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Milligrams of imipenem or cilastatin

4, XP, xd per container

A, X1,000 where: Ax=Area of the imipenem or cilastatin peak

in the chromatogram of the sample (at a retention time equal to that observed for

the standard); Ag=Area of the Imipenem or cilastatin peak

in the chromatogram of the Imipenem or

cilastatin working standard: Pg=Anhydrous Imipenem or cilastatin activ

ity in the Imipenem or cilastatin working standard solution in micrograms per

milliliter; and d=Dilution factor of the sample.

442.202 Sterile cefonicid sodium. 442.21 Cephaloglycin dihydrate. 442.22a Sterile cefmenoxime hydrochloride. 442.23a Sterile cephaloridine. 442.25a Sterile cephalothin sodium. 442.27 Cephalexin monohydrate. 442.28 Cephalexin

hydrochloride monohydrate. 442.29a Sterile cephapirin sodium. 442.40 Cephradine. 442.40a Sterile cephradine. 442.41 Cephradine dihydrate. 442.50a Sterile ceforanide. 442.52 Cefotetan. 442.53a Sterile cefotetan disodium. 442.54 Cefpodoxime proxetil. 442.55 Ceftriaxone sodium. 442.55a Sterile ceftriaxone sodium. 442.58a Sterile cefotiam dihydrochloride. 442.60 Cefpiramide. 442.69 Cefmetazole. 442.70a Sterile cefmetazole sodium. 442.80 Cefprozil.

Subpart B-Oral Dosage Forms

(2) Sterility. Proceed as directed in § 436.20 of this chapter, using the method described in paragraph (e)(1) of that section.

(3) Pyrogens. Proceed as directed in $ 436.32(a) of this chapter, using a solution containing 5.0 milligrams of imipenem per milliliter except inject 10 milliliters per kilogram of rabbit weight.

(4) Loss on drying. Proceed as directed in § 436.200(a) of this chapter.

(5) PH. Proceed as directed in $436.202 of this chapter.

(51 FR 11573, Apr. 4, 1986; 51 FR 22275, June 19, 1986, as amended at 55 FR 11582, Mar. 29, 1990. Redesignated at 58 FR 26669, May 4, 1993]

PART 442-CEPHA ANTIBIOTIC

DRUGS

Subpart A-Bulk Drugs

Sec. 442.4 Cefaclor monohydrate. 442.6 Cefadroxil monohydrate. 442.7 Cefadroxil hemihydrate. 442.8a Sterile cefamandole nafate. 442.9a Sterile cefamandole sodium. 442.10 Cefazolin. 442.11a Sterile cefazolin sodium. 442.12 Cefoperazone sodium. 442.12a Sterile cefoperazone sodium. 442.13 Cefotaxime sodium. 442.13a Sterile cefotaxime sodium. 442.14 Cefoxitin sodium. 442.14a Sterile cefoxitin sodium. 442.15 Cefixime trihydrate. 442.16 Ceftazidime pentahydrate. 442.16a Sterile ceftazidime pentahydrate. 442.17 Ceftizoxime sodium. 442.17a Sterile ceftizoxime sodium. 442.18 Cefuroxime sodium. 442.18a Sterile cefuroxime sodium. 442.19 Cefuroxime axetil.

442.104 Cefaclor monohydrate oral dosage

forms. 442.104a Cefaclor monohydrate capsules. 442.104b Cefaclor monohydrate for oral sus

pension. 442.106 Cefadroxil monohydrate oral dosage

forms. 442.106a Cefadroxil monohydrate capsules. 442.106b Cefadroxil monohydrate tablets. 442.106c Cefadroxil monohydrate for oral

suspension. 442.107 Cefadroxil hemihydrate oral dosage

forms. 442.107a Cefadroxil hemihydrate capsules. 442.107b Cefadroxil hemlhydrate tablets. 442.115 Cefiximetrihydrate oral dosage

