Title: Guidelines for Procedures and Data …

1 1 1 2 ENGLISH ONLY 3 4 Guidelines for Procedures and data requirements for changes to 5 approved vaccines 6 7 NOTE: 8 9 This document has been prepared for the purpose of inviting comments and suggestions on the 10 proposals contained therein, which will then be considered by the Expert Committee on 11 Biological Standardization (ECBS). Publication of this early draft is to provide information about 12 the Guidelines for Procedures and data requirements for Changes to Approved Vaccines to a 13 broad audience and to improve transparency of the consultation process. 14 15 These Guidelines were developed based on the outcomes and consensus of the WHO 16 consultation convened in 2013 with participants from national regulatory authorities, national 17 control laboratories, vaccine manufacturers and academia researchers and comments from the 18 public consultation on WHO website in 2014.

2 19 20 The text in its present form does not necessarily represent an agreed formulation of the 21 Expert Committee on Biological Standardization. Written comments proposing 22 modifications to this text MUST be received by 30 September 2014 in the Comment Form 23 available separately and should be addressed to the World Health Organization, 1211 Geneva 24 27, Switzerland, attention: Department of Essential Medicines and Health Products (EMP). 25 Comments may also be submitted electronically to the Responsible Officer: Dr Dianliang Lei at 26 email: 27 28 The outcome of the deliberations of the Expert Committee will be published in the WHO 29 Technical Report Series. The final agreed formulation of the document will be edited to be in 30 conformity with the "WHO style guide" (WHO/IMD/ ).

3 31 32 33 World Health Organization 2014 34 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World 35 Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 36 4857; e-mail: Requests for permission to reproduce or translate WHO publications 37 whether for sale or for non-commercial distribution should be addressed to WHO Press, at the above 38 address (fax: +41 22 791 4806; e-mail: 39 The designations employed and the presentation of the material in this publication do not imply the expression 40 of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any 41 2 country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. 1 Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.))

4 2 3 The mention of specific companies or of certain manufacturers products does not imply that they are 4 endorsed or recommended by the World Health Organization in preference to others of a similar nature that 5 are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by 6 initial capital letters. 7 8 All reasonable precautions have been taken by the World Health Organization to verify the information 9 contained in this publication. However, the published material is being distributed without warranty of any kind, 10 either expressed or implied. The responsibility for the interpretation and use of the material lies with the 11 reader. In no event shall the World Health Organization be liable for damages arising from its use. 12 13 The named authors [or editors as appropriate] alone are responsible for the views expressed in this 14 publication.

5 15 16 Recommendations published by the World Health Organization are intended to be scientific and advisory. Each of the following sections constitutes guidance for national regulatory authorities (NRAs) and for market authorization holders of vaccines. If an NRA so desires, these recommendations may be adopted as definitive national requirements , or modifications may be justified and made by the NRA. It is recommended that modifications to these recommendations be made only on condition that they ensure that the vaccine is at least as safe and efficacious as when manufactured and labelled in accordance with the recommendations set out in this document. 17 18 3 CONTENTS 1 1. ABBREVIATIONS .. 5 2 2. INTRODUCTION AND SCOPE .. 5 3 Introduction .. 5 4 Scope .. 6 5 3. 6 6 4. GENERAL CONSIDERATIONS .. 10 7 5. REPORTING CATEGORIES FOR QUALITY CHANGES .. 13 8 Major quality changes.

6 14 9 Moderate quality changes .. 14 10 Minor quality changes .. 14 11 6. REPORTING CATEGORIES FOR SAFETY, EFFICACY AND/OR PRODUCT 12 LABELLING INFORMATION CHANGES .. 15 13 Safety and efficacy changes .. 15 14 Product labelling information changes .. 17 15 Urgent product labelling information changes .. 17 16 Administrative product labelling information changes .. 17 17 7. Procedures .. 18 18 Procedures for prior approval supplements .. 21 19 Procedures for minor quality changes .. 24 20 Procedures for urgent product labelling information 24 21 Procedures for administrative product labelling information changes .. 25 22 8. SPECIAL CONSIDERATIONS .. 25 23 Adjuvants .. 25 24 Influenza Vaccines .. 26 25 4 Bridging studies .. 26 1 9. REFERENCES .. 27 2 APPENDIX 1. REPORTING CATEGORIES AND SUGGESTED REVIEW 3 TIMELINES .. 30 4 APPENDIX 2.

