[Federal Register Volume 65, Number 8 (Wednesday, January 12, 2000)]
[Rules and Regulations]
[Pages 1776-1780]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-648]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 314
[Docket No. 94N-0449]
RIN 0910-AA78
New Drug Applications; Drug Master Files
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is revising its
regulation governing drug master files (DMF's). FDA is removing the
provision for submitting Type I DMF's and will no longer permit
information submitted in a Type I DMF to be incorporated by reference
in investigational new drug applications (IND's), new drug applications
(NDA's), abbreviated new drug applications (ANDA's), or amendments or
supplements to any of
[[Page 1777]]
these. This 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.
EFFECTIVE DATE: July 10, 2000.
FOR FURTHER INFORMATION CONTACT:
Lee D. Korb, Center for Drug Evaluation and Research (HFD-7), Food
and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-
594-2041, or
Arthur B. Shaw, Center for Drug Evaluation and Research (HFD-180),
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857,
301-827-7310, or
Robert A. Yetter, Center for Biologics Evaluation and Research
(HFM-10), Food and Drug Administration, 1401 Rockville Pike, Rockville,
MD 20852-1448, 301-827-0373.
SUPPLEMENTARY INFORMATION:
I. Background
A DMF is a voluntary submission to FDA that may be used to provide
confidential, detailed information about the facilities, processes, or
articles used in the manufacturing, processing, packaging, and storing
of one or more human drug products. The regulations in 21 CFR
314.420(a) describe 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
materials. Type IV submissions include information concerning
excipients, colorants, flavors, essences, or materials used in their
preparation. Type V submissions, detailed in the guidance for industry
entitled ``Drug Master Files'' (September 1, 1989), include FDA-
accepted reference information. DMF's allow regulated industry to
submit to FDA information that may be used to support an IND, NDA,
ANDA, another DMF, an export application, or amendments or supplements
to any of these. DMF information may be incorporated by reference into
a drug application or supplement without public disclosure.
FDA intended to use information submitted in a Type I DMF to plan
its on-site inspections of and travel to foreign drug manufacturing
facilities. In December 1992, the Chemistry, Manufacturing, and
Controls Coordinating Committee (CMCCC) of the Center for Drug
Evaluation and Research (CDER) established a DMF task force to review
DMF procedures and consider ways of improving the DMF system. One of
the task force recommendations was that Type I DMF's be eliminated. The
recommendation was based on a number of factors:
1. The information contained in Type I DMF's was often outdated.
2. The Type I DMF was not always easily accessible to FDA
investigators.
3. The review divisions in CDER do not review the information in
most Type I DMF's. Although information from Type I DMF's has often
been incorporated by reference into IND's, NDA's, and abbreviated
applications, the information is not required for review of the
chemistry, manufacturing, and controls section of an application. Under
21 CFR 314.50(d)(1)(i) and (d)(1)(ii), a drug product applicant is
required to furnish in the application the name and location of
facilities used in the manufacture of the drug substance or drug
product.
4. Information concerning the facility is maintained onsite where
it is available for the investigator.
The CMCCC adopted the recommendation of the DMF Task Force and,
subsequently, FDA proposed eliminating Type I DMF's in the Federal
Register of July 3, 1995 (60 FR 34486). FDA also proposed to implement
a procedure by which DMF holders could request that certain information
currently contained in Type I DMF's be transferred to Types II through
V.
FDA is finalizing its proposal to eliminate Type I DMF's. In so
doing, the agency will no longer accept Type I DMF's or correspondence
updating existing Type I DMF's and will no longer permit information
previously submitted in a Type I DMF to be incorporated by reference in
IND's, NDA's, ANDA's, and supplemental applications for drugs approved
under section 505 of the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 355).
The Center for Biologics Evaluation and Research (CBER) has used
Type I Master Files in a manner different from that used by CDER.
Certain biological products, such as gene therapy products, require
review of some facility information to assess their safety for use in
clinical trials under IND. CBER will accept facility information for
such products in Type V Master Files. CBER intends to issue a guidance
on the information that may be submitted in a Type V Master File
without previously obtaining permission.
