[Federal Register Volume 59, Number 100 (Wednesday, May 25, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-12667]


[[Page Unknown]]

[Federal Register: May 25, 1994]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Part 442

[Docket No. 94N-0132]

 

Antibiotic Drugs; Cefotetan and Cefotetan Sodium Injection

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 bulk form of cefotetan, cefotetan, and for its use 
in a new dosage form of cefotetan sodium, cefotetan sodium injection. 
The manufacturer has supplied sufficient data and information to 
establish its safety and efficacy.

DATES: Effective June 24, 1994; written comments, notice of 
participation, and requests for a hearing by June 24, 1994; data, 
information, and analyses to justify a hearing by July 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 (1) a new bulk form of cefotetan, 
cefotetan, and (2) for its use in a new dosage form of cefotetan 
sodium, cefotetan sodium injection. 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 21 CFR part 
442 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 June 24, 1994. However, interested persons may, on or 
before June 24, 1994, 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 24, 1994, a written notice of participation 
and request for a hearing, and (2) on or before July 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 Part 442

    Antibiotics.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
442 is amended as follows:

PART 442--CEPHA ANTIBIOTIC DRUGS

    1. 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).
    2. New Sec. 442.52 is added to subpart A to read as follows:


Sec. 442.52  Cefotetan.

    (a) Requirements for certification--(1) Standards of identity, 
strength, quality, and purity. Cefotetan is (6R,7S)-4-[[2-carboxy-7-
methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-
azabicyclo[4.2.0]oct-2-ene-7-yl]-carbamoyl]-1,3-dithietane-
2,-malonamic acid. It is so purified and dried 
that:
    (i) Its potency is not less than 950 micrograms and not more than 
1,030 micrograms of cefotetan activity per milligram on the anhydrous 
basis.
    (ii) Its moisture content is not more than 2.5 percent.
    (iii) It gives a positive identity test for cefotetan.
    (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 potency, moisture, 
and identity.
    (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. Proceed as directed in 
Sec. 436.216 of this chapter, except use the resolution test solution 
to determine resolution in lieu of the working standard solution. 
Perform the assay at ambient temperature, using an ultraviolet 
detection system operating at a wavelength of 254 nanometers, a column 
packed with microparticulate (3 to 10 micrometers in diameter) reversed 
phase packing material such as octadecyl hydrocarbon bonded silicas, a 
flow rate not exceeding 2.0 milliliters per minute, and a known 
injection volume of between 10 and 20 microliters. Reagents, working 
standard solution, sample solution, resolution test solution, system 
suitability requirements, and calculations are as follows:
    (i)  Reagents--(A) Diluting solution. Mix 
water:methanol:acetonitrile (90:5:5).
    (B) Mobile phase. Mix 0.1M phosphoric acid:glacial acetic 
acid:methanol:acetonitrile (1700:100:105:105). 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. Accurately weigh 
approximately 50 milligrams of the cefotetan working standard into a 
250-milliliter volumetric flask containing 12.5 milliliters of 
methanol. Swirl the flask for several minutes, then add 12.5 
milliliters of acetonitrile. Swirl the flask until the cefotetan is 
dissolved. Dilute to volume with water to obtain a solution containing 
approximately 200 micrograms of cefotetan per milliliter. Mix well. 
Protect the working standard solution from light.
    (B) Sample solution. Dissolve an accurately weighed portion of the 
sample with sufficient diluting solution described in paragraph 
(b)(1)(i)(A) of this section to obtain a concentration of approximately 
200 micrograms of cefotetan per milliliter.
    (C) Resolution test solution. Place 10 milliliters of the working 
standard solution in a stoppered flask containing a few milligrams of 
magnesium carbonate. Close the flask and sonicate for 10 minutes. If 
the solution is not slightly turbid, add more magnesium carbonate and 
repeat sonication. Filter the turbid solution through a 0.5-micron 
filter and use within 2 hours. As this solution stands, the tautomer 
concentration increases.
    (iii)  System suitability requirements--(A) Tailing factor. The 
tailing factor (T) is satisfactory if it is not more than 1.3 at 10 
percent of peak height in lieu of 5 percent of peak height.
    (B) Efficiency of the column. The efficiency of the column (n) is 
satisfactory if it is greater than 1,500 theoretical plates.
    (C) Resolution. The resolution (R) between the peak for cefotetan 
and its tautomer is satisfactory if it is not less than 2.0.
    (D) Coefficient of variation. The coefficient of variation (Sr 
in percent) of five replicate injections is satisfactory if it is not 
more than 2.0 percent. If the system suitability requirements have been 
met, then proceed as described in Sec. 436.216(b) of this chapter. 
Alternate chromatographic conditions are acceptable provided comparable 
system suitability requirements are met. However, the sample 
preparation described in paragraph (b)(1)(ii)(B) of this section should 
not be changed.
    (iv)  Calculation. Calculate the micrograms of cefotetan per 
milligram of sample as follows:

