1. 2006.01.17. Pogány - Hanoi 1/40 Training Workshop on Pharmaceutical Quality and Bioequivalence, 17-19 January 2006 János Pogány, pharmacist, Ph.D. consultant to WHO Hanoi, Vietnam, 17 January 2006 E-mail: pogany@t-online.hupogany@t-online.hu Procedures for Participation in the Prequalification Project

2. 2006.01.17. Pogány - Hanoi 2/40 Abbreviations APIActive Pharmaceutical Ingredient DRADrug Regulatory Authority EoI Expression of Interest FDCFixed-Dose Combination FPPFinished Pharmaceutical Product GMPGood Manufacturing Practices of WHO ICHInternational Conference on Harmonization MAMarketing Authorization PQPrequalification

3. 2006.01.17. Pogány - Hanoi 3/40 Subjects for discussion 1. Expectations of participants 2. Interchangeability of FPPs 3. EoI 4. Global quality issues 5. Illustrative PQ Requirements for Quality of APIs and FPPs 6. Pharmaceutical Quality Information Form 7. Main points again

4. 2006.01.17. Pogány - Hanoi 4/40 Expectations of participants 1. Procedures for participation in the PQ project 2. Expression of Interest 3. Documentation to be discussed  Guidelines for drafting a Site Master File (SMF)  Guidelines on submission of documentation for multi-source (generic) FPPs Quality part Bioequivalence part 4. The workshop should be interactive with questions and answers after each major point of the guidelines.

5. 2006.01.17. Pogány - Hanoi 5/40 Interchangeability (IC) Interchangeability (IC) of multisource FPPs = (Essential similarity with innovator FPP) = Pharmaceutical equivalence ( PE ) + Bioequivalence (BE) IC = PE + BE

6. 2006.01.17. Pogány - Hanoi 6/40 Pharmaceutical equivalence  FPPs meet same or comparable standards (pharmacopoeia, marketing authorization)  Same API (chemical and physical equivalence of specifications)  Same dosage form and route of administration  Same strength  Comparable labeling  WHO-GMP (batch-to-batch uniformity of quality)  Stability equivalence

7. 2006.01.17. Pogány - Hanoi 7/40 High-risk APIs and FPPs  Reference standard/comparator is not available for :  Pharmaceutical (dissolution) 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 national DRA as regards assessment of applications for MA

8. 2006.01.17. Pogány - Hanoi 8/40 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

9. SIXTH EXPRESSION OF INTEREST October 2005 HIV and related diseases Illustrative examples

10. 2006.01.17. Pogány - Hanoi 10/40 EOI – Oral Preparations 1. Antiretrovirals as single-ingredient formulations for use in adults and adolescents 2. Anti-retrovirals as fixed-dose combinations 3. Anti-infective drugs  Antibacterial and antimycobacterial agents  Antiprotozoal and antifungal agents  Antiviral agents  Anti-cancer drugs  Palliative care drugs

11. 2006.01.17. Pogány - Hanoi 11/40 Antiretrovirals Nucleoside/Nucleotide Reverse Transcriptase Inhibitors  Abacavir  Didanosine  Lamivudine  Stavudine  Tenofovir  Zidovudine Only FPPs listed in the EOI are assessed.

12. 2006.01.17. Pogány - Hanoi 12/40 Antiretrovirals Non-Nucleoside Reverse Transcriptase Inhibitors  Efavirenz  Nevirapine Protease Inhibitors  Indinavir  Nelfinavir  Saquinavir  Ritonavir

13. 2006.01.17. Pogány - Hanoi 13/40 Antiretrovirals - paediatric FPPs Reduced and/or scored solid dosage formulations of:  Abacavir  Efavirenz  Lamivudine  Nevirapine  Zidovudine http://www.who.int/3by5/paediatric/en/

