[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
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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.

-----------------------------------------------------------------------

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]]
                                                                                                                
----------------------------------------------------------------------------------------------------------------
     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.                                                                         
  *                    *                    *                    *                    *                    *    
                                                             *                                                  
----------------------------------------------------------------------------------------------------------------
\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