[Federal Register Volume 59, Number 37 (Thursday, February 24, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-4078]


[[Page Unknown]]

[Federal Register: February 24, 1994]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Parts 436 and 442

[Docket No. 93N-0328]

 

Antibiotic Drugs; Cefadroxil Hemihydrate: Cefadroxil Hemihydrate 
Capsules and Cefadroxil Hemihydrate Tablets

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 provide for the inclusion of accepted 
standards for a new antibiotic drug, cefadroxil hemihydrate, and the 
use of the antibiotic drug in two dosage forms, cefadroxil hemihydrate 
capsules and cefadroxil hemihydrate tablets. The manufacturer has 
supplied sufficient data and information to establish its safety and 
efficacy.

DATES: Effective March 28, 1994; written comments, notice of 
participation, and request for a hearing by March 28, 1994; data, 
information, and analyses to justify a hearing by April 25, 1994.

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: Peter A. Dionne, Center for Drug 
Evaluation and Research (HFD-520), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-443-0335.

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, cefadroxil 
hemihydrate, and its use in two dosage forms, cefadroxil hemihydrate 
capsules and cefadroxil hemihydrate tablets. The agency has concluded 
that the data supplied by the manufacturer concerning these antibiotic 
drugs are adequate to establish their safety and efficacy when used as 
directed in the labeling and that the regulations should be amended in 
21 CFR parts 436 and 442 to provide for the inclusion of accepted 
standards for these products.

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 March 28, 1994. However, interested persons may, on or 
before March 28, 1994, 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 March 28, 1994, a written notice of participation 
and request for a hearing, and (2) on or before April 25, 1994, 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 two new 
entries to the table in paragraph (b) and by adding new paragraph 
(c)(17) to read as follows:


Sec. 436.215  Dissolution test.

* * * * *
    (b) * * *

--------------------------------------------------------------------------------------------------------------------------------------------------------
               Dosage form                         Dissolution medium               Rotation rate1          Sampling time(s)            Apparatus       
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                         *******                                                                        
Cefadroxil hemihydrate capsules                        900 mL distilled water                      100                   45 min                        1
Cefadroxil hemihydrate tablets                         900 mL distilled water                       50                   30 min                        2
                                                                         *******                                                                        
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\Rotation rate of basket or paddle stirring element (revolutions per minute).                                                                         

    (c) * * *
    (17) Cefadroxil hemihydrate. Proceed as directed in paragraph 
(c)(1) of this section, except use the cefadroxil working standard and 
measure the absorbance at the absorption peak of approximately 264 
nanometers.
* * * * *

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).

    4. New Sec. 442.7 is added to subpart A to read as follows:


Sec. 442.7  Cefadroxil hemihydrate.

    (a) Requirements for certification--(1) Standards of identity, 
strength, quality, and purity. Cefadroxil hemihydrate is 7-[D-2-amino-
2(p-hydroxyphenyl)acetamido]-3-methyl-8-oxo-5-thia-1-
azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid hemihydrate. It is so 
purified and dried that:
    (i) Its potency is not less than 900 micrograms and not more than 
1,050 micrograms of cefadroxil activity per milligram on an anhydrous 
basis.
    (ii) [Reserved]
    (iii) Its moisture content is not less than 2.4 percent and not 
more than 4.5 percent.
    (iv) The pH of an aqueous solution containing 50 milligrams per 
milliliter is not less than 4.0 and not more than 6.0.
    (v) When calculated on an anhydrous basis, its absorptivity at 264 
nanometers is not less than 95 percent and not more than 104 percent of 
that of the cefadroxil standard similarly treated and corrected for 
potency.
    (vi) It passes the identity test.
    (vii) It is crystalline.
    (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 the batch for cefadroxil 
potency, moisture, pH, absorptivity, identity, and crystallinity.
    (ii) Samples, if required by the Director, Center for Drug 
Evaluation and Research: 10 packages, each containing approximately 500 
milligrams.
    (b) Tests and methods of assay--(1) Potency. Use either of the 
following methods; however, the results obtained from the hydroxylamine 
colorimetric assay shall be conclusive.
    (i) Microbiological agar diffusion assay. Proceed as directed in 
Sec. 436.105 of this chapter, preparing the sample for assay as 
follows: Dissolve an accurately weighed sample in sufficient 1 percent 
potassium phosphate buffer, pH 6.0 (solution 1), to give a stock 
solution of convenient
concentration. Further dilute an aliquot of the stock solution with 
solution 1 to the reference concentration of 20 micrograms of 
cefadroxil per milliliter (estimated).
    (ii) Hydroxylamine colorimetric assay for cefadroxil. Proceed as 
directed in Sec. 442.40(b)(1)(ii), except prepare the working standard 
and sample solutions and calculate the potency of the sample as 
follows:
    (A) Preparation of working standard solutions. Dissolve and dilute 
an accurately weighed portion of the cefadroxil working standard in 
sufficient distilled water to obtain a stock solution of convenient 
concentration. Further dilute an aliquot of this solution with 
distilled water to a concentration of 1 milligram of cefadroxil per 
milliliter.
    (B) Preparation of sample solutions. Dissolve an accurately weighed 
portion of the sample in sufficient distilled water to obtain a stock 
solution of convenient concentration. Further dilute an aliquot of this 
solution with distilled water to a concentration of 1 milligram of 
cefadroxil per milliliter (estimated).
    (C) Calculations. Calculate the potency of the sample in micrograms 
per milligram as follows:

                                                                        
                                                        AU X Pa X 100   
    Micrograms of cefadroxil per milligram       = ---------------------
                                                      AS X WU X (100-m) 
                                                                        

where:
AU = Absorbance of sample solution;
AS = Absorbance of working standard solution;
Pa = Potency of working standard solution in micrograms per 
milliliter;
WU = Milligrams of sample per milliliter of sample solution; 
and
m = Percent moisture content of the sample.
    (2) [Reserved]
    (3) Moisture. Proceed as directed in Sec. 436.201 of this chapter.
    (4) pH. Proceed as directed in Sec. 436.202 of this chapter, using 
an
aqueous solution containing 50 milligrams per milliliter.
    (5) Absorptivity. Determine the absorbance of the sample and 
standard solutions in the following manner: Dissolve accurately weighed 
portions of approximately 50 milligrams each of the sample and standard 
in 250 milliliters of distilled water. Transfer a 10-milliliter aliquot 
to a 100-milliliter volumetric flask and dilute to volume with 
distilled water. Using a suitable spectrophotometer and distilled water 
as the blank, determine the absorbance of each solution at 264 
nanometers. Determine the percent absorptivity of the sample relative 
to the absorptivity of the standard using the following calculations:
Percent relative absorptivity = [Absorbance of sample X milligrams 
standard X potency of standard in micrograms per milligram X 10]/
[Absorbance of standard X milligrams sample X (100-m)]
where:
m = Percent moisture in the samples.
    (6) Identity. Using the sample and working standard solutions 
prepared as described in paragraph (b)(5) of this section and a 
suitable spectrophotometer, record the ultraviolet spectrum from 220 to 
340 nanometers. The spectrum of the sample compares qualitatively with 
that of the cefadroxil working standard.
    (7) Crystallinity. Proceed as directed in Sec. 436.203(a) of this 
chapter.
    5. New Secs. 442.107, 442.107a, and 442.107b are added to subpart B 
to read as follows:


Sec. 442.107  Cefadroxil hemihydrate oral dosage forms.


Sec. 442.107a  Cefadroxil hemihydrate capsules.

    (a) Requirements for certification--(1) Standards of identity, 
strength, quality, and purity. Cefadroxil hemihydrate capsules are 
composed of cefadroxil hemihydrate and one or more suitable and 
harmless lubricants and diluents enclosed in a gelatin capsule. Each 
capsule contains cefadroxil hemihydrate equivalent to 500 milligrams of 
cefadroxil. Its cefadroxil content is satisfactory if it is not less 
than 90 percent and not more than 120 percent of the number of 
milligrams of cefadroxil that it is represented to contain. Its 
moisture content is not more than 7.0 percent. It passes the 
dissolution test. The cefadroxil hemihydrate used conforms to the 
standards prescribed in Sec. 442.7(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 cefadroxil hemihydrate used in making the batch for 
potency, moisture, pH, absorptivity, identity, and crystallinity.
    (B) The batch for content, moisture, and dissolution.
    (ii) Samples, if required by the Director, Center for Drug 
Evaluation and Research:
    (A) The cefadroxil hemihydrate used in making the batch: 10 
packages, each containing approximately 500 milligrams.
    (B) The batch: A minimum of 100 capsules.
    (b) Tests and methods of assay--(1) Cefadroxil content. Use either 
of the following methods; however, the results obtained from the 
hydroxylamine colorimetric assay shall be conclusive.
    (i) Microbiological agar diffusion assay. Proceed as directed in 
Sec. 436.105 of this chapter, preparing the sample for assay as 
follows: Place a representative number of capsules into a high-speed 
glass blender jar containing sufficient 1 percent potassium phosphate 
buffer, pH 6.0 (solution 1), to give a stock solution of convenient 
concentration. Blend for 3 to 5 minutes. Remove an aliquot and further 
dilute with solution 1 to the reference concentration of 20 micrograms 
of cefadroxil per milliliter (estimated).
    (ii) Hydroxylamine colorimetric assay for cefadroxil. Proceed as 
directed in Sec. 442.40(b)(1)(ii), except prepare the working standard 
and sample solutions and calculate the potency of the sample as 
follows:
    (A) Preparation of working standard solutions. Dissolve and dilute 
an accurately weighed portion of the cefadroxil working standard in 
sufficient distilled water to obtain a stock solution of convenient 
concentration. Further dilute an aliquot of this solution with 
distilled water to a concentration of 1 milligram of cefadroxil per 
milliliter.
    (B) Preparation of sample solutions. Blend a representative number 
of capsules in a high-speed glass blender jar with sufficient distilled 
water to obtain a stock solution of convenient concentration. Further 
dilute an aliquot of this solution with distilled water to a 
concentration of 1 milligram of cefadroxil per milliliter (estimated).
    (C) Calculations. Calculate the cefadroxil content as follows:

