34726 Federal Register / Vol. 61, No. 129 / Wednesday, July 3, 1996 / Rules and Regulations

the words ‘‘Publications Services

Division, Civil Aeronautics Board,

Washington, DC 20428,’’ and add in

their place the words ‘‘Foreign Air

Carrier Licensing Division (X–45),

Office of International Aviation,

Department of Transportation, 400

Seventh Street, SW., Washington, DC

20590.

Issued in Washington, DC, on May 31,

1996.

Charles A. Hunnicutt,

Assistant Secretary for Aviation and

International Affairs.

[FR Doc. 96–16808 Filed 7–2–96; 8:45 am]

BILLING CODE 4910–62–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 452

[Docket No. 96N–0117]

Antibiotic Drugs; Clarithromycin

Granules for Oral Suspension

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is amending the

antibiotic drug regulations to include

accepted standards for clarithromycin

for its use in a new dosage form of

clarithromycin, clarithromycin granules

for oral suspension. The manufacturer

has supplied sufficient data and

information to establish its safety and

efficacy.

DATES: Effective August 2, 1996;

comments, notice of participation, and a

request for hearing by August 2, 1996;

data, information, and analyses to

justify a hearing by September 3, 1996.

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:

James M. Timper, Center for Drug

Evaluation and Research (HFD–520),

Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857,

301–827–2193.

SUPPLEMENTARY INFORMATION: FDA has

evaluated data submitted in accordance

with regulations issued under section

507 of the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 357), as

amended, with respect to a request for

approval of a new dosage form of

clarithromycin, clarithromycin granules

for oral suspension. The agency has

concluded that the data supplied by the

manufacturer concerning this antibiotic

dosage form are adequate to establish

the safety and efficacy when used as

directed in the labeling and that the

regulations should be amended in part

452 (21 CFR part 452) to include

accepted standards for this product.

Environmental Impact

The agency has determined under 21

CFR 25.24(c)(6) 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.

Submitting Comments and Filing

Objections

This final rule announces standards

that FDA has accepted in a request for

approval of an antibiotic drug. Because

this final rule is not controversial and

because, when effective, it provides

notice of accepted standards, FDA finds

that notice and comment procedure is

unnecessary and not in the public

interest. This final rule, therefore, is

effective August 2, 1996. However,

interested persons may, on or before

August 2, 1996, submit comments to the

Dockets Management Branch (address

above). 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 Dockets Management Branch

between 9 a.m. and 4 p.m., Monday

through Friday.

Any person who will be adversely

affected by this final rule may file

objections to it and request a hearing.

Reasonable grounds for the hearing

must be shown. Any person who

decides to seek a hearing must file (1)

on or before August 2, 1996, a written

notice of participation and request for a

hearing, and (2) on or before September

3, 1996, the data, information, and

analyses on which the person relies to

justify a hearing, as specified in 21 CFR

314.300. A request for a hearing may not

rest upon mere allegations or denials,

but must set forth specific facts showing

that there is a genuine and substantial

issue of fact that requires a hearing. If

it conclusively appears from the face of

the data, information, and factual

analyses in the request for a hearing that

no genuine and substantial issue of fact

precludes the action taken by this order,

or if a request for hearing is not made

in the required format or with the

required analyses, the Commissioner of

Food and Drugs will enter summary

judgment against the person(s) who

request(s) the hearing, making findings

and conclusions and denying a hearing.

All submissions must be filed in three

copies, identified with the docket

number appearing in the heading of this

order and filed with the Dockets

Management Branch.

The procedures and requirements

governing this order, a notice of

participation and request for a hearing,

a submission of data, information, and

analyses to justify a hearing, other

comments, and grant or denial of a

hearing are contained in 21 CFR

314.300.

All submissions under this order,

except for data and information

prohibited from public disclosure under

21 U.S.C. 331(j) or 18 U.S.C. 1905, may

be seen in the Dockets Management

Branch (address above) between 9 a.m.

and 4 p.m., Monday through Friday.

List of Subjects in 21 CFR Part 452

Antibiotics.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to the Commissioner

of Food and Drugs, 21 CFR part 452 is

amended as follows:

PART 452—MACROLIDE ANTIBIOTIC

DRUGS

1. The authority citation for 21 CFR

part 452 continues to read as follows:

Authority: Sec. 507 of the Federal Food,

Drug, and Cosmetic Act (21 U.S.C. 357).

§ 452.150a [Redesignated from § 452.150]

2. Section 452.150 is redesignated as

§ 452.150a and new §§ 452.150 and

452.150b are added to subpart B to read

as follows:

§ 452.150 Clarithromycin oral dosage

forms.

§ 452.150b Clarithromycin granules for

oral suspension.

(a) Requirements for certification—(1)

Standards of identity, strength, quality,

and purity. Clarithromycin granules for

oral suspension is a dry mixture

containing clarithromycin-coated

particles, suitable and harmless

dispersing agents, diluents,

preservatives, and flavorings. It contains

the equivalent of 25 or 50 milligrams of

clarithromycin activity per milliliter of

the reconstituted suspension. Its

potency is satisfactory if it is not less

than 90 percent and not more than 115

percent of the number of milligrams of

clarithromycin that it is represented to

contain. Its loss on drying is not more

than 2.0 percent. When constituted as

directed in the labeling, its pH is not

less than 4.0 nor more than 5.4. The
Federal Register / Vol. 61, No. 129 / Wednesday, July 3, 1996 / Rules and Regulations 34727

clarithromycin used conforms to the

standards prescribed by § 452.50(a)(1).

(2) Labeling. It shall be labeled in

accordance with the requirements of

§ 432.5 of this chapter.

(3) Requests for certification; samples.

