GUIDELINE FOR DRUG MASTER FILES
Center for Drug Evaluation and Research
Food and Drug Administration
Department of Health and Human Services
September 1989
For further information regarding the guideline please contact:
Food and Drug Administration
Center for Drug Evaluation and Research
Office of Drug Evaluation I (HFD-100)
5600 Fishers Lane
Rockville, Maryland 20857
TABLE OF CONTENTS
I. INTRODUCTION
II. DEFINITIONS
III. TYPES OF DRUG MASTER FILES
IV. SUBMISSIONS TO DRUG MASTER FILES
A. Transmittal Letters
- Original Submissions
- Amendments
B. Administrative Information
- Original Submissions
- Amendments
C. Drug Master File Contents
1. Types of Drug Master Files
a. Type I: Manufacturing Site,
Facilities, Operating Procedures, and Personnel
b. Type II: Drug Substance, Drug Substance Intermediate, and
Material Used in Their Preparation, or Drug Product
c. Type III: Packaging Material
d. Type IV: Excipient, Colorant, Flavor, Essence, or Material
Used in Their Preparation
e. Type V: FDA Accepted Reference Information
2. General Information and Suggestions
A. Environmental Assessment
B. Stability
C. Format, Assembly, and Delivery
V. AUTHORIZATION TO REFER TO A DRUG
MASTER FILE
A. Letter of Authorization to FDA
B. Copy to Applicant, Sponsor, or Other Holder
VI. PROCESSING AND REVIEWING POLICIES
A. Policies Related to Processing Drug
Master Files
B. Drug Master File Review
VII. HOLDER OBLIGATIONS
A. Notice Required for Changes to a
Drug Master File
B. Listing of Persons Authorized To Refer to a Drug Master File
C. Annual Update
D. Appointment of an Agent
E. Transfer of Ownership
IX. CLOSURE OF A DRUG MASTER FILE
GUIDELINE FOR DRUG MASTER FILES
I. INTRODUCTION
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. The submission of
a DMF is not required by law or FDA regulation. A DMF is submitted
solely at the discretion of the holder. The information contained in
the DMF may be used to support an Investigational New Drug
Application (IND), a New Drug Application (NDA), an Abbreviated New
Drug Application (ANDA), another DMF, an Export Application, or
amendments and supplements to any of these.
A DMF is NOT a substitute for an IND, NDA, ANDA, or Export Application. It is not approved or disapproved.
Technical contents of a DMF are reviewed only in connection with the
review of an IND, NDA, ANDA, or an
Export Application.
This guideline does not impose
mandatory requirements (21 CFR 10.90(b)). It does, however, offer
guidance on acceptable approaches to meeting regulatory
requirements. Different approaches may be followed, but the
applicant is encouraged to discuss significant variations in advance
with FDA reviewers to preclude spending time and effort in preparing
a submission that FDA may later determine to be unacceptable.
Drug Master Files are provided for in
21 CFR 314.420. This guideline is intended to provide DMF holders
with procedures acceptable to the agency for preparing and
submitting a DMF. The guideline discusses types of DMF's, the
information needed in each type, the format of submissions to a DMF,
the administrative procedures governing review of DMF's, and the
obligations of the DMF holder.
DMF's are generally created to allow a
party other than the holder of the DMF to reference material without
disclosing to that party the contents of the file. When an applicant
references its own material, the applicant should reference the
information contained in its own IND, NDA, or ANDA directly rather than establishing a new DMF.
II. DEFINITIONS
For the purposes of this guideline, the
following definitions apply:
II.1. Agency means the Food and
Drug Administration.
II.2 Agent or representative
means any person who is appointed by a DMF holder to serve as the
contact for the holder.
II.3. Applicant means any person
who submits an application or abbreviated application or an
amendment or supplement to them to obtain FDA approval of a new drug
or an antibiotic drug and any other person who owns an approved
application (21 CFR 314.3 (b)).
II.4. Drug product means a
finished dosage form, for example, tablet, capsule, or solution,
that contains a drug substance, generally, but not necessarily, in
association with one or more other ingredients (21 CFR 314.3 (b)).