14. 2006.01.17. Pogány - Hanoi 14/40 Anti-retrovirals as FDCs Reverse Transcriptase Inhibitors  Lamivudine + Stavudine  Lamivudine + Zidovudine (Combivir)  Lamivudine + Stavudine + Efavirenz  Lamivudine + Stavudine + Nevirapine  Lamivudine + Zidovudine + Efavirenz  Lamivudine + Zidovudine + Nevirapine  Lamivudine + Zidovudine + Abacavir (Trizivir)  Tenofovir + Emtricitabine Protease Inhibitors  Lopinavir + Ritonavir http://webitpreview.who.int/entity/3by5/publications/documents/arv_guidelines/en/

15. 2006.01.17. Pogány - Hanoi 15/40 Paediatric FDCs Reduced and/or scored solid dosage formulations of: Reverse Transcriptase Inhibitors  Lamivudine + Stavudine  Lamivudine + Zidovudine  Lamivudine + Stavudine + Nevirapine  Lamivudine + Zidovudine + Nevirapine  Lamivudine + Zidovudine + Abacavir Protease Inhibitors  Lopinavir + Ritonavir

16. 2006.01.17. Pogány - Hanoi 16/40 Co-packaged FPPs Co-packaged preparations of the standard ARV combinations, for adult, adolescent and paediatric use are also sought

17. 2006.01.17. Pogány - Hanoi 17/40 EOI requirements  The medicines listed in this Invitation for Expression of Interest are those for which a need has been identified by the HIV/AIDS department, WHO. The submitted products should be of assured pharmaceutical quality and relevant data to support efficacy should be provided. Procedure for submission of EOI: 1. Submit a covering letter expressing the interest to participate in the project, confirming that the information submitted in the product dossiers is correct.

18. 2006.01.17. Pogány - Hanoi 18/40 EOI requirements 2. Submit a product dossier in the recommended format as specified in the „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.” The dossier should be accompanied by a sample of the product to enable analysis (e.g. 1 x 100 Tablets). 3. Submit a Site Master File for each manufacturing site as listed in the product dossier, in the recommended format. http://mednet3.who.int/prequal/

19. 2006.01.17. Pogány - Hanoi 19/40 EOI – assessment criteria  Valid manufacturer’s license for production  Product registered or licensed in accordance with national requirements  Products manufactured in compliance with GMP as certified by the national regulatory authority and/or certified GMP inspectors  Product certificates exist in accordance with the WHO certification scheme on the quality of pharmaceutical products moving in international commerce  Product dossiers of acceptable quality submitted and outcome of the assessment in respect of the pre-qualification procedure  Outcome of the inspection performed by or on behalf of the above-mentioned agencies  Manufacturer demonstrates sound financial standing

20. 2006.01.17. Pogány - Hanoi 20/40 History and current status  First EOI published and assessment of dossiers started in 2001  ARV FPPs [316 applications (15 cancelled) - many approvals as at January 2006]  Generic ARV FPPs were scarcely available at the beginning of the project, while there are many suppliers today  Problems delaying prequalification

21. GLOBAL QUALITY ISSUES FPPs in general

22. 2006.01.17. Pogány - Hanoi 22/40 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 DRA

23. 2006.01.17. Pogány - Hanoi 23/40 Global regulatory issues  Formal stability studies were not required for MA  Biostudies were not required for MA  National Good Manufacturing Practices (GMP) do not comply with WHO-GMP requirements

24. Illustrative Prequalification Requirements for Quality of APIs and FPPs ILLUSTRATIVE EXAMPLES

25. 2006.01.17. Pogány - Hanoi 25/40 WHO general requirements  If the product has been locally developed and manufactured, the NDRA must evaluate the data set itself (p. 23).  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).

26. 2006.01.17. Pogány - Hanoi 26/40 General evaluation issues  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. This is still the situation today for example:  Efavirenz  Emtricitabine  Tenofovir and new monographs are continuously improved  New evaluation issues surfaced with FDC.

