GUIDANCE ON VARIATIONS TO A PREQUALIFIED …

1 Working document RESTRICTED GUIDANCE ON VARIATIONS TO A PREQUALIFIED DOSSIER World Health Organization 2006 All rights reserved. This draft is intended for a restricted audience only, the individuals and organizations having received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including the organizations concerned staff and member organizations) without the permission of WHO.

2 The draft should not be displayed on any website. Please send any request for permission to: Dr Matthias Stahl, Quality Assurance & Safety: Medicines (QSM), Department of Medicines Policy and Standards (PSM), World Health Organization, CH-1211 Geneva 27, Switzerland, Fax: (41-22) 791 4730; e-mail: The designations employed and the presentation of the material in this draft do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.

3 Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The World Health Organization does not warrant that the information contained in this draft is complete and correct and shall not be liable for any damages incurred as a result of its use.

4 Since being presented to the Fortieth meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations in October 2005 this document was sent out for further comments in February 2006. Comments received have been taken into consideration as far as possible and the text has now been revised. This revision is being mailed for comments once again and it would be appreciated if you would send these to Dr M. Stahl, Quality Assurance and Safety: Medicines, Medicines Policy and Standards, World Health Organization, 1211 Geneva 27, Switzerland; fax: (+41 22) 791 4730 or e-mail: by 10 October 2006.

5 Working document page 2 SCHEDULE FOR THE ADOPTION PROCESS OF document ( ): GUIDANCE ON VARIATIONS TO A PREQUALIFIED DOSSIER Deadline First draft of Variation document November 2003 Review of 1st draft (Prequalification assessors' group) February 2004 Two-day meeting to review comments and revise 1st draft 4 - 5 February 2004 Second draft September 2004 Circulation of 2nd draft for comments June 2005 Deadline for comments (Prequalification assessors' group) 26 August 2005 Mailing of collated comments on 2nd draft to experts 26 August 2005 Two-day meeting to review comments and revise 2nd draft 29 - 30 August 2005 Finalization of revision of 2nd draft September 2005 Third draft September 2005 Circulating 3rd draft for comments October 2005 Finalization of draft document October 2005 Publication of draft Variation document (Prequalification web site)

6 18 October 2005 Finalization of Variation document October-November-December 2005 January 2006 Publication of final Variation document (Prequalification web site) 27 January 2006 Final document from the Prequalification Programme mailed for comments, with deadline for receipt of comments of 15 April 2006 February 2006 Collation of comments May-June 2006 Revision of Variation GUIDANCE September 2006 Mailing of revision for comments, with deadline for receipt of comments of 10 October 2006 September 2006 Presentation to Expert Committee October 2006 Working document page 3 Page 3 of 44 Variation Guide 14/09/2006 GUIDANCE ON VARIATIONS TO A PREQUALIFIED DOSSIER PREFACE This GUIDANCE document was technically

7 And structurally inspired by the "Guideline on dossier requirements for type IA and IB notifications"1. It is intended to provide supportive information on how to present an application to implement a change to a PREQUALIFIED product. References to compendial monographs (British Pharmacopoeia (BP), International Pharmacopoeia (PhInt), Japanese Pharmacopoeia (JP), European Pharmacopoeia (PhEur) or United States Pharmacopoeia (USP)] or to guidelines (WHO, ICH-region and associated countries) are inserted to assist applicants. However, it remains the applicant's responsibility to ensure that all relevant legislation and guidelines, as revised or maintained, are taken into account in the preparation of each part of their dossier.)

8 The guidelines referenced in each section provide useful information on the content expected in that section. However, this list should not be regarded as comprehensive. Where a variation requires consequential revision of the Summary of Product Characteristics (SmPC), labelling and package leaflet/insert, this is considered as part of the variation. This GUIDANCE document is applicable only to active pharmaceutical ingredients (APIs) and excipients manufactured by chemical synthesis or semisynthetic processes and finished pharmaceutical products (FPPs) containing such APIs and excipients.

9 Whenever an intended change involves a biological substance (biological API and/or biological excipient) the applicant is asked to refer to GUIDANCE documents that specifically address biological substances ( ICH Q5A2, Q5B3, Q5C4, Q5D5, Q5E6, Q6B7). 1 Guideline on dossier requirements for type IA and IB notifications July 2003 2 ICH Q5A: Note for GUIDANCE on Quality of Biotechnological Products: Viral safety Evaluation of Biotechnology Products derived from Cell Lines of Human or Animal Origin (CPMP/ICH/295/95) [ ] 3 ICH Q5B: Note for GUIDANCE on Quality of Biotechnological Products.

10 Analysis of the Expression Construct in Cell Lines used for Production of r-DNA derived Protein Products (CPMP/ICH/139/95) [ ] 4 ICH Q5C: Note for GUIDANCE on Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products (CPMP/ICH/138/95) [ ] 5 ICH Q5D: Note for GUIDANCE on Quality of Biotechnicological Products: Derivation and Characterization of Cell Substrates used for Production of Biotechnological/Biological Products (CPMP/ICH/294/95) [ ] 6 ICH Q5E: Note for GUIDANCE on Biotechnological/Biological Products Subject to changes in their Manufacturing Process (CPMP/ICH/5721/03) [ ] 7 ICH Q6B: Note For GUIDANCE on Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (CPMP/ICH/365/96) Working document page 4 This GUIDANCE document applies to Multisource (Generic) FPPs that have been PREQUALIFIED by WHO.