Drug Master Files (DMFs)

What is a Drug Master File (DMF) ?

A 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.

Important facts regarding DMFs

• It is submitted to FDA to provide confidential information
• Its submission is not required by law or regulations
• It is neither approved nor disapproved
• A DMF is NOT a substitute for an IND, NDA, ANDA, or Export Application.
• It is filed with FDA to support NDA, IND, ANDA another DMF or amendments and supplements to any of these
• It is provided for in the 21 CFR (Code of Federal Regulations) 314. 420
• It is not required when applicant references its own information

Types of Drug Master Files-

Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel (No longer accepted by FDA)

Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product

Type III: Packaging Material

Type IV : Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation

Type V: FDA Accepted Reference Information  (FDA discourages its use)

Each DMF submission should contain -

1.Transmittal letter

2.Administrative information

1.Transmittal letter

For original submissions, transmittal letter should include-

 a.Identification of submission

 b.Identification of the applications

 c.Signature of the holder or the authorized representative.

 d.Typewritten name and title of the signer

For amendments, transmittal letter should include-

a Identification of submission

b A description of the purpose of submission

c Signature of the holder or the authorized representative

d Typewritten name and title of the signer

2.Administrative information

For original submissions, administrative information should include-

a. Names and addresses of the following:

(i) DMF holder.

(ii) Corporate headquarters.

(iii) Manufacturing/processing facility.

(iv) Contact for FDA correspondence.

(v) 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.  

For amendments, administrative information should include-

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.

Format, Assembly, and Delivery of DMF-

• The DMF must be in the English language. Whenever a submission contains information in another  language, an accurate certified English translation must also be included.

• Each page of each copy of the DMF should be dated and consecutively numbered. An updated table of contents should be included with each submission.

• An original and duplicate are to be submitted for all DMF submissions.

•    Each volume of a DMF should, in general, be no more than 2 inches thick. For multivolume submissions, number each volume. For example, for a 3 volume submission, the volumes would be numbered 1 of 3, 2 of 3, and 3 of 3.

• Drug Master File holders and their agents/representatives should retain a complete reference copy that is identical to, and maintained in the same chronological order as, their submissions to FDA.

• U.S. standard paper size (8-1/2 by 11 inches) is preferred.

 Drug Master File submissions and correspondence should be addressed as follows:

 Drug Master File Staff

 Food and Drug Administration

 5901-B Ammendale Rd.

 Beltsville, MD 20705-1266

AUTHORIZATION TO REFER TO A DRUG MASTER FILE

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 letter of authorization (LOA) should include the following:

The date.

Name of DMF holder.

DMF number.

Name of person(s) authorized to incorporate information in the DMF by reference.

Specific product(s) covered by the DMF.

Submission date(s) of 5, above.

Section numbers and/or page numbers to be referenced.

Statement of commitment that the DMF is current and that the DMF holder will comply with the statements made in it.

Signature of authorizing official.

Typed name and title of official authorizing reference to the DMF.

The holder of DMF should send a copy of LOA to affected applicant, sponsor or other holder who is authorized to incorporate information contained in the DMF. The copy of LOA issued by DMF holder should be included in the application by applicant, sponsor or holder referencing the DMF.

Format and Content of DMF

DMFs may be submitted following the format recommended in the "Guidance for Industry  M4Q: The CTD - Quality".

Incomplete submission

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.

DMF review

•  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.

•  The agency will review information in a DMF only when an IND sponsor, an applicant for an NDA, ANDA, or Export Application, or another DMF holder incorporates material in the DMF by reference.                  

•   If FDA reviewers find deficiencies in the information provided in a DMF, a letter describing the deficiencies is sent to the DMF holder and also the person who relies on the information in the deficient DMF (However, only general subject of deficiency is revealed to the applicant/person referring information in DMF)

• 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.

Holder Obligations

Any change or addition, including a change in authorization related to specific customers, should be submitted in duplicate and adequately cross referenced to previous submission(s). The reference should include the date(s), volume(s), section(s), and/or page number(s) affected.

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.

Listing of Persons Authorized To Refer to a Drug Master File

• A DMF is required to contain a complete list of persons authorized to incorporate information in the DMF by reference. The holder should update the list in the annual report.

• The updated list should contain the holder's name, DMF number, and the date of the update.

• The update should identify by name (or code) the information that each person is authorized to incorporate and give the location of that information by date, volume, and page number.

• Any person whose authorization has been withdrawn during the previous year should be identified under a suitable caption.

 Annual Report

•  The holder should provide an annual report on the anniversary date of the original submission. This report should contain complete list of authorized persons persons referring the DMF and should also identify all changes and additional information incorporated into the DMF since the previous annual report on the subject matter of the DMF. 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 or to assure FDA annually that previously submitted material and lists in the DMF remain current can cause delays in FDA review of a pending IND, NDA, ANDA, Export Application, or any amendment or supplement to such application; and FDA can initiate procedures for closure of the DMF.

 Appointment of an Agent

Domestic DMF holders do not need to appoint an agent or representative, although foreign DMF holders are encouraged to engage a U.S. 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). 

Transfer of Ownership

To transfer ownership of a DMF to another party, the holder should so notify FDA and authorized persons in writing. The letter should include the following:

Name of transferee

Address of transferee

Name of responsible official of transferee

Effective date of transfer

Signature of the transferring official

Typewritten name and title of the transferring official.

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.

MAJOR REORGANIZATION OF A DRUG MASTER FILE

A holder who plans a major reorganization of a DMF is encouraged to submit a detailed plan of the proposed changes and request its review by the Drug Master File Staff. The staff should be given sufficient time to comment and provide suggestions before a major reorganization is undertaken.

CLOSURE OF A DRUG MASTER FILE

• A holder who wishes to close a DMF should submit a request to the Drug Master File Staff stating the reason for the closure. 

• The request should include a statement that the holder's obligations  have been fulfilled.

• 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.

Keywords- FDA, DMF, Types of DMF , CTD., LOA.

References from FDA's Website-

Drug Master Files (DMFs) Guideline for Drug Master Files (DMF)

Drug Master Files (DMFs)