New Drug Applications; Drug Master Files

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.

-----------------------------------------------------------------------

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.

---------------------------------------------------------------------------

\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].

---------------------------------------------------------------------------

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

[[Page 1780]]

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