1. M a n u re H . S .
A s s t . P ro f e s s o r
D e p t . o f P h a r ma c e u t i c s ,
S c h o o l o f P h a r ma c y,
S RT M U n i v e r s i t y, N a n d e d
1
Drug Master File
2. Contents:
2
1. Introduction to DMFs
2. Drug master file process
3. Drug master file format
4. Drug Master File contents:
4.1 Submission of DMF
4.2 Authorization to refer to a drug master file
4.2.1 Format for Letter of authorization to review DMF
4.3. Processing and reviewing policies
4.4. Changes in DMFs
4.5. Closure of a drug master file
4.6. Retiring DMFs
3. 3
5.Electronic Filing of DMFs and CTD
6. Changes in DMF system:
7.Application
8. Difference between application and DMFs
9.European DMFs
10. Difference in European DMFS compare to US DMFs
11. Case study
12. References
13.Study questions
4. 1.Introduction
4
• A Drug Master File (DMF) is a set of documents that provides detailed
information concerning facility protocols and procedures used in the
manufacturing, packaging and storing of pharmaceuticals.
• A Drug Master File (DMF) is a submission to the FDA of information, usually
concerning the Chemistry, Manufacturing and Controls (CMC) of a component
of a drug product, to permit the FDA to review this information.
• Drug product information or other non-CMC information may be filed in a
DMF.
Generally DMFs have two parts:
(1) Applicant’s part : which contain non-confidential information that the license-
holder needs to assess for the marketing.
(2)Restricted part: which contains confidential information about the
manufacturing procedure that only needs to be disclosed to the authorities.
5. Who Must File a DMF?
5
There is no legal or regulatory requirement to file a DMF. A DMF
may be filed to provide Chemistry, Manufacturing and Controls
(CMC) information that the FDA reviews.
It is only for Maintain confidentiality of proprietary information
(e.g., Manufacturing procedure, key ingredients, etc.) for the
holder
6. 2. Drug master file process
6
• Two copies of the Drug Master File with one signed original of the covering
letter and other necessary documents are send to the FDA’s Central Drug
Evaluation and Research (CDRL). [1]
• The Drug Master File staff will audit the non-technical information for
completeness and adequacy for submission. If the key elements are missing,
the staff will contact the proposed holder to try to obtain the necessary
documents in order to file the DMF.
• Once the DMFs are determined to be acceptable for filing, the document
room staff assigns a DMF number and a letter is sent to the contact person
listed in the DMF.
• All DMF submitted in CTD format is accepted by any authorities.
7. Steps for filing the DMF:
7
1. Set the document margins at 3/4 inch for the left (at least) and 1/2 inch for the right.
2. Print the transmittal page, administrative information and DMF information on standard letter-
size paper. If a larger sheet of paper is required for a diagram or schematic, fold the sheet and
attach it to a letter-sized page in a manner that will allow for the page to be opened and refolded.
At a maximum, each volume of a DMF should be no more than 2 inches thick.
3. Number multiple volumes for one submission according to the total number of volumes (if more
than one). (For example, 1 of 3, 2 of 3, etc.)
4. Sign all documents requiring signature (only if you are the DMF holder or authorized
representative).
5. Copy and collate the document; FDA requires you submit both.
6. Punch documents with a standard hole-punch.
7. Cover each original and copy of each volume with a document jacket.
Prepare the submission for shipping and mail to:
Drug Master File Staff
Food and Drug Administration
5901-B Ammendale Rd.
Beltsville, MD 20705-1266
8. 3. Drug master file format
8
The DMF must meet the format requirements.[2] The DMF is submitted as Original
and Duplicate jackets, collated, assembled, paginated, and jacketed, using covers
obtained from the government printing office and are specifically provided for the
DMFs.
Multiple volumes are numbered, and the paper must be standard paper size.
The DMF must be submitted in two copies, one with a blue cover and one with a red
cover. The jacket covers are purchased from the government printing office.
Figure : DMFs Jacket
9. Binders for drug master file
9
Material should have a surface smooth enough to allow printing with a complete bonding
of ink to the surface after drying - Should be free from streaks, blisters, scratches and
mottling -
Binder weight MUST be .023-.025 gauge - Ink colour MUST be BLACK -
Binders include –
FDA Form 3316 - Red - DRUG MASTER FILE ARCHIVAL BINDER
FDA Form 3316a - Blue - DRUG MASTER FILE BINDER
PAPER BINDERS
Front (flat size) - 267 x 292mm (10-1/2 x 11-1/2")
Back (flat size) - 267 x 305mm (10-1/2 x 12") (size includes 13mm (1/2") lip at top [3]
For maroon coloured binder ink should be white and for other binder ink used to print on it
must be black.
10. Conti……
10
Paper Binders for review of DMFs include –
FDA Form 2626a - Red - NDA CHEMISTRY BINDER
FDA Form 2626b - Yellow - NDA PHARMACOLOGY BINDER
FDA Form 2626c - Orange – NDA PHARMACOKINETIC BINDER
FDA Form 2626d - White – NDA MICROBIOLOGY BINDER
FDA Form 2626e - Tan – NDA CLINICAL DATA BINDER
FDA Form 2626f - Green – NDA STATISTICS BINDER
FDA Form 2626h - Maroon – NDA FIELD SUBMISSION
CHEMISTRY BINDER
COVER FORM [3]
11. 4. Drug Master File contents:
11
Types of drug master file :
Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel
Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their
Preparation Or Drug Product
i. Manufacturing section
ii. Quality controls
Inputs (raw/packaging Materials)
Intermediates and in-process
Finished drug substance
iii. Validations
iv. Stability data
v. Impurities
vi. Packaging and labelling
Type III: Packaging Material
Type IV: Excipient, Colorant, Flavour, Essence, or Material Used in Their Preparation
Type V: FDA-Accepted Reference Information
12. 12
Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel
• A Type I DMF is recommended for a person outside of the United States to assist
FDA in conducting on site inspections of their manufacturing facilities. The DMF
should describe the manufacturing site, equipment capabilities, and operational layout.
• A Type I DMF is normally not needed to describe domestic facilities, except in
special cases, such as when a person is not registered and not routinely inspected.
• The description of the site should include actual site address, and a map showing its
location with respect to the nearest city. An aerial photograph and a diagram of the site
may be helpful.
• A diagram of major production and processing areas is helpful for understanding the
operational layout. Major equipment should be described in terms of capabilities,
application, and location. Make and model would not normally be needed unless the
equipment is new or unique.
• A diagram of major corporate organizational elements, with key manufacturing,
quality control, and quality assurance positions highlighted, at both the manufacturing
site and corporate headquarters, is also helpful.
13. 13
Type II: Drug Substance, Drug Substance Intermediate, and Material Used in
Their Preparation, or Drug Product
A Type II DMF should, in general, be limited to a single drug intermediate, drug
substance, drug product, or type of material used in their preparation.
(1) Drug Substance Intermediates, Drug Substances, and Material Used in Their
Preparation
• Guideline for Submitting Supporting Documentation in Drug Applications for the
Manufacture of Drug Substances.
• Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls
Section of an Application.
(2) Drug Product
• Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls
Section of an Application.
• Guideline for Submitting Documentation for the Manufacture of and Controls for Drug
Products
• Guideline for Submitting Samples and Analytical Data for Methods Validation
14. 14
Type III: Packaging Material
• Each packaging material should be identified by the intended
use, components, composition, and controls for its release. The
names of the suppliers or fabricators of the components used in
preparing the packaging material and the acceptance
specifications should also be given. Data supporting the
acceptability of the packaging material for its intended use
should also be submitted as outlined in the
• "Guideline for Submitting Documentation for Packaging for
Human Drugs and Biologics."
• Toxicological data on these materials would be included under
this type of DMF, if not otherwise available by cross reference
to another document.
15. 15
Type IV Excipient, Colorant, Flavor, Essence, or Material Used
in Their Preparation
• Each additive should be identified and characterized by its
method of manufacture, release specifications, and testing
methods.
• Toxicological data on these materials would be included under
this type of DMF, if not otherwise available by cross reference
to another document.
• Usually, the official compendia and FDA regulations for color
additives (21 CFR Parts 70 through 82), direct food additives
(21 CFR Parts 170 through 173), indirect food additives (21
CFR Parts 174 through 178), and food substances (21 CFR
Parts 181 through 186) may be used as sources for release tests,
specifications, and safety.
• Guidelines suggested for a Type II DMF may be helpful for
preparing a Type IV DMF.
16. 16
Type V: FDA Accepted Reference Information
• FDA discourages the use of Type V DMF's for
miscellaneous information, duplicate information, or
information that should be included in one of the other
types of DMF's.
• If any holder wishes to submit information and
supporting data in a DMF that is not covered by Types I
through IV, 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.
17. 4.1 Submission of DMF:
17
A. Transmittal Letters
The following should be included:
1. Original Submissions
a. Identification of submission: Original, the type of DMF as classification and its
subject.
b. Identification of the applications, if known, that the DMF is intended to support,
including the name and address of each sponsor, applicant, or holder, and all relevant
document numbers.
c. Signature of the holder or the authorized representative.
d. Typewritten name and title of the signer.
2. Amendments
a. Identification of submission: Amendment, the DMF number, type of DMF, and the
subject of the amendment.
b. A description of the purpose of submission, e.g., update, revised formula, or
revised process.
c. Signature of the holder or the authorized representative.
d. Typewritten name and title of the signer.
18. Conti……
18
B. Administrative Information
Administrative information should include the following:
1. 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. 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.
19. 4.2 AUTHORIZATION TO REFER TO A DRUG MASTER FILE
19
A. Letter of Authorization to FDA
Before FDA can review DMF information in support of an application, the
DMF holder must submit in duplicate to the DMF a letter of authorization
permitting FDA to reference the DMF. The holder does not need to send a
transmittal letter with its letter of authorization.
The letter of authorization should include the following:
a. The date.
b. Name of DMF holder.
c. DMF number.
d. Name of person(s) authorized to incorporate information in the DMF by reference.
e. Specific product(s) covered by the DMF.
f. Submission date(s) of above.
g. Section numbers and/or page numbers to be referenced.
h. Statement of commitment that the DMF is current and that the DMF holder will
comply with the statements made in it.
i. Signature of authorizing official.
j. Typed name and title of official authorizing reference to the DMF.
20. 4.2.1 Format for Letter of authorization to review
DMF:
20
Food and Drug Administration
Center for Drug Evaluation and Research
Re: DMF ###XXX, Type II
Hair tonic
Dear sir/ madam,
By copy of this letter, DRUG HOLDER ’XYZ’ is authorizing APPLICANT ABC to incorporate by
reference into their NDA/ANDA our DMF ###XXX, date, section, pages 105-115.
We hereby authorize your office to review the aforementioned specific information in DMF ###XXX in
considering the application filed by APPLICANT ABC.
The component/material furnished will be manufactured in accordance with DMF ###XXX and in
compliance with CGMPS.
This DMF holder status that DMF###XXX is current and will comply with all statements made within it.
Sincerely,
XYZ
21. The DMF will be reviewed only when it is referenced in an application or another
DMF.
21
USFDA
send a letter to remind DMF holder
holder obligations
SEND 2 copies of LOA to the FDA
one copy of LOA to the applicant
The applicant submits this copy of LOA in their application.
22. 4.3. Processing and reviewing policies:
22
A. Policies Related to Processing Drug Master Files
An original DMF submission will be examined on receipt to determine whether it meets
minimum requirements for format and content. If the submission is administratively
acceptable, FDA will acknowledge its receipt and assign it a DMF number.
If the submission is administratively incomplete or inadequate, it will be returned to the
submitter with a letter of explanation from the Drug Master File Staff, and it will not be
assigned a DMF number.
B. Drug Master File Review
A DMF is never Approved or Disapproved.
If FDA reviewers find deficiencies in the information provided in a DMF, a letter describing
the deficiencies is sent to the DMF holder. At the same time, FDA will notify the person who
relies on the information in the deficient DMF that additional information is needed in the
supporting DMF.
The general subject of the deficiency is identified, but details of the deficiency are disclosed
only to the DMF holder. When the holder submits the requested information to the DMF in
response to the agency's deficiency letter, the holder should also send a copy of the
accompanying transmittal letter to the affected persons relying on the DMF and to the FDA
reviewing division that identified the deficiencies. The transmittal letter will provide notice
that the deficiencies have been addressed.
23. 4.4 Changes in DMFs:
23
A. Notice Required for Changes to a Drug Master File
A holder must notify each affected applicant or sponsor who has referenced its DMF of any pertinent change in the
DMF. Notice should be provided well before making the change in order to permit the sponsor/applicant to
supplement or amend any affected application(s) as needed.
B. Annual Update
The holder should provide an annual report on the anniversary date of the original submission. All changes and
additional information incorporated into the DMF since the previous annual report on the subject matter of the DMF
should be provided. 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.
C. Appointment of an Agent
When an agent is appointed, the holder should submit a signed letter of appointment to the DMF
giving the agent's name, address, and scope of responsibility (administrative and/or scientific).
Domestic DMF holders do not need to appoint an agent or representative, although foreign DMF
holders are encouraged to engage an agent.
D. Transfer of Ownership
To transfer ownership of a DMF to another party, the holder should so notify FDA and authorized persons in writing.
The new holder should submit a letter of acceptance of the transfer and an update of the information contained in the
DMF, where appropriate. Any change relating to the new ownership (e.g., plant location and methods) should be
included.
24. 4.5 Closure of a DMFs:
24
• A holder who wishes to close a DMF should submit a request to the Drug Master File Staff
stating the reason for the closure.
• or
• The Agency may close a DMF that does not contain an annual update of persons authorized to
incorporate information in the DMF by reference and a list of changes made since the previous
annual report. The holder will be notified of FDA's intent to close the DMF.
• Any changes will be send to FDA.
25. 4.6 Retiring DMFs:
25
If a DMF has had no activity (amendment or annual report) in three years FDA
will initiate retirement procedure
Note: LOA does not count for activity
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 destroyed.
