Submitting a DMF using Electronic Common Technical Document (eCTD)
Please contact firstname.lastname@example.org with all DMF-related submission questions. Please include the DMF number, if applicable.
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.
Beginning on May 5, 2018, new DMFs, as well as all documents submitted to existing DMFs, must be submitted using the Electronic Common Technical Document (eCTD). DMF submissions that are not submitted in eCTD format after this date will be rejected.
Guidance for Industry
Guidance for Industry: Providing Regulatory Submissions in Electronic Format —Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (PDF) (April 2017).
Information for current DMF holders
If a DMF is in paper format with FDA, the same submission does not need to be resubmitted in eCTD format. However, starting May 5, 2018, any new submissions to the existing DMF must be done in eCTD format. The DMF holder may continue to use the same DMF number. If the existing number is four-digits, e.g., 1234, the DMF holder will need to pad left with zeroes to convert the DMF number to a g-digit format, e.g., 001234 when the DMF is converted to eCTD format. In addition, if the DMF holder chooses to resubmit all of an existing paper DMF in eCTD format, and there are any changes in the content of the DMF as a result of the reformatting (e.g., addition of new or updated information), the Cover Letter for the submission should specify what areas of information have been updated.
For more information, refer to Reporting Changes to a DMF.
- Fact Sheets
- Tips Sheet (PDF - 602KB)
- New Requirements for Electronic Submissions of DMFs (PDF - 208KB)
NOTE: On 4/7/2017 the FDA announced that it is extending the compliance date for submitting DMFs in eCTD format to May 5, 2018. Presentations on submitting in eCTD format created prior to April 7, 2017 will have the incorrect compliance date for DMFs .
The current list contains DMFs RECEIVED by March 31, 2017 for which acknowledgment letters were sent before April 10, 2017.
The list of DMFs is current through DMF 31627. Changes to the DMF activity status, DMF type, holder name, and subject made since the last update of December 31, 2016 are included.
The list, which is updated quarterly, is available in Microsoft Excel and in ASCII (tab-delimited).
STATUS OF DMFs
“A” = Active. This means that the DMF was found acceptable for filing, administratively, and has not been closed.
“I” = Inactive. This means a DMF that has been closed, either by the holder or by the FDA.
Numbers for DMFs that are Cancelled, Preassigned and Pending or have been transferred to another center in the FDA are not included in the list. The status conveys no information about whether a DMF has been reviewed for technical content or whether it has undergone a Completeness Assessment. All inquiries concerning the status of a DMF that is being reviewed for a Completeness Assessment should be sent to DMFOGD@fda.hhs.gov. See GDUFA below
TYPES OF DMFs
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
There appears to be some confusion regarding when a Type III DMF (packaging material) should be submitted. It is not required that packaging information be submitted to the FDA in a DMF. The responsibility for providing information about packaging components rests foremost with the applicant of an NDA, ANDA or BLA, or the sponsor of an IND. This information may be provided to the applicant by the manufacturer of a packaging component or material of construction and may be included directly in the application. Any information that a manufacturer does not wish to share with the applicant or sponsor (i.e., because it is considered proprietary) may be placed in a Type III DMF and incorporated into the application by a letter from the manufacturer to the applicant which authorizes reference to the DMF.
Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
Type V FDA Accepted Reference Information
“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.”
The DMF Guidance recommends that DMF holders update their DMFs annually (see below under Annual Reports).
In order to ensure that DMFs are current, FDA sends “Overdue Notification Letters” (ONLs) to DMF holders for DMFs that have not had an Annual Report submitted in the past thirty-six (36) months. If a DMF holder does not respond with the submission of an Annual report to this letter within 90 days, the DMF may be closed by the FDA.
An Inactive DMF can be returned to ACTIVE status only by submission of a REACTIVATION, which should contain a complete resubmission of the DMF, updated to meet current Guidances. The cover letter must specify that the submission is a "REACTIVATION." Alternatively the DMF holder can submit a new DMF.
