[Federal Register Volume 59, Number 40 (Tuesday, March 1, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-4518]
[[Page Unknown]]
[Federal Register: March 1, 1994]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 450
[Docket No. 89N-0440]
Antibiotic Drugs; New Tests and Specifications for Doxorubicin
Hydrochloride and its Dosage Forms
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 by revising the accepted standards for
doxorubicin hydrochloride bulk and its dosage forms to reflect advances
in analytic chemistry and improvements in the manufacturing technology
of this antibiotic drug. These actions are being taken at the request
of a manufacturer and will provide better quality control of this
product.
DATES: Effective March 1, 1994; written comments, notice of
participation, and request for a hearing by March 31, 1994; data,
information, and analyses to justify a hearing by May 2, 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:
I. Background
In the Federal Register of May 3, 1990 (55 FR 18617), FDA proposed
to amend the antibiotic drug regulations for doxorubicin hydrochloride
bulk and its dosage forms to reflect the significant improvement in the
extraction and chromatographic separation methods since the original
promulgation of regulations for doxorubicin hydrochloride in 1976. This
improvement in manufacturing technology and analytical testing
methodology has resulted in the production of highly purified drug
substances and finished dosage forms.
Specifically, FDA proposed to amend the regulations for doxorubicin
hydrochloride bulk to: (1) Revise the doxorubicin hydrochloride content
limits from 900 to 1,100 micrograms per milligram (g/mg) on
the anhydrous basis to 970 to 1,020 g/mg on the anhydrous and
solvent-free basis; (2) revise the high-pressure liquid chromatography
(HPLC) test currently specified for determining the content of
doxorubicin hydrochloride; (3) revise the pH range limits from a range
of 3.8 to 6.5 to a range of 4.0 to 5.5; (4) add a total solvent residue
test with an upper limit of not more than 2.5 percent; (5) add a
chromatographic purity test with a total impurity specification of not
more than 3.0 percent; (6) delete the microbiological agar diffusion
assay for determining microbiological activity; and (7) revise the
solution used for the disposition of waste material from synthetic
detergent to dilute sodium hypochlorite.
FDA also proposed to amend the regulations for doxorubicin
hydrochloride for injection to: (1) Revise the HPLC test currently
specified for determining the content of doxorubicin hydrochloride; (2)
revise the pH range limits from a range of 3.8 to 6.5 to a range of 4.5
to 6.5; (3) add a provision to the product description permitting the
product to contain methylparaben; (4) replace the pyrogen test with the
U.S. Pharmacopeia (U.S.P.) Bacterial Endotoxin Test with an upper limit
of not more than 2.2 U.S.P. endotoxin units/mg of doxorubicin
hydrochloride; (5) delete the microbiological activity specification
for the doxorubicin hydrochloride used in making the product; (6)
delete the depressor substances test for the product and add the
depressor substances specification for the doxorubicin hydrochloride
used in making the product; and (7) revise the solution used for the
disposition of waste material from synthetic detergent to dilute sodium
hypochlorite.
FDA also proposed to the amend the regulation for doxorubicin
hydrochloride injection to: (1) Revise the HPLC test currently
specified for determining the content of doxorubicin hydrochloride; (2)
replace the pyrogen test with the U.S.P. Bacterial Endotoxin Test with
an upper limit of not more than 2.2 U.S.P. endotoxin units/mg of
doxorubicin hydrochloride; (3) delete the microbiological activity
specification for the doxorubicin hydrochloride used in making the
product; and (4) revise the solution used for the disposition of waste
material from synthetic detergent to dilute sodium hypochlorite.
Interested persons were given until July 2, 1990, to submit written
comments on this proposal and until June 4, 1990, to submit requests
for an informal conference. One comment was received from the
manufacturer requesting the proposed changes. This comment involved the
description of the preparation of the resolution test solution and the
system suitability requirements for the new HPLC method. The
manufacturer requested that the preparation method in U.S.P. XXII,
supp. I, be used and that the system suitability requirements be those
in U.S.P. XXII, supp. I.
