General Overview to the CTD and Module 1 Gudrun Dora Gisladottir Director Regulatory Affairs

1. General Overview to the CTD and Module1 Gudrun Dora Gisladottir Director Regulatory Affairs

2. Using CTD format Actavis group hf • International generic pharmaceutical company • First EU submissions in early ’90’s • Captopril first MRP 1994 • Finalize 10 – 20 new development projects per year • CTD format in EU since 2002 • First eCTD submitted

3. Using CTD format • Already reformatted most of the “older” dossiers • New markets • Variations • Renewals • Mixed format • >70 dossiers in CTD format

4. CTD FormatWhat is it? Common Technical Document (CTD) is; • A common format for presentation of technical documentation according to agreed international standards • Built around ICH and a mixture of FDA/EU/Japanese standards It is not; • A single file that will meet the needs of authorities – regionalrequirements and guidelines still apply where not covered by ICH

5. CTD FormatWhy use it? • It is a regulatory requirement in EU! • Logical order, representing sequential development path. • User friendly review • Theoretically possible to create “global dossier”! • Queries and deficiency letters simpler to answer • Agreement on defined terms assists the harmonization process between regions • Electronic submission should be easier to prepare • Encourages implementation of ICH guidelines

6. CTD – Is it worth it? From the Industry’s perspective; • YES! For new submissions • For dossiers already compiled in the NtA format, probably NO! • Mixed format • Variations Authorities • ?

7. CTD outline of structure • The CTD is organized into five modules • Administrative, regional or national information is provided in Module 1 – content specified by individual authorities • EU application form, the proposed SmPC, the labelling and package leaflet • Modules 2, 3, 4 and 5 are intended to be common for all regions

9. CTD outline of structure • Chemical, Pharmaceutical and Biological documentation is provided in the Quality Overall Summary from Module 2 and by Module 3 (previously Part II) • Toxicological and Pharmaceutical Documentation is provided in the Non-clinical Written Summary from Module 2 and by the Non-clinical Study Reports in Module 4 (part III) • The clinical documentation is provided in the Clinical Written Summary form Module 2 and in the Clinical Study Reports Module 5 (part IV)

10. CTD Module 2Generic applications Module 2 contains high level summaries • Quality Overall Summary, QOS (Module 2.3) • Non clinical Overview / Summary, NCOS (Module 2.4) • Clinical Overview / Summary COS (Module 2.5)

11. CTD Module 2 • EU legal requirement that dossiers should be prepared by suitably qualified and experienced experts • Though CTD format does not mention expert reports the content is expected to be given in the QOS, NCOS, COS • Experts have to sign and give their CV

12. CTD Module 3 • Replaces Part II • See correlation table for full details • Splits Drug Substance from Drug Product • S (DMF) and P • Follows logic of Development process

13. Module 3Drug Master File (DMF) • What is a DMF? • DMF is divided into two parts – the applicants part “open” and the drug substance manufacturers part “closed” part (confidential only to be reviewed by authorities) • Applicant’s part provides sufficient information to allow evaluation of the suitability of the specification to control the quality • Brief information on manufacturing • Information on impurities arising from manufacturing method • Information on degradation products • Information on toxicity of impurities where applicable

14. Module 3Drug Master File (DMF) • Drug substance manufacturer gives permission to the authorities to access data in closed part as “Letter of Access” (LoA) • Applicant submits the open part • Use CTD format

15. Module 3Drug Master File (DMF) 3.2.S.1 General Information 3.2.S.1.1 Nomenclature 3.2.S.1.2 Structure 3.2.S.1.3 General Properties 3.2.S.2 Manufacture 3.2.S.2.1 Manufacturer(s) 3.2.S.2.2 Description of Manufacturing Process and Process Controls 3.2.S.3 Control of Materials 3.2.S.3.1 Elucidation of Structure and Other Characteristics 3.2.S.3.2 Impurities 3.2.S.4 Control of Drug Substance 3.2.S.4.1 Specification 3.2.S.4.2 Analytical Procedure 3.2.S.4.3 Validation of Analytical Procedures 3.2.S.4.4 Batch Analyses 3.2.S.4.5 Justification of Specification 3.2.S.5 Reference standards or Materials 3.2.S.6 Container Closure System 3.2.S.7 Stability

16. Module 3Certificate of Suitability • Used for pharmacoepial substances (actives or excipients) • Documentation submitted directly to Ph. Eur. Secretariat • Avoid repeated assessment of same DMF by various authorities • Certification scheme includes requirements for a declaration concerning GMP and willingness to be inspected • Applicant includes the Certificate of Suitability (CoS) in the dossier

17. CTD Module 3Drug Product 3.2.P.1 Description and Composition of the Drug Product 3.2.P.2 Pharmaceutical Development 3.2.P.2.4 Controls and Critical Steps 3.2.P.3 Manufacture 3.2.P.3.1 Manufacturer(s) 3.2.P.3.2 Batch Formula 3.2.P.3.3 Description of Manufacturing Process and Process Controls 3.2.P.3.4 Controls of Critical Steps and Intermediates 3.2.P.3.5 Process validation and/or evaluation