Guideline for Drug Master Files (DMF guidance) 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 questions regarding the DMF Guidance to email@example.com.
MORE INFORMATION ABOUT DMFs
NOTE: On 4/7/2017 the FDA announced that it is extending the compliance date for submitting DMFs in eCTD format to May 5, 2018. Presentations on submitting in eCTD format created prior to April 7, 2017 will have the incorrect compliance date for DMFs.
CDER’s Small Business Assistance Office Webinar: “Drug Master Files (DMFs) under Generic Drug User Fee Amendments (GDUFA)” (2/11/2013)
CDER’s Small Business Assistance Office Webinar: “Stay Compliant! Electronic Submission of Drug Master Files (DMFs) is MANDATORY starting May 5, 2017: What You Need to Know.” (8/4/2016)
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 four categories:
Category 1: Recommendations which 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 was not in effect when the Guidance was written.
Category 4: Information related to the Generics Drug User Fee Act (GDUFA)
Food and Drug Administration
Center for Drug Evaluation and Research
Central Document Room
5901-B Ammendale Road
Drug Master File Staff
Beltsville MD 20705-1266
This address should be used when submitting electronic DMFs via disc. See Electronic DMFs.
Review of DMFs (Category 3)
The FDA does not send a notification to the submitter when any submission, including a DMF, is received by the document room. After receipt, the original DMF undergoes an administrative review to determine whether it is administratively complete. This administrative review may take 2-3 weeks. See "Administrative Information in a DMF" below. If the DMF is acceptable from an administrative point of view, an Acknowledgement Letter will be issued, notifying the holder of the DMF number. At this point the DMF is "ACTIVE." If it is not acceptable from an administrative point of view, the holder will be notified of what deficiencies need to be corrected in order to make the DMF "Active".
FDA does not acknowledge, whether via e-mail or letter, any submission after the original DMF. All submissions to an existing DMF undergo an administrative review to determine whether they are administratively complete. If a submission to an existing DMF is not acceptable from an administrative point of view, the holder will be notified of what deficiencies need to be corrected in order to make the submission acceptable.
DMFs are subject to a complete review for technical information only under the following circumstances:
1. The DMF is ACTIVE.
2. The DMF holder submits a Letter of Authorization (LOA) in two copies (if a paper submission) to the DMF. If the DMF is in CTD format, whether electronic or paper, the LOA should be submitted in Section 1.4.1. This LOA should contain the DMF number.
3. The holder sends a copy of the LOA to the authorized party.
4. The authorized party submits an application to the FDA that contains a copy of the LOA. The copy of the LOA should be submitted in Section 1.4.2. of the application.
Type II DMFs to support ANDAs under GDUFA are subject to an initial "Completeness Assessment" under the conditions specified in the Final Guidance “Completeness Assessments for Type II API DMFs Under GDUFA." (CA Guidance)
The Generic Drug User Fee Amendments (GDUFA) section of the Food and Drug Administration Safety and Innovation Act” (S.3187 ) includes provisions for fees for DMFs, an initial completeness assessment , and communications with DMF holders. GDUFA applies only to Type II DMFs for drug substances (Active Pharmaceutical Ingredients (APIs)) used to support Abbreviated New Drug Applications (ANDAs). See definition of API below. GDUFA and the fee requirement do NOT apply to any of the following DMFs:
- Type III, IV or V DMFs
- Any of the following Type II DMFs:
- used to support only NDAs or INDs
- API intermediates
- material used in the preparation of APIs
- drug product manufacturing intermediates
- drug products.
See also Slide 48 in CDER’s Small Business Assistance Office Webinar entitled “Drug Master Files (DMFs) under Generic Drug User Fee Amendments (GDUFA)”
See also the following Web sites:
- GDUFA Web Site
- Draft Guidance for Industry: Generic Drug User Fee Amendments of 2012: Questions and Answers
- Draft Guidance for Industry: Self-Identification of Generic Drug Facilities, Sites, and Organizations
- Q&A for DMFs under GDUFA
- Final Guidance “Completeness Assessments for Type II API DMFs Under GDUFA”
The list of DMFs that have passed the Completeness Assessment and are available for reference by ANDAs under GDUFA is available at http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM332875.xls.
