Pt. 442 21 CFR Ch. I (4–1–97 Edition)
Micrograms of PART 442—CEPHA ANTIBIOTIC A× P × d DRUGS imipenem or cilastatin = u s AW×1, 000 × per milligram s s Subpart A—Bulk Drugs where: Sec. Au=Area of the imipenem or cilastatin peak 442.4 Cefaclor monohydrate. in the chromatogram of the sample (at a 442.6 Cefadroxil monohydrate. retention time equal to that observed for 442.7 Cefadroxil hemihydrate. the standard); 442.8a Sterile cefamandole nafate. As=Area of the imipenem or cilastatin peak 442.9a Sterile cefamandole sodium. in the chromatogram of the imipenem or 442.10 Cefazolin. cilastatin acid working standard; 442.11a Sterile cefazolin sodium. Ps=Anhydrous imipenem or cilastatin activ- 442.12 Cefoperazone sodium. ity in the respective working standards 442.12a Sterile cefoperazone sodium. solutions in micrograms per milliliter; 442.13 Cefotaxime sodium. d=Dilution factor for the 10 samples; and 442.13a Sterile cefotaxime sodium. Ws=Net contents of 10 containers in grams 442.14 Cefoxitin sodium. (gross weight of 10 containers in grams– 442.14a Sterile cefoxitin sodium. tare weight of 10 containers in grams). 442.15 Cefixime trihydrate. 442.16 Ceftazidime pentahydrate. (b) Calculate the imipenem or 442.16a Sterile ceftazidime pentahydrate. cilastatin content of the container as 442.17 Ceftizoxime sodium. follows: 442.17a Sterile ceftizoxime sodium. 442.18 Cefuroxime sodium. 442.18a Sterile cefuroxime sodium. Milligrams of A× P × d imipenem or cilastatin = u s 442.19 Cefuroxime axetil. × 442.20a Sterile cefonicid sodium. per container As 1, 000 442.21 Cephaloglycin dihydrate. where: 442.22a Sterile cefmenoxime hydrochloride. 442.23a Sterile cephaloridine. A =Area of the imipenem or cilastatin peak u 442.25a Sterile cephalothin sodium. in the chromatogram of the sample (at a 442.27 Cephalexin monohydrate. retention time equal to that observed for 442.28 Cephalexin hydrochloride the standard); monohydrate. As=Area of the imipenem or cilastatin peak 442.29a Sterile cephapirin sodium. in the chromatogram of the imipenem or 442.40 Cephradine. cilastatin working standard: 442.40a Sterile cephradine. Ps=Anhydrous imipenem or cilastatin activ- 442.41 Cephradine dihydrate. ity in the imipenem or cilastatin work- 442.50a Sterile ceforanide. ing standard solution in micrograms per 442.52 Cefotetan. milliliter; and 442.53a Sterile cefotetan disodium. d=Dilution factor of the sample. 442.54 Cefpodoxime proxetil. (2) Sterility. Proceed as directed in 442.55 Ceftriaxone sodium. 442.55a Sterile ceftriaxone sodium. § 436.20 of this chapter, using the meth- 442.58a Sterile cefotiam dihydrochloride. od described in paragraph (e)(1) of that 442.60 Cefpiramide. section. 442.69 Cefmetazole. (3) Pyrogens. Proceed as directed in 442.70a Sterile cefmetazole sodium. § 436.32(a) of this chapter, using a solu- 442.80 Cefprozil. tion containing 5.0 milligrams of Subpart B—Oral Dosage Forms imipenem per milliliter except inject 10 milliliters per kilogram of rabbit 442.104 Cefaclor monohydrate oral dosage weight. forms. 442.104a Cefaclor monohydrate capsules. (4) Loss on drying. Proceed as directed 442.104b Cefaclor monohydrate for oral sus- in § 436.200(a) of this chapter. pension. (5) pH. Proceed as directed in § 436.202 442.106 Cefadroxil monohydrate oral dosage of this chapter. forms. 442.106a Cefadroxil monohydrate capsules. [51 FR 11573, Apr. 4, 1986; 51 FR 22275, June 19, 442.106b Cefadroxil monohydrate tablets. 1986, as amended at 55 FR 11582, Mar. 29, 1990. 442.106c Cefadroxil monohydrate for oral Redesignated at 58 FR 26669, May 4, 1993] suspension. 442.107 Cefadroxil hemihydrate oral dosage forms.
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442.107a Cefadroxil hemihydrate capsules. 442.222 Cefmenoxime hydrochloride for in- 442.107b Cefadroxil hemihydrate tablets. jection. 442.115 Cefixime trihydrate oral dosage 442.223 Sterile cephaloridine. forms. 442.225 Cephalothin sodium injectable dos- 442.115a Cefixime trihydrate for oral suspen- age forms. sion. 442.225a Sterile sodium cephalothin. 442.115b Cefixime trihydrate tablets. 442.225b Cephalothin sodium injection. 442.119 Cefuroxime axetil oral dosage forms. 442.225c Cephalothin sodium for injection. 442.119a Cefuroxime axetil tablets. 442.229 Sterile cephapirin sodium. 442.119b Cefuroxime axetil for oral suspen- 442.240 Cephradine injectable dosage forms. sion. 442.240a Cephradine for injection. 442.121 Cephaloglycin dihydrate oral dosage 442.240b Sterile cephradine. forms. 442.250 Ceforanid for injection. 442.121a Cephaloglycin dihydrate capsules. 442.253 Cefotetan injectable dosage forms. 442.121b Cephaloglycin dihydrate for oral 442.253a Sterile cefotetan disodium. suspension. 442.253b Cefotetan sodium injection. 442.127 Cephalexin monohydrate oral dosage 442.255 Ceftriaxone injectable dosage forms. forms. 442.255a Sterile ceftriaxone sodium. 442.127a Cephalexin monohydrate tablets. 442.255b Ceftriaxone sodium injection. 442.127b Cephalexin monohydrate capsules. 442.258 Cefotiam dihydrochloride for injec- 442.127c Cephalexin monohydrate for oral tion. suspension. 442.260 Cefpiramide sodium for injection. 442.128 Cephalexin hydrochloride 442.270 Cefmetazole injectable dosage forms. monohydrate tablets. 442.270a Sterile cefmetazole sodium. 442.140a Cephradine for oral suspension. 442.270b Cefmetazole sodium injection. 442.140b Cephradine capsules. AUTHORITY: Sec. 507 of the Federal Food, 442.140c Cephradine tablets. Drug, and Cosmetic Act (21 U.S.C. 357). 442.141 Cephradine dihydrate capsules. 442.154 Cefpodoxime proxetil oral dosage SOURCE: 39 FR 19040, May 30, 1974, unless forms. otherwise noted. 442.154a Cefpodoxime proxetil tablets. 442.154b Cefpodoxime proxetil granules for Subpart A—Bulk Drugs oral suspension. 442.180 Cefprozil oral dosage forms. § 442.4 Cefaclor monohydrate. 442.180a Cefprozil tablets. 442.180b Cefprozil for oral suspension. (a) Requirements for certification—(1) Standards of identity, strength, quality, Subpart C—Injectable Dosage Forms and purity. Cefaclor monohydrate is the monohydrate form of (6R, 7R)-7-[(R)-2- 442.208 Cefamandole nafate for injection. amino-2-phenylacetamido]-3-chloro-8- 442.209 Cefamandole sodium for injection. oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene- 442.211 Cefazolin sodium injectable dosage forms. 2-carboxylic acid. It is so purified and 442.211a Sterile cefazolin sodium. dried that: 442.211b Cefazolin sodium injection. (i) Its potency is not less than 860 442.212 Cefoperazone injectable dosage micrograms and not more than 1,050 forms. micrograms of cefaclor per milligram 442.212a Sterile cefoperazone sodium. on an ‘‘as is’’ basis. 442.212b Cefoperazone sodium injection. (ii) Its moisture content is not less 442.213 Cefotaxime injectable dosage forms. than 3.0 percent and not more than 8.0 442.213a Sterile cefotaxime sodium. percent. 442.213b Cefotaxime sodium injection. 442.214 Cefoxitin injectable dosage forms. (iii) Its pH in an aqueous suspension 442.214a Sterile cefoxitin sodium. containing 25 milligrams per milliliter 442.214b Cefoxitin sodium injection. is not less than 3.0 and not more than 442.216 Ceftazidime injectable dosage forms. 4.5. 442.216a Ceftazidime pentahydrate for injec- (iv) It gives a positive identity test. tion. (v) It is crystalline. 442.216b Ceftazidime sodium injection. (2) Labeling. It shall be labeled in ac- 442.217 Ceftizoxime injectable dosage forms. cordance with the requirements of 442.217a Sterile ceftizoxime sodium. 442.217b Ceftizoxime sodium injection. § 432.5 of this chapter. 442.218 Cefuroxime injectable dosage forms. (3) Requests for certification; samples. 442.218a Sterile cefuroxime sodium. In addition to complying with the re- 442.218b Cefuroxime sodium injection. quirements of § 431.1 of this chapter, 442.220 Sterile cefonicid sodium. each such request shall contain:
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(i) Results of tests and assays on the Wu = Milligrams of sample per milliliter of batch for potency, moisture, pH, iden- sample solution. tity, and crystallinity. (2) Moisture. Proceed as directed in (ii) Samples required: 10 packages, § 436.201 of this chapter. each containing approximately 300 mil- (3) pH. Proceed as directed in § 436.202 ligrams. of this chapter, using an aqueous sus- (b) Tests and methods of assay—(1) Po- pension containing 25 milligrams per tency. Use either of the following meth- milliliter. ods; however, the results obtained from (4) Identity. Proceed as directed in the hydroxylamine colorimetric assay § 436.211 of this chapter, using the sam- shall be conclusive. ple preparation described in paragraph (i) Microbiological agar diffusion assay. (b)(2) of that section. Proceed as directed in § 436.105 of this (5) Crystallinity. Proceed as directed chapter, preparing the sample for assay in § 436.203(a) of this chapter. as follows: Dissolve an accurately weighed sample in sufficient 1 percent [46 FR 3832, Jan. 16, 1981] potassium phosphate buffer, pH 6.0 (so- § 442.6 Cefadroxil monohydrate. lution 1), to obtain a stock solution containing 1 milligram of cefaclor per (a) Requirements for certification—(1) milliliter (estimated). Further dilute Standards of identity, strength, quality, an aliquot of the stock solution with and purity. Cefadroxil monohydrate is solution 1 to the reference concentra- 7-[D-2-amino-2(p-hydroxy- tion of 5.0 micrograms of cefaclor per phenyl)acetamido] - 3 - methyl - 8 - milliliter (estimated). oxo- 5-thia-1-azabicyclo[4.2.0] oct-2-ene- (ii) Hydroxylamine colorimetric assay. 2-carboxylic acid monohydrate. It is so Proceed as directed in § 442.40(b)(1)(ii) purified and dried that: of this chapter, except prepare the (i) Its potency is not less than 900 working standard and sample solutions micrograms and not more than 1,050 and calculate the cefaclor content as micrograms of cefadroxil per milligram follows: on an anhydrous basis. (a) Preparation of working standard so- (ii) [Reserved] lution. Dissolve and dilute an accu- (iii) Its moisture content is not less rately weighed portion of the cefaclor than 4.2 percent and not more than 6.0 working standard in sufficient 0.1M po- percent. tassium phosphate buffer, pH 4.5 (as de- (iv) Its pH in an aqueous solution scribed in § 436.101(a)(4) of this chapter) containing 50 milligrams per milliliter to obtain a concentration of 1 milli- is not less than 4.0 and not more than gram of cefaclor per milliliter. 6.0. (b) Preparation of sample solution. Dis- (v) When calculated on an anhydrous solve an accurately weighed portion of basis, its absorptivity at 264 the sample in sufficient 0.1M potassium nanometers is not less than 95 percent phosphate buffer, pH 4.5 (as described and not more than 104 percent of that in § 436.101(a)(4) of this chapter) to ob- of the cefadroxil standard similarly tain a concentration of 1 milligram of treated and corrected for potency. cefaclor per milliliter. (vi) It passes the identity test. (c) Calculations. Calculate the (vii) It is crystalline. cefaclor content in micrograms per (2) Labeling. It shall be labeled in ac- milligram as follows: cordance with the requirements of § 432.5 of this chapter. (3) Requests for certification; samples. Micrograms of AP× cefaclor per milligram = u a In addition to complying with the re- × quirements of § 431.1 of this chapter, of sample AsW u each such request shall contain: where: (i) Results of tests and assays on the A = Absorbance of sample solution; batch for potency, moisture, pH, ab- u sorptivity, identity, and crystallinity. Pa = Potency of working standard solution in micrograms per milliliter; (ii) Samples required: 10 packages, As = Absorbance of working standard solu- each containing approximately 500 mil- tion; ligrams.
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(b) Tests and methods of assay—(1) Po- (3) Moisture. Proceed as directed in tency. Use either of the following meth- § 436.201 of this chapter. ods; however, the results obtained from (4) pH. Proceed as directed in § 436.202 the hydroxylamine colorimetric assay of this chapter, using an aqueous solu- shall be conclusive. tion containing 50 milligrams per mil- (i) Microbiological agar diffusion assay. liliter. Proceed as directed in § 436.105 of this (5) Absorptivity. Determine the chapter, preparing the sample for assay absorbance of the sample and standard as follows: Dissolve an accurately solutions in the following manner: Dis- weighed sample in sufficient 1 percent solve accurately weighed portions of potassium phosphate buffer, pH 6.0 (so- approximately 50 milligrams each of lution 1), to give a stock solution of the sample and standard in 250 milli- convenient concentration. Further di- liters of distilled water. Transfer a 10- lute an aliquot of the stock solution milliliter aliquot to a 100-milliliter vol- with solution 1 to the reference con- umetric flask and dilute to volume centration of 20 micrograms of with distilled water. Using a suitable cefadroxil per milliliter (estimated). spectrophotometer and distilled water (ii) Hydroxylamine colorimetric assay as the blank, determine the absorbance for cefadroxil. Proceed as directed in of each solution at 264 nanometers. De- § 442.40(b)(1)(ii) of this chapter, except termine the percent absorptivity of the prepare the working standard and sam- sample relative to the absorptivity of ple solutions and calculate the potency the standard using the following cal- of the sample as follows: culations: (a) Preparation of working standard so- lutions. Dissolve and dilute an accu- Percent relative absorptivity=[Absorbance of rately weighed portion of the sample × milligrams standard × potency cefadroxil working standard in suffi- of standard in micrograms per milligram × 10]/[Absorbance of standard × milli- cient distilled water to obtain a stock grams sample × (100-m)] solution of convenient concentration. Further dilute an aliquot of this solu- where: tion with distilled water to a con- m=Percent moisture in the samples. centration of 1 milligram of cefadroxil (6) Identity. Using the sample and per milliliter. working standard solutions prepared as (b) Preparation of sample solutions. described in paragraph (b)(5) of this Dissolve an accurately weighed portion section and a suitable of the sample in sufficient distilled spectrophotometer, record the ultra- water to obtain a stock solution of con- violet spectrum from 220 to 340 venient concentration. Further dilute nanometers. The spectrum of the sam- an aliquot of this solution with dis- ple compares qualitatively with that of tilled water to a concentration of 1 the cefadroxil working standard. milligram of cefadroxil per milliliter (7) Crystallinity. Proceed as directed (estimated). in § 436.203(a) of this chapter. (c) Calculate the potency of the sam- [43 FR 20977, May, 16, 1978; 43 FR 27180, June ple in micrograms per milligram as fol- 23, 1978, as amended at 50 FR 19919, May 13, lows: 1985]
Micrograms § 442.7 Cefadroxil hemihydrate. AP× ×100 of cefadroxil = u a (a) Requirements for certification—(1) per milligram A×W ×()100 − m Standards of identity, strength, quality, of sample s u and purity. Cefadroxil hemihydrate is 7- where: [D-2-amino-2(p- hydroxyphenyl)acetamido]-3-methyl-8- Au=Absorbance of sample solution; Pa=Potency of working standard solution in oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- micrograms per milliliter; 2-carboxylic acid hemihydrate. It is so As=Absorbance of working standard solution; purified and dried that: Wu=Milligrams of sample per milliliter of (i) Its potency is not less than 900 sampe solution; micrograms and not more than 1,050 m=Percent moisture in sample. micrograms of cefadroxil activity per (2) [Reserved] milligram on an anhydrous basis.
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(ii) [Reserved] solution of convenient concentration. (iii) Its moisture content is not less Further dilute an aliquot of this solu- than 2.4 percent and not more than 4.5 tion with distilled water to a con- percent. centration of 1 milligram of cefadroxil (iv) The pH of an aqueous solution per milliliter. containing 50 milligrams per milliliter (B) Preparation of sample solutions. is not less than 4.0 and not more than Dissolve an accurately weighed portion 6.0. of the sample in sufficient distilled (v) When calculated on an anhydrous water to obtain a stock solution of con- basis, its absorptivity at 264 venient concentration. Further dilute nanometers is not less than 95 percent an aliquot of this solution with dis- and not more than 104 percent of that tilled water to a concentration of 1 of the cefadroxil standard similarly milligram of cefadroxil per milliliter treated and corrected for potency. (estimated). (vi) It passes the identity test. (C) Calculations. Calculate the po- (vii) It is crystalline. tency of the sample in micrograms per (2) Labeling. It shall be labeled in ac- milligram as follows: cordance with the requirements of § 432.5 of this chapter. Micrograms of AP× ×100 (3) Requests for certification; samples. cefadroxil = U a In addition to complying with the re- per milligram A× W ×()100 − m quirements of § 431.1 of this chapter, s U where: each such request shall contain: A =Absorbance of sample solution; (i) Results of tests and assays on the U AS=Absorbance of working standard solution; batch for cefadroxil potency, moisture, Pa=Potency of working standard solution in pH, absorptivity, identity, and crys- micrograms per milliliter; tallinity. WU=Milligrams of sample per milliliter of (ii) Samples, if required by the Direc- sample solution; and tor, Center for Drug Evaluation and m=Percent moisture content of the sample. Research: 10 packages, each containing (2) [Reserved] approximately 500 milligrams. (3) Moisture. Proceed as directed in (b) Tests and methods of assay—(1) Po- § 436.201 of this chapter. tency. Use either of the following meth- (4) pH. Proceed as directed in § 436.202 ods; however, the results obtained from of this chapter, using an aqueous solu- the hydroxylamine colorimetric assay tion containing 50 milligrams per mil- shall be conclusive. liliter. (i) Microbiological agar diffusion assay. (5) Absorptivity. Determine the Proceed as directed in § 436.105 of this absorbance of the sample and standard chapter, preparing the sample for assay solutions in the following manner: Dis- as follows: Dissolve an accurately solve accurately weighed portions of weighed sample in sufficient 1 percent approximately 50 milligrams each of potassium phosphate buffer, pH 6.0 (so- the sample and standard in 250 milli- lution 1), to give a stock solution of liters of distilled water. Transfer a 10- convenient concentration. Further di- milliliter aliquot to a 100-milliliter vol- lute an aliquot of the stock solution umetric flask and dilute to volume with solution 1 to the reference con- with distilled water. Using a suitable centration of 20 micrograms of spectrophotometer and distilled water cefadroxil per milliliter (estimated). as the blank, determine the absorbance (ii) Hydroxylamine colorimetric assay of each solution at 264 nanometers. De- for cefadroxil. Proceed as directed in termine the percent absorptivity of the § 442.40(b)(1)(ii), except prepare the sample relative to the absorptivity of working standard and sample solutions the standard using the following cal- and calculate the potency of the sam- culations: ple as follows: Percent relative absorptivity = (A) Preparation of working standard [Absorbance of sample X milligrams solutions. Dissolve and dilute an accu- standard X potency of standard in rately weighed portion of the micrograms per milligram X 10]/ cefadroxil working standard in suffi- [Absorbance of standard X milli- cient distilled water to obtain a stock grams sample X (100-m)]
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where: the hydroxylamine colorimetric assay m = Percent moisture in the samples. shall be conclusive. (6) Identity. Using the sample and (i) Hydroxylamine colorimetric assay. working standard solutions prepared as Proceed as directed in § 442.40(b)(1)(ii) described in paragraph (b)(5) of this of this chapter, except use the section and a suitable cefamandole working standard. spectrophotometer, record the ultra- (ii) Polarographic assay. Proceed as violet spectrum from 220 to 340 directed in § 436.324 of this chapter. nanometers. The spectrum of the sam- (iii) Microbiological agar diffusion ple compares qualitatively with that of assay. Proceed as directed in § 436.105 of the cefadroxil working standard. this chapter, preparing the sample for (7) Crystallinity. Proceed as directed assay as follows: Dissolve an accu- in § 436.203(a) of this chapter. rately weighed sample in sufficient 0.1M potassium phosphate buffer, pH [59 FR 8857, Feb. 24, 1994] 8.0 (solution 3), to obtain a concentra- tion of 1 milligram of cefamandole per § 442.8a Sterile cefamandole nafate. milliliter (estimated). Hydrolyze this (a) Requirements for certification—(1) solution in a 37° C constant tempera- Standards of identity, strength, quality, ture water bath for 60 minutes. Further and purity. Sterile cefamandole nafate dilute a portion of the hydrolyzed solu- is the sodium salt of 7-D-mandelamido- tion with 1 percent potassium phos- 3-[[(1-methyl-1H- tetrazol-5- phate buffer, pH 6.0 (solution 1), to the yl)thio]methyl]-8-oxo-5-thia-1- reference concentration of 2.0 azabicyclo[4.2.0]-oct-2-ene-2- micrograms of cefamandole per milli- carboxylate formate (ester). It is so pu- liter (estimated). rified and dried that: (2) Sterility. Proceed as directed in (i) Its potency is not less than 810 § 436.20 of this chapter, using the meth- micrograms and not more than 1,000 od described in paragraph (e)(1) of that micrograms of cefamandole per milli- section. gram on an anhydrous basis. (3) Pyrogens. Proceed as directed in (ii) It is sterile. § 436.32(b) of this chapter, using a solu- (iii) It is nonpyrogenic. tion containing 50 milligrams of (iv) [Reserved] cefamandole per milliliter. (v) Its moisture content is not more (4) [Reserved] than 2.0 percent. (5) Moisture. Proceed as directed in (vi) Its pH in an aqueous solution § 436.201 of this chapter. containing 100 milligrams per milliliter (6) pH. Proceed as directed in § 436.202 is not less than 3.5 and not more than of this chapter, using an aqueous solu- 7.0. tion containing 100 milligrams per mil- (vii) It passes the identity test. liliter. (2) Labeling. It shall be labeled in ac- (7) Identity. Proceed as directed in cordance with the requirements of § 436.211 of this chapter, using the min- § 432.5 of this chapter. eral oil mull prepared as described in (3) Requests for certification; samples. paragraph (b)(2) of that section. In addition to complying with the re- quirements of § 431.1 of this chapter, [47 FR 32708, June 1, 1982, as amended at 50 each such request shall contain: FR 19919, May 13, 1985] (i) Results of tests and assays on the batch for potency, sterility, pyrogens, § 442.9a Sterile cefamandole sodium. moisture, pH, and identity. (a) Requirements for certification—(1) (ii) Samples required: Standards of identity, strength, quality, (a) For all tests except sterility: 10 and purity. Sterile cefamandole sodium packages, each containing approxi- is 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- mately 500 milligrams. carboxylic acid, 7- (b) For sterility testing: 20 packages, [(hydroxyphenylacetyl)amino]-3-[[(1- each containing equal portions of ap- methyl-1H-tetrazol-5-yl)thio]methyl]-8- proximately 250 milligrams. oxo-, monosodium salt [6R-[6α, 7β(R*)]]- (b) Tests and methods of assay—(1) Po- . It is so purified and dried that: tency. Use any of the following meth- (i) Its cefamandole content is not less ods; however, the results obtained from than 860 micrograms and not more
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than 1,000 micrograms of cefamandole 3, 4-thiadiazol-2-yl)-thio]methyl]-7-[2- per milligram on an anhydrous basis. (1H-tetrazol-1-yl) acetamido]-3-cephem- (ii) It is sterile. 4-carboxylic acid. It is so purified and (iii) It is nonpyrogenic. dried that: (iv) [Reserved] (i) Its cefazolin content is not less (v) Its moisture content is not more than 950 micrograms and not more than 3.0 percent. than 1,030 micrograms of cefazolin per (vi) Its pH in an aqueous solution milligram calculated on an anhydrous containing 100 milligrams per milliliter basis. is not less than 3.5 and not more than (ii) Its moisture content is not more 7.0. than 2 percent. (vii) It passes the identity test. (iii) Its heavy metals content is not (2) Labeling. It shall be labeled in ac- more than 20 parts per million. cordance with the requirements of (iv) It gives a positive identity test § 432.5 of this chapter. for cefazolin. (3) Requests for certification; samples. (2) Labeling. It shall be labeled in ac- In addition to complying with the re- cordance with the requirements of quirements of § 431.1 of this chapter, § 432.5 of this chapter. each such request shall contain: (3) Requests for certification; samples. (i) Results of tests and assays on the In addition to complying with the re- batch for cefamandole content, steril- quirements of § 431.1 of this chapter, ity, pyrogens, moisture, pH, and iden- each such request shall contain: tity. (i) Results of tests and assays on the (ii) Samples required: batch for cefazolin content, moisture, (a) For all tests except sterility: 10 heavy metals, and identity. packages, each containing approxi- (ii) Samples, if required by the Direc- mately 500 milligrams. tor, Center for Drug Evaluation and (b) For sterility testing: 20 packages, Research: Nine packages, each contain- each containing equal portions of ap- ing approximately 500 milligrams, and proximately 250 milligrams. one package containing approximately (b) Tests and methods of assay—(1) 5 grams. Cefamandole content. Proceed as di- (b) Tests and methods of assay—(1) rected in § 436.324 of this chapter. Cefazolin content. Proceed as directed in (2) Sterility. Proceed as directed in § 436.342 of this chapter. § 436.20 of this chapter, using the meth- (2) Moisture. Proceed as directed in od described in paragraph (e)(1) of that § 436.201 of this chapter. section. (3) Heavy metals. Proceed as directed (3) Pyrogens. Proceed as directed in in § 436.208 of this chapter. § 436.32(b) of this chapter, using a solu- (4) Identity. The high-pressure liquid tion containing 50 milligrams of chromatogram of the sample deter- cefamandole per milliliter. mined as directed in paragraph (b)(1) of (4) [Reserved] this section compares qualitatively to (5) Moisture. Proceed as directed in that of the cefazolin working standard. § 436.201 of this chapter. [48 FR 33479, July 22, 1983, as amended at 55 (6) pH. Proceed as directed in § 436.202 FR 11582, Mar. 29, 1990] of this chapter, using an aqueous solu- tion containing 100 milligrams per mil- § 442.11a Sterile cefazolin sodium. liliter. (a) Requirements for certification—(1) (7) Identity. Proceed as directed in Standards of identity, strength, quality, § 436.211 of this chapter, using the min- and purity. Sterile cefazolin sodium is eral oil mull prepared as described in the sodium salt of 3-[[(5-methyl - 1,3,4 - paragraph (b)(2) of that section. thiadiazol - 2 - yl) - thio]methyl] - 7 - [2 [47 FR 20756, May 14, 1982, as amended at 50 - (1H - tetrazol-1-yl)acetamido] - 3 - FR 19919, May 13, 1985] cephem - 4 - carboxylic acid. It is so pu- rified and dried that: § 442.10 Cefazolin. (i) Its potency is not less than 850 (a) Requirements for certification—(1) micrograms and not more than 1050 Standards of identity, strength, quality, micrograms of cefazolin per milligram and purity. Cefazolin is 3-[[(5-methyl-1, calculated on an anhydrous basis. If it
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is packaged for dispensing, its cefazolin stock solution of convenient con- content is satisfactory if it contains centration; also if it is packaged for not less than 90 percent and not more dispensing, reconstitute as directed in than 115 percent of the number of milli- the labeling. Then using a suitable grams of cefazolin that it is rep- hypodermic needle and syringe, remove resented to contain. all of the withdrawable contents. Di- (ii) It is sterile. lute with sufficient solution 1 to give a (iii) It is nonpyrogenic. stock solution of convenient con- (iv) [Reserved] centration. (v) Its moisture content is not more (ii) Assay procedure. Use either of the than 6 percent. following methods; however, the re- (vi) Its pH in an aqueous solution sults obtained from the micro- containing 100 milligrams of cefazolin biological agar diffusion assay shall be per milliliter is not less than 4.5 and conclusive. not more than 6.0. (a) Microbiological agar diffusion (vii) The specific rotation in a 0.1M assay. Proceed as directed in § 436.105 of sodium bicarbonate solution contain- this chapter, diluting an aliquot of the ing 50 milligrams of cefazolin per milli- stock solution with solution 1 to the liter at 25° C. is ¥17°±7° calculated on reference concentration of 1.0 an anhydrous basis. micrograms of cefazolin per milliliter (viii) It gives a positive identity test (estimated). for cefazolin. (b) Hydroxylamine colorimetric assay. (2) Labeling. It shall be labeled in ac- Proceed as directed in § 436.205 of this cordance with the requirements of chapter, preparing the working stand- § 432.5 of this chapter. ard solution as follows: Dissolve an ac- (3) Requests for certification; samples. curately weighed portion of approxi- In addition to complying with the re- mately 30 milligrams of cefazolin quirements of § 431.1 of this chapter, working standard in 3 milliliters of 10 each such request shall contain: percent potassium phosphate buffer, pH (i) Results of tests and assays on the 6.0 (solution 6), and further dilute with batch for potency, sterility, pyrogens, solution 1 to the final concentration. moisture, pH, specific rotation, and (2) Sterility. Proceed as directed in identity. § 436.20 of this chapter, using the meth- (ii) Samples required: od described in paragraph (e)(1) of that (a) If the batch is packaged for re- section. packing or for use in the manufacture (3) Pyrogens. Proceed as directed in of another drug: § 436.32(b) of this chapter, using a solu- (1) For all tests except sterility: 9 tion containing 50 milligrams of packages, each containing approxi- cefazolin per milliliter. mately 500 milligrams, and 1 package (4) [Reserved] containing approximately 5 grams. (5) Moisture. Proceed as directed in (2) For sterility testing: 20 packages, § 436.201 of this chapter. each containing approximately 300 mil- (6) pH. Proceed as directed in § 436.202 ligrams. of this chapter, using an aqueous solu- (b) If the batch is packaged for dis- tion containing 100 milligrams of pensing: cefazolin per milliliter. (1) For all tests except sterility: A (7) Specific rotation. Proceed as di- minimum of 15 immediate containers, rected in § 436.210 of this chapter, using except if each contains less than 1.0 a solution containing 50 milligrams of gram, a minimum of 24 immediate con- cefazolin per milliliter in 0.1M sodium tainers. bicarbonate and a polarimeter tube 1.0 (2) For sterility testing: 20 immediate decimeter in length. Calculate the spe- containers, collected at regular inter- cific rotation on an anhydrous basis. vals throughout each filling operation. (8) Identity. Using a 0.002 percent so- (b) Tests and methods of assay—(1) Po- lution of the sample in 0.1M sodium bi- tency—(i) Sample preparation. Dissolve carbonate solution and a suitable an accurately weighed sample in suffi- spectrophotometer, record the ultra- cient 1.0 percent potassium phosphate violet spectrum from 220 to 340 buffer, pH 6.0 (solution 1), to give a nanometers. The spectrum compares
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qualitatively to that of the cefazolin tion containing 250 milligrams per mil- working standard similarly tested. liliter. (4) Identity. From the high-perform- [39 FR 19040, May 30, 1974, as amended at 42 FR 18059, Apr. 5, 1977; 50 FR 19919, May 13, ance liquid chromatograms of the sam- 1985] ple and the cefoperazone working standard determined as directed in § 442.12 Cefoperazone sodium. paragraph (b)(1) of this section, cal- (a) Requirements for certification—(1) culate the adjusted retention times of Standards of identity, strength, quality, the cefoperazone in the sample and and purity. Cefoperazone sodium is the standard solutions as follows: sodium salt of (6R, 7R)-7-[(R)-2-(4-ethyl- Adjusted retention time of 2,3-dioxo-1-piperazinecarboxamido)-2- cefoperazone=t¥ta (p-hydroxyphenyl)acetamido]-3-[[(1- where: methyl-1H-tetrazol-5-yl)thio]methyl]-8- t=Retention time measured from point of in- oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- jection into the chromatograph until the 2-carboxylate. It is a white to off-white maximum of the cefoperazone sample or working standard peak appears on the crystalline powder or a lyophilized chromatogram; and powder. It is so purified and dried that: ta=Retention time measured from point of (i) Its cefoperazone content is not injection into the chromatograph until less than 870 micrograms and not more the maximum of nonretarded solute ap- than 1,015 micrograms of cefoperazone pears in the chromatogram. per milligram on an anhydrous basis. (ii) Its moisture content is not more The sample and the cefoperazone work- than 5.0 percent, except if it is the ing standard should have corresponding lyophilized powder, its moisture con- adjusted cefoperazone retention times tent is not more than 2.0 percent. within ±3.0 percent. (iii) The pH of an aqueous solution (5) Crystallinity. Proceed as directed containing 250 milligrams per milliliter in § 436.203(a) of this chapter. is not less than 4.5 and not more than [51 FR 36688, Oct. 15, 1986, as amended at 55 6.5. FR 11583, Mar. 29, 1990] (iv) It passes the identity test if the retention times of the sample and § 442.12a Sterile cefoperazone sodium. ± working standard agree within 3.0 per- (a) Requirements for certification—(1) cent. Standards of identity, strength, quality, (v) It is crystalline, except if it is the and purity. Sterile cefoperazone sodium lyophilized powder. is the sodium salt of (6R, 7R)-7-[(R)-2-(4- (2) Labeling. It shall be labeled in ac- ethyl-2,3-dioxo-1- cordance with the requirements of piperazinecarboxamido)-2-(p- § 432.5 of this chapter. hydroxyphenyl)acetamido]-3-[[(1-meth- (3) Requests for certification; samples. yl-1H-tetrazol-5-yl)thio]methyl]-8-oxo- In addition to complying with the re- 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- quirements of § 431.1 of this chapter, carboxylate. It is a white to off-white each such request shall contain: crystalline powder or it may be a (i) Results of tests and assays on the lyophilized powder. It is so purified and batch for cefoperazone content, mois- dried that: ture, pH, identity, and crystallinity (if (i) If the cefoperazone sodium is not it is not the lyophilized powder). packaged for dispensing, its (ii) Samples, if required by the Direc- cefoperazone content is not less than tor, Center for Drug Evaluation and 870 micrograms and not more than 1,015 Research: 10 packages, each containing micrograms of cefoperazone per milli- approximately 500 milligrams. gram on an anhydrous basis. If the (b) Tests and methods of assay—(1) cefoperazone sodium is packaged for Cefoperazone content. Proceed as di- dispensing, its cefoperazone content is rected in § 436.338 of this chapter. not less than 870 micrograms and not (2) Moisture. Proceed as directed in more than 1,015 micrograms of § 436.201 of this chapter. cefoperazone per milligram on an an- (3) pH. Proceed as directed in § 436.202 hydrous basis and also, each container of this chapter, using an aqueous solu- contains not less than 90 percent and
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not more than 120 percent of the num- tion containing 10 milligrams of ber of milligrams of cefoperazone that cefoperazone per milliliter. it is represented to contain. (4) Moisture. Proceed as directed in (ii) It is sterile. §436.201 of this chapter. (iii) It is nonpyrogenic. (5) pH. Proceed as directed in §436.202 (iv) Its moisture content is not more of this chapter, using an aqueous solu- than 5.0 percent, except if it is the tion containing 250 milligrams per mil- lyophilized powder, its moisture con- liliter. tent is not more than 2.0 percent. (6) Identity. From the high-pressure (v) Its pH in an aqueous solution con- liquid chromatograms of the sample taining 250 milligrams per milliliter is and the cefoperazone working standard not less than 4.5 and not more than 6.5. determined as directed in paragraph (vi) It passes the identity test if the (b)(1) of this section, calculate the ad- retention times of the sample and justed retention times of the working standard agree within ±3 per- cefoperazone in the sample and stand- cent. ard solutions as follows: (vii) It is crystalline, except if it is Retention time of cefoperazone=ts¥tu the lyophilized powder, it is not crys- where: talline. ts=Retention time of working standard meas- (2) Labeling. It shall be labeled in ac- ured from point of injection into the cordance with the requirements of chromatograph until the peak maximum § 432.5 of this chapter. appears on the chromatogram; and (3) Requests for certification; samples. tu=Retention time of sample measured from In addition to complying with the re- point of injection into the chro- quirements of §431.1 of this chapter, matograph until the peak maximum ap- pears on the chromatogram. each such request shall contain: (i) Results of tests and assays on the (7) Crystallinity. Proceed as directed batch for cefoperazone content, steril- in §436.203(a) of this chapter. ity, pyrogens, moisture, pH, identity, [48 FR 790, Jan. 7, 1983; 43 FR 7439, Feb. 22, and crystallinity (if it is not the 1983; 48 FR 28250, June 21, 1983, as amended at lyophilized powder). 55 FR 11583, Mar. 29, 1990] (ii) Samples, if required by the Direc- tor, Center for Drug Evaluation and § 442.13 Cefotaxime sodium. Research: (a) Requirements for certification—(1) (a) If the batch is packaged for re- Standards of identity, strength, quality, packing or for manufacturing use: and purity. Cefotaxime sodium is the (1) For all tests except sterility: 10 sodium salt of 5-thia-1- packages, each containing approxi- azabicyclo[4.2.0]oct-2-ene-2-carboxylic mately 500 milligrams. acid, 3-[(acetyloxy)methyl]-7-[[(2- (2) For sterility testing: 20 packages, amino-4-thiazolyl) ( each containing equal portions of ap- (methoxyimino)acetyl]amino]-8-ox- proximately 300 milligrams. o,[6R-[6 alpha, 7 beta(Z)]]-. It is so puri- (b) If the batch is packaged for dis- fied and dried that: pensing: (i) Its potency is not less than 855 (1) For all tests except sterility: A micrograms and not more than 1,002 minimum of 10 immediate containers micrograms of cefotaxime per milli- of the batch. gram on an anhydrous basis. (2) For sterility testing: 20 immediate (ii) Its moisture content is not more containers collected at regular inter- than 6.0 percent. vals throughout each filling operation. (iii) Its pH in an aqueous solution is (b) Tests and methods of assay—(1) not less than 4.5 and not more than 6.5. Cefoperazone content. Proceed as di- (iv) It gives a positive identity test. rected in §436.338 of this chapter. (2) Labeling. It shall be labeled in ac- (2) Sterility. Proceed as directed in cordance with the requirements of §436.20 of this chapter, using the meth- § 432.5 of this chapter. od described in paragraph (e)(1) of that (3) Requests for certification; samples. section. In addition to complying with the re- (3) Pyrogens. Proceed as directed in quirements of § 431.1 of this chapter, §436.32(b) of this chapter, using a solu- each such request shall contain:
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(i) Results of tests and assays on the (3) pH. Proceed as directed in § 436.202 batch for potency, moisture, pH, and of this chapter, using an aqueous solu- identity. tion containing 100 milligrams per mil- (ii) Samples, if required by the Direc- liliter. tor, Center for Drug Evaluation and (4) Identity. Proceed as directed in Research; 10 packages, each containing § 436.323 of this chapter, except prepare approximately 500 milligrams. spotting solutions as follows: Prepare (b) Tests and methods of assay—(1) Po- solutions of the sample and working tency. Use either of the following meth- standard, each containing 1 milligram ods; however, the results obtained from of cefotaxime per milliliter in distilled the hydroxylamine colorimetric assay water. shall be conclusive. (i) Microbiological agar diffusion assay. [50 FR 45109, Oct. 30, 1985, as amended at 55 Proceed as directed in § 436.105 of this FR 11583, Mar. 29, 1990] chapter, preparing the sample for assay as follows: Dissolve an accurately § 442.13a Sterile cefotaxime sodium. weighed sample in sufficient 1.0 per- (a) Requirements for certification—(1) cent potassium phosphate buffer, pH 6.0 Standards of identity, strength, quality, (solution 1), to obtain a stock solution and purity. Cefotaxime sodium is the of convenient concentration. Further sodium salt of 5-thia-1- dilute an aliquot of the stock solution azabicyclo[4.2.0]oct-2-ene-2-carboxylic with solution 1 to the reference con- acid, 3-[(acetyloxy)methyl]-7-[[(2- centration of 2.0 micrograms of amino-4-thiazolyl) cefotaxime per milliliter (estimated). (methoxyimino)acetyl]amino]-8-oxo- (ii) Hydroxylamine colorimetric assay. ,[6R-[6α, 7β(Z)]]-. It is so purified and Proceed as directed in § 442.40(b)(1)(ii), dried that: except prepare the working standard (i) Its potency is not less than 855 and sample solutions and calculate the micrograms and not more than 1,002 potency of the sample as follows: micrograms of cefotaxime per milli- (a) Preparation of the working standard gram on an anhydrous basis. If it is solution. Dissolve and dilute an accu- packaged for dispensing, its content is rately weighed portion of the satisfactory if it is not less than 90 per- cefotaxime working standard in suffi- cent and not more than 110 percent of cient distilled water to obtain a con- the number of milligrams of centration of 1 milligram of cefotaxime cefotaxime that it is represented to per milliliter. contain. (b) Preparation of sample solution. Dis- solve and dilute an accurately weighed (ii) It is sterile. portion of the sample in sufficient dis- (iii) It is nonpyrogenic. tilled water to obtain a concentration (iv) [Reserved] of 1 milligram of cefotaxime per milli- (v) Its moisture content is not more liter (estimated). than 6.0 percent. (c) Calculation. Calculate the (vi) Its pH in an aqueous solution is cefotaxime content in micrograms per not less than 4.5 and not more than 6.5. milligram as follows: (vii) It gives a positive identity test. (2) Labeling. It shall be labeled in ac- Micrograms of AP× cordance with the requirements of cefotaxime per milligram = u a § 432.5 of this chapter. × of sample AsW u (3) Requests for certification; samples. where: In addition to complying with the re- quirements of § 431.1 of this chapter, Au=Absorbance of sample solution; each such request shall contain: Pa=Potency of working standard solution in micrograms per milliliter; (i) Results of tests and assays on the As=Absorbance of working standard solution; batch for potency, sterility, pyrogens, and moisture, pH, and identity. Wu=Milligrams of sample per milliliter of (ii) Samples required: sample solution. (a) If the batch is packaged for re- (2) Moisture. Proceed as directed in packing or for use as an ingredient in § 436.201 of this chapter. the manufacture of another drug:
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(1) For all tests except sterility: 10 of 1 milligram of cefotaxime per milli- packages, each containing approxi- liter (estimated). mately 1 gram. (c) Calculations—(1) Calculate the (2) For sterility testing: 20 packages, cefotaxime content in micrograms per each containing approximately 1 gram. milligram as follows: (b) If the batch is packaged for dis- pensing: Micrograms of AP× (1) For all tests except sterility: A cefotaxime per milligram = u a minimum of 10 immediate containers. × AsW u (2) For sterility testing: 20 immediate of sample containers, collected at regular inter- where: vals throughout each filling operation. Au =Absorbance of sample solution; (b) Tests and methods of assay—(1) Po- Pa =Potency of working standard solution in tency. Use either of the following meth- micrograms per milliliter;
ods; however, the results obtained from As =Absorbance of working standard solu- the hydroxylamine colorimetric assay tion; shall be conclusive. Wu =Milligrams of sample per milliliter of (i) Microbiological agar diffusion assay. sample solution. Proceed as directed in § 436.105 of this (2) Calculate the cefotaxime content chapter, preparing the sample for assay of the single-dose vial as follows: as follows: Dissolve an accurately weighed sample in sufficient 1.0 per- Milligrams of cefota xime A× P × d cent potassium phosphate buffer, pH 6.0 = u a (solution 1), to obtain a stock solution per single-dose vial A ×1, 000 of convenient concentration; also, if it s is packaged for dispensing, reconsti- where:
tute as directed in the labeling. Then Au =Absorbance of sample solution; using a suitable hypodermic needle and Pa =Potency of working standard solution in syringe, remove all of the micrograms per milliliter; withdrawable contents if it is rep- As =Absorbance of working standard solu- resented as a single-dose container; or, tion; if the labeling specifies the amount of d=Dilution factor of the sample. potency in a given volume of the re- (3) Calculate the cefotaxime content sultant preparation, remove an accu- of the multiple-dose vial as follows: rately measured representative portion from each container. Dilute with solu- Milligrams of A× P × d tion 1 to obtain a stock solution of con- cefotaxime per = u a venient concentration. Further dilute × × an aliquot of the stock solution with multiple-dose vial As 1, 000 n solution 1 to the reference concentra- where: tion of 2.0 micrograms of cefotaxime A =Absorbance of sample solution; per milliliter (estimated). u Pa =Potency of working standard solution in (ii) Hydroxylamine colorimetric assay. micrograms per milliliter;
Proceed as directed in § 442.40(b)(1)(ii) As =Absorbance of working standard solu- of this chapter, except prepare the tion; working standard and sample solutions d=Dilution factor of the sample; and calculate the potency of the sam- n=Volume of sample solution assayed. ple as follows: (a) Preparation of the working standard (2) Sterility. Proceed as directed in solution. Dissolve and dilute an accu- § 436.20 of this chapter, using the meth- rately weighed portion of the od described in paragraph (e)(1) of that cefotaxime working standard in suffi- section. cient distilled water to obtain a con- (3) Pyrogens. Proceed as directed in centration of 1 milligram of cefotaxime § 436.32(b) of this chapter, using a solu- per milliliter. tion containing 50 milligrams of (b) Preparation of sample solution. Dis- cefotaxime per milliliter. solve and dilute an accurately weighed (4) [Reserved] portion of the sample in sufficient dis- (5) Moisture. Proceed as directed in tilled water to obtain a concentration § 436.201 of this chapter.
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(6) pH. Proceed as directed in § 436.202 to obtain a solution containing 1 milli- of this chapter, using an aqueous solu- gram of cefoxitin per milliliter. tion containing 100 milligrams per mil- (ii) Sample solution. Dissolve an accu- liliter. rately weighed portion of the sample (7) Identity. Proceed as directed in with water to obtain a solution con- § 436.323 of this chapter, except prepare taining 1 milligram of cefoxitin per spotting solutions as follows: Prepare milliliter (estimated). solutions of the sample and working (iii) Calculations. Calculate the standard, each containing 1 milligram micrograms of cefoxitin per milligram of cefotaxime per milliliter in distilled of sample as follows: water. × [46 FR 25606, May 8, 1981, as amended at 50 Micrograms of cefoxitin per = APu s FR 19919, May 13, 1985] milligram × ACs u § 442.14 Cefoxitin sodium. where: (a) Requirements for certification—(1) Au=Area of the cefoxitin peak in the chro- Standards of identity, strength, quality, matogram of the sample (at a retention time equal to that observed for the and purity. Cefoxitin sodium is the so- standard); dium salt of 3-(hydroxymethyl)-7α- As=Area of the cefoxitin peak in the chro- methoxy-8-oxo-7-[2-(2- matogram of the cefoxitin working thienyl)acetamido]-5-thia-1- standard; azabicyclo[4.2.0]oct-2-ene-2-carboxylic Ps=Cefoxitin activity in the cefoxitin work- acid carbamate (ester). It is so purified ing standard solution in micrograms per and dried that: milliliter; and (i) Its cefoxitin content is not less Cu=Milligrams of sample per milliliter of than 850 micrograms and not more sample solution (estimated). than 1,000 micrograms of cefoxitin per (2) Moisture. Proceed as directed in milligram. § 436.201 of this chapter, using the titra- (ii) Its moisture content is not more tion procedure described in paragraph than 2.0 percent. (e)(1) of that section, except add about (iii) Its pH in an aqueous solution 25 milliliters of methanol in lieu of sol- containing 100 milligrams per milliliter vent A to a dry titrating vessel and is not less than 4.2 and not more than proceed as directed in titration proce- 7.0. dure 1. (iv) It gives a positive identity test. (3) pH. Proceed as directed in § 436.202 (v) It is crystalline. of this chapter, using an aqueous solu- (2) Labeling. It shall be labeled in ac- tion containing 100 milligrams per mil- cordance with the requirements of liliter. § 432.5 of this chapter. (4) Identity. Proceed as directed in (3) Requests for certification; samples. § 436.326 of this chapter. In addition to complying with the re- (5) Crystallinity. Proceed as directed quirements of § 431.1 of this chapter, in § 436.203(a) of this chapter. each such request shall contain: (i) Results of tests and assays on the [49 FR 47827, Dec. 7, 1984, as amended at 55 batch for cefoxitin content, moisture, FR 11583, Mar. 29, 1990] pH, identity, and crystallinity. (ii) Samples, if required by the Direc- § 442.14a Sterile cefoxitin sodium. tor, Center for Drug Evaluation and (a) Requirements for certification—(1) Research: 10 packages, each containing Standards of identity, strength, quality, approximately 500 milligrams. and purity. Cefoxitin sodium is the so- (b) Tests and methods of assay—(1) dium salt of 3-(hydroxymethyl) - 7α- Cefoxitin content. Proceed as directed in methoxy - 8 - oxo - 7 - [2 - (2 - thienyl) § 436.347 of this chapter, preparing the acetamido] - 5 - thia - 1 - working standard and sample solutions azabicyclo[4.2.0]oct-2-ene-2-carboxylic and calculating the cefoxitin content acid carbamate (ester). It is so purified as follows: and dried that: (i) Working standard solution. Dissolve (i) Its potency is not less than 850 an accurately weighed portion of the micrograms and not more than 1,000 cefoxitin working standard with water micrograms of cefoxitin per milligram.
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If it is packaged for dispensing, its po- also if it is packaged for dispensing, re- tency is satisfactory if it is not less constitute as directed in the labeling. than 90 percent and not more than 120 Then using a suitable hypodermic nee- percent of the number of milligrams of dle and syringe, remove all of the cefoxitin that it is represented to con- withdrawable contents if it is rep- tain. resented as a single-dose container; or, (ii) It is sterile. if the labeling specifies the amount of (iii) It is nonpyrogenic. potency in a given volume of the re- (iv) [Reserved] sultant preparation, remove an accu- (v) Its moisture content is not more rately measured representative portion than 2.0 percent. from each container. Dilute with dis- (vi) Its pH in an aqueous solution is tilled water to obtain a solution con- not less than 4.2 and not more than 7.0. taining 1 milligram of cefoxitin per (vii) It gives a positive identity test. milliliter (estimated). (viii) It is crystalline. (iii) Calculations—(a) Calculate the (2) Labeling. It shall be labeled in ac- cefoxitin content in micrograms per cordance with the requirements of milligram as follows: § 432.5 of this chapter. × (3) Requests for certification; samples. Micrograms of = APu s In addition to complying with the re- cefoxitin per milligram × quirements of § 431.1 of this chapter, ACs u each such request shall contain: where: (i) Results of tests and assays on the Au=Area of the cefoxitin peak in the chro- batch for potency, sterility, pyrogens, matogram of the sample (at a retention moisture, pH, identity, and crystallin- time equal to that observed for the standard); ity. As=Area of the cefoxitin peak in the chro- (ii) Samples required: matogram of the cefoxitin working (a) If the batch is packaged for re- standard; packing or for use as an ingredient in Ps=Cefoxitin activity in the cefoxitin work- the manufacture of another drug: ing standard solution in micrograms per (1) For all tests except sterility: 10 milliliter; and packages, each containing approxi- Cu=Milligrams of sample per milliliter of sample solution (estimated). mately 1 gram. (2) For sterility testing: 20 packages, (b) Calculate the cefoxitin content of each containing approximately 1 gram. the vial as follows: (b) If the batch is packaged for dis- × × pensing: Milligrams of = Au P s d (1) For all tests except sterility: A cefoxitin per vial × minimum of 10 immediate containers. As 1, 000 (2) For sterility testing: 20 immediate where: containers, collected at regular inter- Au=Area of the cefoxitin peak in the chro- vals throughout each filling operation. matogram of the sample (at a retention time equal to that observed for the (b) Tests and methods of assay—(1) Po- standard); tency. Proceed as directed in § 436.347 of As=Area of the cefoxitin peak in the chro- this chapter, preparing the working matogram of the cefoxitin working standard and sample solutions and cal- standard; culating the cefoxitin content as fol- Ps=Cefoxitin activity in the cefoxitin work- lows: ing standard solution in micrograms per (i) Working standard solution. Dissolve milliliter; and an accurately weighed portion of the d=Dilution factor of the sample. cefoxitin working standard with dis- (2) Sterility. Proceed as directed in tilled water to obtain a solution con- § 436.20 of this chapter, using the meth- taining 1 milligram of cefoxitin per od described in paragraph (e)(1) of that milliliter. section. (ii) Sample solutions. Dissolve an accu- (3) Pyrogens. Proceed as directed in rately weighed portion of the sample § 436.32(b) of this chapter, using a solu- with distilled water to obtain a solu- tion containing 50 milligrams of tion containing 1 milligram of cefoxitin per milliliter. cefoxitin per milliliter (estimated); and (4) [Reserved]
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(5) Moisture. Proceed as directed in quirements of § 431.1 of this chapter, § 436.201 of this chapter, using the titra- each such request shall contain: tion procedure described in paragraph (i) Results for tests and assays on the (e)(1) of that section, except add about batch for potency, moisture, pH, crys- 25 milliliters of methanol in lieu of sol- tallinity, specific rotation, and iden- vent A to a dry titrating vessel and tity. proceed as directed in titration proce- (ii) Samples, if required by the Direc- dure 1. tor, Center for Drug Evaluation and (6) pH. Proceed as directed in § 436.202 Research: 10 packages, each containing of this chapter, using an aqueous solu- approximately 500 milligrams, and 1 tion containing 100 milligrams per mil- package containing approximately 5 liliter. grams. (7) Identity. Proceed as directed in (b) Tests and methods of assay—(1) Po- § 436.326 of this chapter, preparing the tency. Proceed as directed in § 436.216 of sample as follows: Prepare a solution this chapter, using an ultraviolet de- containing about 2.5 milligrams of tection system operating at a wave- cefoxitin per milliliter in distilled length of 254 nanometers, and a column water. (typically 3 centimeters × 4.6 millime- (8) Crystallinity. Proceed as directed ters) packed with a 3-micron octadecyl in § 436.203(a) of this chapter. hydrocarbon bonded silica or equiva- lent at ambient temperature. Re- [44 FR 10374, Feb. 20, 1979, as amended at 50 agents, working standard, test and FR 19919, May 13, 1985; 51 FR 27532, Aug. 1, sample solutions, system suitability 1986] requirements, and calculations are as § 442.15 Cefixime trihydrate. follows: (i) Reagents—(A) Phosphoric acid solu- (a) Requirements for certification—(1) tion. Add 10 milliliters of concentrated Standards of identity, strength, quality, phosphoric acid to 90 milliliters of and purity. Cefixime trihydrate is the water. α trihydrate form of [6R-[6 , 7B(Z)]]-7- (B) Tetrabutylammonium hydroxide so- [[(2-amino-4-thiazolyl) lution. Dilute 25 milliliters of 0.4M [(carboxymethoxy)imino]acetyl tetrabutylammonium hydroxide solu- ]amino]-3-ethenyl-8-oxo-5-thia- tion to 1,000 milliliters with water. Ad- azabicyclo[4.2.0]oct-2-ene-2-carboxylic just the pH to 7.0 with phosphoric acid acid. It is so purified and dried that: solution. (i) Its potency is not less than 950 (C) Mobile phase. Add 775 milliliters of micrograms and not more than 1,030 the tetrabutylammonium hydroxide so- micrograms of cefixime activity per lution to 225 milliliters of acetonitrile. milligram, on an anhydrous basis. Filter the mobile phase through a suit- (ii) Its moisture content is not less able glass filter or equivalent which is than 9.0 percent and not more than 12.0 capable of removing particulate con- percent. tamination greater than 0.5 micron in (iii) The pH of an aqueous solution diameter. Degas the mobile phase just containing the equivalent of 0.7 milli- prior to its introduction into the chro- gram per milliliter is not less than 2.6 matograph. and not more than 4.1. (D) 0.1M Phosphate buffer, pH 7.0. Add (iv) It is crystalline. 6.8 milliliters of concentrated phos- (v) The specific rotation in a 2.0 per- phoric acid to 300 milliliters of water. cent sodium bicarbonate solution con- Adjust the pH to 7.0 with 10N sodium taining 10.0 milligrams of cefixime per hydroxide. Dilute to 1,000 milliliters milliliter at 25 °C is between ¥75° and with water. ¥88° calculated on an anhydrous basis. (ii) Preparation of working standard, (vi) It gives a positive identity test test and sample solutions—(A) Working for cefixime. standard solution. Dissolve an accu- (2) Labeling. It shall be labeled in ac- rately weighed portion of the cefixime cordance with the requirements of standard with sufficient 0.1M phos- § 432.5 of this chapter. phate buffer, pH 7.0, to obtain a solu- (3) Requests for certification; samples. tion of known concentration contain- In addition to complying with the re- ing approximately 2 milligrams of
