DRUG MASTER FILES

Arthur B. Shaw, Ph.D.

FDA DMF Expert
Adapted from DIA Webinar March 19, 2007
Revised November 7, 2008
 Drug Master Files
• A Drug Master File (DMF) is a submission to
the FDA of information, usually concerning
the Chemistry, Manufacturing and Controls
(CMC) of a component of a drug product, to
permit the FDA to review this information in
support of a third party’s submission. Drug
product information or other non-CMC
information may be filed in a DMF.
 Type of DMFs
• Originally Five Types
• I Manufacturing plant information
• II Drug substance, drug product,
intermediates and material used in their
manufacture
• III Packaging
• IV Excipients
• V Other Usually clinical, tox
 Current Types of DMFs
• Now Four Types (Numbering retained to
avoid confusion)
• II Drug substance, drug product,
intermediates and material used in their
manufacture
• III Packaging
• IV Excipients
• V Other Sterile manufacturing plants,
biotech contract facilities, clinical, tox
 Facts about DMFs

• As of January 6, 2007, there were 19784 DMFs

• Percentage has remained constant over the past 3
years
Active DMF January 6, 2007

Active
41%

Inactive
59%
Types of Active DMFs

Active DMF January 6, 2007

TYPE V
TYPE IV 2%
8%

TYPE III
22%

TYPE II
68%
 Requirements for a DMF
Who Must File a DMF?
NOBODY
There is no legal or regulatory requirement
to file a DMF. A DMF may be filed to
provide CMC information that the FDA
reviews. Example: novel excipient
 When is a DMF Usually Not
Necessary
• Normally the CMC for a compendial
excipient is not reviewed
• CMC for some drug substances used in
some Over-the Counter drug products is
not reviewed (see Slide 11)
 Who’s Who?
• The person or company who submits a
DMF is the HOLDER
• The person or company who represents a
DMF HOLDER is the AGENT
• The person or company who references
the DMF is the APPLICANT or the
CUSTOMER or the AUTHORIZED PARTY
(AP)
 What’s What?
• Application = Investigational New Drug
Application (IND), New Drug Application
(NDA), Abbreviated New Drug Application
(ANDA)
• Supplement to an A/NDA = A report of a
change in an approved A/NDA Since a DMF
is not approved, there can be no supplements
to a DMF, only amendments
• Amendment to an application = Additional
information to an existing IND, a pending
A/NDA or a pending A/NDA supplement
 Non-prescription Drugs
• Some non-prescription drug products (Over-the-
Counter = OTC) drug products are marketed
after approval of NDAs e.g. OTC Tagamet.
CMC information for such OTC products is
reviewed by FDA
• Some OTC drug products are marketed without
prior approval by FDA under the OTC
monograph system. e.g. aspirin CMC
information for such OTC products is NOT
reviewed by FDA
 Reasons for a DMF
• Maintain confidentiality of proprietary
information (e.g., Manufacturing
procedure) for the holder
• Permit review of information by reviewers
in the Center for Drug Evaluation and
Research (CDER) to support applications
submitted by one or more applicants
 How the System Works
Holder sends the DMF (NO FEE two copies) to
Central Document Room
Center for Drug Evaluation and Research
5901-B Ammendale Road
Beltsville, MD 20705-1266
Containing:
–Transmittal (cover) letter
–Administrative information
–Technical information
All subsequent submissions (amendments, Annual
Reports, Letters of Authorization) are sent to the same
address. Two copies
Follow the Guideline at www.fda.gov/cder/guidance/dmf.htm
Binders recommended
http://www.fda.gov/cder/ddms/binders.htm
Fasteners must be obtained separately. 2 Piece Prong Fasteners, 8
1/2" Center to Center, 3 1/2" Capacity
 How the System Works (cont)
• Strongly recommend including telephone and
fax numbers and e-mail address for the
responsible individual (contact person)
• DMF reviewed for administrative purposes
ONLY by Office of Business Process Support
(OBPS) staff. Most common delay: No
statement of commitment, lack of COMPLETE
ORIGINAL SIGNATURE
• DMF entered into DMF database, assigned a
number, and acknowledgement letter sent
• Usual processing time is 2-3 weeks
• E-mail: dmfquestion@cder.fda.gov
 Acknowledgement Letter
• Assigns number and type. Includes Title
(Subject) and Holder of DMF. Will appear
on list posted on web site (see next slide)
• Reminder of obligations of holder
– Submit all changes as amendments
– Notify FDA of change in holder name or address
– Notify FDA of change in agent/representative
– SUBMIT ANNUAL UPDATE (Annual Report)
– Submit Letter of Authorization (LOA) for each item
referenced for each customer
– Notify authorized parties of changes
 DMF Web Site
• List of DMFs
• http://www.fda.gov/cder/dmf/index.htm
• Updated quarterly
• Contains additional information about
DMFs
 Letter of Authorization (LOA)
• The DMF will be reviewed ONLY when it is
referenced in an Application or another DMF.
• The holder MUST submit an LOA (2 copies) to
the DMF DO NOT NEGLECT THIS!!!
