1. WHO Prequalification of APIs - Shanghai 2014 1 |1 | 1 1 3.2.S.3.2 Impurities, Malaysia, 29 September 2011 Active Pharmaceutical Ingredient (API) Prequalification Dr Antony Fake WHO Prequalification Team - Medicines

2. WHO Prequalification of APIs - Shanghai 2014 2 |2 | 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 Abbreviations

3. WHO Prequalification of APIs - Shanghai 2014 3 |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. WHO Prequalification of APIs - Shanghai 2014 4 |4 | 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. Prequalification Programme

5. WHO Prequalification of APIs - Shanghai 2014 5 |5 | API Prequalification

6. WHO Prequalification of APIs - Shanghai 2014 6 |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. WHO Prequalification of APIs - Shanghai 2014 7 |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. WHO Prequalification of APIs - Shanghai 2014 8 |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 6 th 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. WHO Prequalification of APIs - Shanghai 2014 9 |9 | 6th Invitation for EOI Invited Active Pharmaceutical IngredientTherapeutic area Abacavir, Atazanavir, Darunavir, Dolutegravir, Efavirenz, Emtricitabine, Etravirine, Lamivudine, Lopinavir, Nelfinavir, Nevirapine, Raltegravir, Ritonavir, Stavudine, Tenofovir, Zidovudine HIV Amodiaquine, Artemether, Artesunate, Dihydroartemisinin, Lumefantrine, Mefloquine, Piperaquine, Pyrimethamine, Pyronaridine, Sulfadoxine Anti-malarial Amikacin, Capreomycin, Clofazimine, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Kanamycin, Levofloxacin, Linezolid, Moxifloxacin, PAS, PAS Sodium, Prothionamide, Pyrazinamide, Rifampicin, Streptomycin, Terizidone Anti-tuberculosis Desogestrel, Estradiol cypionate, Estradiol valerate, Ethinylestradiol, Etonogestrel, Levonorgestrel, Medroxyprogesterone acetate, Mifepristone, Misoprostol, Norethisterone enanthate, Norgestrel, Oxytocin Reproductive health Albendazole, Diethylcarbamazine citrate, Mebendazole, Praziquante NTD Zinc Sulphate Zinc Oseltamivir, Zanamivir Influenza

10. WHO Prequalification of APIs - Shanghai 2014 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. WHO Prequalification of APIs - Shanghai 2014 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. WHO Prequalification of APIs - Shanghai 2014 12 | Prequalification of Medicines website http://www.who.int/prequal

13. WHO Prequalification of APIs - Shanghai 2014 13 | What is API Prequalification? API Manufacturer API Prequalification It is a scheme for API manufacturers only There is no involvement by FPP manufacturers

14. WHO Prequalification of APIs - Shanghai 2014 14 |ApplicationApplication Invitation Application Assessment (GMP) Assessment (Quality) Decision Publishing

15. WHO Prequalification of APIs - Shanghai 2014 15 |ApplicationApplication 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. WHO Prequalification of APIs - Shanghai 2014 16 | Assessment – Quality (APIMF) Invitation Application Assessment (GMP) Assessment (Quality) Decision Publishing

17. WHO Prequalification of APIs - Shanghai 2014 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/Generic Guideline_Quality.pdf

18. WHO Prequalification of APIs - Shanghai 2014 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. WHO Prequalification of APIs - Shanghai 2014 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. WHO Prequalification of APIs - Shanghai 2014 20 |PublishingPublishing Invitation Application Assessment (GMP) Assessment (Quality) Decision Publishing

21. WHO Prequalification of APIs - Shanghai 2014 21 |PublishingPublishing List of PQ APIs Website (Public) Confirmation Document (Private) + WHOPIRs Website (Public)

22. WHO Prequalification of APIs - Shanghai 2014 22 |PublishingPublishing 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 Prequalification of APIs - Shanghai 2014 23 | WHO List of Prequalified APIs 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 Publically available

24. WHO Prequalification of APIs - Shanghai 2014 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. WHO Prequalification of APIs - Shanghai 2014 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. May 2014Dec 2013Dec 2012Dec 2011 1081006936Total number of applications 6151288Number of PQ APIs

26. WHO Prequalification of APIs - Shanghai 2014 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. WHO Prequalification of APIs - Shanghai 2014 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. WHO Prequalification of APIs - Shanghai 2014 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. WHO Prequalification of APIs - Shanghai 2014 29 | 谢谢你