II. Comments on the Proposed Rule
The agency received seven comments on the proposed rule and
several of these raised multiple issues. A number of comments expressed
general support for the proposal. A summary of the comments and the
agency's responses follows.
1. One firm stated that it will be manufacturing drug products for
other U.S. and non-U.S. companies and needs a means to submit
confidential, technical information to FDA (e.g., information regarding
the firm's new manufacturing facility, including, but not limited to,
air handling systems, milling, blending, and filling technology). The
firm emphasized that if Type I DMF's are eliminated, confidential
information regarding the facilities, processes, or articles used in
the manufacturing, processing, packaging, and storing of drugs for
human use would not be available for referencing by sponsors of IND's
or NDA's with which the firm will contract. In addition, FDA's review
divisions will not be able to rely on the applications themselves for
information typically included in a Type I DMF. The firm noted that
without a Type I DMF, a Type II DMF (intermediates, drug substances,
and drug products) might be the only alternative for supplying the
agency with certain information and that it would be forced to file a
Type II DMF for each company for which it does drug product
manufacturing. The firm also stated that the submission of multiple
Type II DMF's instead of a single Type I would place an unnecessary
paper burden on the agency. The firm further noted that if the agency
relies on preapproval inspections, it faces the possibility of multiple
inspections in any given year, placing unnecessary burdens on valuable
FDA resources (i.e., multiple inspections of the same facility).
One comment noted that it is irrelevant that field investigators do
not use Type I DMF's and that, since Type I submissions are voluntary,
the agency should continue to allow firms the convenience of
referencing Type I submissions. Another comment suggested that instead
of FDA eliminating Type I DMF's, industry should be required to keep
the information current. The comment stated that the privilege of
incorporating Type I DMF information by reference should be denied on a
case-by-case basis to those firms that do not keep information current.
The agency believes that several of these comments are based on a
misunderstanding of the agency's
[[Page 1778]]
reliance on information contained in Type I DMF's during the drug
application review process. Information contained in Type I DMF's is
not reviewed by CDER reviewers, and it plays no role in processing a
drug product application.
The Type I DMF was intended to assist FDA in conducting onsite
inspections of foreign manufacturing facilities. As noted above, the
agency determined that the Type I DMF was not always easily accessible
to investigators and that information in the document was often out-of-
date. The drug product application is required to provide information
on the location of manufacturing facilities and it is this current,
product-specific information that is used by CDER review divisions.
Continuing to maintain Type I DMF's when the information is not used by
the agency provides no benefit to either regulated industry or the
agency.
If a firm is performing different processing steps for a customer,
a Type I DMF would not provide the information necessary for adequate
review. Moreover, the elimination of Type I DMF's does not mean that a
firm would be required to file a Type II DMF for each company for which
it manufactures drug products. Reviewers examine the details of the
manufacturing process as they apply to each individual product and
procedures used in the manufacture of more than one drug product may be
included in the same Type II DMF.
Concerns about a possible strain on FDA resources because of
multiple inspections are not relevant to the Type I DMF issue since
inspections are conducted in accordance with current agency inspection
policy, which applies whether or not a firm has a Type I DMF. The
current agency policy on inspections is described in the agency's
Investigations Operations Manual. Prior to the approval of a drug
product, the facility that will manufacture the product will generally
be inspected by FDA unless there has been a recent inspection for other
reasons.
2. One comment stated that the production of ``Generic Compounds''
(which could conceivably be manufactured in smaller, stand-alone
facilities possibly located in remote areas) is generally not
adequately described in drug product applications and other written
material submitted to FDA. The comment stated that such inadequate
descriptions could increase the risk of problems resulting from
admixing imported products that may not have been manufactured in a
facility for which a DMF has been filed. The comment noted that a full
description of a facility enhances FDA's ability to identify facilities
that do not meet FDA criteria.
CDER believes that a current, accurate facility description at the
manufacturing site and an inspection of the facility are the best
sources of information for assessing a facility's ability to meet FDA
standards. Current, accurate information is particularly important when
a facility is remote.
