[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]
=======================================================================
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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