                                                                        
                                                      AU X PS X 100     
Micrograms of cefotetan             =            -----------------------
     per milligram                                   AS X CU X (100-m)  
                                                                        

where:
AU = Area of the cefotetan peak in the chromatogram of the 
sample (at a retention time equal to that observed for the 
standard);
AS = Area of the cefotetan peak in the chromatogram of the 
cefotetan working standard;
PS = Cefotetan activity in the cefotetan working standard 
solution in micrograms per milliliter;
CU = Milligrams of sample per milliliter of sample solution; 
and
m = Percent moisture content of the sample.
    (2) Moisture. Proceed as directed in Sec. 436.201 of this chapter.
    (3) Identity. Proceed as directed in Sec. 436.211 of this chapter 
using a mineral oil mull prepared as described in Sec. 436.211(b)(2).


Sec. 442.253a  [Redesignated from Sec. 442.253]

    3. Section 442.253 is redesignated as Sec. 442.253a and new 
Secs. 442.253 and 442.253b are added to subpart C to read as follows:


Sec. 442.253  Cefotetan injectable dosage forms.


Sec. 442.253b  Cefotetan sodium injection.

    (a) Requirements for certification--(1) Standards of identity, 
strength, quality, and purity. Cefotetan sodium injection is a frozen, 
aqueous, iso-osmotic solution of cefotetan and sodium bicarbonate. It 
contains one or more suitable and harmless buffer substances and a 
tonicity adjusting agent. Each milliliter contains cefotetan disodium 
equivalent to 20 milligrams or 40 milligrams of cefotetan per 
milliliter. Its cefotetan content is satisfactory if it is not less 
than 90 percent and not more than 120 percent of the number of 
milligrams of cefotetan that it is represented to contain. It is 
sterile. It contains not more than 0.17 endotoxin units per milligram 
of cefotetan. Its pH is not less than 4.0 and not more than 6.5. It 
passes the identity test. The cefotetan used conforms to the standards 
prescribed by Sec. 442.52(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 cefotetan used in making the batch for cefotetan potency, 
moisture, and identity.
    (B) The batch for cefotetan potency, sterility, bacterial 
endotoxins, pH, and identity.
    (ii) Samples, if required by the Director, Center for Drug 
Evaluation and Research:
    (A) The cefotetan used in making the batch: 10 packages, each 
containing approximately 500 milligrams.
    (B) The batch:
    (1) For all tests except sterility: A minimum of 12 immediate 
containers.
    (2) For sterility testing: 20 immediate containers, collected at 
regular intervals throughout each filling operation.
    (b) Tests and methods of assay. Thaw the sample as directed in the 
labeling. The sample solution used for testing must be at room 
temperature.
    (1) Cefotetan potency. Proceed as directed in Sec. 442.52(b)(1), 
except prepare the sample solution and calculate the cefotetan content 
as follows:
    (i)  Preparation of sample solution. Using a suitable hypodermic 
needle and syringe, remove an accurately measured portion from each 
container immediately after thawing and reaching room temperature and 
dilute with mobile phase to obtain a solution containing 200 micrograms 
of cefotetan per milliliter (estimated). Prepare the sample solution 
just prior to its introduction into the chromatograph.
    (ii) Calculation. Calculate the milligrams of cefotetan per 
milliliter of sample as follows:

                                                                        
                                                      AU X PS X 100     
Micrograms of cefotetan             =            -----------------------
     per milligram                                   AS X CU X (100-m)  
                                                                        

where:
AU = Area of the cefotetan peak in the chromatogram of the 
sample (at a retention time equal to that observed for the 
standard);
AS = Area of the cefotetan peak in the chromatogram of the 
cefotetan working standard;
PS = Cefotetan activity in the cefotetan working standard 
solution in micrograms per milliliter;
CU = Milligrams of sample per milliliter of sample solution; 
and
m = Percent moisture content of the sample.
    (2) Sterility. Proceed as directed in Sec. 436.20 of this chapter, 
using the method described in paragraph (e)(1) of that section.
    (3) Bacterial endotoxins. Proceed as directed in the U.S. 
Pharmacopeia bacterial endotoxins test.
    (4) pH. Proceed as directed in Sec. 436.202 of this chapter, using 
the undiluted solution.
    (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 cefotetan working standard.

    Dated: May 17, 1994.
Gayle R. Dolecek,
Acting Director, Office of Compliance, Center for Drug Evaluation and 
Research.
[FR Doc. 94-12667 Filed 5-24-94; 8:45 am]
BILLING CODE 4160-01-F