1–4 1–4, 7–10 Vmin

25b.2 None 1–4, 7–10 Vmaj


1. No change in unctional characteristics o the pharmaceutical orm.

2. Onlyminoradjustments(seeAppendix2)aremadetothequantitative

composition o the FPP; any minor adjustment to the ormulation to maintain the

total weight is made using an excipient which currently makes up a major part o the FPP ormulation.

3. Stability studies have been started under conditions according to WHO Guidelines

on submission o documentation or a multisource (generic) fnished pharmaceutical

product or the WHO Prequalifcation o Medicines Programme: quality part 10 (with

indication o batch numbers) and relevant stability parameters have been assessed

in at least two pilot- or production-scale batches, satisactory stability data

covering at least 3 months are at the disposal o the applicant, and the stability

profle is similar to that o the currently accepted product.

4. The dissolution profle o the proposed product determined on a minimum o twopilot-scale batches is similar to the dissolution profle o the biobatch.

5. The change is not the result o stability issues and/or does not result in potential

safetyconcerns,i.e.dierentiationbetweenstrengths.




onbioequivalence.

2. (P.1)DescriptionandcompositionoftheFPP.

3. (P.2)Discussiononthecomponentsoftheproposedproduct(e.g.choiceof

excipients, compatibility o API and excipients), comparative multipoint in vitro

dissolution profles obtained on at least two batches o pilot- or production-scale

o the proposed product and the biobatch (depending on the solubility and

permeability o the drug, dissolution in the routine release medium or in multiple

media covering the physiological pH range).

4. (P.3) Batch ormula, description o manuacturing process and process controls,


evaluation.

5. (P.4) Control o excipients, i new excipients are proposed.

Table continued

continues

10 See footnote 3.

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8 1 , 2 0 1 3


Table continued

continues

Documentation required6. (P.4.5)Ifapplicable,eitheraCEPforanynewcomponentofanimalorigin

susceptibletoTSEriskor,whereapplicable,documentedevidencethatthespecic

sourceoftheTSEriskmaterialhasbeenpreviouslyassessedbyanNMRAintheICH

region or associated countries and shown to comply with the scope o the current

guidelines in the countries o the ICH region or associated countries. The ollowing

inormation should be included or each such material: name o manuacturer,

species and tissues rom which the material is derived, country o origin o the

source animals and its use.

7. (P.5) Copies o FPP release and shel-lie specifcations and certifcates o analysis

or a minimum o two pilot- or production-scale batches. I applicable, data

to demonstrate that the new excipient does not interere with the analytical

procedures or the FPP.

8. (P.8.1) Results o stability testing generated on at least two pilot- or production-

scale batches with a minimum o 3 months o accelerated (and intermediate, as

appropriate) and 3 months o long-term testing.


place the frst production-scale batch o each strength o the proposed product

into the long-term stability programme (bracketing and matrixing or multiple

strengths and packaging components could be applied, i scientifcally justifed).


changes highlighted as well as relevant pages o the executed production

documents or one batch, and confrmation that there are no changes to the

production documents other than those highlighted.


be ulflled

Documentation

required

Reporting

type

26 Change or addition o imprints, embossing or other markings, includingreplacement or addition o inks used or product markings and change in

scoring confguration involving:

26a changes in imprints,

embossing or other

markings

1–3 1–2, 5–6 IN

26b deletion o a scoreline 2–5 1, 5–6 IN

26c.1 addition o a scoreline 2–4 1, 3, 5–6 Vmin

26c.2 None 1, 3–6 Vmaj

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133

Table continued

continues

Conditions to be ulflled1. Any ink complies with section 3.2.P.4 o the WHO Guidelines on submission o

documentation or a multisource (generic) fnished pharmaceutical product or the

WHO Prequalifcation o Medicines Programme: quality part .11

2.Thechangedoesnotaectthestabilityorperformancecharacteristics(e.g.release

rate) o the FPP.

3. Changes to the FPP specifcations are those necessitated only by the change to the

appearance or to the scoring.

4. Addition or deletion o a score line rom a generic product is consistent with a

similarchangeinthecomparatorproductorwasrequestedbyWHO/PQP.5.ThescoringisnotintendedtodividetheFPPintoequaldoses.


1. Sample o the FPP.

2. (P.1.) Qualitative composition o the ink, i purchased as a mixture.

3.(P.2)Demonstrationoftheuniformityofthedosageunitsofthetabletportions,

wherethescoringisintendedtodividetheFPPintoequaldoses.

4.(P.2)Demonstrationofthesimilarityofthereleaserateofthetabletportionsfor

gastro-resistant, modifed or prolonged release products.5. (P.5) Copies o revised FPP release and shel-lie specifcations.


changes highlighted as well as relevant pages o the executed production

documentation or one batch and confrmation that there are no changes to the



be ulflled

Documentation

required

Reporting

type

27 Changeindimensionswithoutchangeinqualitativeorquantitative

composition and mean mass o:

27a tablets, capsules,

suppositories and

pessaries other than those

stated in change no. 27b

1–2 2–6 IN

27b gastro-resistant, modifed

or prolonged-release FPPsand scored tablets

1–2 1–6 Vmin

11 See footnote 3.

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8 1 , 2 0 1 3


Table continued

continues

Conditions to be ulflled1. Specifcations or the FPP are updated only with respect to dimensions o the FPP.

2. Multipoint in vitro dissolution profles o the current and proposed versions o the

product (determined in the routine release medium, on at least one batch o pilot-

or production-scale), are comparable.


1. For gastro-resistant, modifed or prolonged release FPPs, justifcation or not


onbioequivalence.Forscoredtabletswherethescoringisintendedtodividethe

FPPintoequaldoses,demonstrationoftheuniformityofthetabletportions.2. Sample o the FPP.

3.(P.2)Discussiononthedierencesinmanufacturingprocess(es)betweenthe

currently accepted and proposed products and the potential impact on product

perormance.

4. (P.2) Comparative multipoint in vitro dissolution profles in the routine release

medium, on at least one batch o pilot- or production-scale o the current and

proposed products.

5. (P.5) Copies o revised FPP release and shel-lie specifcations.

6. (R.1) Copies o relevant sections o blank master production documents

with changes highlighted as well as relevant pages o executed production

documentation or one batch and confrmation that there are no changes to the


3.2. P.3 Manufacture


be ulflled

Documentation

required

Reporting

type

28 Addition or replacement o a manuacturing site or part or all o the

manuacturing process or an FPP involving:

28a secondary packaging o

all types o FPPs

2–3 1 IN

28b primary packaging site o :

28b.1 solid FPPs (e.g. tablets,capsules), semi-solid FPPs

(e.g. ointments, creams)andsolutionliquidFPPs

2–4 1, 8 IN

28b.2 otherliquidFPPs(suspensions, emulsions)

2–5 1, 5, 8 IN

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Annex 3

135

Table continued

continues



Reportingtype

28c all other manuacturing

operations except batch

control and/or release

testing

1–3, 5 1–9 Vmin


1. No change in the batch ormula, description o manuacturing process and processcontrols,equipmentclassandprocesscontrols,controlsofcriticalstepsand

intermediates, or FPP specifcations.2. Satisactory inspection in the last three years either by WHO or an SRA.

3. Site appropriately authorized by an NMRA (to manuacture the pharmaceutical ormand the product concerned).

4. The change does not concern a sterile FPP.

5. Validation protocol is available or validation o the manuacturing process atthe new site has been successully carried out on at least three production-scalebatches in accordance with the current protocol.


1.Evidencethattheproposedsitehasbeenappropriatelyauthorizedinthelastthreeyears, or the pharmaceutical orm and the product concerned:

• acopyofthecurrentmanufacturingauthorization,aGMPcerticateorequivalentdocumentissuedbytheNMRA;

• aGMPstatementorequivalentissuedbyWHOoranSRA;

• date o the last satisactory inspection concerning the packaging acilities byWHO or an SRA in the last three years.

2.Dateandscope(withindicationastowhetherscopewase.g.product-specicorrelated to a specifc pharmaceutical orm) o the last satisactory inspection.

3. (P.2) Where applicable, forsemisolidandliquidformulationsinwhichtheAPIispresent in non-dissolved orm, appropriate validation data including microscopicimaging o particle size distribution and morphology.

4. (P.2) For solid dosage orms, data on comparative dissolution tests in the routinerelease medium, with demonstration o similarity o dissolution profles with thoseo the biobatch, perormed on one production-scale batch each rom current andproposed manuacturing sites and comparison with the biobatch results, withcommitment to generate dissolution profles on two more production-scale batches.

5. (P.3.5) Process validation reports or validation protocol (scheme) or three batcheso the proposed batch size, which includes comparative dissolution against the

biobatch results with 2 calculation as necessary.6. (P.5.1) Copies o release and shel-lie specifcations.

7. (P.5.4) Batch analysis data on one production-scale batch rom the proposed siteand comparative data on the last three batches rom the previous site.

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8 1 , 2 0 1 3


Table continued

Documentation required8. (P.8.2) Updated post-acceptance stability protocol and stability commitment to

place the frst production-scale batch o the FPP produced at the new site into the

long-term stability programme (bracketing and matrixing or multiple strengths and

packaging components could be applied, i scientifcally justifed).

9.(R.1)ExecutedproductiondocumentsforonebatchoftheFPPmanufacturedatthe

new site.


be ulflled

Documentation

required

Reporting

type

29 Replacement or addition

o a site involving batch

control testing

1–2 1–3 AN


1. Site is appropriately authorized by the NMRA and satisactorily inspected either by

WHO or an SRA.

2. Transer o methods rom the current testing site to the proposed testing site has

been successully completed.


1.Clearidenticationofthecurrentlyacceptedandproposedqualitycontrolsiteson

the letter accompanying the application.

2.DocumentedevidencethatthesiteisappropriatelyauthorizedbytheNMRAand

satisactorily inspected either by WHO or an SRA.

3.(P.5.3)Documentedevidenceofsuccessfultransferofanalyticalproceduresfromthe

current to the proposed site.


be ulflled

Documentation

required

Reporting

type

30 Change in the batch size o the FPP involving:

30a up to and including a

actor o 10 compared to

the biobatch

1–7 2, 5–6 IN

30b downscaling 1–5 2, 6 AN

30c other situations 1–7 1–7 Vmin


1.Thechangedoesnotaectthereproducibilityand/orconsistencyoftheproduct.

continues

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Annex 3

137

Conditions to be ulflled2. The change pertains only to immediate-release oral pharmaceutical orms and to

non-sterileliquidforms.

3. Changes to the manuacturing method and/or to the in-process controls are onlythosenecessitatedbythechangeinbatchsize,e.g.useofdierent-sizedequipment.

4. A validation protocol is available or validation o the manuacture o threeproduction-scale batches has been successully undertaken in accordance with thecurrent validation protocol.

5. The change is not necessitated by unexpected events arising during manuacture orbecause o stability concerns.

6.Thechangedoesnotrequiresupportinginvivodata.7. The biobatch size was at least 100 000 units in the case o solid oral dosage orms.