27. 2006.01.17. Pogány - Hanoi 27/40 Synthesis deficiencies  Potential synthesis impurities (e.g., by-products, solvents) were not tested and representative batch scale were not provided  The final purification, crystallization and subsequent operations were not described in details.  Existence/absence of polymorphs, particle size, bulk and tapped density and hygroscopicity were not submitted

28. 2006.01.17. Pogány - Hanoi 28/40 Specifications  Stress stability (forced degradation) tests were not submitted to identify existence or absence degradants and to substantiate specificity of the impurity test method.  Degradants, dissolution rate and profile, water content, hardness, microbiological attributes, etc. of FPPs were not tested or quantified.  No adequate information was provided on the preparation and quality specification of primary (absolute) and secondary (working) analytical standards. (For instance, lack of complete CoA, assay by two different validated methods, detailed information on storage, etc.).

29. 2006.01.17. Pogány - Hanoi 29/40 Development pharmaceutics  A report was not submitted to identify and describe the critical product 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 (bioequivalence), stability and validation studies was not presented and, in case of formulation changes, dissolution profiles was not provided..

30. 2006.01.17. Pogány - Hanoi 30/40 Concurrent validation  The progress from pre-formulation → formulation → pilot manufacture → production scale manufacture was not shown in the submission.  There was no validation report on not less the than first three (3) production scale batches to establish the nature and specifications of subsequent in-process acceptance criteria and final tests as well as provide assurance that the manufacturing process met expected results.

31. 2006.01.17. Pogány - Hanoi 31/40 Retrospective validation Annual quality review data and analysis were not submitted to prove that the manufacturing processes —including equipment, buildings, personnel and materials— are capable of achieving the intended results on a consistent and continuous basis.

32. 2006.01.17. Pogány - Hanoi 32/40 SmPC and PIL  A national DRA-approved Summary of Product Characteristics (SmPC) type information for health professionals was not submitted or it was not based on documented facts and figures.  Patient Information Leaflet (PIL) was not based on the SmPC

33. PREQUALIFICATION QUALITY REQUIREMENTS FPPs in general

34. 2006.01.17. Pogány - Hanoi 34/40 Prequalification guidelines (1) 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

35. 2006.01.17. Pogány - Hanoi 35/40 Prequalification guidelines (2) 2. WHO/DMP/RGS/98.5 Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products: A Manual for Drug Regulatory Authorities (The Blue Book) 3. 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.

36. 2006.01.17. Pogány - Hanoi 36/40 Annexes to Generic Guide 1. Model Certificate of a Pharmaceutical Product 2. Model Batch Certificate of a Pharmaceutical Product 3. Model Stability Report of Active Pharmaceutical Ingredient (API) 4. Model Stability Report of Capsules/Tablets 5. Suggested Structure of the Summary of Product Characteristics 6. Suggested Structure of the Package Information Leaflet 7. Presentation of bioequivalence trial information 8. Presentation of pharmaceutical quality information

37. 2006.01.17. Pogány - Hanoi 37/40 Prequalification guidelines (3) 4. Supplement 1 [for use from July 2005 (CPH25)] - Dissolution testing 5. Supplement 2 [for use from July 2005 (CPH25)] - 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.

38. 2006.01.17. Pogány - Hanoi 38/40 Prequalification guidelines (4) 5. Guidance on Variations to a Prequalified Dossier 6. 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.

39. 2006.01.17. Pogány - Hanoi 39/40 MAIN POINTS AGAIN 1. The workshop deals with selected aspects of procedures of prequalification 2. The EoI limits the number of FPPs to the list 3. National DRA have not assessed generic FPPs –used in the treatment of HIV/AIDS, malaria and tuberculosis– and most manufacurers have not had dossiers for MA, at the beginning of PQ. 4. It has taken time to get into prequalification compliance  Develop new formulation  Data to be generated, tests carried out  GMP upgrade needed 5. Generic ARV FPPs are widely available as a result of PQ.

40. 2006.01.17. Pogány - Hanoi 40/40 THANK YOU