This is the only notification that the DMF has passed the Completeness Assessment.
Currently, the list is updated weekly.
DMFs for APIs submtted under GDUFA that have passed the Administrative review (have an active status) and have had the user fee paid are placed in the queue for a Completeness Assessment. It is not necessary for there to be an LOA for the DMF to undergo a Completeness Assessment review. The time frame for the Completeness Assessment depends on workload and may take a number of weeks.
DMF holders wishing to submit an electronic DMF must obtain a pre-assigned number. See “Requesting a Pre-Assigned Application number.” DMF holders can request a pre-assigned number for a paper DMF as well.
Companies wishing to obtain a pre-assigned DMF number for a Type V DMF should obtain clearance to file a Type V DMF (with the exception of a DMF for information regarding manufacturing site, facilities, operating procedures, and personnel for sterile manufacturing plants which do not require clearance.) See Type V DMFs below. For Type V DFMFs that do not require clearance the request for a pre-assigned number should specify what the DMF covers e.g., Sterile Processing Facility.
Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application (Category 1)
DMFs should be submitted following the Common Technical Document (CTD) format recommended in the "Guidance for Industry M4Q: The CTD - Quality" (CTD-Q) and the “Draft Guidance for Industry Submitting Marketing Applications According to the ICH-CTD Format —General Considerations” (CTD Guidance).
A Manual of Policies and Procedures (MAPP 5015.10) covering reviewer responsibilities for review of applications submitted using the Question-based Review (QbR) format has been issued. All Type II DMFs for Drug Substances and Drug Products may be submitted using the QbR format, although this is not required.
Companies may convert an existing paper DMF in non-CTD format to paper CTD format. In such cases DMF holders are advised to submit an amendment containing all sections specified in the CTD format that are applicable to the material covered by the DMF. Each section should be complete and contain up-to-date information. For drug substances and excipients all sections of 3.2.S in Module 3 and of 2.3.S in Module 2 should be submitted. For drug products all sections of 3.2.P in Module 3 and of 2.3.P in Module 2 should be submitted. If there are any changes in the technical content of the DMF as a result of the reformatting, e.g. addition of new information, the cover letter for the new submission should specify what areas of technical information have been changed.
DMFs in CTD format should follow the recommendations in the Appendix “Granularity” the ICH Harmonised Tripartite Guideline: Organisation Of The Common Technical Document For The Registration Of Pharmaceuticals For Human Use: M4. This supersedes the recommendation in the DMF Guidance.
For conversion of a paper DMF to electronic CTD format, see Electronic DMF.
It is not necessary to submit all Modules i.e. it is not necessary to submit Module 4 and 5. However, Module 1 and all Sections within Modules 2 and 3 S or P (as appropriate) should be submitted for ALL types of DMFs.
DMF holders submitting DMFs for Sterile Manufacturing can consult the following Guidances
- Question-based Review (QbR) for Sterility Assurance of Aseptically Processed Products: Quality Overall Summary Outline (PDF - 25KB)
- Sterility Assurance - Quality Overall Summary (SA-QOS) Outline for Terminally Sterilized Products (PDF - 21KB)
- QbR for Sterility Assurance of Terminally Sterilized Products: Frequently Asked Questions (PDF - 115KB)
Products manufactured at separate facilities do not need to be filed as separate DMFs unless the manufacturing processes are different. Note that the Initial CA Guidance contains recommendations regarding the submission of DMFs for multiple processes.
Module 1 should contain the following information
- Section 1.2
- Cover Letter
- Statement of Commitment
- Generic Drug User Fee Cover Sheet (3794), where applicable
“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.“
- Section 1.3: Administrative Information
- 1.3.1 Contact/sponsor/Applicant information
- 126.96.36.199 Change of address or corporate name
Can be used to supply addresses of DMF holder.