FDA believes that both the method in the proposal and the U.S.P.
method of preparation for the resolution test solution give
satisfactory production of doxorubicinone and, therefore, will present
both methods in this final rule. FDA believes that the term ``asymmetry
factor'' is the correct one because measurements are being made on both
sides of the HPLC peak and not just the tailing side. This final rule
will, therefore, use the term ``asymmetry factor'' and will not be the
same as the U.S.P., which uses the term ``tailing factor.'' To be
consistent with the U.S.P., however, this final rule will use limits of
not less than 0.7 and not more than 1.2 instead of not less than 0.9
and not more than 1.2 that were proposed. FDA also believes that column
efficiency should be stated as absolute column efficiency (hr) and
not as theoretical plates (n), because the number of theoretical plates
varies with the length and particle size of the packing in the column.
If the column is packed with 10-micrometer (m) particles and
is 25 centimeters (cm) long, then a column efficiency of not greater
than 10.0 is equivalent to 2,500 theoretical plates which is close to
the 2,250 plates stated in the U.S.P. The efficiency of the column,
which will be stated in the final rule as absolute column efficiency
(hr), is satisfactory if it is not greater than 10.0, equivalent
to 2,500 theoretical plates for a 25-cm column of 10-m
particles. To be consistent with the U.S.P., the proposed resolution of
not less than 8.0 between the peaks of doxorubicin and doxorubicinone
has been changed in the final rule to not less than 5.5.
II. 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.
III. Economic Impact
The agency has considered the economic impact of this final rule
and has determined that it does not require a regulatory flexibility
analysis, as defined in the Regulatory Flexibility Act (Pub. L. 96-
354). Specifically, the final rule would impose an insubstantial
amendment to existing requirements and would refine existing technical
provisions without imposing more stringent requirements. Accordingly,
the agency certifies that this rulemaking will not have a significant
economic impact on a substantial number of small entities.
IV. Submitting Comments and Filing Objections
Any person who will be adversely affected by this regulation 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 31, 1994, a written notice of participation
and request for a hearing, and (2) on or before May 2, 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 (address above).
The procedures and requirements governing this document, 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 document, 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 450.24 is amended by revising paragraphs (a)(1)(i),
(a)(1)(ii), and (a)(1)(v); by adding new paragraph (a)(1)(viii); by
revising paragraph (a)(3)(i), the last sentence in the introductory
text of paragraph (b), paragraphs (b)(1) and (b)(2); and by adding new
paragraph (b)(8) to read as follows:
Sec. 450.24 Doxorubicin hydrochloride.
(a) * * *
(1) * * *
(i) Its doxorubicin hydrochloride content is not less than 970
micrograms and not more than 1,020 micrograms of doxorubicin
hydrochloride per milligram on the anhydrous and solvent free basis.
(ii) Its total solvent residue (as acetone and alcohol) is not more
than 2.5 percent.
* * * * *
(v) The pH of an aqueous solution containing 5 milligrams per
milliliter is not less than 4.0 and not more than 5.5.
* * * * *
(viii) The total of any impurities detected by high-pressure liquid
chromatography assay is not more than 3.0 percent.
* * * * *
(3) * * *
(i) Results of tests and assays on the batch for doxorubicin
hydrochloride content, solvent residue, depressor substances, moisture,
pH, crystallinity, identity, and total impurities.
* * * * *
(b) * * * Dispose of all waste material by dilution with large
volumes of dilute sodium hypochlorite (bleach) solution.
(1) Doxorubicin hydrochloride content (high-performance liquid
chromatography). Proceed as directed in Sec. 436.216 of this chapter,
using ambient temperature, an ultraviolet detection system operating at
a wavelength of 254 nanometers, a 4.6-millimeter X 25-centimeter column
packed with microparticulate (5 to 10 micrometers in diameter) packing
material, such as trimethylsilane chemically bonded to porous silica, a
flow rate of not more than 2.0 milliliters per minute, and a known
injection volume of between 10 and 20 microliters. Mobile phase,
working standard and sample solutions, resolution test solution, system
suitability requirements, and calculations are as follows:
(i) Mobile phase. Prepare a suitable mixture of water,
acetonitrile, methanol, and phosphoric acid (540:290:170:2). Dissolve 1
gram of sodium lauryl sulfate in 1,000 milliliters of this solution,
adjust with 2N sodium hydroxide to a pH of 3.60.1. Filter
through a suitable filter capable of removing particulate matter to 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. Dissolve an accurately
weighed quantity of doxorubicin hydrochloride working standard in
mobile phase to obtain a solution having a known concentration of 0.1
milligram of doxorubicin hydrochloride per milliliter.
(B) Sample solution. Transfer approximately 20 milligrams of
sample, accurately weighed, to a 200-milliliter volumetric flask, add
mobile phase to volume, and mix. This yields a solution containing 0.1
milligram of doxorubicin hydrochloride per milliliter (estimated).