1. (P.2) For solid dosage orms: dissolution profle data, in the routine release medium,on a minimum o one representative production-scale batch and comparison o thedata with the biobatch results and one production-scale batch o the previous batchsize.Dataonthenexttwofullproduction-scalebatchesshouldbeavailableonrequestandshouldbereportediftheydonotmeetdissolutionprolesimilarity(f2)requirements.Forsemi-soliddosageforms(e.g.lotions,gels,creamsandointments),

containing the API in the dissolved or non-dissolved orm, comparative in vitro dataonmembranediusion(membranereleasetesting)shouldbesubmittedorbeavailableonrequest.

2. (P.3.5) Process validation reports or three batches o the proposed batch size orvalidation protocol (scheme).

3. (P.5.1) Copies o release and shel-lie specifcations.

4. (P.5.4) Batch analysis data (in a comparative tabular ormat) on a minimum o oneproduction-scale batch manuactured to both the currently accepted and theproposed batch sizes. Batch data on the next two ull production-scale batchesshouldbeavailableonrequestandshouldbereportedimmediatelybythesupplier

o the product, i outside specifcations (with proposed remedial action).5. (P.8.2) Updated post-acceptance stability protocol (approved by authorized

personnel) and stability commitment to place the frst production-scale batcho each strength at the proposed scale into the long-term stability programme(bracketing and matrixing or multiple strengths and packaging components couldbe applied, i scientifcally justifed).

6. (R.1) Copies o relevant sections o blank master production documents withchanges highlighted as well as relevant pages o the executed productiondocumentationforonebatch(ifmanufacturedasrequiredbydocumentation4)(above) and confrmation that there are no changes to the production documents

other than those highlighted.7. Supporting clinical or comparative bioavailability data or justifcation or not

submittinganewbioequivalencestudyaccordingtothecurrentWHOguidelinesonbioequivalence.

continues

Table continued

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8 1 , 2 0 1 3




Reportingtype

31a Change in the

manuacturing process o

the FPP

1–9 1–4, 6–7 AN

31b 1–3, 5–9 1–7 Vmin


1.Thechangedoesnotrequiresupportinginvivodata.

2.Nochangeinqualitativeandquantitativeimpurityproleorinphysicochemical

properties; dissolution profles are similar to those o the biobatch.

3. The manuacturing processes or the currently accepted and proposed products

use the same principles (e.g. a change rom wet to dry granulation, rom direct

compression to wet or dry granulation or vice versa would be considered a change

in manuacturing principle), the same processing intermediates and there are no

changes to any manuacturing solvent used in the process.

4.Thesameclassesofequipment,operatingprocedures,in-processcontrols(withno

widening or deleting o limits) are used or the currently accepted and proposed

products; no change in critical process parameters.

5. No change in the specifcations o the intermediates or the FPP.

6. The change is not necessitated by ailure to meet specifcations resulting romunexpected events arising during manuacture, or because o stability concerns.

7. The change does not involve packaging or labelling where the primary packaging

provides a metering and/or delivery unction.

8. The change does not concern a gastro-resistant, modifed or prolonged-release FPP.

9.ThechangedoesnotaectthesterilizationparametersofasterileFPP.




onbioequivalence.

2.(P.2)Discussiononthedevelopmentofthemanufacturingprocess;where

applicable:

• comparative in vitro testing, e.g. multipoint dissolution profles in the routine

release medium or solid dosage units (one production batch and comparative

data on one batch rom the previous process and the biobatch results; data on

thenexttwoproductionbatchesshouldbeavailableonrequestorreportedif

outside specifcation);

• comparativeinvitromembranediusion(membranereleasetesting)for

non-sterile semisolid dosage orms containing the API in the dissolved or non-dissolved orm (one production batch and comparative data on one batch

rom the previous process and the biobatch results; data on the next two

productionbatchesshouldbesubmittedorbeavailableonrequest);

continues

Table continued

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Annex 3

139

Table continued

continues

Documentation required• microscopic imaging o particles to check or visible changes in morphology

andcomparativesizedistributiondataforliquidproductsinwhichtheAPIis

present in non-dissolved orm.

3. (P.3) Batch ormula, description o manuacturing process and process controls,


evaluation.

4. (P.5) Specifcation(s) and certifcate o analysis or one production-scale batch

manuactured according to the currently accepted process and or a batch

manuactured according to the proposed process.

5. (P.8.1) Results o stability testing generated on at least two pilot batches (or

uncomplicated products, one pilot batch; the other one can be smaller) with a

minimum o 3 months o accelerated (and intermediate, as appropriate) and 3

months o long-term testing.


place the frst production-scale batch o the proposed product into the long-term

stability programme.


changes highlighted as well as executed production documentation or one batch

and confrmation that there are no changes to the currently accepted production

documents other than those highlighted.


be ulflled

Documentation

required

Reporting

type

32 Change to in-process tests or limits applied during the manuacture o the FPP

or intermediate involving:

32a tightening o in-processlimits

1–2, 5 1 AN

32b deletion o a test 2, 4 1, 6 AN

32c addition o new tests and

limits

2–3 1–6 AN

32d revision or replacement o

a test

2–3 1–6 IN

Conditions to be ulflled1. The change is within the range o acceptance limits.



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8 1 , 2 0 1 3


Conditions to be ulflled3.Anynewtestdoesnotconcernanovel,non-standardtechniqueorastandard

techniqueusedinanovelway.

4. The deleted test has been demonstrated to be redundant with respect to the

remaininganalyticalprocedures(e.g.colour)anddoesnotaectthecriticalquality

attributes o the product (e.g. blend uniormity, weight variation).

5. No change in the analytical procedure.


1. (P.5.1) Copy o the proposed in-process specifcations dated and signed by

authorized personnel and a comparative table o currently accepted and proposed

specifcations.

2. (P.5.2) Copies or summaries o analytical procedures, i new analytical procedures

are used.

3. (P.5.3) Copies or summaries o validation reports, i new analytical procedures are

used.

4. (P.5.3) Where an in-house analytical procedure is used and a pharmacopoeial

standardisclaimed,resultsofanequivalencestudybetweenthein-houseand

pharmacopoeial methods.

5.(P.5.4)Descriptionofthebatches,certicatesofanalysisforatleastonebatch

(minimum pilot-scale) and comparative summary o results, in tabular ormat, or

one batch using current and proposed methods, i new analytical procedures are

implemented.

6. (P.5.6) Justifcation or the addition or deletion o the tests and limits.

3.2. P.4 Control of excipients


be ulflled

Documentation

required

Reporting

type

33 Change in source o an

excipientfromaTSEriskto

a material o vegetable or

synthetic origin.

1 1 AN


1. No change in the excipient and FPP release and shel-lie specifcations.


1.Declarationfromthemanufactureroftheexcipientthatitisentirelyofvegetableor

synthetic origin.

Table continued

continues

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141



Reportingtype

34 Change in the specications or analytical procedures or an excipient involving:

34a deletion o a non-signicant

in-house parameter

2 1–3 AN

34b addition o a new test

parameter or analytical

procedure

2–3 1–2 AN

34c tightening o specicationlimits

1–2, 4 1–2 AN

34d change or replacement o


2–3 1–2 Vmin



2. The change is not necessitated by ailure to meet specications resulting rom


3.Anynewanalyticalproceduredoesnotconcernanovel,non-standardtechniqueorastandardtechniqueusedinanovelway.

4. No change in the analytical procedure.


1. Justication or the change.

2. (P.5) Comparative table o currently accepted and proposed specications,

justication o the proposed specications and details o procedure and summary

o validation o any new analytical procedure (i applicable).

3. Justication to demonstrate that the parameter is not critical.


be ulflled

Documentation

required

Reporting

type

35 Change in specications

o an excipient to comply

with an ofcially recognized

pharmacopoeia

1 1 AN


1.Nochangetothespecifcationsotherthanthoserequiredtocomplywiththe

pharmacopoeia (e.g. no change in particle size distribution).


1. Comparative table o currently accepted and proposed specications or the excipient.

Table continued

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3.2. P.5 Control of FPP


be ulflled

Documentation

required

Reporting

type

36a Change in the standard

claimed or the FPP

rom an in-house to an

ofcially recognized

pharmacopoeial standard

1–3 1–5 AN

36b Update to the

specications to comply

with an ofcially recognized

pharmacopoeial

monograph as a result o an

update to this monograph

to which the FPP is

controlled

None 1, 3, 5 AN


1. The change is made exclusively to comply with the ofcially recognizedpharmacopoeia.

2. No change to the specications that results in a potential impact on the

perormance o the FPP (e.g. dissolution test).

3. No deletion o or relaxation o any o the tests, analytical procedures or acceptance

criteria o the specications. Any deletion or relaxation o the tests should meet the

conditions o 37a or 37d and should ollow the corresponding reporting types.


1. (P.5.1) Copy o the proposed FPP specications dated and signed by authorized

personnel and a comparative table o currently accepted and proposed

specications.




3.(P.5.4)Descriptionofthebatches,certicatesofanalysisforatleastonebatch


one batch using current and proposed procedures, i new analytical procedures are

implemented.

4. (P.5.6) Justication or the proposed FPP specications.

5.(P.5.3)DemonstrationofthesuitabilityofthemonographtocontroltheFPP.

continues

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143



Reportingtype

37 Change in the specifcations o the FPP involving test parameters and

acceptance criteria:

37a deletion o a test

parameter

5 1, 6 AN

37b addition o a test

parameter

2–4, 7 1–6 AN

37c tightening o an


1–2 1, 6 AN

37d relaxation o an


2, 4, 6–7 1, 5–6 IN

37e replacement o a test

parameter

2–4, 6-7 1–6 IN







4. No additional impurity ound over the ICH identifcation threshold.

5. The deleted test has been demonstrated to be redundant with respect to the

remaining tests.

6.Thechangetothespecicationsdoesnotaectthestabilityand the perormance

o the product.



1. (P.5.1) Copy o the proposed FPP specifcations dated and signed by authorized

personnel and a comparative table o currently accepted and proposed

specifcations.


are used.

3. (P.5.3) Copies or summaries o validation reports, i new analytical procedures are

used.4. (P.5.3) Where an in-house analytical procedure is used and a pharmacopoeial



continues

Table continued

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8 1 , 2 0 1 3


Table continued

continues

Documentation required5.(P.5.4)Descriptionofthebatches,certicatesofanalysisforatleastonebatch


one batch using currently accepted and proposed procedures, i new analytical

procedures are implemented.

6. (P.5.6) Justication or the proposed FPP specications.


be ulflled

Documentation

required

Reporting

type

38 Change in the analytical procedures or the FPP involving:

38a deletion o an analytical

procedure

5 1, 6 AN

38b addition o an analytical

procedure

3–4, 6–7 1–5 AN

38c.1 modication or

replacement o an


1–4, 6–7 1–5 AN

38c.2 2–4, 6–7 1–5 Vmin

38d updating the analytical

procedure with an

ofcially recognized

pharmacopoeial

monograph as a result

o an update to that

monograph

None 1–5 AN

38e change rom an in-house

analytical procedure toan analytical procedure

in an ofcially recognized

pharmacopoeial

monograph or rom the

analytical procedure in

one ofcially recognized

pharmacopoeial

monograph to an


in another ofciallyrecognized

pharmacopoeial

monograph

2, 7 1–3, 5 IN

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Conditions to be ulflled1.Themethodofanalysisisbasedonthesameanalyticaltechniqueorprinciple(e.g.



rangesoradierenttypeofcolumnandmethod),andnonewimpuritiesare

detected.

