Transcript DMF Procedures and Communication between API, FFP

DMF Procedures and
Communication between API,
FP Manufacturers and
Regulatory Authorities
Beijing, March 30, 2010
Jean-Louis ROBERT
National Health Laboratory
L – 1011 LUXEMBOURG
CHMP co-opted member
Chair CHMP/CVMP QWP
Submission of Data: Module 3, Certificate of
Suitability, AS Master File
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Module 3: full documentation on the API (AS) is provided in the
file for MA
Certificate European Pharmacopoeia (CEP):
AS described in the European Pharmacopoeia (EP) can undergo
certification procedure in order to confirm compliance with the
EP
AS Master File (ASMF):
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Restricted part submitted by the AS Manufacturer
Applicant’s part submitted by AS Manufacturer and Applicant
For a pharmacopoeial substance in all cases compliance with the
monograph has to be demonstrated whatever the route of
submission.
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Overview of topics addressed
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References
EU ASMF: principle
Content of the guideline
How to use
General considerations
Recommendations
Conclusion
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References
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Directives 2001/83 EC as amended
Guidelines:
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Active Substance Master File Procedure (ASMF)
Summary of Requirements for Active Substances in the
Quality Part of the dossier
Various guidelines in relation to the Active Substance
Active Substance Master File (ASMF)/European Drug
Master File (EDMF): synonymous
See EMEA website: www.emea.europa.eu
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Structure ASMF Module 3.2.S
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S1 General Information
S2 Manufacture
S3 Characterisation
S4 Control of Drug Substance
S5 Reference Materials
S6 Container Closure System
S7 Stability
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ASMF Guideline - Structure
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Introduction
Content of the active substance master file
Use of the ASMF procedure
Content of the MA dossier when the ASMF procedure is used
Changes and updates to the ASMF
Annex 1:
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Annex 2:
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Template letter of access
Annex 3:
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Overview EDMF contents
Part of covering letter
Annex 4:
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List of abbreviations
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Within Scope
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New active substances
Existing active substances (pharmacopoeial/non
pharmacopoeial)
Herbals
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Out of Scope
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Biological Active Substances
Excipients including novel excipients
AS mixed with an excipient unless necessary for the
stability of the active substance e.g. nitroglycerin
Packaging materials
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EU ASMF: Principle
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Marketing Authorisation Holder (MAH):
Full responsibility for the medicinal product and the
quality and quality control of the active substance
Active Substance Manufacturer (ASM):
Allowance of valuable confidential intellectual property
of know how to be protected
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Applicants Part (AP)
Restricted Part (RP)
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Restricted (confidential) Part
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Manufacture
 Detailed description
 Control of Materials
 Control of critical steps and intermediates
 Process Validation
 Manufacturing Process Development
Impurities: for those impurities which do not need to be
controlled in the final active substance and which are related to
detailed description of the manufacturing process.
Justification of specification: for information related to detailed
description of manufacturing process, control of materials and
process validation.
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Restricted (confidential) Part (2)
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Exceptions
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Validation data of sterilisation process may be required
in Applicant’s part when no further sterilisation process
of the final product (GMP certification to be added)
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Procedure - Use
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ASMF can only be submitted in relation with a MA
Can also be used when no confidentiality issue between
MAH and ASM
MAA: either CEP or ASM should be submitted
Additional information might be requested from the
Applicant by the Authorities in addition to the ASMF:
e.g. particle size (when not present in a ASMF)
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Procedure – Use (2)
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ASMF holders → Applicant/MA Holder
Copy of latest version of the AP
 Copy of QOS (latest version of AP)
 Letter of access:
Permission of ASMF holder to competent Authorities to
access the data in the ASMF in relation to a specific
application (Annex).
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Procedure – Use (3)
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ASMF holder → Competent Authorities
 The ASMF (applicant + restricted part) either once or
for each MA application (depends on national
requirements)
 Letter of access
Discussion between ASMs and competent authorities/
EMEA related to ASMF “legally” not possible
however ………..
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General considerations (1)
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Responsibility of ASMF holder:
 One identical version ASMF in EU for same API (for
different applications in different member states)
 Version number AP MP dossier should be most recent
and identical to version number AP ASMF: responsibility
of the applicant
 Request for harmonisation requested by member states
possible
Update of ASMF
 Responsibility of ASMF holder
 Information to applicant and competent authority
Full supplier chain described in finished product file
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General considerations (2)
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The quality control methods should be kept in line with the
current regulatory and scientific requirements
Compliance with GMP
 Responsibility of Manufacturing Authorisation Holder
(finished product)
MAH can use different QC methods
 full description needed in application file
In case of more than one supplier, there should be one
single compiled specification for each supplier:
responsibility MAH
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General considerations (3)
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MA holder legally bears full responsibility MP on the market
 MA holder also responsible for the active substance
 MA holder cannot share this responsibility with ASMF
 MA holder responsible that active substance from any source is
continuously manufactured and controlled in conformity with MPD
 Thus variations to ASMF can legally only be initiated by MA
holder
 Thus ASMs should continuously inform MA holders of any
changes
New Variation Regulation in EU: Classification guideline not yet
definitively adopted by EU Commission
ASMF holders should precisely know with MA holders are linked to
their ASMFs!
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Recommendation to API industry
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Keep the information the same for all MA-holders
Keep a clear administration of MA holders/countries
connected to a certain ASMF
Inform MA-holders and authorities in case of variations
directly
“As for medicinal products, EDMF holders should
keep the content of their EDMFs updated with respect
to the actual synthesis/manufacturing process”
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Structure MPD with linked ASMFs
MA dossier CTD
Module 1
Module 2
Module 3
Module 4
Module 5
regional administrative
QOS/summaries
quality
non-clinical
clinical
3.1
3.2
3.3
table of content
body of data
literature references
3.2.S
3.2.P
3.2.A
3.2.R
active substance
drug product
appendices
regional information
name ASMs
MA holders specifications, methods & validation
MA holders batch analyses if relevant
reference to ASMF / data from AP ASMF
copy AP ASMF
LoA from ASMF holder to
MA holder for named product
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Conclusion
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ASMF: one possibility to submit information on the
API to Competent Authorities
Preferred option of authorities:
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CEPs
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