[Federal Register Volume 59, Number 191 (Tuesday, October 4, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-24543]


[[Page Unknown]]

[Federal Register: October 4, 1994]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 450

[Docket No. 94N-0302]

 

Antibiotic Drugs; Bleomycin Sulfate

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 standards of an antibiotic 
drug, bleomycin sulfate bulk drug substance. The manufacturer has 
supplied sufficient data and information to establish its safety and 
efficacy.

DATES: Effective November 3, 1994; written comments, notice of 
participation, and request for a hearing by November 3, 1994; data, 
information, and analyses to justify a hearing by December 5, 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: 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 to provide for bleomycin sulfate bulk 
drug substance. The agency has concluded that the data supplied by the 
manufacturer concerning the 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 450 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 on November 3, 1994. However, interested persons may, on 
or before November 3, 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 November 3, 1994, a written notice of 
participation and request for a hearing, and (2) on or before December 
5, 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 450

    Antibiotics.

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

PART 450--ANTITUMOR ANTIBIOTIC DRUGS

    1. The authority citation for 21 CFR part 450 continues to read as 
follows:

    Authority:  Sec. 507 of the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 357).

    2. Section 450.10 is added to subpart A to read as follows:


Sec. 450.10  Bleomycin sulfate.

    (a) Requirements for certification--(1) Standards of identity, 
strength, quality, and purity. Bleomycin sulfate is the amorphous 
sulfate salt of bleomycin. Bleomycin has been separated into several 
similar glyco-peptide molecules. It is a cream-colored powder that is 
so purified and dried that:
    (i) Its potency is not less than 1.5 units and not more than 2.0 
units of bleomycin per milligram.
    (ii) It contains no depressor substances.
    (iii) Its loss on drying is not more than 6.0 percent.
    (iv) Its pH in an aqueous solution containing 10 units per 
milliliter is not less than 4.5 and not more than 6.0.
    (v) Its copper content is not greater than 0.1 percent.
    (vi) Its content of various bleomycins is as follows: Bleomycin 
A2  is not less than 55 percent and not more than 70 percent; 
bleomycin B2 is not less than 25 percent and not more than 32 
percent; bleomycin B4 is not more than 1 percent. Bleomycins 
A2 and B2 should comprise not less than 85 percent of the 
total bleomycins.
    (vii) It passes the identity test.
    (2) Labeling. It shall be labeled in accordance with the 
requirements of Sec. 432.5(b) 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, depressor 
substances, loss on drying, pH, copper, content of various bleomycins, 
and identity.
    (ii) Samples required: For all tests: A minimum of 20 immediate 
containers.
    (b) Tests and methods of assay--(1) Potency. Proceed as directed in 
Sec. 436.105 of this chapter, preparing the sample for assay as 
follows: Dissolve an accurately weighed sample in sufficient 0.1M 
potassium phosphate buffer, pH 7.0 (solution 16), to provide a stock 
solution of convenient concentration. Dilute the sample thus obtained 
with solution 16 to provide a stock solution of convenient 
concentration. Further dilute an aliquot of the stock solution with 
solution 16 to the reference concentration of 0.04 unit of activity per 
milliliter (estimated).
    (2) Depressor substances. Proceed as directed in Sec. 436.35 of 
this chapter.
    (3) Loss on drying. Proceed as directed in Sec. 436.200(a) of this 
chapter, using the total contents of two or three vials.
    (4) pH. Proceed as directed in Sec. 436.202 of this chapter, using 
an aqueous solution containing 10 units per milliliter.
    (5) Copper content--(i) Reagents. Dissolve 10 milligrams of zinc 
dibenzyldithiocarbamate in 100 milliliters of carbon tetrachloride.
    (ii) Preparation of standard copper solution. Accurately weigh 
1.965 grams of cupric sulfate pentahydrate and transfer to a 1-liter 
volumetric flask. Dissolve the material in 0.1N hydrochloric acid, 
dilute to volume with 0.1N hydrochloric acid, and mix well. Transfer 3 
milliliters of this stock solution to a 1-liter volumetric flask, 
dilute to volume with 0.1N hydrochloric acid, and mix well. This 
standard copper solution contains 0.0015 milligram of copper per 
milliliter. Transfer 10 milliliters of the standard copper solution to 
a 60-milliliter separatory funnel.
    (iii) Preparation of the sample. Accurately weigh approximately 15 
milligrams of sample into a 60-millilter separatory funnel. Dissolve 
the sample in 10 milliliters of 0.1N hydrochloric acid.
    (iv) Procedure. To the separatory funnels containing the sample 
solution and standard copper solution, add 10 milliliters of the zinc 
dibenzyldithiocarbamate solution and shake the funnels vigorously for 1 
minute. Allow the phases to separate. Filter the carbon tetrachloride 
phase (lower phase) through 1 gram of anhydrous sodium sulfate to 
remove excess water. Using a suitable spectrophotometer equipped with 
1-centimeter cells, and carbon tetrachloride as a blank, measure the 
absorbance of the standard copper solution and the sample solution at 
435 nanometers. Calculate the percent copper as follows:

                                                                        
                                                   Absorbance of sample 
                                                      solution X 1.5    
                                                 -----------------------
    Percent copper                  =             Absorbance of standard
                                                     copper solution X  
                                                     Sample weight in   
                                                        milligrams      
                                                                        

    (6) Content of various bleomycin fractions. Proceed as directed in 
Sec. 436.339 of this chapter.
    (7) Identity test. Proceed as directed in Sec. 436.211 of this 
chapter, using the method described in paragraph (b)(1) of that 
section, using a 1 percent mixture.

    Dated: September 27, 1994.
David B. Barr,
Acting Director, Office of Compliance, Center for Drug Evaluation and 
Research.
[FR Doc. 94-24543 Filed 10-3-94; 8:45 am]
BILLING CODE 4160-01-F