[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outdated information, duplicate information contained in marketing 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