2. Comparative studies demonstrate that the proposed analytical procedure is at least

equivalenttothecurrentlyacceptedanalyticalprocedure.





currently accepted analytical procedure.



7. No new impurities have been detected.


1. (P.5.1) A copy o the proposed FPP specifcations dated and signed by authorized

personnel and a comparative table o currently accepted and proposedspecifcations.


are used.

3. (P.5.3) Copies or summaries o validation reports, including verifcation data or

assay or purity methods, i new analytical procedures are used.




5.(P.5.4)Descriptionofthebatches,certicatesofanalysisforatleastonebatch(minimum pilot-scale) and comparative summary o results, in tabular ormat, or

one batch using currently accepted and proposed analytical procedures.

6. Justifcation or the deletion o the analytical procedure, with supporting data.

3.2. P.7 Container-closure system


be ulflled

Documentation

required

Reporting

type

39a Replacement or addition o

a primary packaging type

1 1–2, 4–6 Vmin

39b None 1–6 Vmaj

continues

Table continued

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8 1 , 2 0 1 3


Conditions to be ulflled1. The change does not concern a sterile FPP.


1. Samples o the product as packaged in the new container-closure system.

2.(P.2)Dataonthesuitabilityofthecontainer-closuresystem(e.g.extractable/

leachabletesting,permeationtesting,lighttransmission)demonstratingequivalent

or superior protection compared to the current packaging system. For changes to

unctional packaging, data to demonstrate the unctioning o the new packaging.

3. (P.3.5) For sterile FPPs, process validation and/or evaluation studies.

4. (P.7) Inormation on the proposed primary packaging type (e.g. description,materials o construction o primary packaging components, specifcations, and

results o transportation studies, i appropriate).

5. (P.8.1) Stability summary and conclusions, results or a minimum o two batches

o pilot- or production-scale, o 3 months o accelerated (and intermediate, as

appropriate) and 3 months o long-term testing and where applicable, results o

photostability studies.


place the frst production-scale batch o the proposed product into the long-term

stability programme, unless data were provided in documentation 5.


be ulflled

Documentation

required

Reporting

type

40 Change in the package size involving:

40a change in the number

o units (e.g. tablets,

ampoules, etc.) in a package

1–2 1–2 IN

40b.1 change in the fll weightor fll volume o non-

parenteral multidose

products

1–3 1–2 IN

40b.2 1–2 1–2 Vmin


1. The change is consistent with the posology and treatment duration accepted in the

SmPC.

2. No change in the primary packaging material.

3. No increase in the headspace or surace/volume ratio.


1. Justifcation or the new pack-size, indicating that the new size is consistent with the

dosage regimen and duration o use as accepted in the SmPC.

Table continued

continues

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147

Table continued

Documentation required2. (P.8.2) A written commitment that stability studies will be conducted in accordance

withtheWHOguidelinesforproductswherestabilityparameterscouldbeaected.


be ulflled

Documentation

required

Reporting

type

41 Change in the shape or dimensions o the container or closure or:

41a non-sterile FPPs 1–2 1–3 AN

41b sterile FPPs 1–2 1–4 Vmin


1.Nochangeinthequalitativeorquantitativecompositionofthecontainerand/or

closure.

2. The change does not concern a undamental part o the packaging material, which

couldaectthedelivery,use,safetyorstabilityoftheFPP.


1. Samples o the product packaged in the new container-closure system.

2. (P.7) Inormation on the proposed container-closure system (e.g. description,

materials o construction, and specifcations).

3. (P.8.1) In the case o changes to the thickness o a packaging component or or

sterile FPPs: stability summary and conclusions, results or a minimum o two

batches o pilot- or production-scale, o 3 months o accelerated (and intermediate,

as appropriate) and 3 months o long-term testing and, where applicable, results o

photostability studies. In the case o a change in the headspace or a change in the

surace/volume ratio or non-sterile FPPs, a commitment or the above studies.

4.(P.3.5)Evidenceofrevalidationstudiesinthecaseofterminallysterilizedproducts.

The batch numbers o the batches used in the revalidation studies should be

indicated, where applicable.


be ulflled

Documentation

required

Reporting

type

42 Changeinqualitativeand/orquantitativecompositionoftheimmediate

packaging material or:

42a solid FPPs 1–3 1–3 IN

42b semisolidandliquidFPPs 1–3 1–3 Vmin

continues

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8 1 , 2 0 1 3


Conditions to be ulflled1. The change does not concern a sterile FPP.

2. No change in the packaging type and material (an example o an allowable change

is blister to blister).

3.Therelevantpropertiesoftheproposedpackagingareatleastequivalenttothose

o the currently accepted material.


1.(P.2)Datademonstratingthesuitabilityoftheproposedpackagingmaterial(e.g.

extractable/leachable testing, light transmission, permeation testing or oxygen,carbon dioxide, and moisture).

2. (P.7) Inormation on the proposed packaging material (e.g. description, materials o

construction, and specifcations).

3. (P.8.1) Stability summary and conclusions, results o (or a commitment to study in

thecaseofdemonstratedequivalentormoreprotectivepackaging)aminimum

o two batches o pilot- or production-scale, o 3 months o accelerated (and

intermediate, as appropriate) and 3 months o long-term testing and, where

applicable, results o photostability studies.


be ulflled

Documentation

required

Reporting

type

43 Change in the specifcations o the immediate packaging involving:

43a tightening o specifcation

limits

1–2 1 AN

43b addition o a test parameter 2–3 1–2 AN

43c deletion o a non-critical

parameter

2 1, 3 AN








1. (P.7) Comparative table o currently accepted and proposed specifcations,

justifcation o the proposed specifcations.

continues

Table continued

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149

Documentation required2.(P.7)Descriptionoftheanalyticalprocedureandsummaryofvalidationofthenew

analytical procedure.

3.Documentationtodemonstratethattheparameterisnotcritical.


be ulflled

Documentation

required

Reporting

type

44 Change to an analytical procedure on the immediate packaging involving:

44a minor change to an


1–3 1 AN

44b other changes to an


including addition

or replacement of an


2–4 1 AN

44c deletion of an analytical

procedure

5 2 AN


1.Themethodofanalysisisbasedonthesameanalyticaltechniqueorprinciple(e.g.




2. Appropriate (re)validation studies have been performed in accordance with the

relevant guidelines.

3.Comparativestudiesindicatethenewanalyticalproceduretobeatleastequivalentto the former procedure.






1.(P.7)Descriptionofthemethodandcomparativevalidationresultsdemonstrating

thatthecurrentlyacceptedandproposedmethodsareatleastequivalent.2.Documentationtodemonstratetheequivalenceofthedeletedmethodanda


Table continued

continues

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Table continued



Reportingtype

45 Change in any part o

the (primary) packaging

material not in contact with

the FPP ormulation (e.g.

colourofip-ocaps,colour

code rings on ampoules, or

change o needle shield).

1 1–2 IN


1. The change does not concern a undamental part o the packaging material, which

aectsthedelivery,use,safetyorstabilityoftheFPP.


1. (P.7) Inormation on the proposed packaging material (e.g. description, materials o

construction, and specifcations).

2. Sample o the FPP.


be ulflled

Documentation

required

Reporting

type

46 Change to an administration or measuring device that is not an integral part

o the primary packaging (excluding spacer devices or metered dose inhalers)

involving:

46a addition or replacement 1, 2 1–2 IN

46b deletion 3 3 IN

Conditions to be ulflled1.Theproposedmeasuringdeviceisdesignedtoaccuratelydelivertherequireddose

or the product concerned in line with the posology, and results o such studies are

available.

2. The proposed device is compatible with the FPP.

3. The FPP can be accurately delivered in the absence o the device.


1.(P.2)Datatodemonstrateaccuracy,precisionandcompatibilityofthedevice.

2. Sample o the device.3. Justifcation or the deletion o the device.

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151

3.2. P.8 Stability


be ulflled

Documentation

required

Reporting

type

47 Change in the shel-lie o the FPP (as packaged or sale) involving:

47a reduction 3 1–3 IN

47b extension 1–2 1–3 Vmin


1. No change to the primary packaging type in direct contact with the FPP and to therecommended conditions o storage.

2. Stability data were generated in accordance with the currently accepted stability

protocol.




1. (P.5.1) Copy o the currently accepted shel-lie specications.

2. (P 8.1) Proposed shel-lie, summary o long-term stability testing according

to currently accepted protocol and test results or a minimum o two pilot- or

production-scale batches or a period sufcient to support the proposed shel-lie.

3. (P.8.2) Updated post-acceptance stability protocol and stability commitment and

justication o change.


be ulflled

Documentation

required

Reporting

type

48 Change in the in-use period o the FPP (ater rst opening or ater

reconstitution or dilution):

48a reduction 1 1 IN

48b extension None 1–2 Vmin





1. (P 8) Proposed in-use period, test results and justication o change.

2. (P 5.1) Copy o currently accepted end o shel-lie FPP specications and, where

applicable, specications ater dilution or reconstitution.

continues

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Reportingtype

49 Change in the labelled

storage conditions o the

FPP (as packaged or sale),

the product during the in-

use period or the product

ater reconstitution or

dilution

1 1–2 Vmin

Conditions to be ulflled1. The change is not necessitated by ailure to meet specifcations resulting rom



1. (P.8.1) I applicable, stability and/or compatibility test results to support the change

to the storage conditions.

2. (P.8.2) Updated post-acceptance stability protocol and stability commitment and

justifcation o change.

Table continued

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Appendix 1

Examples of changes that make a new application orextension application necessary


be ulflled

Documentation

required

Reporting

type

1. Change of the API to a

dierentAPI2. Inclusion of an additional API

in a multicomponent product

3. Removal of one API from a

multicomponent product

4. Change in the dose and/or

strength of one or more APIs

5. Change from an immediate-

release product to an

extended or delayed-releasedosage form or vice versa

6.Changefromaliquidtoa

powder for reconstitution or

vice versa

7. Changes in the route of

administration

None 1 New

application/extension

application


None


1.DocumentsinfullmentoftherequirementsoutlinedintheWHO Guidelines on

submission o documentation or a multisource (generic) fnished pharmaceutical

product or the WHO Prequalifcation o Medicines Programme: quality part .12

12 See footnote 3.

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Ap p e n dix 2

Changes to excipients

Excipient Percentage excipient (w/w) out of total

target dosage form core weight

Filler ± 5.0

Disintegrant

• starch• other

± 3.0± 1.0

Binder ± 0.5

Lubricant

• Ca or Mg Stearate

• other

± 0.25

± 1.0

Glidant

• talc

• other

± 1.0

± 0.1

■ Tese percentages are based on the assumption that the active

pharmaceutical ingredient (API) in the nished pharmaceutical

product (FPP) is ormulated to 100.0% o label/potency declaration.

Te total additive efect o all changes to excipients should be not more

than 5.0% relative to the target dosage orm weight (e.g. in a product

consisting o API, lactose, microcrystalline cellulose and magnesium

stearate, the lactose increases by 2.5% and microcrystalline cellulosedecreases by 2.5%).

■ I an excipient serves multiple unctions (e.g. microcrystallinecellulose as a ller and as a disintegrant), then the mostconservative recommended range should be applied (e.g. ± 1.0% ormicrocrystalline cellulose should be applied in this example). I awider range is proposed, scientic justication and supporting datashould be provided to demonstrate that the wider range will not

afect the other unction o the excipient.

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Annex 4

Collaborative procedure between the World HealthOrganization Prequalifcation o Medicines Programmeand national medicines regulatory authorities in theassessment and accelerated national registration o WHO-prequalifed pharmaceutical products

1. Defnitions 156

2. Background inormation 156

3. Principles o collaboration 158

4. Steps in the collaboration or national registration o a

pharmaceutical product 163

5. Collaboration mechanisms or post-registration variations 168

6. Withdrawals, suspensions or delistings o prequalifed pharmaceutical

products and national deregistrations 169

Appendix 1. NMRA participation agreement and undertaking or NMRA ocal point(s) 170

Appendix 2. Consent o WHO prequalifcation holder or WHO to share inormation with

NMRA confdentially under the Procedure 179

Appendix 3. Expression o interest to NMRA or the assessment and accelerated national

registration, acceptance by NMRA and notifcation o procedure outcomes 181

Appendix 4. Report on post-registration actions in respect o a product registered under

the Procedure 187

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1. Defnitions

Collaborative procedure (Procedure)Procedure or collaboration between the WHO Prequalication o MedicinesProgramme (WHO/PQP) and interested national medicines regulatory authorities(NMRAs) in the assessment and accelerated national registration o WHO-prequalied pharmaceutical products.

Participating authorities or participating NMRAsNMRAs that voluntarily agree to implement this collaborative procedure and

accept the task o processing applications or registration o WHO-prequaliedpharmaceutical products in accordance with the terms o the Procedure. A list o participating authorities is posted on the WHO/PQP web site (http://www.who.int/prequal/).

2. Background inormation

National assessment o applications or registration o pharmaceutical products

(marketing authorization) is the key regulatory process that enables NMRAs toevaluate and monitor the quality, saety and ecacy o pharmaceutical products.For most countries the approach to registration o pharmaceutical products is acombination o two components:

■ the NMRA's own assessment o application documentation combinedwith verication o compliance with relevant good practices by inspections (mostly ocusing on good manuacturing practices(GMP) and inspections o manuacturing sites);

■ consideration by the NMRA o decisions and outcomes o assessments and inspections made by NMRAs in other countries.

Consideration o the outcomes o assessments and inspections by trusted authorities substantially contributes to savings in regulatory resourcesand improvements in the quality o regulatory decisions, while retaining theprerogative o NMRAs to conclude their assessment by sovereign decisions,which refect their own judgement o the benet–risk balance as it relates to theirspecic country situation and the legislation in place.

Taking into consideration the regulatory decisions o other NMRAsrequires setting up a system that will permit:

■ identication o reerence authorities whose regulatory decisionsare based on acceptable standards and identication o documents

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associated with such regulatory decisions, which are relevant tothe regulatory environment in the country wishing to rely on such

decisions; ■ assurance that the product or which the decision has been taken by

the reerence NMRA is identical to the product being assessed, or, i it is not identical, that a clear understanding exists o the diferencesbetween the products subjected to assessment in the two regulatory environments;

■ ecient use o available scientic expertise and human and nancialresources to decide, with reasonable certainty, on the benet–risk

prole o an evaluated pharmaceutical product when used in a givencountry;

■ the choice by each NMRA o the approaches that will make best useo the resources, workload and competence o individual NMRAs.Approaches could range rom completely independent data reviewsand inspections to adoption o regulatory decisions o trustedauthorities without any urther scientic review. A pragmaticapproach is to assess only those areas which relate to use o theproduct in the country concerned and where ailure to comply with

regulatory standards could pose health risks. In the other areas, theoutcomes o trusted authorities may be adopted.

Tis Procedure is based on the above-mentioned considerations. In linewith the Procedure or prequalifcation o pharmaceutical products,1 it aims atproviding a convenient tool or NMRAs wishing to enhance their pre-marketingevaluation and registration system by taking advantage o the scientic assessmentwork conducted by WHO/PQP. Te present procedure is complementary tothe WHO/PQP collaboration procedure with NMRAs in inspection activities

(http://www.who.int/prequal, “Inspections”).It is expected that enhanced collaboration and inormation exchangebetween NMRAs and WHO/PQP will benet both partners. Subject to theagreement o the WHO prequalication holders concerned, NMRAs will gainaccess to assessment outcomes that are not in the public domain and that havebeen prepared in conormity with the WHO recommended standards on whichthe Procedure or prequalifcation o pharmaceutical products is based. Suchreports will help NMRAs to make their decisions and may also assist in educatingnational regulatory staf. At the same time, eedback rom NMRAs on the

inormation and documentation received rom WHO/PQP under the Procedure

1 Procedure or prequalifcation o pharmaceutical products. In: WHO Expert Committee on Specifcations or Pharmaceutical Preparations. Forty‑fth report . Geneva, World Health Organization, 2011 (WHO TechnicalReport Series, No. 961), Annex 10.

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will allow WHO/PQP to improve its work and to ensure that the outcomes o prequalication assessments are relevant to NMRAs. As a consequence patients

will benet rom this collaboration by gaining aster access to medicines whichhave been ound acceptable in principle or procurement by United Nationsagencies. Depending on available resources, participating authorities may begiven the opportunity to participate in the assessment process and in inspectionsorganized by WHO/PQP.

Tis collaborative procedure also benets manuacturers o prequaliedmedicines through aster and better harmonized regulatory approvals inparticipating countries. Tis Procedure, when combined with the CollaborationProcedure with NMRAs in inspection activities, may also alleviate the burden o

national inspections on manuacturers.

3. Principles of collaboration

3.1 Tis collaborative procedure is limited to those pharmaceutical productsthat have been assessed and inspected by WHO/PQP in line with theprocedures and standards available at www.who.int/prequal (“Inormationor applicants”) and have been ound to be acceptable in principle orprocurement by United Nations agencies as listed in the List o WHO prequalifed medicines available at www.who.int/prequal. It is not, however,applicable to medicines which have been listed as prequalied on the basiso approval by stringent regulatory authorities.2 Although it is expected thatthe Procedure will mostly serve to accelerate the assessment and registrationo multisource (generic) pharmaceutical products,3 it is also applicableto any pharmaceutical product or which the saety and efcacy has beendocumented to WHO/PQP by the submission o preclinical and clinicaldata. Te Procedure has three major stakeholders: WHO/PQP, interestedNMRAs and those WHO prequalication holders/applicant4 who agreethat this procedure is used or applications or national registration o theirWHO-prequalied product submitted to an NMRA.

2 Products listed as prequalifed according to the procedures described in the Guidelines on submissiono documentation or prequalifcation o innovator fnished pharmaceutical products approved by stringent regulatory authorities.

3 Guideline on submission o documentation or prequalifcation o multisource (generic) fnished pharmaceutical products (FPPs) approved by stringent regulatory authorities (http://www.who.int/prequal/); and in: WHOExpert Committee on Specifcations or Pharmaceutical Preparations. Forty‑fth report . Geneva, World HealthOrganization, 2011 (WHO Technical Report Series, No. 961), Annex 11.

4 I the applicant or national registration is not the same as the WHO prequalifcation holder, the WHOprequalifcation holder must confrm to the NMRA and WHO/PQP by an authorization letter (as per thetemplate annexed to Appendix 3, Part A) that the applicant is acting or, or pursuant to rights derived rom,the WHO prequalifcation holder and that the prequalifcation holder agrees with the application o theprocedure in the country concerned.

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3.2 WHO/PQP and participating authorities receive applications or the samepharmaceutical product. Within the context o this Procedure, the same

pharmaceutical product is characterized by:

■ the same product dossier;5

■ the same manuacturing chain, processes and control o materials;

■ the same active pharmaceutical ingredient (API) and fnishedpharmaceutical product (FPP) specifcations;

■ the same essential elements o product inormation.6

3.3 WHO/PQP, with the agreement o the WHO prequalifcation holder, sharesthe ull outcome, o prequalifcation assessments and inspections, includingfnal assessment and inspection reports, with participating authorities, underappropriate obligations o confdentiality and restrictions on use (see below).As regards sharing the outcomes o assessments and inspections, only dataowned by the WHO prequalifcation holder are shared. Sharing o any otherdata is subject to additional agreement o the data owners concerned.

3.4 For the purpose o this collaborative procedure, participating authoritiesaccept the product documentation and reports, in the ormat in which

they are routinely prepared by WHO in accordance with the Procedure or prequalifcation o pharmaceutical products published on WHO/PQP's website at www.who.int/prequal, and as Annex 10 in WHO Technical ReportSeries, No. 961. It should be noted, however, that participating authoritiesmay require applicants to comply with specifc requirements or localregulatory review. Each participating authority should make such specifcrequirements public.

3.5 Fees to be paid by the applicants to participating authorities will continue

to ollow standard national procedures. Similarly, the submission by manuacturers o samples or laboratory testing – i required – will continueto ollow standard procedures as defned in national legislation and/or asdefned by national regulatory authorities.

5 Only the technical data included in the dossier must be the same. There may be country-specicdiferences in administrative data, or i required by NMRAs under exceptional circumstances, additionaltechnical data can be provided (e.g. bioequivalence with a country-specic comparator).

6 The essential elements o product inormation include in particular the indications, contraindications,posology (dosing), special warnings and precautions or use, adverse reactions, storage conditions,primary packaging and shel-lie. Diferences in brand name, the name o applicant or prequalicationholder, language, ormat and degree o detail o the product inormation, labelling o internal and externalpackaging, among others, are not considered essential or the purposes o this procedure. The language o the product inormation may be diferent as long as the inormation content is the same as that approvedby WHO/PQP.

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3.6 Consistent with the terms o Appendix 1A and Appendix 3, Part B, each

participating authority commits itsel:

■ to treat any inormation and documentation provided to it by

WHO/PQP pursuant to this Procedure as condential in accordance

with the terms o Appendix 1A, and to allow access to such

inormation and documentation only to persons:7

– who have a need to know or the purpose o the assessment and

accelerated registration o the product in question in the country

and any post-registration processes that may be required;

– who are bound by condentiality undertakings in respect o such

inormation and documentation which are no less stringent than

those reproduced in Appendix 1A;

– to issue its national regulatory decision on a given prequalied

pharmaceutical product (whether positive or negative) within

90 calendar days afer being given access to the condential

inormation and documentation concerning each product.8

Tese commitments are provided by each participating authority toWHO/PQP in writing by entering into the agreement or participation in

this Procedure as reproduced in Appendix 1A and are reconrmed or each

pharmaceutical product or which collaboration is sought (see Appendix 3,

Part B).

Each participating NMRA nominates a maximum o two ocal points

who will access the restricted-access web site, through which WHO/PQP will

communicate all condential inormation and documentation. Focal points

designated by the NMRA must sign the undertaking reproduced in Appendix 1B

beore they will be granted access to the restricted-access web site. Any change in

designated ocal points must be communicated to WHO/PQP in writing without

delay and must be accompanied by an undertaking (Appendix 1B) signed by the

new ocal point(s).