In addition to complying with the

requirements of § 431.1 of this chapter,

each such request shall contain:

(i) Results of tests and assays on:

(A) The clarithromycin used in

making the batch for potency, moisture,

pH, residue on ignition, heavy metals,

specific rotation, identity, and

crystallinity.

(B) The batch for content, loss on

drying, pH, and identity.

(ii) Samples, if required by the

Director, Center for Drug Evaluation and

Research:

(A) The clarithromycin used in

making the batch: 10 packages, each

containing approximately 500

milligrams.

(B) The batch: A minimum of six

immediate containers.

(b) Tests and methods of assay—(1)

Clarithromycin content. Proceed as

directed in § 452.50(b)(1), except use a

known injection volume between 10

and 60 microliters. Also, prepare the

mobile phase, working standard

solution, and sample solution, and use

system suitability requirements and

calculation as follows:

(i) Mobile phase. Add 600 milliliters

of methanol and 400 milliliters of

0.067M potassium phosphate,

monobasic, to a suitable container, mix

well, and adjust the pH to 3.5 with

phosphoric acid. Filter through a

suitable filter capable of removing

particulate matter to 0.5 micron in

diameter. Degas the mobile phase just

before its introduction into the

chromatographic system.

(ii) Preparation of standard solution.

Dissolve an accurately weighed portion

of the clarithromycin working standard

in sufficient methanol to obtain a

solution having a known concentration

of approximately 2.1 milligrams per

milliliter of clarithromycin.

Quantitatively transfer and dilute an

aliquot of this solution with mobile

phase and mix to obtain a solution of

known concentration of approximately

415 micrograms of clarithromycin per

milliliter.

(iii) Preparation of sample solution.

Constitute as directed in the labeling.

Accurately measure a representative

portion of the suspension that contains

about 1 to 2 grams of clarithromycin

activity and, using approximately 330

milliliters of 0.067M potassium

phosphate, dibasic, quantitatively

transfer into a 1,000 milliliter

volumetric flask containing

approximately 50 milliliters of 0.067M

potassium phosphate, dibasic. Shake for

30 minutes. Dilute to volume with

methanol. Mix well and place in an

ultrasonic bath for 30 minutes. Cool to

room temperature and adjust to volume

with methanol. Add a magnetic stirring

bar and stir for 60 minutes. Allow

excipients to settle and dilute an

appropriate aliquot of the solution with

mobile phase to obtain a solution

containing 500 micrograms of

clarithromycin activity per milliliter

and mix well. Filter through a suitable

filter capable of removing particulate

matter 0.5 micron in diameter.

(iv) System suitability requirements—

(A) Tailing factor. The tailing factor (T)

is satisfactory if it is not less than 1.0

and not greater than 1.7 for the

clarithromycin peak.

(B) Efficiency of the column. The

efficiency (n) is satisfactory if it is

greater than 2,100 theoretical plates for

the clarithromycin peak.

(C) Capacity factor. The capacity

factor (k′) is satisfactory if it is between

2.5 and 6 for the clarithromycin peak.

(D) Coefficient of variation (relative

standard deviation). The coefficient of

variation (SR in percent of three

replicate injections) is satisfactory if it is

not more than 2.0 percent.

(v) Calculations. Calculate the

clarithromycin content as follows:

Milligrams of

clarithromycin

per milliliter

=

AU X PS X D

AS X V

where:

AU = Area of the clarithromycin peak in the

chromatogram of the sample;

AS = Area of the clarithromycin peak in the

chromatogram of the clarithromycin

working standard;

PS = Clarithromycin activity in the

clarithromycin working standard

solution in micrograms per milliliter;

D = Dilution factor of the sample test

solution; and

V = Volume, in milliliters, of the portion of

suspension taken.

(2) Loss on drying. Proceed as directed

in § 436.200(a) of this chapter, using a

sample weight of approximately 1 gram,

weighing in a normal laboratory

atmosphere.

(3) pH. Proceed as directed in

§ 436.202 of this chapter, using the

suspension prepared as directed in the

labeling. Stir the suspension for 10

minutes with the electrode immersed

and record the pH.

(4) Identity. Using the highperformance liquid chromatographic

procedure described in paragraph (b)(1)

of this section, the retention times for

the clarithromycin peak must be within

2 percent of the retention time for the

peak of the reference standard.

Dated: June 20, 1996.

Janet Woodcock,

Director, Center for Drug Evaluation and

Research.

[FR Doc. 96–16977 Filed 7–2–96; 8:45 am]

BILLING CODE 4160–01–F

21 CFR Parts 520, 522, 529, and 558

Animal Drugs, Feeds, and Related

Products; 29 Various New Animal Drug

Products and Type A Medicated

Articles

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is amending the

animal drug regulations to remove those

portions reflecting approval of 29 new

animal drug applications (NADA’s) held

by Bayer Corp., Agriculture Division,

Animal Health (formerly Miles, Inc.,

Agriculture Division, Animal Health

Products), Hubbard Milling Co.,

Hoffmann-LaRoche, Inc., and Ohmeda,

Inc. The NADA’s provide for the use of

29 various new animal drug products

and Type A medicated articles used to

manufacture finished medicated animal

feeds. In a notice published elsewhere

in this issue of the Federal Register,

FDA is withdrawing approval of the

NADA’s.

EFFECTIVE DATE: July 15, 1996.

FOR FURTHER INFORMATION CONTACT:

Mohammad I. Sharar, Center for

Veterinary Medicine (HFV–216), Food

and Drug Administration, 7500 Standish

Pl., Rockville, MD 20855, 301–827–

0159.

SUPPLEMENTARY INFORMATION: In a notice

published elsewhere in this issue of the

Federal Register, FDA is withdrawing

approval of the following NADA’s: