By Federal Drug Administration Tuesday, February 2, 2010

Drug Master Files (DMFs)

There is no requirement to file DMFs in electronic format. Paper DMFs will continue to be accepted. If this policy changes there will be advance notification.

• Important Guidance Information
• Download DMF Files

This site contains lists of Drug Master Files (DMFs) as well as information concerning submission of DMFs. The list is updated quarterly, although there may be delays of up to a month. See below for information regarding the current DMF Guideline.

QUESTIONS OR COMMENTS ABOUT DMFs

Please address ALL comments or questions regarding DMFs to dmfquestion@cder.fda.gov. All inquiries MUST have an entry in the "Subject" field of the e-mail. Due to concerns about viruses and the amount of "spam" received by this account, e-mails with subject fields that are blank or contain meaningless text strings or contain only question marks will not be opened.  If the inquiry concerns a specific DMF the DMF number should be in the subject field of the message.

Other inquiries unrelated to DMFs should go to druginfo@fda.hhs.gov.

The list of DMFs is current as of January 29, 2010, through DMF 23453. Changes to the DMF activity status, DMF type, holder name, and subject made since the last update of October 31, 2009 are included.

People who downloaded the previous list (through DMF 23193 October 31, 2009) and do not wish to download the entire updated lists can use the following lists:

1. New DMFs since the last list.
2. A list of changes in DMF activity status, DMF type, holder name, and subject.

The lists are available in Microsoft Excel and in ASCII (tab-delimited). Please note that only ACTIVE DMFs have been sorted into different types.

For the Excel files, the following lists are provided as different worksheets within one Excel file.

• All DMFs
• Active DMFs
• Active Type II DMFs
• Active Type III DMFs
• Active Type IV DMFs
• Active Type V DMFs

The following lists are still provided as separate files.

• New DMFs since the last list
• Changes

The types of DMFs are:

• Type I Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer applicable)
• 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

“A” = Active. This means that the DMF was found acceptable for filing, administratively, and is up-to-date.
“I” = Inactive
“N” = Not an assigned number
“P” = DMF Pending Filing Review

INACTIVE STATUS OF DMFs

There are three reasons for a DMF to be listed as INACTIVE:

1. CLOSED BY THE HOLDER: The holder requested that the DMF be closed (or retired, closed, inactivated, or withdrawn.)
2. CLOSED BY THE FDA: The holder did not respond to an Overdue Notification Letter within 90 days to update the DMF.
3. OVERDUE FOR UPDATE: For DMFs submitted before December 31, 2006, a DMF is considered OVERDUE FOR UPDATE when there have been no technical amendments or annual reports submitted since that date.

Note that submission of a Letter of Authorization or an Administrative amendment (see below) is not sufficient to update a DMF.

Note that the status “INACTIVE” in the list does not distinguish among the reasons listed above.

According to the regulations regarding DMFs (21 CFR 314.420(c)):

“Any addition, change, or deletion of information in a drug master file (except the list required under paragraph (d) of this section) is required to be submitted in two copies and to describe by name, reference number, volume, and page number the information affected in the drug master file.”

As discussed in the "Guideline for Drug Master Files" (September 1989), DMF holders should update their DMFs annually (see below under Annual Reports).

Overdue Notification Letters:  FDA is in the process of sending “Overdue Notification Letters” (ONLs) to DMF holders for DMFs that are OVERDUE FOR UPDATE (see above). If a DMF holder does not respond to this letter within 90 days, the DMF will be considered “CLOSED BY THE FDA.” It will then be RETIRED.

Note that there is a backlog in sending out ONLs. DMF holders can forestall the sending of an ONL by updating their DMFs, following the procedure below under “Retaining the Activity of a DMF.” Some DMFs may be listed as inactive which are, in fact, still active. Every effort will be made to correct any errors.

Retirement of DMFs

A DMF can be RETIRED ONLY if it has been CLOSED BY THE FDA or CLOSED BY THE HOLDER. A RETIRED DMF is unavailable for review.

Retaining the Activity of a DMF

A DMF holder that wants to retain the activity of a DMF that is listed as Inactive and that was not CLOSED BY THE HOLDER or CLOSED BY THE FDA should submit an Annual Report (two copies).  This process should also be used to respond to an ONL:

The cover letter should specify that it is an “Annual Report.”  If other types of information are provided in addition to the Annual Report, these should be listed in the cover letter.  See specific information below.

The Annual Report should contain:

1. One of the following

• Date(s) of the most recent amendment(s) reporting changes

Or

• A statement that no amendments have been submitted since the last Annual Report.