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cefixime activity per milliliter. Fur- (L )(10 , 000 ) ther dilute quantitatively to a final ()h = concentration of 0.2 milligram of r cefixime activity per milliliter in 0.1 M (n )( d p ) phosphate buffer, pH 7.0. Prepare the where: working standard solution just prior to L=Length of the column in centimeters; its introduction into the chro- n=number of theoretical plates; and
matograph. (dp)=Average diameter of the particles in the (B) System suitability test solution. Dis- column in micrometers. solve an accurately weighed portion of cefixime working standard in distilled The absolute efficiency (hr) is satisfac- water to obtain a solution containing tory if it is not more than 15 for the approximately 1.0 milligram of cefixime peak. cefixime activity per milliliter. Heat (C) Resolution. The resolution (R) be- this solution at 95 °C (in an oil bath) tween the peak for cefixime and the for 45 minutes. This procedure allows peak for the (E)-isomer of cefixime the (E)-isomer of cefixime to be gen- (generated in situ) is not less than 1.1. erated in situ. Prepare the test solution (D) Coefficient of variation (relative just prior to its introduction into the standard deviation). The coefficient of chromatograph. variation (SR) in percent) of five rep- (C) Sample solution. Accurately weigh licate injections is satisfactory if not approximately 100 milligrams of the more than 2.0 percent sample into a 50-milliliter volumetric (E) Capacity factor (k). Calculate the flask. Dilute to volume with 0.1M phos- capacity factor (k) for cefixime as fol- phate buffer, pH 7.0, to obtain a stock lows: solution containing approximately 2 milligrams of cefixime activity per t− t = r m milliliter. Mix well. Immediately prior ()k to chromatography, further dilute 10 tm milliliters of stock solution to 100 mil-
liliters with 0.1 M phosphate buffer, pH tr=Retention time of solute; and 7.0 to obtain a solution containing 0.2 tm=Retention time of solvent or unretained milligram of cefixime activity per mil- substance, calculated as follows: liliter (estimated). (iii) System suitability requirements— 2 = (31416 . )(DL )( )( 0 . 75 ) (A) Asymmetry factor. Calculate the tm asymmetry factor (As), measure data 4F point that is 10 percent of the cefixime where: peak height from the baseline, as fol- D=Column diameter in centimeters; lows: L=Column length in centimeters; 0.75=Average total column porosity; and + = a b F=Flow rate in milliliters per minute. As 2a The capacity factor (k) for cefixime is satisfactory if it is not less than 5 a=Horizontal distance from point of ascent and not more than 11. to point of maximum peak height; and If the system suitability require- b=horizontal distance from the point of max- ments have been met, then proceed as imum peak height to point of descent. described in § 436.216(b) of this chapter.
The asymmetry factor (As) is satis- Alternate chromatographic conditions factory if it is not less than 0.85 and are acceptable provided that the sys- not more than 1.5. tem suitability parameters are met. (B) Efficiency of the column. From the However, the sample preparation de- number of theoretical plates (n) cal- scribed in paragraph (b)(1)ii)(C) of this culated as described in § 436.216(c)(2) of section should not be changed. this chapter calculate the reduced (iv) Calculations. Calculate the plate height (hr) for the cefixime peak micrograms of cefixime anhydrous free as follows: acid per milligram as follows:
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pentahydrate. It is so purified and Micrograms of × × dried that: APu s 100 cefixime = (i) Its potency is not less than 950 × × − per milligram As C u ()100 m micrograms and not more than 1,020 where: micrograms of ceftazidime activity per
Au=Area of the cefixime peak in the chro- milligram on an anhydrous basis. matogram of the sample (at a retention (ii) Its loss on drying is not less than time equal to that observed for the 13.0 percent and not more than 15.0 per- standard); cent. As=Area of the cefixime peak in the chro- matogram of the cefixime working (iii) The pH of an aqueous solution standard; containing 5 milligrams of ceftazidime
Ps=Cefixime activity in the cefixime working per milliliter is not less than 3.0 and standard solution in micrograms per mil- not more than 4.0. liliter; (iv) It is crystalline. Cu=Milligrams of sample per milliliter of (v) It gives a positive identity test sample solution; and for ceftazidime. m=Percent moisture content of the sample. (vi) Its high molecular weight poly- (2) Moisture. Proceed as directed in mer content is not more than 0.05 per- § 436.201 of this chapter. cent. (3) pH. Proceed as directed in § 436.202 (2) Labeling. It shall be labeled in ac- of this chapter, using an aqueous solu- cordance with the requirements of tion containing 0.7 milligram per milli- § 432.5 of this chapter. liter. (3) Requests for certification; samples. (4) Crystallinity. Proceed as directed In addition to complying with the re- in § 436.203(a) of this chapter. quirements of § 431.1 of this chapter, (5) Specific rotation. Dissolve and di- each such request shall contain: lute an accurately weighed sample (i) Results of tests and assays on the with sufficient 2 percent sodium bicar- batch for potency, loss on drying, pH, bonate to obtain a concentration of ap- crystallinity, identity, and high molec- proximately 10 milligrams of cefixime ular weight polymer content. per milliliter. Proceed as directed in (ii) Samples, if required by the Direc- § 436.210 of this chapter, using a 1.0-dec- imeter polarimeter tube. Calculate the tor, Center for Drug Evaluation and specific rotation on the anhydrous Research: 10 packages, each containing basis. approximately 500 milligrams. (6) Identity. Proceed as directed in (b) Tests and methods of assay—(1) Po- § 436.211 of this chapter, using a potas- tency. Proceed as directed in sium bromide disc containing 0.5 per- § 442.16a(b)(1). cent of cefixime. Dissolve 5 to 6 milli- (2) Loss on drying. Proceed as directed grams of cefixime in 2 milliliters of in § 436.200(a) of this chapter. methanol. Triturate to insure solution. (3) pH. Proceed as directed in § 436.202 Evaporate the solvent to dryness and of this chapter, using an aqueous solu- using the dried sample, prepare the po- tion containing 5 milligrams of tassium bromide disc. ceftazidime per milliliter. [53 FR 24257, June 28, 1988; 53 FR 26712, July (4) Crystallinity. Proceed as directed 14, 1988; 54 FR 47205, Nov. 13, 1989] in § 436.203(a) of this chapter. (5) Identity. The high performance § 442.16 Ceftazidime pentahydrate. liquid chromatogram of the sample de- (a) Requirements for certification—(1) termined as directed in paragraph Standards of identity, strength, quality, (b)(1) of this section compares quali- and purity. Ceftazidime pentahydrate is tatively to that of the ceftazidime pyridinium, 1-[[7-[[(2-amino-4-thiazolyl) working standard. [1-carboxy-1- (6) High molecular weight polymer con- methylethoxy)imino]acetyl]-amino]-2- tent. Proceed as directed in carboxy-8-oxo-5-thia-1- § 442.16a(b)(8). azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-, hydroxide, inner salt, [6R-[6α,7β(Z)]]-, [54 FR 40652, Oct. 3, 1989]
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§ 442.16a Sterile ceftazidime in diameter) reversed phase packing pentahydrate. material such as hexyl, octyl, or (a) Requirements for certification—(1) octaldecyl hydrocarbon bonded silicas, Standards of identity, strength, quality, a flow rate of 2.0 milliliters per minute, and purity. Sterile ceftazidime and a known injection volume of 20 pentahydrate is pyridinium, 1-[[7-[[(2- microliters. Reagents, working stand- amino-4-thiazolyl)[(1-carboxy-1- ard and sample solutions, system suit- methylethoxy)imino]acetyl]amino]-2- ability requirements, and calculations carboxy-8-oxo-5-thia-1- are as follows: azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-, (i) Reagents—(a) Phosphate buffer, pH hydroxide, inner salt, [6R-[6α, 7β(Z)]]-, 7.0. Dissolve 42.59 grams of sodium pentahydrate. It is so purified and phosphate, dibasic anhydrous and 27.22 dried that: grams of potassium phosphate, (i) Its potency is not less than 950 monobasic, in water and dilute to 1,000 micrograms and not more than 1,020 milliliters. micrograms of ceftazidime activity per (b) Mobile phase. Mix 40 milliliters of milligram on an anhydrous basis. acetonitrile and 200 milliliters of phos- (ii) It is sterile. phate buffer, pH 7.0, and dilute to 2,000 (iii) It is nonpyrogenic. milliliters with water. Filter the mo- (iv) Its loss on drying is not less than bile phase through a suitable glass 13.0 and not more than 15.0 percent. fiber filter or equivalent that is capa- (v) Its pH in an aqueous solution con- ble of removing particulate contamina- taining 5 milligrams of ceftazidime per tion to 1 micron in diameter. Degas the milliliter is not less than 3.0 and not mobile phase just prior to its introduc- more than 4.0. tion into the chromatograph pumping (vi) It is crystalline. system. (vii) It gives a positive identity test (ii) Preparation of working standard for ceftazidime. and sample solutions—(a) Working stand- (viii) Its high molecular weight poly- ard solution. Accurately weigh mer content is not more than 0.05 per- ceftazidime working standard equiva- cent. lent to approximately 100 milligrams of (2) Labeling. It shall be labeled in ac- the ceftazidime activity into a 100-mil- cordance with the requirements of liliter volumetric flask containing 10 § 432.5 of this chapter. milliliters of phosphate buffer, pH 7.0. (3) Requests for certification; samples. Shake until dissolved. Dilute to vol- In addition to complying with the re- ume with water to obtain a stock solu- quirements of § 431.1 of this chapter, tion containing approximately 1,000 each such request shall contain. micrograms of ceftazidime activity per (i) Results of tests and assays on the milliliter. Mix well. Immediately prior batch for potency, sterility, pyrogens, to chromatography, further dilute 5 loss on drying, pH, crystallinity, iden- milliliters of stock solution to 50 milli- tity, and high molecular weight poly- liters with water to obtain a solution mer content. containing 100 micrograms of (ii) Samples, if required by the Direc- ceftazidime activity per milliliter. tor, Center for Drug Evaluation and (b) Sample solution. Accurately weigh Research: approximately 115 milligrams of the (a) For all tests except sterility: 10 sample into a 100-milliliter volumetric packages, each containing approxi- flask containing 10 milliliters of phos- mately 500 milligrams. phate buffer, pH 7.0. Shake until dis- (b) For sterility testing: One package solved. Dilute to volume with water to containing approximately 6 grams of a obtain a stock solution containing ap- composite sample. proximately 1,000 micrograms of (b) Tests and methods of assay—(1) Po- ceftazidime per milliliter. Mix well. tency. Proceed as directed in § 436.356 of Immediately prior to chromatography, this chapter, using ambient tempera- further dilute 5 milliliters of stock so- ture, an ultraviolet detection system lution to 50 milliliters with water to operating at a wavelength of 254 obtain a solution containing 100 nanometers, a column packed with micrograms of ceftazidime activity per microparticulate (3 to 10 micrometers milliliter (estimated).
