[Federal Register Volume 60, Number 99 (Tuesday, May 23, 1995)]
[Rules and Regulations]
[Pages 27221-27223]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-12604]
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Rules and Regulations
Federal Register
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This section of the FEDERAL REGISTER contains regulatory documents
having general applicability and legal effect, most of which are keyed
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Federal Register / Vol. 60, No. 99 / Tuesday, May 23, 1995 / Rules
and Regulations
[[Page 27221]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 436 and 442
[Docket No. 94N-0352]
Antibiotic Drugs; Cefuroxime Axetil 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 the accepted standards for
cefuroxime axetil for its use in a new dosage form of cefuroxime
axetil, cefuroxime axetil for oral suspension. The manufacturer has
supplied sufficient data and information to establish its safety and
efficacy.
DATES: Effective June 22, 1995; written comments, notice of
participation, and requests for a hearing by June 22, 1995; data,
information, and analyses to justify a hearing by July 24, 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 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 dosage form of cefuroxime
axetil, cefuroxime axetil for oral suspension. 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
parts 436 and 442 (21 CFR parts 436 and 442) to include the 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 June 22, 1995. However interested persons may, on or
before June 22, 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 June 22, 1995, a written notice of participation
and request for a hearing, and (2) on or before July 24, 1995, 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 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 Parts 436 and 442
Antibiotics.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts
436 and 442 are amended as follows:
PART 436--TESTS AND METHODS OF ASSAY OF ANTIBIOTIC AND ANTIBIOTIC-
CONTAINING DRUGS
1. The authority citation for 21 CFR part 436 continues to read as
follows:
Authority: Sec. 507 of the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 357).
2. Section 436.215 is amended by alphabetically adding a new entry
to the table in paragraph (b) and by revising paragraph (c)(9) to read
as follows:
Sec. 436.215 Dissolution test.
* * * * *
(b) * * *
[[Page 27222]]
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Dosage form Dissolution medium Rotation rate 1 Sampling time(s) Apparatus
----------------------------------------------------------------------------------------------------------------
* * * * * *
*
Cefuroxime axetil for 900 mL Sorenson's 50................... 30 min............... 2
oral suspension. Modified Phosphate
Buffer, pH 7.0.
* * * * * *
*
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\1\ Rotation rate of basket or paddle stirring element (revolutions per minute).
(c) * * *
(9) Cefuroxime axetil tablets and powder for oral suspension--(i)
Preparation of working standard solution--(a) Cefuroxime axetil
tablets. Accurately weigh approximately 60 milligrams of cefuroxime
axetil working standard into a suitable-sized volumetric flask.
Dissolve in 5 milliliters of methanol and dilute to volume with 0.07N
hydrochloric acid to obtain a known concentration equivalent to 0.01 to
0.02 milligram of cefuroxime activity per milliliter.
(b) Cefuroxime axetil for oral suspension. Accurately weigh
approximately 15 milligrams of cefuroxime axetil working standard into
a 100-milliliter volumetric flask. Dissolve in 5 milliliters of
methanol and dilute to volume with Sorenson's Modified Phosphate
Buffer, pH 7.0 (4.2 grams of sodium dihydrogen orthophosphate dihydrate
and 14.3 grams of hydrogen disodium orthophosphate dodecahydrate per
liter of water).
(ii) Preparation of sample solution--(a) Cefuroxime axetil tablets.
Filter through a 0.45-micron filter and dilute an accurately measured
portion of the filtrate with sufficient 0.07N hydrochloric acid to
obtain a concentration equivalent to 0.01 to 0.02 milligram of
cefuroxime activity per milliliter (estimated).
(b) Cefuroxime axetil for oral suspension. Filter the sample
through an 8-micron filter. A coarse prefilter may be used to prevent
clogging. Use the filtrate solution without further dilution.
(iii) Procedure--(a) Cefuroxime axetil tablets. Using a suitable
spectrophotometer and 0.07N hydrochloric acid as the blank, determine
the absorbance of each standard and sample solution at the absorbance
peak at approximately 280 nanometers. Determine the exact position of
the absorption peak for the particular instrument used.
(b) Cefuroxime axetil for oral suspension. Using a suitable
spectrophotometer and Sorenson's Modified Phosphate Buffer, pH 7.0 (4.2
grams of sodium dihydrogen orthophosphate dihydrate and 14.3 grams of
hydrogen disodium orthophosphate dodecahydrate per liter of water) as
the blank, determine the absorbance of each standard and sample
solution at the absorbance peak at approximately 280 nanometers.
Determine the exact position of the absorption peak for the particular
instrument used.