- 188.8.131.52 Change in contact/agent
Can be used to supply the name and address of contact persons and/or agents, including Agent Appointment Letter.
- 1.3. Debarment Certification.
- 184.108.40.206 Change of address or corporate name
- 1.3.1 Contact/sponsor/Applicant information
- Section 1.4: Reference Section
1.4.1 - Letter of Authorization (LOA)
Submission by the owner of information, giving authorization for the information to be used by Authorized Party. 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
This section should be completed in an application (IND, NDA, ANDA, or DMF) submitted by the Authorized Party that references a DMF. It should contain a copy of the Letter of Authorization from the holder giving the Authorized Party permission to reference the DMF. If a DMF holder references other DMFs a list of those DMFs can be provided in this section, similar to Section 30 on Form 356h used for NDAs and ANDAs. This is not the same as the list of authorized parties to be provided in 1.4.3.
1.4.3 - List of authorized persons to incorporate by reference
This is a list of companies for whom LOAs have been submitted to the DMF. This list should be submitted in DMF annual reports.
This does NOT mean a list of individuals within the DMF holder’s company who are authorized to submit information to the DMF.
As stated in 21 CFR 314.420(d):
"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."
The term “reference number” means any code or number used by the holder to identify a particular item in a DMF, where applicable.
- Section 1.5 Application Status
- 1.5.3 - Reactivation request
- 1.5.5 - Withdrawal of an unapproved BLA, NDA, ANDA or Supplement
Can be used to close a DMF.
- Section 1.6. Meetings
- 1.6.1 Meeting Request
- 1.6.2 Meeting background materials
- 1.6.3 Communication regarding meetings
- Section 1.11: Information Amendment: Information not covered under modules 2 to 5
- 1.11.1 Quality information amendment
- 1.11.2 Nonclinical information amendment
- 1.11.3 Clinical information amendment
- 1.11.4 Multiple module information amendment
- Section 1.12 Other Communication
- 1.12.4 Request for comments and advice
- 1.12.14 Environmental Analysis: See Environmental Assessment
Section 1.13: Annual Report
- 1.13.5 Summary of manufacturing changes
- Section 1.14: Labeling
- 1.14.2 Final labeling
Can be used to provide a copy of the product label.
- 1.14.2 Final labeling
English Translations of DMF in a Foreign Language (Category2)
FDA regulations (21 CFR.1(a)(1)) state:
“If any part of the application is in a foreign language, an accurate and complete English translation shall be appended to such part.”
The same is true for DMFs.
Debarment Certification for DMF Holders (Category 3)
According to the Draft Guidance for Industry: Submitting Debarment Certification Statements, DMF Holders are included in the category of “Persons whose services were used in any capacity in connection with the application” required under Section 306(k)(1) of the Food Drug and Cosmetic Act. DMF holders may include a Debarment Certification statement in their DMF.
TYPES OF DMFs
Type I DMFs (Category 1)
Holders of Type II, III, and IV DMFs do not need to place information regarding facilities, personnel or general 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 and Drug Substance intermediates
Type II DMFs for drug substances should be submitted in the format for "Drug substance" in the "Guidance for Industry M4Q: The CTD - Quality". (Category 3)
It is not necessary to include a Methods Validation Package (3.2.R.3). Methods Validation information should be submitted in Section 3.2.S.4.3.
See also the ICH Guidance “Q11 Development and Manufacture of Drug Substances" and the Guidance for Industry: ANDAs: Stability Testing of Drug Substances and Products: Questions and Answers DRAFT GUIDANCE.
Note that GDUFA includes requirements for Type II DMFs for Active Pharmaceutical Ingredients (APIs).
Drug Product and Drug Product Intermediate
Type II DMFs for drug products should be submitted in the format for "Drug product" in the "Guidance for Industry M4Q: The CTD - Quality". (Category 3)
It is not necessary to include a Methods Validation Package (3.2.R.3). Methods Validation information should be submitted in Section 3.2.P.5.3.
Separate DMFs should be submitted for drug substances and drug products.
Active Pharmaceutical Ingredient (API) (Category 4)
The term ‘active pharmaceutical ingredient’ means (SEC.744A(2) in GDUFA):
(A) a substance, or a mixture when the substance is unstable or cannot be transported on its own, intended—
(i) to be used as a component of a drug; and
(ii) to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the human body; or
(B) a substance intended for final crystallization, purification, or salt formation, or any combination of those activities, to become a substance or mixture described in subparagraph (A)”
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)
A Manual of Policies and Procedures covering reviewer responsibilities for review of Type III DMFs has been implemented. MAPP 5015.5 CMC Reviews of Type III DMFs for Packaging Materials This MAPP instructs reviewers to look for information regarding many packaging materials in the application (IND, NDA, or ANDA) for the drug product that utilizes the packaging material before reviewing the DMF. Much of the information needed for review can be provided directly to the applicant for inclusion in the application, thereby avoiding the need to review the DMF.
CTD format: Single components and materials of construction may be submitted as if they were drug substances i.e., the preparation of the item should be in S.2. An assembled container closure systems may be treated as if it were a drug product e.g. the Materials of construction would be in P.1, the finished packaging material release specification would be in P.5.
See relevant section in the DMF Guidance CTD format: Single entities may be submitted as if they were drug substances e.g., the preparation of the item should be in S.2. Mixtures e.g., as flavor mixtures, may be treated as if it were a drug product, i.e.. the Components and Composition would be in P.1, the finished material release specification would be in P.5.
If toxicology studies are submitted in the same DMF (in paper) as the CMC information, they should be in a separate volume or volumes, although it is preferable for holders to submit such information as a separate Type V DMF . Toxicology studies in an electronic DMF for an excipient should be submitted in the appropriate module. See also the “Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients”
Note that, in keeping with the recommendation in the DMF Guidance, components of flavor mixtures should include a CFR citation, where applicable, in addition to any other reference, e.g. GRAS or FEMA references.
Type V DMFs (Category 3)
As specified in 21 CFR 314.420(a)(5), DMF holders wishing to submit a Type V DMF must obtain clearance from the FDA (See below for an exception to this requirement for sterile processing facilities). Prospective Type V DMF holders should send their request to firstname.lastname@example.org, including the following:
- An explanation of the necessity for filing the information in a Type V DMF
- The proposed Subject (Title) of the DMF
- The rationale for not submitting the information in an IND, NDA, or ANDA.
- The clinical division that will be reviewing the information, if applicable.
Information regarding manufacturing site, facilities, operating procedures, and personnel for sterile manufacturing plants can be filed as a Type V DMF without clearance. The Subject field should specify what the DMF covers e.g., “Sterile Processing Facility.”
The 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:
- Mailing Address
- Telephone number
- Fax number
- E-mail address
- The name and address of the agent (if applicable)
- For the contact person at the agent (if applicable):
- Mailing Address
- Telephone number
- Fax number
- E-mail address
- Statement of Commitment
The appointment of an Agent is optional. See discussion below under “Agents”.
To facilitate processing of documents that are submitted to an existing DMF, list the Submission Type and the Category/Subcategory of the Amendment (Supporting Document) in bold type in the header on the Cover Letter (transmittal letter). See list below. More than one Submission Type/Category/Subcategory can be used but all should be listed.
Example: If updated stability data is submitted at the same time as a Letter of Authorization, the heading of the Cover Letter should state:
Letter of Authorization
Important New Information: Annual Reports for DMFs in eCTD can be submitted on the same date as any other submission but they must have a different Sequence Number.
FDA’s database is structured as follows:
Amendment (called "Supporting Document") in the database
Amendments (Supporting Documents) are named by a Category and Subcategory
For the Application Type “Drug Master File” the Submission Types are:
- Original: Amendments containing changes to technical information are filed in the “Original” submission and the Category/Subcategory should be specified in the header of the Cover Letter. A new DMF does not need a “Category/Subcategory” designation by the holder. See Categories and Subcategories below.
- Annual Report: There is only one Category with two Subcategories:
- Annual Report
- Letter of Authorization: There is only one Category with two Subcategories:
- Letter of Authorization
- Withdrawal of Authorization
- General Information (Reactivation, Closure Request, Administrative Information)
- Categories of Amendments (Supporting Documents) in General Information
- Category: Closure Request
- Category: Reactivation (Used only when a DMF has been Closed.)
- Category: Administrative
Subcategories under Administrative Category
- change in the holder name
- change in holder address
- change in ownership of the DMF (either internal name change, or change in ownership)
- change in the agent name or address.
- change in the contact person at the holder or agent.
- change in the subject of the DMF.
- change in the type of DMF
- response to an Administrative Filing Letter
- Categories of Amendments (Supporting Documents) in General Information
Categories of Amendments (Supporting Documents) in Original Submission:
Subcategories under Quality Category (with corresponding CTD Sections, where applicable).
Applicable Section in modules 2 and 3
Changes to a Subsection not specifically listed below should be reported as the next level up e.g. changes in Control of Materials (S.2.3) should be reported as Manufacture Information S.2. Subcategory
New item: Additional item e.g. flavor added to a multi-item DMF
Controls Information (specifications)
S.4 and P.5
Dissolution Data (Usually applies to drug product only)
Facility Information (changes in manufacturing and or testing sites)
S.2.1 and P.3.1
Formulation Information (Usually applies to drug product only)
P.1 and related sections
Lot Release (batch analysis)
S.4.4 and P.5.4
S.2 and P.3
New Strength (Usually applies to drug product only)
P.1 and related sections
Quality (Not covered by other subcategories)
Packaging Information (Applies to packaging of the material that is the subject of the DMF e.g. plastic bags for packaging a bulk drug substance in a Type II DMF)
S.6 and P.7
S.7 and P.8
Response to Information Request
Response to Deficiency Letter
|Response to Complete Response Letter|
- Carcinogenicity Information
Submissions that cover multiple DMFs should have a copy submitted for each DMF.
When a change is made to one part of a DMF the entire DMF does not need to be resubmitted. For DMFs in CTD format, the entire changed “Document” (Section) should be submitted e.g. a change in the material used in the synthesis should be included in a resubmission of Section S.2.3.
All submissions should be paginated within the submission. Pages that replace an already-numbered page from a previous submission should also contain the page number in the current submission (e.g. a page replacing Page 10 in the original submission may be page 14 in the new submission). For DMFs in CTD format, only the pages within the changed “Document” (Section) are subject to re-numbering.
No pages are ever physically replaced in a paper DMF.
Response to Overdue Notice Letter
Any addition, change, or deletion of information in a DMF is required to be submitted to the DMF. In addition the DMF holder must notify each person authorized to reference the DMF (authorized party) (See 21 CFR 314.420(c)) There are no reporting categories for DMFs. All changes must be reported as amendments. The DMF holder should notify each authorized party of the nature of the changes, providing as much detail as is consistent with the confidentiality agreement between the DMF holder and the authorized party, so that the authorized party can determine how to report the changes in their approved NDA or ANDA. See 21 CFR 314.70 and related Guidances.
Also Guidance for Industry: Changes to an Approved NDA or ANDA and the Q&A
CMC Postapproval Manufacturing Changes Reportable in Annual Reports (Draft Guidance)
ELECTRONIC DMFs (Category 3)
The FDA has published a Final Guidance, "Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications" (5/15/2015) regarding electronic submissions. See the Guidance for further information regarding requirements for electronic DMF submissions (eCTD Guidance). The Guidance applies to ALL DMFs, whether or not they are being referenced by an application. The compliance date for submitting a DMF in electronic format is May 5, 2018.
