1. 2004.05.03. Dr. Pogány - Geneva 1/30 PREQUALIFICATION OF ANTIMALARIAL DRUG PRODUCTS János Pogány, pharmacist, Ph.D. Geneva, 03 May 2004 E-mail: pogany@axelero.hupogany@axelero.hu Assessment of product dossiers – Quality part

2. 2004.05.03. Dr. Pogány - Geneva 2/30 SUBJECTS FOR DISCUSSION 1.Expression of Interest for Antimalarial Drugs 2.Prequalification Requirements for Quality of Active Pharmaceutical Ingredients (APIs) and Finished Pharmaceutical Products (FPPs) 3.Quality Issues  Global issues  APIs  FPPs 4.Major Conclusions

3. EXPRESSION OF INTEREST ANTIMALARIAL FPPs

4. 2004.05.03. Dr. Pogány - Geneva 4/30 EXPRESSION OF INTEREST (cont.) Dihydroartemisinin (tablets, capsules, paediatric granules, suppositories) Artemether (oral FPPs ) Artemether (intramuscular FPPs ) Artemether + Lumefantrine (oral FPPs) Artemotil (injectable FPPs)

5. 2004.05.03. Dr. Pogány - Geneva 5/30 (cont.) EXPRESSION OF INTEREST Artesunate (oral FPPs) Artesunate + Mefloquine (oral FPPs) Artesunate + Amodiaquine (oral FPPs) Artesunate + Sulphadoxine/Pyrimethamine (oral FPPs)

6. 2004.05.03. Dr. Pogány - Geneva 6/30 HISTORY and CURRENT STATUS First EOI published on 8 May 2002 Assessment of dossiers started on July 2002 FPPs (37 applications - 2 approvals as at 31 March 2004) WHO-GMP inspection of the manufacturing sites of the applicants

7. PREQUALIFICATION QUALITY REQUIREMENTS ANTIMALARIAL DRUGS

8. 2004.05.03. Dr. Pogány - Geneva 8/30 PREQUALIFICATION REQUIREMENTS 1. http://www.who.int/medicines/library/qsm/ma nual-on-marketing/who-dmp-rgs-985.doc 2. http://www.who.int/medicines/organization/qs m/activities/qualityassurance/gmp/gmpcover.h tml 3. WHO/HTP/EDM/QSM/2001: Standard Operating Procedure: Assessing Product Files 4. International Conference on Harmonization (ICH) guidelines

9. 2004.05.03. Dr. Pogány - Geneva 9/30 PREQUALIFICATION 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).

10. 2004.05.03. Dr. Pogány - Geneva 10/30 PREQUALIFICATION REQUIREMENTS Summary of Product Characteristics (SmPC) Package insert Labels Preferably approved by the NDRA

11. GLOBAL REGULATORY ISSUES ARTEMISIN DERIVATIVES

12. 2004.05.03. Dr. Pogány - Geneva 12/30 GLOBAL REGULATORY ISSUES (cont.) API OR FPP ORIGINATE „LEGALLY” FROM COUNTRIES WHERE: Manufacture of APIs is not regulated Pharmaceutical exports and imports are not regulated

13. 2004.05.03. Dr. Pogány - Geneva 13/30 (cont.) GLOBAL REGULATORY ISSUES Marketing Authorization (MA) of FPPs is issued without evaluation by the National Drug Regulatory Authority (NDRA) Biostudies are not required for MA National Good Manufacturing Practices (GMP) do not comply with WHO-GMP requirements

14. 2004.05.03. Dr. Pogány - Geneva 14/30 ARTEMISIN-DERIVATIVE ISSUES NO INNOVATOR FPP IS REGISTERED IN THE ICH REGION. NO COMPARATOR IS AVAILABLE FOR:  PHARMACEUTICAL EQUIVALENCE STUDIES  BIOEQUIVALENCE STUDIES THE APIs and FPPs ARE NOT OFFICIAL IN THE INTERNATIONALLY USED MAJOR PHARMACOPOEIAS WHO GUIDES/SOPs APPLY TO MULTISOURCE FPPs. ICH GUIDES SHOULD BE USED.

15. ILLUSTRATIVE API QUALITY ISSUES EXAMPLE OF ARTESUNATE

16. 2004.05.03. Dr. Pogány - Geneva 16/30 ARTEMISININ - ARTESUNATE ArtemisininArtesunate

17. 2004.05.03. Dr. Pogány - Geneva 17/30 SYNTHESIS DEFICIENCIES Potential synthesis by-products, solvents 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 are not submitted.

18. 2004.05.03. Dr. Pogány - Geneva 18/30 SPECIFICATIONS OF API AND FPP MANUFACTURERS (1) 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 monograph but not in the DMF.

19. 2004.05.03. Dr. Pogány - Geneva 19/30 SPECIFICATIONS OF API AND FPP MANUFACTURERS (2) 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.

20. 2004.05.03. Dr. Pogány - Geneva 20/30 INTERNATIONAL PHARMACOPOEIA ARTEMETHER ARTEMISININ ARTEMOTIL ARTENIMOL ARTESUNATE MEFLOQUINE HYDROCHLORIDE PROGUANIL HYDROCHLORIDE

21. 2004.05.03. Dr. Pogány - Geneva 21/30 STABILITY Stress stability (forced degradation) tests were not submitted to identify existence or absence degradants and to substantiate specificity of the impurity test method. “Room temperature and accelerated tests are in progress.” Results were not submitted.

22. 2004.05.03. Dr. Pogány - Geneva 22/30 CORRESPONDENCE WITH MANUFACTURERS Substantial degradation was observed at high temperature and under intensive light. Class2 solvents: pyridine and chloroform are used in the synthesis. Impurities: “Further efforts are made to improve the process.” The currently available stabilty data reveal possible decomposition and justify only a one (1) year re-test date.

23. ILLUSTRATIVE FPP QUALITY ISSUES EXAMPLE OF ARTESUNATE TABLETS

24. 2004.05.03. Dr. Pogány - Geneva 24/30 REGULATORY ISSUES Marketing authorization in the country of manufacture is not issued. Marketing authorization in the country of manufacture and Certificate of Pharmaceutical Product (CPP) is issued by the NDRA without assessment of the FPP quality.

25. 2004.05.03. Dr. Pogány - Geneva 25/30 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.

26. 2004.05.03. Dr. Pogány - Geneva 26/30 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 the first three (3) full scale batches to establish the nature and specifications of subsequent in-process and final tests as well as provide assurance that the manufacturing process met expected results.

27. 2004.05.03. Dr. Pogány - Geneva 27/30 STABILITY and SmPC Degradants, dissolution rate and profile, water content, hardness, microbiological attributes, etc. were not tested or quantified. A NDRA-approved Summary of Product Characteristics (SmPC) type information for health professionals was not submitted.

28. 2004.05.03. Dr. Pogány - Geneva 28/30 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.”

29. 2004.05.03. Dr. Pogány - Geneva 29/30 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.

30. 2004.05.03. Dr. Pogány - Geneva 30/30 MAJOR CONCLUSIONS (cont.) Initially, artemisinin-derived FPPs did not meet basic standards of quality It takes time to get into compliance  Develop new formulation  Data to be generated, tests carried out  GMP upgrade needed One FPP is prequalified from a DC; another is registered in the ICH region.