forms. 442.115a Cefixime trihydrate for oral suspen

sion. 442.115b Cefixime trihydrate tablets. 442.119 Cefuroxime axetil oral dosage forms. 442.119a Cefuroxime axetil tablets. 442.119b Cefuroxime axetil for oral suspen

sion. 442.121 Cephaloglycin dihydrate oral dosage

forms. 442.121a Cephaloglycin dihydrate capsules. 442.121b Cephaloglycin dihydrate for oral

suspension. 442.127 Cephalexin monohydrate oral dosage

forms. 442.127a Cephalexin monohydrate tablets. 442.127b Cephalexin monohydrate capsules. 442.127c Cephalexin monohydrate for oral

suspension. 442.128 Cephalexin

hydrochloride monohydrate tablets. 442.140a Cephradine for oral suspension. 442.140b Cephradine capsules. 442.140C Cephradine tablets. 442.141 Cephradine dihydrate capsules.

Subpart A-Bulk Drugs

442.154 Cefpodoxime proxetil oral dosage

forms. 442.154a Cefpodoxime proxetil tablets. 442.154b Cefpodoxime proxetil granules for

oral suspension. 442.180 Cefprozil oral dosage forms. 442.180a Cefprozil tablets. 442.180b Cefprozil for oral suspension.

Subpart C-Injectable Dosage Forms

442.208 Cefamandole nafate for injection. 442.209 Cefamandole sodium for injection. 442.211 Cefazolin sodium injectable dosage

forms. 442.211a Sterile cefazolin sodium. 442.211b Cefazolin sodium injection. 442.212 Cefoperazone injectable dosage

forms, 442.212a Sterile cefoperazone sodium. 442 2b Cefoperazone sodium injection. 442.213 Cefotaxime injectable dosage forms. 442.213a Sterile cefotaxime sodium. 442.213b Cefotaxime sodium injection, 442.214 Cefoxitin injectable dosage forms. 442.214a Sterile cefoxitin sodium. 442.214b Cefoxitin sodium injection. 442.216 Ceftazidime injectable dosage forms. 442.216a Ceftazidime pentahydrate for injec

tion. 442.216b Ceftazidime sodium injection. 442.217 Ceftizoxime injectable dosage forms. 442.217a Sterile ceftizoxime sodium. 442.217b Ceftizoxime sodium injection. 442.218 Cefuroxime injectable dosage forms. 442.218a Sterile cefuroxime sodium. 442.218b Cefuroxime sodium injection. 442.220 Sterile cefonicid sodium. 442.222 Cefmenoxime hydrochloride for in

jection. 442.223 Sterile cephaloridine. 442.225 Cephalothin sodium injectable dos

age forms. 442.225a Sterile sodium cephalothin. 442.225b Cephalothin sodium injection. 442.225C Cephalothin sodium for injection. 442.229 Sterile cephapirin sodium. 442.240 Cephradine injectable dosage forms. 442.240a Cephradine for injection. 442.240b Sterile cephradine. 442.250 Ceforanide for injection. 442.253 Cefotetan injectable dosage forms. 442.253a Sterile cefotetan disodium. 442.253b Cefotetan sodium injection. 442.255 Ceftriaxone injectable dosage forms. 442.255a Sterile ceftriaxone sodium. 442.255b Ceftriaxone sodium injection. 442.258 Cefotiam dihydrochloride for injec

tion. 442.260 Cefpiramide sodium for injection. 442.270 Cefmetazole injectable dosage forms. 442.270a Sterile cefmetazole sodium. 442.270b Cefmetazole sodium injection.

8 442.4 Cefaclor monohydrate.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Cefaclor monohydrate is the monohydrate form of (6R, 7R)-7-[(R)-2amino-2-phenylacetamido)-3-chloro-8oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene2-carboxylic acid. It is so purified and dried that:

(1) Its potency is not less than 860 micrograms and not more than 1,050 micrograms of cefaclor per milligram on an "as is” basis.

(ii) Its moisture content is not less than 3.0 percent and not more than 8.0 percent.

(iii) Its pH in an aqueous suspension containing 25 milligrams per milliliter is not less than 3.0 and not more than 4.5.

(iv) It gives a positive identity test. (v) It is crystalline.

(2) Labeling. It shall be labeled in accordance with the requirements of 8 432.5 of this chapter.

(3) Requests for certification; samples. In addition to complying with the requirements of $431.1 of this chapter, each such request shall contain:

(i) Results of tests and assays on the batch for potency, moisture, pH, identity, and crystallinity.

(ii) Samples required: 10 packages, each containing approximately 300 milligrams.

(b) Tests and methods of assay-(1) Potency. Use either of the following methods; however, the results obtained from the hydroxylamine colorimetric assay shall be conclusive.

(1) Microbiological agar diffusion assay. Proceed as directed in $436.105 of this chapter, preparing the sample for assay

follows: Dissolve an accurately weighed sample in sufficient 1 percent potassium phosphate buffer, pH 6.0 (80lution 1), to obtain a stock solution containing 1 milligram of cefaclor per milliliter (estimated). Further dilute an aliquot of the stock solution with solution 1 to the reference concentration of 5.0 micrograms of cefaclor per milliliter (estimated).

(ii) Hydroxylamine colorimetric assay. Proceed as directed in $442.40(b)(1)(11) of this chapter, except prepare the working standard and sample solutions

as

AUTHORITY: 21 U.S.C. 357.

SOURCE: 39 FR 19040, May 30, 1974, unless otherwise noted.

and calculate the cefaclor content as follows:

(a) Preparation of working standard solution. Dissolve and dilute an accurately weighed portion of the cefaclor working standard in sufficient 0.1M potassium phosphate buffer, pH 4.5 (as described in 8436.101(a)(4) of this chapter) to obtain a concentration of 1 milligram of cefaclor per milliliter.

(6) Preparation of sample solution. Dissolve an accurately weighed portion of the sample in sufficient 0.1M potassium phosphate buffer, pH 4.5 (as described in § 436.101(a)(4) of this chapter) to obtain a concentration of 1 milligram of cefaclor per milliliter.

(c) Calculations. Calculate the cefaclor content in micrograms per milligram as follows:

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micrograms of cefadroxil per milligram on an anhydrous basis.

(ii) [Reserved]

(iii) Its moisture content is not less than 4.2 percent and not more than 6.0 percent.

(iv) Its pH in an aqueous solution containing 50 milligrams per milliliter is not less than 4.0 and not more than 6.0.

(v) When calculated on an anhydrous basis, its absorptivity at 264 nanometers is not less than 95 percent and not more than 104 percent of that of the cefadroxil standard similarly treated and corrected for potency.

(vi) It passes the identity test. (vii) It is crystalline.

(2) Labeling. It shall be labeled in accordance with the requirements of $ 432.5 of this chapter.

(3) Requests for certification; samples. In addition to complying with the requirements of $ 431.1 of this chapter, each such request shall contain:

(1) Results of tests and assays on the batch for potency, moisture, pH, absorptivity, identity, and crystallinity.

(ii) Samples required: 10 packages, each containing approximately 500 milligrams.

(b) Tests and methods of assay-(1) Potency. Use either of the following methods; however, the results obtained from the hydroxylamine colorimetric assay shall be conclusive.

(i) Microbiological agar diffusion assay. Proceed as directed in $436.105 of this chapter, preparing the sample for assay as follows: Dissolve an accurately weighed sample in sufficient 1 percent potassium phosphate buffer, pH 6.0 (80lution 1), to give a stock solution of convenient concentration. Further dilute an aliquot of the stock solution with solution 1 to the reference concentration of 20 micrograms of cefadroxil per milliliter (estimated).

