1. Sultan Ghani WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Dossier Requirements for Generic Medicines and Quality Guidelines

2. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Focus of Presentation Part A: Organization and principal of assessment Part B: Organization of data and regulatory dossier Part C: Introduction to PQP Guidelines Part D: Other Relevant Documents and Guidelines

3. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. PART A: PART A: Organization and principal of assessment

4. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E.Introduction WHO Procedure of assessment is based on the following principles:  Reliance of the information supplied by DRA  Understanding of production and quality control of the manufacturer  Assessment of data and information on safety, efficacy and quality  GMP compliance of sites for APIs and FPPs  GCP / GLP compliance  Random sampling and testing  Distribution recalls and complaints

5. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Steps of the Procedure

6. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Testing of Samples Random Sampling In case of failure investigation WHO will provide written report and recommendation for action Relevant DRA will be invited to participate in inspection or investigation

7. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Other Issues Cost recovery Confidentiality and undertaking (inspectors and evaluators) Conflict of interest

8. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. PART B: Organization of data and regulatory dossier

9. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. CTD FORMAT – ICH Requirements The CTD is not a “Global Dossier” ! It is an agreed-upon common format for the “modular” presentation of summaries, reports and data Incorporates relevant ICH guidelines It is organized into five sections:  All “modules” harmonized except Module 1 – regional specific  Raw data per regional requirements

10. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Module 1 Regional Administrative Information Nonclinical Overview Quality Overall Summary Clinical Summary Module 3 Quality Module 4 Nonclinical Study Reports Module 5 Clinical Study Reports Clinical Overview Nonclinical Summaries Not Part of CTD CTD Module 2 NDS Result was the CTD Triangle

11. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. CTD Structure Full dossier contains 5 “Modules” - - - Only Modules 2-5 are “CTD”  Module 1 – region-specific but always included in complete CTD structure  Module 2- All summaries / overviews  Module 3 – CMC (“Quality”)  Module 4 – Preclinical  Module 5 - Clinical

12. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Module 2 - CTD Summaries 2.1Overall CTD ToC 2.2CTD Introduction 2.3Quality Overall Summary 2.4Non-Clinical Overview 2.5Clinical Overview 2.6Non-Clinical Written and Tabulated Summaries 2.7Clinical Summary

13. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. 2.2CTD Introduction General introduction to the pharmaceutical, including  Pharmacologic class  Mode of action  Proposed clinical use Typically 1 page

14. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. 2.3Quality Overall Summary - Content A Summary that follows the scope and outline of the Body of Data in Module 3 Emphasize and discuss critical key parameters of the product Discuss key issues to integrate information from Module 3 and other modules Typically 40 pages, excluding tables, figures

15. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. 2.3Quality Overall Summary - Format 2.3Introduction 2.3.SDrug Substance 2.3.PDrug Product 2.3.AAppendices 2.3.RRegional Information

16. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Submission of CMC Information in CTD Format 3.2.S 3.2.S.1 3.2.S.2 3.2.S.3 3.2.S.4 3.2.S.5 3.2.S.6 3.2.S.7 DRUG SUBSTANCE General Information Manufacture Characterization Control of Drug Substance Reference Standards or Materials Container Closure System Stability

17. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Submission of CMC Information in CTD Format (cont’d) 3.2.P 3.2.P.1 3.2.P.2 3.2.P.3 3.2.P.4 3.2.P.5 3.2.P.6 3.2.P.7 3.2.P.8 DRUG PRODUCT Description and Composition of the Drug Product Pharmaceutical Development Manufacture Control of Excipients Control of Drug Product Reference Standards or Materials Container Closure System Stability

18. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Submission of CMC Information in CTD Format (cont’d) 3.2.A 3.2.A.1 3.2.A.2 3.2.A.3 3.2.R APPENDICES Facilities and Equipment Adventitious Agents Safety Evaluation Excipients REGIONAL INFORMATION

19. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Submission of CMC Information in CTD Format The CTD Quality Module is unique in that it is a combination of historical development and future commitments that apply to the commercial, post- approval production period.

20. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Impact of the CTD The ICH CTD represents one of the most ambitious and successful international harmonization activities undertaken It will significantly reduce time and resources needed by industry to compile applications for global registration

21. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Benefits of the CTD More “reviewable” applications Complete, well-organized submissions More predictable format More consistent reviews Easier analysis across applications Easier exchange of information Facilitates electronic submissions

22. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. CTD FORMAT – WHO Documents Requirements 1.Characteristics of the Finished Pharmaceutical Product (FPP) 1.1 Detail of the Product - Names, Dosage Forms & Strength - Description of Product & Packaging (Bottle, Blister, Bulk) 1.2 Sample - all proposed market presentations 1.3 Regulatory Situation in Other Countries - CANADA, USFDA, PEPFAR, EU, etc.

23. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. 2.Active Pharmaceutical Ingredient(s) (APIs) 2.1 Nomenclature - INN, Compendial Name, Chemical Name, Drug Substance Code, USAN, CAS Number. 2.2 Properties of APIs - API not described in Pharmacopoeia - API described in Pharmacopoeia - Structure Elucidation, Isomerism, Polymorphs, Particle Size Distribution (PSD), Critical additional characteristics (solubility, partition coefficient, etc.), Literature references. CTD FORMAT – WHO Documents Requirements (cont’d)

24. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. CTD FORMAT – WHO Documents Requirements (cont’d) 2.Active Pharmaceutical Ingredient(s) (APIs) 2.3 Site(s) of Manufacture - DMF(s), API-MF, GMP Certificate & Manufacturing licence, - - Specify: if inspected by WHO or any other Regulatory Agency. 2.4 Route(s) of API Synthesis - Specifications of Raw Materials & Intermediates - Controls of Critical Steps & Intermediates - Process Validation or Evaluation. - Impurities (organic, inorganic, catalysts, etc.). - Residual Solvents.

25. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. 2.Active Pharmaceutical Ingredient(s) (APIs) 2.5 Specifications - Complete specifications, signed & dated - Batch analysis - Summary of analytical results of relevant batches used in clinical or comparative studies. - Justification of specifications. - Reference Standards or Materials. CTD FORMAT – WHO Documents Requirements (cont’d)

26. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. 2.Active Pharmaceutical Ingredient(s) (APIs) 2.6 Container Closure System - Specifications & Test Methods - IR identification tests to be performed. 2.7 Stability Testing -Stress testing, Accelerated testing, long-term testing CTD FORMAT – WHO Documents Requirements (cont’d)

27. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. 3.Finished Pharmaceutical Product (FPP) 3.1 Marketing & Manufacturing Authorization 3.2 Pharmaceutical Development -API characterization studies -Compatibility of API & Excipients -Selection of excipients -Formulation development -Overages CTD FORMAT – WHO Documents Requirements (cont’d)

28. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. 3.Finished Pharmaceutical Product (FPP) 3.3 Formulation - Standard unit composition - Clinical batch composition - Proposed commercial batch - Highlight differences (if any) CTD FORMAT – WHO Documents Requirements (cont’d)

29. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. 3.Finished Pharmaceutical Product (FPP) 3.4 Site(s) of Manufacture - Name & address of the facility 3.5 Manufacturing Process - Flow chart of manufacturing process- In-process control - Identification of critical steps - Target limits (if any) CTD FORMAT – WHO Documents Requirements (cont’d)

30. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. 3.Finished Pharmaceutical Product (FPP) 3.6 Control of Critical Steps & Intermediates -Tests (according to dosage form) -Methods (compendial, In-house, etc.) 3.7 Process Validation -Types of validation -Purpose -Validation Protocol -Batch Size -Batch Number -Commitment CTD FORMAT – WHO Documents Requirements (cont’d)

31. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. 3.Finished Pharmaceutical Product (FPP) 3.8 Specifications of Excipients -Pharmacopoeial Grade -Non-Pharmacopoeial Grade 3.9 Control of FPP -Specifications -Justification of specifications -Test Methods 3.10 Container Closure System -Type of container closure system -Blister, HDPE Bottle, Bulk CTD FORMAT – WHO Documents Requirements (cont’d)

32. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. 3.Finished Pharmaceutical Product (FPP) 3.11 Stability Testing -Stability protocol -Stability specifications -Selection of batches -Long term conditions -Accelerated conditions -Proposed shelf-life pf FPP commitment batches -Stability studies 3.12 Container Labelling -outer, inner labels CTD FORMAT – WHO Documents Requirements (cont’d)

33. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. 3.Finished Pharmaceutical Product (FPP) 3.13Product Information for Health Professionals 3.14Patient Information & Package Insert 3.15Differences in the product in various countries issuing the submitted WHO-type certificate(s). CTD FORMAT – WHO Documents Requirements ( cont’d)

34. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. PART C: Introduction to PQP Guidelines

35. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Introduction to PQP Guidelines PQP Dossier Submission Requirements: Prequalification website address www.who.int/prequal/

36. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Introduction to PQP Guidelines Covering letter Product Dossier Product Sample e.g. 1 x 100 tablets Site Master File

37. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. PART D: Other Relevant Documents and Guidelines

38. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Relevant Documents and Guidelines Marketing Authorizations of Pharmaceutical Products with Special Reference to Multi-source (Generic) products. A Manual for Drug Regulatory Authority – Regulatory support series No. 5 (WHO / DMP / RGS / 98.5) Quality Assurance of Pharmaceuticals. A compendium of guidelines and related materials, Vol. 2, Good Manufacturing Practices and Inspection, Geneva. World Health Organization Guidance for Industry – Q7A Guidance for Good Manufacturing Practices for Active Pharmaceutical Ingredients, August 2001

39. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Relevant Documents and Guidelines (cont’d) World Health Organization WHO Technical Report Series No. 850 Annex 3, Guidelines for Good Clinical Trials on Pharmaceutical Products World Health Organization WHO Technical Report Series No. 902, 2002 Annex 3, Good Practices for National Pharmaceutical Control Laboratories UNDP / World Bank / WHO Special Programme for Research and Training in Tropical Diseases (TDR) Handbook. Good Laboratory Practices (GLP) Pre-assessment of Product Files (new submission) multi- source (generic) products, January 2007 (SOP)

40. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Relevant Documents and Guidelines (cont’d) World Health Organization WHO Technical Report Series No. 937, 2006, Annex 7, Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability Guidelines on Submission of Documentation for Pre- Qualification of Multisourced generic finished product used in the treatment of HIV / AIDS, malaria and tuberculosis World Health Organization WHO Technical Report Series No. 943, 2005, WHO Expert Committee on Specifications for Pharmaceutical Preparations

41. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Relevant Documents and Guidelines (cont’d) Procedure for Assessing the Acceptability, in principle, of Active Pharmaceutical Ingredients for use in Pharmaceutical Products (draft – under discussion) Pharmaceutical Development for Multisource (generic) Pharmaceutical Products. Draft. Good Trade and Distribution Practices for Pharmaceutical Ingredients. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-eight report. Geneva, 2004. Technical Report series No. 917, Annex 2.

42. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Relevant Documents and Guidelines (cont’d) WHO Pharmaceutical Active Ingredients Certification Scheme (SMACS) Guideline on Implementation. In: WHO Expert Committee on Specification for Pharmaceutical Preparation. Thirty-eight report. WHO 2004. Technical Report Series N. 917, Annex. 3 WHO Good Manufacturing Practices: Main Principles for Pharmaceutical Products. In: WHO Expert Committee on Specification of Pharmaceutical Preparations. Thirty- seventh Report. WHO 203. Technical Report Series No. 908. Annex 4 ICH Quality Guidelines, e.g. Q1, Q6A, Q8, etc.

43. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E. Thank you

44. WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E.