[Federal Register Volume 60, Number 127 (Monday, July 3, 1995)]
[Proposed Rules]
[Pages 34486-34488]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-16206]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 314
[Docket No. 94N-0449]
New Drug Applications; Drug Master Files
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to revise
its regulations governing drug master files (DMF's), which are referred
to in the review and approval of new drugs and antibiotic drugs for
human use. A DMF is a voluntary submission to 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 information contained in a DMF
may be referred to in support of an investigational new drug
application (IND), a new drug application (NDA), an abbreviated new
drug application (ANDA), or amendments or supplements to any of these.
FDA has defined five distinct categories of submissions that it will
accept and maintain, and it has designated these as Type I through Type
V DMF's.
In December 1992, the Center for Drug Evaluation and Research's
(CDER's) Chemistry, Manufacturing, Controls Coordinating Committee
(CMCCC) established a DMF Task Force to perform a review and to explore
ways of improving all aspects of the system. One of the Task Force
recommendations, which was adopted by the CMCCC, was to eliminate Type
I DMF's. Type I DMF's contain information about manufacturing sites,
facilities, operating procedures, and personnel. The Task Force
concluded that Type I DMF's should be eliminated because they contain
outdated information, duplicate information contained in marketing
applications, and are not used by CDER's review divisions or FDA's
field inspectors. Under the proposed rule, FDA would no longer permit
information submitted in a Type I DMF to be incorporated by reference
in IND's, NDA's, ANDA's, abbreviated antibiotic applications (AADA's),
and supplemental applications. This proposed rule is intended to
eliminate submissions of information that are not necessary either to
conduct inspections of manufacturing facilities or to review the
chemistry, manufacturing, and controls sections of IND's, NDA's, and
abbreviated applications. This proposed rule would not apply to master
file systems that are operated by the Center for Biologics Evaluation
and Research, the Center for Veterinary Medicine, and Center for Device
and Radiological Health.
DATES: Written comments by October 2, 1995. FDA proposes that any final
rule based on this proposal become effective 60 days after its date of
publication in the Federal Register.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Howard P. Muller, Center for Drug
Evaluation and Research (HFD-362), Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855, 301-594-1046.
SUPPLEMENTARY INFORMATION:
I. Introduction
DMF's allow regulated industry to submit to FDA information that
may be used to support an IND, NDA, ANDA, AADA, another DMF, an export
application, or amendments or supplements to any of these. FDA does not
require industry to submit DMF's; a DMF is submitted solely at the
discretion of the holder. DMF's allow industry to provide confidential,
detailed information about facilities, processes, or articles used in
the manufacturing, processing, packaging, and storing of drugs for
human use. This information is then incorporated by reference in a drug
application or supplement without public disclosure.
FDA regulations in Sec. 314.420(a) (21 CFR 314.420(a)) define five
types of DMF's according to the kind of information to be submitted.
Type I submissions include manufacturing site, facilities, operating
procedures, and personnel information. Type II submissions include
information regarding drug substances, drug substance intermediates,
and materials used to prepare them, or drug products. Type III
submissions include information about packaging material. Type IV
submissions include information concerning excipients, colorants,
flavors, and essences, or material used in their preparation. Type V
submissions, detailed in the ``Guideline for Drug Master Files''
(1989), include FDA-accepted reference information.
Under Sec. 314.420, FDA recommended that foreign drug manufacturing
facilities file with FDA information concerning their manufacturing
sites, facilities, operating procedures, and personnel in a Type I DMF.
FDA requested this information to plan its on-site inspections of and
travel to foreign drug manufacturing facilities. FDA believed that
inspections would be conducted more efficiently if FDA inspectors knew
in advance the location, plant layout, equipment type, and personnel at
the foreign manufacturing site. FDA did not request that domestic firms
submit Type I DMF's because FDA inspectors regularly visit firms in
their district and are familiar with both their personnel and
manufacturing sites. Nonetheless, some domestic pharmaceutical firms
have submitted Type I DMF's. Currently, CDER has approximately 1,700
Type I DMF's.
[[Page 34487]]
Recently, FDA evaluated the usefulness of Type I DMF's. The agency
determined that its inspectors were not using Type I DMF's to plan
foreign inspections because the Type I DMF was not easily accessible or
information contained in the Type I DMF was outdated. Instead, FDA now
requests foreign firms to submit a preinspection document package that
includes both current facility and product-specific information. FDA
inspectors use the preinspection package to plan their inspection.
Although submission of the package is voluntary, foreign firms comply
with the agency's request because the information helps inspectors to
conduct inspections quickly and efficiently. The agency concluded that
Type I DMF's could be eliminated without adversely affecting
inspections of foreign manufacturing facilities.
