Drug Master Files (DMFs) provide confidential information to regulatory agencies to support drug approvals. There are different types of DMFs for drug substances, products, packaging, and excipients. DMFs are submitted voluntarily to the FDA and are kept confidential. They are reviewed only when referenced in an application such as an NDA. Applicants submit a Letter of Authorization to the FDA and DMF holder to access the DMF information during review. DMF holders must provide annual updates to keep the information current.

1. Drug Master Files
Global Perspectives
1

2. Drug Submissions: US, Canada, EU
TYPES OF DRUG SUBMISSIONS: US, Canada, EU
USA New Drug Application (NDA), for new drugs
Accelerated New Drug Application (ANDA)-for generics
Biologic License Application (BLA), for biologic
Canada New Drug Submission (NDS)―for both drugs and biologic
products
EU Marketing Authorization Application (MAA)―via the
Centralized Procedure for eligible products. For other products,
via the decentralized, mutual recognition or national
authorization are applicable.

3. Role of DMFs
Supporting documents for the registration /
approval of drug products
In the Chemistry, Manufacturing and Controls (CMC) sections of the drug submission, the DMF documents the
drugs identity, purity, strength and quality.
Protect Proprietary and Confidential Information

4. DMFs Globally
Highly Regulated Markets (Drug Master Files used to support approval process)
United States:
Canada:
Australia
Japan
Europe: China is developing its own DMF system
Nearly Regulated Markets (Technical Package / Registration Dossier)
Brazil
Russia
South Africa
Less Regulated Markets (No Drug Master Files used in registration process)
India and many others

5. Drug Master Files: USA
Drug Master File (DMF): is a submission to the Food and Drug Administration (FDA) that may be
used to provide confidential, detailed information about facilities, processes, or articles used in
the manufacturing, processing, packaging, and storing of one or more human drugs.
There is no legal or regulatory requirement to file a DMF.
A DMF may be filed to provide CMC information that the FDA reviews instead of including this
information in the Application (IND, NDA, ANDA).
A DMF is neither approved nor disapproved by the FDA.
It is provided for in 21 CFR 314.420 (Code of Federal Regulations)

6. The US DMF System
“Closed”

7. DMF – US: Important Facts
DMFs are Confidential (Closed)
DMF Stakeholders
DMF Holder: Company or Person who submits the DMF
Applicant: Company or person who references the DMF in an application or another DMF
Information contained in a DMF may be used to :
Support an Investigational New Drug Application (IND))
Support a New Drug Application(NDA)
Support an Abbreviated New Drug Application (ANDA)
Support another DMF
Support an Export Application
Support amendments and supplements to any of these.
7

8. How the US DMF System Works
Filing the DMF
Holder sends two copies of the DMF to FDA
DMF is reviewed for administrative purposes only by Central Document Room staff
DMF entered into database, assigned a number and acknowledgment letter sent to holder
A DMF is neither approved or disapproved
Accessing the DMF: Letter of Authorization (LOA)
The DMF will be reviewed only when it is referenced in an Application or another DMF
The Holder must submit a two copies of the LOA to the DMF, plus a copy to the Applicant
The Applicant submits a copy of the LOA in their Application
The LOA is the only mechanism to trigger a review of the DMF by the FDA
DMF Review Procedure
The DMF is reviewed only if referenced by an Applicant or another DMF
If the reviewer finds deficiencies in the DMF, the deficiencies are detailed in a letter to the Holder
The Applicant will be notified that deficiencies exist, but the nature of the deficiencies are not communicated to the
Applicant

9. US DMFs - Types
Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel
No longer accepted by the FDA (as of January 2000)
Type II – Drug Substance, Drug Substance Intermediate, and Material Used
in Their Preparation, or Drug Product
Type III – Packaging
Type IV – Excipients, Colorant, Flavor, Essence, or Material Used in Their
Preparation
Type V – FDA Accepted Reference Information
Used for sterile manufacturing plants and contract facilities for biotech products
9

10. US DMF’s – Statistics
1
0
Considerado o status de Inativo para os DMFs sem atividade pelos últimos 3 anos, ou sob
exigência do detentor do DMF. Todos os dados são para 4T 2011
Description DMF Type No of DMFs
Manufacturing site, facilities, operating procedures, and personnel I 1,826
Drug substance, drug substance intermediate, and materials used in the preparation, or Drug Product II 15,230
Packaging Material III 4,511
Excipient, Color, Flavor, Essence or material used in their preparation IV 1,749
FDA Accepted reference information V 355
Blanks Blanks 1,969
GRAND TOTAL 25,640

11. US DMFs – Type II
Active / Inactive US Type II DMFs -- 2011
Active US Type II DMFs -- 2011

12. Global DMF Trends
Not Yet Harmonized:
US FDA: 2 copies of each Type II DMF u sing CTD format, but not in CTD module form. FDA format combines
Modules 2 & 3 as there is no Applicant vs Restricted part.
FDA moving towards eCTD applications
EU: has separate portions for Modules 2 & 3 (Applicant / Restricted), but some countries in EU have different
requirements
EU wants electronic format but there are several formats; some countries still require paper
Overhead: DMFs often run in excess of 1,000
pages. Storage and care of them can be a major
burden.

13. Who Must File a DMF?
NOBODY
1
3
There is no legal or regulatory requirement to file a DMF. A DMF may be
filed to provide CMC information that the FDA reviews.
The information contained in DMF may be used to support an IND / NDA
/ANDA ,another DMF,an export application or amendments and
supplements of any of these.
Remember that,
DMF is NOT a substitute for IND / NDA / ANDA or export application.
Technical contents of a DMF are reviewed only in connection with the
review of IND /NDA /ANDA or an export application.
/ 45

14. II. Some basic terminologies
HOLDER: The person /company who submits DMF.
AGENT : The person / company who represents a DMF HOLDER.
(Also called Representative.)
APPLICANT / CUSTOMER / AUTHORISED PARTY (AP ) :The person / company who references
the DMF.
APPLICATION:Investigational New Drug Application (IND), New Drug Application (NDA),
Abbreviated New Drug Application (ANDA)
SUPPLEMENT TO AN ANDA / NDA: A report of change in an approved ANDA / NDA.
AMENDMENT TO AN APPLICATION: Additional information to…
an existing IND,
a pending ANDA / NDA
a pending ANDA / NDA supplement.
1
4 / 45

15. III. Types of DMFS with their
contents
Type I : plant information
Points included:
Manufacturing site
Equipment capabilities
Operational layout
Actual site address
A map showing its location with respect to the nearest city
Corporate headquarters
As per Jan. 12, 2000 FR notice : Elimination of Type I DMFs done
by July 10, 2000.
1
5 / 45

16. TYPE II DMF
1
6
CONTENTS:
(1)Drug Substance Intermediates, Drug Substances, and Material Used in Their Preparation.
It Summarizes all significant steps in the manufacturing and controls of
the drug intermediate or substance.
Detailed guidance on what should be included in a Type II DMF for drug substances and
intermediates may be found in the following guidelines:
1.Guideline for Submitting Supporting Documentation in Drug Applications for the
Manufacture of Drug Substances.
2.Guideline for the Format and Content of the Chemistry, Manufacturing, and
Controls Section of an Application.
/ 45

17. (2) Drug Product (finished dosage forms)
1
7
Manufacturing procedures and
controls for finished dosage forms
should
ordinarily be
submitted in an IND,
NDA, ANDA, or
Export Application.
If can not be
submitted to above
documents
It should be submitted in a DMF
/ 45

18. For a drug product, the applicant/sponsor should follow the
guidance provided in the following guidelines:
1.Guideline for the Format and Content of the Chemistry,
Manufacturing, and Controls Section of an Application.
2.Guideline for Submitting Documentation for the Manufacture of
and Controls for Drug Products.
3.Guideline for Submitting Samples and Analytical Data for Methods
Validation.
1
8 / 45

19. GENERAL POINTS INCLUDED IN TYPE II DMF
1
9
Manufacturing
Section
Quality
Controls
Validations Stability
data
Impurities Packaging &
Labeling
Inputs Intermediates
& In-process
Finished Drug
Substance
Raw
materials
Packaging
materials
(1) (2) (3) (4) (5) (6)
a. b. c.
a.1 a.2
/ 45