II.5. Drug substance means an
active ingredient that is intended 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, but does not include intermediates
used in the synthesis of such ingredient (21 CFR 314.3 (b)).
II.6. Export application means
an application submitted under section 802 of the Federal Food,
Drug, and Cosmetic Act to export a drug that is not approved for
marketing in the United States.
II.7. Holder means a person who
owns a DMF.
II.8. Letter of authorization
means a written statement by the holder or designated agent or
representative permitting FDA to refer to information in the DMF in
support of another person's submission.
II.9. Person includes
individual, partnership, corporation, and association. (Section
201(e) of the Federal Food, Drug, and Cosmetic Act.)
II.10. Sponsor means a person
who takes responsibility for and initiates a clinical investigation.
The sponsor may be an individual or pharmaceutical company,
governmental agency, academic institution, private organization, or
other organization (21 CFR 312.3 (b)).
III. TYPES
OF DRUG MASTER FILES
There are five types of DMF's:
Type I Manufacturing Site, Facilities,
Operating Procedures, and Personnel
Type II Drug Substance, Drug Substance
Intermediate, and Material 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
Each DMF should contain only one type
of information and all supporting data. See Section IV.C of the
guideline for more detailed descriptions of the kind of information
desired in each type. Supporting information and data in a DMF can
be cross referenced to any other DMF (see Part V).
IV. SUBMISSIONS TO DRUG MASTER FILES
Each DMF submission should contain a
transmittal letter, administrative information about the submission,
and the specific information to be included in the DMF as described
in this section.
The DMF must be in the English
language. Whenever a submission contains information in another
language, an accurate certified English translation must also be
included.
Each page of each copy of the DMF
should be dated and consecutively numbered. An updated table of
contents should be included with each submission.
IV. A. Transmittal Letters
The following should be included:
IV. A.1. Original Submissions
a. Identification of submission:
Original, the type of DMF as classified in Section III, and its
subject.
b. Identification of the applications,
if known, that the DMF is intended to support, including the name
and address of each sponsor, applicant, or holder, and all relevant
document numbers.
c. Signature of the holder or the
authorized representative.
d. Typewritten name and title of the
signer.
IV. A. 2. Amendments
a. Identification of submission:
Amendment, the DMF number, type of DMF, and the subject of the
amendment.
b. A description of the purpose of
submission, e.g., update, revised formula, or revised process.
c. Signature of the holder or the
authorized representative.
d. Typewritten name and title of the
signer.
IV. B. Administrative Information
Administrative information should
include the following:
IV. B.1. Original Submissions
a. Names and addresses of the
following:
(1) DMF holder.
(2) Corporate headquarters.
(3) Manufacturing/processing facility.
(4) Contact for FDA correspondence.
(5) Agent(s), if any.
b. The specific responsibilities of
each person listed in any of the categories in Section a.
c. Statement of commitment.
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.
IV. B2. Amendments
a. Name of DMF holder.
b. DMF number.
c. Name and address for correspondence.
d. Affected section and/or page numbers
of the DMF.
e. The name and address of each person
whose IND, NDA, ANDA, DMF, or Export Application relies on the subject of the
amendment for support.
f. The number of each IND, NDA, ANDA, DMF, and Export Application that relies on the subject of
the amendment for support, if known.
g. Particular items within the IND, NDA, ANDA, DMF, and Export Application that are affected, if known.
IV. C. Drug Master File Contents
IV. C.1. Types of Drug Master Files
IV. C.1.a. Type I:
Manufacturing Site, Facilities, Operating Procedures, and
Personnel
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. The DMF should
describe the manufacturing site, equipment capabilities, and
operational layout.
A Type I DMF is normally not needed to
describe domestic facilities, except in special cases, such as when
a person is not registered and not routinely inspected.
The description of the site should
include acreage, actual site address, and a map showing its location
with respect to the nearest city. An aerial photograph and a diagram
of the site may be helpful.