7 CHANGES TO THE ANTIGEN .. 33 5 REFERENCES .. 46 6 APPENDIX 3. CHANGES TO THE FINAL PRODUCT .. 48 7 APPENDIX 4. SAFETY, EFFICACY AND PRODUCT LABELLING INFORMATION 8 CHANGES .. 66 9 10 11 5 1. ABBREVIATIONS 1 2 AEFI Adverse Event Following Immunization 3 BSE Bovine Spongiform Encephalopathy 4 CTD Common Technical Document (eCTD, electronic CTD) 5 GCP Good Clinical Practice 6 GLP Good Laboratory Practice 7 GMP Good Manufacturing Practice 8 HPLC High Performance Liquid Chromatography 9 ICH International Conference on Harmonisation (of Technical requirements for 10 Registration of Pharmaceuticals for Human Use) 11 MA Market Authorization 12 MCB Master Cell Bank 13 MSL Master Seed Lot 14 NCL National Control Laboratory 15 NRA National Regulatory Authority 16 PAS Prior Approval Supplement 17 QC Quality Control 18 QA Quality Assurance 19 SOP Standard Operating Procedures 20 TSE Transmissible Spongiform Encephalopathy 21 WCB Working Cell Bank 22 WHO World Health Organization 23 WSL Working Seed Lot 24 25 2.

8 INTRODUCTION AND SCOPE 26 27 Introduction 28 29 Changes to the vaccine manufacturing process or product labelling information often 30 need to be implemented after a new vaccine has been approved ( licensed or market 31 authorization received). Changes may be made for a variety of reasons, such as to 32 maintain routine production of vaccines ( replenishment of cell banks, seed lots, 33 reference standards), to improve the quality attributes of the vaccine or the efficiency of 34 manufacture ( changes in the manufacturing process, equipment or facility), or to 35 update product labelling information ( to add a new indication, improve the 36 management of risk by adding a warning, limiting the target population, changing the 37 dosage regimen, adding information on co-administration with other vaccines or 38 medicines). 39 40 National regulatory authorities (NRAs) and market authorization (MA) holders should 41 recognize that: 42 any change to a vaccine may impact on the quality, safety and efficacy of that 43 vaccine; and 44 6 any change to the information associated with the vaccine ( product 1 labelling information) may impact on the safe and effective use of that 2 vaccine.

9 3 4 Regulation of changes to approved vaccines is one of the most important elements in 5 ensuring that vaccines of constant quality, safety and efficacy are distributed after they 6 receive authorization or licensure. WHO provides support to its Member States through 7 the provision of written standards and Guidelines (1, 2, 3). However, the NRAs of the 8 Member States requested further guidance on data needed to support changes to 9 approved vaccines to ensure the comparability with respect to quality, safety and 10 efficacy of the vaccines manufactured with the change. Although it is difficult to 11 provide a set of Guidelines that apply to all national situations, an attempt has been made 12 to cover a range of possible changes in manufacture, quality control, safety, efficacy and 13 product labelling information. 14 15 This document is intended to serve as a guide for establishing national requirements for 16 the regulation of post-approval changes.

10 The categories of changes and reporting 17 Procedures are provided in the main body of the document and the data requirements to 18 support the proposed changes are provided in the appendices. If an NRA so desires, these 19 Guidelines may be adopted as definitive national requirements . It is possible that 20 modifications to this document may be justified due to risk-benefit and legal 21 considerations specific to each NRA. In such cases, it is recommended that modifications 22 to the principles and technical specifications of these Guidelines be made only on 23 condition that the modifications ensure vaccine quality, safety and efficacy equivalent to 24 that in these Guidelines ( that the risks of introducing vaccines for use in public health 25 programmes are no greater than as outlined in the Guidelines set out below). 26 27 Scope 28 29 This document provides Guidelines for NRAs and MA holders on the regulation of 30 changes to the original MA dossier or product license for an approved vaccine on: 1) 31 Procedures and criteria for the appropriate categorization and reporting of changes; and 32 2) the data required to enable NRAs to evaluate the impact of the change on the quality, 33 safety and efficacy of the vaccine.