• THEN send a copy to the APPLICANT
• The applicant submits copy of LOA in their
Application. This is the ONLY mechanism to
trigger review of the DMF
• In some cases a DMF holder will call the
permission to reference a DMF a “Letter of
Access.” (Phrase used in Europe). An LOA
does not permit anyone except FDA to “Access”
i.e. “read” the DMF.
 LOA (cont)
• LOA must contain a specific reference to a
particular item in the DMF.
• This is especially important for large Type III
or IV DMFs that contain many products
• Specify the item by its code name, page
number and, most importantly, DATE OF
THE SUBMISSION as it appears on the
cover letter of that submission (not an
internal document date) Volume number
usually not helpful since volume numbers are
generated in CDR
 Differences between
Applications and DMFs
• Applications
– Submitted to a particular review division
– Each submission (including supplement) is entered into
the application database and assigned to a reviewer and
an acknowledgement letter sent
– Each submission has a due date.
• DMFs
– Submitted to CDR
– Each submission is entered into a database (different
from application database) and NO acknowledgement
letter sent
– Reviewed ONLY when referenced. No assignment to a
reviewer, no due date
 Review of the DMF
• When the reviewer receives an application that
references a DMF, the reviewer requests the DMF
from the CDR.
• Contrast with application, where document is
delivered automatically to reviewer.
• Delivery of DMF can take a couple of days.
Reviewers are in three different buildings in
Maryland near Washington DC.
• Highlights importance of specifying the date of the
submission being referenced,especially for
multivolume DMFs.
 DMF Review Procedure
• The DMF is reviewed using same regulatory and
scientific criteria as review of applicaiton
• If there are deficiencies
– The detailed deficiencies are communicated to the holder
– The APPLICANT is notified that deficiencies exist in either an
Information Request (IR) or a Complete Response (CR) letter.
– The nature of the deficiencies is not communicated to the
applicant.
• If no deficiencies
– No letter to DMF holder
– Applicant not notified.
 IR and CR Letters to Applicant
• Not strictly a DMF issue but this affects how
responses are dealt with
• IR Letter: Review clock for NDA is not stopped.
Responses may be reviewed at reviewer’s
discretion depending on timing relative to the
due date.
• CR Letter: Review Clock is stopped.
Application (and supporting DMFs) will be
reviewed only when all issues in CR Letter
(including DMF deficiencies) have been
addressed
 Changes to a DMF
• Amendment = A report of a change or addition of
technical or administrative information. NOT a
supplement (Supplements apply only to approved
applications)
• Annual Update = Annual Report See slide below
• All amendments and annual update 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)
• NO PAGES ARE EVER PHYSICALLY REPLACED IN A
DMF
 Technical Amendments to the DMF
Amendment in Response to Letter to Holder
• Holder submits amendment to DMF.
• Cover letter with the DMF amendment should
reference date of Agency’s letter to holder
• Holder notifies applicant that the DMF has been
amended.
• Holder may notify reviewer, if that was requested in
letter to holder
• Desk copy
– A copy of the amendment (desk copy) can be sent to the
reviewer ONLY if requested.
– If a desk copy is sent to a reviewer the cover letter should
contain
• a) a statement that the desk copy is an exact copy of the
amendment submitted to the DMF and
• b) a statement that the amendment was shipped to the DMF
Central Document Room on the same day the desk copy was
sent to the reviewer.
 Technical Amendments to the DMF
Amendment in Response to Letter to Holder
• If the Applicant was sent an IR Letter.
– If the applicant did not submit an amendment to the NDA: DMF
Amendment may be reviewed if the reviewer was notified by the
holder that an amendment to the DMF had been submitted
– If the applicant submitted an amendment to the NDA: DMF
amendment will be reviewed.
• If the Applicant was sent a CR Letter.
– The DMF amendment will be reviewed ONLY when the
applicant submits a complete response to their letter CR letter.
Rationale: Applicant’s letter may contain other deficiencies e.g..
Clinical issues.
– The amendment must be a COMPLETE RESPONSE to letter
from FDA. It cannot be a notification that the DMF WILL be
amended.
 Technical Amendments to the DMF
Spontaneous Amendment
• Holder
• Cover letter should contain list of specific changes
• A new LOA specifying the date of the amendment is
usually not necessary
• Notify APPLICANT of types of changes
– FDA
• Amendment entered into database by CDR
• NO ASSIGNMENT, no review until submission of
– Amendment to a pending application
Or
– Supplement or annual report to an approved application
 Administrative Amendments
• Administrative:
– Change in holder name and/or address
– Agent appointment or termination
– Authorization termination
– Request for closure
– Not necessary to report personnel changes
except for contact person or responsible
official
• Recommend: Submit EACH change as a
separate AMENDMENT. Do not include
ANY changes in Annual Report
 Annual Updates
• Not required by regulation. RECOMMENDED in DMF
Guideline (Section VII) Includes:
– List of authorized parties, what they are authorized to reference,
and the date of the LOA
– List of changes reported during the past year. Note that this is
NOT a list of changes MADE but a list of changes already
REPORTED. Stability updates should be reported as
amendments.
• If the anniversary date is missed FDA will not send a
reminder (unlike applications) (See below “Retiring a
DMF”)
• If no changes, send update with a statement to that
effect
 Agents for DMFs
• Not required, although recommended to facilitate
communication for foreign company
• Holder appoints agent
• Responsibilities of agent should be defined in Agent
Appointment Letter
• Agent for DMF purposes NOT the same as agent for
Drug Registration and Listing
http://www.fda.gov/cder/drls/registration_listing.htm
• Do not use the word “authorize” in appointing an
agent. This can be easily confused with a Letter of
Authorization. Use the word is “appoint.”
 Agents as Holders
• The holder of a DMF is expected to be the manufacturer
of the material described in a DMF.
• 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 (as well as the agent), the DMF must include
statements from both companies that Company B
– Takes full responsibility for
• the accuracy and currency of all the information in the DMF
• all the processes and testing performed by the manufacturer
– Will submit all changes to the DMF as required under 21 CFR
314.420(c).
• The title of the DMF which will appear on the list of
DMFs will be “MATERIAL manufacture by COMPANY A
in LOCATION OF COMPANY A for COMPANY B.”
 Technical Information for
Holders
• Holder must follow appropriate regulations
• Recommend that holder follow appropriate
Guidances and CTD-Q
• Facilities information (former Type I) not
necessary. Address is sufficient. Statement of
cGMP Compliance is required.
• Environmental Assessment (EA) not necessary
See slide below
• Completed batch records for Type II are
expected
 Common Technical Document
(CTD)
• CTD documents are not intended to indicate what data or studies
are required. “The text following the section titles is intended to be
explanatory and illustrative only.” The CTD Guidance indicate an
appropriate format for the data that have been acquired.
http://www.fda.gov/cder/guidance/4707dft.pdf
• Module 1 Administrative information that applies to DMFs. There
are no forms for DMFs.
– Comprehensive table of contents
– Administrative documents
• Addresses of DMF holder and manufacturing and testing facilities
• Name and address of contact persons and/or agents
• Agent Appointment letter (where applicable)
• Letters of Authorization.
• List of authorized parties (where applicable)
• Statement of commitment
• Environmental assessment or request for categorical exclusion
 Common Technical Document
(CTD) Continued
• See M4Q CTD-Q
http://www.fda.gov/cder/guidance/4539Q.htm
• Module 2 = Quality Overall Summary (QOS)
Expected to be submitted.
• 3.2.S Body of Data for Drug Substance
• 3.2.R Regional Information:
– Executed Batch Records
– Method Validation Package: Not usually submitted for
DMFs. Complete Methods Validation information
should be included in 3.2.S.4.3
– Comparability Protocols: Not usually submitted for
DMFs
 Environmental Assessment
(EA)
• The National Environmental Policy Act (NEPA)
requires that all government agencies prepare an
Environmental Impact Statement (EIS) or a Finding of
No Significant Impact (FONSI) when they take an
action e.g., approving a drug application. Companies
submitting an application are required to submit an EA
(or a waiver request) to permit FDA to determine
whether an EIS or a FONSI is needed. See Guidance
for Industry: Environmental Assessment of Human
Drug and Biologics Applications
http://www.fda.gov/cder/guidance/1730fnl.pdf
• Since DMFs are not approved, FDA does not take an
action, therefore no EA needed.
• DMF should include a statement that holder will
comply with all local environmental regulations
 Environmental Assessment
(continued)
• EA usually applies to impact of USE of the
drug on the environment, not production.
• There are circumstances (e.g. use of an
endangered species as a starting material)
under which production of the drug requires an
EA See EA Guidance
• DMF holder’s responsibility is to provide
sufficient information to customer to permit
customer to file an EA.
• In general new drugs qualify for waiver. All
generics qualify
 Administrative and Technical
Information for Applicants
• Applicants should notify suppliers (DMF
holders) of company name change. Will
require new LOAs
• Submit amendment to application when
DMF amended in response to deficiency
letter
• Notify FDA of technical changes in DMF
reported by DMF holder appropriately.
 Issues of Concern for Drug
Manufacturers
• Type V DMFs
• Confidentiality of Information in DMFs
• Intermediates
• Reporting Changes
• Additional Manufacturing Site
• Inspections
• Novel and Compendial Excipients
• Type III DMFs
• Inactivation of DMFs
• Electronic DMFs
• Quality by Design
 Type V DMF
• Regulation 21 CFR 314.410(a)(5) states:
“A person wishing to submit information and
supporting data in a drug master file (DMF) that is
not covered by Types II through IV DMF's must first
submit a letter of intent to the Drug Master File Staff,
Food and Drug Administration, 5901-B Ammendale
Rd., Beltsville, MD 20705-1266.) FDA will then
contact the person to discuss the proposed
submission.”
• This can be done via e-mail to
dmfquestion@cder.fda.gov
 Type V DMF (cont)
• When a request is submitted, the clinical review
division affected by the proposed DMF will be
contacted
• Safety and clinical data should be submitted to
the NDA or IND not in a DMF.
• Types of information that are usually accepted:
– Safety data for a novel excipient that may be used in
a number of different products
– CV’s for a large group of clinical investigators
involved in a large clinical trial
 Type V DMF (cont)
• Exception to the requirement to receive
permission to submit a Type V DMF
• Information about manufacturing facilities that
were formerly covered as “Type I” DMFs. Most
Type I DMFs covered information that is not
reviewed by CDER or CBER. However two
types of facility require review by CDER and
CBER
– Facilities performing sterile processing
– Facilities preparing biotech materials. See “Guidance
for Industry: Submitting Type V Drug Master Files to
the Center for Biologics Evaluation and Research
(Draft) http://www.fda.gov/cber/gdlns/dmfv.htm
 DMFs for Intermediates
• If a chemical in the synthetic pathway is defined as
an “intermediate” rather than a starting material, it is
expected to be manufactured under CGMP. In
general an intermediate is not accepted based on
specifications alone. Usually more information
regarding the manufacturing is needed to ensure
that the intermediate is acceptable for further
processing to the drug substance.
• Therefore a DMF is “needed” if the intermediate
comes from a third party.
• It is useful (within the limits of confidentiality) to have
intermediate manufacturer submit LOA to applicant.
Otherwise submit LOA to drug substance
manufacturer.
 Confidentiality of Information in
DMFs
• There are no “Open” and “Closed” parts of a DMF in the
US
• 21 CFR 314.420(e) states:
“The public availability of data and information in a drug
master file, including the availability of data and
information in the file to a person authorized to
reference the file, is determined under part 20 and Sec.
314.430”
• Manufacturing information is covered under those parts
of the CFR.
• Since DMFs usually cover manufacturing information
they are not usually considered releasable via a
Freedom of Information Act (FOIA) request
• Release of safety information e.g. toxicology studies, by
the Freedom of Information Office is determined by
current regulations.
 Designation of an Intermediate
as a Starting Material
• Definition of a Starting Material (SM) is in Drug
Substance Guideline.
• Change from Intermediate to Starting Material is
reported to the DMF like any other change and
needs to be reported in applications supported
by the DMF like any other post-approval change.
• Useful to meet with review division.
• ICH Q7A is a useful guide. However this applies
to CGMP, which is the responsibility of the Office
of Regulatory Affairs (inspectors). DMFs are
reviewed by CDER.
 Post-approval Changes
• Some post-approval changes (PAC) to an approved
application must be reported. Some PAC’s are not
reportable but must be available in the manufacturing
plant. Non-reportable changes are not reviewed by
CDER.
• The category of reportable changes varies depending
on their POTENTIAL (not actual) impact on Identity,
Purity, Quality, Strength, and Potency (IPQSP) of the
DRUG PRODUCT as they relate to Safety and
Efficacy (S&E)
• Changes can be made to drug product (e.g.
manufacture with changed drug substance) but it
cannot be marketed until the appropriate filing and
action has occurred
Post-approval Changes (continued)
• See regulations at 21 CFR 314.70 and Guidance for
Industry: Changes to an Approved NDA or ANDA
http://www.fda.gov/cder/guidance/2766fnl.htm
Guidance specifies
– Reporting Categories e.g. Annual Report
for different
– Categories of Manufacturing Changes that need to reported
e.g., change in manufacturing site
• Note that Annual Reports (ARs) for approved
applications are required by regulation. Not the same