A diagram of major production and
processing areas is helpful for understanding the operational
layout. Major equipment should be described in terms of
capabilities, application, and location. Make and model would not
normally be needed unless the equipment is new or unique.
A diagram of major corporate
organizational elements, with key manufacturing, quality control,
and quality assurance positions highlighted, at both the
manufacturing site and corporate headquarters, is also helpful.
IV. C.1.b.Type II: Drug
Substance, Drug Substance Intermediate, and Material Used in Their
Preparation, or Drug Product
A Type II DMF should, in general, be
limited to a single drug intermediate, drug substance, drug product,
or type of material used in their preparation.
IV. C.1.b.(1) Drug Substance
Intermediates, Drug Substances, and Material Used in Their
Preparation
Summarize all significant steps in the
manufacturing and controls of the drug intermediate or substance.
Detailed guidance on what should be included in a Type II DMF for
drug substances and intermediates may be found in the following
guidelines:
Guideline for Submitting Supporting
Documentation in Drug Applications for the Manufacture of Drug
Substances.
Guideline for the Format and Content
of the Chemistry, Manufacturing, and Controls Section of an
Application.
IV. C.1.b.(2) Drug Product
Manufacturing procedures and controls
for 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. When a Type II
DMF is submitted for a drug product, the applicant/sponsor should
follow the guidance provided in the following guidelines:
Guideline for the Format and Content
of the Chemistry, Manufacturing, and Controls Section of an
Application.
Guideline for Submitting
Documentation for the Manufacture of and Controls for Drug Products
Guideline for Submitting Samples and
Analytical Data for Methods Validation
IV. C.1.c.Type III: Packaging
Material
Each packaging material should be
identified by the intended use, components, composition, and
controls for its release. The names of the suppliers or fabricators
of the components used in preparing the packaging material and the
acceptance specifications should also be given. Data supporting the
acceptability of the packaging material for its intended use should
also be submitted as outlined in the "Guideline for Submitting
Documentation for Packaging for Human Drugs and Biologics."
Toxicological data on these materials
would be included under this type of DMF, if not otherwise available
by cross reference to another document.
IV. C.1.d.Type IV Excipient,
Colorant, Flavor, Essence, or Material Used in Their Preparation
Each additive should be identified and
characterized by its method of manufacture, release specifications,
and testing methods.
Toxicological data on these materials
would be included under this type of DMF, if not otherwise available
by cross reference to another document.
Usually, the official compendia and FDA
regulations for color additives (21 CFR Parts 70 through 82), direct
food additives (21 CFR Parts 170 through 173), indirect food
additives (21 CFR Parts 174 through 178), and food substances (21
CFR Parts 181 through 186) may be used as sources for release tests,
specifications, and safety. Guidelines suggested for a Type II DMF
may be helpful for preparing a Type IV DMF. The DMF should include
any other supporting information and data that are not available by
cross reference to another document.
IV. C.1.e.Type V: FDA Accepted
Reference Information
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. If any
holder wishes to submit information and supporting data in a DMF
that is not covered by Types I through IV, a holder must first
submit a letter of intent to the Drug Master File Staff (for
address, see D.5.a. of this section). FDA will then contact the
holder to discuss the proposed submission.
IV. C.2. General Information and
Suggestions
IV. C.2.a. Environmental Assessment
Type II, Type III, and Type IV DMF's
should contain a commitment by the firm that its facilities will be
operated in compliance with applicable environmental laws. If a
completed environmental assessment is needed, see 21 CFR Part 25.
IV. C.2.b. Stability
Stability study design, data,
interpretation, and other information should be submitted, when
applicable, as outlined in the "Guideline for Submitting
Documentation for the Stability of Human Drugs and Biologics."
IV. D. Format, Assembly, and Delivery
IV. D.1.
An original and
duplicate are to be submitted for all DMF submissions.
Drug Master File holders and their
agents/representatives should retain a complete reference copy that
is identical to, and maintained in the same chronological order as,
their submissions to FDA.
IV. D.2.
The original and
duplicate copies must be collated, fully assembled, and individually
jacketed.
Each volume of a DMF should, in
general, be no more than 2 inches thick. For multivolume
submissions, number each volume. For example, for a 3 volume
submission, the volumes would be numbered 1 of 3, 2 of 3, and 3 of
3.
IV. D.3.
U.S. standard
paper size (8-1/2 by 11 inches) is preferred.
Paper length should not be less than 10
inches nor more than 12 inches. However, it may occasionally be
necessary to use individual pages larger than standard paper size to
present a floor plan, synthesis diagram, batch formula, or
manufacturing instructions. Those pages should be folded and mounted
to allow the page to be opened for review without disassembling the
jacket and refolded without damage when the volume is shelved.
IV.D.4.
The agency's system for filing DMF's
provides for assembly on the left side of the page. The left margin
should be at least three fourths of an inch to assure that text is
not obscured in the fastened area. The right margin should be at
least one half of an inch. The submitter should punch holes 8 1/2
inches apart in each page. See the page measurements shown in the
following figure:
IV.D.5. Delivery to FDA
IV.D.5.a.
Drug Master File
submissions and correspondence should be addressed as follows:
Drug Master File Staff
Food and Drug Administration
5901-B Ammendale Rd.
Beltsville, MD 20705-1266
IV.D.5.b. Delivery charges to the above
address must be prepaid.
V. AUTHORIZATION TO REFER TO A DRUG
MASTER FILE
V. A. Letter of Authorization to FDA
Before FDA can review DMF information
in support of an application, the DMF holder must submit in
duplicate to the DMF a letter of authorization permitting FDA to
reference the DMF. If the holder cross references its own DMF, the
holder should supply in a letter of authorization the information
designated by items 3, 5, 6, 7, and 8 of this section. The holder
does not need to send a transmittal letter with its letter of
authorization.
The letter of authorization should
include the following:
- The date.
- Name of DMF holder.
- DMF number.
- Name of person(s)
authorized to incorporate information in the DMF by reference.
- Specific product(s)
covered by the DMF.
- Submission date(s) of
5, above.
- Section numbers and/or
page numbers to be referenced.
- Statement of commitment
that the DMF is current and that the DMF holder will comply with
the statements made in it.
- Signature of
authorizing official.
- Typed name and title of
official authorizing reference to the DMF.
V. B. Copy to Applicant, Sponsor, or
Other Holder
The holder should also send a copy of
the letter of authorization to the affected applicant, sponsor, or
other holder who is authorized to incorporate by reference the
specific information contained in the DMF. The applicant, sponsor,
or other holder referencing a DMF is required to include a copy of
the DMF holder's letter of authorization in the application.
VI. PROCESSING AND REVIEWING POLICIES
VI. A. Policies Related to Processing
Drug Master Files
VI. A.1.
Public
availability of the information and data in a DMF is determined
under 21 CFR Part 20, 21 CFR 314.420(e), and 21 CFR 314.430.
VI. A.2.
An original DMF
submission will be examined on receipt to determine whether it meets
minimum requirements for format and content. If the submission is
administratively acceptable, FDA will acknowledge its receipt and
assign it a DMF number.
If the submission is administratively
incomplete or inadequate, it will be returned to the submitter with
a letter of explanation from the Drug Master File Staff, and it will
not be assigned a DMF number.
VI. B. Drug Master File
Review
A DMF IS NEVER APPROVED OR
DISAPPROVED.
The agency will review information in a
DMF only when an IND sponsor, an applicant for an NDA, ANDA, or
Export Application, or another DMF holder incorporates material in
the DMF by reference. As noted, the incorporation by reference must
be accompanied by a copy of the DMF holder's letter of
authorization.
If FDA reviewers find deficiencies in
the information provided in a DMF, a letter describing the
deficiencies is sent to the DMF holder. At the same time, FDA will
notify the person who relies on the information in the deficient DMF
that additional information is needed in the supporting DMF. The
general subject of the deficiency is identified, but details of the
deficiency are disclosed only to the DMF holder. When the holder
submits the requested information to the DMF in response to the
agency's deficiency letter, the holder should also send a copy of
the accompanying transmittal letter to the affected persons relying
on the DMF and to the FDA reviewing division that identified the
deficiencies. The transmittal letter will provide notice that the
deficiencies have been addressed.
