Removal of Regulations Regarding Certification of Antibiotic Drugs

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 430, 431, 432, 433, 436, 440, 441, 442, 443, 444, 446,

448, 449, 450, 452, 453, 455, and 460

[Docket No. 98N-0211]

Removal of Regulations Regarding Certification of Antibiotic

Drugs

AGENCY: Food and Drug Administration, HHS.

ACTION: Direct final rule.

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SUMMARY: The Food and Drug Administration (FDA) is repealing its

regulations governing certification of antibiotic drugs. The agency is

taking this action in accordance with provisions of the Food and Drug

Administration Modernization Act of 1997 (FDAMA). FDAMA repealed the

statutory provision in the Federal Food, Drug, and Cosmetic Act (the

act) under which the agency certified antibiotic drugs. FDAMA also made

conforming amendments to the act.

DATES: The direct final rule is effective September 24, 1998. Submit

written comments on or before July 27, 1998. If no timely significant

adverse comments are received, the agency will publish a document in

the Federal Register before August 25, 1998, confirming the effective

date of the direct final rule. If timely significant adverse comments

are received, the agency will publish a document of significant adverse

comment in the Federal Register withdrawing this direct final rule

before August 25, 1998.

ADDRESSES: Submit written comments to the Dockets Management Branch

(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,

Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Wayne H. Mitchell or Christine F.

Rogers, Center for Drug Evaluation and Research (HFD-7), Food and Drug

Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. FDAMA

On November 21, 1997, the President signed FDAMA (Pub. L. 105-115).

Section 125(b) of FDAMA repealed section 507 of the act (21 U.S.C.

357). Section 507 of the act was the section under which the agency

certified antibiotic drugs. Section 125(b) of FDAMA also made

conforming amendments to the act.

FDA has determined that it will be most efficient to make changes

in its regulations to reflect the repeal of section 507 of the act in

phases. In this first phase, this direct final rule removes parts 430

through 460 (21 CFR parts 430 through 460). These regulations provide

the procedures and standards used to certify antibiotic drugs,

including FDA's antibiotic drug monographs. FDA plans to initiate a

second phase direct final rulemaking procedure to make various,

noncontroversial conforming amendments to the balance of Title 21 of

the Code of Federal Regulations (CFR), such as removing citations to

section 507 of the act and references to the certification of

antibiotics. The agency recognizes that as it implements the transition

from regulating the premarket review and approval of antibiotic drugs

under section 507 of the act to section 505 of the act (21 U.S.C. 355),

other issues may arise that could require additional rulemaking. These

issues will be addressed in the third phase of implementation.

II. Direct Final Rulemaking

FDA has determined that the subject of this rulemaking is suitable

for a direct final rule. The repeal of section 507 of the act

eliminates the statutory provision on which the agency relied to

certify antibiotic drugs. FDA will, therefore, remove all provisions of

Title 21 of the CFR that were issued primarily to carry out the

agency's program for the certification of antibiotic drugs under former

section 507 of the act. The actions taken should be noncontroversial

and the agency does not anticipate receiving any significant adverse

comments on this rule.

If FDA does not receive significant adverse comment on or before

July 27, 1998, the agency will publish a document in the Federal

Register before August 25, 1998, confirming the effective date of the

direct final rule. A significant adverse comment is one that explains

why the rule would be inappropriate, including challenges to the rule's

underlying premise or approach, or would be ineffective or unacceptable

without a change. A comment recommending a rule change in addition to

this rule will not be considered a significant adverse comment, unless

the comment states why this rule would be ineffective without the

additional change. If timely significant adverse comments are received,

the agency will publish a notice of significant adverse comment in the

Federal Register withdrawing this direct final rule before August 25,

1998.

Elsewhere in this issue of the Federal Register, FDA is publishing

a companion proposed rule, which is identical to the direct final rule,

that provides a procedural framework within which the rule may be

finalized in the event the direct final rule is withdrawn because of

significant adverse comment. The comment period for the direct final

rule runs concurrently with that of the companion proposed rule. Any

comments received under the companion proposed rule will be treated as

comments regarding the direct final rule. Likewise, significant adverse

comments submitted to the direct final rule will be considered as

comments to the companion proposed rule and the agency will consider

such comments in developing a final rule. FDA will not

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provide additional opportunity for comment on the companion proposed

rule.

