Workshop on Quality Assurance and GMP of Multisource HIV /AIDS medicines

1. János Pogány, pharmacist, PhD, consultant to WHO Shanghai, 01 March 2005 E-mail: pogany@axelero.hu Workshop on Quality Assurance and GMP of Multisource HIV/AIDSmedicines Experience with prequalification of HIV/AIDS products: product dossier assessment Dr. Pogány - WHO, Shanghai

2. ABBREVIATIONS and NOTES API(s) Active pharmaceutical ingredient(s) ARV Antiretroviral EOI Expression of interest FPP(s) Finished pharmaceutical product(s) ICH International Conference on Harmonization MLEM Model List of Essential Medicines NDRA National Drug Regulatory Authority Ph.Eur. European Pharmacopoeia IP International Pharmacopoeia USP United States Pharmacopeia Text in green refers to WHO guidelines or requirements Text in yellow indicates an assessment issue Dr. Pogány - WHO, Shanghai

3. SUBJECTS FOR DISCUSSION • Interchangeability of FPPs • Classification of ARV FPPs • Deficiencies observed in the evaluation of dossiers • Regulatory issues • Correspondence with FPP manufacturers • Conclusions Dr. Pogány - WHO, Shanghai

4. INTERCHANGEABILITYOF FPPs Pharmaceutical equivalence

5. INTERCHANGEABILITY (IC) INTERCHANGEABILITY (IC) OF MULTISOURCE FPPs = (ESSENTIAL SIMILARITY WITH INNOVATOR FPP) = PHARMACEUTICAL EQUIVALENCE (PE) + BIOEQUIVALENCE (BE) IC = PE+ BE Dr. Pogány - WHO, Shanghai

6. PHARMACEUTICAL EQUIVALENCE • FPPs MEET SAME ORCOMPARABLESTANDARDS (pharmacopoeia, marketing authorization) • SAME API (chemical and physical equivalence) • SAME DOSAGE FORM AND ROUTE OF ADMINISTRATION • SAMESTRENGTH • COMPARABLE LABELING • WHO-GMP(batch-to-batch uniformity of quality) • STABILITY EQUIVALENCE Dr. Pogány - WHO, Shanghai

7. FACTORS INFLUENCING PE INACTIVE INGREDIENTS ACTIVE INGREDIENTS PACKING MATERIALS GMP standards Manufacturing authorization FPP MANUFACTURER Marketing authorization Pharmacopeiastandards NATIONAL DRA1 NATIONAL DRA2 Dr. Pogány - WHO, Shanghai

8. Classification of ARV FPPs 13th MODEL LIST OF ESSENTIAL MEDICINESandEXPRESSION OF INTEREST(January 2004)

9. BLUE BOOK DEFINITIONS MULTISOURCE1 (generic) pharmaceutical products are pharmaceutically equivalent products that may or may not be therapeutically equivalent. Multisource pharmaceutical products that are therapeutically equivalent are interchangeable. 1 Many manufacturers by definition. Dr. Pogány - WHO, Shanghai

10. BLUE BOOK DEFINITIONS WELL-ESTABLISHED drug products • have been marketed for at least five years in countries that undertake active post­marketing monitoring; • have been widely used to permit the assumption that safety and efficacy are well known; and • have the same route of administration and strength, and the same or similar indications as in those countries where the innovator FPP was approved. Dr. Pogány - WHO, Shanghai

11. WELL-ESTABLISHED CRITERION • Zidovudine (Retrovir™, 19 March 1987*) • Didanosine (Videx™, 9 October 1991*) • Stavudine(Zerit™, 24 June 1994*) • Lamivudine (Epivir™, 17 November 1995*) • Saquinavir (Invirase™, 6 December 1995*) • Indinavir (Crixivan™, 13 March 1996*) • Nevirapine (Viramune™, 21 June 1996*) • Ritonavir (Norvir™, 1 March 1996*) *Approval date of the first pharmaceutical dosage form for sales in the USA Dr. Pogány - WHO, Shanghai

12. WELL-ESTABLISHED CRITERION • Nelfinavir(Viracept™, 14 March 1997*) • Abacavir (Ziagen™, 17 December 1998 *) • Efavirenz (Sustiva™, 17 September 1998 *) • Lopinavir + Ritonavir (Kaletra™, 15 September 2000*) • Tenofovir(new class, Viread™, 26 October 2001*) *Approval date of the first pharmaceutical dosage form for sales in the USA Dr. Pogány - WHO, Shanghai