All electronic submissions must have an application number. For a new DMF, the holder must request a pre-assigned number in order to populate the US Regional.xml. The ECTD format provides the backbone for the submission and a guide as to where to place information. It is not necessary to submit modules that are not applicable to the subject of the DMF e.g. it is not necessary to submit Module 4 and 5 for a Type II DMF for a drug substance. For new electronic DMFs, all Sections within Modules 1, 2 and 3 should be submitted. DMF holders are encouraged to submit all subsequent submissions electronically after the initial electronic submission. See also Electronic Common Technical Document (eCTD). Electronic signatures are accepted for electronic DMFs.
Electronic DMFs may be submitted either through the Gateway or by sending a disc (one copy) to the Central Document Room at the address provided above. DMF holders are reminded of the following requirement in the ECTD Guidance:
- “For all submissions that are 10 gigabytes (GB) or smaller, you must use the FDA ESG .For submissions that are greater than 10 GB, refer to the FDA technical specification "Specification for Transmitting Electronic Submissions using eCTD Specifications.”
It is not necessary for a DMF holder to submit a form with the DMF for automated processing. The DMF will be automatically processed in the absence of a form. If a DMF in eCTD format is flagged with a validation error due to the form heading element not being included in the index.xml when there is no physical form in the eCTD directory, the DMF holder should ignore the error message and continue to submit.
CONVERSION OF PAPER DMFS TO ELECTRONIC DMFS (Category 3)
An existing DMF number may be used when converting a paper DMF to electronic format. If the existing number is 4-digits, e.g. 1234, the DMF holder should pad left with zeroes to convert to a 6-digit format, e.g. 001234. There is no requirement to submit or resubmit DMFs in electronic format. However, if a paper DMF is converted to eCTD format, and there are any changes in the technical content of the DMF as a result of reformatting, e.g. addition of new information, the cover letter for the new submission should specify what areas of technical information have been changed. The numbering of the submissions should start with 0001.
LETTERS OF AUTHORIZATION (Category 2)
All Letters of Authorization (LOAs) should be submitted in two copies to the DMF, if the DMF is in paper format. If the DMF is in CTD format, whether in paper or eCTD, the LOA should be submitted in Section 1.4.1. A copy of the LOA must then be sent by the DMF holder to the Authorized Party (company or individual authorized to incorporate the DMF by reference). Failure to submit the original LOA to the DMF may result in a delay in review of the DMF. LOAs should specify the name of the specific item being referenced and the date of the submission of information about that item. The LOA should not be called a “Letter of Access.”
An LOA should be submitted even if the DMF holder is the same company as the authorized party.
LOAs should NOT be submitted with original paper DMFs (unless the DMF has received a pre-assigned number) because the LOA should contain the DMF number. Therefore, if there is no pre-assigned number, DMF holders should wait before submitting an LOA until they have received an acknowledgment letter containing the DMF 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 changes its name, whether this represents a change in ownership or not, new LOAs should be submitted to the DMF and copies sent to the authorized party(ies).
If an authorized party changes its name, the new authorized party should request a new LOA from the DMF holder. Failure to do so may result in a delay in review of the DMF.
If there has been a name change, it is not necessary to submit a Withdrawal of Authorization Letter for the holder or authorized party’s previous name.
If a company has a Master File submitted to another Center in the FDA, e.g. a Biologics Master File (MF) submitted to the Center for Biologics Evaluation and Research, the Letter of Authorization should be submitted to the Master File in that other Center rather than CDER.
Note: The “Subject” field in the Letter Templates refers to the Subject of the DMF, not the Item within the DMF being referenced. The Item name should be included in the body of the letter.
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 unless the same person or company is the agent for both the DMF and DRLS. 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 should be signed 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.”
Agents for DMF purposes are not required to be located in the United States, although this is recommended.
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” or "Contact Person" 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, the DMF holder should issue a new Agent Appointment Letter.
A different agent can be appointed for different DMFs submitted by the same holder.
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 DMF Guidance 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 holder changes names, whether this represents a change in ownership or not, new LOAs should be submitted to the DMF and copies sent to the authorized party.