7 This includes the ocal point(s) and all other persons in the NMRA who have access to any inormationand documentation provided by WHO/PQP.

8 Participating authorities should issue their national regulatory decisions at the earliest opportunity aterbeing given access to the confdential inormation and documentation on a given prequalifed product.Although a time limit o 90 days is defned in the Procedure, the decision should normally be taken within60 days. This deadline can be extended to a maximum o 90 days i predefned dates o technical ordecision-making meetings do not allow a participating authority to issue its decision within 60 days. I aparticipating authority does not issue its decision within 90 days and does not communicate valid reasonsor the delay to WHO/PQP, WHO/PQP will ollow up with the head o the NMRA to clariy the situation.

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3.7 Te decision whether or not to register a given product in a particularcountry remains the prerogative and responsibility o each participating

authority. Accordingly, a participating authority may come to a diferentconclusion rom that reached by WHO/PQP. Within 30 calendar days o having taken its decision, the participating authority reports this decision,together with the dates o submission and registration and, i applicable,any deviations rom the WHO/PQP's decision on prequalication and thereasons or such deviations,9 to WHO/PQP. It does so through the restricted-access web site by completing the orm in Part C o Appendix 3. Te NMRAprovides a copy o the completed orm to the applicant.

3.8 Participation by WHO prequalication holders/applicants is voluntary,through the submission to a participating NMRA o the expression o interestreproduced in Part A o Appendix 3. For each product, such participationwill be subject to the WHO prequalication holder/applicant accepting theterms o this Procedure, including the condential exchange o inormationand documentation between WHO/PQP and the NMRA (see Appendix 2).Te WHO prequalication holder/applicant can cease participation in thisprocedure at any time provided that he or she inorms WHO/PQP and theparticipating NMRAs in writing o his or her decision. In such a case theNMRA shall cease all use o the inormation disclosed to it or the respectiveproduct(s) as per the terms o the participation agreement (see Appendix 1).

3.9 Te requirements and procedures in case o a variation (as dened in theWHO guidelines on variations to a prequalifed product 10) may difer betweenNMRAs and WHO/PQP. Te present collaborative procedure includes a

variation procedure (see below under “Post-registration processes”) which isaimed at promoting consistency between variations accepted by WHO/PQPand variations accepted by participating authorities. Tere could be situationsin which a manuacturer o a WHO-prequalied pharmaceutical productsubmits a variation application to a participating authority and not to WHO/PQP, or vice versa. In such a case, the conditions o the national registration,which were initially “harmonized” with the WHO prequalication decision,

9 This reers to a decision not to approve the marketing authorization o a WHO-prequalied product and toa decision to approve the marketing authorization, but with deviations in indications, contraindications,posology (dosing), special warnings and precautions or use, adverse drug reactions, storage conditionsand shel-lie. Diferences in brand name, name o applicant or prequalication holder, ormat o productinormation, level o detail o product inormation, labelling o internal and external packaging andlanguage o product inormation are not considered to be deviations rom the prequalication conclusions.

10 WHO guidelines on variations to a prequalied product. In: WHO Expert Committee on Specifcations or Pharmaceutical Preparations. Forty‑seventh report . Geneva, World Health Organization, 2013 (WHO TechnicalReport Series, No. 981), Annex 3 (and any updates thereto).

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may become essentially diferent through the product lie-cycle. In such acase a pharmaceutical product registered and procured in a participating

country would no longer be the same as the “WHO-prequalied” productbecause the specications and/or other essential parameters would nolonger be the ones accepted by WHO/PQP. As a result, applicants arerequired to submit the variations which are submitted to WHO/PQPwithout delay to participating authorities, and participating authorities areencouraged to ollow the outcomes o the WHO variation procedures ornationally-approved WHO-prequalied products. WHO/PQP will inormthe NMRA which registered individual prequalied products, through therestricted-access web site, about variations to the prequalication status o such products, i and when regulatory action is deemed to be justied. I a national variation procedure results in the nationally registered productbeing no longer the same11 as the WHO-prequalied product, or in the eventthat a variation o a WHO-prequalied product is not ollowed by the same

variation o the nationally registered product, the participating authority inorms WHO/PQP o the situation by submitting the orm in Appendix 4,clearly speciying the deviations. Other participating NMRAs, which haveregistered the WHO-prequalied product in question pursuant to this

Procedure, will be made aware o such deviations through the restricted-access web site. In addition, i the act that a WHO-prequalied product hasbeen registered in a particular country pursuant to this Procedure has beenmade public, any subsequent deviations should also be made public.

3.10 I a prequalied product is withdrawn by the WHO prequalicationholder, or is suspended or delisted by WHO/PQP, WHO/PQP will inormeach participating authority which has approved, or is in the process o reviewing, the product pursuant to this collaborative procedure, o thewithdrawal, suspension or delisting and the reasons or taking this action,through the restricted-access web site and subject to the obligations o condentiality contained in Appendix 1A. Similarly, when an NMRAderegisters or suspends the registration o a prequalied pharmaceuticalproduct or any reason, it will inorm WHO/PQP o this decision and o itsreasons through the restricted-access web site. Other participating NMRAswhich have registered the WHO-prequalied product in question pursuantto this Procedure will be made aware o such national deregistration orsuspension through the restricted-access web site. In addition, i the act

11 Within the context o this Procedure, the same pharmaceutical product is characterized by the sameproduct dossier, the same manuacturing chain, processes and control o materials, the same APIand FPP specifcations and the same essential elements o product inormation, as urther described inparagraph 3.2 above.

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that a WHO-prequalied product has been registered in a country pursuantto this Procedure has been made public, any subsequent deregistration or

suspension should also be made public.

3.11 Participation in this Procedure does not exempt applicants or nationalregistration and holders o national registration rom the respectivenational regulatory requirements. Participating authorities retain the rightto assess submitted data and organize site inspections to the extent they deem appropriate.

4. Steps in the collaboration for nationalregistration of a pharmaceutical product12

4.1 Te applicant submits the product dossier or a WHO-prequaliedpharmaceutical product to a participating NMRA. Te technical part o the dossier is updated to refect the data submitted to WHO/PQP duringthe initial prequalication procedure, and consecutive variation proceduresand requalication (where applicable). Te applicant must provide theparticipating authority with:

■ an application dossier complying with established nationalrequirements, including the same technical inormation as thatsubmitted to WHO/PQP. o the extent that national regulatory requirements allow, the technical part o the dossier will be identicalto the current version o the WHO/PQP dossier;

■ an expression o interest reproduced in Part A o Appendix 3;

■ country-specic data;

■ any ees that may be payable to the NMRA pursuant to national

requirements.

Wherever possible, to minimize the workload o the NMRA and acilitatethe process, applicants should ensure that they express their interest to usethe Procedure (Appendix 3, Part A) to the NMRA and to WHO/PQP beoresubmitting a national application or registration. I acceptable to NMRAs,not only should the technical content o the dossiers be the same, but also theormat in which data are presented should closely ollow the common technicaldocument (CD) ormat in which dossiers are submitted to WHO/PQP.

In situations where the applicant wishes to apply the Procedure to anapplication which is already pending within the NMRA, the applicant should

12 In addition, to complement the steps of this collaborative procedure, joint inspections may be arrangedunder the collaborative procedure for joint inspections posted on the WHO/PQP web site (www.who.int/prequal, “Inspections”).

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rst update the dossier to ensure that the technical part o the inormation is thesame as that submitted to WHO/PQP. It is the decision o individual NMRAs

whether to apply the Procedure in such cases.

4.2 For each application under this Procedure, WHO/PQP is inormed by the WHO prequalication holder/applicant about the submission to theparticipating NMRA by providing a copy o completed Appendix 3, PartA. Te WHO prequalication holder provides WHO at this time with itswritten consent or WHO/PQP to provide the product-related inormationin compliance with the applicable condentiality requirements to theNMRA o the country concerned (see Appendix 2).

4.3 Te participating NMRA inorms WHO/PQP and the respective applicanto each application which it accepts or declines to include in this Procedure,and requests WHO/PQP to provide it with the necessary inormationand documentation (Appendix 3, Part B). Te Procedure applies only toapplications that the NMRA has accepted as complete.

4.4 Within 30 calendar days o receipt o the above-mentioned request WHO/PQP shares the most recent product-related inormation and assessment

and inspection outcomes through the restricted-access web site with theparticipating authority. Tis inormation is subject to the obligationso condentiality and restrictions on use and may include assessmentreport(s), variation assessment report(s) i applicable, ull inspectionreport(s) o the most recent inspection(s) and the letter o prequalicationor requalication. At the request o the participating authority, WHO/PQPprovides explanations and/or more detailed inormation.

4.5 Afer receiving the inormation and documentation rom WHO/PQP, the

participating authority undertakes an accelerated assessment o the productin question. For each application, the participating authority is requiredto issue the relevant national decision within 90 calendar days rom theday it received access to the complete prequalication documentation.Within 30 days o having taken its decision, the participating authority reports this decision, together with an indication o the dates o submissionand registration, and, i applicable, any deviations rom the WHOprequalication conclusion and the reasons or such deviations, to WHO/PQP through the restricted-access web site. Tis report is provided to WHO/

PQP using Part C o Appendix 3 and is copied to the applicant. WHO/PQPlists pharmaceutical products registered according to this Procedure by participating NMRAs on its public web site. Te steps in the collaborationor national registrations o a pharmaceutical product are summarized inFigure 1.

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Figure 1

Flowchart showing the principal steps of the collaborative procedure

The national medicines regulatory authority (NMRA) confrms to the WHO

PrequalicationofMedicinesProgramme(WHO/PQP)itsinterestinparticipating

in the collaborative procedure and nominates ocal point(s) or access to the

restricted-access web site. The NMRA completes, signs, and submits to WHO/PQP,

the agreement reproduced in Appendix 1A. The ocal person(s) who are nominated

to access the restricted-access web site complete and submit the undertaking

reproduced in Appendix 1B, to WHO/PQP.

Appendix 1, Part A and Appendix 1, Part B

WHO/PQP lists the participating NMRAs on its public web site.

Registration process

TheapplicantsubmitstheapplicationfornationalregistrationoftheWHO-prequalied

pharmaceutical product to the participating authority, and inorms the authority o

its interest in ollowing the collaborative procedure by completing the expression o

interest reproduced in Appendix 3, Part A. I the applicant or national registration is

notthesameastheWHOprequalicationholder,theWHOprequalicationholder

confrms to the NMRA and WHO/PQP by an authorization letter (as per the orm

annexed to Appendix 3, Part A) that the applicant is acting or, or pursuant to rights

derivedfrom,theWHOprequalicationholderandthattheprequalicationholder

agrees with the application o the procedure in the country concerned.

Appendix 3

TheWHOprequalicationholder/applicantinformsWHO/PQPaboutthesubmission

o its application to the NMRA(s) (by providing a copy o completed Appendix 3,

Part A) and, or each product and country, provides WHO/PQP with its written

consent to share the product-related inormation and documentation, under

condentialcover,withtheparticipatingauthority.TheWHOprequalicationholder

completes and signs the consent orm reproduced in Appendix 2 and submits it to

WHO.