                                                                        
                                                         AU X PS X d    
     Milligrams of cefadroxil per capsule        = ---------------------
                                                       AS X 1,000 X n   
                                                                        

where:
AU = Absorbance of sample solution;
AS = Absorbance of working standard solution;
PS = Potency of working standard solution in micrograms per 
milliliter;
d = Dilution factor of the sample;
n = Number of capsules in the sample assayed.
    (2) Moisture. Proceed as directed in Sec. 436.201 of this chapter.
    (3) Dissolution. Proceed as directed in Sec. 436.215 of this 
chapter. The quantity Q (the amount of cefadroxil dissolved) is 75 
percent within 45 minutes.


Sec. 442.107b  Cefadroxil hemihydrate tablets.

    (a) Requirements for certification--(1) Standards of identity, 
strength, quality, and purity. Cefadroxil hemihydrate tablets are 
composed of cefadroxil hemihydrate and one or more suitable and 
harmless binders and lubricants, with or without coloring and film-
coating substances. Each tablet contains cefadroxil hemihydrate 
equivalent to 1,000 milligrams of cefadroxil. Its cefadroxil content is 
satisfactory if it is not less than 90 percent and not more than 120 
percent of the number of milligrams of cefadroxil that it is 
represented to contain. Its moisture content is not more than 8.0 
percent. It passes the dissolution test. The cefadroxil hemihydrate 
used conforms to the standards prescribed in Sec. 442.7(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 cefadroxil hemihydrate used in making the batch for 
potency, moisture, pH, absorptivity, identity, and crystallinity.
    (B) The batch for content, moisture, and dissolution.
    (ii) Samples, if required by the Director, Center for Drug 
Evaluation and Research:
    (A) The cefadroxil hemihydrate used in making the batch: 10 
packages, each containing approximately 500 milligrams.
    (B) The batch: A minimum of 100 tablets.
    (b) Tests and methods of assay--(1) Cefadroxil content. Use either 
of the following methods; however, the results obtained from the 
hydroxylamine colorimetric assay shall be conclusive.
    (i) Microbiological agar diffusion assay. Proceed as directed in 
Sec. 436.105 of this chapter, preparing the sample for assay as 
follows: Place a representative number of tablets into a high-speed 
glass blender jar containing sufficient 1 percent potassium phosphate 
buffer, pH 6.0 (solution 1), to give a stock solution of convenient 
concentration. Blend for 3 to 5 minutes. Remove an aliquot and further 
dilute with solution 1 to the reference concentration of 20 micrograms 
of cefadroxil per milliliter (estimated).
    (ii) Hydroxylamine colorimetric assay for cefadroxil. Proceed as 
directed in Sec. 442.40(b)(1)(ii), except prepare the working standard 
and sample solutions and calculate the potency of the sample as 
follows:
    (A) Preparation of working standard solutions. Dissolve and dilute 
an accurately weighed portion of the cefadroxil working standard in 
sufficient distilled water to obtain a stock solution of convenient 
concentration. Further dilute an aliquot of this solution with 
distilled water to a concentration of 1 milligram of cefadroxil per 
milliliter.
    (B) Preparation of sample solutions. Blend a representative number 
of tablets in a high-speed glass blender jar with sufficient distilled 
water to obtain a stock solution of convenient concentration. Further 
dilute an aliquot of this solution with distilled water to a 
concentration of 1 milligram of cefadroxil per milliliter (estimated).
    (C) Calculations. Calculate the cefadroxil content as follows:

                                                                        
                                                         AU X PS X d    
     Milligrams of cefadroxil per tablet         = ---------------------
                                                       AS X 1,000 X n   
                                                                        

where:
AU = Absorbance of sample solution;
AS = Absorbance of working standard solution;
PS = Potency of working standard solution in micrograms per 
milliliter;
d = Dilution factor of the sample; and
n = Number of tablets in the sample assayed.
    (2) Moisture. Proceed as directed in Sec. 436.201 of this chapter.



    (3) Dissolution. Proceed as directed in Sec. 436.215 of this 
chapter. The quantity Q (the amount of cefadroxil dissolved) is 75 
percent within 30 minutes.

    Dated: February 9, 1994.
 Stephanie R. Gray,
 Acting Director, Office of Compliance, Center for Drug Evaluation and 
Research.
[FR Doc. 94-4078 Filed 2-23-94; 8:45 am]
BILLING CODE 4160-01-F