If the authorized party changes its name the new authorized party should request a new LOA from the DMF holder. Failure to do so may result in a delay in review of the DMF.
It is not necessary to submit a Withdrawal of Authorization Letter for the holder or authorized party’s previous name.
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 DMF Guidance). Therefore the old owner of the DMF is expected to transfer that copy to the new owner of the DMF.
In general FDA expects the manufacturer to be the holder. If a manufacturer (Company A) of a MATERIAL wishes to have the DMF submitted by another company (Company B) and Company B wishes to act as the holder, the DMF should include statements from both companies that Company B takes full responsibility for all the information in the DMF and for all the processes and testing performed by the manufacturer.
If Company B changes its name, whether through an internal name change or a through sale of the company, the new holder should notify the FDA of the name change. This submission should contain a statement that the new holder of the DMF takes full responsibility for all the information in the DMF and for all the processes and testing performed by the manufacturer.
ANNUAL REPORTS (Category 2)
According to the DMF Guidance, Annual Reports are NOT to be used to report changes in the DMF. As noted above, Annual Reports submitted at the same time as amendments in eCTD must have separate Sequence Numbers.
The Annual Report should contain (for Cover Letter see Templates below):
1. An administrative page containing the Administrative Information specified above (Administrative Information in a DMF)
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.
- 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 by reference and the date of the LOA.
- 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 should contain a COMPLETE list of Authorized Parties, even if the list of Authorized Parties is unchanged.
BIOLOGICS MASTER FILES (Category 3)
Master Files submitted in support of products regulated by the Center for Biologics Evaluation and Research (CBER) should be submitted as MFs. See the CBER web site for the products regulated by CBER.
BINDERS (Category 2)
The “binders” are actually covers. These may be ordered from the U.S. Government Printing Office (GPO) Web site: http://bookstore.gpo.gov/ or by calling 202-512-1800 to speak with a GPO customer service representative. The binders may be obtained from another supplier, provided they meet the requirements specified on the GPO Web site.
The direct links for online ordering are
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.
If a DMF is submitted using any other kind of binder, it should be a loose-leaf type of binder so that the pages can be removed and placed in FDA-approved binders. DMFs should not be submitted as “bound” books.
FEES (Category 4)
GDUFA requires DMF fees for Type II DMFs for drug substances (Active Pharmaceutical Ingredients (APIs)) used to support Abbreviated New Drug Applications (ANDAs). See definition of API above.
Since GDUFA does not apply to any other type of DMF or to Type II DMFs used to exclusively support NDAs or INDs, there are no fees for these types of DMFs.
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 and the Generic Drug User Fee Cover Sheet. The latter applies only to Type II DMF submitted to support ANDAs under GDUFA.
CONFIDENTIALITY OF DMFs (Category 2)
The public availability of the contents of DMFs is covered in 21 CFR 314.430(g). There are no “open” or “closed” parts of DMFs filed with the FDA. The decision as to how much information DMF holders share with their authorized parties is a business decision between the parties involved and is not covered by FDA regulations or Guidances. All requests for information about DMFs beyond that provided in the Drug Master File lists 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 is subject to the regulations regarding filing of ANDAs.
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.
See Drug Master File Letter Templates below.
Drug Master File Letter Templates
Change in Holder Name letter(DOC - 33KB) Holder Transfer Letter(DOC - 32KB) New Holder Acceptance Letter(DOC - 34KB) Letters of Authorization Template(DOC - 37KB) Request for Closure Letter(DOC - 32KB) Agent Appointment Template(DOC - 34KB) Cover Letter for Original Drug Master Files(DOC - 31KB) Cover Letter for Subsequent Amendments and Annual Reports(DOC - 53KB)
- Cover Letter for Reactivation of a Closed Drug Master File (DOC - 35KB)
Cover Letter for Subsequent Submissions(PDF - 10KB) Withdrawal of Authorization(DOC - 34KB)