1. 2006.08.21. Pogány - Tanzania 1/36 WHO Training Workshop on Pharmaceutical Quality, GMP and Bioequivalence János Pogány, pharmacist, PhD consultant to WHO Tanzania, 21 August 2006 E-mail: pogany.janos@chello.hupogany.janos@chello.hu Expression of Interest and Guidelines on Assessment of Applications for Prequalification

2. 2006.08.21. Pogány - Tanzania 2/36 Abbreviations APIActive Pharmaceutical Ingredient DRADrug Regulatory Authority EoI Expression of Interest FDCFixed-Dose Combination FPPFinished Pharmaceutical Product GMPGood Manufacturing Practices ICHInternational Conference on Harmonization MAMarketing Authorization PQPrequalification TRSTechnical Report Series Yellow → emphasis Green → WHO Blue → ICH region

3. 2006.08.21. Pogány - Tanzania 3/36 Objectives of the workshop WHO Prequalification Program is motivated:  to involve countries that want to benefit from the (currently free-of-charge) PQ Program, and  to provide more information to African regulators about the ongoing activities and discuss how countries could cooperate in the area of do ssier assessment and GMP inspection.

4. 2006.08.21. Pogány - Tanzania 4/36 Subjects for discussion 1. Interchangeability of multisource (generic) FPPs 2. EoI for Antimalarial Drugs 3. Global quality issues 4. Prequalification Experience – Illustrative deficiencies 5. Pharmaceutical Quality Information Form 6. Main points again

5. 2006.08.21. Pogány - Tanzania 5/36 Interchangeability (IC) Interchangeability (IC) of multisource FPPs = (Essential similarity with innovator FPP) = Pharmaceutical equivalence ( PE ) + Bioequivalence (BE) IC = PE + BE

6. 2006.08.21. Pogány - Tanzania 6/36 INACTIVE INGREDIENTS ACTIVE INGREDIENTS PACKING MATERIALS FPP Manufacturing process Manufacturin g authorization Marketing authorization GMP standards Pharmacopeia standards NATIONAL DRA1 NATIONAL DRA2 CRITICAL VARIABLES OF FPP QUALITY

7. 2006.08.21. Pogány - Tanzania 7/36 Pharmaceutical equivalence  FPPs meet same or comparable standards (pharmacopoeia, marketing authorization)  Same API (chemical and physical equivalence)  Same dosage form and route of administration  Same strength  Dissolution profile equivalence, when applicable  Comparable labeling  WHO-GMP (batch-to-batch uniformity of quality)  Stability equivalence

8. 2006.08.21. Pogány - Tanzania 8/36 High quality-risk APIs  FPP is not registered in the ICH region and associated countries  API is not official in the internationally used major pharmacopoeias and ICH guidelines should be used for evaluation  Reference standard/comparator is not available for:  Pharmaceutical equivalence studies  Bioequivalence studies  Require particular attention by NDRA as regards assessment of applications for marketing authorization

9. 2006.08.21. Pogány - Tanzania 9/36 Low quality-risk APIs 1. Certificate of suitability (CEP) is submitted (DRA) 2. Drug Master File  Open part (APPLICANT)  Closed part (DRA) 3. Pharmacopeia monograph is available  Literature evidence of stability  Synthesis impurities and degradants are controlled by monograph  Class1 solvents excluded; class2 / class 3 solvents controlled 4. FPP is registered in the ICH region (DRA)

10. EXPRESSION of INTEREST (4th edition, May 2005) Artemisinin-based Antimalarial FPPs

11. 2006.08.21. Pogány - Tanzania 11/36 EoI – Oral Preparations  Artesunate* + Amodiaquine  Artemether* + Lumefantrine*  Artesunate* + Mefloquine  Artesunate* + SP (sulphadoxine / pyrimethamine) * Assessed originally by ICH guidelines * High quality-risk API +... FDC or co-blistered (co-packaged) FPPs All oral FPPs include paediatric formulations. (EOI is included in the Notes Page of this and the subsequent slides)

12. 2006.08.21. Pogány - Tanzania 12/36 EoI – Other dosage forms  Artemether Injection and rectal FPPs  Artemotil (arteether) Injection  Artesunate Injection and rectal FPPs Only FPPs listed in the EOI are assessed.