Appendix 2

continues

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Figure 1 continued

The participating authority inorms WHO/PQP and the applicant o its consentto apply the procedure to the application or registration o the product, on the

understanding that the application is accepted as complete, or o its reusal. I the

NMRAagreestoapplytheprocedure,itrequestsWHO/PQPtoshareproduct-specic

inormation, by completing and signing Part B o Appendix 3.

Appendix 3

Within30calendardaysofreceiptoftheabove-mentionedrequesttheWHO/PQP provides the participating authority with product-related inormation and

documentation,andprovidesadditionalexplanations,ifrequested,throughthe

restricted-access web site, and subject to the obligations o confdentiality and

restrictions on use in place between WHO and the NMRA.

The participating authority uses the product-related inormation and

documentation provided by WHO/PQP 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 o receipt o the aoresaid inormation and

documentation.

Within 30 calendar days o having taken its decision, the participating authority

inorms WHO/PQP and the applicant o this decision, together with an indication o

the dates o submission and registration, and, i applicable, any deviations rom the

WHOprequalicationconclusionsandthereasonsforsuchdeviations,throughtherestricted-access web site. This report is provided to WHO/PQP by completing Part C

o Appendix 3.

Appendix 3

WHO/PQP lists pharmaceutical products registered by participating NMRAs

according to this procedure on its public web site.

continues

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13 See footnote 11.

14 See footnote 11.

Figure 1 continued

Post-registration processes

TheWHOprequalicationholder/applicantsubmitsvariationssimultaneouslytoWHO/PQP and relevant participating authorities. I regulatory action is deemed tobe justifed, WHO/PQP promptly provides the participating authorities concerned,through the restricted-access web site, and subject to the above-mentionedobligations o confdentiality and restrictions on use, with variation assessmentreportsandpost-prequalicationinspectionreports,andanyrelatedinformationitconsiders relevant. I a national variation procedure results in the nationally-registeredproduct being no longer the same 13astheWHO-prequaliedproduct,orintheeventthatavariationofaWHO-prequaliedproductisnotfollowedbythesame

variation o the nationally-registered product, the participating authority inormsWHO o the situation within 30 calendar days o obtaining access to the inormationand documentation provided by WHO/PQP, by submitting the orm reproduced inAppendix 4, clearly speciying the deviations. Other participating NMRAs which haveregisteredtheWHO-prequaliedproductinquestionpursuanttothisprocedurewillbe made aware o such deviations through the restricted-access web site.

Appendix 4

WHO/PQP inorms the participating authority, through the restricted-accessweb site, and subject to the above-mentioned obligations o confdentiality andrestrictionsonuse,aboutwithdrawals,suspensionsordelistingsofprequaliedpharmaceutical products. The participating authority inorms WHO/PQP, through therestricted-access web site, o national deregistration or suspension (or any reason)ofaprequaliedpharmaceuticalproductandthereasonsfordoingso.

OtherparticipatingNMRAswhichhaveregisteredtheWHO-prequaliedproductinquestionpursuanttothisprocedurewillbemadeawareofsuchnationalderegistration or suspension, through the restricted-access web site.

Appendix 4

WHO/PQP removes a product rom the list published in line with this procedure:

• i the nationally-registered product is no longer the same14 as theWHO-prequaliedproduct,or

• iftheNMRAderegistersaWHO-prequaliedproduct,or

• ifWHO/PQPdelistsaWHO-prequaliedproduct.WHO/PQP will also publish the reasons or the removal rom the list.

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5. Collaboration mechanisms for post-

registration variations5.1 Post-prequalication variations submitted to WHO/PQP are expected to

be submitted simultaneously to any relevant participating authorities, and

vice versa. Submission o variations to NMRAs should respect nationalregulatory requirements.

5.2 WHO/PQP promptly shares the variation assessment reports and post-prequalication inspection reports, through the restricted-access web site,

and subject to the above-mentioned obligations o condentiality andrestrictions on use, with the relevant participating authorities, in all cases

in which variation (including “notication” according to WHO/PQP’s variation procedure15) requires regulatory action (e.g. where product saety,ecacy or patient inormation materials are concerned). Within 30 days o

obtaining access to the inormation and documentation rom WHO/PQP,

each participating authority inorms WHO/PQP through the restricted-

access web site i and to what extent a variation o a WHO-prequaliedproduct is not ollowed by the same variation o the nationally-registered

product and, as a consequence, the nationally-registered product is nolonger the same16 as the WHO-prequalied product.

5.3 I a national variation procedure results in the nationally-registered

product being no longer the same17 as the WHO-prequalied product, the

participating authority inorms WHO/PQP within 30 days about the subject

and outcome o this national variation procedure.

5.4 Deviations under 5.2 and 5.3 above may include change o source o active

ingredients and/or manuacturing sites, product specications, testingmethods, storage conditions, shel-lie, packaging material, indications,

contraindications, posology (dosing), special warnings and precautions or

use, and adverse reactions. Diferences in brand name, name o applicant or

WHO prequalication holder, ormat o product inormation, level o detail

o product inormation, labelling o internal and external packaging andlanguage o product inormation are not considered to be deviations rom

the prequalication conclusions.

15 Guidance on variations to prequalifed dossiers is available at: http://www.who.int/prequal/ino_applicants/ino_or_applicants_guidelines.htm

16 See ootnote 11.17 See ootnote 11.

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5.5 WHO/PQP removes a product rom the list published in line with thisprocedure i the nationally-registered product is no longer the same 18 as

the WHO-prequalied product.

6. Withdrawals, suspensions or delistings o prequalifedpharmaceutical products and national deregistrations

6.1 I a WHO-prequalied product is withdrawn rom prequalication by theWHO prequalication holder, or i a product is suspended or delisted by WHO/PQP, WHO/PQP will promptly, through the restricted-access web

site, and subject to the above-mentioned obligations o condentiality andrestrictions on use, inorm relevant participating authorities accordingly,providing the reasons whenever needed.

6.2 In the case that a participating NMRA deregisters or suspends the registrationo a prequalied pharmaceutical product or any reason, the participatingauthority inorms WHO/PQP o the decision (together with an indicationo the reasons), through the restricted-access web site. Te inormationshould be provided promptly whenever product quality, saety or efcacy

are concerned and in all other cases within 30 working days. A participatingauthority is encouraged to consult WHO/PQP beore adopting a decisionabout deregistration or suspension o registration o a WHO-prequaliedproduct.

6.3 In case a WHO-prequalied product is deregistered at the national level, orin case WHO/PQP delists a prequalied product, WHO/PQP adjusts theinormation about this product on its web site accordingly.

18 See footnote 11.

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Ap p e n dix 1

NMRA participation agreement and undertakingfor NMRA focal point(s)

Appendix 1, Part A Agreement to participate in the collaborative procedure between the World Health

Organization Prequalifcation o Medicines Programme and national medicines

regulatory authorities (NMRAs) in the assessment and accelerated national registration o WHO-prequalifed pharmaceutical products

Details of national medicines regulatory authority (NMRA)

Name o NMRA (“the NMRA”)

Postal address:

Country: (“the Country”)

Telephone number (please include codes):

E-mail:

Scope of agreement

Applicants or national registration o a WHO-prequalied pharmaceutical

product (hereafer reerred to as “Applicants”) may express their interest to the

NMRA or the assessment and accelerated registration o this product (“the

Product”) in the Country under the “collaborative procedure between the World

Health Organization Prequalication o Medicines Programme (WHO/PQP)

and national medicines regulatory authorities in the assessment and accelerated

national registration o WHO-prequalied pharmaceutical products” (hereafer

reerred to as “the Procedure”).1

Subject to the NMRA agreeing to conduct such assessment and consider

such accelerated registration o the Product under the Procedure (by submitting

the orm reproduced in Part B o Appendix 3 attached to the Procedure to WHO/

PQP through the restricted-access web site), the NMRA hereby conrms or each

1 I the applicant or national registration is not the same as the WHO prequalifcation holder, the WHOprequalifcation holder must confrm to the NMRA and to WHO/PQP by an authorization letter (as perthe template annexed to Appendix 3, Part A) that the applicant is acting or, or pursuant to rightsderived rom, the WHO prequalifcation holder, and that the WHO prequalifcation holder agrees with theapplication o the Procedure in the country concerned.

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such Product that it will adhere to, and collaborate with the WHO/PQP and theapplicant o the Product in accordance with, the terms o the Procedure.

Confdentiality o inormation

Any inormation and documentation relating to the Product and providedby WHO/PQP to the NMRA under the Procedure may include but shall notnecessarily be limited to:

■ the ull WHO/PQP assessment and inspection outcomes (reports);

■ inormation and documentation on variations (as dened in the

WHO guidelines on variations to a prequalifed product , WHOechnical Report Series, No. 981, and any updates thereto), as wellas inormation and documentation on any actions taken by WHO/PQP or NMRAs post-prequalication o the Product;

■ all such data, reports, inormation and documentation beinghereinafer reerred to as “the Inormation”.

As regards sharing the outcomes o assessments and inspections, only data owned by the WHO prequalication holder are shared. Sharing o any other

data is subject to additional agreement o the data owners concerned.WHO/PQP agrees to make such Inormation available to the NMRA

through a restricted-access web site exclusively or the purpose o the assessmentand accelerated registration o the Product in the Country and any post-registration processes that may be required, in accordance with and subjectto the terms o the Procedure (“the Purpose”). Te NMRA agrees to treat any Inormation provided by WHO/PQP as aoresaid as strictly condential andproprietary to WHO/PQP, the WHO prequalication holder/applicant and/orparties collaborating with WHO/PQP and/or the WHO prequalication holder/

applicant. In this regard, the NMRA agrees to use such Inormation only orthe Purpose and to make no other use thereo. Tus, the NMRA undertakes tomaintain the Inormation received rom WHO/PQP in strict condence, and totake all reasonable measures to ensure that:

■ the Inormation received rom WHO/PQP shall not be used or any purpose other than the Purpose;

■ the Inormation shall only be disclosed to persons who have a needto know or the aoresaid Purpose and are bound by condentiality undertakings in respect o such inormation and documentationwhich are no less stringent than those contained herein.

Te NMRA warrants and represents that it has adequate procedures inplace to ensure compliance with its aoresaid obligations.

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Te obligations o confdentiality and restrictions on use contained herein

shall not cease on completion o the Purpose.

Te obligations o confdentiality and restrictions on use containedherein shall not apply to any part o the Inormation which the NMRA is clearly

able to demonstrate:

■ was in the public domain or the subject o public knowledge at

the time o disclosure by WHO/PQP to the NMRA under the

Procedure; or

■ becomes part o the public domain or the subject o public

knowledge through no ault o the NMRA; or ■ is required to be disclosed by law, provided that the NMRA shall

in such event immediately notiy WHO/PQP and the applicant in

writing o such obligation and shall provide adequate opportunity

to WHO/PQP and/or the applicant to object to such disclosure or

request confdential treatment thereo (provided always, however,

that nothing contained herein shall be construed as a waiver o

the privileges and immunities enjoyed by WHO/PQP and/or as

submitting WHO/PQP to any national court jurisdiction).Upon completion o the Purpose, the NMRA shall cease all use and make

no urther use o the Inormation disclosed to it under the Procedure, and shall

promptly destroy all o the Inormation received rom WHO/PQP which is in

tangible or other orm, except that the NMRA may retain copies o the Inormation

in accordance with its established archival procedures, subject always, however,

to the above-mentioned obligations o confdentiality and restrictions on use.