(C) Resolution test solution. Use either of the following
preparation methods:
(1) To 2 milliliters of a 1.0 milligram per milliliter solution of
doxorubicin hydrochloride, add 20 microliters of 1N hydrochloric acid.
Hold for 30 minutes at 95 deg.C in an oil bath.
(2) Dissolve about 10 milligrams of doxorubicin hydrochloride in 5
milliliters of water, add 5 milliliters of phosphoric acid, and allow
to stand for about 30 minutes. Adjust with 2N sodium hydroxide (about
37 milliliters) to a pH of 2.60.1, add 15 milliliters of
acetonitrile and 10 milliliters of methanol, mix, and filter. (Note:
Portions of this solution may be frozen until needed, then thawed and
mixed before use.)
(3) The procedures in paragraphs (b)(1)(ii)(C)(1) and
(b)(1)(ii)(C)(2) of this section generate doxorubicinone, the aglycone
of doxorubicin. Use this solution to determine the resolution
requirement for the chromatographic system.
(iii) System suitability requirements--(A) Asymmetry factor. The
asymmetry factor (AS) for the doxorubicin peak measured at a point
5 percent of the peak height is not less than 0.7 and not more than
1.2.
(B) Efficiency of the column. The absolute column efficiency
(hr) is satisfactory if it is not greater than 10.0, equivalent to
2,500 theoretical plates for a 25-centimeter column of 10-micrometer
particles.
(C) Resolution. The resolution (R) between the peaks of
doxorubicin and doxorubicinone (generated in situ) is satisfactory if
it is not less than 5.5.
(D) Capacity factor. The capacity factor (k) for doxorubicin is
satisfactory if it is in the range between 1.0 and 5.0.
(E) Coefficient of variation. The coefficient of variation
(relative standard of deviation in percent) of 5 replicate injections
is satisfactory if it is not more than 1.0 percent. If the system
suitability parameters have been met, then proceed as described in
Sec. 436.216(b) of this chapter.
(iv) Calculations. Calculate the micrograms of doxorubicin
hydrochloride per milligram of sample as follows:
AU X PS X 100
Micrograms of doxorubicin hydrochloride = ------------------------
per milligram AS X CU X (100-m-X)
where:
AU = Area of the doxorubicin hydrochloride peak in the
chromatogram of the sample (at a retention time equal to that
observed for the standard);
AS = Area of the doxorubicin hydrochloride peak in the
chromatogram of the doxorubicin hydrochloride working standard;
PS = Doxorubicin hydrochloride activity in the doxorubicin
hydrochloride working standard solution in micrograms per
milliliter;
CU = Milligrams of the sample per milliliter of sample
solution;
m = Percent moisture content of the sample; and
X = Percent solvent residue determined as directed in paragraph
(b)(2) of this section.
(2) Residue solvent (as acetone and alcohol)--(i) Standard
preparation. Transfer to a 100-milliliter volumetric flask about 200
milligrams of acetone, 300 milligrams of dehydrated alcohol, and 1,000
milligrams of dioxane, each accurately weighed, and mix. Dilute with
water to volume, and mix. Transfer 5.0 milliliters of the resulting
solution to a 50-milliliter volumetric flask, dilute with water to
volume, and mix. This solution contains about 0.2 milligram of acetone,
0.3 milligram of alcohol, and 1 milligram of dioxane per milliliter.
(ii) Solvent. Transfer about 100 milligrams of dioxane, accurately
weighed to a 100-milliliter volumetric flask, dilute with water to
volume, and mix.
(iii) Test preparation. Dissolve about 200 milligrams of
doxorubicin hydrochloride sample in 3.0 milliliters of solvent.
(iv) Chromatographic system (see United States Pharmacopeia
(U.S.P.) Chromatography (621)). The gas chromatograph is equipped with
a flame-ionization detector and a 4-millimeter X 2-meter column packed
with 8-percent liquid phase G16 (see U.S.P. Chromatographic Reagents--
Phases) on 100- to 120-mesh support S1AB (potassium hydroxide-washed)
(see U.S.P. Chromatographic Reagents--Supports). The column is
maintained at about 60 deg.C, and helium is used as the carrier gas.