(iv) Calculations. Determine the total amount of cefuroxime
activity dissolved as follows:
[GRAPHIC][TIFF OMITTED]TR23MY95.002
where:
T = Total milligrams of cefuroxime activity dissolved;
AU = Absorbance of sample;
c = Cefuroxime activity of working standard solution in milligrams
per milliliter;
d = Dilution factor of sample filtrate; and
As = Absorbance of standard.
* * * * *
PART 442--CEPHA ANTIBIOTIC DRUGS
3. The authority citation for 21 CFR part 442 continues to read as
follows:
Authority: Sec. 507 of the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 357).
Sec. 442.119a [Redesignated from Sec. 442.119]
4. Section 442.119 is redesignated as Sec. 442.119a and new
Secs. 442.119 and 442.119b are added to subpart B to read as follows:
Sec. 442.119 Cefuroxime axetil oral dosage forms.
Sec. 442.119b Cefuroxime axetil for oral suspension.
(a) Requirements for certification--(1) Standards of identity,
strength, quality, and purity. Cefuroxime axetil for oral suspension is
cefuroxime axetil with one or more suitable and harmless diluents,
suspending and sweetening agents, and flavorings. When reconstituted as
directed in the labeling, it contains cefuroxime axetil equivalent to
25 milligrams of cefuroxime per millimeter. Its potency is satisfactory
if it is not less than 90 percent and not more than 115 percent of the
number of milligrams of cefuroxime that it is represented to contain.
It passes the dissolution test. Its moisture content is not more than
0.2 percent. When reconstituted as directed in the labeling, its pH is
not less than 3.5 and not more than 5.5. It passes the identity test.
The cefuroxime axetil used conforms to the standards prescribed by
Sec. 442.19(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 cefuroxime axetil used in making the batch for potency,
isomer A ratio, moisture, crystallinity, and identity.
(B) The batch for cefuroxime potency, dissolution, moisture, pH of
constituted suspension, and identity.
(ii) Samples, if required by the Director, Center for Drug
Evaluation and Research:
(A) The cefuroxime axetil used in making the batch: 10 packages,
each containing approximately 500 milligrams.
(B) The batch: A minimum of 12 immediate containers.
(b) Tests and methods of assay--(1) Potency. Proceed as directed in
Sec. 442.19(b)(1). Working standard and sample solutions and
calculations are as follows:
(i) Preparation of working standard solution. Dissolve
approximately 15 milligrams of the cefuroxime axetil working standard,
accurately weighed, in 20.0 milliliters of methanol in a 50-milliliter
volumetric flask. Dilute to volume with deionized water, and swirl to
mix. Store for no more than 8 hours under refrigeration and protected
from light.
(ii) Preparation of sample solution. Reconstitute the sample as
directed in [[Page 27223]] the labeling. Transfer an accurately
measured representative portion of the suspension equivalent to one
dose into a 200-milliliter volumetric flask. Add 10 milliliters of
methanol and disperse the sample. Dilute to volume with methanol.
Dilute 20.0 milliliters of this solution to volume in a 50-milliliter
volumetric flask with deionized water, swirl to mix, and allow to stand
for 10 minutes. (Note: A white turbidity is formed.) Filter this
solution via a suitable disposable filter unit, discarding the first 5
milliliters. Store for no more than 8 hours under refrigeration and
protect from light.
(iii) Calculations. Calculate the milligrams of cefuroxime per dose
(5 milliliters) as follows:
[GRAPHIC][TIFF OMITTED]TR23MY95.001
where:
AU = Sum of the areas of the cefuroxime axetil sample isomer A
and isomer B peaks;
AS = Sum of the peak areas of the cefuroxime axetil working
standard isomer A and isomer B peaks;
PS = Cefuroxime activity in the cefuroxime axetil working
standard solution in micrograms per milliliter; and
d = Dilution factor of the sample.
(2) Dissolution. Proceed as directed in Sec. 436.215 of this
chapter. The quantity Q (the amount of cefuroxime activity dissolved)
is 60 percent at 30 minutes.
(3) Moisture. Proceed as directed in Sec. 436.201 of this chapter.
(4) pH. Reconstitute as directed in the labeling and proceed as
directed in Sec. 436.202 of this chapter.
(5) Identity. The high-performance liquid chromatogram of the
sample determined as directed in paragraph (b)(1) of this section
compares qualitatively to that of the cefuroxime axetil working
standard.
Dated: May 9, 1995.
Murray M. Lumpkin,
Deputy Director, Center for Drug Evaluation and Research.
[FR Doc. 95-12604 Filed 5-22-95; 8:45 am]
BILLING CODE 4160-01-F