3. One comment noted that agency investigators of foreign
manufacturers had stated that the Type I DMF was of immense value
because of the information provided. The comment noted that ``having
more information was preferable to having none,'' and that the Type I
format was superior in providing that information.
The agency agrees that accurate manufacturing information is
important in evaluating drug product applications and preparing for
inspections. FDA does not agree, for reasons explained above and in the
proposed rule, that the Type I DMF is the most effective method of
providing this information.
4. One comment stated that the proposed rule should be
reconsidered because it is not globally oriented. The comment stated
that, at the present time, several foreign governments link approval
and acceptance of U.S. products to the data listed in Type I DMF's.
It is not clear from the comment how foreign governments link
approval and acceptance of U.S. products to the data listed in Type I
DMF's since these data are not reviewed in the approval process for
U.S. products. Foreign governments that have previously relied on the
information in a Type I DMF can request that the firm provide a
description of the manufacturing facility to them.
5. One comment asserted that switching information from one type
of DMF to another would not result in a reduction in paperwork, because
there would be no basic change in the system. The comment suggested
that a proposal to prompt industry to withdraw inactive Type I Master
Files might be more appropriate. The comment observed that there would
be a reduction in paperwork if the amount of information incorporated
in a Type I DMF were limited to that specified in the proposed rule as
appropriate for transfer to a Type V DMF. Another comment observed that
the elimination of Type I DMF's will increase the paperwork burden for
industry if information about facilities, processes, or articles used
in the manufacturing, processing, packaging, and storing of human drugs
can no longer be reported in a Type I DMF and incorporated by
reference.
Because FDA investigators and CDER review divisions do not rely on
information in a Type I DMF document for inspection or approval
purposes, the agency finds that the mere withdrawal of inactive Type I
DMF's would not address the agency's concern that the Type I DMF is an
inadequate vehicle for information. To address this concern, the agency
is eliminating the production and maintenance of all Type I DMF
documents. Therefore, based on FDA's experience, the agency concludes
that it is reasonable to anticipate a reduction in the paperwork burden
by eliminating the requirement that industry produce and maintain the
Type I DMF document.
6. One comment asserted that the proposal would require a rewrite
of the current guidance to provide industry with information regarding
the format and content of the Type V DMF's. The agency notes that the
guidance for industry on DMF's is currently undergoing revision and any
changes regarding Type V DMF's will require no significant additional
resources. The agency advises that the only Type I DMF's that may be
converted to Type V's are those covering sterile processing facilities
and other special cases. As detailed in the discussion on
implementation below, these will be examined on a case-by-case basis to
decide if transferring them is justified. The agency does not
anticipate that substantial agency resources will be required to
evaluate requests for the transfer of information currently included in
Type I DMF's to Types II, III, IV, or V DMF's.
III. Implementation of the Rule
7. One comment suggested that the proposed implementation date of
60 days after publication should be reconsidered because this timeframe
does not permit adequate time to revise operating procedures. One
comment suggested that the proposed rule should be implemented in
conjunction with an educational effort, including a workshop on DMF's
and publicity to prepare those affected by the new requirements. One
comment asserted that the transfer of information from a Type I DMF to
another type would require a review of written requests by the DMF
staff and that this could result in a significant economic impact on
the agency. One comment asserted that the proposed rule did not address
those current applications which reference Type I DMF's.
Based on comments and FDA's own evaluation, the agency has
concluded
[[Page 1779]]
that the proposed implementation period is inadequate, particularly for
foreign firms seeking approval where Type I DMF's were referenced. Some
firms will need time to develop alternative procedures. The agency has
determined that the effective date will be 180 days after the date of
publication of the final rule in the Federal Register.
After the effective date of the rule, the agency will no longer
accept new Type I DMF's or correspondence updating existing Type I
DMF's. Type I DMF's will be transferred to the Federal Records Center
and the information in Type I DMF's currently on file may no longer be
incorporated by reference into new applications, amendments, or
supplements. These changes will supersede all information regarding
Type I DMF's detailed in the current guidance for industry on DMF's.
To accommodate firms that have submitted information under a Type I
DMF that should have been filed under DMF Types II through V, a list of
all CDER Type I DMF's is available for public review in the Dockets
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852, under the docket number found in
brackets in the heading of this document. The list is also available on
the CDER Internet site at http://www.fda.gov/cder/dmf/index.htm. If a
DMF holder believes that its Type I DMF should be recategorized or
transferred to another type of DMF, the DMF holder may contact the Drug
Master File Staff within 180 days of publication of this rule in the
Federal Register \1\. FDA will consider recategorizing 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.
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\1\ Food and Drug Administration, 12229 Wilkins Ave., Rockville,
MD 20852. The Drug Master File Staff may also be reached at 301-827-
4210 or at DMFT[email protected].
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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, or ANDA 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 will
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. For instance, DMF's concerned with
sterilization procedures for rubber stoppers would be reclassified as
Type III DMF's (packaging materials). Contract manufacturers of sterile
drug substances and sterile finished drug products including
biotechnology products filed as DMF's, 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 may 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
guidance for industry entitled ``Submission of Documentation for
Sterilization Process Validation Applications for Human and Veterinary
Drug Products'' (November 1, 1994).
CBER intends to administratively recategorize current Type I
Master Files that are still needed to other Master File Types as
appropriate. CBER will make a list of those Type I Master Files that
have not been recategorized available for public review in the Dockets
Management Branch (address above), under the docket number found in
brackets in the heading of this document, no later than 30 days after
date of publication of this document in the Federal Register. The list
will also be available on the CBER Internet site at www.fda.gov/CBER.
If a holder of a Type I Master File believes that the Master File
should be recategorized, the holder may contact the Division of
Manufacturing and Product Quality (DMPQ) (HFM-207), Office of
Compliance and Biologics Quality, CBER, 1401 Rockville Pike, Rockville,
MD 20852-1448. DMPQ may also be reached at 301-827-3031.
The agency advises that applicants who have current approved
applications that reference Type I DMF's transferred to Type V DMF's
may notify the agency of this change in an annual report as provided in
21 CFR 314.70.
FDA has examined the possible impact of these changes and believes
that a review of requests to transfer DMF's can be handled without
placing a significant burden on the agency.
The agency agrees with the suggestion that the final rule should
be implemented in conjunction with an educational effort and will work
with the press and industry trade associations to publicize the
obligations and options provided by the regulation. Based on industry
response and requests for further information, FDA will determine
whether to provide further educational opportunities such as workshops.
IV. Environmental Impact
The agency has determined under 21 CFR 25.30(h) 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.
V. Paperwork Reduction Act of 1995
This final rule contains no collections of information. Therefore,
clearance by the Office of Management and Budget under the Paperwork
Reduction Act of 1995 is not required.
VI. Analysis of Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).
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 final rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the final
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 final rule will lessen paperwork and
recordkeeping burdens and impose no significant new burdens, the agency
certifies that the regulation 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.
The Unfunded Mandates Reform Act (Public Law 104-4) requires that
agencies prepare a written statement including an assessment of
anticipated costs and benefits before proposing any rule that may
result in an annual expenditure by State, local, and tribal
governments, in the aggregate, or by the private sector, of $100
million or more. This final rule does not impose any mandates on State,
local, or tribal
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governments, or the private sector that will result in an annual
expenditure of $100 million or more.
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
does not contain policies that have federalism implications as defined
in the order and, consequently, a Federalism summary impact statement
is not required.
VII. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
does not contain policies that have federalism implications as defined
in the order and, consequently, a federalism summary impact statement
is not required.
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, 21 CFR part
314 is amended as follows:
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG
1. The authority citation for 21 CFR part 314 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 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, 12229 Wilkins Ave.,
Rockville, MD 20852). * * *
* * * * *
Dated: September 1, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 00-648 Filed 1-11-00; 8:45 am]
BILLING CODE 4160-01-F