This document provides information on drug master files (DMFs), including: - There are 5 types of DMFs which contain information on drug substances, packaging materials, excipients, and other reference materials. - A Type II DMF contains information about drug substances and products, and must be submitted in ICH CTD format. - Modules 1-3 of the CTD are included in a DMF, with Module 1 containing administrative information, Module 2 providing a quality overall summary, and Module 3 containing detailed information on manufacturing, characterization, and controls. - DMF holders must notify authorized parties of any amendments and provide annual reports on the anniversary of the original submission.

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TOPICS COVERED:
Ø Definition
Ø Regulatory requirement
Ø Type of DMFs
Ø Content of DMF
Ø Submission(s)
Ø DMF Review
Ø Approval
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TYPE OF DMFS:
Manufacturing Site, Facilities, Operating Procedures, and Personnel
TYPE I
Drug Substance, Drug Substance Intermediate, and Material Used in
Their Preparation, or Drug Product
TYPE II
Packaging Material
TYPE
III
Excipient, Colorant, Flavor, Essence, or Material Used in Their
PreparationTYPE
IV
FDAAccepted Reference Information
TYPE V
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TYPE I DMF
Type I:
Manufacturing Site, Facilities, Operating Procedures, and Personnel
Ø A Type I DMF is recommended for a person outside of the United States to assist
FDA in conducting on site inspections of their manufacturing facilities.
Ø The DMF should describe the manufacturing site, equipment capabilities, and
operational layout.
NO LONGER ACCEPTED PER A FINAL RULE PUBLISHED JANUARY 12, 2000 (65 FR 1776)
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TYPE II DMF
Type II:
Drug Substance, Drug Substance Intermediate, and Material Used in Their
Preparation, or Drug Product
Ø Drug Substance (DS) and Drug Substance intermediates
Summarize all significant steps in the manufacturing and controls of drug
intermediate or substance.
It should be submitted in the format for "Drug substance" in the "Guidance for
Industry M4Q: The CTD - Quality".
Ø Drug Product and Drug Product Intermediate
Manufacturing procedures and controls of finished dosage forms should ordinarily
be submitted in an IND, NDA, ANDA or Export Application.
If this information cannot be submitted in an IND, NDA, ANDA or Export
Application, it should be submitted in a DMF.
It should be submitted in the format for "Drug product" in the "Guidance for
Industry M4Q: The CTD - Quality".
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TYPE III DMF
Type III:
Packaging Material
Ø Each packaging material should be identified by the intended use, components,
composition, and controls for its release.
Ø Toxicological data on these materials would be included under this type of DMF, if
not otherwise available by cross reference to another document.
Ø 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.
Ø 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.
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TYPE IV DMF
Type IV:
Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
Ø Each additive should be identified and characterized by its method of
manufacture, release specifications, and testing methods.
Ø Toxicological data on these materials would be included under this type of DMF, if
not otherwise available by cross reference to another document.
Ø 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”
Ø 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.
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TYPE V DMF
Type V:
FDAAccepted Reference Information
Ø If any holder wishes to submit information and supporting data in a DMF that is not
covered by Types I through IV
Ø 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 dmfquestion@cder.fda.gov, including the following:
1. An explanation of the necessity for filing the information in a Type V DMF
2. The proposed Subject (Title) of the DMF
3. The rationale for not submitting the information in an IND, NDA, or ANDA.
4. The clinical division that will be reviewing the information, if applicable.
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TYPE V DMF
Type V:
FDAAccepted Reference Information
Ø 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.”
See Guidance for Industry for the Submission Documentation for Sterilization
Process Validation in Applications for Human and Veterinary Drug Products
Ø FDA discourages the use of Type V DMF's for miscellaneous information,
duplicate information, or information that should be included in one of the other
types of DMF's.
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CONTENT OF DMF:
ICH CTD Triangle:
Module 1, 2 & 3 are applicable for drug substance (API) and intermediates.
