Transcript 36pt Trebuchet MS Bold

General Overview to the CTD and
Module 1
Gudrun Dora Gisladottir
Director Regulatory Affairs
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
Using CTD format
• Already reformatted most of the “older”
dossiers
• New markets
• Variations
• Renewals
• Mixed format
• >70 dossiers in CTD format
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
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
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
• ?
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
Diagrammatic Representation of the Organization of the ICH CTD
Common Technical Document
Module 1
Regional
Administrative
Information
1
1.1 Submission
T of C
Not part of the CTD
CTD Table of Contents
2.1
CTD Introduction
Module 2
2.2
Quality
Overall
Summary
2.3
Module 3
Quality
3
3.1 T of C
Nonclinical
Overview
2.4
Nonclinical Written
and Tabulated
Summaries
2.6
Module 4
Nonclinical
Study Reports
4
4.1 T of C
Clinical
Overview
2.5
Clinical
Summary
2.7
Module 5
Clinical
Study Reports
5
5.1 T of C
CTD
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)
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)
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
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
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
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
Module 3
Drug Master File (DMF)
3.2.S.1
3.2.S.1.1
3.2.S.1.2
3.2.S.1.3
3.2.S.2
3.2.S.2.1
3.2.S.2.2
3.2.S.3
3.2.S.3.1
3.2.S.3.2
3.2.S.4
3.2.S.4.1
3.2.S.4.2
3.2.S.4.3
3.2.S.4.4
3.2.S.4.5
3.2.S.5
3.2.S.6
3.2.S.7
General Information
Nomenclature
Structure
General Properties
Manufacture
Manufacturer(s)
Description of Manufacturing Process and Process Controls
Control of Materials
Elucidation of Structure and Other Characteristics
Impurities
Control of Drug Substance
Specification
Analytical Procedure
Validation of Analytical Procedures
Batch Analyses
Justification of Specification
Reference standards or Materials
Container Closure System
Stability
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
CTD Module 3
Drug Product
3.2.P.1
3.2.P.2
3.2.P.2.4
3.2.P.3
3.2.P.3.1
3.2.P.3.2
3.2.P.3.3
3.2.P.3.4
3.2.P.3.5
Description and Composition of the Drug
Product
Pharmaceutical Development
Controls and Critical Steps
Manufacture
Manufacturer(s)
Batch Formula
Description of Manufacturing Process and
Process Controls
Controls of Critical Steps and Intermediates
Process validation and/or evaluation
CTD Module 3
Drug Product
3.2.P.4
3.2.P.4.5
3.2.P.4.6
3.2.P.5
3.2.P.5.1
3.2.P.5.2
3.2.P.5.3
3.2.P.5.4
3.2.P.5.5
3.2.P.5.6
3.2.P.6
3.2.P.7
3.2.P.8
Control of excipients
Excipients of Human or Animal Origin
Novel Excipients
Control of Drug Product
Specification(s)
Analytical Procedures
Validation of Analytical Procedures
Batch Analyses
Characterisation of Impurities
Justification of Specification(s)
Reference Standards or Materials
Container Closure System
Stability
Module 4
• For Generic Application
• Only literature review
• EU authorities – different opinion on whether
this is needed in the application
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
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
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
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)
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
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
Electronic Dossiers
eCTD
• CTD makes it possible to agree upon
standard for an electronic submission
• XML backbone plus PDF files
• Are authorities ready?
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!
Module 1
Regional Information - EU
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
•
Table of Content
Typical 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
1.5.2
Information about the Experts
Information for abridged applications
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.
Application Form
EU - Region
1.
1.1
1.2
1.3
Type of application
This application concerns
Orphan medicinal product designation
Referring to Annex II of Regulations (EC) N° 1084/2003 or1085/2003[1]
2.
2.1
2.2
Marketing authorisation application particulars
Name(s) and ATC code
Strength, pharmaceutical form, route of administration, container and
pack sizes
Legal status
Marketing authorisation holder, Contact persons, Company
Manufacturers
Qualitative and quantitative composition
2.3
2.4
2.5
2.6
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
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.
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 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.
Module 1
New 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.
Module 1
New 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)
1. Locate the information in the PIL
2. Understand it
3. Know how to act on it
•
Might have to revise the PIL based on the outcome
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
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
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)
60- 90 days
• Fundamental Variations (New application)
• Urgent safety restriction
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
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
Thank You!