[Federal Register Volume 60, Number 227 (Monday, November 27, 1995)]
[Rules and Regulations]
[Pages 58229-58234]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-28893]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 430, 436, and 442
[Docket No. 95N-0186]
Antibiotic Drugs; Cefpodoxime Proxetil, Cefpodoxime Proxetil
Tablets, and Cefpodoxime Proxetil Granules for Oral Suspension
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 include accepted standards for a new
antibiotic drug, cefpodoxime proxetil, and its use in two dosage forms,
cefpodoxime proxetil tablets and cefpodoxime proxetil granules for oral
suspension. The manufacturer has supplied sufficient data and
information to establish its safety and efficacy.
DATES: Effective December 27, 1995; written comments, notice of
participation, and request for a hearing by December 27, 1995; data,
information, and analyses to justify a hearing by January 26, 1996.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,
Rockville, MD 20857.
[[Page 58230]]
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 of a new antibiotic drug, cefpodoxime
proxetil, and its use in two dosage forms, cefpodoxime proxetil tablets
and cefpodoxime proxetil granules for oral suspension. 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 430, 436, and 442 to include 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 December 27, 1995. However, interested persons may, on or
before December 27, 1995, 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 December 27, 1995, a written notice of
participation and request for a hearing, and (2) on or before January
26, 1996, 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
21 CFR Part 430
Administrative practice and procedure, Antibiotics.
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 430, 436, and 442 are amended as follows:
PART 430--ANTIBIOTIC DRUGS; GENERAL
1. The authority citation for 21 CFR part 430 continues to read as
follows:
Authority: Secs. 201, 501, 502, 503, 505, 507, 701 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353,
355, 357, 371); secs. 215, 301, 351 of the Public Health Service Act
(42 U.S.C. 216, 241, 262).
2. Section 430.4 is amended by adding new paragraph (a)(70) to
read as follows:
Sec. 430.4 Definitions of antibiotic substances.
(a) * * *
(70) Cefpodoxime proxetil. Cefpodoxime proxetil is an antibiotic
substance having the chemical structure described by the following
name: ()-1-Hydroxyethyl(+)-(6R,7R)-7-[2-(2-amino-4-
thiazolyl)glyoxylamido]-3-(methoxymethyl)-8-oxo-5-thia-1-
azabicyclo[4.2.0]oct-2-ene-2-carboxylate,72-(Z)-(O-methyloxime),
isopropyl carbonate (ester).
* * * * *
3. Section 430.5 is amended by adding new paragraphs (a)(105) and
(b)(107) to read as follows:
Sec. 430.5 Definitions of master and working standards.
(a) * * *
(105) Cefpodoxime proxetil. The term ``cefpodoxime proxetil
master standard'' means a specific lot of the (R) isomer of cefpodoxime
proxetil that is designated by the Commissioner as the standard of
comparison in determining the potency of the cefpodoxime proxetil
working standard.
(b) * * *
(107) Cefpodoxime proxetil. The term ``cefpodoxime proxetil working
standard'' means a specific lot of a homogeneous preparation of
cefpodoxime proxetil.
4. Section 430.6 is amended by adding new paragraph (b)(107) to
read as follows:
Sec. 430.6 Definitions of the terms ``unit'' and ``microgram'' as
applied to antibiotic substances.
-* -* * * *
(b) * * *
(107) Cefpodoxime proxetil.- The term ``microgram'' applied to
cefpodoxime proxetil means the cefpodoxime (potency) contained in 1.304
micrograms of the cefpodoxime proxetil master standard when dried.
PART 436--TESTS AND METHODS OF ASSAY OF ANTIBIOTIC AND ANTIBIOTIC-
CONTAINING DRUGS
5. 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).
6. Section 436.215 is amended by alphabetically adding a new entry
to the table in paragraph (b) and by adding new paragraph (c)(19) to
read as follows:
Sec. 436.215 Dissolution test.
-* * * * *
[[Page 58231]]
(b) * * *
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Dosage form Dissolution medium Rotation rate\1\ Sampling times(s) Apparatus
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* * * * * *
*
Cefpodoxime proxetil tablets.... 900 mL pH 3.0 glycine 75 30 min............... 2
buffer.
