[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) *  *  *

                                                                                                                
----------------------------------------------------------------------------------------------------------------
            Dosage form               Dissolution medium    Rotation rate\1\    Sampling times(s)     Apparatus 
----------------------------------------------------------------------------------------------------------------
  *                    *                    *                    *                    *                    *    
                                                             *                                                  
  Cefpodoxime proxetil tablets....  900 mL pH 3.0 glycine                 75  30 min...............            2
                                     buffer.                                                                    
  *                    *                    *                    *                    *                    *    
                                                             *                                                  
----------------------------------------------------------------------------------------------------------------
\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