VII. HOLDER OBLIGATIONS
Any change or addition, including a
change in authorization related to specific customers, should be
submitted in duplicate and adequately cross referenced to previous
submission(s). The reference should include the date(s), volume(s),
section(s), and/or page number(s) affected.
VII. A. Notice Required for Changes to
a Drug Master File
A holder must notify each affected
applicant or sponsor who has referenced its DMF of any pertinent
change in the DMF (21 CFR 314. 420(c)). Notice should be provided
well before making the change in order to permit the
sponsor/applicant to supplement or amend any affected application(s)
as needed.
VII. B. Listing of Persons Authorized
To Refer to a Drug Master File
VII. B.1.
A DMF is
required to contain a complete list of persons authorized to
incorporate information in the DMF by reference [21 CFR 314.420(d)].
The holder should update the list in the annual update. The updated
list should contain the holder's name, DMF number, and the date of
the update. The update should identify by name (or code) the
information that each person is authorized to incorporate and give
the location of that information by date, volume, and page number.
VII. B.2.
Any person whose
authorization has been withdrawn during the previous year should be
identified under a suitable caption.
VII. B.3.
If the list is
unchanged on the anniversary date, the DMF holder should also submit
a statement that the list is current.
VII. C. Annual Update
The holder should provide an annual
report on the anniversary date of the original submission. This
report should contain the required list as described in B.1., and
should also identify all changes and additional information
incorporated into the DMF since the previous annual report on the
subject matter of the DMF. If the subject matter of the DMF is
unchanged, the DMF holder should provide a statement that the
subject matter of the DMF is current.
Failure to update or to assure FDA
annually that previously submitted material and lists in the DMF
remain current can cause delays in FDA review of a pending IND, NDA,
ANDA, Export Application, or any amendment or supplement to such
application; and FDA can initiate procedures for closure of the DMF
(see Section IX).
VII. D. Appointment of an Agent
When an agent is appointed, the holder
should submit a signed letter of appointment to the DMF giving the
agent's name, address, and scope of responsibility (administrative
and/or scientific). Domestic DMF holders do not need to appoint an
agent or representative, although foreign DMF holders are encouraged
to engage a U.S. agent.
VII. E. Transfer of Ownership
To transfer ownership of a DMF to
another party, the holder should so notify FDA and authorized
persons in writing. The letter should include the following:
- Name of transferee
- Address of transferee
- Name of responsible
official of transferee
- Effective date of
transfer
- Signature of the
transferring official
- Typewritten name and
title of the transferring official.
The new holder should submit a letter
of acceptance of the transfer and an update of the information
contained in the DMF, where appropriate. Any change relating to the
new ownership (e.g., plant location and methods) should be included.
VIII. MAJOR REORGANIZATIONOF A DRUG
MASTER FILE
A holder who plans a major
reorganization of a DMF is encouraged to submit a detailed plan of
the proposed changes and request its review by the Drug Master File
Staff. The staff should be given sufficient time to comment and
provide suggestions before a major reorganization is undertaken.
IX. CLOSURE OF A DRUG MASTER FILE
A holder who wishes to close a DMF
should submit a request to the Drug Master File Staff stating the
reason for the closure. See Section IV.D.5.a for the address.
The request should include a statement
that the holder's obligations as detailed in Section VII have been
fulfilled.
The Agency may close a DMF that does
not contain an annual update of persons authorized to incorporate
information in the DMF by reference and a list of changes made since
the previous annual report. The holder will be notified of FDA's
intent to close the DMF.
Many of the guidelines referred to in
the text and a current list of available guidelines may be obtained
from the following:
Legislative, Professional, and Consumer
Affairs Branch (HFD-365)
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Copies of the Code of Federal
Regulations (CFR) may be purchased from the following:
Superintendent of Documents
U.S. Government Printing Office
Washington, D.C. 20402
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