(ii) Hydroxylamine colorimetric assay for cefadroxil. Proceed as directed in $ 442.40(b)(1)(ii) of this chapter, except prepare the working standard and sample solutions and calculate the potency of the sample as follows:

(a) Preparation of working standard solutions. Dissolve and dilute an accurately weighed portion of the cefadroxil working standard in sufficient distilled water to obtain a stock

(2) Moisture. Proceed as directed in $ 436.201 of this chapter.

(3) PH. Proceed as directed in $436.202 of this chapter, using an aqueous suspension containing 25 milligrams per milliliter.

(4) Identity. Proceed as directed in $436.211 of this chapter, using the sample preparation described in paragraph (b)(2) of that section.

(5) Crystallinity. Proceed as directed in $ 436.203(a) of this chapter.

[46 FR 3832, Jan. 16, 1981)

$ 442.6 Cefadroxil monohydrate.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Cefadroxil monohydrate is 7-[D-2-amino-2-hydroxyphenyl)acetamido] - 3-methyl - 8 oxo-5-thia-1-azabicyclo(4.2.0) oct-2-ene2-carboxylic acid monohydrate. It is so purified and dried that:

(i) Its potency is not less than 900 micrograms and not more than 1,050

where:

m=Percent moisture in the samples.

solution of convenient concentration. Further dilute an aliquot of this solution with distilled water to a concentration of 1 milligram of cefadroxil per milliliter.

(6) Preparation of sample solutions. Dissolve an accurately weighed portion of the sample in sufficient distilled water to obtain a stock solution of convenient concentration. Further dilute an aliquot of this solution with distilled water to a concentration of 1 milligram of cefadroxil per milliliter (estimated).

(c) Calculate the potency of the sample in micrograms per milligram as follows:

(6) Identity. Using the sample and working standard solutions prepared as described in paragraph (b)(5) of this section and a suitable spectrophotometer, record the ultraviolet spectrum from 220 to 340 nanometers. The spectrum of the sample compares qualitatively with that of the cefadroxil working standard.

(7) Crystallinity. Proceed as directed in $436.203(a) of this chapter.

(43 FR 20977, May, 16, 1978; 43 FR 27180, June 23, 1978, as amended at 50 FR 19919, May 13, 1985]

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(2) [Reserved)

(3) Moisture. Proceed as directed in $ 436.201 of this chapter.

(4) pH. Proceed as directed in $436.202 of this chapter, using an aqueous solution containing 50 milligrams per milliliter.

(5) Absorptivity. Determine the absorbance of the sample and standard solutions in the following manner: Dissolve accurately weighed portions of approximately 50 milligrams each of the sample and standard in 250 milliliters of distilled water. Transfer a 10milliliter aliquot to a 100-milliliter volumetric flask and dilute to volume with distilled water. Using a suitable spectrophotometer and distilled water as the blank, determine the absorbance of each solution at 264 nanometers. Determine the percent absorptivity of the sample relative to the absorptivity of the standard using the following calculations:

8 442.7 Cefadroxil hemihydrate.

(a) Requirements for certification (1) Standards of identity, strength, quality, and purity. Cefadroxil hemihydrate is 7[D-2-amino-2(phydroxyphenyl)acetamido)-3-methyl-8oxo-5-thia-1-azabicyclo[4.2.O]oct-2-ene2-carboxylic acid hemihydrate. It is so purified and dried that:

(i) Its potency is not less than 900 micrograms and not more than 1,050 micrograms of cefadroxil activity per milligram on an anhydrous basis.

(ii) [Reserved]

(iii) Its moisture content is not less than 2.4 percent and not more than 4.5 percent.

(iv) The pH of an aqueous solution containing 50 milligrams per milliliter is not less than 4.0 and not more than 6.0.

(v) When calculated on an anhydrous basis, its absorptivity at 264 nanometers is not less than 95 percent and not more than 104 percent of that of the cefadroxil standard similarly treated and corrected for potency.

(vi) It passes the identity test. (vii) It is crystalline.