If a significant adverse comment applies to part of this rule and

that part may be severed from the remainder of the rule, FDA may adopt

as final those parts of the rule that are not the subject of a

significant adverse comment. A full description of FDA's policy on

direct final rule procedures may be found in a guidance document

published in the Federal Register of November 21, 1997 (62 FR 62466).

III. Description of the Rule

This rule eliminates Part 430--Antibiotic Drugs; General, in its

entirety. Part 430 provided definitions used in the certification of

antibiotic drugs and contains Sec. 430.10, which carried out former

section 507(h) of the act and was intended to address the certification

or release of antibiotic drugs affected by the Drug Amendments of 1962

(Pub. L. 87-781).

This rule also eliminates Part 431--Certification of Antibiotic

Drugs, which provided various administrative and procedural

requirements for the antibiotic certification program, established

conditions on the effectiveness of a certification issued by the

agency, and set the fees needed to maintain the agency's antibiotic

certification program (see former section 507(b) of the act). Subpart D

of Part 431--Confidentiality of Information, is also being eliminated

because it is duplicative of the provisions in 21 CFR 312.130 governing

the disclosure of information in or about an investigational new drug

application.

Part 433--Exemptions from Antibiotic Certification and Labeling

Requirements is removed by this rule. Part 433 set the conditions for

exempting antibiotic drugs from the general requirement of

certification as well as from other, more specific, regulatory

requirements (see former section 507(c) and (d) of the act).

This rule eliminates Part 436--Tests and Methods of Assay of

Antibiotic and Antibiotic-Containing Drugs. Part 436 contained

sterility test methods, biological test methods, microbiological assay

methods, and chemical tests for antibiotic drugs generally and for

specific antibiotic drugs and antibiotic drug dosage forms. These tests

and methods of assay established the means by which the agency would

certify that a given batch of antibiotic drug was in compliance with

applicable standards of identity, strength, quality, and purity (see

former section 507(a) and (b) of the act).

This rule also repeals the following parts: Part 440--Penicillin

Antibiotic Drugs; Part 441--Penem Antibiotic Drugs; Part 442--Cepha

Antibiotic Drugs; Part 443--Carbacephem Antibiotic Drugs; Part 444--

Oligosaccharide Antibiotic Drugs; Part 446--Tetracycline Antibiotic

Drugs; Part 448--Peptide Antibiotic Drugs; Part 449--Antifungal

Antibiotic Drugs; Part 450--Antitumor Antibiotic Drugs; Part 452--

Macrolide Antibiotic Drugs; Part 453--Lincomycin Antibiotic Drugs; Part

455--Certain Other Antibiotic Drugs; and Part 460--Antibiotic Drugs

Intended for Use in Laboratory Diagnosis of Disease. These parts

contain the standards of identity, strength, quality, and purity that

served as the agency's basis for batch certifying or otherwise

authorizing the marketing of drugs that were subject to former section

507 of the act, including the classes of penicillin; penem; cepha;

carbacephem; oligosaccharide; tetracycline; peptide; antifungal;

antitumor; macrolide; and lincomycin antibiotic drugs; several

antibiotic drugs not included in the parts listed above; and antibiotic

susceptibility discs, powders, and test panels, respectively (see

former section 507(a) and (b) of the act).

With the repeal of part 436 and parts 440 et seq., the test methods

and assays contained in the approved marketing application and, when

applicable, the United States Pharmacopeia (USP) will be used to

determine if antibiotic drugs meet the standards of identity, strength,

quality, and purity found in the approved marketing application for the

drug and, when applicable, the USP.

