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Drug Master File

Prepared By:
Trupti k. Kanani
M. Pharm, Q.A., Sem-II
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Guided By:
Dr. Rina Gokani
M.Pharm, Ph.D
S. J. Thakkar Pharmacy College-Rajkot.
Contents:
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
5.Electronic Filing of DMFs and CTD
6. Changes in DMF system:
7.Application
8. Difference in European DMFS compare to us DMFs
9. European DMFs
10. Difference in European DMFS compare to US DMFs
11. Case study
12. References
13.Study questions




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1.Introduction
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) Applicants 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.




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Who Must File a DMF?

NOBODY

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



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2. Drug master file process

Two copies of the Drug Master File with one signed original of the
covering letter and other necessary documents are send to the FDAs
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.


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Steps for filing the DMF:
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

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3. Drug master file format

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.

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Figure : DMFs Jacket
Binders for drug master file
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.


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Conti
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]

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4. Drug Master File contents:

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


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4.1 Submission of DMF:

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.

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Conti
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.


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4.2 AUTHORIZATION TO REFER TO A DRUG MASTER FILE

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.

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4.2.1 Format for Letter of authorization
to review DMF:
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
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The DMF will be reviewed only when it is referenced in an application
or another DMF.

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.

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4.3. Processing and reviewing policies

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.

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4.4 Changes in DMFs:

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.

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4.5 Closure of a DMFs
[4,5]


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.


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4.6 Retiring DMFs

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.

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5.Electronic Filing of DMFs and CTD

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.

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6. Changes in DMF system:
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

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7.Application:
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.

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8. Difference between application and DMFs
[6]


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.
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9. European DMFs
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 applicants part and an ASM Restricted Part. The applicants 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 applicants part and the ASM Restricted Part
of the DMF are submitted to the authorities.

a) Applicants 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.
[7]

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10. Difference in European DMFS compare to US DMFs
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 countrys Authority
or EU Authority).

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11. Case study
[8]


Here is example for PCM tablets :
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12.References:
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/drugmasterfilesdmfs/uc
m073080.htm

4.http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/ucm04.pdf

5.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072877.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








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13. Study questions:
1. What is DMFs ? Describe various types of it?
2. Write difference between application and DMFs.
3. Describe opening and closing part of European
DMFs?
4. Give details about letter of authorization.
5. Describe the submission, review and retiring of
DMF.
6. Short note on DMFs.
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