Variations to a prequalified product Hua YIN Prequalification of Medicines Programme QSM / EMP / HSS

1. Variations to a prequalified product Hua YIN Prequalification of Medicines ProgrammeQSM / EMP / HSS WHO Prequalification Programme: Training workshop March 2010, Beijing

2. What and Why ? Variation: A change to a prequalified product Throughout the lifecycle of a medicinal product, the marketing authorization holder : • is required to take into account technical and scientific progress and make any amendments required to enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods • May wish to alter / improve the medicinal product or to introduce additional safeguard • To meet the market requirements-- scale up, add manufactuing site. • Others, such as revise SmPC due to DAR observed

3. Changes may have potential impact on the quality, safety or efficacy of medicinal products Any change to prequalified products are subject to approval by WHO (Currently)

4. To learn variation guideline before dossier submission • Helps in planning the submission and in preparing the dossier • The principles established in the variation guidance document can be applied to similar quality changes that occur during the development of the drug and the recommended supporting data be included in the drug submission. • For example: different batch sizes (Pilot batch size –Commercial batch size), multiple API sources---refer to the variation guideline for the documentation requirements. • A change made to a dossier while application for prequalification is still ongoing is considered additional data. No difference to the variation requirements from a technical point of view.

5. Guidance on Variation to a prequalified dossier WHO Guidance on Variation to a prequalified dossier is technically and structurally inspired by EMEA “Guideline on dossier requirements for type IA and IB notification”—issued in 2003 • Gives assistance in how to adequately document variations • Applicable since January 2007 • Applies to Multisourece (Generic) FPPs that have been prequalified by WHO • Chinese version availablehttp://www.who.int/prequal/

6. Guidance on Variation to a prequalified dossier Three categories of variations according to their potential impact on pharmaceutical quality • Notification(mainly administrative) • Minor change (minor impact on quality) • Major change (major impact on quality), but not always as the option is used "by default" • Certain variations are considered "so major" that a new application is necessary

7. Guidance on Variation to a prequalified dossier To facilitate classification of various types of changes, the variation guide is composed of 4 Appendixes • Appendix I: lists minor changes, including notification (N). • Appendix II: definition and examples of major changes • Appendix III: changes that make a new application /extension application necessary • Appendix IV: stability requirements for variations and changes to Pre-qualified FPPs

8. Appendix I – Minor changes • Minor change is a variation which can be found listed in Appendix I. There are 40. • Notifications designed by letter "N" • Evaluation in 3 months • Considered as approved if no correspondance by WHO with the applicant has been initiated within 3 months • If validity of the change cannot be acknowledged, correspondance will be started before the period of 3 months

9. Appendix I – Minor changes • Each change is numbered and subcategories depicted by letters and numbers. Conditions necessary for a given change are outlined for each subcategory and listed below each change.Documentation to be submitted is identified including all parts of the dossier that are affected by the variation according to the structure of the Pharmaceutical Quality Information Form (PQIF)

10. Appendix I – Minor changes Example - Change in batch size of FPP • Identifythe variation number/subcategory • Confirm the fulfillment of the conditions, provide justification when appropriate • Provide the documentation as required

11. Conditions • The change does not affectreproducibility and/or consistency of the product. • The change relates only to standardimmediate-release oral pharmaceutical forms and to non-sterile liquid forms. • Any changes to the manufacturing method and/or to the in-process controls are only those necessitated by the change in batch size, e.g. use of different sized equipment. • Validation protocol is available or validation of the manufacture has been successfully carried out according to the current protocol with at least three batchesat the proposed new batch size in accordance with the WHO guideline on validation of manufacturing processes. • The change should not be the result of unexpected events arising during manufacture or because of stability concerns. • Relevant stability studies in accordance with the relevant guidelines have been started with at least one pilot scale or production scale batch and at least three months’ stability data are at the disposal of the applicant. Assurance is given that these studies will be finalized and that the data will be provided immediately to WHO if outside specifications or potentially outside specifications at the end of the prequalified shelf life (with proposed action).

12. Documentation • Replacement of the relevant pages of the dossier according to the structure as listed in the PQIF. • Batch analysis data(in a comparative tabulated format) on a minimum of one production batch manufactured to both the prequalified and the proposed sizes. Batch data on the next two full production batches should be available on request and should be reported immediately by the supplier of the prequalified product if outside specifications (with proposed action). • Copy of prequalified release and end-of-shelf life specifications. • The batch numbers (3) used in the validation study should be indicated or validation protocol (scheme) be submitted. • The batch numbers of batches used in the stability studies should be indicated. • For solid dosage forms: dissolution profile data on a minimum of one representative production batch and comparative data of the last three batches from the previous process; data on the next two full production batches should be available on request or reported if outside dissolution profile similarity requirements.

