1. 2005.03.01. Dr. Pogány - WHO, Shanghai 1/35 Workshop on Quality Assurance and GMP of Multisource HIV/AIDS medicines János Pogány, pharmacist, PhD, consultant to WHO Shanghai, 01 March 2005 E-mail: pogany@axelero.hupogany@axelero.hu Experience with prequalification of HIV/AIDS products: product dossier assessment

2. 2005.03.01. Dr. Pogány - WHO, Shanghai 2/35 ABBREVIATIONS and NOTES API(s)Active pharmaceutical ingredient(s) ARVAntiretroviral EOIExpression of interest FPP(s)Finished pharmaceutical product(s) ICHInternational Conference on Harmonization MLEMModel List of Essential Medicines NDRANational Drug Regulatory Authority Ph.Eur.European Pharmacopoeia IPInternational Pharmacopoeia USPUnited States Pharmacopeia Text in green refers to WHO guidelines or requirements Text in yellow indicates an assessment issue

3. 2005.03.01. Dr. Pogány - WHO, Shanghai 3/35 SUBJECTS FOR DISCUSSION 1.Interchangeability of FPPs 2.Classification of ARV FPPs 3.Deficiencies observed in the evaluation of dossiers  Regulatory issues  Correspondence with FPP manufacturers 4.Conclusions

4. INTERCHANGEABILITY OF FPPs Pharmaceutical equivalence

5. 2005.03.01. Dr. Pogány - WHO, Shanghai 5/35 INTERCHANGEABILITY (IC) INTERCHANGEABILITY (IC) OF MULTISOURCE FPPs = (ESSENTIAL SIMILARITY WITH INNOVATOR FPP) = PHARMACEUTICAL EQUIVALENCE ( PE ) + BIOEQUIVALENCE (BE) IC = PE + BE

6. 2005.03.01. Dr. Pogány - WHO, Shanghai 6/35 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  COMPARABLE LABELING  WHO-GMP (batch-to-batch uniformity of quality)  STABILITY EQUIVALENCE

7. 2005.03.01. Dr. Pogány - WHO, Shanghai 7/35 INACTIVE INGREDIENTS ACTIVE INGREDIENTS PACKING MATERIALS FPP MANUFACTURER Manufacturin g authorization Marketing authorization GMP standards Pharmacopei astandards NATIONAL DRA1 NATIONAL DRA2 FACTORS INFLUENCING PE

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

9. 2005.03.01. Dr. Pogány - WHO, Shanghai 9/35 BLUE BOOK DEFINITIONS MULTISOURCE 1 (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.

10. 2005.03.01. Dr. Pogány - WHO, Shanghai 10/35 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.

11. 2005.03.01. Dr. Pogány - WHO, Shanghai 11/35 WELL-ESTABLISHED CRITERION  Zidovudine (Retrovir™, 19 March 1987* )*  Didanosine (Videx™, 9 October 1991*)*  Stavudine  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

12. 2005.03.01. Dr. Pogány - WHO, Shanghai 12/35 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

13. 2005.03.01. Dr. Pogány - WHO, Shanghai 13/35 FIXED-DOSE COMBINATIONS (EOI) 1 STAVUDINE  LAMIVUDINE + STAVUDINE  LAMIVUDINE + ZIDOVUDINE STAVUDINE  LAMIVUDINE + STAVUDINE + EFAVIRENZ STAVUDINE  LAMIVUDINE + STAVUDINE + NEVIRAPINE  LAMIVUDINE + ZIDOVUDINE + EFAVIRENZ  LAMIVUDINE + ZIDOVUDINE + NEVIRAPINE 1 There is n o innovator for the above FDCs. Well-established criterion refers to co-administration.

14. 2005.03.01. Dr. Pogány - WHO, Shanghai 14/35 CLASSIFICATION MATRIX Market availability of FPP Therapeutic experience Quality standard Monopoly Limited to well established Innovator’s specification Oligopoly Less than five yearsIn-house generic specification Oligopoly, innovator exists Well establishedIn-house generic specification Oligopoly, innovator does not exist Well establishedIn-house generic specification MultisourceWell establishedOfficial compendia

15. 2005.03.01. Dr. Pogány - WHO, Shanghai 15/35 ARV APIs and FPPs  are typically available from more than one manufacturer but not always from many suppliers;  except (Lopinavir + Ritonavir) and Tenofovir, others are well-established by WHO criteria;  FPPs contain an API not yet official in an internationally recognized pharmacopoeia.

16. 2005.03.01. Dr. Pogány - WHO, Shanghai 16/35 LOW-RISK APIs 1.CERTIFICATE OF SUITABILITY (DRA) 2.DRUG MASTER FILE  OPEN PART (APPLICANT)  CLOSED PART (DRA) 3.PHARMACOPEIA MONOGRAPH  LITERATURE EVIDENCE OF STABILITY  SYNTHESIS IMPURITIES ARE CONTROLLED BY MONOGRAPH (toxicology of additional impurities)  CLASS1 SOLVENTS EXCLUDED, CLASS2 SOLVENTS CONTROLLED 4.FPP IS REGISTERED IN THE ICH REGION

17. 2005.03.01. Dr. Pogány - WHO, Shanghai 17/35 HIGH-RISK APIs and FPPs  Reference standard/comparator is not available for :  Pharmaceutical equivalence studies  Bioequivalence studies  APIs and FPPs are not official in the internationally used major pharmacopoeias  WHO guides/SOPs apply to multisource FPPs. ICH guides should be used for evaluation.  Require particular attention by NDRA as regards assessment of applications for marketing authorization.

