2. Theo Dekker -- Jiaxing, China --September 2007 2 |2 | WHO workshop on Quality, good manufacturing practice and bioequivalence with a focus on antituberculotics Jiaxing, China 5 to 9 November 2007 Introduction to: Dossier requirements and guidelines for generics (quality part) Theo Dekker, D.Sc. Research Institute for Industrial Pharmacy North-West University, Potchefstroom, South Africa

3. Theo Dekker -- Jiaxing, China --September 2007 3 |3 | The patient matters The joint efforts of WHO, manufacturers, procurement agencies & other role players should cover all activities aimed at ensuring that the patient receives a product that meets established standards of efficacy, safety & quality

4. Theo Dekker -- Jiaxing, China --September 2007 4 |4 | Abbreviations APIActive pharmaceutical ingredient APIMFAPI master file BCSBiopharmaceutics classification system BEBioequivalence BPBritish Pharmacopoeia CEPCertificate of suitability (Ph.Eur.) CPPWHO-type Certificate of a Pharmaceutical Product EOIExpression of interest FDCFixed-dose combination FPPFinished pharmaceutical product GMPGood manufacturing practices ICHInternational Conference on Harmonization PhEurEuropean Pharmacopoeia PhIntInternational Pharmacopoeia PILPatient information leaflet PQIFPharmaceutical quality information form SmPCSummary of product characteristics TBTuberculosis USPUnited States Pharmacopeia

5. Theo Dekker -- Jiaxing, China --September 2007 5 |5 | Objective To give brief overview of –Guidelines used in Prequalification Programme The guidelines are important for –Product development Safety, efficacy & quality –Preparation of submissions, for example Dossier PQIF (Pharmaceutical Quality Information Form) BTIF (Bioequivalence Trial Information Form) –Good manufacturing practices (GMP) –Good laboratory practices (GLP of BE studies)

6. Theo Dekker -- Jiaxing, China --September 2007 6 |6 | Where to find ? All information on the Prequalification Program? e.g. Guidelines Other training material on prequalification –Very useful for applicants and regulators Also –Current invitation for expression of interest –Assessment meeting dates

7. Theo Dekker -- Jiaxing, China --September 2007 7 |7 | Prequalification Programme website http://who.int/prequal/

8. Theo Dekker -- Jiaxing, China --September 2007 8 |8 | Focus – Quality aspects Multisource (generic) medicines –For Tuberculosis (TB) –Mainly first line TB medicines Rifampicin, isoniazid, pyrazinamide & ethambutol hydrochloride –Mainly oral solid dosage forms –Emphasis on fixed-dose combinations (FDCs)

9. Theo Dekker -- Jiaxing, China --September 2007 9 |9 | Important definitions Current WHO definitions Used throughout the presentations

10. Theo Dekker -- Jiaxing, China --September 2007 10 | WHO Technical Report Series 937 (2006) Multisource (generic) pharmaceutical products –Pharmaceutically equivalent or pharmaceutically alternative products that may or may not be therapeutically equivalent –Multisource pharmaceutical products that are therapeutically equivalent are interchangeable Pharmaceutical equivalent products –Contain the same API(s) in the same molar amount(s) in the same dosage form –Meet similar quality standards –Are intended for the same route of administration… –May or may not be therapeutically equivalent

11. Theo Dekker -- Jiaxing, China --September 2007 11 | WHO Technical Report Series 937 (2006) Pharmaceutical alternative products contain –the same molar amount of the same active pharmaceutical moiety(s), but differ in dosage form (e.g. tablets versus capsules) and/or differ in chemical form (e.g. different salts, different esters). Pharmaceutical alternatives –deliver the same active moiety by the same route of administration but are otherwise not pharmaceutically equivalent They may or may not be bioequivalent or therapeutically equivalent to the comparator product.

12. Theo Dekker -- Jiaxing, China --September 2007 12 | Product ingredients Active Pharmaceutical Ingredient (API) A substance or compound intended to be used in the manufacture of a pharmaceutical product as a therapeutically active compound (ingredient) Excipient A substance or compound, other than the API and packaging materials, that is intended or designated to be used in the manufacture of a pharmaceutical product

13. Theo Dekker -- Jiaxing, China --September 2007 13 | The product Pharmaceutical Product Any preparation for human or veterinary use that is intended to modify or explore physiological systems or pathological states for the benefit of the recipient Finished Pharmaceutical Product (FPP) A pharmaceutical product that has undergone all stages of production, including packaging in its final container & labelling

14. Theo Dekker -- Jiaxing, China --September 2007 14 | Guideline on generics Main generic guideline Guideline on submission of documentation for prequalification of multi-source (Generic) Finished Pharmaceutical Products (FPPs) used in treatment of HIV/AIDS, Malaria and Tuberculosis –with 8 annexes [under revision] –Supplement 1: Dissolution testing –Supplement 2: Extension of the WHO list of stable APIs (not easily degradable) [stability testing]