(2) Labeling. It shall be labeled in accordance with the requirements of $ 432.5 of this chapter.

(3) Requests for certification; samples. In addition to complying with the requirements of $431.1 of this chapter, each such request shall contain:

(i) Results of tests and assays on the batch for cefadroxil potency, moisture, pH, absorptivity, identity, and crystallinity.

(ii) Samples, if required by the Director, Center for Drug Evaluation and

Percent relative absorptivity=[Absorbance of

sample x milligrams standard x potency of standard in micrograms per milligram x 10]/[Absorbance of standard x milligrams sample x(100-m)]

Research: 10 packages, each containing approximately 500 milligrams.

(b) Tests and methods of assay-(1) Potency. Use either of the following methods; however, the results obtained from the hydroxylamine colorimetric assay shall be conclusive.

(1) Microbiological agar diffusion assay. Proceed as directed in $ 436.105 of this chapter, preparing the sample for assay as follows: Dissolve an accurately weighed sample in sufficient 1 percent potassium phosphate buffer, pH 6.0 (solution 1), to give a stock solution of convenient concentration. Further dilute an aliquot of the stock solution with solution 1 to the reference concentration of 20 micrograms of cefadroxil per milliliter (estimated).

(ii) Hydroxylamine colorimetric assay for cefadroxil. Proceed as directed in $ 442.40(b)(1)(ii), except prepare the working standard and sample solutions and calculate the potency of the sample as follows:

(A) Preparation of working standard solutions. Dissolve and dilute an accurately weighed portion of the cefadroxil working standard in sufficient distilled water to obtain a stock solution of convenient concentration. Further dilute an aliquot of this solution with distilled water to a concentration of 1 milligram of cefadroxil per milliliter.

(B) Preparation of sample solutions. Dissolve an accurately weighed portion of the sample in sufficient distilled water to obtain a stock solution of convenient concentration. Further dilute an aliquot of this solution with distilled water to a concentration of 1 milligram of cefadroxil per milliliter (estimated).

(C) Calculations. Calculate the potency of the sample in micrograms per milligram as follows:

(2) (Reserved)

(3) Moisture. Proceed as directed in $ 436.201 of this chapter.

(4) pH. Proceed as directed in $ 436.202 of this chapter, using an aqueous solution containing 50 milligrams per milliliter.

(5) Absorptivity. Determine the absorbance of the sample and standard solutions in the following manner: Dissolve accurately weighed portions of approximately 50 milligrams each of the sample and standard in 250 milliliters of distilled water. Transfer a 10milliliter aliquot to a 100-milliliter volumetric flask and dilute to volume with distilled water. Using a suitable spectrophotometer and distilled water as the blank, determine the absorbance of each solution at 264 nanometers. Determine the percent absorptivity of the sample relative to the absorptivity of the standard using the following calculations: Percent relative absorptivity = [Ab

sorbance of sample X milligrams standard X potency of standard in micrograms per milligram X 10]/[Absorbance of standard X milligrams sample X (100-m)]

where: m = Percent moisture in the samples.

(6) Identity. Using the sample and working standard solutions prepared as described in paragraph (b)(5) of this section and a suitable spectrophotometer, record the ultraviolet spectrum from 220 to 340 nanometers. The spectrum of the sample compares qualitatively with that of the cefadroxil working standard.

(7) Crystallinity. Proceed as directed in 8436.203(a) of this chapter.

(59 FR 8857, Feb. 24, 1994)

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§ 442.8a Sterile cefamandole nafate.

(a) Requirements for certification (1) Standards of identity, strength, quality, and purity. Sterile cefamandole nafate is the sodium salt of 7-D-mandelamido3-[[(1-methyl-1H

tetrazol-5yl)thio]methyl)-8-oxo-5-thia-1azabicyclo[4.2.0)-oct-2-ene-2carboxylate formate (ester). It is so purified and dried that:

(1) Its potency is not less than 810 micrograms and not more than 1,000

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