1. General Overview to the CTD and Module 1
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. Common Technical Document (CTD) is;
CTD Format What 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 – regional requirements and guidelines still apply where not covered by ICH

5. CTD Format Why 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 2 Generic 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 Splits Drug Substance from Drug Product
See correlation table for full details
Splits Drug Substance from Drug Product
S (DMF) and P
Follows logic of Development process

13. Module 3 Drug 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 3 Drug 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 3 Drug Master File (DMF)
3.2.S.1 General Information
3.2.S.1.1 Nomenclature
3.2.S.1.2 Structure
3.2.S 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 3 Certificate 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 3 Drug 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 3 Drug 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 Document Detailed 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 Presentations General 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 Presentation Organisation 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 Presentation Organisation 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 Presentation Organisation 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 Dossiers eCTD
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. Regional Information - EU
Module 1
Regional Information - EU

29. Table of Content Typical 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 Content Typical Module 1 – Actavis cont.
1.3 Summary of Product Characteristics, Labelling and Package Leaflet.
SPC
Labelling
PIL
Readability Justification
Information about the Experts
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 Form EU - 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 Form EU - 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 Form EU - 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 Form EU - 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 and from the Qualified Person of each of the manufacturing authorisation holders (i.e. located in EEA) listed in Section where the active substance is used as a starting material that the active substance manufacturer(s) referred to in Section 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 1 New Requirements
For each active substance, attach a declaration from the Qualified Person of the manufacturing authorisation holder in Section and from the Qualified Person of each of the manufacturing authorisation holders (i.e. located in EEA) listed in Section where the active substance is used as a starting material that the active substance manufacturer(s) referred to in Section 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 1 New Requirements
Readability testing PIL
Typical testing
Participants (preferably patients) read the PIL
Two rounds of interviews (10 in the first and 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 Mutual Recognition
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. Variations Maintaining 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. Variations Maintaining the MAA
New EU regulation regarding variations since Oct 2003
Type IA (minor) 14 days
Type IB (minor) 30 days
Type II (major) days
Fundamental Variations (New application)
Urgent safety restriction

41. Variations Maintaining 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. Variations Maintaining 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!