[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
