[Federal Register Volume 61, Number 129 (Wednesday, July 3, 1996)]
[Rules and Regulations]
[Pages 34726-34727]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-16977]


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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.

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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).

Sec. 452.150a  [Redesignated from Sec. 452.150]

    2. Section 452.150 is redesignated as Sec. 452.150a and new 
Secs. 452.150 and 452.150b are added to subpart B to read as follows:


Sec. 452.150  Clarithromycin oral dosage forms.


Sec. 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

[[Page 34727]]

clarithromycin used conforms to the standards prescribed by 
Sec. 452.50(a)(1).
    (2) Labeling. It shall be labeled in accordance with the 
requirements of Sec. 432.5 of this chapter.
    (3) Requests for certification; samples. In addition to complying 
with the requirements of Sec. 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 Sec. 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                             AU X PS X D            
    clarithromycin per         =    ------------------------------------
        milliliter                                  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 Sec. 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 Sec. 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 high-performance 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