[Federal Register Volume 60, Number 186 (Tuesday, September 26, 1995)]
[Rules and Regulations]
[Pages 49507-49509]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-23737]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Part 453
[Docket No. 95N-0081]
Antibiotic Drugs; Clindamycin Phosphate Vaginal Cream
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 a new
antibiotic drug, clindamycin phosphate vaginal cream. The manufacturer
has supplied sufficient data and information to establish its safety
and efficacy.
DATES: Effective October 26, 1995; written comments, notice of
participation, and request for a hearing by October 26, 1995; data,
information, and analyses to justify a hearing by November 27, 1995.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,
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, 301-443-6714.
SUPPLEMENTARY INFORMATION: FDA has evaluated data submitted in
accordance with regulations promulgated 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 antibiotic drug, clindamycin
phosphate vaginal cream. The agency has concluded that the data
supplied by the manufacturer concerning this antibiotic drug are
adequate to establish its safety and efficacy when used as directed in
the labeling and that the regulations should be amended in part 453 (21
CFR part 453) to provide for the inclusion of 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 October 26, 1995. However, interested persons may, on or
before October 26, 1995, submit written 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 October 26, 1995, a written notice of
participation and request for a hearing, and (2) on or before November
27, 1995, the data, information, and
[[Page 49508]]
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 a 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 document 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 453
Antibiotics.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
453 is amended as follows:
PART 453--LINCOMYCIN ANTIBIOTIC DRUGS
1. The authority citation for 21 CFR part 453 continues to read as
follows:
Authority: Sec. 507 of the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 357).
2. New Sec. 453.522d is added to subpart F to read as follows:
Sec. 453.522d Clindamycin phosphate vaginal cream.
(a) Requirements for certification--(1) Standards of identity,
strength, quality, and purity. Clindamycin phosphate vaginal cream
contains clindamycin phosphate in a suitable and harmless cream
vehicle. Each gram contains clindamycin phosphate equivalent to 20
milligrams of clindamycin activity. Its clindamycin content is
satisfactory if it is not less than 90 percent and not more than 110
percent of the number of milligrams of clindamycin that it is
represented to contain. Its pH is not less than 3.0 and not more than
6.0. It passes the identity test. The clindamycin phosphate used
conforms to the standards prescribed by Sec. 453.22(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 clindamycin phosphate used in making the batch for
clindamycin content, microbiological activity, moisture, pH,
crystallinity, and identity.
(B) The batch for clindamycin content, pH, and identity.
(ii) Samples, if required by the Director, Center for Drug
Evaluation and Research:
(A) The clindamycin phosphate used in making the batch: 10
packages, each containing approximately 300 milligrams.
(B) The batch: a minimum of six immediate containers.
(b) Tests and methods of assay --(1) Clindamycin content (high
performance liquid chromatography assay). Proceed as directed in
Sec. 436.216 of this chapter, using ambient temperature, an ultraviolet
detection system operating at a wavelength of 210 nanometers, a 25-
centimeter long x 4.6 millimeter ID column packed with microparticulate
(5 to 10 micrometers in diameter) reverse phase octylsilane hydrocarbon
bonded silica packing material, a flow rate of 1.0 milliliter per
minute, and a known injection volume of 20 microliters. The retention
time of clindamycin phosphate, and clindamycin are approximately 6 and
9 minutes, respectively. Reagents, working standards and sample
solutions, resolution test solution, system suitability requirements,
and calculations are as follows:
(i) Reagents--(A) 0.1M Potassium phosphate monobasic buffer.
Dissolve 13.61 grams of potassium phosphate monobasic in 775
milliliters of water. Adjust the pH to 2.5 with phosphoric acid.
Further dilute with water to a volume of 1,000 milliliters.
(B) Mobile phase. Mix 225 milliliters of acetonitrile and 775
milliliters of 0.1M potassium phosphate, pH 2.5 buffer (225:775).
