1. Lynda Paleshnuik | January 2011 1 |1 | Assessment Workshop Copenhagen – January 2011 The new PQP quality guideline

2. Lynda Paleshnuik | January 2011 2 |2 | Overview  Background (PQP quality guidelines)  Guideline development process  Introduction to the two documents: I: the preparation guideline II: the quality guideline

3. Lynda Paleshnuik | January 2011 3 |3 | Overview Continued  Key changes from the previous PQP quality guideline  Questions raised

4. Lynda Paleshnuik | January 2011 4 |4 | New guidelines “Preparation” guideline: 10.375: Guideline on submission of documentation for a multisource (generic) finished pharmaceutical product (FPP): Preparation of product dossiers (PDs) in Common Technical Document (CTD) Format; “Quality” guideline: 10.373: Guideline on submission of documentation for a multisource (generic) finished pharmaceutical product (FPP): Quality part

5. Lynda Paleshnuik | January 2011 5 |5 | Background  Previous generic guideline: “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”  Published in 2005: policy/approaches to assessment change continually over time due to harmonization efforts, scientific advances, development of approaches - e.g. process validation (≈2002), pharmaceutical development approaches have changed dramatically over the past 10 years

6. Lynda Paleshnuik | January 2011 6 |6 | Background ICH: International Conference on Harmonization ► joint regulatory-industry initiative to harmonise regulatory requirements ► issued the Common Technical Document (CTD) - Quality (ICH M4Q) guideline resulting in considerable harmonization on the organization of the Quality Module of the registration documents ► CTD format has become widely accepted by regulatory authorities within and beyond the ICH regions.

7. Lynda Paleshnuik | January 2011 7 |7 | Background This common format for submitting dossiers to agencies (CTD) affects: - the assessment report – based on the dossier template (QOS) -the dossier data, enabling the logical organization of data and a single dossier to be submitted to multiple agencies A guideline updated according to current requirements, and adopting CTD format, was needed.

8. Lynda Paleshnuik | January 2011 8 |8 | Guideline development process  guideline drafted in CTD format (crafting of preparation document, plus formatting of quality document) → draft  guideline populated with quality technical guidance - updated according to current practice - including additional information on how to meet the requirements → new draft Clarity and transparency of requirements significantly improves the quality of dossiers

9. Lynda Paleshnuik | January 2011 9 |9 | Guideline development process  Consultation process with PQP senior assessors → new draft  External consultation process (formal EC circulation) → final draft  Presentation to EC on Specifications for Pharmaceutical Preparations Currently: guidelines provisionally accepted for pilot use in PQP

10. Lynda Paleshnuik | January 2011 10 | Introduction to the two documents I: the preparation guideline This guideline:  assists applicants with the preparation of product dossiers (PDs) for multisource products by providing general guidance on the format of these dossiers;  describes and adopts the modular format of the CTD as developed by ICH;

11. Lynda Paleshnuik | January 2011 11 | Introduction to the two documents I: the preparation guideline

12. Lynda Paleshnuik | January 2011 12 | Adapting the CTD-NDS (new drug) to CTD-ANDS (generic) Regional Admin Information Module 1 Nonclinical Overview Nonclinical Summary Clinical Overview Clinical Summary Quality Overall Summary Quality Nonclinical Study Reports Clinical Study Reports Module 3Module 4Module 5 Module 2 Not Part of the CTD The CTD

13. Lynda Paleshnuik | January 2011 13 | Introduction to the two documents I: the preparation guideline  Provides guidance on the location of regional information (Module 1) and other general data requirements.  Primarily addresses the organization of the information to be presented in PDs for multisource products. It is not intended to indicate what studies are required. It indicates an appropriate format for the data that have been acquired.

14. Lynda Paleshnuik | January 2011 14 | Introduction to the two documents II: the quality guideline This guideline:  assists applicants with the preparation of the Quality Module of PDs for multisource products by providing general guidance on the format;  adopts the modular format of the Common Technical Document - Quality (M4Q) as developed by ICH; and  provides guidance on the technical and other general data requirements (including preparation of the QOS-PD). 