* * * * * *
*
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\1\ Rotation rate of basket or paddle stirring element (revolutions per minute).
(c) * * *
(19) Cefpodoxime proxetil--(i) Dissolution fluid: 0.04 molar
glycine buffer, pH 3.0--(A) Stock solution. Dissolve 54.5 grams of
glycine (aminoacetic acid) and 42.6 grams of sodium chloride in about
500 milliliters of deionized water in a 1-liter volumetric flask. Add
cautiously, and with swirling, 14.2 milliliters of concentrated
hydrochloric acid. Cool to room temperature. Dilute to volume with
deionized water and mix. Check the pH of the solution obtained by
diluting 50 milliliters of the stock solution to 900 milliliters with
deionized water. The pH should be 3.00.1. If necessary,
adjust the pH of the stock solution with 50 percent sodium hydroxide or
concentrated hydrochloric acid. Recheck that the pH of the working
solution is 3.00.1.
(B) Working solution. Dilute 50 milliliters of stock solution to
900 milliliters with deionized water.
(ii) Preparation of the working standard solutions. Accurately
weigh approximately 28 milligrams for the 100-milligram tablets and 56
milligrams for the 200-milligram tablets of the cefpodoxime proxetil
working standard and dissolve in 10 milliliters of methanol. Dilute to
200 milliliters with dissolution fluid. Prepare fresh daily.
(iii) Sample solutions. Filter the sample solutions through a
0.45-micron filter before use. Use the sample solution as it is removed
from the dissolution vessel without further dilution.
(iv) Procedure. Using a suitable spectrophotometer and water as
the blank, determine the absorbance of each standard and sample
solution at the absorbance peak at approximately 259 nanometers.
Determine the exact position of the absorption peak for the particular
instrument used.
(v) Calculations. Determine the percent of label dissolved as
follows:
Percent dissolved = (Asam/Astd) X (Cs/L) X V X P X
F1
where:
Asam = Absorbance of the sample at 259 nanometers;
Astd = Absorbance of the working standard solution at 259
nanometers;
Cs = Concentration of the working standard preparation in
milligrams per milliliter;
L = Tablet strength, in milligrams per tablet;
P = Purity of the reference standard in percent;
V = Volume of dissolution fluid used in milliliters (900); and
F1 = 0.7666 (conversion factor to free acid equivalents).
PART 442--CEPHA ANTIBIOTIC DRUGS
7. 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).
8. New Sec. 442.54 is added to subpart A to read as follows:
Sec. 442.54 Cefpodoxime proxetil.
(a) Requirements for certification--(1) Standards of identity,
strength, quality, and purity. Cefpodoxime proxetil is ()-
1-hydroxyethyl(+)-(6R,7R)-7-[2-(2-amino-4-thiazolyl)glyoxylamido]-3-
(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylate,72-(Z)-(O-methyloxime), isopropyl carbonate (ester).
It is so purified and dried that:
(i) Its potency is not less than 690 micrograms and not more than
804 micrograms of cefpodoxime activity per milligram, on an anhydrous
basis.
(ii) The ratio of its R-epimer to total cefpodoxime is not less
than 0.5 and not more than 0.6.
(iii) Its moisture content is not more than 3 percent.
(iv) It gives a positive identity test.
(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 cefpodoxime
potency, isomer ratio, 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, using a suitable thermostatted column
heating mechanism to maintain a column temperature of 40 deg.C, an
ultraviolet detection system operating at a wavelength of 254
nanometers, a 15 centimeter X 4.6 millimeter (i.d.) column packed with
microparticulate (5 micrometers in diameter) reversed phase packing
material such as octadecyl silane bonded to silicas, a flow rate of 0.8
milliliter per minute, and a known injection volume of 2 microliters.
The retention time for the S-epimer is approximately 22 minutes and the
retention time for R-epimer is approximately 28 minutes. The internal
standard (propylparaben) has a retention time of 34 minutes. Mobile
phase, dilution solvent, resolution solution, internal standard
solution, working standard and sample solutions, system suitability
requirements, and calculations are as follows:
(i) Mobile phase. The mobile phase consists of 420 milliliters of
methanol, 580 milliliters of deionized water, and 230 milligrams of L-
histidine hydrochloride. The pH is adjusted to 2.50.1 using
2N sulfuric acid. The mobile phase must be at room temperature for a
correct pH measurement. The methanol concentration may be adjusted to
achieve comparable retention times from column to column. Increasing
methanol reduces retention times. Filter the mobile phase through a
suitable filter capable of removing particulate matter 0.5 micron in
diameter and degas it just before its introduction into the
chromatograph.
(ii) Dilution solvent. Prepare a solvent for dilution by
thoroughly mixing 495 milliliters of deionized water, 495 milliliters
of acetonitrile, and 10 milliliters of acetic acid in an appropriate
container.
(iii) Resolution solution. Prepare a 1 milligram per milliliter
solution of any bulk containing ANTI-A in dilution solvent. Use this
solution to determine the resolution between ANTI-A and the
[[Page 58232]]
later-eluting drug epimer (R-epimer). Alternately, the resolution
factor can be determined between the R and S isomers.
(iv) Internal standard solution. Prepare a solution of
propylparaben in dilution solvent at a concentration of 10 milligrams
per milliliter.
(v) Preparation of working standard solutions. Accurately weigh
approximately 42 milligrams of the cefpodoxime proxetil working
reference standard add 3 milliliters of internal standard solution and
25 milliliters of dilution solvent. The standard solution is stable for
at least 48 hours. Refrigeration is not recommended.
(vi) Sample solution. Accurately weigh approximately 42 milligrams
of the sample, add 3 milliliters of internal standard and 25
milliliters of dilution solvent. The sample solution is stable for at
least 48 hours. Refrigeration is not recommended.
(vii) System suitability requirements--(A) Asymmetry factor.The
asymmetry factor (As) is satisfactory if it is not less than 0.8
and not more than 1.1 for the R-epimer of cefpodoxime peak.
(B) Efficiency of the column. The absolute efficiency (hr)
is satisfactory if it is not more than 5 for the R-epimer peak.
(C) Resolution factor. The resolution factor (R) between the peak
for ANTI-A and the peak for the R-epimer is satisfactory if it is not
less than 1.3. Alternately, the resolution factor (R) between the peak
for the R-epimer and the peak for the S-epimer of cefpodoxime is not
less than 11.
(D) Coefficient of variation (Relative standard deviation). The
coefficient of variation (SR in percent of 5 replicate injections)
is satisfactory if it is not more than 2 percent.
(E) Capacity factor (k'). The capacity factor (k') for the R-epimer
of cefpodoxime is satisfactory if it is not less than 10.4 and not more
than 15.6.
(F) If the system suitability parameters in this paragraph
(b)(1)(iv) have been met, then proceed as described in Sec. 436.216(b)
of this chapter.
(viii) Calculations. Calculate the micrograms of cefpodoxime
proxetil per milligram of sample on an anhydrous basis as follows:
Ru X Ps X 100
Micrograms of cefpodoxime = -----------------------------------
proxetil per milligram Rs X Cu X (100-m)
where:
Ru = Ratio of cefpodoxime proxetil peaks area (sum of both
epimers) to the internal standard peak response in the sample
solution;
Rs = Ratio of cefpodoxime proxetil peaks area (sum of both
epimers) to the internal standard peak response in the working
standard solution;
Ps = Cefpodoxime proxetil activity of the 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) Isomer ratio. Using the procedure described in paragraph
(b)(1) of this section, calculate the ratio of the R-epimer (Ab) to the
sum of the S-epimer and R-epimer (Aa and Ab), by the equation
Isomer Ratio = Ab/(Aa + Ab)
where:
Aa = Area of the early eluting S-epimer peak; and
Ab = Area of the late eluting R-epimer peak.
(3) Moisture. Proceed as directed in Sec. 436.201 of this chapter,
except use 30 milliliters of solvent C instead of 20 milliliters of
solvent A.
(4) Identity. Proceed as directed in Sec. 436.211 of this chapter,
using the mineral oil mull prepared as described in paragraph (b)(2) of
that section.