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MODULE 1 CONTENTS
Module 1. Administrative Information and Prescribing Information
Module 1 should contain the following information
ü Cover Letter
ü Administrative Information
§ Addresses of DMF Holder and Manufacturing & Testing facilities
§ Responsible and Contact persons
ü Statement of Commitment
ü Generic Drug User Fee Cover Sheet (3794), where applicable
ü Letter of Authorization, where applicable
ü US Agent Appointment Letter
ü Debarment Certification [Section 306(k)(1)]
ü Environmental Statement
ü Specimen Product Label
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MODULE 2 CONTENTS
Module 2. Quality Overall Summary (QOS)
Ø The Quality Overall Summary (QOS) is a summary that follows the scope and the
outline of the Body of Data in Module 3.
Ø The QOS should include sufficient information from each section to provide the
Quality reviewer with an overview of Module 3.
Ø The QOS should not include information, data or justification that was not already
included in Module 3 or in other parts of the CTD.
Ø The QOS should also emphasise critical key parameters of the product and
provide, for instance, justification in cases where guidelines were not followed.
Ø This QOS normally should not exceed 40 pages of text, excluding tables and
figures.
Ø QOS should be submitted using the Question-based Review (QbR) format,
although this is not required.
Ø 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.
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MODULE 3 CONTENTS
Module 3. Quality
Module 3 mainly comprises of 7 sections as follows:
3.2.S.1 General Information
3.2.S.1.1 Nomenclature
3.2.S.1.2 Structure
3.2.S.1.3 General Properties
3.2.S.2 Manufacture
3.2.S.2.1 Manufacturer(s)
3.2.S.2.2 Description of Manufacturing Process and Process Controls
3.2.S.2.3 Control of Materials
3.2.S.2.4 Controls of Critical Steps and Intermediates
3.2.S.2.5 Process Validation and/or Evaluation
3.2.S.2.6 Manufacturing Process Development
3.2.S.3 Characterisation
3.2.S.3.1 Elucidation of Structure and other Characteristics
3.2.S.3.2 Impurities
Continued in next slide
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MODULE 3 CONTENTS
3.2.S.4 Control of Drug Substance
3.2.S.4.1 Specification
3.2.S.4.2 Analytical Procedures
3.2.S.4.3 Validation of Analytical Procedures
3.2.S.4.4 Batch Analyses
3.2.S.4.5 Justification of Specification
3.2.S.5 Reference Standards or Materials
3.2.S.6 Container Closure System
3.2.S.7 Stability
3.2.S.7.1 Stability Summary and Conclusions
3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment
3.2.S.7.3 Stability Data
3.2.R REGIONAL INFORMATION
Any additional drug substance and/or drug product information specific to each region
should be provided in section R of the application (Example: Executed Batch Records).
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MODULE 3 CONTENTS
Relevant information shall be presented in respective sections as prescribed in ICH
M4Q CTD guideline and should comply with "Completeness Assessment" under the
conditions specified in the Final Guidance “Completeness Assessments for Type II API
DMFs Under GDUFA." (CA Guidance).
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/M4_R1_Quality/M4Q
__R1_.pdf
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SUBMISSION(S):
Ø Amendment(s)
§ 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.
Guidance for Industry: Changes to an Approved NDA or ANDA and the Q&A
CMC Postapproval Manufacturing Changes Reportable in Annual
Reports (Draft Guidance)
§ For each submission covering letter should be prepared to facilitate
processing of documents, 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)
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SUBMISSION(S):
Ø Annual Report(s)
§ The holder should provide an annual report on the anniversary date of the
original submission.
§ Annual Reports are NOT to be used to report changes in the DMF.
§ The Annual Report should contain
ü An administrative page containing the Administrative Information
ü Date(s) of the amendment(s) reporting changes since the last Annual
Report or the original DMF filing date, whichever is most recent.
ü A statement that no amendments have been submitted since the last
Annual Report or the original DMF filing date, whichever is most recent.
(Only if no amendments have been submitted since last annual report)
ü A complete list of all parties authorized to make reference to the DMF
ü A statement that there are no Authorized Parties (Only if Letter of
Authorization (LOA) has been not issued to any party)
ü List of all parties whose authorization has been withdrawn.