18. CTD Module 3Drug Product 3.2.P.4 Control of excipients 3.2.P.4.5 Excipients of Human or Animal Origin 3.2.P.4.6 Novel Excipients 3.2.P.5 Control of Drug Product 3.2.P.5.1 Specification(s) 3.2.P.5.2 Analytical Procedures 3.2.P.5.3 Validation of Analytical Procedures 3.2.P.5.4 Batch Analyses 3.2.P.5.5 Characterisation of Impurities 3.2.P.5.6 Justification of Specification(s) 3.2.P.6 Reference Standards or Materials 3.2.P.7 Container Closure System 3.2.P.8 Stability

19. Module 4 • For Generic Application • Only literature review • EU authorities – different opinion on whether this is needed in the application

20. Module 5 For a generic application • Reports from literature • BE report • Justification and discussion regarding design and results • 5.3.2 comparative BA and bioequivalence study

21. Common Technical DocumentDetailed Structure Fine details of requirements for each module: • Revised Notice to Applicants Volume 2B published in June 2004 • Sections in Part R; Regional information • References are to ICH and CPMP guidelines • Various Q and A documents available

22. CTD PresentationsGeneral Considerations • Throughout the display of information should be unambiguous and transparent, to facilitate the review • Use margins that allow the document to be printed on A4 paper • The left hand margin should be sufficiently large that information is not obscured through binding • Font sizes for text and tables should be of style and size that are large enough to be easily legible even after photocopying • Acronyms and abbreviations should be defined the first time they are used in each module

23. CTD PresentationOrganisation of sections • ICH Guideline M4: CTD for the registration of Pharmaceuticals for human use; organisation of common technical document implemented 2003 – incorporates “Granularity Document” • Defines how to split sections down into separate documents • Prepares the way for electronic submission • The Granularity guideline defines “Document” and states that each document should be paginated separately (electronic file)

24. CTD PresentationOrganisation of sections Practical experience In deciding whether one or more documents or files are appropriate, it should be considered that once a particular approach has been adopted the same approach should be used throughout the life of the dossier since it is the intention that replacement documents/files be provided when information is changed

25. CTD PresentationOrganisation of sections • For Module 3 the situation can be very complicated • For a drug product containing more than one drug substance the information requested for part “S” should be provided in its entirety for each drug substance • More than one Drug Substance supplier • More than one manufacturing site for the finished product

26. Electronic DossierseCTD • CTD makes it possible to agree upon standard for an electronic submission • XML backbone plus PDF files • Are authorities ready?

27. Global Dossier Major Challenges • Level of details (U.S.A) e.g. description of synthesis, in process controls, raw materials, container • Compendial differences – not all monographs are harmonized (USP, Ph. Eur.) • GMP issues • Stability, US requires site specific data, 3 months v.s. 6 months Plus the BE study!

28. Module 1 Regional Information - EU

29. Table of ContentTypical Module 1 - Actavis 1.1 Comprehensive Table of Contents 1.2 Application Form Annexed Documents 6.3 Proof of establishment of MA holder 6.4 Letter of authorisation for communication 6.5 Curriculum Vitae of the Qualified Person for Pharmacovigilance 6.6 Manufacturing Authorisation 6.7 Justification for more than one manufacturer responsible for batch release 6.8 Flow-chart indicating the different sites involved in the manufacturing process 6.10 Letter of Access to DMF 6.11 Copy of written confirmation of the AIM 6.15 Copy of Marketing Authorization(s) required under Directive 2001/83/EC Proof of first Authorisation of essential similar medical product in EU 6.22 Declaration from the Qualified Person of the manufacturing authorisation holder

30. Table of ContentTypical Module 1 – Actavis cont. 1.3 Summary of Product Characteristics, Labelling and Package Leaflet. 1.3.1 SPC 1.3.2 Labelling 1.3.3 PIL 1.3.4 Readability Justification 1.4 Information about the Experts 1.5.2 Information for abridged applications

31. Module 1 The application form is to be used for an application for a marketing authorisation of a medicinal product for human use submitted to (a) the European Agency for the Evaluation of Medicinal Products under the centralised procedure or (b) a Member State (as well as Iceland, Lichtenstein and Norway) under either a national, mutual recognition procedure or decentralised procedure.

