EU FDA: CMC Differences

1
EU FDA CMC Differences

• Mary Y. Jarosz, R.Ph, RAC, FTOPRA
• Jarosz Regulatory Services, Inc (www.jrsweb.com)
• AAPS Chicagoland Pharmaceutical Discussion Group
  (CPDG) symposium
• April 11, 2008, Skokie, IL

2
Objectives

• To understand the general differences between the
  EU and the US FDA CMC CTD
• To take home practical suggestions for
  constructing CMC Module 2.3 and Module 3

3
(No Transcript)
4
EU and FDA

• EU multiple agencies
• European Medicines Evaluation Agency (EMEA)
  administrative organization
• Committee for Medicinal Products for Human Use
  (CHMP) of the EMEA scientific input
• National Health Agencies
• FDA one agency

5
EU and FDA

• EU multiple registration procedures
• Centralized
• European Community
• Decentralized/Mutual Recognition
• At least 2 Member States
• National
• 1 Member State
• FDA one registration procedure

6
EU and FDA

• CTD
• More similar than different
• Bulk of the CMC data will be the same for both
  agencies

7
CTD Defined

• It is a harmonized format (template) for
  presenting data in the ICH regions
• It is not a list of data requirements for
  applications
• Result ? differences remain

8
CTD CMC Structure

• ICH M4Q Quality
• EU (CPMP/ICH/2887/99)
• FDA (M4 QA guidance June 2004)
• 2.3 QOS Quality Overall Summary (QOS)
• 3.2.S Drug Substance (DS)
• 3.2.P Drug Product (DP)
• 3.2.A Appendices
• 3.2.R Regional
• 3.3 Literature References

9
CTD CMC Structure

• CTD can accommodate
• Differences in content
• Differences in review styles
• Local particulars
• Specifications
• Package configurations

10
Differences in Content

• ICH Q4A Pharmacopeial Harmonization
• Harmonize compendial test chapters
• Interchangeable in the 3 ICH regions
• Pharmacopeial Discussion Group (PDG) ? USP, JP,
  EP (PhEur)
• 11 General Test Chapters in ICH Q6A
• PDG submits pharmacopeial text proposals to ICH
  Q4B Expert Working Group (EWG)

11
Differences in Content

• ICH Q4B Evaluation Recommendation
• Expert Working Group (ICH Q4B EWG) evaluates
  pharmacopeial text proposals from PDG and
  assesses regulatory impact
• Dialogue between PDG and Q4B EWG
• Q4B EWG makes conclusions and recommendations in
  the ICH regions

12
www.edqm.eu
13
Differences in Review Styles

• EMEA is an administrative framework, and National
  Agencies are the scientific reviewers
  differences in culture and medical practices
• FDA reviewers are within the same Agency
• EU top down, FDA bottum up
• EU benefit/risk of entire data, FDA more specific
  (2 adequate and well-controlled studies)
• Same data package to both will probably not
  result in the same outcome

14
Comparison of EU and US CTD

• Module 1 Administrative (not CTD)
• Application Form, Labeling, DMF Letters of
  Access, Environmental Risk Assessment
• Module 2.3 QOS
• Key review document
• 40-80 pages Attachments
• EU focus (the old Expert Reports)
• Module 3 Quality (CMC)

15
Module 2.3 QOS

• Discussion/assessment of data
• Opportunity for the sponsor to highlight and
  explain data
• Impurities, justify deviations from EU/FDA
  guidelines, integrate nonclinical and clinical
• Reviewed across disciplines ? influences
  reviewers perceptions
• Ideally written after Module 3 completed
• Final review in conjunction with Module 3
• May be excerpted for public disclosure

16
Module 3 Drug Master File

• EU Active Substance Master File
• Commonly, European Drug Master File (EDMF)
• CPMP/QWP/227/02/rev.1
• Applicants Part (manufacturer MAH)
• Restricted Part (manufacturer only)
• Certificate of Suitability (CEP)
• European Directorate for the Quality of Medicines
  Health Care (EDQM)

17
Module 3 Drug Master File

• US DMF
• Type 2 drug substance, intermediate, source
  material, drug product
• Type 3 packaging
• Type 4 excipient, colorant, flavor

18
EU CEP and TSE CEP

• Certification by EDQM
• Governed by Resolution AP-CSP(07)1 and Directives
  2001/83/EC, 2001/82/EC, 2003/63/EC
• Manufacturers or suppliers of active substances
  or excipients
• Any product with transmissible spongiform
  encephalopathy (TSE) risk
• CEP
• EDQM evaluates the suitability of the PhEur
  monograph to control the chemical purity and
  microbiological quality or
• TSE CEP
• Evaluates the reduction of TSE risk or
• Both

