Introduction

To keep this site up-to-date, this section provides an opportunity to ask questions about the use of Drug Master Files. The section contains two parts; Frequently Asked Questions (FAQ), and New Questions (NQ) specific to your own needs.

The Frequently Asked Questions were gathered from the workshop held in March 2002, and the FAQ is updated from specific questions that you ask our panel of respondents.

Frequently Asked Questions (FAQ)

1. What is a Drug Master File?
A Drug Master File is a package of proprietary information filed voluntarily by a company with the FDA. It is held by them in confidential closed files until such time as an FDA reviewer requests a review of the DMF. This is done only by FDA reviewers in conjunction with their review of a specific Investigational New Drug Application (IND), New Drug Application (NDA), Amended New Drug Application (ANDA) or Biologics License Application (BLA). The DMF may be reviewed in conjunction with some medical device applications.

2. What is a DMF "Type"?
There are four DMF "Types". They are referred to by their numbers in Roman Numerals. Type II DMF is for companies who supply drug substances, drug products, intermediates, and material used in their manufacture. AType III DMF is for companies who supply packaging (container closure systems) for human drugs and biologics. A Type IV DMF is for companies who supply excipients. A Type V DMF is for companies who supply clinical services, sterile manufacturing, etc. Type I is an obsolete number once used for a category that no longer exists because it was found to easily fit into and overlap with the other four categories.

3. Who is required to file a DMF with FDA?
No one is required to file a DMF. Filing a DMF is a voluntary action on the part of the supplier for the purpose of protecting proprietary information while supplying the necessary information in support of the Chemistry, Manufacturing and Control (CMC) sections of INDs, NDAs, ANDAs, and BLAs when doing business with pharmaceutical customers. The DMF is a way for FDA to access your company's proprietary information in a timely manner without sharing proprietary information with the applicants.

4. Why file a DMF?
A) To protect proprietary information while doing business with drug manufacturers. B) To allow a timely, seamless review of information referenced by a number of applicants at one time.

5. Why is DMF a good idea?
Federal law requires drug manufacturers to file a New Drug Application (NDA) for every drug product they market. The NDA must contain details about the drug, its manufacture and its packaging that are pertinent to the safety, purity and efficacy of the drug. Some of the details required may be proprietary information (trade secrets) of a supplier to the drug manufacturer. Therefore, FDA is willing to keep a file of that proprietary information. This is the Drug Master File.

6. How does the DMF information find its way into the NDA?
The drug manufacturer references the Drug Master File in its NDA. Here is a description of the process for container closure systems (Type III DMF):

The drug manufacturer first makes a determination of the material or container that it finds compatible with its drug product and then requests the supplier to grant access to that material or container manufacturer's Drug Master File. If a DMF exists, the manufacturer provides a Letter of Authorization (LOA) to the pharmaceutical manufacturer and this letter is placed in the appropriate section of the application to fulfill the information requirements for that portion of the application. When the NDA is submitted, a listing of the DMFs referenced is required to show on the Form 356h. After the application is deemed reviewable and the sections are divided among the appropriate reviewers, the Letter of Authorization will trigger a request to the appropriate FDA file room and a copy of the documents listed will be distributed to the reviewer. DMFs are then reviewed as they apply to that individual application, taking into consideration other applications in conjunction with which they may have been used. Notes added by previous reviewers are also considered. An FDA reviewer WILL NOT review a DMF unless the holder of the DMF has given written permission to the applicant to cite the DMF.

7. What are the FDA requirements for a Drug Master File?
FDA has a guideline dated 1989 (Guideline for Drug Master Files) which gives basic format information. FDA has not published any recent guidance on content. For content, FDA refers to its 1987 guideline, "Format and Content of the Chemistry, Manufacturing and Controls Section of an Application". More recently (May 1999) FDA has published "Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics, Chemistry, Manufacturing and Controls Documentation", which also refers to the NDA.

FDA's view is that the requirements for the New Drug Application state what must be submitted for review, and they expect the applicant to provide that information either directly or by way of reference to a Drug Master File. The applicant is expected to assure that all the information required for its NDA is contained in the DMF. If it is not, the applicant can request the holder to update the information. The applicant may place the missing information directly into the application.

8. What is a Holder?
A Holder is the supplier company who prepares, owns, files and maintains the DMF with the FDA.

9. What is an Applicant?
An Applicant is the drug manufacturer who is preparing or revising a New Drug or Biologic Application (NDA or BLA). This is the company who requests permission for FDA to access the DMF. The Applicant is sometimes referred to as the Customer, or the Authorized Party.

10. What is an Agent?
An Agent is a person or company (e.g. attorney, consultant or regulatory professional) who is the responsible representative for the DMF Holder. An Agent is needed if: (1) the DMF holder does not have the expertise within its organization to write and maintain a DMF or (2) the Holder is a foreign manufacturer or supplier and does not have any facilities or offices in the U.S.

11. How often must a DMF be updated?
Whenever there is a change in the materials, equipment or procedures that may affect drug safety, purity, or efficacy.

12. How do I get my DMF approved?
A DMF is never approved or disapproved. FDA receives and files every DMF submitted. The FDA reviewers then read the file only when it is referenced in an application, so it is considered only in the context of that application at that time.

13. How do I submit my DMF?
Send it to Drug Master File Staff, Food and Drug Administration, 5901-B Ammendale Road, Beltsville, MD 20705-1266. Follow the Guideline for Drug Master Files, available at www.fda.gov/cder/guidance/dmf.htm.

14. What is a Letter of Authorization (LOA)?
It is a signed letter from the DMF Holder authorizing a drug manufacturer (Applicant) to reference a specific DMF in its application. This authorization must contain the drug product name as it appears in the application, application number if available, the address of the applicant, the number of the DMF to be referenced. When the DMF is very large, it should also contain specific volume and page number information to help the reviewer to locate the specific information that applies.

 

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New Questions (NQ)

Specific questions are answered by the following members of the panel of respondents. These questions may be about DMFs of Types II, III, IV or V.

Hugh Lockhart, Professor, School of Packaging - Moderator
Dwain Sparks, Eli Lilly Company
Robert Bergeson, Pfizer
Amy Fortenberry, Paul, Hastings, Janofsky & Walker
Aileen Gilbert, Becton Dickinson Pharmaceutical Systems Division
Maxine Gallagher, West Pharmaceutical Services

To ask a question, address it to the Moderator, Hugh Lockhart, at his e-mail address: lckhrt@msu.edu. He will forward it to the appropriate panel members, who will answer you directly at your e-mail address. A copy of the reply will go to the Moderator for possible inclusion in the FAQ.

 

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