15. Theo Dekker -- Jiaxing, China --September 2007 15 | Generic Guideline Administrative part A:Covering letter by responsible person –Statement: information is true and correct B:Application (requirements for product dossier) 1.Four main sections (with subsections) 2.Keep to the sections/subsections as prescribed 3.Sections/subsections should be clearly marked preferably with securely fixed tags 4.Number all pages (essential) 5.Table of contents List sections, subsections – with page numbers 6.Include Annexes 7 & 8 (hard copy and CD-ROM)

16. Theo Dekker -- Jiaxing, China --September 2007 16 | Generic guideline Dossier requirements – main sections Section 1 Characteristics of the FPP (3/26) Section 2 Active Pharmaceutical Ingredients (APIs) (4/26) Section 3 Finished Pharmaceutical Products (FPPs) (10/26) Section 4 Interchangeability (Bioequivalence) (25/26)

17. Theo Dekker -- Jiaxing, China --September 2007 17 | Generic guideline Annexes (1 - 6) Annex 1: Model Certificate of a Pharmaceutical Product (CPP) Annex 2: Model Batch Certificate of Pharmaceutical Product Annex 3: Model Stability Report of API Annex 4: Model Stability Report of Capsules/Tablets Annex 5: Suggested Structure of the Summary of Product characteristics (SmPC) Annex 6: Suggested structure of the Package Information Leaflet (PIL)

18. Theo Dekker -- Jiaxing, China --September 2007 18 | Generic guideline Annexes (7 & 8) Annex 7: Presentation of Bioequivalence Trial Information (BTIF) (Zip Word file) Annex 8: Presentation of Pharmaceutical Quality Information (PQIF) (Zip Word file) Applicant must properly complete BTIF and PQIF –Provide detailed & accurate information, referenced to dossier Submit with application / dossier the following: 1.Hard copy of BTIF and PQIF – original & duly signed 2.Electronic (Word) copy of each on CD-ROM BTIF and PQIF are used for assessment reports (CD-ROM)

19. Theo Dekker -- Jiaxing, China --September 2007 19 | PQIF – example 1 Grey parts for assessors only Applicant fills out white parts ETH-400 Tablets Etambutol 400mg Tablets

20. Theo Dekker -- Jiaxing, China --September 2007 20 | Main guideline Annex 8 (PQIF) – Example 2 1001 1002 1003 Ethambutol hydrochloride Maize starch 400 20 1001 1002 1003 1001 80 4 4 4

21. Theo Dekker -- Jiaxing, China --September 2007 21 | Example of mock-up PQIF On Prequalification website (by Dr. J. Pogány): Training Workshop on Pharmaceutical Quality and Bioequivalence - Hanoi, Vietnam, 17 - 19 January 2006 –PQIF (API) –PQIF (FFP) Example shows how PQIF is: –filled out by applicant (typed in black) –assessed by first assessor (typed in red) –assessed by second assessor (typed in blue)

22. Theo Dekker -- Jiaxing, China --September 2007 22 | Copy from mock-up PQIF

23. Theo Dekker -- Jiaxing, China --September 2007 23 | Other guidelines on PQ website (1) Quality related Guideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure –Implemented since January 2007 Guidance on variations to a prequalified dossier –The prequalification process is dynamic, taking into account that changes to the original dossier may become necessary during the lifetime of the product –Any changes or variations are subject to approval within the prequalification program Some variations are notifications

24. Theo Dekker -- Jiaxing, China --September 2007 24 | Other guidelines on PQ website (2) Quality related Guidelines for registration of fixed-dose combination medicinal products (TRS 943) Innovators approved by ICH & associated DRAs –Guide on Submission of Documentation for Prequalification of 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 inter alia the EU, Japan and USA

25. Theo Dekker -- Jiaxing, China --September 2007 25 | ICH guidelines ICH guidelines are used when a quality aspect cannot be (fully) assessed by the WHO guidelines, for instance: –Q3A(R2). Impurities in new drug substances –Q3B(R2). Impurities in new drug products –Q3C(R3). Impurities: Guideline for residual solvents –Q6A. Specifications: Test procedures and acceptance criteria for new drug substances and new drug products: chemical substances (with decision trees)

26. Theo Dekker -- Jiaxing, China --September 2007 26 | Closing remarks 1.The dossier submitted must conform to the requirements set out in the current WHO guidelines, as posted on the Prequalification website –PQIF & BTIF (Word format) –APIMF procedure 2.The assessment of data is based on the current WHO guidelines –ICH guidelines are used when a quality aspect cannot be assessed by the WHO guidelines 3.The quality assessment includes variations or changes to already prequalified products 4.Quality is built in by design, not tested in

27. Theo Dekker -- Jiaxing, China --September 2007 27 | the patient matters