20. Type III: Packaging Material
Contents:-
 Packaging material intended for which use.
 Its components and composition.
 Names of the suppliers or fabricators of the components used in
preparing the packaging material.
 Acceptance specifications.
 Toxicological data on these materials.
 FOLLOW THE GUIDELINE: "Guideline for Submitting Documentation
for Packaging for Human Drugs and Biologics."
2
0 / 45

21. BUT REMEMBER THAT,
Responsibility for compatibility and safety of
packaging components in finished drug product is the
responsibility of the AUTHORISED PARTY(AP).
It is not the responsibility of DMF HOLDER.
2
1 / 45

22. Type IV Excipients
 CMC for a compendial excipient is usually not
reviewed and therefore a DMF is not necessary.
 Exceptions: New route of administration or total dosing
that may affect safety and efficacy. E.G..RESPITOSE,
lactose for dry powder inhalation products.
 CMC requirements for a novel excipient should be
submitted same as type II DMF.
2
2 / 45

23. Type V DMF
FDA discourages the use of Type V DMFs for miscellaneous
information, duplicate information, or information that should
be included in one of the other types of DMFs.
2
3
TO SUBMIT THE DATA
WHICH IS NOT COVERED IN
TYPE I TO IV DMF
(CLINICAL / TOXICITY DATA)
A holder
must first submit
a letter of intent
to the drug master file staff
FDA will then contact the
holder to discuss the
proposed submission. / 45

24. IV. SUBMISSIONS OF DRUG MASTER FILES
How the System Works ?
 Holder sends the DMF (NO FEE two copies) 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
2
4
Follow the Guideline at www.fda.gov/cder/guidance/dmf.htm
Binders recommended http://www.fda.gov/cder/ddms/binders.htm
NEW ADDRESS
/ 45

25. 1 – Transmittal (cover) letter
Original Submissions and Amendments
 Identification of submission.
(Original /supportive to original DMF / Amendment)
 Type of DMF and subject (update, revised formula, or revised process)
 The name and address of each sponsor, applicant, or holder, and all
relevant document numbers.
 Signature of the holder or the authorized representative.
 Typewritten name and title of the signer2
5 / 45

26. 2 – Administrative information
Original Submissions:
a. Names and addresses of the following:
(1) DMF holder.
(2) Corporate headquarters.
(3) Manufacturing/processing facility.
(4) Contact for FDA correspondence.
(5) Agent(s), if any.
b. The specific responsibilities of each person listed in any of the categories in Section a.
c. Statement of commitment.
A signed statement by the holder certifying that the DMF is current and that the DMF
holder will comply with the statements made in it.
2
6 / 45

27. 2 – Administrative information
2
7
Amendments
a. Name of DMF holder.
b. DMF number.
c. Name and address for correspondence.
d. Affected section and/or page numbers of the DMF.
e. The name and address of each person whose IND, NDA, ANDA, DMF, or Export
Application relies on the subject of the amendment for support.
f. The number of each IND, NDA, ANDA, DMF, and Export Application that relies
on the subject of the amendment for support, if known.
g. Particular items within the IND, NDA, ANDA, DMF, and Export Application that
are affected, if known. / 45

28. DMF reviewed for administrative purposes ONLY by Central
Document Room (CDR) staff.
DMF entered into DMF DATABASE, assigned a number,
and a letter sent to the HOLDER.
If no response from FDA side,…
DMF HOLDER can put a query on the e-mail:
dmfquestion@cder.fda.gov
2
8 / 45

29. Letter sent by FDA to DMF HOLDER consists of …
• 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.2
9 / 45

30. Letter of Authorization (LOA)
The DMF will be reviewed ONLY when it is referenced in an Application or another
DMF.
3
0
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.
/ 45

31. IMPORTANCE OF LOA
 Sending LOA is the only mechanism which triggers the review
procedure of DMF.
 A letter of authorization permits the FDA to reference the DMF.
 If the holder cross references its own DMF, the holder should supply
following information in a LOA.
-DMF number
-Specific product(s) covered by the DMF
-Section numbers and/or page numbers to be referenced
In Europe, the permission to reference a DMF is called a Letter of
Access.
3
1 / 45