as Annual Updates to DMFs.
 Post-approval Changes
(continued)
Potential Impact Reporting Applicant Responsibility Marketing status of
on IPQSP as they Category drug product
relate to S&E
Minor Annual Report change in AR Market immediately
Report without waiting for AR
to be filed
Moderate CBE-0 Submit a CBE Market when
supplement reporting supplement
change submitted
CBE-30 Submit a CBE Market only 30 days
supplement reporting after submission of
change supplement
Major PAS Submit a Prior Approval Market only after
Supplement reporting approval of
change supplement
 Reporting Changes for Type II
DMFs: Holder’s Role
• Holder can implement the change when notification is
submitted to the DMF.
• Holder can ship “Post-Change Drug Substance” (PCDS)
to customer
• Holder must notify the customer that a change has been
made
• Holder should determine the appropriate Reporting
Category for the manufacturing change and notify the
customer of the nature of the change, providing sufficient
detail to enable the customer to report the change
appropriately. The level of detail in the notification to the
customer is determined by the contractual agreement
between the holder and the customer.
 Reporting Changes for Type II
DMFs (cont)
• The APPLICANT has the responsibility of
submitting the appropriate document to
the FDA as an Annual Report or
Supplement.
• Drug product manufactured using PCDS
can be marketed ONLY under the
conditions described in Slide 46
 Reporting Changes for Type II
DMFs (cont)
• If there are multiple customers, notify the FDA
before making change in order to coordinate
reviews of supplements.
• A “Meeting Request” sent to the DMF will not be
seen.
• Not the same as a “bundled” supplement, which
cover the same change (e.g. change in resin
supplier for a bottle) used in many A/NDAs held
by the same applicant.
 Additional Manufacturing Site
Same Process Multiple Processes
(minor differences)
Same Site One DMF One DMF
Identify differences Identify differences
Multiple Sites One DMF Separate DMFs
Identify differences
 Inspections
• Inspections of drug substance
manufacturers are usually triggered when
there is an application under review that
references a DMF for the manufacture of
that drug substance.
 Type IV DMFs
• CMC for a compendial excipient is usually
not reviewed and therefore a DMF is not
necessary.
• Exceptions: New route of administration
or total dosing that may affect safety and
efficacy, e.g. RESPITOSE, lactose for dry
powder inhalation products
Type IV DMFs Novel Excipients
• IPEC has prepared a draft guideline for
comment NOT OFFICIAL FDA policy
• CMC requirements for a novel excipient (one not
used in an approved drug product) are the same
as those for a new drug substance.
• Safety testing (submitted in a Type V) is the
subject of an FDA Guidance.
http://www.fda.gov/cder/guidance/5544fnl.htm
 Type III DMFs
• In general, a Type III DMF should contain
sufficient CMC information to determine whether
the components used in the manufacture of the
item are safe e.g. HDPE for use in packaging
solid oral dosage forms meets food contact regs
• Typically, provide chemical components with
identification corresponding to appropriate CFR
citation (i.e. not simply trade names)
• Information regarding packaging materials can
be submitted directly to the applicant for
inclusion in their NDA. DMF NOT required
 Type III DMFs (cont’d)
• Can include extraction data in DMF but responsibility for
compatibility and safety of packaging components in
finished drug product is the responsibility of the
CUSTOMER
• Assemblies (e.g. valve systems for pumps) can
reference DMFs for components
• In general, all suppliers of components and or chemicals
should provide LOAs directly to NDA (within limits of
confidentiality)
• See Guidance for Container/Closure Systems
http://www.fda.gov/cder/guidance/1714fnl.htm
• Guidance drafted in DMF Workshop (2002) is not official
FDA guidance
 Retiring DMFs
• If a DMF has had no activity (amendment
or annual report) in three years FDA will
initiate retirement procedure Note: LOA
does not count for activity
 DMF Retirement Procedure
• FDA sends overdue notice to holder and/or
agent using most recent address. Highlights the
importance of keeping holder/agent name and
address up-to-date.
• If no response in 90 days, one copy of DMF is
sent to Federal Records Center (FRC) and the
other is destroyed.
• Response: Close DMF or submit annual update
to keep it open.
 Electronic Filing of DMFs and
CTD-Q
• CTD-Q not required for paper DMFs, although
acceptable. Required for electronic DMFs
• Electronic DMFs are accepted
http://www.fda.gov/cder/regulatory/ersr/ectd.htm
• DMFs originally submitted in paper can be
resubmitted as electronic DMFs. Entire DMF
must be resubmitted.
• Once a DMF has been submitted in electronic
form NO paper documents (including LOAs) may
be submitted.
 Quality by Design