32. Application FormEU - Region 1. Type of application 1.1 This application concerns 1.2 Orphan medicinal product designation 1.3 Referring to Annex II of Regulations (EC) N° 1084/2003 or1085/2003[1] 2. Marketing authorisation application particulars 2.1 Name(s) and ATC code 2.2 Strength, pharmaceutical form, route of administration, container and pack sizes 2.3 Legal status 2.4 Marketing authorisation holder, Contact persons, Company 2.5 Manufacturers 2.6 Qualitative and quantitative composition

33. Application FormEU - Region 3. Scientific advice 4. Paediatric Development Programme 5. Other marketing authorisation applications Appended documents 6.1 Proof of payment 6.2 Informed consent letter of marketing authorisation holder of authorised medicinal product. 6.3 Proof of establishment of the applicant in the EEA. 6.4 Letter of authorisation for communication on behalf of the applicant/MAH 6.5 Curriculum Vitae of the Qualified Person for Pharmacovigilance 6.6 Manufacturing Authorisation required under Article 40 of Directive 2001/83/EC (or equivalent, outside of the EEA where MRA or other Community arrangements apply). A reference to EudraGMP will suffice when available. 6.7 Justification for more than one manufacturer responsible for batch release in the EEA

34. Application FormEU - Region 6.8 Flow-chart indicating all sites involved in the manufacturing process of the medicinal product or active substance (including sites involved in sampling and testing for batch release of products manufactured in third countries). Note: ALL manufacturing and control sites mentioned throughout the whole dossier MUST be consistent regarding their names, detailed addresses and activities. 6.9 Statement (or GMP Certificate issued by an EEA inspectorate, when available) from the competent authority which carried out the inspection of the manufacturing site(s) (not older than 3 years). References to EudraGMP will suffice when available. Where applicable a summary of other GMP inspections performed in the last 2 years 6.10 Letter(s) of access to Active Substance Master File(s) or copy of Ph. Eur. Certificate(s) of suitability 6.11 Copy of written confirmation from the manufacturer of the active substance to inform the applicant in case of modification of the manufacturing process or specifications according to Annex I of Directive 2001/83/EC. 6.12 Ph. Eur. Certificate(s) of suitability for TSE 6.13 Written consent(s) of the competent authorities regarding GMO release in the environment.

35. Application FormEU - Region 6.14 Scientific Advice given by CHMP 6.15 Copy of Marketing Authorization(s) required under Article 8(j)-(L) of Directive 2001/83/EC in the EEA and the equivalent in third countries on request (a photocopy of the pages which give the marketing authorization number, the date of authorisation and the page which has been signed by the authorizing competent authority will suffice). 6.16 Correspondence with European Commission regarding multiple applications. 6.17 List of Mock-ups or Samples/specimens sent with the application, as appropriate (see Notice to Applicants, volume 2A, chapter 7) 6.18 Copy of the Orphan Designation Decision. 6.19 List of proposed (invented) names and marketing authorisation holders in the concerned member states 6.20 Copy of EMEA certificate for a Vaccine Antigen Master File (VAMF) 6.21 Copy of EMEA certificate for a Plasma Master File (PMF) 6.22 For each active substance, attach a declaration from the Qualified Person of the manufacturing authorisation holder in Section 2.5.1 and from the Qualified Person of each of the manufacturing authorisation holders (i.e. located in EEA) listed in Section 2.5.2 where the active substance is used as a starting material that the active substance manufacturer(s) referred to in Section 2.5.3 operate in compliance with the detailed guidelines on good manufacturing practice for starting materials. This does not apply to Blood or blood components.

36. Module 1New Requirements • For each active substance, attach a declaration from the Qualified Person of the manufacturing authorisation holder in Section 2.5.1 and from the Qualified Person of each of the manufacturing authorisation holders (i.e. located in EEA) listed in Section 2.5.2 where the active substance is used as a starting material that the active substance manufacturer(s) referred to in Section 2.5.3 operate in compliance with the detailed guidelines on good manufacturing practice for starting materials. This does not apply to Blood or blood components.

37. Module 1New Requirements • Readability testing PIL • Typical testing • Participants (preferably patients) read the PIL • Two rounds of interviews (10 in the first and 10-20 in the second round) • Locate the information in the PIL • Understand it • Know how to act on it • Might have to revise the PIL based on the outcome

38. Type of MA Application • National • Single member state (MS) • Older well established products • Mutual Recognition • Approved in one MS, Reference Member State (RMS) • Multiple identical MAs in many Concerned Member States (CMS) • Harmonised MA granted • Decentralised - New procedure! • RMS and CMS • Approved in all selected MS at the same time • Centralised • Mainly biotech products • Single MA in all MS • MA issued bye EMEA via the commission

39. VariationsMaintaining the MAA • Activities post approval • Changing the way the product is made • Additional manufacturing site • Additional Drug Substance supplier– Dual sourcing policy • Improve safety • New indications • Additional warnings • Improve quality • New stability results from commercial batches

40. VariationsMaintaining the MAA New EU regulation regarding variations since Oct 2003 • Type IA (minor) 14 days • Type IB (minor) 30 days • Type II (major) 60- 90 days • Fundamental Variations (New application) • Urgent safety restriction

41. VariationsMaintaining the MAA • Type IA (notification) “tell and do” • Type IB (notification) “tell, wait and do” • Type II (approval) “tell and wait” RMS is responsible for processing Type IA and IB on behalf of CMS

42. VariationsMaintaining the MAA For each Type I variation, the guideline indicates; • Details of the change • Conditions/remarks attached to the change • Documentation to be supplied • 46 types of variations A variation is only regarded as Type I if the conditions are met AND the relevant supporting data are provided The variation will be considered Type II if either of these conditions are not met

43. Thank You!