15. Lynda Paleshnuik | January 2011 15 | Key changes from the previous guideline  CTD format adopted  Updating of requirements  Elaboration of how to meet quality requirements, including full elaboration on the three ways to submit API data: - CEP - APIMF - full API data provided in the dossier

16. Lynda Paleshnuik | January 2011 16 | Key changes from the previous guideline Reductions in requirements: - fewer batches required to establish the FPP shelf-life - process validation report for pilot batches no longer required (replaced by uniformity demonstration for the biolot) - reduced process validation/pharmaceutical development requirements for “established” generics

17. Lynda Paleshnuik | January 2011 17 | Navigating through the quality guideline  Text includes bolded ICH M4Q text, and unbolded additional WHO text  ICH M4Q text revised to use WHO terminology: ► API/FPP, FDC, PD ► Generally refers to BE instead of clinical batches  Presentation of the data is described for various scenarios e.g. multiple APIs, multiple FPP strengths, co-blistered FPPs, etc.

18. Lynda Paleshnuik | January 2011 18 | Quality document: quality summaries QIS/QOS Section 3: introduces the QIS/QOS  The instructions for the QOS-PD run throughout the quality guideline  Instructions for the QIS are in Section 3.2 and preface the QIS template

19. Lynda Paleshnuik | January 2011 19 | Quality Data Sections Socratic principle: You are only as educated as the extent to which you understand how little you know

20. Lynda Paleshnuik | January 2011 20 | Quality document: Section 4 – module 3 Section 4: QUALITY data in CTD format Section 4 is divided (according to CTD structure) into: 3.2.S Drug substance (or API), and 3.2.P Drug product (or FPP)

21. Lynda Paleshnuik | January 2011 21 | Quality document: Section 4 – module 3 Three options for API information: 1. CEP – PhEur certificate of suitability 2. APIMF – API master file 3. Full details in the PD

22. Lynda Paleshnuik | January 2011 22 | Quality document: Section 4 – module 3 For CEP option (preferred option) – full description of the sections and details for PD and QOS-PD given in the intro For APIMF option, “the applicant/FPP manufacturer should complete the following sections in the PD and QOS-PD in full according to the guidance provided unless otherwise indicated in the respective sections:” S.1.1-S.1.3 S.2/S.2.1/S2.2/S.2.4 S.3.1/S.3.2 S.4.1-S.4.5; S5; S6; S7.1-S.7.3

23. Lynda Paleshnuik | January 2011 23 | Quality document: Section 4 – module 3 For full details in the PD option: Information on the 3.2.S API sections should be submitted in the PD as outlined in subsequent sections of this guideline.

24. Lynda Paleshnuik | January 2011 24 | Reduced requirements Reductions in requirements: 1fewer batches required to establish the FPP shelf-life 2process validation report for pilot batches no longer required (replaced by uniformity demonstration for the biolot) 3reduced process validation/pharmaceutical development requirements for “established” generics

25. Lynda Paleshnuik | January 2011 25 | FPP batches to support the shelf-life Complicated FPPs: ► sterile products, metered dose inhaler products, dry powder inhaler products and transdermal delivery systems. ► ritonavir/lopinavir FDC tablets and FDCs containing rifampicin or an artemisinin. Two pilot batches required

26. Lynda Paleshnuik | January 2011 26 | FPP batches to support the shelf-life Uncomplicated FPPs: ► e.g. immediate-release solid FPPs (with noted exceptions), non-sterile solutions One pilot batch and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or capsules) are required

27. Lynda Paleshnuik | January 2011 27 | Biobatch uniformity demonstration Process validation report for pilot batches no longer required (replaced by uniformity demonstration for the biolot); Uniformity (biolot) can be demonstrated via blend uniformity testing or extensive post-compression uniformity testing or suitable sampling of packaged product.

28. Lynda Paleshnuik | January 2011 28 | Established generics Products that have been marketed by the applicant or manufacturer associated with the dossier for at least 5 years, and either 10 batches were produced in the past year, or 25 batches were produced in the past 3 years. Instead of process validation and certain pharmaceutical development data, data provided as in Appendix 2, ie a product quality review (PQR). The PQR replaces the developmental pharmaceutics data in the sections on 1) formulation development (P.2.2.1 a)) and 2) manufacturing process development (P.2.3 a)). In addition, it replaces the section on process validation, P.3.5.

29. Lynda Paleshnuik | January 2011 29 | Elaboration of Requirements  Setting down specific requirements for each of the options for API data  Acceptance criteria for particle size distribution limits  Options for qualification of impurities  Verification of compendial methods  Information on preparing and analysing the primary reference standard  Stress testing  Establishing the suitability of container closure system for FPP

30. Lynda Paleshnuik | January 2011 30 | Questions raised

31. Lynda Paleshnuik | January 2011 31 | THE END? Good guidelines are dynamic; they must be updated at regular intervals, considering feedback from all stakeholders.