Adjust the column temperature and carrier gas flow rate so that dioxane
elutes in about 6 minutes. Chromatograph the standard preparation, and
record the peak responses as directed under procedure; the resolution
(R) between adjacent peaks is not less than 2.0; the relative standard
deviations of the ratios of the peak responses of the acetone and
dioxane peaks and of the alcohol and dioxane peaks for replicate
injections is not more than 4.0 percent; and the tailing factor for the
alcohol peak is not more than 1.5.
(v) Procedure. (Note: Use peak areas where peak responses are
indicated.) Separately inject equal volumes (about 1 microliter) of the
standard preparation and the test preparation into the chromatograph,
record the chromatograms, and measure the responses for the major
peaks. The relative retention times are about 0.2 for acetone, 0.5 for
alcohol, and 1.0 for dioxane. Calculate the percentage, by weight, of
acetone and alcohol, respectively, in the sample as follows:
X = Percent acetone or alcohol = 100(CA/CD)(DU/
WU)(RU/RS)
where:
CA = Concentration of acetone or alcohol in the standard
preparation in milligrams per milliliter;
CD = Concentration of dioxane in the standard preparation in
milligrams per milliliter;
DU = Total quantity of dioxane in the test preparation, in
milligrams;
WU = Quantity of doxorubicin hydrochloride taken to prepare the
test preparation, in milligrams;
RU = Response ratio of the analyte peak (acetone or alcohol) to
the dioxane peak obtained from the test preparation; and
RS = Response ratio of the analyte peak (acetone or alcohol) to
the dioxane peak obtained from the standard preparation.
The total of acetone and alcohol is not greater than 2.5 percent. Use
the result obtained to calculate the doxorubicin hydrochloride content
of the sample on the solvent-free basis.
* * * * *
(8) Chromatographic purity. Proceed as directed in paragraph (b)(1)
of this section, except prepare the sample solution by dissolving the
sample to be tested in mobile phase to obtain a solution containing
approximately 0.5 milligram of doxorubicin hydrochloride per
milliliter. Calculate the percentage of impurities as follows:
Percent total impurities = (100 S)/(S + r)
where:
S = The sum of the responses of the minor component peaks; and
r = The response of the major doxorubicin hydrochloride peak.
The total related impurities detected is not more than 2.0 percent.
3. Section 450.224a is amended by revising paragraphs (a)(1),
(a)(3)(i)(a), (a)(3)(i)(b), the last sentence in the introductory text
of paragraph (b), paragraphs (b)(1) and (b)(3); and by removing and
reserving paragraph (b)(4) to read as follows:
Sec. 450.224a Doxorubicin hydrochloride for injection.
(a) Requirements for certification--(1) Standards of identity,
strength, quality, and purity. Doxorubicin hydrochloride for injection
is a freeze-dried powder whose components are doxorubicin hydrochloride
and lactose. It may also contain methylparaben. Its doxorubicin
hydrochloride content is satisfactory if it is not less than 90 percent
and not more than 115 percent of the number of milligrams of
doxorubicin hydrochloride that it is represented to contain. It is
sterile. It contains not more than 2.2 U.S.P. endotoxin units per
milligram of doxorubicin hydrochloride. Its moisture content is not
more than 4.0 percent. When reconstituted as directed in the labeling,
its pH is not less than 4.5 and not more than 6.5. It passes the
identity test. The doxorubicin hydrochloride used conforms to the
standards prescribed by Sec. 450.24(a)(1).
* * * * *
(3) * * *
(i) * * *
(a) The doxorubicin hydrochloride used in making the batch for
doxorubicin hydrochloride content, residue solvents, depressor
substances, moisture, pH, crystallinity, identity, and total related
impurities.
(b) The batch for doxorubicin hydrochloride content, sterility,
bacterial endotoxins, moisture, pH, and identity.
* * * * *
(b) * * * Dispose of all waste material by dilution with large
volumes of sodium hypochlorite (bleach) solution.
(1) Doxorubicin hydrochloride content (high-performance liquid
chromatography). Proceed as directed in Sec. 450.24(b)(1), preparing
the sample solution and calculating the doxorubicin hydrochloride
content as follows:
(i) Sample solution. Prepare the sample solution by rinsing the
contents of the vial into an appropriate sized volumetric flask with
sufficient mobile phase to obtain a concentration of 0.1 milligram of
doxorubicin hydrochloride per milliliter (estimated).