19
Module 3 EU Focus

• EDMF only for drug substances
• CEP for a pharmacopeial drug substances
• TSE CEP (or BSE/TSE documentation)
• Process Validation Scheme
• EU supply chain
• Standard Terms for containers, dosage forms, and
  routes of administration

20
Module 3 FDA Focus

• Reference to DMF(s)
• Drug Substance container closure
• Sterility Assurance Validation package
• 3.2.P.3.5 Process Validation or
• 3.2.R.1 Regional
• Executed Batch records
• Comparability Protocols
• Methods Validation Package

21
3.2.S Drug Substance

• Essentially same for EU and US
• Unless
• reference to DMF or CEP
• Link documents from different development sources
  for DS and DP
• In-house and third-parties

22
3.2.S Drug Substance

• 3.2.S.2.1 Manufacturer
• Establishment Registration Number for US
  applications
• 3.2.S.2.5 Process Validation
• Commercial scale batches for FDA
• 3.2.S.4.1/4.2/5 Specifications/Analytical
  Procedures/Reference Standards
• Possible differences in USP and Ph.Eur

23
3.2.S Drug Substance

• 3.2.S.7 Stability
• Less data on existing active substances for FDA
  (1 pilot scale, 3 months accelerated)
• In the EU, 2 options
• 6 months at time of submission of accelerated and
  long term data on 2 production scale batches OR
• 6 month at time of submission of accelerated and
  long term data on 3 pilot scale batches

24
3.2.P.1 Description and Composition

• EU Composition of colors, film coating,
  printing ink (detailed in 3.2.P.4.1)
• US DMF reference
• Reference to compendia
• Diluents
• EU separate part P for diluents composed of
  more than one component
• FDA incorporate within 3.2.P.1

25
3.2.P.2 Pharmaceutical Development

• Excipients (colorants)
• Nomenclature of excipients (USP and PhEur)
• Use of preservatives
• Type of packaging
• Pack sizes
• Sterilization process

26
3.2.P Drug Product

• 3.2.P.3 Manufacturer
• May be different
• 3.2.P.3.5 Process Validation
• Results at pre-approval inspection for US
• Protocol at submission for EU
• 3.2.P.4 Control of Excipients
• Specifications and TMs possible differences in
  USP and PhEur

27
3.2.P.4.5 Excipients of Human/Animal Origin

• TSE risk emphasized in EU
• TSE CEP

28
3.2.P.5 Control of Drug Product

• Specifications and TMs possible differences in
  USP and PhEur
• Release and shelf-life specs (EU)
• Release and shelf-life specs are the same (US)
• Skip and Parametric Release testing may be viewed
  differently

29
3.2.A Appendices

• 3.2.A.1 Facilities and Equipment for Biotech
  products
• 3.2.A.2 Adventitious Agents Safety Evaluation
• non-viral and viral
• risk assessment of potential contamination with
  adventitious agents
• 3.2.A.3 Excipients

30
3.2.R Regional EU

• Process Validation Scheme on commercial scale
• Reference to Medical Device

31
3.2R Regional US (DS)

• Executed Batch Record
• In English
• Method Validation Package
• For non-USP
• Comparability Protocols (draft guidance)

32
3.2.R Regional US (DP)

• Executed Batch Records
• In English
• Including equipment, packaging records, labeling
  procedures, batch and label reconciliation
• Information on Components
• Comparability Protocol (draft guidance)
• Methods Validation Package
• For non-USP

33
Electronic CTD (eCTD)

• EU 22 Jan 2008
• Electronic-only submissions/eCTD
• Centralized Procedure (EMEA/5633/2007)
• 1 July 2008 accepted ( paper)
• 1 Jan 2009 strongly recommended (paper an
  exception)
• European Regulatory Network end 2009
• FDA preferred format
• IND, NDA, BLA, ANDA, Master Files, Annual Reports

34
eCTD

• Templates
• Editing of MS Word documents to repair styles
• Generating PDF documents
• Optical character recognition (OCR) of scanned
  PDF documents
• Bookmarks and hyperlinks
• Publishing software / new lingo

35
Summary

• CTD format is the standard
• CMC for EU and FDA is more similar than different
• There are EU / FDA CMC differences that should be
  addressed
• CTD can accommodate EU and FDA differences in
  content, review styles, local particulars
• eCTD is here