Finally, the agency is eliminating Part 432--Packaging and Labeling

of Antibiotic Drugs, which sets forth special packaging requirements

and additional labeling requirements (in addition to the requirements

prescribed by 21 CFR 201.100) for drugs that were subject to batch

certification or release under former section 507 of the act. With the

repeal of section 507 of the act, there is no need to maintain separate

or additional labeling and packaging requirements for antibiotic drug

products. As with other drug products, labeling of antibiotic drugs

will be governed by the agency's general labeling provisions found in

21 CFR part 201 and by applicable over-the-counter drug monographs and

approved marketing applications.

Part 432 also included Sec. 432.9, which conditionally authorized

the batch certification of antibiotic drugs intended for export, even

if the drug failed to meet certain labeling requirements, and provided

additional guidance on the labeling of antibiotic drugs for export. In

light of the repeal of the batch certification requirement, Sec. 432.9

may also be eliminated without affecting the export of antibiotic drug

products.

It should be noted, however, that differences remain between the

application of the export provisions in sections 801 and 802 of the act

(21 U.S.C. 381 and 382) to antibiotic drugs and the application of

those provisions to other new drugs. Prior to the repeal of section 507

of the act, these differences were based on the fact that antibiotic

drugs were not subject to premarket approval under section 505 and,

therefore, could be exported under section 801(e)(1) of the act.

Antibiotic drugs did not have to meet the export requirements in

section 802 that apply to unapproved new drugs. Thus, manufacturers

could export antibiotic drugs that had not been certified, released, or

exempted from certification, subject only to the provisions of section

801(e)(1) of the act. Section 125(c) of FDAMA preserved the export

status of antibiotic drugs (which are now subject to approval under

section 505 of the act) by expressly exempting them from section 802.

(Section 125(c) of FDAMA included the same exemption for insulin

products.) In the second phase of the implementation of section 125 of

FDAMA, the agency will consider making appropriate amendments to its

regulations to reflect this difference between the application of the

export provisions of the act to antibiotic drugs (and insulin products)

as opposed to all other new drugs.

The removal of parts 430 et seq. is not expected to result in any

immediate, significant changes in the manufacturing, packaging,

labeling, or marketing of antibiotic drug products. Since 1982, the

agency has conditionally exempted all antibiotic drugs from batch

certification (47 FR 39155, September 7, 1982). With limited

exceptions, such as in the areas of export and generic drug approvals,

the agency has imposed much the same regulatory requirements on

exempted antibiotic drug products as it has on all other drug products.

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. Analysis of Impacts

FDA has examined the impacts of the direct final rule under

Executive Order 12866, the Regulatory Flexibility Act (5

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U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.

104-4). 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). Executive

Order 12866 classifies a rule as significant if it meets any one of a

number of specified conditions, including having an annual effect on

the economy of $100 million or adversely affecting in a material way a

sector of the economy, competition, or jobs, or if it raises novel

legal or policy issues. As discussed below, the agency believes that

this final rule is consistent with the regulatory philosophy and

principles identified in the Executive Order. In addition, the direct

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 that if a rule has a

significant impact on a substantial number of small entities, the

agency must analyze regulatory options to minimize the economic impact

on small entities. The agency certifies, for the reasons discussed

below, that the direct final rule will not have a significant impact on

a substantial number of small entities. Therefore, under the Regulatory

Flexibility Act, no further analysis is required.

The Unfunded Mandates Reform Act requires an agency to prepare a

budgetary impact statement before issuing any rule likely to result in

a Federal mandate that may result in expenditures by State, local, and

tribal governments or the private sector of $100 million (adjusted

annually for inflation) in any 1 year. The elimination of the

regulations governing the certification of antibiotic drugs will not

result in any increased expenditures by State, local, and tribal

governments or the private sector. Because this rule will not result in

an expenditure of $100 million or more on any governmental entity or

the private sector, no budgetary impact statement is required.

