1) The document discusses submitting electronic DMF/ASMF dossiers to regulatory agencies in the US, Canada, EU, and Switzerland. It defines DMF/ASMF and describes the different types used across regions. 2) Key differences in DMF types and structures between regions are explained, including the division of dossiers into open/applicants parts and closed/restricted parts. CTD sections to be included in each part are provided for examples. 3) Conversion timelines and requirements for electronic submission formats like eCTD are outlined for each region. Canada and EU now require eCTD format for new submissions, while FDA accepts both eCTD and paper.

1. Submitting electronic DMF/ASMF
dossiers
(US / CA / EU / CH)
Michiel Stam & Joyce van Gerven, PhD
IRISS Monthly Webinar - April 13th 2016

2. Who are we?
Michiel Stam Joyce van Gerven
Regulatory Information Scientist Regulatory Affairs Scientist
eCTDconsultancy B.V.
The Netherlands

3. Introduction to this Webinar

4. Outline of this Webinar
• Definition and purpose of DMF/ASMF
• What types of DMF are in place?
• US DMF types
• CA DMF types
• EU ASMF
• CH DMF
• DMF dossier structure and differences between ICH countries
• Folder structures for electronic dossiers
• CTD sections to be included
• Electronic particulars concerning DMF submissions
• Closing remarks & Conclusions

5. Definition and purpose of DMF/ASMF

6. Definition of DMF & ASMF
• Drug Master File (DMF) a submission to the FDA & Health Canada
to provide confidential CMC information
• Covers substances (both API’s and excipients), facilities, processes,
packaging components or finished products sourced from a third-party
manufacturer
• Active Substance Master File (ASMF) is a type of DMF and is the
currently recognized term in the EU:
• Contains data on the manufacture, quality control and stability of a drug
substance sourced from a third-party manufacturer that is used in the
manufacture of a medicine.
• Formerly known as European Drug Master File (EDMF).

7. Purpose of a DMF/ASMF
• Protect intellectual property or 'know-how' of the third-party supplier
(DMF Holder), whilst;
• Providing Competent Authorities complete information for assessment
• Allowing Applicant/MA holder to take full responsibility and control over the
Quality of the medicinal product

8. Other definitions
• DMF/ASMF Holder: Person or Company who submits the DMF (third
party supplier)
• Agent: Company who represents the DMF/ASMF Holder
• Applicant/ Authorized Party/ Marketing Authorization Holder/
Customer: Person or Company who references the DMF/ASMF
• Letter of Access/Authorization (LOA): Authorization letter from
Holder to refer to a DMF in an Application

9. DMF/ASMF High-Level Process
Holder sends DMF
(AP+RP+LOA) to
Health Authority
Health Authority
administrative review
of DMF
HA enters DMF in
database and sends
response to Holder
Holder receives
confirmation/DMF no.
from HA
Holder provides LOA
(& Applicants part) to
Applicant
Applicant includes LOA
(& AP) in application
Applicant submits
application to HA
HA reviews DMF in
context of application
and checks for
deficiencies
1.
2.

10. DMF/ASMF in context of the application
• A DMF/ASMF can only be submitted (will only be reviewed) in
support of an Application
• The relationship between the quality of the active substance and its use in
the medicinal product needs to be justified in this MAA.
• Although procedure is developed to protect intellectual property of the Holder;
It is also permissible to use the procedure when there is no confidentiality
issue between the Applicant/MA holder and the ASM (e.g. when the
Applicant/MA holder synthesizes the active substance himself).

11. What types of DMFs are in place
across the various Regions?

12. Types of DMFs in ICH countries
Type I Type II Type III Type IV Type V
US Manufacturing
Site, Facilities,
Operating
Procedures, and
Personnel (not
longer active 
use Type V)
Drug Substance,
Drug Substance
Intermediate, and
Material Used in
Their Preparation,
or Drug Product
Packaging
Material
Excipient,
Colorant, Flavor,
Essence, or
Material Used in
Their Preparation
FDA Accepted
Reference
Information
CA Drug Substance Container Closure
Systems and
Components
Excipients Drug Product
EU Only ASMF needed for Active Substances
CH Only DMF needed for Active Substances
Other countries include Australia (TGA), Japan (PMDA), GCC, Russia (and many more…)

13. US DMF types

14. General
• US DMFs are neither approved nor disapproved but must be current
at the time of review
• The application (IND/NDA/ANDA) supported by the DMF will be approved
instead
• No legal requirement to submit DMF
• Submitted to CDR instead of particular review division
• Annual updates and changes send as amendments
• FDA sends overdue notification letters for DMFs that are overdue for
update
• Submit LOA for each reference to DMF

15. FDA – Review of DMFs
• Administrative Review (at receipt)
• The FDA does not send a notification
• The original DMF undergoes an administrative review to determine it is
administratively complete (2-3 weeks)
• If the DMF is acceptable, an Acknowledgement Letter will be issued
• DMF is "ACTIVE"
• If the DMF is not acceptable, a notification of what deficiencies need to be
corrected is sent
• Technical Review (in context of IND/NDA/ANDA)
• DMF must be ACTIVE.
• DMF holder submits a LOA to DMF and a copy of LOA to applicant
• Applicant submits an application to the FDA that contains a copy of the LOA

16. Type II - Drug Substance, Drug Substance
Intermediate, and Material Used in Their Preparation,
or Drug Product
• Limited to a single drug intermediate, drug substance, drug product,
or type of material used in their preparation
• Separate DMFs should be submitted for drug substances and drug
products
• Drug Products should ordinarily be submitted in an IND, NDA, ANDA
 Use DMF if not possible

17. Type III - Packaging Material
• Identify each material by intended use, components, composition and
release controls
• Provide names of suppliers/fabricators of components used in
preparing packaging material and provide acceptance specifications
• Submit data supporting acceptability of the material for intended use
Note: compatability and safety remains the responsibility of the
Applicant, not the Holder!

18. Type IV - Excipient, Colorant, Flavor, Essence, or
Material Used in Their Preparation
• Identify and characterize each additive by method of manufacture,
release specifications and testing methods
• Official compendia and FDA regulations may be used as sources for
release tests, specifications, and safety
• Compendial excipients are usually not reviewed and therefore no DMF
required; exceptions e.g. new Route of Administration
• Guidelines for Type II DMF may be helpful for preparing Type IV DMF
for Novel Excipients
Additional information:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM261078.pdf
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM366082.pdf

19. Type V - FDA Accepted Reference Information
• FDA discourages the use of Type V DMFs for:
• Miscellaneous information
• Duplicate information
• Information that should be included in one of the other types of DMFs
• When there is an intent to submit a type V DMF:
• Submit a letter of intent to obtain clearance from FDA
• FDA will contact the holder to discuss the proposed submission
• Exceptions to requirement for obtaining clearance to file a Type V
DMF:
• Information regarding manufacturing site, facilities, operating procedures, and
personnel for sterile manufacturing plants and biotechnology products
Additional information:
http://www.ecfr.gov/cgi-bin/text-
idx?SID=3ee286332416f26a91d9e6d786a604ab&mc=true&tpl=/ecfrbrowse/Title21/21tab_02.tpl

20. CA DMF types

21. General
• DMF Owners or Agents will not be informed that the DMF is
acceptable to support the submission
• Holders Module 1 documents are treated as Restricted information
• Dossier ID should be "HC6-24-" followed by a letter and seven digits
• DMF may be subjected to a preliminary evaluation when a drug
submission referencing a DMF undergoes business validation
• 5-Yearly update
• HC fee form lists biannual DMF update
• Significant changes to be submitted immediately
• If no changes  a simple statement confirming this is sufficient

22. General
• Comments on AP for discussion between Sponsor and HC
• Comments on RP or AP impacting Quality for discussion between
Holder and HC (deficiency letter or clarifax)
• Sponsor(s) will be notified about outstanding issues to be resolved before
acceptance
• No need to rename original DMF files received from holder