13. FIXED-DOSE COMBINATIONS (EOI)1 • LAMIVUDINE + STAVUDINE • LAMIVUDINE + ZIDOVUDINE • LAMIVUDINE + STAVUDINE + EFAVIRENZ • LAMIVUDINE + STAVUDINE + NEVIRAPINE • LAMIVUDINE + ZIDOVUDINE + EFAVIRENZ • LAMIVUDINE + ZIDOVUDINE + NEVIRAPINE 1 There is no innovator for the above FDCs. Well-established criterion refers to co-administration. Dr. Pogány - WHO, Shanghai

14. CLASSIFICATION MATRIX Dr. Pogány - WHO, Shanghai

15. ARV APIs and FPPs • are typically available from more than one manufacturerbut not always from many suppliers; • except (Lopinavir + Ritonavir) and Tenofovir, others are well-establishedby WHO criteria; • FPPs containan API not yet official in an internationally recognized pharmacopoeia. Dr. Pogány - WHO, Shanghai

16. LOW-RISK APIs • CERTIFICATE OF SUITABILITY (DRA) • DRUG MASTER FILE • OPEN PART (APPLICANT) • CLOSED PART(DRA) • PHARMACOPEIA MONOGRAPH • LITERATURE EVIDENCE OF STABILITY • SYNTHESIS IMPURITIES ARE CONTROLLED BY MONOGRAPH (toxicology of additional impurities) • CLASS1 SOLVENTS EXCLUDED, CLASS2 SOLVENTS CONTROLLED • FPP IS REGISTERED IN THE ICH REGION Dr. Pogány - WHO, Shanghai

17. HIGH-RISK APIs and FPPs • Reference standard/comparator is not available for: • Pharmaceutical equivalence studies • Bioequivalence studies • APIsand FPPsarenot official inthe internationally used major pharmacopoeias • WHO guides/SOPsapply to multisource FPPs. ICH guidesshould be used for evaluation. • Require particular attention by NDRA as regards assessment of applications for marketing authorization. Dr. Pogány - WHO, Shanghai

18. HIGH-RISK ARV APIs • Abacavir • Efavirenz • Indinavir • Lopinavir • Nelfinavir • Ritonavir • Stavudine • Tenofovir Dr. Pogány - WHO, Shanghai

19. HIGH-RISK ARV FPPs • ABACAVIRtablets 300mg, oral solution 20 mg/ml • TENOFOVIR tablets 300mg • LAMIVUDINE +STAVUDINE • LAMIVUDINE + ZIDOVUDINE • LAMIVUDINE + STAVUDINE + EFAVIRENZ • LAMIVUDINE + STAVUDINE + NEVIRAPINE • LAMIVUDINE + ZIDOVUDINE + EFAVIRENZ • LAMIVUDINE + ZIDOVUDINE + NEVIRAPINE Dr. Pogány - WHO, Shanghai

20. Deficiencies observed in the evaluation of dossiers REGULATORY ISSUES

21. GLOBAL ISSUES API or FPP originate „LEGALLY” from countries where: • Manufacture of APIsisnot regulated • Pharmaceutical exports and importsare not regulated • Marketing Authorizations [MA(s)] of FPPs areissued without evaluation by the national drug regulatory authority (NDRA) for locally developed andmanufacturedFPPs • Nevertheless, WHO-type certificates are issued Dr. Pogány - WHO, Shanghai

22. GLOBAL ISSUES • Pharmaceutical R + D studiesarenotyetrequiredfor MA • Stability studieswere not requiredfor MA • Validation studies arenotyetrequired for MA • Bioequivalence studies arenotyetrequiredfor MA • NationalGood Manufacturing Practices are not commensurate WHO-GMP requirements Dr. Pogány - WHO, Shanghai

