Drug Master File

A DMF can be retired only if it is closed. A retired DMF is unavailable for review.

A DMF holder that wants to retain the activity of a DMF listed as Inactive and not closed must submit an annual report (two copies). This is also the process used to respond to an ONL. The cover letter must specify that it is an annual report.

A company can return a closed DMF to active status only by submitting a reactivation. The reactivation must contain a complete re-submission of the DMF, updated to meet current guidance.

For drug master files, the version posted on the web is the current version. The address for submitting DMF documentation to the FDA in the Guidance is dmfquestion@cder.fda.gov.

FDA regulations require that all foreign language submissions to INDs and NDAs have complete, accurate translations. The same is true for DMFs. The FDA does not require a certified translation.

DMF guidance recommendations, in general, still apply. However, the information below provides additional information or clarification in three categories:

• Category 1: Recommendations no longer applicable due to changes in regulations or guidances
• Category 2: Additional clarification of recommendations in the Guidance
• Category 3: New information for DMF filing aspects not in effect when the company wrote the Guidance

Mailing address for filing original DMFs and all subsequent DMF documents (Category 3):

Food and Drug Administration

Center for Drug Evaluation and Research

Central Document Room

5901-B Amendale Road

Beltsville MD 20705-1266

Companies send two paper copies of all submissions to an existing paper DMF to the address above. The FDA does not accept submissions via e-mail or CDs. Companies may submitted two-sided copies of DMFs.

When the FDA receives a DMF, they review it for administrative content. This may take 2–3 weeks. If the DMF is acceptable from an administrative point of view, the FDA issues an acknowledgement letter, which notifies the holder of the DMF number. If the FDA finds the DMF not acceptable from an administrative view, they notify the holder of the deficiencies they must correct.

The FDA reviews the DMF for technical information only after the following events occur:

1. The DMF holder submits a Letter of Authorization (LOA) in two copies to the FDA. This LOA must contain the DMF number.
2. The holder sends a copy of the LOA to the authorized party (customer).
3. The customer submits an application to the FDA that contains a copy of the LOA.

The FDA grants requests for preassigned DMF numbers for electronic or paper DMFs. (See Requesting a Pre-Assigned Application number.)

Companies submit DMFs following the format recommended in the Guidance for Industry M4Q: The CTD - Quality.

Companies may convert an existing DMF in non-CTD format to CTD format. In such cases, the FDA advises DMF holders to submit an amendment that contains all applicable CTD-specified sections to the material in the DMF. Each section must be complete and current. For drug substances and excipients, companies must submit all sections of 3.2.S in Module 3. For drug products, companies must submit all sections of 3.2.P in Module 3. If the reformatting causes changes in the DMFs technical content—e.g., adds new information—the cover letter for the new submission must describe these changes. DMFs in CTD format must follow CTD Guidance, e.g., be paginated within each section. This supersedes DMF guidance.

For conversion of a paper DMF to electronic CTD format, see Electronic DMF.

DMFs that cover multiple items, e.g., Type III DMFs for components of container-closure systems or Type IV DMFs for flavors, can be submitted in CTD format. Technical information can be in Module 3, following the outline in the Drug Substance Section. Sections within 3.2.S. can be populated as appropriate. Each product, such as different flavors, must have a different name—e.g. 3.2.S.[Flavor 1], 3.2.S.[Flavor 2]. Information common to different products—e.g., analytical procedures—can be accessed by reference (or links in the case of an Electronic DMF) from the relevant section for that product, e.g., 3.2.4.2 [Flavor 1].

DMF holders who submit DMFs for sterile manufacturing can consult the Manual of Policies and Procedures 5040.1: Product Quality Microbiology Information in the Common Technical Document - Quality (CTD-Q). Companies don't have to file separate sections for the same product manufactured at separate facilities unless the manufacturing processes are different.

Module 1 must contain the following information Section 1.2: Cover Letter and Statement of Commitment Section 1.3: Administrative Information

1.3.1 Contact/sponsor/Applicant information 1.3.1.1 Change of address or corporate name Can be used to supply addresses of DMF holder and manufacturing and testing facilities

1.3.1.2 Change in contact/agent Can be used to supply the name and address of contact persons and/or agents, including Agent Appointment Letter. 1.4.1 - Letter of Authorization (LOA) Submission by the owner of information, giving authorization for the information to be used by another. An Agent Appointment Letter is NOT an LOA and should not be called “Letter of Authorization” and should not be submitted in Section 1.4.1 1.4.2 - Statement of Right of Reference Submission by recipient of a Letter of Authorization with a copy of the LOA and statement of right of reference. Submitted in a DMF only when another DMF is referenced. 1.4.3 - List of authorized persons to incorporate by reference This list should be submitted in DMF annual reports. Section 1.12.14 Environmental Analysis: See Environmental Assessment

The language in the following sentence in the DMF Guidance, Section VII.B.1, has confused some DMF holders:

“A DMF is required to contain a complete list of persons authorized to incorporate information in the DMF by reference [21 CFR 314.420(d)].”

