The document provides an overview of Drug Master Files (DMFs) and Certificates of Suitability (CEPs) for drug substances. It describes that a DMF is a confidential submission to regulatory agencies containing manufacturing and quality control information about a substance or component. It discusses the different types of DMFs, how they are submitted and reviewed, annual reporting requirements, and retirement. It also describes that a CEP is issued by EDQM and demonstrates that a substance's purity is controlled according to European Pharmacopoeia monographs, easing approval in Europe.

1. M. Radhika Choudhary
Regulatory Affairs Associate
A Brief Introduction to
DMF and CEP

2. CTD
Format for submission
for INDs and marketing
applications like NDA, ANDA, BLA,
etc.
Introduction to CTD
3.1 Table of
Contents
3.2 Body of
Data
3.2.S Drug Substance
3.2.P Drug Product
3.2.A Appendices
3.2.R Regional
Information
3.3 Literature
References
MODULE-3 (DRUG SUBSTANCE PART)
3.2.S.1 General Information
3.2.S.2 Manufacture
3.2.S.3 Characterization
3.2.S.4 Control of Drug Substance
3.2.S.5 Reference Standards or Materials
3.2.S.6 Container Closure Systems
3.2.S.7 Stability

3. Filings in FDA
(Substance part)

5. Nature of Drug
Substance, Drug
Product.
Manufacturing
process is shown
to be in control
Manner in which
they are made
DMF (Drug Master File)`
A Drug Master File (DMF) is a submission to the FDA of
information, usually concerning the confidential detailed
information about Chemistry, Manufacturing and Controls
(CMC) of the component of a drug Product.
Used as support for various applications.
C M C?Who must file a DMF….?
NOBODY.

6. Types of DMFs
Originally Five Types… for US Market
I. Plant information (Withdrawn)
II. Drug substance, intermediates and material used in their
manufacturing.
III. Packaging
IV. Excipients.
V. Other information which is generally not covered by type I to
type IV drug master files.
(Usually clinical, toxicity data are covered)

7. How the System Works ?
 Holder sends the DMF to
Central Document Room
Center for Drug Evaluation and Research
5901-B Ammendale Road
Beltsville, MD 20705-1266
 Containing:
1 – Transmittal (cover) letter
2 – Administrative information
3 – Technical information
NEW ADDRESS
Submissions of Drug Master File

8. DMF is reviewed for administrative purposes ONLY by
Central Document Room (CDR) staff.
Entered into DMF DATABASE, Assigned a number, and
a letter is sent to the HOLDER.
If the DMF Holder does not receive any response from
FDA
HOLDER can put a query on the e-mail:
dmfquestion@cder.fda.gov

9. • Number given to DMF in database and Type.
• Reminder of obligations (responsibilities) of holder :
– Submit all changes as amendments.
– Notify FDA of change in holder name or address.
– Notify FDA of change in agent/representative.
– SUBMIT ANNUAL UPDATE (Annual Report).
– Submit Letter of Authorization (LOA) for each item
referenced.
Letter sent by FDA to DMF HOLDER consists of...

10. Letter of Authorization (LOA)
The DMF will be reviewed ONLY when it is referenced in an Application or another DMF.
DMF HOLDERUS FDA Send a letter to
remind holder
obligations
Send 2 copies of LOA to the FDA
1 copy of LOA to the APPLICANT
The applicant submits THIS
copy of LOA in their
Application.

11. Letter of Authorization (LOA)
DMF HOLDER
1 copy of LOA to the APPLICANT
The applicant submits THIS
copy of LOA in their
Application.
LOA to the FDA
Key points - LOA
 Sending LOA is the only mechanism
which triggers the review procedure of
DMF.
 If the holder cross references its own DMF,
the holder should supply following
information in the LOA.
• DMF number
• Specific product(s) covered by the DMF
• Section numbers and/or page numbers to
be referenced
[Authorization to refer to a DMF]

12. Sample LOA

13. Review of the DMF
REVIEWER
When reviewer receives an application
(IND/NDA/ANDA) with an LOA that
references a DMF
Requests the DMF from
the CDR (central document room)
but Delivery of DMF can
take a couple of days.
This review procedure of DMF
is in Contrast with
APPLICATION, where
document is delivered
automatically to reviewer.
Next slide

14. After getting DMF,the
Reviewer starts the
review procedure
If Reviewer found any
deficiency in the
content of DMF
The DETAILED DEFICIENCIES
are communicated to the holder
The APPLICANT is also notified
but, the nature of the deficiencies is
not communicated to the applicant
If no deficiencies, no letter, applicant not notified.
HOLDER should submit the
REQUESTED INFORMATION to
the DMF in response to the agency's
deficiency letter along with
transmittal letter having subject
matter.

15. DMF - Annual Update
The holder should provide an annual report on the
anniversary date of the original submission.
If the subject matter of the DMF is unchanged, the DMF
holder should provide a statement that the subject matter
of the DMF is current.
Failure to update can cause delays in FDA review of a
pending IND, NDA, ANDA or any amendment or
supplement to such application.

16. Retiring DMFs
If a DMF has no activity (amendment or annual report) in three
years FDA will initiate Retirement Procedure.
FDA sends overdue notice letter (ONL) to holder and/or agent using
most recent address.
If no response in 90 days, one copy of DMF is sent to Federal
Records Center (FRC) and the other is destroyed.
(Note: LOA is not counted for activity)

17. PARTS OF DRUG MASTER FILE
APPLICANT’S PART RESTRICTED PART
2 PARTS
OPEN PART CLOSED PART
What neXt?...
Information in the Drug Master File…

18. APPLICANT’S PART OF DMF
OPEN PART
( AVAILABLE TO APPLICANT )
ACTIVE SUBSTANCE
MANUFACTURER
SUPPLIES INFORMATION
TO THE APPLICANT
THE INFORMATION INCLUDES:
- outline of the manufacturing method
- impurities originating from the manufacturing method,
isolation procedure and degradation
- information on the toxicity of specific impurities

19. THE INFORMATION INCLUDES:
Detailed information about…
Individual steps of the manufacturing method such as
Reaction conditions, temperature,
Validation and evaluation data for certain critical steps of
the manufacturing method, etc.
(Such information is supplied to the authorities only)
RESTRICTED PART OF DMF
CLOSED PART
( NOT AVAILABLE TO APPLICANT )

20. Filings in EMA
(Substance part)

22. ASMF (Active Substance Master File)
 Sometimes called as EDMF (European Drug Master File)
 This is generally used for Non-Pharmacopoeial
substances in Europe.
 In Europe, the permission to reference an ASMF is called
Letter of Access.

23. CEP (Certificate of Suitability)
Role
To demonstrate that the purity of the given API is suitably controlled
by the relevant monographs of European Pharmacopoeia.
Advantages
 Full confidentiality of the submitted data.
 Centralised evaluation by EDQM (European Directorate for the
Quality of Medicines & HealthCare).
 Easing management of applications for MAA in Eu-countries.
 prevents duplication of assessment by the individual national
authorities.
-Issued by EDQM
It’s a Separate registration process for an API with EMA

24. CEP (Certificate of Suitability)
Scope of the procedure
Substances covered by a specific Ph. Eur. Monographs :
Active, excipients, herbal drugs/herbal preparations
 TSE risk products (starting materials, intermediates,
reagents,…)
Not applicable for biotechnological products, products from
human tissues, semi-finished or finished products, substances
not included in Ph. Eur.
-Issued by EDQM
It’s a Separate registration process for an API with EMA

25. How does the process of Evaluation by
EDQM work Flow?
DMF - Application
Certification Division of the EDQM
Validated and listed for assessment
EDQM may send queries to the applicant
When the queries have been resolved
EDQM sends the applicant the CEP
Inspection program for manufacturing
sites covered by a certificate (CEP)
Checks compliance with current Good
Manufacturing Practices (GMP) and
the CEP application dossier

26. A CEP looks
like this 

27. Is my CEP valid?

28. Thank you for your attentive listening!

Thank you for your attentive listening!
Hope Our Paths will
Cross Again!