26. 5.Electronic Filing of DMFs and CTD:
26
CTD (Common Technical Document) format not required for paper DMFs, although
acceptable. Required for electronic DMFs
Electronic DMFs are accepted http://www.fda.gov/cder/regulatory/ersr/ectd.htm
DMFs originally submitted in paper can be resubmitted as electronic DMFs. Entire
DMF must be resubmitted.
Once a DMF has been submitted in electronic form NO paper documents (including
LOAs) to be submitted.
27. 6. Changes in DMF system:
27
There have been some changes in the DMF system to help make it work better.
• Changes in the DMF system and procedure:
• Creation of Review Cover Form
• Elimination of Type I DMFs
• Creation of DMF list on website
• Unchanged:
• Review only when referenced in application
• DMFs are neither approved nor disapproved
• The holder must notify customer of changes
28. 7.Application:
28
• The DMF can be referenced by drug manufacturers in support of
their NDAs, ANDAs and clinical trial applications.
• Maintain confidentiality of proprietary information (e.g.,
Manufacturing procedure) for the holder.
• Permit review of information by reviewers in the Center for Drug
Evaluation and Research (CDER) to support applications
submitted by one or more applicants.
29. 8. Difference between application and DMFs [6]
29
Applications DMFs
Comes under regulatory status. Must be filed
by applicant.
Not come regulatory . it is not compulsory to
file a DMF.
Each application and its supplement are
entered into a common database.
DMFs are entered in to database as per their
types. (separate database for each type of
DMFs).
Submitted to a particular review division. Submitted to FDA -CDER.
Assignment to a reviewer and watch
submission had a due date.
No assignment to a reviewer, no due date.
Review procedure quite different then DMF. DMFs are review only when referenced by
application or another DMF.
If the anniversary date for annual update is
missed FDA sends a reminder.
If the anniversary date for annual update is
missed FDA will not send a reminder.
30. 9. European DMFs
30
The DMF contains information which includes valuable know-how which should be kept confidential
and submitted to the authorities only. Therefore, it should be divided into 2parts – an applicant’s part
and an ASM Restricted Part. The applicant’s part of a DMF is provided by the ASM (Active
Substance Manufacturer)to the applicant directly and becomes part of the application for marketing
authorization. Both the applicant’s part and the ASM Restricted Part of the DMF are submitted to the
authorities.
a) Applicant’s part of a DMF – opening part
The applicant must be supplied by the ASM with sufficient information to be able to take
responsibility for an evaluation of the suitability of the active substance specification to control the
quality of the substance. This normally includes a brief outline of the manufacturing method,
information on potential impurities originating from the manufacturing method, from the isolation
procedure (natural products) or from degradation and, where applicable, information on the toxicity
of specific impurities.
b) ASM Restricted Part of DMF – closing part
Detailed information on the individual steps of the manufacturing method such as reaction conditions,
temperature, validation and evaluation data for certain critical steps of the manufacturing method,
etc. and on quality control during manufacture may contain valuable know-how. Such information
may therefore be supplied to the authorities only.
31. 10. Difference in European DMFS compare to US DMFs
31
• About DMF filing in EU (called EDMF), it is different to DMF filing in FDA.
• Whenever DMF is filed by person or firm is checked by FDA and if it is containing
all necessary documents, FDA accept DMF file and give a DMF number. It is the
identification of DMF for applicant who want to review that DMF.
BUT
• EU Authority (EMEA) does not give DMF number. If the API is in Eu.
Pharmacopoeia, EMEA can accept EDMF filing and issue a “Certificate of
Suitability” for it.
• If the API is not in Eu. P. EMEA would not accept DMF filing alone. – Paclitaxel is
not in Eu. P yet.
• So if you apply for Marketing Authorization in EU countries, you need to reach
agreement with the API supplier to provide you the entire DMF file (which is
technological confidential property of the API factory). So you can including its
content into your Marketing Authorization application dossier to submit to EU
authority (either your country’s Authority or EU Authority).
33. 12.References:
33
1. Guideline for Drug Master Files, Center for Drug Evaluation and Research, Food and Drug
Administration, Department of Health and Human Services, Office of Drug Evaluation I (HFD-
100), 5600 Fishers Lane, Rockville, Maryland 20857, September 1989.
2. dmfquestion@cder.fda.gov
3.http://www.fda.gov/drugs/developmentapprovalprocess/formssubmissionrequirements/drugmasterfil
esdmfs/ucm073080.html
4.http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/ucm0
4.pdf
5.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm0
72877.pdf
6.http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122886.htm
7.http://www.erigone.com/Vet%20folder/3aq7aen.pdf
8. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/form/dmff_fmmf-eng.php