• FDA is working with industry on the Quality by Design (QbD)

initiative
• Guidances:
– ICH Q8, Pharmaceutical Development,
http://www.ich.org/LOB/media/MEDIA1707.pdf
– ICH Q9, Quality Risk Management
http://www.ich.org/LOB/media/MEDIA1957.pdf
• The principles of QbD can be applied to drug substance
manufacture.
• Process understanding links input variables (raw material attributes)
and process parameters to Critical Quality Attributes
(CQAs)/specifications and hence to the desired performance of the
finished product
• Implementation of QbD, including establishment of design space
and control strategy, by drug substance manufacturers in a DMF
could lead to less need for reporting changes to DMF.
 Changes in the DMF System
and Procedures
• Elimination of Type I DMFs
• Post-Approval Changes Guidance
• Creation of DMF List Website
• Creation of DMFQUESTION
• Establish Position of DMF Expert
• Transfer of BB-MFs to CDER when some
review functions transferred to CDER
 Unchanged
• Review only when referenced in
application
• No Open and Closed parts
• DMFs are neither approved nor
disapproved
• The holder must notify customer of
changes
 Summary
• The DMF system presents challenges for
both the industry and the FDA
• Problems can be minimized if holders and
applicants
– Understand their responsibilities
– Adhere to the regulations
– Follow the recommendations in the Guidances
– Communicate with each other