23. Type I – Drug Substance &
Type IV – Drug Product
• Each AP for API or DP should be in its own 3.2.S or 3.2.P section, if
Sponsor references multiple DMFs
• Sponsor’s own documents on API or DP should be in a separate
3.2.S or 3.2.P section with appropriate attributes to distinguish from
DMF owner(s) section

24. Type II – Container Closure & Type III - Excipients
• No Applicant's Part
• Sponsor(s) are not informed about deficiencies
• Container Closure:
• Two options for providing multiple components in M3
• "3.2.P Drug Product (Component X)“ branch per component
• Separate subfolder per component in "3.2.P.7 Container Closer System"
• Excipients:
• Separate 3.2.P.4 folder for each excipient

25. EU ASMF (by Joyce van Gerven)
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidelin
e/2012/07/WC500129994.pdf

26. EU ASMFs
• Can be used for new, EU/NCA pharmacopoeial and non-
pharmacopoeial active substances, except for biologicals
• Holder sends LoA and ASMF AP & RP to NCA/EMA for assessment
of the data in relation to a specific MAA
• Each version of AP and RP should have unique version control numbers
• Holder submits copy of AP, QOS and LoA to the Applicant/MA holder
• Holder may have both ASMF and CEP for single active substance
• MAH to refer to either ASMF or CEP
• Except when CEP contains too little information and NCA/EMA requests
additional information

27. ASMF maintenance
• To be kept up to date in relation to manufacturing process
• QC methods to be kept in line with current regulatory and scientific
requirements
• Contents cannot be changed during other on-going procedures
• Holder should provide explanation and new data to MA holder and NCA/EMA
and request later date of implementation
• At 5-year renewal, ASMF holders declare:
• “The quality of the product has been regularly updated to take account of
technical and scientific progress”
• “No changes have been made to the product particulars other than those
approved by the NCA/EMA”

28. CH DMF

29. CH DMF
• MA holder must ensure that DMF holder submits the current version,
synchronized with the MA application
• MA approval only possible if full DMF (AP & RP) and LoA is submitted
• DMF only to be submitted in context of initial MAA, variation or
periodic review
• To be received within 7 days before and 3 days after receipt of the
accompanying submission
• If no MA application referencing the DMF is received, a reminder will
be sent to the MA holder
• DMF will be returned at cost of sender after 120 calendar days

30. CH DMF
• Open part is submitted by the MAH as part of Module 3
• MAH may omit submission of open part, if stated in cover letter
• Restricted part is submitted directly (and independently) by Holder
• In most cases the DMF Holder also submits open part
Note
DMF application form is updated
• Previous version still accepted during a transitional period until 31 May 2016
• Holders should now indicate if DMF application / variation will be submitted to
competent authorities in Australia, Canada or Singapore or EMA

31. DMF Dossier Structures and
differences between ICH countries

32. Differences between AP & RP across countries
• FDA: No “open” or “closed” parts of DMFs filed with the FDA
• CA (Type II & III): Only Restricted Part
• CA (Type I & IV), CH and EU
• Scientific information to be physically divided into separate parts
• Open or Applicants Part (AP), non-confidential to the Applicant/MA holder
• Closed or Restricted Part (RP), confidential to the Applicant/MA holder
• AP should contain sufficient information to take full responsibility for an evaluation
• RP contains remaining information, including details on;
• Individual steps of manufacturing method
• Quality controls for manufacturing of substances
Note: The Agency may not accept that particular information has not been
disclosed to the applicant, and may therefore ask for an amendment to the AP

33. Drug Substance Folder Structure
CA
EU & CH

34. QOS in DMFs
• The DMF should contain a separate summary for the AP and the RP,
presented as a Quality Overall Summary (QOS)
• MA Applicant should merge QOS DMF Open part in company’s QOS
for the application
• Allowed to submit a maximum of 5 Summary documents
• Administrative
• QOS Drug substance
• QOS Drug product
• Non-Clinical
• Clinical