23. Deficiencies observed in the evaluation of dossiers ILLUSTRATIVE EXAMPLES FROM CORRESPONDENCE WITH MANUFACTURERS

24. CRITICAL API DEFICIENCIES • Synthesis impurities, including residual solvents, which may be present in API, were not characterised and analysed. • Residual solventswere included in the DMF but not in the API specification (skip testing). • Class2 solvents: pyridine and chloroform were used in the synthesis and not tested in the API. • “Further efforts are made to improve the process.” Dr. Pogány - WHO, Shanghai

25. CRITICAL API DEFICIENCIES • 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%). • The preparation and quality specification of primary (absolute) and secondary (working) standardswere not described. Analytical validation information-including experimental data for the analytical procedures used for testing the API and impurities-were not provided. Dr. Pogány - WHO, Shanghai

26. CRITICAL API DEFICIENCIES • Forced degradation studies were not done: • to document the intrinsic stability of the molecule (sensitivity of the API to potential effects of the external environment – selection of containers) • to identify the likely degradants • for demonstration of the stability-indicating power of assay method • for the stability studies of the FPP • Available stability data revealed possible degradation and justified only a one (1) year re-test date. Dr. Pogány - WHO, Shanghai

27. CRITICAL FPP DEFICIENCIES • Pharmaceutical R + D data were only exceptionallysubmitted. When provided, they did not capture the failures. • A dissolutionmethod wasnot integrated inthe quality control and stability programs. • A tabulated summary of the compositions of the pivotal (clinical, bioequivalence and validation) FPP batches and presentation of the relevant dissolution profileswere not provided. Batch size!!! Dr. Pogány - WHO, Shanghai

28. CRITICAL FPP DEFICIENCIES • Documented evidencewasnot providedthat packaging materialshad been selected to ensure the quality of the FPP throughout its shelf life. • Validation reportswerenot providedon pilot batches and the first three production scale baches. • Annual quality reviewdata and analysiswerenot submitted. Dr. Pogány - WHO, Shanghai

29. SPECIFICATION DEFICIENCIES • The maximum acceptable deviation in the API content of the FPP was frequently reported as±10% of the label claim at batch release. • Degradation productswere not reported and justificatication was not offered for their absence. • Analytical methods were frequently not validated,or not properly validated, or not verified. • Microbiological purity was not tested (skip testing) Dr. Pogány - WHO, Shanghai

30. STABILITY DEFICIENCIES • A systematic approach was not adopted in the presentation and evaluation of the stability information, which did not include results from the physical, chemical, biological and microbiological tests, and excluded particular attributes of the dosage form (e.g., dissolution rate for solid oral dosage forms, hardness of tablets, LOD, etc.). • Data for all attributes were not organizedseparately and each attribute was not evaluated in the report. • Shelf life acceptance criteria were not derived from consideration of all available stability information. Dr. Pogány - WHO, Shanghai

31. HEALTH INFORMATION DEFICIENCIES • A Summary of Product Characteristics (SmPC) –aimed at medical practitioners and other health professionals and approved by the competent authority at the time of licensing–was not submitted, a major deficiency when an innovator product does not exist, e.g., generic ARV FDCs. • The package insertsdistributed to the patientswere not in conformity with the SmPC and the stability results (e.g., storage conditions). Dr. Pogány - WHO, Shanghai

32. Main points again • When a multisource FPP does not meet requirements for pharmaceutical equivalence, then it is not interchangeable with the innovator FPP. • Many ARV APIsarenotyet officialin internationally used major pharmacopoeias and specificationshave to be developed in house, including reference standards, validated analytical methods for assay and impurity tests. • For FDC FPPs without innovator product, pharmaceutical R + D rather than pharmaceutical equivalence should be demonstrated. Dr. Pogány - WHO, Shanghai

33. Main points again • Regulatory requirements ofNDRAsarenot commensurate with those of theinternational standards of WHO. • ARV FPPshad been on the market for years but most of them did not meet basic standards of qualityat the beginning of the project. • Lack ofSmPC for health professionals and leaflets for patients information are critical deficiencies in case of FPPs without innovator product. Dr. Pogány - WHO, Shanghai

34. CONCLUSIONS • It takes time to get into compliance • Develop new formulations • Data to be generated, tests carried out • GMP upgrade needed • Success with antiretroviral FPPs justifies joint efforts of manufacturers and WHO Dr. Pogány - WHO, Shanghai

35. THANK YOU 谢谢! Dr. Pogány - WHO, Shanghai