13. 2006.08.21. Pogány - Tanzania 13/36 History and Current Status  First EOI published on 8 May 2002  Assessment of dossiers started in July 2002  FPPs [51 applications (2 cancelled) - five (three FPPs) approvals as at 1 July 2006]. Antimalarial FPPs –manufactured in Africa – have not yet been prequalified.  Problems delaying prequalification are discussed in forthcoming slides

14. GLOBAL QUALITY ISSUES ANTIMALARIAL FPPs

15. 2006.08.21. Pogány - Tanzania 15/36 Global regulatory issues  If the product has been locally developed and manufactured, the national DRA must evaluate the data set itself (p. 23) 1.  If an evaluation report —critical summary and interpretation of the data, with conclusions— is not available it is not possible to seek a WHO-type certificate (p. 23) 1.

16. 2006.08.21. Pogány - Tanzania 16/36 Global regulatory issues API or FPP originate „legally” from countries where:  Manufacture of APIs is not regulated  Pharmaceutical exports and imports are not regulated  MA of FPPs is issued without evaluation or with a check-list assessment by the national NDRA

17. 2006.08.21. Pogány - Tanzania 17/36 Global regulatory issues  Formal stability studies are not required for MA  Biostudies are not required for MA  National Good Manufacturing Practices (GMP) do not comply with WHO-GMP requirements  API was not official in internationally used major pharmacopoeias (artemisinines and ARVs)

18. 2006.08.21. Pogány - Tanzania 18/36 Artemisin-derivative issues  No innovator FPP is registered in the ICH region. No comparator was available for:  Pharmaceutical equivalence studies  Bioequivalence studies  The APIs and FPPs were not official in the internationally used major pharmacopoeias  WHO guides/SOPs apply to multisource FPPs. ICH guides had to be used.

19. PREQUALIFICATION EXPERIENCE ILLUSTRATIVE EXAMPLES OF DEFICIENCIES

20. 2006.08.21. Pogány - Tanzania 20/36 Chemical synthesis  Detailed information on the synthesis of non- compendial APIs —or a flow chart and textbook- level narrative on official APIs— was not provided.  The final purification, crystallization and subsequent operations were not described in details.  Existence/absence of polymorphs, hydrates/solvates, solubility in water and organic solvents at 25 o C, pK a, hygroscopicity data were not submitted.

21. 2006.08.21. Pogány - Tanzania 21/36 Stability testing  Stress stability (forced degradation) testing was limited to analytical method validation studies and were conducted under harsh conditions to produce degradants that may not be observed under the accelerated stress studies.  “Room temperature and accelerated stability tests are in progress.”

22. 2006.08.21. Pogány - Tanzania 22/36 Specifications of API  The melting point is 143-145 o C (p.4) as opposed to 131-134 o C ± 1.5 o C in the DMF.  Individual impurity limits were not based on batch analysis results and they were not in line with the ICH guidelines (e.g., NMT 1.0% instead of NMT 0.1%).  Residual solvents were included in the in-house monograph but not in the DMF.

23. 2006.08.21. Pogány - Tanzania 23/36 Specifications of API  No adequate information was provided on the preparation and quality specification of primary (absolute) and secondary (working) standards. (For instance, lack of complete CoA, assay by two different validated methods, detailed information on storage, etc.).  HPLC method is described as an alternative assay to titration but acceptance limits are 97- 103% as opposed to 98-102% in the DMF.

24. 2006.08.21. Pogány - Tanzania 24/36 Development pharmaceutics  A report was not submitted to identify and describe the formulation and process attributes that can influence batch reproducibility, product performance and FPP quality, including stability.  A tabulated summary of the compositions of the FPP used in clinical trials or stability studies and a presentation of dissolution profiles was not provided.. Dissolution time was not studied at all.

