1. 1 TG Dekker – WHO, UkraineOctober 2005 Introduction to Dossier Requirements and Guidelines within the Prequalification Project (quality part) World Health Organization Training Workshop on Pharmaceutical Quality, GMP and Bioequivalence Kiev - Ukraine 3 to 7 October 2005 Theo Dekker, D.Sc., consultant to WHO Research Institute for Industrial Pharmacy North-West University, Potchefstroom, South Africa iiftgd@puk.ac.za

2. 2 TG Dekker – WHO, UkraineOctober 2005 Some abbreviations used in all presentations APIActive pharmaceutical ingredient BPBritish Pharmacopoeia CEPEU certificate of suitability CPPWHO-type Certificate of a Pharmaceutical Product EOIExpression of interest FDCFixed-dose combination FPPFinished pharmaceutical product ICHInternational Conference on Harmonization Int.Ph.International Pharmacopoeia IRInfrared Ph.Eur.European Pharmacopoeia SmPCSummary of product characteristics TBTuberculosis USPUnited States Pharmacopeia XRPDX-ray powder diffractogram

3. 3 TG Dekker – WHO, UkraineOctober 2005 Prequalification website http://mednet3.who.int/prequal/

4. 4 TG Dekker – WHO, UkraineOctober 2005 PQ Website – menu Bio group GMP group publication on QC testing Jan 06

5. 5 TG Dekker – WHO, UkraineOctober 2005 PQ Website – product dossiers Frequently asked questions  Which products do we prequalify?  What data and information needs to be submitted in a dossier for a generic product?  What data and information needs to be submitted in a dossier for an innovator product?  What does a manufacturer have to submit to prove efficacy of a multi-source generic product?  How often are dossiers assessed? Click on question to get to answer

6. 6 TG Dekker – WHO, UkraineOctober 2005 PQ Website – menu Bio group GMP group publication on QC testing Jan 06 ✔

7. 7 TG Dekker – WHO, UkraineOctober 2005 Guidelines for submission (from web) 1 2

8. 8 TG Dekker – WHO, UkraineOctober 2005 Guideline (“Main”) FPPs not approved by ICH/associated DRA Guideline on Submission of Documentation for Prequalification of Multisource (Generic) Finished Pharmaceutical Products (FPPs) used in the Treatment of HIV/AIDS, Malaria and Tuberculosis (“main guideline”, hand-out) Based on Marketing Authorization of Pharmaceutical Products with special Reference to Multisource (Generic) Products: a Manual for a Drug Regulatory Authority (WHO Blue Book, current edition)

9. 9 TG Dekker – WHO, UkraineOctober 2005 Multisource products: Blue Book  Multisource products are pharmaceutically equivalent  Pharmaceutically equivalent products  Contain the same API(s) in the same amount(s) in the same dosage form  Meet similar quality standards  Are intended for the same route of administration  Multisource products that are therapeutically equivalent are interchangeable

10. 10 TG Dekker – WHO, UkraineOctober 2005 Main guideline Administrative 1/50 A:Covering letter by responsible person  Statement: information is true and correct B:Application (Product dossier)  Four main sections (with subsections)  Keep to the sections/subsections as prescribed  Sections/subsections should be clearly marked preferably with securely fixed tags  Number all pages (essential)  Table of contents List sections, subsections – with page numbers

11. 11 TG Dekker – WHO, UkraineOctober 2005 Main Guideline Dossier requirements – main sections Section 1 Characteristics of the FPP (3/50) Section 2 Active Pharmaceutical Ingredients (APIs) (4/50) Section 3 Finished Pharmaceutical Products (FPPs) (10/50) Section 4 Interchangeability (Bioequivalence) (25/50)

12. 12 TG Dekker – WHO, UkraineOctober 2005 Main guideline Annexes Annex 1: Model Certificate of a Pharmaceutical Product 27/50 Annex 2: Model Batch Certificate of a Pharmaceutical Product 31/50 Annex 3: Model Stability Report of Active Pharmaceutical Ingredient (API) 33/50 Annex 4: Model Stability Report of Capsules/Tablets 36/50 Annex 5: Suggested Structure of the Summary of Product Characteristics (SmPC) 40/50 Annex 6: Suggested structure of the Package Information Leaflet (PIL) 43/50 Annex 7: Recommended presentation of bioequivalence trial information 45/50

13. 13 TG Dekker – WHO, UkraineOctober 2005 Main guideline: Supplements Supplement 1 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 Dissolution Testing for use from July 2005 (CPH25)

14. 14 TG Dekker – WHO, UkraineOctober 2005 Main guideline: Supplements Supplement 2 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 Extension of the WHO List of Stable (not easily degradable ARV) APIs (for stability testing) for use from July 2005 (CPH25)

15. 15 TG Dekker – WHO, UkraineOctober 2005 Guideline FPPs 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

16. 16 TG Dekker – WHO, UkraineOctober 2005 PQ Website – menu Bio group GMP group publication on QC testing Jan 06 ✔ ✔

17. 17 TG Dekker – WHO, UkraineOctober 2005 Guidelines: FDCs Fixed-Dose Combinations (FDCs) Draft guidelines for registration of fixed-dose combination medicinal products (WHO, 2005) comprehensive on all aspects of safety, efficacy and quality Scientific and Technical Principles for Fixed Dose Combination Drug Products for Treatment of HIV/AIDS, Malaria, and Tuberculosis (HHS, UNAIDS, WHO & SADC, 2004) (“Botswana Principles”)

18. 18 TG Dekker – WHO, UkraineOctober 2005 ICH guidelines ICH guidelines are used when a quality aspect cannot be (fully) assessed by the WHO guidelines, for instance:  Q3A(R). Impurities in new drug substances  Q3B(R). Impurities in new drug products  Q3C. 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)

19. 19 TG Dekker – WHO, UkraineOctober 2005 Prequalification project Variation Guideline To be published soon on PQ website  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 may involve administrative and/or more substantial changes and are subject to approval within the prequalification program

20. 20 TG Dekker – WHO, UkraineOctober 2005 Prequalification project Variation Guideline (2)  ANNEX I  List of minor changes The conditions which must apply is stipulated The relevant part of the dossier to be resubmitted or updated, with the documentation required, is listed  ANNEX II  Lists major changes in general  ANNEX III  Lists types of changes which may require a new application

21. 21 TG Dekker – WHO, UkraineOctober 2005 Closing remarks 1.The dossier submitted must conform to the requirements set out in the current WHO guidelines, as posted on web 2.The assessment of quality and safety/efficacy data presented is based on the current WHO guidelines 3.ICH guidelines are used when a quality aspect cannot be assessed by the WHO guidelines 4.The quality assessment includes variations or changes to already prequalified products