Te Purpose or each product shall be deemed completed as soon as:

■ the WHO prequalifcation holder/Applicant discontinues participation

in the Procedure or the particular product;

■ the Product is deregistered by the NMRA and/or delisted by WHO/

PQP.

Te access right o the NMRA’s ocal person(s) to the restricted-access

web site will cease automatically upon the NMRA ceasing to participate in the

Procedure. I and as soon as an NMRA ocal point is replaced by a new ocal

point or ceases to be an employee o the NMRA, such ocal point's access to therestricted-access web site shall automatically terminate.

Te NMRA agrees that it has no right in or to the Inormation and that

nothing contained herein shall be construed, by implication or otherwise, as the

grant o a licence to the NMRA to use the Inormation other than or the Purpose.

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Timelines

In respect o each Product which the NMRA accepts to assess and consider oraccelerated registration under the Procedure, the NMRA undertakes to abide by the terms o the Procedure, including but not limited to the ollowing timelinesor processing each application:

■ within 90 calendar days o obtaining access (through the restricted-access web site) to:

– the data submitted to WHO/PQP or prequalifcation o theProduct and owned by the WHO prequalifcation holder,

– the ull WHO/PQP assessment and inspection outcomes(reports), the NMRA undertakes to take a decision on thenational registration o the Product;

■ within 30 working days o the NMRA’s decision on nationalregistration o the Product, the NMRA undertakes to inormWHO/PQP o this decision and o any deviations rom the WHOprequalifcation conclusions (with an indication o the reasons orsuch deviations) by completing and submitting the orm attached

as Appendix 3, Part C to the Procedure to WHO/PQP through therestricted-access web site;

■ i a national variation procedure results in the nationally registeredproduct being no longer the same2 as the WHO-prequalifedproduct, or i and to the extent a variation o a WHO-prequalifedproduct is not ollowed by a variation o the nationally-registeredproduct and as a consequence, the nationally-registered productis no longer the same2 as the WHO-prequalifed product, the

NMRA undertakes to inorm WHO/PQP thereo (together with anindication o the reasons or such deviations) within 30 days o theconclusion o the national variation procedure or within 30 dayso having received access to the inormation and documentationprovided by WHO/PQP, as the case may be (i.e. by completing andsubmitting the orm attached to the Procedure as Appendix 4 toWHO/PQP through the restricted-access web site);3

2 Within the context o this Procedure, the same pharmaceutical product is characterized by the sameproduct dossier, the same manuacturing chain, processes and control o materials, the same API and FPPspecifcations and the same essential elements o product inormation, as urther described in paragraph3.2 o the Procedure.

3 I the act that a WHO-prequalifed product has been registered in a country pursuant to this Procedure hasbeen made public any subsequent deviations should be made public also.

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■ the NMRA undertakes to inorm WHO/PQP in case the NMRA

deregisters or suspends the registration o the Product in the

Country, by completing and submitting the orm attached to theProcedure as an Appendix 4 to WHO/PQP through the restricted-

access web site, and to do so promptly i this decision is based on

quality, saety o efcacy concerns, and within 30 working days i

this decision is based on other reasons.

Focal points for access to restricted-access web site

Te NMRA has designated the person(s) listed below to act as ocal point(s) or

access to WHO/PQP's restricted-access web site. Te undertaking(s) completedand signed by the ocal point(s) is(are) attached hereto as an Appendix to this

agreement.

Any change in designated ocal points must be communicated to WHO/

PQP without delay in writing and will be subject to the new ocal point having

signed and submitted to WHO the undertaking reproduced in Appendix 1B to

the Procedure. Te NMRA also undertakes to inorm WHO/PQP i and as soon

as a designated ocal point ceases to be an employee o the NMRA.

Focal point for inspections

I applicable, this should be the same ocal point as or the “WHO/PQP collaborative

procedure between WHO/PQP and selected NMRAs in inspection activities” (http://

who.int/prequal).

Mr/Ms/Dr:First name (and initials):

Surname/amily name:itle in NMRA:

E-mail:Phone:

A signed undertaking is attached

Focal point for dossier assessment

Te same person as above may be nominated. I a diferent person is nominated,

please complete details below.

Mr/Ms/Dr:First name (and initials):

Surname/amily name:

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itle in NMRA:E-mail:

Phone:

A signed undertaking is attached

Miscellaneous

Te NMRA agrees that WHO/PQP may list its name on the WHO/PQP web site

as a participant in the Procedure. Except as provided hereinbeore, neither party

shall, without the prior written consent o the other party, reer to the relationship

o the parties under this Agreement and/or to the relationship o the other party to the Product, the Inormation and/or the Purpose, in any statement or material

o an advertising or promotional nature.

Tis Agreement shall not be modied except by mutual agreement

o WHO and the NMRA in writing. Te NMRA urthermore undertakes to

promptly inorm WHO/PQP o any circumstances or change in circumstances

that may afect the implementation o this Agreement.

Te parties shall use their best eforts to settle amicably any dispute

relating to the interpretation or execution o this Agreement. In the event o

ailure o the latter, the dispute shall be settled by arbitration. Te arbitration shallbe conducted in accordance with the modalities to be agreed upon by the parties

or in the absence o agreement, with the UNCIRAL Arbitration Rules in efect

on the date o this Agreement. Te parties shall accept the arbitral award as nal.

It is agreed urthermore that nothing contained in this Agreement shall

be construed as a waiver o any o 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 the NMRA

Signature:Name:itle:Place and date:

Attachments:1. Signed undertakings o NMRA ocal point(s) (Appendix 1, Part B).

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Appendix 1, Part B

Undertaking for NMRA focal point(s)

The undersigned:

Mr/Ms/Dr:First name (and initials):Surname/amily name:itle in NMRA:

Name o NMRA (“the NMRA”)

Country: (“the Country”)E-mail:Phone:

Applicants or national registration o WHO-prequalied pharmaceutical products(hereafer reerred to as “Applicants”) may express their interest to the NMRAor the assessment and accelerated national registration o such productsunder the “collaborative procedure between the World Health OrganizationPrequalication o Medicines Programme (WHO/PQP) and national medicines

regulatory authorities (NMRAs) in the assessment and accelerated nationalregistration o WHO-prequalied pharmaceutical products” (hereafer reerredto as “the Procedure”).1

Subject to the NMRA agreeing to conduct such assessment and considersuch accelerated registration o a WHO-prequalied product under the Procedure,WHO/PQP will communicate condential Inormation (as hereinafer dened)relating to each such product to the NMRA, and the NMRA will communicateoutcomes o the national registration procedure and post-registration actionsin respect o such products to WHO/PQP, through a restricted-access web

site, which can be accessed only by the ocal points designated by the NMRA,including the undersigned. For the purpose o accessing the restricted-access website and downloading Inormation and uploading reports in accordance with andsubject to the terms o the Procedure, WHO/PQP will provide the undersignedwith a secret access code. Te undersigned undertakes to treat this access codeas strictly condential and not to disclose it to any other person whatsoever. Teundersigned urthermore undertakes to take all precautionary measures that may be needed to prevent any other person whatsoever rom obtaining the aoresaid

1 I the applicant or national registration is not the same as the WHO prequalifcation holder, the WHOprequalifcation holder must confrm to the NMRA and to WHO/PQP by an authorization letter (as per thetemplate annexed to Appendix 3, Part A) that the applicant is acting or, or pursuant to rights derived rom,the WHO prequalifcation holder, and that the prequalifcation holder agrees with the application o theProcedure in the country concerned.

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secret access code and rom accessing the restricted-access web site (i.e. exceptor the other designated ocal points who have signed this undertaking).

“Inormation” as aoresaid means any inormation and documentationrelating to a WHO-prequalied product to be provided by WHO/PQP to theNMRA under the Procedure, including but not necessarily limited to:


■ inormation and documentation on subsequent variations (as denedin the WHO guidelines on variations to a prequalifed product , WHOechnical Report Series, No. 981, and any updates thereto), as well asinormation and documentation on any actions taken by WHO/PQP

or NMRAs post-prequalication o the Product.

As regards sharing the outcomes o assessments and inspections, only data owned by the WHO prequalication holder are shared. Sharing o any otherdata is subject to additional agreement o the data owners concerned.

Te undersigned conrms that:

1. the NMRA has bound him or her to obligations o condentiality and restrictions on use no less stringent than those contained in

Appendix 1A to the Procedure; and that2. the aoresaid obligations o condentiality and restrictions on use

shall not cease on completion o the assessment and acceleratedregistration o any product in the Country, nor on completiono any post-registration processes that may be required, nor onthe undersigned ceasing to be an employee o (or ceasing to haveanother relationship with) the NMRA.

Te undersigned shall automatically cease having the right to access

the restricted-access web site when the NMRA designates a new ocal point toreplace the undersigned or when the undersigned ceases to be an employee o the NMRA.

Tis Undertaking shall not be modied except by mutual agreement o WHO and the undersigned in writing. Te undersigned urthermore undertakesto promptly inorm WHO/PQP o any circumstances or change in circumstancesthat may afect the implementation o this Undertaking.

Te parties shall use their best eforts to settle amicably any disputerelating to the interpretation or execution o this Undertaking. In the event o

ailure o the latter, the dispute shall be settled by arbitration. Te arbitrationshall be conducted in accordance with the modalities to be agreed upon by theparties or in the absence o agreement, with the UNCIRAL Arbitration Rules inefect on the date o this Undertaking. Te parties shall accept the arbitral awardas nal.

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It is agreed furthermore that nothing contained in this Undertakingshall 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 NMRA:

Place and date:

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Appendix 2

Consent o WHO prequalifcation holder or WHO toshare inormation with NMRA confdentially under theProcedure

Reerence is made to the attached expression o interest or the assessment and

accelerated national registration under the Procedure o the ollowing WHO-

prequalied pharmaceutical product (hereafer reerred to as "the Product") in[country ].1

WHO prequalifcation details:

WHO prequalication reerence number:

Date o prequalication (dd/mm/yyyy):

Date o requalication (i applicable):

WHO prequalication holder:2

Application details:

Name o entity: (“the Applicant”)

Street:

City and country:

E-mail:

Phone:

Te WHO prequalication holder hereby consents to WHO/PQP providing theollowing inormation and documentation to the NMRA o

[country ] (“the NMRA”) or the assessment and accelerated registration o the

Product in the country under the Procedure and to reely discuss the same with

the aoresaid NMRA or this purpose:


1 Please complete a separate orm o this Annex or each country.2 I the applicant or national registration is not the same as the WHO prequalifcation holder, the WHO

prequalifcation holder must confrm to the NMRA and to WHO/PQP by an authorization letter (as per thetemplate annexed to Appendix 3, Part A) that the applicant is acting or, or pursuant to rights derivedrom, the WHO prequalifcation holder, and that the prequalifcation holder agrees with the application o the Procedure in the country concerned.

