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Drug Master File

Prepared By:

Trupti k. Kanani

M. Pharm, Q.A., Sem-II

1

Guided By:

Dr. Rina Gokani

M.Pharm, Ph.D

S. J. Thakkar Pharmacy College-Rajkot.

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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 2

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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 themanufacturing, 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 aDMF.

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 andControls (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 FDAsCentral 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 thenecessary 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 standardletter-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

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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 andmottling -

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 - OrangeNDA PHARMACOKINETIC

BINDER

FDA Form 2626d - WhiteNDA MICROBIOLOGY BINDER

FDA Form 2626e - TanNDA CLINICAL DATA BINDER

FDA Form 2626f - GreenNDA STATISTICS BINDER

FDA Form 2626h - MaroonNDA 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. Impuritiesvi. 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 10

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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 classificationand its subject.

b. Identification of the applications, if known, that the DMF is intended tosupport, 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 ofDMF, and the subject of the amendment.

b. A description of the purpose of submission, e.g., update, revisedformula, 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 InformationAdministrative 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 holderwill 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 ExportApplication 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 DMFholder must submit in duplicate to the DMF a letter of authorization permittingFDA to reference the DMF. The holder does not need to send a transmittal letterwith 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 byreference.

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 willcomply 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,

XYZ14

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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 holderholder 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 meetsminimum 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.16

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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 pertinentchange in the DMF. Notice should be provided well before making the change in order to permit thesponsor/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 changesand additional information incorporated into the DMF since the previous annual report on the subject matterof 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 tothe DMF giving the agent's name, address, and scope of responsibility (administrativeand/or scientific). Domestic DMF holders do not need to appoint an agent orrepresentative, although foreign DMF holders are encouraged to engage an agent.

D. Transfer of OwnershipTo 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 informationcontained in the DMF, where appropriate. Any change relating to the new ownership (e.g., plantlocation 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 theprevious 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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http://www.fda.gov/cder/regulatory/ersr/ectd.htmhttp://www.fda.gov/cder/regulatory/ersr/ectd.htm

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6. Changes in DMF system:

There have been some changes in the DMF system to help make it work better.

Changesin 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 applicationssubmitted 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 DMFsThe 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) Applicantspart of a DMFopening part

Theapplicant must be supplied by the ASM with sufficient information to be able to takeresponsibility 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 DMFclosing 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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