U.S. Department of Health and
Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
November 1999
CMC
Guidance for Industry
Drug Master Files for
Bulk Antibiotic Drug Substances
Additional copies are
available from:
Office of Training and Communications
Division of Communications Management
Drug Information Branch, HFD-210
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
(Internet)
http://www.fda.gov/cder/guidance/index.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
November 1999
CMC
Guidance for Industry
Drug Master Files for Bulk Antibiotic Drug Substances
I. INTRODUCTION
This guidance is intended for those in
industry whose approved applications for bulk antibiotic drug
substances (i.e., bulk applications) were converted to Type
II Drug Master Files (DMFs) when section 507 of the Federal Food,
Drug, and Cosmetic Act was repealed as part of the enactment of
section 125 of Title I of the Food and Drug Administration
Modernization Act on November 21, 1997.
This guidance explains the purpose of DMFs, discusses the type of
information expected in a Type II DMF, outlines administrative
procedures governing review of DMFs, and clarifies your
responsibilities as a DMF holder. The information presented in
this guidance is also relevant to the submission of new DMFs for
bulk antibiotic drug substances.
II.
BACKGROUND
Prior to the repeal of section 507, bulk
antibiotic drug substances were handled differently from other
bulk drug substances. Bulk antibiotic drug substances were either
batch certified or exempted from batch certification through the
approval of an antibiotic drug application. Information about
other bulk drug substances, drug substance intermediates, and
materials used in their preparation were filed and maintained as
Type II DMFs according to 21 CFR 314.420, or drug substance
information could be filed as part of the marketing application
for the finished dosage form of the drug. With the repeal of
section 507 in the Modernization Act, bulk antibiotic drug
substances are being handled in the same way as all other bulk
drug substances under section 505 of the Federal Food, Drug, and
Cosmetic Act.
With the implementation of the Modernization
Act, the agency administratively converted all bulk antibiotic
applications to DMFs. Following the conversion of these
applications, the Agency gave each affected holder the newly
assigned DMF number. Persons holding bulk applications were not
required to take any action for their application to be converted
to a DMF. However, following conversion, holders were expected to
reference the new DMF number on all letters of authorization (LOAs)
or other correspondence relating to the DMF for the bulk
antibiotic drug substance and maintain the DMF in accordance with
21 CFR 314.420. Holders who did not wish to maintain a DMF were
allowed to incorporate the information into one or more dosage
form applications, or close their application in accordance with
Agency record keeping practices. The incorporation of DMF
information into a dosage form application usually applies to
situations where the manufacturer of the bulk antibiotic drug
substance and the dosage form applicant are the same corporate
entity.
III.
WHAT IS A DRUG MASTER FILE (DMF)?
A Drug Master File (DMF) is a submission to
the Agency of confidential detailed information for the following
purposes (21 CFR 314.420(a)):
·
A DMF allows you (the holder) to incorporate
information by reference when you submit an application
(investigational new drug application (IND), new drug application
(NDA), abbreviated new drug application (ANDA), another DMF,
export application, or amendments and supplements to these).
·
A DMF allows you to authorize other persons
(applicants) to reference information in your DMF in support of a
submission to the Agency without having to disclose the
information to the applicant.
IV. WHAT IS A
TYPE II DMF AND WHAT INFORMATION SHOULD BE INCLUDED IN IT?
There are multiple types of DMFs, but you
should submit information pertaining to the manufacture of bulk
antibiotic drug substances as Type II DMFs (21 CFR
314.420(a)(2)). A Type II DMF is used to provide information on
drug substances, drug substance intermediates, and materials used
in their preparation. It should include information on the
following:
·
physical, chemical, biological (e.g.,
anti-microbial), and stability characteristics of the drug
substance;
·
the name and location of the manufacturing site(s);
·
the method of manufacture (e.g., microbial strain
used, fermentation process, isolation process) and/or synthesis,
and purification;
·
the process controls used during manufacturing and
packaging; and
·
the specifications used to ensure the identity,
strength and/or potency, quality, and purity of the drug
substance.
For additional guidance on information that
should be submitted in a Type II DMF, see 21 CFR 312.23(a)(7) and
314.50(d)(1)(i) and relevant CDER guidances such as the guidance
on Submitting Supporting Documentation in Drug Applications
for the Manufacture of Drug Substances (February 1987).
For guidance on information and data that should be submitted in
support of sterility assurance for a sterile bulk antibiotic drug
substance, see CDER and CVM's guidance on Submission of
Documentation for Sterilization Process Validation in Applications
for Human and Veterinary Drug Products (November 1994).