18. 2005.03.01. Dr. Pogány - WHO, Shanghai 18/35 HIGH-RISK ARV APIs  Abacavir  Efavirenz  Indinavir  Lopinavir  Nelfinavir  Ritonavir  Stavudine  Tenofovir

19. 2005.03.01. Dr. Pogány - WHO, Shanghai 19/35 HIGH-RISK ARV FPPs  ABACAVIR tablets 300mg, oral solution 20 mg/ml  TENOFOVIR tablets 300mg STAVUDINE  LAMIVUDINE + STAVUDINE  LAMIVUDINE + ZIDOVUDINE STAVUDINE  LAMIVUDINE + STAVUDINE + EFAVIRENZ STAVUDINE  LAMIVUDINE + STAVUDINE + NEVIRAPINE  LAMIVUDINE + ZIDOVUDINE + EFAVIRENZ  LAMIVUDINE + ZIDOVUDINE + NEVIRAPINE

20. Deficiencies observed in the evaluation of dossiers REGULATORY ISSUES

21. 2005.03.01. Dr. Pogány - WHO, Shanghai 21/35 GLOBAL ISSUES API or FPP originate „LEGALLY” from countries where:  Manufacture of APIs is not regulated  Pharmaceutical exports and imports are not regulated  Marketing Authorizations [MA(s)] of FPPs are issued without evaluation by the national drug regulatory authority (NDRA) for locally developed and manufactured FPPs,  Nevertheless, WHO-type certificates are issued

22. 2005.03.01. Dr. Pogány - WHO, Shanghai 22/35 GLOBAL ISSUES  Pharmaceutical R + D studies are not yet required for MA  Stability studies were not required for MA  Validation studies are not yet required for MA  Bioequivalence studies are not yet required for MA  National Good Manufacturing Practices are not commensurate WHO-GMP requirements

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

24. 2005.03.01. Dr. Pogány - WHO, Shanghai 24/35 CRITICAL API DEFICIENCIES  Synthesis impurities, including residual solvents, which may be present in API, were not characterised and analysed.  Residual solvents were 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.”

25. 2005.03.01. Dr. Pogány - WHO, Shanghai 25/35 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) standards were not described. Analytical validation information - including experimental data for the analytical procedures used for testing the API and impurities - were not provided.

26. 2005.03.01. Dr. Pogány - WHO, Shanghai 26/35 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.

27. 2005.03.01. Dr. Pogány - WHO, Shanghai 27/35 CRITICAL FPP DEFICIENCIES  Pharmaceutical R + D data were only exceptionally submitted. When provided, they did not capture the failures.  A dissolution method was not integrated in the 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 profiles were not provided. Batch size!!!

28. 2005.03.01. Dr. Pogány - WHO, Shanghai 28/35 CRITICAL FPP DEFICIENCIES  Documented evidence was not provided that packaging materials had been selected to ensure the quality of the FPP throughout its shelf life.  Validation reports were not provided on pilot batches and the first three production scale baches.  Annual quality review data and analysis were not submitted.

29. 2005.03.01. Dr. Pogány - WHO, Shanghai 29/35 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 products were 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)

30. 2005.03.01. Dr. Pogány - WHO, Shanghai 30/35 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 organized separately and each attribute was not evaluated in the report.  Shelf life acceptance criteria were not derived from consideration of all available stability information.

31. 2005.03.01. Dr. Pogány - WHO, Shanghai 31/35 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 inserts distributed to the patients were not in conformity with the SmPC and the stability results (e.g., storage conditions).

32. 2005.03.01. Dr. Pogány - WHO, Shanghai 32/35 Main points again 1. When a multisource FPP does not meet requirements for pharmaceutical equivalence, then it is not interchangeable with the innovator FPP. 2. Many ARV APIs are not yet official in internationally used major pharmacopoeias and specifications have to be developed in house, including reference standards, validated analytical methods for assay and impurity tests. 3. For FDC FPPs without innovator product, pharmaceutical R + D rather than pharmaceutical equivalence should be demonstrated.

33. 2005.03.01. Dr. Pogány - WHO, Shanghai 33/35 Main points again 4. Regulatory requirements of NDRAs are not commensurate with those of the international standards of WHO. 5. ARV FPPs had been on the market for years but most of them did not meet basic standards of quality at the beginning of the project. 6. Lack of SmPC for health professionals and leaflets for patients information are critical deficiencies in case of FPPs without innovator product.

34. 2005.03.01. Dr. Pogány - WHO, Shanghai 34/35 CONCLUSIONS 7. It takes time to get into compliance  Develop new formulations  Data to be generated, tests carried out  GMP upgrade needed 8. Success with antiretroviral FPPs justifies joint efforts of manufacturers and WHO

35. 2005.03.01. Dr. Pogány - WHO, Shanghai 35/35 THANK YOU 谢谢 !