Filter through a suitable filter capable of removing particulate matter
greater than 0.5 micron in diameter. Degas the mobile phase just prior
to its introduction into the chromatograph.
(ii) Preparation of working standard, sample, and resolution test
solutions--(A) Working standard solution. Dissolve an accurately
weighed portion of the clindamycin phosphate working standard in
sufficient mobile phase (prepared as directed in paragraph (b)(1)(i)(B)
of this section) to obtain a solution containing 200 micrograms of
clindamycin activity per milliliter.
(B) Sample solutions. Accurately weigh and transfer approximately
1.0 gram of the sample into a 125-milliliter Erlenmeyer flask. Add
100.0 milliliters of mobile phase (prepared as directed in paragraph
(b)(1)(i)(B) of this section), accurately measured, and 8 to 10 glass
beads (4 to 5 millimeters). Close the flask securely using a plastic
stopper and shake vigorously by mechanical means for 1 hour at 50
deg.C. Cool in an ice bath for approximately 20 minutes. Centrifuge a
portion of the mixture. Use the lower cloudy solution for
chromatographic analysis. Filter a few milliliters of the centrifuged
solution through an appropriate 2 micron filter.
(C) Resolution test solution. Place 15 milligrams each of
clindamycin phosphate and clindamycin hydrochloride in a 25-milliliter
volumetric flask and dissolve and dilute to volume with mobile phase
and mix well. Use this solution to determine the resolution factor.
(iii) System suitability requirements--(A) Asymmetry factor.
Calculate the asymmetry factor (AS), measured at a point 5 percent
of the peak height from the baseline as follows:
a + b
As = --------
2a
where:
a = Horizontal distance from point of ascent to point of maximum
peak height; and
b = Horizontal distance from point of maximum peak height to point
of descent.
The asymmetry factor (As) is satisfactory if it is not less
than 1.0 and not more than 1.3.
(B) Efficiency of the column. From the number of theoretical plates
(n) calculated as described in Sec. 436.216(c)(2) of this chapter,
calculate the reduced plate height (hr) as follows:
(L)(10,000)
hr = ----------------
(n)(dp)
where:
L = Length of the column in centimeters;
[[Page 49509]]
n = Number of theoretical plates; and
dp = Average diameter of the particles in the analytical
column packing in micrometers.
The absolute efficiency (hr) is satisfactory if it is not more
than 15.
(C) Resolution factor. The resolution factor (R) between the peak
for clindamycin phosphate and the peak for clindamycin (hydrochloride)
in the chromatogram of the resolution test solution is satisfactory if
it is not less than 6.0.
(D) Coefficient of variation (relative standard deviation). The
coefficient of variation (SR in percent) of 5 replicate injections
of the working standard solution is satisfactory if it is not more than
2.5 percent. If the system suitability parameters have been met, then
proceed as described in Sec. 436.216(b) of this chapter.
(iv) Calculation. Calculate the clindamycin content as follows:
Au X Ps X d
Milligrams of clindamycin = -------------
per gram As X 1,000
where:
Au = Area of the clindamycin phosphate peak in the
chromatogram of the sample (at a retention time equal to that observed
for the standard);
As = Area of the clindamycin phosphate peak in the
chromatogram of the clindamycin phosphate working standard;
Ps = Clindamycin activity in the clindamycin phosphate working
standard solution in micrograms per milliliter; and
d = Dilution factor of the sample.
(2) pH. Proceed as directed in Sec. 436.202 of this chapter, using
the undiluted cream.
(3) Identity. The high-pressure liquid chromatogram of the sample
determined as directed in paragraph (b)(1) of this section compares
qualitatively to that of the clindamycin phosphate working standard.
Dated: September 5, 1995.
Murray M. Lumpkin,
Deputy Director, Center for Drug Evaluation and Research.
[FR Doc. 95-23737 Filed 9-25-95; 8:45 am]
BILLING CODE 4160-01-F