This rule is intended to eliminate regulatory procedures and

standards that the agency, as a result of the repeal of section 507 of

the act, is no longer required to maintain. The elimination of the

above listed parts is expected to streamline the regulation of

antibiotic drugs by making these products subject to the same

regulatory standards as all other drugs for human use. Many of the

provisions that are being eliminated by this rulemaking have not had a

material impact on the marketing of antibiotic drugs since 1982, when

all antibiotic drugs were conditionally exempted from the batch

certification requirement. Other provisions, such as the standards of

identity, strength, quality, and purity, have in some instances not

been kept up-to-date, are duplicative of USP standards, or have been

incorporated into approved marketing applications for specific

antibiotic drug products. For these reasons, the agency believes that

this rule is necessary and that it is consistent with the principles of

Executive Order 12866; that it is not a significant regulatory action

under that Order; that it will not have a significant impact on a

substantial number of small entities; and that it is not likely to

result in an annual expenditure in excess of $100 million.

VI. Paperwork Reduction Act of 1995

This direct final rule contains no collection of information.

Therefore, clearance by the Office of Management and Budget under the

Paperwork Reduction Act of 1995 (Pub. L. 104-13) is not required.

VII. Request for Comments

Interested persons may, on or before July 27, 1998, submit to the

Dockets Management Branch (address above) written comments regarding

this rule. 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.

List of Subjects

21 CFR Part 430

Administrative practice and procedure, Antibiotics.

21 CFR Part 431

Administrative practice and procedure, Antibiotics, Confidential

business information, Reporting and recordkeeping requirements.

21 CFR Part 432

Antibiotics, Labeling, Packaging and containers.

21 CFR Part 433

Antibiotics, Labeling, Reporting and recordkeeping requirements.

21 CFR Parts 436, 440, 441, 442, 443, 444, 446, 448, 449, 450, 452,

453, 455, and 460

Antibiotics.

Therefore, under the Federal Food, Drug, and Cosmetic Act, the Food

and Drug Administration Modernization Act, and under authority

delegated to the Commissioner of Food and Drugs, 21 CFR chapter I is

amended as follows:

PART 430--ANTIBIOTIC DRUGS; GENERAL

1. Part 430 is removed.

PART 431--CERTIFICATION OF ANTIBIOTIC DRUGS

2. Part 431 is removed.

PART 432--PACKAGING AND LABELING OF ANTIBIOTIC DRUGS

3. Part 432 is removed.

PART 433--EXEMPTIONS FROM ANTIBIOTIC CERTIFICATION AND LABELING

REQUIREMENTS

4. Part 433 is removed.

PART 436--TESTS AND METHODS OF ASSAY OF ANTIBIOTIC AND ANTIBIOTIC-

CONTAINING DRUGS

5. Part 436 is removed.

PART 440--PENICILLIN ANTIBIOTIC DRUGS

6. Part 440 is removed.

PART 441--PENEM ANTIBIOTIC DRUGS

7. Part 441 is removed.

PART 442--CEPHA ANTIBIOTIC DRUGS

8. Part 442 is removed.

PART 443--CARBACEPHEM ANTIBIOTIC DRUGS

9. Part 443 is removed.

PART 444--OLIGOSACCHARIDE ANTIBIOTIC DRUGS

10. Part 444 is removed.

PART 446--TETRACYCLINE ANTIBIOTIC DRUGS

11. Part 446 is removed.

PART 448--PEPTIDE ANTIBIOTIC DRUGS

12. Part 448 is removed.

PART 449--ANTIFUNGAL ANTIBIOTIC DRUGS

13. Part 449 is removed.

PART 450--ANTITUMOR ANTIBIOTIC DRUGS

14. Part 450 is removed.

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PART 452--MACROLIDE ANTIBIOTIC DRUGS

15. Part 452 is removed.

PART 453--LINCOMYCIN ANTIBIOTIC DRUGS

16. Part 453 is removed.

PART 455--CERTAIN OTHER ANTIBIOTIC DRUGS

17. Part 455 is removed.

PART 460--ANTIBIOTIC DRUGS INTENDED FOR USE IN LABORATORY DIAGNOSIS

OF DISEASE

18. Part 460 is removed.

Dated: May 1, 1998.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 98-12543 Filed 5-11-98; 8:45 am]

BILLING CODE 4160-01-F