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.
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SUBMISSION(S):
Ø Annual Report(s)
Failure to submit an Annual Report to the
DMF in the past thirty-six (36) months, FDA
will sends “Overdue Notification Letters”
(ONLs) to DMF holders.
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.
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DMF REVIEW:
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DMF REVIEW:
2. Initial "Completeness Assessment"
ü 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) If administratively complete, OBI sends an acknowledgement
letter.
ü DMFs for APIs submitted 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.
ü It is not necessary for there to be an LOA for the DMF to undergo a
Completeness Assessment review.
ü The time frame for the Completeness Assessment depends on workload and
may take a number of weeks.
ü If the DMF is found incomplete as per the GDUFA Completeness Assessment
Checklist, then the OGD will issue a “GDUFA DMF INCOMPLETE
COMMENTS” describing all issues causing the DMF to fail the completeness
assessment and sent to DMF Holder.
ü Amendments must be submitted using normal procedures for DMFs in
response to this letter and must address all issues raised.
ü If the DMF is found complete, FDA will post the DMF number on a publicly
available list on FDA’s web site and will be available for reference by ANDAs.
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DMF REVIEW:
ü 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.
ü This is the only notification that the DMF has passed the Completeness
Assessment.
ü ANDAs can only be filed by OGD if all DMFs for the drug substance(s) are
“available for reference”
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DMF REVIEW:
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DMF REVIEW
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DMF REVIEW
3. Technical Review
ü DMFs are subjected to a complete review for technical information ONLY when
it is referenced in an Application or another DMF.
ü The DMF is reviewed using same regulatory and scientific criteria as review of
application.
ü Reference must be accompanied by a copy of the DMF holder’s Letter of
Authorization (LOA)
ü LOAs should specify the DMF number, name of the specific item being
referenced, and the date of submission of information about that item..
ü The DMF holder should submit LOA to the FDA and one copy to the authorized
party (company or individual authorized to incorporate the DMF by reference).
ü The authorized party submits an application to the FDA that contains a copy of
the LOA.
ü Failure to submit the original LOA to the DMF may result in a delay in review of
the DMF.
ü The LOA should not be called a “Letter of Access.”
ü An LOA should be submitted even if the DMF holder is the same company as
the authorized party.
ü During review, If more information is needed to complete the review, a list of
the information needed is communicated to the holder in an Information
Request (IR) Letter
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DMF REVIEW
3. Technical Review
ü If the information in the DMF cannot support approval of the application that
references it, FDA sends a Deficiency Letter (DEF) or Complete Response
(CR) Letter (specific for Type II DMFs under GDUFA)
ü Holder should submit amendment to DMF in response to IR, DEF or CR
ü Holder should notify applicant that the DMF has been amended.
ü If the Applicant was sent an IR Letter.
§ Applicant should submit an amendment to APPLICATION notifying FDA
that DMF was amended. Reviewer receives assignment to review
APPLICATION AMENDMENT. DMF amendment may be reviewed
depending on timing relative to due date of A/NDA
ü If the Applicant was sent a CR Letter.
§ The DMF amendment will be reviewed ONLY when the APPLICANT
submits a Resubmission (Complete Response) to their CR letter.
Rationale: CR letter may contain other deficiencies e.g.. Clinical issues. If
these are not addressed then the DMF amendment does not need to be
reviewed
§ The amendment to the DMF must be a Complete Response to DMF letter
from FDA. Cannot be a notification that the DMF or sections thereof WILL
be amended.
§ If amendment to DMF is not complete, then the Resubmission to the
A/NDA is not a Complete Response.
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APPROVAL:
DMFs ARE NEITHER
APPROVED
NOR
DISAPPROVED
NO CONFUSION:
As stated in 21 CFR 314.420 (a), a
DMF is reviewed to determine
whether it is adequate to support the
particular Application (IND/
NDA/ANDA) that references it.
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QUOTE OF THE DAY:

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