13. General considerations for variation applications • A justificationshould always be given why the change needs to be introduced • Comparisonof "present/prequalified“ and "proposed“ state in tabular format (transparency)

14. General considerations for variation applications • Some changes affectthe pharmaceutical particulars in the Summary of Product Characteristics (SmPC), labelling and/or package leaflet/insert Modification of these documents are to be considered part of the change. • Some changes are consequentialtherefore the application for variation should include documentation for all concerned variations:e.g.Change in test method along with change in specification, Variations 35 + 34

15. General considerations for variation applications • Conditions frame a particular variation • In case all conditions are met the variation is considered minor • In case one of all conditions is not met the variation is considered major • Documentation requirements beyond those of Variation Guide • Essential to clarify whether the conditions are met

16. Appendix I – Minor changes Experience with the Variation Guide in PQ • Only few types of variation predominantly occur • Change in batch size of FPP (No.29) • Additional new API source (No.12) • Extension shelf life of FPP (No.39) • Addition of FPP manufacturing site (No.5)

17. Appendix II – Major changes • Major changes • Exceed the scope of minor changes—doesn't fulfil the conditions • Do not yet reach the scope of Appendix III—new application necessary • Examples: • Change in themanufacturing process of the API • Change in the composition of the FPP • Change to the immediate primary packaging of the FPP • Applicant's responsibility to provide the relevant documentation to prove that the intended change will not affect the quality of the prequalified product negatively.

18. Appendix III – Changes making a new application/extension application necessary • Changes to the API • Change of the API to a different API, e.g. different salt/ester/derivative, different isomer • Changes to the pharmaceutical form/ dosage form • Change from an immediate-release product to a modified release dosage form or vice versa • Change from a liquid to a powder for reconstitution, or vice versa • Change or addition of a new route of administration

19. Appendix IV -Stability requirementsfor variations to Pre-qualified FPPs Responsibility of the pre-qualified supplierto investigate whether or not the intended change will have an impact on the quality characteristics of APIs and /or FPPs and consequently on their stability. • Base on the knowledge and experience acquired on APIs and FPPs (Stress testing, supportive data, accelerated and long-term testing) • At the time of submission, 3 or 6 months stability data should be provided according to the nature of the change, stability of the API, dosage form of the FPP,etc

20. Appendix IV -Stability requirementsfor variations to Pre-qualified FPPs Major changes requiring generation of new stability data • At least 1st production batch to be placed on long term stability testing using the approved protocol • Stability studies should be always continued to cover the entire shelf life accorded • Results should be made available to WHO on request and WHO should be informed immediately in case of OoS results

21. Guidance on Variation to a prequalified dossier • Categorize the variations based on the significance of the change and therefore the potential impact on quality as it relates to safety and efficacy of the product • Guidance are intended to gives assistance in how to adequately document variations, the recommended supporting data and change examples should not be considered exhaustive • It remains the applicant's responsibility to provide the relevant documentation to prove the intended change will not have a negative impact. • Pre-submission consultation with the agency –for classifying a change

22. Variation Guidance – Not a Panacea • There is no hormonized guidance for handling Variations • Guidance should be viewed only as recommendations, not be considered as exhaustive • Difficulty in classifying certain changes—grey areas • Update EMEA variation Guidance was official on Jan 2010 • PQ variation Guidance is under review • Consult guidance of other agencies for reference

23. Reference Guidelines EMEA update guidance, New Variations guidance implemented in January 2010. • Minor Type IA (IAIN ): "do and tell" • Minor Type IB : "tell ,wait and do" • Major Type II :prior approval • Extensions : As new submission • Urgent safety restriction : product information

24. Reference Guidelines Chinese SFDA: Variation guidance to pharmaceutical products (一)—issued in 2008. Categories : • I: minor; • II: Moderate; • III: major.

25. Reference Guidelines USFDA: Guidance for Industry • Change to an approved NDA or ANDA 2004 • SUPAC (Scale up and postapproval changes ) 1995 Catergories • Major: Prior approval supplement; (substantial potential to have adverse effect) • Moderate: changes being effected in 30 days & change being effected; • Minor: annual report.

26. Reference Guidelines Health Canada: Post-Notice of Compliance (NOC) changes—Quality documents, effective on 30 Sept. 2009 Catergories • Level 1: Supplemental New drug submission (Major); • Level 2: Notifiable change (moderate); • Level 3: Notice of change (No data submission, but should be available, minor); • Level 4: without notification. (not listed in level 1-3, manufacturers are expected to maintain a list of level 4 changes)

27. CONCLUSION • Any change to the content of the pre-qualified dossier should be reported • The change should not adversely affect the quality, safety and efficacy of the pre-qualified product • Position correctly the variation and to submit necessary data • Contact prequalification for assistance in classifying an unforeseen change pre-submission. Prequalassessment@who.int • No fees Charged to date

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