It does not mean to say that a company must list all individuals in the DMF holder's company who are authorized to submit information to the DMF.

The language in the CFR is clearer:

“The drug master file is required to contain a complete list of each person currently authorized to incorporate by reference any information in the file, identifying by name, reference number, volume, and page number the information that each person is authorized to incorporate.”

At this time, the FDA doesn't require that companies file DMFs electronically. They continue to accept paper DMFs. Beginning May 5, 2017 new DMFs and submissions to existing DMFs must be submitted using the eCTD standard.[6] See Electronic Common Technical Document (eCTD)'

All electronic submissions must have a pre-assigned number to populate in the US regional.xml. If a company converts a paper DMF to electronic format, they don't need to request a pre-assigned number.

See also Guidance for Industry: Providing Regulatory Submissions in Electronic Format—Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications. To make sure you have the most recent versions of the specifications referenced in this guidance please check Electronic Common Technical Document (eCTD). Companies are encouraged to submit their DMFs in electronic form, including updating current paper DMFs. Note that all applications to CDER, including DMFs that are submitted in electronic format MUST be in ECTD format, unless a waiver is granted. Waivers are not granted for DMFs.

All Letters of Authorization for electronic DMFs should specify that the DMF has been submitted in electronic format. A company may not submit an electronic resubmission to a paper DMF unless they resubmit the entire DMF in electronic format. Companies may convert an existing DMF in paper format to electronic format (ECTD only). See “Conversion to CTD” above.

The ECTD format provides the backbone for the submission, and a guide as to where to place information. Companies need not submit all modules, nor submit all sections within a module. However, the FDA requires Module 1 for all eCTD submissions, as it contains the administrative information that identifies the DMF. Electronic signatures are accepted for electronic DMFs.

The company must submit two copies of all letters of authorization (LOAs) to the DMF. The DMF holder must then send a copy of the LOA to the authorized party (company or individual authorized to incorporate the DMF by reference). Failure to submit the LOA to the DMF may delay review of the DMF. LOAs must specify the name of the specific item referenced, and the date of the submission of information about that item. The LOA must not be called a letter of access. An LOA is required, even if the DMF holder is the same company as the authorized party.

Companies must not submit LOAs with original paper DMFs, because the LOA must contain the DMF number. Therefore, DMF holders must wait to submit an LOA until they receive an acknowledgment letter with the DMF number. An LOA can be submitted with the original DMF if the DMF has received a pre-assigned number. It is not necessary to reissue LOAs if there have been no changes in the holder, authorized party, subject of the DMF or item referenced.

If the holder or authorized party changes names, whether this represents a change in ownership or not, they should submit new LOAs to the DMF and copies sent to the authorized party.

LOA Template AGENTS (Category 2)

There is no regulatory requirement for an agent for any DMF, foreign or domestic. An agent for DMF purposes is not the same as an agent for the purposes of the Drug Listing and Registration System. (DRLS). Holders should not include the name of the agent for Registration purposes in the DMF. Also note that in the US, the process of “Registration” applies ONLY to “registering” an establishment with the FDA.

All “Agent Appointment Letters” for DMFs MUST be sent by the holder. FDA recommends that such letters include the phrase “appoint AGENT NAME as the agent for DMF” rather than “authorize AGENT NAME to act as the agent for DMF,” since the latter can be confused with a “Letter of Authorization.” An “Agent Appointment Letter” may be included in an original DMF.

If possible, the word “Agent” should be used for the legal entity (whether a company or an individual) who is authorized to act on behalf of the DMF holder. The word “Representative” should be used for an individual who is employed by the Agent or Holder as the contact point for FDA.

If a company acting as an Agent changes its name, FDA recommends that the DMF holder issue a new Agent Appointment Letter.

A different agent can be appointed for different DMFs submitted by the same holder.

Agent Appointment Template HOLDER NAMES (Category 2)

When the company that owns a DMF (DMF holder) changes its name, whether through sale of the company or simply a change in the company's name, the DMF holder must notify FDA. See Section VII.E. in the Guideline for DMFs for further recommendations on the procedure for transferring ownership. A change in the name of a company for registration purposes under DRLS will not change the DMF holder name.

When a DMF is transferred from one company to another, the original holder should submit an administrative amendment stating that they are TRANSFERRING the DMF to the new holder. The new holder should then submit an administrative amendment stating that they are ACCEPTING the DMF from the former holder.

If the DMF holder changes its name and there is no transfer of ownership, the holder may submit a single Holder Name Change amendment.

A DMF holder is expected to retain a complete reference copy that is identical to, and maintained in the same chronological order as, their submissions to FDA (See Section IV.D.1 in the Guideline for DMFs). Therefore, the old owner of the DMF is expected to transfer that copy to the new owner of the DMF.