9. New Secs. 442.154, 442.154a, and 442.154b are added to subpart B
to read as follows:
Sec. 442.154 Cefpodoxime proxetil oral dosage forms.
Sec. 442.154a Cefpodoxime proxetil tablets.
(a) Requirements for certification--(1) Standards of identity,
strength, quality, and purity. Cefpodoxime proxetil tablets are
composed of cefpodoxime proxetil and one or more suitable and harmless
diluents, binders, lubricants, colorings, and coating substances. Each
tablet contains cefpodoxime proxetil equivalent to either 100
milligrams or 200 milligrams of cefpodoxime. Its cefpodoxime proxetil
content is satisfactory if it is not less than 90 percent and not more
than 110 percent of the number of milligrams of cefpodoxime that it is
represented to contain. Its loss on drying is not more than 5 percent.
It passes the dissolution test. It passes the identity test. The
cefpodoxime proxetil used conforms to the standards prescribed by
Sec. 442.54(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 cefpodoxime proxetil used in making the batch for potency,
isomer ratio, moisture, and identity.
(B) The batch for content, loss on drying, dissolution, and
identity.
(ii) Samples, if required by the Director, Center for Drug
Evaluation and Research:
(A) The cefpodoxime proxetil 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) Cefpodoxime content. Proceed as
directed in Sec. 442.54(b)(1), preparing the sample solution and
calculating the cefpodoxime content as follows:
(i) Preparation of sample solution. Obtain the average tablet
weight of at least 20 tablets. Grind the tablets using a mortar and
pestle. Weigh approximately 660 milligrams into a suitable container.
Add 30 milliliters of internal standard solution. Shake for 30 minutes
using a horizontal platform shaker or equivalent. Centrifuge for about
10 minutes at 3,000 revolutions per minute until the particulate matter
has settled. Withdraw a 1 milliliter aliquot of the supernatant and
dilute with 9 milliliters of dilution solvent. The sample solutions are
stable for at least 48 hours. Refrigeration is not recommended.
(ii) Calculations. Calculate the cefpodoxime content as follows:
Milligrams of cefpodoxime per tablet = (Rsam/Rstd) X (Wstd/Wsam) X (F1/F3) X F2 X F4 X P
[[Page 58233]]
where:
Rsam = Ratio of cefpodoxime proxetil peaks area (sum of both
epimers) to the internal standard peak area in the sample
preparation;
Rstd = Ratio of cefpodoxime proxetil peaks area (sum of both
epimers) to the internal standard peak area in the standard
preparation;
Wstd = Weight of cefpodoxime proxetil reference standard, in
milligrams;
Wsam = Weight of sample, in milligrams;
F1 = Volume of internal standard used in the sample
preparation, in milliliters;
F2 = 0.766; The ratio of molecular weight for free-acid
cefpodoxime over the molecular weight of cefpodoxime proxetil
(427.46/557.61);
F3 = Volume of internal standard used in the standard
preparation, in milliliters;
F4 = Average tablet weight, i.e., weight of tablets used in
sample preparation divided by the number of tablets; and
P = Purity of the cefpodoxime proxetil reference standard, expressed
as a decimal.
(2) Loss on drying. Proceed as directed in Sec. 436.200(a) of this
chapter, except dry the sample at a temperature of 80 deg.C and a
pressure of 5 millimeters of mercury or less for 16 hours.
(3) Dissolution test. Proceed as directed in Sec. 436.215 of this
chapter. The quantity Q (the amount of cefpodoxime activity dissolved)
is 70 percent within 30 minutes.
(4) Identity. Using the high-performance liquid chromatographic
procedure described in paragraph (b)(1) of this section, the retention
times for the peaks of the active ingredients must be within 2 percent
of the retention times for the peaks of the corresponding reference
standards.
Sec. 442.154b Cefpodoxime proxetil granules for oral suspension.
(a) Requirements for certification--(1) Standards of identity,
strength, quality, and purity. Cefpodoxime proxetil granules for oral
suspension is cefpodoxime proxetil and one or more suitable and
harmless preservatives, sweeteners, suspending agents, buffers, and
flavorings. When constituted as directed in the labeling, each
milliliter contains the equivalent of either 10 or 20 milligrams
cefpodoxime activity. Its cefpodoxime proxetil content is satisfactory
if it is not less than 90 percent and not more than 110 percent of the
number of milligrams of cefpodoxime that it is represented to contain.
Its loss on drying is not more than 0.5 percent. When constituted as
described in the labeling, the pH of the suspension is not less than 4
and not more than 5.5. It passes the identity test. The cefpodoxime
proxetil used conforms to the standards prescribed by
Sec. 442.54(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 cefpodoxime proxetil used in making the batch for potency,
isomer ratio, moisture, and identity.
(B) The batch for content, loss on drying, pH, and identity.
(ii) Samples, if required by the Director, Center for Drug
Evaluation and Research:
(A) The cefpodoxime proxetil used in making the batch: 10 packages,
each containing approximately 500 milligrams.
(B) The batch: A minimum of 10 intermediate containers.
(b) Tests and methods of assay--(1) Cefpodoxime content. Proceed
as directed in Sec. 442.54(b)(1), preparing the sample solution and
calculating the cefpodoxime content as follows:
(i) Preparation of sample solution. Reconstitute as directed in
the labeling. Immediately before sampling the suspension, shake
vigorously for several seconds. Into a suitable container, accurately
weigh out 6 grams of the 50 milligrams per 5 milliliters suspension, or
3 grams of the 100 milligrams per 5 milliliters suspension. Add 5
milliliters of internal standard solution and 25 milliliters of
dilution solvent. Shake for 30 minutes using a horizontal platform
shaker or equivalent. Centrifuge for about 10 minutes at 3,000
revolutions per minute until the particulate matter has settled.
Withdraw a 1 milliliter aliquot of the supernatant and dilute with 1
milliliter of dilution solvent. The sample solutions are stable for at
least 48 hours. Refrigeration is not recommended.
(ii) Calculations. Calculate the cefpodoxime content as follows:
Milligrams of cefpodoxime per 5 milliliters of
suspension = (Rsam/Rstd) X (Wstd/Wsam) X (F1/F3) X (F2/F4) X F5 X P
where:
Rsam = Ratio of cefpodoxime proxetil peaks area (sum of both
epimers) to the internal standard peak area in the sample
preparation;
Rstd = Ratio of cefpodoxime proxetil peaks area (sum of both
epimers) to the internal standard peak area in the standard
preparation;
Wstd = Weight of cefpodoxime proxetil reference standard, in
milligrams;
Wsam = Weight of sample, in grams;
F1 = Volume of internal standard used in the sample;
preparation, in milliliters;
F2 = 0.766; The ratio of molecular weight for free-acid
cefpodoxime over the molecular weight of cefpodoxime proxetil
(427.46/557.61);
F3 = Volume of internal standard used in the standard
preparation, in milliliters;
F4 = 0.2; Factor to convert to 5 milliliters;
F5 = Specific gravity of suspension for milligram per 5
milliliter calculated on the air-free basis (specific gravity is
determined on a sample of suspension that has been shaken gently on
a platform shaker under vacuum for 2 hours); and
P = Purity of the cefpodoxime proxetil reference standard, expressed
as a decimal.
(2) Loss on drying. Proceed as directed in Sec. 436.200(a) of
this chapter, except dry the sample at a temperature of 80 deg.C and a
pressure of 5 millimeters of mercury or less for 16 hours.
(3) pH. Proceed as directed in Sec. 436.202 of this chapter,
using the drug constituted as directed in the labeling.
[[Page 58234]]
(4) Identity. Using the high-performance liquid chromatographic
procedure described in paragraph (b)(1) of this section, the retention
times for the peaks of the active ingredients must be within 2 percent
of the retention times for the peaks of the corresponding reference
standards.
Dated: November 13, 1995.
Murray M. Lumpkin,
Deputy Director, Center for Drug Evaluation and Research.
[FR Doc. 95-28893 Filed 11-24-95; 8:45 am]
BILLING CODE 4160-01-F