(ii) Calculations. Calculate the doxorubicin hydrochloride content
per vial as follows:
AU X PS X d
Milligrams of doxorubicin hydrochloride per = ---------------------
vial AS X 1,000
where:
AU = Area of the doxorubicin hydrochloride peak in the
chromatogram of the sample (at a retention time equal to that
observed for the standard);
AS = Area of the doxorubicin hydrochloride peak in the
chromatogram of the doxorubicin hydrochloride working standard;
PS = Doxorubicin hydrochloride activity in the doxorubicin
hydrochloride working standard solution in micrograms per
milliliter; and
d = Dilution factor of the sample.
* * * * *
(3) Bacterial endotoxins. Proceed as directed in the United States
Pharmacopeia (U.S.P.) Bacterial Endotoxin Test, using a solution of
doxorubicin hydrochloride for injection containing 1.1 milligrams of
doxorubicin hydrochloride per milliliter. The specimen under test
contains not more than 2.2 U.S.P. endotoxin units per milligram of
doxorubicin hydrochloride.
(4) [Reserved]
* * * * *
4. Section 450.224b is amended by revising paragraphs (a)(1),
(a)(3)(i)(A), (a)(3)(i)(B), the last sentence in the introductory text
of paragraph (b), and paragraph (b)(1); by removing and reserving
paragraph (b)(2); and by revising paragraph (b)(4) to read as follows:
Sec. 450.224b Doxorubicin hydrochloride injection.
(a) Requirements for certification--(1) Standards of identity,
strength, quality, and purity. Doxorubicin hydrochloride injection is
an aqueous solution of doxorubicin hydrochloride in an isosmotic
diluent. Each milliliter contains doxorubicin hydrochloride equivalent
to 2 milligrams of doxorubicin hydrochloride. Its doxorubicin
hydrochloride content is satisfactory if it is not less than 90 percent
and not more than 115 percent of the number of milligrams it is
represented to contain. It is sterile. It contains not more than 2.2
U.S.P. endotoxin units per milligram of doxorubicin hydrochloride. Its
pH is not less than 2.5 and not more than 3.5. It passes the identity
test. The doxorubicin hydrochloride used conforms to the standards
prescribed by Sec. 450.24(a)(1).
* * * * *
(3) * * *
(i) * * *
(A) The doxorubicin hydrochloride used in making the batch for
doxorubicin hydrochloride content, residue solvents, depressor
substances, moisture, pH, crystallinity, identity, and total related
impurities.
(B) The batch for doxorubicin hydrochloride content, sterility,
bacterial endotoxins, pH, and identity.
* * * * *
(b) * * * Dispose of all waste material by dilution with large
volumes of sodium hypochlorite (bleach) solution.
(1) Doxorubicin hydrochloride content (high-performance liquid
chromatography). Proceed as directed in Sec. 450.24(b)(1), preparing
the sample solution and calculating the doxorubicin hydrochloride
content as follows:
(i) Sample solution. Dilute an accurately measured volume of
sample equivalent to not less than 2 milligrams of doxorubicin
hydrochloride, quantitatively with mobile phase to obtain a solution
containing 0.1 milligram of doxorubicin hydrochloride per milliliter
(estimated).
(ii) Calculations. Calculate the milligrams of doxorubicin
hydrochloride per milliliter of sample as follows:
AU X PS X d
Milligrams of doxorubicin hydrochloride per = ---------------------
milliliter AS X 1,000
where:
AU = Area of the doxorubicin hydrochloride peak in the
chromatogram of the sample (at a retention time equal to that
observed for the standard);
AS = Area of the doxorubicin hydrochloride peak in the
chromatogram of the doxorubicin hydrochloride working standard;
PS = Doxorubicin hydrochloride activity in the doxorubicin
hydrochloride working standard solution in micrograms per
milliliter; and
d = Dilution factor of the sample.
(2) [Reserved]
* * * * *
(4) Bacterial endotoxins. Proceed as directed in the United States
Pharmacopeia (U.S.P.) Bacterial Endotoxin Test, using a test solution
prepared by diluting doxorubicin hydrochloride injection with sterile
water for injection to obtain a concentration of 1.1 milligrams of
doxorubicin hydrochloride per milliliter. The specimen under test
contains not more than 2.2 U.S.P. endotoxin units per milligram of
doxorubicin hydrochloride.
* * * * *
Dated: February 18, 1994.
Albert Rothschild,
Acting Director, Office of Compliance, Center for Drug Evaluation and
Research.
[FR Doc. 94-4518 Filed 2-28-94; 8:45 am]
BILLING CODE 4160-01-F