If a holder name change affects multiple DMFs, all documentation must be submitted to each DMF as separate submissions.

In general, the FDA expects that the manufacturer is the holder. If a manufacturer (company A) of a material wants another company (Company B) to submit the DMF, and Company B wishes to act as the holder—the DMF must include statements from both companies that Company B is responsible for all information in the DMF, and for all processes and testing performed by the manufacturer. The title of the DMF that appears on the list of DMFs is the format Material manufactured in [LOCATION OF COMPANY A] for [COMPANY B].

ANNUAL REPORTS (Category 2)

According to the DMF Guideline, companies must not use annual reports to report changes in the DMF. However, as described above, companies can submit an annual report at the same time as other information. The annual report must contain (for cover letter see Templates below):

1. An administrative page that contains:

Holder name

Manufacturing site name if different from holder

U.S. agent company name (if applicable)

Name of contact person for each of the above

Mailing address, phone number, fax and email address of responsible individuals

AND 2. One of the following

Date(s) of the amendment(s) reporting changes since the last Annual Report or the original DMF filing date, whichever is most recent.

Or

A statement that no amendments have been submitted since the last Annual Report or the original DMF filing date, whichever is most recent.

And

3. 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 the original DMF filing date, whichever is most recent.

Or

A statement that there are no authorized parties.

And

4. List of all parties whose authorization has been withdrawn

Note that the DMF Guidance uses the terms “Annual Update” and “Annual Report” interchangeably. All submissions of Annual Reports should be labeled “Annual Report.” The term “Annual Update” should not be used.

Note that the annual report must list the authorized parties. If the list is long and the holder wants to list only authorized parties added since the last annual report, they should highlight this in the cover letter. There should be a statement that there have been no changes in the list of authorized parties previously submitted.

BIOLOGICS MASTER FILES (Category 3)

Master Files submitted in support of products regulated by the Center for Biologics Evaluation and Research (CBER) must be submitted as BB-MFs. See the CBER web site for the products regulated by CBER.

BINDERS (Category 2)

See ”FDA IND, NDA, ANDA, or Drug Master File Binders “The “binders” are actually covers. These may be ordered from the

U.S. Government Printing Office (GPO) Washington, DC 20404-0001 (202) 512-1800

In addition these can be ordered online using the following links

Red Binder Blue Binder One copy of the DMF should use the blue cover and one should use the red cover.

Fasteners must be obtained separately. Use 2 Piece Prong Fasteners, 8 1/2" Center to Center, 3 1/2" Capacity. Binders should be used for all subsequent submissions to FDA that are more than 10 pages.

FEES (Category 3)

There are no fees or charges for filing a DMF or any subsequent documents.

FORMS (Category 2)

Certain forms are required for submission of NDAs and INDs. However, there are no forms required or available for DMFs, except for the forms discussed above under Binders.

CONFIDENTIALITY OF DMFs (Category 2)

The public availability of the contents of DMFs is covered in 21 CFR 314.430(e). All requests for information about DMFs beyond that provided in the tables above must be made through the CDER Freedom of Information Web site. FILING DMFs AND PATENT EXPIRATION AND EXCLUSIVITY ISSUES (Category 2)

DMFs may be filed at any time. The Patent Expiration date and the Exclusivity Expiration dates listed in the Orange Book have no impact on DMF filing. The submission of Abbreviated New Drug Applications (ANDAs) that reference DMFs are subject to the regulations regarding filing of ANDAs.

ENVIRONMENTAL ASSESSMENTS (Category 2) Since DMFs are neither approved nor disapproved, there is no need to file an Environmental Assessment. However the DMF should contain a commitment by the firm that its facilities will be operated in compliance with applicable environmental laws.

REORGANIZATION OF A DMF (Category 1) The advice in the Guidance does not apply. It is not necessary to consult with FDA before reorganizing a DMF.

REQUEST FOR CLOSURE OF A DMF BY THE HOLDER (Category 2).

It is not necessary to include a statement that "the holder's obligations as detailed in Section VII have been fulfilled," as recommended in the DMF Guidance. It is sufficient to include a statement that all of the parties authorized to reference the DMF have been notified that the DMF is being closed..

LETTER TEMPLATES AND COVER LETTERS (Category 2)

Note that a “Transmittal Letter” and a “Cover Letter” are the same thing.

Cover Letter for Original DMFs Cover Letter for Subsequent Amendments and Annual Reports (Not applicable to Holder Transfer, New Holder Acceptance, Holder Name Change, Letter of Authorization, and Closure Requests)

Cover Letter for Reactivation of a Closed Drug Master File The following Letters do not require a Cover Letter

Holder Transfer New Holder Acceptance Holder Name Change Letter of Authorization Closure Request Withdrawal of Authorization