32. Review of the DMF
3
2
REVIEWER
When reviewer receives an application
(IND/NDA/ANDA) 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
/ 45

33. 3
3
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.
/ 45

34. 3
4
Differences between Applications
and DMFs
/ 45

35. 3
5
Applications DMFs
1. COMES UNDER REGULATORY
STATUS.MUST BE FILED BY APPLICANT.
1.NOT COME UNDER REGULATORY
STATUS.IT IS NOT MANDATORY TO FILE
A DMF.
2. EACH APPLICATION AND ITS
SUPPLEMENT ARE ENTERED INTO
A COMMON DATABASE.
2. DMFs ARE ENTERED IN TO DATABASE
AS PER THEIR TYPES.
(SEPARATE DATABASE FOR EACH TYPE
OF DMF)
3.SUBMITTED TO A PARTICULAR
REVIEW DIVISION.
3.SUBMITTED TO CDR.
4. ASSIGNMENT TO A REVIEWER AND EACH
SUBMISSION HAS A DUE DATE.
4.NO ASSIGNMENT TO A REVIEWER, NO
DUE DATE.
5.REVIEW PROCEDURE QUITE DIFFERENT
THAN DMF.
5.DMFs ARE REVIEWED ONLY WHEN
REFERENCED BY APPLICATION OR
ANOTHER DMF
6.IF THE ANNIVERSARY DATE FOR ANNUAL
UPDATE IS MISSED FDA
WILL NOT SEND A REMINDER.
6.IF THE ANNIVERSARY DATE FOR ANNUAL
UPDATE IS MISSED FDA
SENDS A REMINDER.
/ 45

36. Annual Update of DMF
 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; and FDA can initiate
procedures for closure of the DMF.
3
6 / 45

37. Retiring DMFs
If a DMF has no activity (amendment or
annual report) in three years FDA will initiate
retirement procedure.
Note: LOA is not counted for activity.
3
7 / 45

38. DMF 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.
3
8 / 45

39. Summary
 The DMF system presents challenges for both the
industry and the FDA.
 Some of the changes have made the system smoother
(hopefully for both industry and FDA).
 Problems can be minimized:
– With full understanding of their responsibilities and
adherence to Guidances on the part of holders and
applicants.
– With adherence to policies and procedures on the part of
reviewers.3
9 / 45

40. THIS WAS ALL ABOUT
WHAT USFDA SAYS
ABOUT DMF.
4
0 / 45

41. NOW,…
What European Drug Master File Procedure for Active
Substances says about the DMF…
4
1
CONTENT OF DRUG MASTER FILE
APPLICANT’S PART OF DMF ASM RESTRICTED PART OF DMF
2 PARTS
OPEN PART CLOSED PART
/ 45

42. APPLICANT’S PART OF DMF
OPEN PART
( AVAILABLE TO APPLICANT)
4
2
ACTIVE SUBSTANCE
MANUFACTURER
SUPPLIES INFORMATION
TO THE APPLICANT
THIS INFORMATION INCLUDES:
-outline of the manufacturing method
-impurities originating from the manufacturing method, isolation
procedure and degradation
-information on the toxicity of specific impurities / 45

43. The applicant’s part of a DMF is provided by the
ASM to the applicant directly and becomes part of
the application for marketing authorization.
The applicant’s part of the DMF is still a confidential
document which cannot be submitted to third parties
without the written agreement of the ASM.
4
3 / 45

44. ASM Restricted Part of DMF
4
4
CLOSED PART
( NOT AVAILABLE TO THE APPLICANT)
IT 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. / 45

45. MODEL QUESTIONS
1. What are DMFs? Describe various types of DMFs.
2. Write a short note on type II DMFs.
3. Give details about latter of authorization.
4. What are the differences between DMFs and
APPLICATIONS?
5. What are the open and closed part of DMF as per
European guidelines?
6. Describe the submission, review and retiring of DMF.
4
5 / 45

46. REFERENCES
• www.fda.gov/cder/guidance/dmf.html
• www.emea.eu.int/htms/vet
• http://www.fda.gov/cder/Offices/ONDQA/prese
ntations/shaw.pdf
4
6 / 45

47. 4
7