[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