25. 2006.08.21. Pogány - Tanzania 25/36 Stability of FPP and SmPC  Degradants, dissolution rate and profile, water content, hardness, microbiological attributes, etc. were not tested or quantified.  A national DRA-approved Summary of Product Characteristics (SmPC) type information for health professionals was not submitted.

26. 2006.08.21. Pogány - Tanzania 26/36 Correspondence with manufacturers  The stress data show that the blister pack does not protect the tablets even if overwrapped by additional protective packing. Supplier reduced expiry date.  Analysis of the tests for microbiological purity on „two (2) batches showed contamination with an invading yeast.”

27. PREQUALIFICATION QUALITY REQUIREMENTS STANDARDS, GUIDELINES and TEMPLATES

28. 2006.08.21. Pogány - Tanzania 28/36 International Pharmacopoeia  Artemether  Artemisinin  Artemotil  Artenimol  Artesunate  Mefloquine Hydrochloride  Proguanil Hydrochloride BP

29. 2006.08.21. Pogány - Tanzania 29/36 International quality standards  Amodiaquine USP  Amodiaquine Hydrochloride USP  Lumefantrine  Pyrimethamine BP, PhEur, PhInt, USP  Sulphadoxine BP, PhEur, PhInt, USP

30. 2006.08.21. Pogány - Tanzania 30/36 Prequalification quality guidelines 1. Guide on Submission of Documentation for Prequalification of innovator Finished Pharmaceutical Products (FPPs) used in the treatment of HIV/AIDS, malaria and tuberculosis and approved by Drug Regulatory Authorities (DRAs) in the International Conference on Harmonization (ICH) region and associated countries, including among others the EU, Japan and USA

31. 2006.08.21. Pogány - Tanzania 31/36 Prequalification quality guidelines 2. Guideline on Submission of Documentation for Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis, together with eight (8) annexes. 3. Guidance on Variations to a Prequalified Dossier

32. 2006.08.21. Pogány - Tanzania 32/36 Prequalification quality guidelines 4. Supplement 1 [for use from July 2005 (CPH25)] - Dissolution testing 5. Supplement 2 – Revision 1[for use from May 2006 (CPH31)] - Extension of the WHO List of Stable (not easily degradable ARV) APIs 1 1 World Health Organization, WHO Technical Report Series, No. 863, 1996. Annex 5 Guidelines for stability testing of pharmaceutical products containing well-established drug substances in conventional dosage forms.

33. 2006.08.21. Pogány - Tanzania 33/36 Annex 8 to the Generic Guideline Pharmaceutical Quality Information Form The PQIF contains summary information provided by the applicant on critical pharmaceutical quality attributes –chemistry, pharmaceutical formulation, manufacturing process and product performance– and their relevance to safety and efficacy, following the structure of the Generic Guideline and frequently in tabulated forms. Focus on analytical and stability issues, development pharmaceutics and specifications.

34. 2006.08.21. Pogány - Tanzania 34/36 Main points again 1. WHO provides information to African regulators and pharmaceutical manufacturers about the ongoing activities of the PQ program and discuss how countries could further benefit from cooperation in the area of dossier assessment and GMP inspection. 2. The EoI limits the number of FPPs. 3. Many DRAs did not assess generic FPPs –used in the treatment of HIV/AIDS, malaria and tuberculosis– and most manufacurers did not have dossiers for MA, at the beginning of PQ.

35. 2006.08.21. Pogány - Tanzania 35/36 Main points again 4. Artemisinin-derived APIs and FPPs were marketed at global level for decades without meeting basic standards of quality. 5. It takes time to get into prequalification compliance  Develop new formulation  Data to be generated, tests carried out  GMP upgrade needed 6. Increase in the number of prequalified Artesunate Tablets is expected because there has been an official comparator since 2005.

36. 2006.08.21. Pogány - Tanzania 36/36 PLEASE MAKE USE OF THE OPPORTUNITY TO PARTICIPATE IN THE PREQUALIFICATION PROJECT