FDA has also determined that its review divisions do not rely on
Type I DMF's. Although Type I DMF's are often incorporated by reference
into IND's, NDA's, and abbreviated applications, the information that
the agency requested to be submitted under Type I DMF's is not required
for chemistry, manufacturing, and controls review. Under 21 CFR
314.50(d)(1)(i) and (d)(1)(ii), a drug product applicant is required to
furnish the name and location of facilities used in the manufacture of
the drug substance or product. Unlike a Type I DMF submission, this
information, when submitted as part of an application, is current and
product-specific. Therefore, review divisions rely on the applications
themselves for this information.
Accordingly, the agency proposes to amend Sec. 314.420 to eliminate
Type I DMF's. The agency would no longer accept new Type I DMF's, or
correspondence updating existing Type I DMF's. The information in Type
I DMF's currently on file could no longer be incorporated by reference
into new applications, amendments, or supplements, and the Type I DMF's
would be transferred to the Federal Records Center, Suitland, MD. These
proposed changes would supersede all information regarding Type I DMF's
detailed in the ``Guideline for Drug Master Files.''
The agency acknowledges that some firms may have submitted
information under a Type I DMF that should have been filed under Types
II through V DMF's. Therefore, FDA is proposing to make available a
list of all CDER Type I DMF's for public review in the Dockets
Management Branch under the docket number found in brackets in the
heading of this document. If a DMF holder believes that its Type I DMF
should be categorized as another type of DMF, the DMF holder should
submit a request to the Drug Master File Staff, Food and Drug
Administration, rm. 2-14, 12420 Parklawn Dr., Rockville, MD 20857,
within 30 days of publication of any final rule based on this proposal.
This request should: (1) Be submitted by the responsible official or
designated U.S. agent; (2) briefly identify the subject of the DMF; and
(3) propose the DMF Type (i.e., Type II, III, IV, or V) to which
information in the Type I DMF should be transferred. If the information
should be incorporated into an existing Type II through Type V DMF, the
file number of that DMF should be provided. FDA would consider
transferring an entire Type I DMF to another type only if the Type I
DMF contains substantive information other than information concerning
manufacturing site, facilities, operating procedures, and personnel.
The agency also recognizes that some Type I DMF's currently on file
contain information concerning sterilization process validation and
other information relevant to the review, evaluation, and assurance of
the sterility of sterile products. For sterile items that are not the
subject of an IND, NDA, ANDA, or AADA, and that are sold to a second
party (e.g., rubber closures that are sterilized by the manufacturer
and sold to a second party), CDER would consider transferring product-
specific and general information concerning sterilization process
validation to the DMF file or DMF type (i.e., II through IV) under
which manufacturing information for the specific item is filed.
Contract manufacturers of sterile finished drug products, contract
sterilization firms (e.g., ethylene oxide, gamma radiation, and
electron beam radiation), and manufacturers of sterile finished drug
products that are the subject of a drug product application could
request a transfer from Type I to Type V DMF of nonproduct-specific
information and procedures that are submitted to support a claim of
sterility. Where applicable, the content and format of such transferred
information should follow FDA's guideline entitled ``Guideline for
Submitting Documentation for Sterilization Process Validation in
Applications for Human and Veterinary Drug Products.'' The mechanism
for requesting a transfer would be the same as the mechanism for
recategorizing Type I DMF's, as described in the preceding paragraph.
II. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
III. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this proposed rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the proposed
rule is not a significant regulatory action as defined by the Executive
Order and so is not subject to review under the Executive Order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the proposed regulation, if finalized, would
lighten paperwork and recordkeeping burdens, the agency certifies that
the proposed rule will not have a significant economic impact on a
substantial number of small entities. Therefore, under the Regulatory
Flexibility Act, no further analysis is required.
IV. Effective Date
FDA proposes that any final rule based on this proposal become
effective 60 days after its date of publication in the Federal
Register.
V. Request for Comments
Interested persons may, on or before October 2, 1995, submit to the
Dockets Management Branch (address above) written comments regarding
this proposal. Two copies of any comments are to be submitted, except
that individuals may submit one copy. Comments are to be identified
with the docket number found in brackets in the heading of this
document. Received comments may be seen in the office above between 9
a.m. and 4 p.m., Monday through Friday.
[[Page 34488]]
List of Subjects in 21 CFR Part 314
Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR part 314 be amended as follows:
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN
ANTIBIOTIC DRUG
1. The authority citation for 21 CFR part 314 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701,
704, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321,
331, 351, 352, 353, 355, 356, 357, 371, 374, 379e).
2. Section 314.420 is amended by removing and reserving paragraph
(a)(1), and by revising the second sentence of paragraph (a)(5) to read
as follows:
Sec. 314.420 Drug master files.
(a) * * *
(1) [Reserved]
* * * * *
(5) * * * (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, 12420 Parklawn Dr.,
rm. 2-14, Rockville, MD 20857. * * *)
* * * * *
Dated: June 26, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-16206 Filed 6-30-95; 8:45 am]
BILLING CODE 4160-01-F