35. CTD sections to be included

36. Example on EU - Drug Substance
CTD section AP RP
3.2.S.1 General Information X
3.2.S.1.1 Nomenclature X
3.2.S.1.2 Structure X
3.2.S.1.3 General properties X
3.2.S.2 Manufacture X X
3.2.S.2.1 Manufacturer(s) X
3.2.S.2.2 Description of Manufacturing Process and Process controls 1 2
3.2.S.2.3 Control of Materials X
3.2.S.2.4 Control of Critical Steps and Intermediates 3 4
3.2.S.2.5 Process validation and/or Evaluation X
3.2.S.2.6 Manufacturing Process Development X

37. Example on CA - Type IV Drug Product
CTD section AP RP
3.2.P.1 Description and Composition of the Drug Product X 3
3.2.P.2 Pharmaceutical Development 4 3
3.2.P.2.1 Components of the Drug Product 5 X
3.2.P.2.2 Drug Product X
3.2.P.2.3 Manufacturing Process Development X
3.2.P.2.4 Container Closure System X
3.2.P.2.5 Microbiological Attributes X
3.2.P.2.6 Compatibility X
3.2.P.3 Manufacture X X
3.2.P.3.1 Manufacturer(s) X X
3.2.P.3.2 Batch Formula X X
3.2.P.3.3 Description of Manufacturing Process and Process Controls 2 3
3.2.P.3.4 Controls of Critical Steps and Intermediates 4 6
3.2.P.3.5 Process Validation and/or Evaluation X

38. Electronic particulars concerning DMF
submissions

39. Format and submission methods
Submission method
(April 13th 2016)
CA CH EU US
Paper X X
CD/DVD X (NeeS only) X X (NeeS only,
CHMP/PRAC)
X (optional for >10GB)
Gateway X X (ESG for CHMP/PRAC
also)
X (mandatory for <10GB)
Submission format
(April 13th 2016)
CA CH EU US
CTD (Paper) Not since 1st January 2016 X X (until 5th May 2017)
NeeS X Until 1st July 2016 for CP
eCTD X X X X (mandatory for new)
Other X (type III packaging,
until 5th May 2017)

40. CA - Conversion to electronic format
• New DMFs and updates on existing DMFs should be provided in NeeS or
eCTD
• All existing DMFs in paper format must be replaced by a complete DMF
conversion in NeeS or eCTD format (March 31st 2016)
• Failure will result in the DMF being suspended
• If filed in eCTD format, following requirements should be met:
• Sample eCTD submission must be provided
• Pre-technical meeting is recommended, and mandatory for Type II and III DMFs
• Dossier ID to be requested
• Must be sent via CESG
• Questions related to eCTD format to be directed to ereview@hc-sc.gc.ca

41. FDA - Conversion to (e)CTD format
• Companies may convert existing DMF in non-CTD format to CTD
format.
• DMF holders should submit amendment with relevant and current CTD
sections
• For drug substances and excipients, companies must submit all 3.2.S
sections
• For drug products, companies must submit all 3.2.P sections
• Content changes caused by reformatting should be described in cover letter
• No baseline requirement for conversion of paper DMF to eCTD
format
• All types of new DMFs should be submitted in eCTD

42. EU – Conversion to eCTD format
• The mandatory format for ASMF submissions for human medicines is
now eCTD or structured NeeS
• It is strongly recommended to provide all submissions in eCTD format
• It is strongly recommended to provide a baseline submission, containing the
current status of all previously submitted content

43. CH – Conversion to eCTD format
• No requirements yet on conversion to eCTD
• If you consider conversion:
• Swissmedic recommends MA applicants to convert paper-based drug product
submissions into eCTD before collective application is submitted
• Paper copy can be omitted if the DMF is submitted in eCTD format

44. Closing remarks & Conclusions

45. Closing remarks & Conclusions
• DMFs/ASMFs used across many regions
• Scope and definitions vary
• Review and authorization procedures vary
• Formats and submission methods vary
• eCTD is accepted in all regions (and may become the mandatory
format everywhere)
• DMF holders should consider in house eCTD publishing or outsourcing
• Presentation reflects current status, ongoing developments should be
monitored

46. Thank you for your attention!