In addition to providing the specific
information described above, each submission to your DMF should
include a transmittal letter and administrative details about the
submission. For information on these additional items, as well as
the format, assembly and delivery of DMF submissions, see CDER's
guidance on Drug Master Files (September 1989).
V. WHEN ARE LETTERS OF AUTHORIZATION NEEDED?
Before the Agency can review information in
your DMF, you must send an LOA to the applicant who is
incorporating information by reference from your DMF (21 CFR
314.420(b)). The applicant must include a copy of the LOA in
their submission (21 CFR 314.50(g)(1)). The LOA permits FDA to
access the information in your DMF. The LOA is required even if
the applicant is also the holder of the DMF. A copy of the LOA
should also be submitted to your DMF. For details on information
that should be included in the LOA see CDER's guidance on Drug
Master Files.
VI. WHAT ARE
THE POLICIES RELATED TO PROCESSING AND REVIEWING DMFs?
Ordinarily, the information in your DMF is
reviewed only in conjunction with an application that references
the information through an LOA. The Agency neither approves or
disapproves your DMF, but makes a judgment on the adequacy of the
referenced information in support of the application that
references it (21 CFR 314.420(a)). If upon review, the
information provided in your DMF is determined to be inadequate,
you will receive a letter from the Agency describing the
deficiencies. At the same time, the Agency will notify the
applicant who relies on information in your DMF of the inadequate
status, but details of the deficiencies are not disclosed to the
applicant. When you submit the requested information to your DMF
in response to the Agency’s letter, a copy of the transmittal
letter should be sent to the FDA review division issuing the
letter, and the affected applicant should be notified that the
response was submitted. This provides notice to the applicant and
review division that the DMF has been amended and the deficiencies
have been addressed.
VII. WHAT ARE MY RESPONSIBILITIES AS A DMF HOLDER ?
As a DMF holder you have a number of
obligations. Failure to meet these obligations may delay approval
of applications that rely on the information in your DMF or result
in the Agency closing your DMF. The following discusses your
responsibilities.
A. Changes to your DMF
Any addition,
deletion, or change to information in your DMF is required to be
submitted to the Agency in duplicate (21 CFR 314.420(c)). This
includes changes you formerly reported to the Agency under 21 CFR
314.70 when the information was part of an approved bulk
application. The submission describing the change should include
appropriate cross-references to the affected information in
previous submissions, including the date(s), volume(s), section(s),
and/or page number(s). Additionally, you must notify each person
(applicant) authorized to reference information in your DMF of
pertinent changes (21 CFR 314.420(c)). Notification should be
provided well in advance to give the affected persons (applicants)
ample time to amend or supplement their applications as necessary
under 21 CFR 314.70.
B. Annual Update
You should update
your DMF on an annual basis. The update should identify all
changes and additional information incorporated into your DMF
since the previous update. If no changes were made to your DMF,
you should provide a statement that the information remains
current. For more information on annual updates see CDER's
guidance on Drug Master Files.
C. Listing of Persons Authorized to Reference your DMF
Your DMF must
contain a complete list of persons currently authorized to
reference information in your DMF (21 CFR 314.420(d)). For more
information on this topic see CDER's guidance on Drug Master
Files.
D. Appointment of an Agent
If you have an
appointed agent for your DMF, you should include a signed letter
of appointment in your DMF that includes the agent’s name,
address, and scope of responsibility (administrative and/or
scientific).
E. Transfer of Ownership
If you intend to
transfer ownership of your DMF to another party, you should notify
the Agency and persons authorized to reference the DMF
(applicants) in writing. Details regarding information to be
included in the letter are provided in CDER's guidance on Drug
Master Files.
F. Incorporation of Information into a Dosage Form
Application
If you do not wish to
maintain a DMF, the information may be filed as part of one or
more dosage form applications (IND, NDA, or ANDA). The dosage
form applicant is then responsible for ensuring this information
meets regulatory requirements. If the information is certified as
being current and there have been no changes, it may be submitted
to the dosage form application(s) as an annual report. If the
information is not current or changes have been made, the DMF
information should be filed as (1) a prior approval supplement,
changes being effected supplement, or annual report for an NDA or
ANDA or (2) an information amendment or annual report for an IND.
The reporting category would depend on the nature of the change.
GLOSSARY
Letter of Authorization: A written
statement by the holder or designated agent permitting other
persons to refer to information in a DMF in support of
applications.