Insight of Drug Master Files (DMF)

1. Basics of Drug
Master Files (DMF)
Presented by
Divyesh Detroja

2. Table of Contents
• Introduction
• Types of DMFs
• DMF Submissions Format and Delivery
• DMF Original Submissions’ eCTD Modules and their contents.
• DMFs Subsequent Submissions.
• DMF Review Process.
• DMF Annual Reports.
• DMF Closure.
• Status indicators of DMF Database as per USFDA.
• EDMF (European DMF) or ASMF (Active Substance Master File).
• Glossary.
• Reference.

3. Introduction
• Drug Master File is a type of voluntary submission of
confidential information in length to the FDA that
includes data on the facilities, processes, or articles used in
the developing, processing, packaging, and storing of
drug items.
• DMFs can contain other types of information as well
(e.g., toxicology information, shared system REMS (Risk
Evaluation and Mitigation Strategy)
• DMFs are used to support regulatory submissions of
NDAs, ANDAs, INDs and BLAs.

4. Types of DMFs
DMF Type Content of DMF
Type I* Manufacturing Site, Facilities, Operating
Procedures, and Personnel
Type II Drug Substance, drug substance intermediate and
materials 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
* Type I DMFs have been discontinued in year 2000 but the numbering of
the other DMF types has not changed.

5. DMF Submissions Format and
Delivery
• DMFs may be submitted following the format
recommended in the “Guidance for Industry M4Q: the
CTD – Quality”. The Common Technical Document
(CTD) is a set of specification for application dossier for
the registration of Medicines and designed to be used
across Europe, Japan and the United States.
• It was developed by the European Medicines Agency
(EMA, Europe), the Food and Drug Administration
(FDA, U.S.) and the Ministry of Health, Labour and
Welfare (Japan).

6. DMF Submissions Format and
Delivery
• Different countries follow different DMF
formats and submissions.
• In US there are no different sections as an
“Applicant’s Part” or “Restricted Part” followed
unlike European DMF format.
• It’s suggested to submit drug master file in
Electronic format as submission of the data in a
mixed format of paper and electronic may delay its
review.

7. DMF Submissions Format and
Delivery
• The standard electronic format for DMFs is electronic common
technical document (eCTD) format.
• DMF submissions less than 10 GB can be submitted through
ESG (Electronic Submissions Gateway).
• DMF submissions over 10 GB can be submitted through ESG
or they can be submitted on physical media (e.g. CD-ROM)
accompanied by cover letter with prepaid delivery charges.
• Before submitting an original DMF in eCTD, DMF holders
must obtain a pre-assigned number from FDA.
• DMF submissions include Original submission (i.e. Initial
submissions) and Subsequent submissions. (i.e. amendments)

8. DMF Original Submissions’ eCTD
Modules and their contents
Module Content
Module 1 Cover letter, Administrative information, DMF holder / Contact
/ Agent details, manufacturer details, debarment certification,
references, Letter of Authorization (LOA), information not
covered under modules 2 through 5, other correspondence,
shipping label details and REMS related documents if any.
Module 2 Summaries of Module 3, 4 and 5 section whichever is applicable
Module 3 Quality documents, CMC information
Module 4 Non clinical evaluations (In Type II, IV and V DMFs)
Module 5 Clinical information such as in Type V DMF

9. DMFs Subsequent Submissions
• They include Cover Letter.
• Administrative amendments if any.
• Changes to the DMF subject if any.
• Changes to the DMF type if any.
• Quality Amendments if any.
• Conversion of existing DMFs to comply with eCTD format if
needed.
• All amendments and LOAs should reference the updated DMF.
• A cumulative change history should be submitted with each
subsequent submission.

10. DMF Review Process
• The DMF review process is divided into two parts. i.e. Administrative
review and Technical review.
• If the administrative information in an original DMF is found acceptable
FDA sends acknowledgment letter to DMF holder.
• FDA does not send acknowledgment letter for subsequent submissions.
• FDA performs a complete review of the referenced technical information
in a DMF when an authorized party submits a copy of the DMF holder’s
LOA in its application.
• While reviewing NDA, ANDA or BLA, if reviewers find that additional
information is needed with respect to DMF to continue the respective
review, FDA will contact the DMF holder if needed.

11. DMF Annual Reports
• DMF holder has to compulsory submit the annual reports for
its filed DMF.
• Annual reports help to assure FDA that the statement of
commitment is current. Failure to submit this report annually
may result in the termination Of A DMF.
• DMF holder should submit a cover letter when submitting the
Annual report.
• The annual report should also include the appropriate
administrative information, dates of amendments, reporting
changes since last annual report and list of authorized parties.

12. DMF Closure
• DMFs may be closed either because the DMF holder
requests closure or because FDA cannot be assured that
the DMF is current.
• If DMF holder is unable to submit the annual report,
FDA could close the DMF and would notify the holder or
agent, as applicable, of this action.
• A closed DMF cannot be reviewed.
• If a DMF has been closed, the holder can submit a new
DMF to FDA to replace the closed DMF.
• The new DMF should reference the closed DMF number.

13. Status indicators of DMF Database
as per USFDA
Status Indicator Meaning
A Active. This means that the DMF is not
closed and FDA is still accepting
C Complete
I Inactive. This suggests the Holder or FDA
has closed the DMF submission
P Pending
N Not an assign number

14. EDMF (European DMF) or ASMF
(Active Substance Master File)
DMF Part Content
Restricted part (Closed part)
(Confidential Part)
Manufacture name, Manufacturer(s)/site of
manufacture , Detailed description of the
manufacturing process and process controls,
Control of materials (Starting material of the
API, reagents, solvents, other materials used),
Control of critical steps and intermediates
Process validation and/or evaluation
Manufacturing process development
Applicant’s part (Open part)
(Non-Confidential Part)
General information, Characterization, Control
of API, Reference standards or materials,
Container Closure System and Stability

15. Glossary
• Agent: - A legal entity, whether a company or an
individual, that is not employed but is appointed to act on
behalf of a DMF holder.
• DMF Holder: - A person who owns a DMF.
• Letter Of Authorization (LOA): - A letter from a DMF
holder that authorizes an applicant or another to
incorporate by reference all or part of the DMF’s
contents to support an application, supplement, or
another DMF or an amendment to any of these
documents. The LOA also authorizes FDA to review
applicable portions of the DMF.

16. Glossary
• Risk Evaluation and Mitigation Strategy
(REMS): - A required risk management strategy that
employs tools beyond prescribing information to
ensure that the benefits of a drug outweigh its risks.

17. References
• US FDA Guidance
• EU Guidance