2. One of the following:

• A complete list of all parties authorized to make reference to the DMF, identifying by name, reference number, volume, date, and page number the information that each person is authorized to incorporate

Or

• A statement that no changes have been made to the list of Authorized Parties since the last Annual Report.

Or

• A statement that there are no Authorized Parties.

3. List of all parties whose authorization has been withdrawn

The Annual Report may contain new technical and/or administrative information provided the cover letter specifies the types of information being submitted.  The types of information should be specified as listed below:

There may be a lag time between closure of a DMF (either by lack of timely response to an ONL or closure by the holder) and its being RETIRED by FDA. DMF holders who wish to reactivate a CLOSED DMF should contact dmfquestion@cder.fda.gov to determine whether the DMF has been RETIRED by FDA.

GUIDANCES

 Guideline for Drug Master Files The version posted on the web is the current version. Note that the address for submitting DMF documentation to the FDA in the Guidance has been superseded by the Beltsville address below. Please address question regarding the DMF Guideline to dmfquestion@cder.fda.gov.

Note: FDA regulations require that all submissions to INDs and NDAs that are in a foreign language have “complete and accurate translations.” The same is true for DMFs. A “certified” translation is not required.

MORE INFORMATION ABOUT DMFs

See Presentation from Art Shaw

The recommendations in the DMF Guidance are, in general, still applicable. However the information below provides additional information or clarification of the recommendations in the Guidance. This information provided below falls into three categories

Category 1: Recommendations that are no longer applicable due to changes in regulations or guidances.
Category 2: Additional clarification of recommendations in the Guidance.
Category 3: New information for aspects of DMF filing that were not in effect when the Guidance was written.

Address for Filing Original DMFs and Subsequent DMF Documents (Category 3)

Food and Drug Administration
Center for Drug Evaluation and Research
Central Document Room
5901-B Ammendale Road
Beltsville MD 20705-1266

Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application (Category 1)

The “Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application” cited in the DMF Guidance has been withdrawn. DMFs may be submitted following the format recommended in the "Guidance for Industry M4Q: The CTD - Quality".

TYPES OF DMFs

Type I DMFs (Category 1)
Type I DMFs are no longer accepted per a Final Rule published January 12, 2000 (65 FR 1776). See Type V DMFs below.

Holders of Type II, III, and IV DMFs should not place information regarding facilities, personnel or operating procedures in these DMFs. Only the addresses of the DMF holder and manufacturing site and contact personnel should be submitted. See Administrative Information in a DMF.

Type II DMFs (Category 1)

Drug Substance

Type II DMFs may be submitted in the format for "Drug substance" in the "Guidance for Industry M4Q: The CTD - Quality".(Category 3) Drug Substance:

See the current Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances.

For Type II DMFs filed in CTD-Q format, Module 2 is expected.

Drug Product:  See the Guideline For Submitting Supporting Documentation In Drug Applications For The Manufacture Of Drug Products.

Type III DMFs (Category 1)

The applicable Guidance for Type III DMFs is the “Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics: CHEMISTRY, MANUFACTURING, AND CONTROLS DOCUMENTATION” and Questions and Answers. (Category 3)

 Type V DMFs (Category 3)

The following types of DMFs may be filed as Type V DMFs without requesting prior clearance from FDA.

• Manufacturing Site, Facilities, Operating Procedures, and Personnel for sterile manufacturing plants. See Guidance for Industry for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products.
• Contract Facilities for the manufacture of biotech products. See Draft Guidance for Industry: Submitting Type V Drug Master Files to the Center for Biologics Evaluation and Research

For other submissions as Type V DMFs the holder must request permission from FDA before filing a Type V DMF.  Prospective Type V DMF holders may send their request to dmfquestion@cder.fda.gov, explaining the necessity for filing the information in a Type V DMF.

Administrative Information in a DMF (Category 3)

The only elements of the administrative information that should be in a DMF are:

• The name and address of the holder
• The name and address of manufacturing facility
• For the contact person:
  • Name
  • Address
  • Telephone number
  • Fax number
  • E-mail address

The appointment of an Agent is optional. See discussion below under “Agents”

Submission of Amendments, Annual Reports, and Letters of Authorization (Category 3)

To facilitate processing of documents that are submitted to an existing DMF, please list the contents of the document in bold type on the transmittal letter. More than one document category/subcategory can be used. Please use the following as a guide.

• Annual Report
• Letter of Authorization
• Amendment: The types of information should be specified as follows:

• Category: Quality

Subcategory under Quality Category

SOURCE

E-mail: