WHO TRS (Technical Report Series) 981, 2013 Annex 3


WHO TRS (Technical Report Series) 981, 2013 Annex 3

WHO guidelines on variations to a prequalified product


The variation guidelines have been completely updated and expanded, bringing them into line with the principles of the new generic quality guidelines, WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part.

The guidelines retain the basic structure and function of the previous variation guidelines, and have been expanded to include the classification of additional post-approval/post-prequalification changes and to establish the level of risk inherent to each change. Although the general requirements have not significantly changed, the additional details help the reader to classify changes that may occur related to all the major sections of a quality dossier, to understand the considerations necessary to assess the risk of each change, and to determine the documentation required to support the change. 

In some cases, changes that previously were considered major changes by default are now classified minor variations or notifications, and some minor variations have been reclassified as notifications. In addition, for some categories that previously required acceptance of the change prior to implementation, the applicant can now implement the change immediately upon notification.

The change categories are organized according to the structure of the common technical document (CTD). The specific CTD sections associated with individual data requirements have been identified in order to assist in the filing of documentation (reproduced with corresponding numbers in bold). Presentation corresponds to section 1.4 in Annex 4 of WHO Technical Report Series, No. 970.

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Table of Contents


1. Background 

2. Guidance for implementation 

3. Glossary 

4. Administrative changes 

5. Changes to a CEP or to a confirmation of API-prequalification document

6. Quality changes 

3.2. S Drug substance (or API) 

3.2. S.2 Manufacture 

3.2. S.4 Control of the API by the API manufacturer 

3.2. S.4 Control of the API by the FPP manufacturer 

3.2. S.6 Container-closure system 

3.2. S.7 Stability 

3.2. P Drug product (or FPP) 

3.2. P.1 Description and composition of the FPP 

3.2. P.3 Manufacture 

3.2. P.4 Control of excipients 

3.2. P.5 Control of FPP

3.2. P.7 Container-closure system 

3.2. P.8 Stability 

Appendix 1. Examples of changes that make a new application or extension application necessary 

Appendix 2. Changes to excipients 

WHO TRS (Technical Report Series) 981, 2013 Annex 3:


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