3.2.S.3.2 Impurities, Malaysia, 29 September 2011

1. Active Pharmaceutical Ingredient (API) Prequalification Dr Antony Fake WHO Prequalification Team - Medicines 3.2.S.3.2 Impurities, Malaysia, 29 September 2011 1

2. Abbreviations • API – Active Pharmaceutical Ingredient (drug substance) • FPP – Finished Pharmaceutical Product (drug product) • APIMF – Active Pharmaceutical Ingredient Master File (DMF) • API-PQ –Active Pharmaceutical Ingredient Prequalification • SRA – Stringent Regulatory Authority • GMP – Good Manufacturing Practice • PQP – Prequalification Team - Medicines

3. Prequalification Programme The Prequalification Team – Medicines (PQP) is responsible for ensuring that Medicines available to procurers (and national authorities) are of good quality. In order to have good quality medicines you must have: • Good quality Active Pharmaceutical Ingredients.

4. Prequalification Programme The programme has two primary objectives: • To ensure there is available essential APIs and FPPs that are of good quality. • To support manufacturers of essential APIs and FPPs to meet international regulatory standards.

5. API Prequalification

6. What is API Prequalification? • It is a scheme for manufacturers of APIs that are used in medicinal products for HIV, TB, Reproductive Health, Malaria, Neglected Tropical diseases and Zinc. • It seeks to verify and identify APIs that are of good quality and manufactured in compliance with GMP. • It commenced as a pilot project in October 2010.

7. Why is Prequalification of APIs needed? • There is a relative scarcity of API. • There are significant geographical distances between API and FPP manufacturers, i.e. between China and India. • The quality and GMP status of the API manufacturer may not be clear. Medicine manufacturers involved in the PQ programme (and in general) have difficulties in finding sources of quality APIs for Malaria, HIV, Reproductive Health and TB, because: This creates basic problems for FPP manufacturers to find and establish contact with potential API manufacturers.

8. 6th Invitation for EOI • Not all APIs are invited to apply for prequalification. • APIs are publicly invited through a published invitation for expression of interest (EOI). • A 6th invitation for Expressions of Interest (EOI) has now been announced. • It essentially covers those APIs listed in the associated FPP EOIs for HIV, anti-TB, Malaria, reproductive health neglected tropical diseases and Zinc. • See website for the invitation: http://www.who.int/prequal/info_applicants/API_info_applicants.htm

9. 6th Invitation for EOI

10. Benefits to API manufacturers • API’s can be prequalified independent of an FPP application. • Public recognition as a source of quality API, manufactured in compliance with GMP. • Serves as a point of difference between good quality and poor quality APIs. • Opportunities to verify compliance with GMP. • Opportunities to compile, revise and refine their regulatory documentation, leading to quicker acceptance by other national regulatory agencies. • API PQ is increasingly recognised by National authorities.

11. Benefits to FPP manufacturers • Ease of identifying potential sources of quality API. • Identifying API manufacturers with robust quality systems in place. • Identifying API manufacturers that maintain good regulatory documentation, which may be used in regulatory submissions.

12. Prequalification of Medicines website http://www.who.int/prequal

13. What is API Prequalification? It is a scheme for API manufacturers only API Prequalification API Manufacturer There is no involvement by FPP manufacturers

14. Application Invitation Application Assessment (GMP) Assessment (Quality) Decision Publishing

15. Application • The PQ application form. • An APIMF (if not previously provided). • A Site Master File (if not previously provided). • Any further evidence of GMP at the facility (optional). An application should consist of:

16. Assessment – Quality (APIMF) Invitation Application Assessment (GMP) Assessment (Quality) Decision Publishing

17. APIMF - Technical content Excellent technical guidance can be found in the module 3.2.S sections (pages 11 to 31) of the recently published guideline : Guideline on submission of documentation for a multisource (generic) finished pharmaceutical product (FPP): quality part. http://www.who.int/prequal/info_general/documents/generic_guide/GenericGuideline_Quality.pdf

18. Assessment – GMP • By providing evidence of current compliance: • GMP certificates, inspection reports, CAPAs, the most recently completed Product Quality Review (PQR) report. or • By inspection by the WHO. There are two ways to demonstrate GMP compliance at the API manufacturing facility.

19. Assessment – GMP • Inspections performed previously by WHO, a member of PIC/S, or an SRA. • Inspection must have occurred within 3 years of application. • Inspections must be API specific. Assessment of GMP compliance at the site of API manufacture takes into account: The WHO will perform an inspection if, after assessment and requests for information, GMP compliance can not be established.

20. Publishing Invitation Application Assessment (GMP) Assessment (Quality) Decision Publishing

21. Publishing + WHOPIRs Website (Public) List of PQ APIs Website (Public) Confirmation Document (Private)

22. Publishing The date of prequalification is the date when the API is published on the WHO List of Prequalified Active Pharmaceutical ingredients. http://www.who.int/prequal/info_applicants/API_PQ-List.htm

23. WHO List of Prequalified APIs Publically available • WHO application number. • INN name. • Date of prequalification. • Name of the applicant • Sites of API manufacture. • The APIMF version number. • The API specification version number. • The primary and secondary packaging components. • The assigned re-test period. • The recommended storage conditions. • Confirmation of API PQ document issue date Intended for: UN agencies, National medicine authorities, FPP manufacturers, public

24. Confirmation of API PQ document • The assigned WHO application number. • The INN name of the active pharmaceutical ingredient. • API manufacturer company name. • The API specification version number. • A copy of the API specifications. • The assigned re-test period. • The recommended storage conditions. • A copy of the assay and related substances test methods. Provided to the API manufacturer for distribution at their discretion Intended for: UN agencies, National medicine authorities, FPP manufacturers

25. Future of API Prequalification • There is very positive feedback from FPP manufacturers whenever PQ of APIs is discussed. • Applications and the number of prequalified APIs continues to increase.

26. New procedures and guidance • Elimination of paper based submission for APIs • Introduction of electronic document requirements http://www.who.int/prequal/info_applicants/API_procedural_guidance.htm • Introduction of a new Amendment guidance http://www.who.int/prequal/info_applicants/API_amendment_introduction.htm

27. Use among NMRAs • Efforts are being undertaken to increase the recognition of PQ APIs by NMRAs to further increase the value of participation and to reduce regulatory burden on NMRAs. • This includes the use of Prequalified APIs in non-PQP FPPs. • CPQs are now recognised by regulators of the East African Community as a means of submitting API information. • CPQs are actively considered by many Southern African Regulators as a means of verifying API information. • South Africa is currently considering recognition of CPQs.

28. Further information The PQ website is a good source of information, please read. http://www.who.int/prequal/info_applicants/API_info_applicants.htm AND, ALSO Please email me (or visit) if you have any questions. Fakea@who.int One email could save you a lot of time.

29. 谢谢你