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■ inormation and documentation on subsequent variations (asdened in the WHO guidelines on variations to a prequalifed product ,

WHO Technical Report Series, No. 981, and any updates thereto),as well as inormation and documentation on any actions taken by WHO/PQP post-prequalication o the Product.

■ all such data, reports, inormation and documentation beinghereinaer reerred to as “the Inormation”.

As regards sharing the outcomes o assessments and inspections, only data owned by the WHO prequalication holder are shared. Sharing o any otherdata is subject to additional agreement o the data owners concerned.3

Such consent is subject to the NMRA having entered into an agreementwith WHO/PQP as per Appendix 1A to the Procedure and having agreed toconduct the assessment and consider the accelerated registration o the Productunder the Procedure, by having submitted the orm reproduced in Part B o Appendix 3 to the Procedure to WHO.

I a national variation procedure results in the nationally-registeredproduct being no longer the same4 as the WHO-prequalied Product, or i a

variation o the WHO-prequalied Product is not ollowed by a variation o the

nationally-registered product and, as a consequence, the nationally-registeredproduct is no longer the same, the WHO prequalication holder/Applicant willinorm WHO/PQP o the diferences and their reasons.

For the WHO prequalifcation holder

Signature:Name:Title:Place:

Date (dd/mm/yyyy):

3 In case that certain data submitted to WHO/PQP by the WHO prequalifcation holder in relation toprequalifcation o the Product are not in his/her ownership, the WHO prequalifcation holder specifessuch data in an annex to this declaration o consent.

4 Within the context o this Procedure, the same pharmaceutical product is characterized by the sameproduct dossier, the same manuacturing chain, processes and control o materials, the same API and FPPspecifcations and the same essential elements o product inormation, as urther described in paragraph3.2 o the Procedure.

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Appendix 3

Expression o interest to NMRA or the assessment andaccelerated national registration, acceptance by NMRAand notifcation o Procedure outcomes

Appendix 3, Part AExpression o interest to the national medicines regulatory authority (NMRAs)

or the assessment and accelerated national registration o a WHO-prequalifed pharmaceutical product

In line with the Procedure, the undersigned Applicant1 expresses its interest inthe application of the above-mentioned Procedure by the NMRA of [country] (“the NMRA”) in respect of the following submission for nationalregistration:


Name of entity: (“the Applicant”)Street:City and country:E-mail):Phone:Date of application:(dd/mm/yyyy, e.g. 31/07/2011):Product name in national system (if known):National reference number (if known):

Product details:

API(s) (INN):

Dosage form and strength:Packaging:Manufacturing site(s), including block(s)/unit(s)

if appropriate:

1 I the applicant or national registration is not the same as the WHO prequalifcation holder, the WHOprequalifcation holder must confrm to the NMRA and to WHO/PQP by an authorization letter (as perthe template annexed to Appendix 3, Part A) that the applicant is acting or, or pursuant to rights derivedrom, the WHO prequalifcation holder, and that the prequalifcation holder agrees with the application o the Procedure in the country concerned.

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WHO prequalication reerence number:Date o prequalication (dd/mm/yyyy):

WHO prequalication holder:

Te Applicant conrms that the inormation and documentation provided in

support o the above-mentioned submission or national registration is true

and correct, that the pharmaceutical product submitted or national registration

is the same2 as the WHO-prequalied product and that the technical part o

the inormation is the same3 as that submitted to the WHO Prequalication

o Medicines Programme (WHO/PQP). Non-essential diferences4 rom the

inormation submitted to WHO/PQP, are the ollowing:

Subject to the NMRA agreeing to conduct the assessment and consider the

accelerated registration o the Product under the Procedure, the Applicant:

1. undertakes to adhere to, and collaborate with the NMRA and WHO/PQP in accordance with the terms o the Procedure; and

2. will authorize WHO/PQP5 to provide the NMRA condential

access to the ollowing inormation and documentation and to reely

discuss the same with the aoresaid NMRA or the above-mentioned

Purpose:

– the ull WHO/PQP assessment and inspection outcomes (reports);

2 Within the context o this Procedure, the same pharmaceutical product is characterized by the sameproduct dossier, the same manuacturing chain, processes and control o materials, the same API and FPPspecications and the same essential elements o product inormation, as urther described in paragraph3.2 o the Procedure.

3 Only the technical data included in the dossier must be the same. There may be country-specicdiferences in administrative data, or i required by NMRAs under exceptional circumstances, additionaltechnical data can be provided (e.g. bioequivalence with a country-specic comparator).

4 As dened in Section 3.2 o the Procedure, diferences in administrative inormation, brand name, nameo applicant/prequalication holder (provided that the applicant is acting or, and has the authority to

represent the WHO prequalication holder), ormat o product inormation, level o detail o productinormation, labelling o internal and external packaging and language o product inormation are notconsidered to be essential diferences.

5 I the applicant or national registration is not the same as the WHO prequalication holder, thenthe authorization to WHO/PQP must be provided by the WHO prequalication holder or their legalrepresentative.

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– inormation and documentation on subsequent variations (asdefned in the WHO guidelines on variations to a prequalifed

product , WHO echnical Report Series, No. 981, and any updatesthereto), as well as inormation and documentation on any actions taken by WHO/PQP post-prequalifcation o the Product.

As regards sharing the outcomes o assessments and inspections, only data owned by the WHO prequalifcation holder are shared. Sharingo any other data is subject to additional agreement o the data ownersconcerned.

3. authorizes the NMRA to reely share and discuss all registration

and the Product related inormation provided by the Applicantto the NMRA, with WHO/PQP, subject to the obligations o confdentiality and restrictions on use as contained in the NMRA'sparticipation agreement and ocal points' undertakings.

Te application or national registration was submitted beore the Applicantdecided to apply the Procedure to the Product and thereore at the timeo submission the registration dossier did not respect conditions o theProcedure. Steps taken to update the submission to the NMRA to make the

dossier “the same” as required by the Procedure, are listed and reerenced inthe attached letter.

Te applicant is not the WHO prequalifcation holder. An authorizationletter rom the WHO prequalifcation holder is attached.

For the Applicant

Signature:Name:

itle:Place:Date (dd/mm/yyyy):

Template for authorization letter

(o be provided i the applicant is not the WHO prequalifcation holder. Pleaseprovide a separate letter or each NMRA concerned, with a copy to WHO/PQP).

Tis is to confrm that (name o applicant )

seeking registration or prequalifed product number(WHO/PQ number ) in (name country )

under the WHO collaborative procedure or acceleratedregistration o WHO prequalifed products, is acting or, or pursuant to rightsderived rom (name o WHO prequalifcation holder )

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and that (name o WHO prequalifcationholder ) agrees with the application o the procedure in the

country concerned.

For (name o WHO Prequalifcation holder ) :

SignatureNameTitleDate

Appendix 3, Part B

Acceptance by the NMRA to apply the Procedure to a specifed WHO-prequalifed pharmaceutical product and request or access to product-specifc inormation and documentation

I there have been changes to the details as completed in Part A, please completethe relevant elds below. Where elds below are lef blank, the data in Part A areconsidered to be valid.


Name o entity: (“the Applicant”)Street:City and country:E-mail:Phone:Date o application:

(dd/mm/yyyy, e.g. 31/07/2011):Product name in national system (i known):National reerence number (i known):

Product details:

API(s) (INN):Dosage orm and strength:Packaging:

Manuacturing site(s), including block(s)/unit(s)i appropriate:


WHO prequalication reerence number:

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Date o prequalication (dd/mm/yyyy):WHO prequalication holder

Please complete either section A or section B below:

Section A

Te NMRA agrees to conduct the assessment and the accelerated registration o the above-mentioned product (“the Product”) under the Procedure and requestsaccess to product-specic inormation, in accordance with and subject to theterms o the Procedure and the Agreement between WHO/PQP and the NMRAdated / / (dd/mm/yyyy).

Section B

Te NMRA has decided not to apply the Procedure to the above-mentionedProduct or the ollowing reasons:

For the NMRA

Signature:Name:

itle:Place:Date (dd/mm/yyyy):

Appendix 3, Part CNotifcation o outcomes o national registration procedure by the NMRA

Product and application details as completed in Parts A and B above apply.

Please complete either Section A or B below:

Section A

Registration has been granted, and the above-mentioned product (“the Product”)is identied as ollows in the national medicines register:Name of the Product National registration number Date of registration (dd/mm/yyyy)

Product details (i diferent rom those specied inParts A and B):

API(s) (INN)Dosage orm and strengthPackaging

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Manuacturing site(s), including block(s)/unit(s)i appropriate

Registration holder (i diferent rom the Applicant asspecied in Parts A and B:

Name o entity StreetCity and country E-mailPhone

Are the national registration conclusions dierent rom prequalifcation

outcomes?6

(Yes/No)

If you answered Yes to the above question:

Deviation Reason

Please speciy whether registration is subject to specic commitments, theregistration is provisional or conditional, use o the Product is limited by specicprescribing restrictions, or additional clinical trials or additional data are required:

Section B

Te application or registration o the Product was rejected or the ollowing

reasons:

For the NMRA

Signature:Name:itle:Place:Date: (dd/mm/yyyy)

6 This reers to deviations in indications, contraindications, posology (dosing), special warnings andprecautions or use, adverse drug reactions, storage conditions and shel-lie. Diferences in brand name,name o applicant/prequalication holder, ormat o a product inormation, level o detail o productinormation, labelling o internal and external packaging and language o product inormation are notconsidered to be a deviation rom the prequalication conclusions.

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Ap p e n dix 4

Report on post-registration actions in respect of aproduct registered under the Procedure

■ Variation o the national registration resulting in the nationalregistration conditions being inconsistent with the WHO/PQPprequalifcation conclusions

■ Deregistration or suspension o the registration o the product

Product details:

Product name in national system: (“the Product”)National registration number:Date o registration (dd/mm/yyyy):


WHO prequalifcation reerence number:Date o prequalifcation (dd/mm/yyyy):WHO prequalifcation holder:

Te national variation procedure has resulted in the nationally-registeredProduct being no longer the same1 as the WHO-prequalifed product.

Deviations2 Reasons

1 Within the context o this Procedure, the same pharmaceutical product is characterized by the sameproduct dossier, the same manuacturing chain, processes and control o materials, the same API and FPPspecications and the same essential elements o product inormation, as urther described in paragraph3.2 o the Procedure.

2 This reers to deviations in indications, contraindications, posology (dosing), special warnings andprecautions or use, adverse drug reactions, storage conditions and shel-lie. Diferences in brand name,name o applicant/prequalication holder, ormat o product inormation, level o detail o productinormation, labelling o internal and external packaging and language o product inormation are notconsidered to be a deviation rom the prequalication conclusions.

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Te variation notied to NMRA by WHO/PQP has not been ollowed by a variation o the nationally-registered Product and, as a consequence,

the nationally-registered product is no longer the same3 as the WHO-prequalied product.

Deviations4 Reasons

Te Product has been deregistered or the registration o the Product hasbeen suspended.