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(iii) System suitability requirements— (4) Loss on drying. Proceed as directed (a) Tailing factor. The tailing factor (T) in § 436.200(a) of this chapter. is satisfactory if it is not more than 1.5 (5) pH. Proceed as directed in § 436.202 at 5 percent of peak height. of this chapter, using an aqueous solu- (b) Efficiency of the column. The effi- tion containing 5 milligrams of ciency of the column (n) is satisfactory ceftazidime per milliliter. if it is greater than 1,500 theoretical (6) Crystallinity. Proceed as directed plates. in § 436.203(a) of this chapter. (c) Resolution. The resolution (R) be- (7) Identity. The high-performance tween the peak for ceftazidime and its liquid chromatogram of the sample de- nearest eluting impurity is satisfac- termined as directed in paragraph tory if it is not less than 2.0. (b)(1) of this section compares quali- (d) Coefficient of variation. The coeffi- tatively to that of the ceftazidime working standard. cient of variation (SR in percent) of five replicate injections is satisfactory if it (8) High molecular weight polymer con- is not more than 1.0 percent. tent. Proceed as directed in § 436.360 of this chapter, using a constant tempera- If the system suitability requirements ture between 20 and 25 °C, an ultra- have been met, then proceed as de- violet detection system operating at a scribed in § 436.356(b) of this chapter. wavelength of 235 nanometers, a col- Alternate chromatographic conditions umn packed with a hydrophilic gel for are acceptable provided reproducibility gel permeation chromatography (such and resolution are provided comparable as Fractogel TSK HW–40(F), Merck) or to the system. However, the sample equivalent, a flow rate of 1.0 milliliter preparation described in paragraph per minute, and a known injection vol- (b)(1)(ii)(b) of this section should not be ume of 100 microliters. Reagents, work- changed. ing standard and sample solutions, sys- (iv) Calculations. Calculate the tem suitability requirements, and cal- micrograms of ceftazidime per milli- culations are as follows: gram of sample as follows: (i) Reagents—(a) Mobile phase. Adjust a 0.1M solution of potassium phos- Micrograms of AP× ×100 phate, dibasic, to pH 7.0±0.1 with phos- ceftazidime per = u s phoric acid. × − (b) Blue dextran system suitability test milligram As C u ()100 m solution. Prepare a solution in mobile phase containing 100 micrograms per Au=Area of the ceftazidime peak in the chro- matogram of the sample (at a retention milliliter of blue dextran (with a mean time equal to that observed for the molecular weight of approximately standard); 2,000,000).
As=Area of the ceftazidime peak in the chro- (ii) Preparation of working standard matogram of the ceftazidime working and sample solutions—(a) Working stand- standard; ard solution. Accurately weigh high mo- Ps=Ceftazidime activity in the ceftazidime lecular weight polymer working stand- working standard solution in ard equivalent to approximately 400 micrograms per milliliter; micrograms of high molecular weight Cu=Milligrams of sample per milliliter of polymer into a 100-milliliter volu- sample solution; and metric flask and add 80 milliliters of m=Percent loss on drying content of the sample. mobile phase. Shake until dissolved and dilute to volume with mobile phase (2) Sterility. Proceed as directed in to obtain a solution containing ap- § 436.20 of this chapter, using the meth- proximately 4 micrograms of high mo- od described in paragraph (e)(1) of that lecular weight polymer per milliliter. section, except dissolve the sample in Store the solution at ambient tempera- approximately 200 milliliters of dilut- ture and inject into the chromatograph ing fluid H. within one hour of preparation. (3) Pyrogens. Proceed as directed in (b) Sample solution. Accurately weigh § 436.32(i) of this chapter, using a solu- approximately 400 milligrams of the tion containing 80 milligrams of sample into a 100-milliliter volumetric ceftazidime per milliliter. flask and add 80 milliliters of mobile
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phase. Shake until dissolved, dilute to (ii) Its moisture content is not more volume with mobile phase, and imme- than 8.5 percent. diately inject the solution into the liq- (iii) Its pH in an aqueous solution uid chromatograph. containing 100 milligrams per milliliter (iii) System suitability requirements— is not less than 6.0 and not more than (a) Tailing factor. The tailing factor (T) 8.0 is satisfactory if it is not more than 1.5 (iv) It gives a positive identity test. for blue dextran. (v) It is crystalline. (b) Efficiency of the column. The effi- (2) Labeling. It shall be labeled in ac- ciency of the column (n) is satisfactory cordance with the requirements of if it is greater than 1,500 theoretical § 432.5 of this chapter. plates for blue dextran. (3) Requests for certification; samples. (c) Coefficient of variation. The coeffi- In addition to complying with the re- cient of variation (SR in percent) of five quirements of § 431.1 of this chapter, replicate injections of blue dextran is each such request shall contain: satisfactory if it is not more than 4 (i) Results of tests and assays on the percent. batch for ceftizoxime content, mois- If the system suitability requirements ture, pH, identity, and crystallinity. have been met, then proceed as de- (ii) Samples, if required by the Direc- scribed in § 436.360(b) of this chapter. tor, Center for Drug Evaluation and (iv) Calculations. Calculate the per- Research: 10 packages, each containing cent of high molecular weight polymer approximately 500 milligrams, and 1 content as follows: package containing approximately 5 grams. High molecular weight HP× × 0. 1 (b) Tests and methods of assay—(1) = u s polymer content in percent × Ceftizoxime content. Proceed as directed HCs u in § 436.345 of this chapter, preparing the sample solution and calculating
Hu=Height of the high molecular weight the ceftizoxime content as described in polymer peak in the chromatogram of paragraphs (e)(1) and (g)(1), respec- the sample (at a retention time equal to tively, of that section. that observed for the standard); (2) Moisture. Proceed as directed in Hs=Mean height of the high molecular weight polymer peaks in the § 436.201 of this chapter. chromatograms of the high molecular (3) pH. Proceed as directed in § 436.202 weight polymer working standard; of this chapter, using an aqueous solu- Ps=High molecular weight polymer content tion containing 100 milligrams per mil- of the high molecular weight polymer liliter. working standard solution in (4) Identity. The high-pressure liquid micrograms per milliliter; and chromatogram of the sample deter- Cu=Milligrams of sample per milliliter of sample solution. mined as directed in paragraph (b)(1) of this section, compares qualitatively to [50 FR 48399, Nov 25, 1985; 50 FR 53308, Dec. 31, that of the ceftizoxime working stand- 1985; 51 FR 2478, Jan. 17, 1986, as amended at ard. 55 FR 11583, Mar. 29, 1990] (5) Crystallinity. Proceed as directed § 442.17 Ceftizoxime sodium. in § 436.203(a) of this chapter. (a) Requirements for certification—(1) [49 FR 49285, Dec. 19, 1984, as amended at 55 Standards of identity, strength, quality, FR 11583, Mar. 29, 1990] and purity. Ceftizoxime sodium is the sodium salt of [6R-[6α, 7β(Z)]]-7-[[(2,3- § 442.17a Sterile ceftizoxime sodium. dihydro-2-imino-4-thiazolyl) (a) Requirements for certification—(1) (methoxyimino)acetyl]amino]-8-oxo-5- Standards of identity, strength, quality, thia-1-azabicyclo[4.2.0]oct-2-ene-2-car- and purity. Ceftizoxime sodium is the boxylic acid. It is so purified and dried sodium salt of [6R-[6α,7β(Z)]]-7-[[(2,3- that: dihydro-2-imino-4-thiazolyl) (i) Its ceftizoxime content is not less (methoxyimino) acetyl]amino]-8-oxo-5- than 850 micrograms and not more thia-1-azabicyclo [4.2.0]oct-2-ene-2-car- than 995 micrograms of ceftizoxime per boxylic acid. It is so purified and dried milligram on an anhydrous basis. that:
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(i) If the ceftizoxime is not packaged (b) Tests and methods of assay—(1) for dispensing, its ceftizoxime content Ceftizoxime content. Proceed as directed is not less than 850 micrograms and not in § 436.345 of this chapter. more than 995 micrograms of (2) Sterility. Proceed as directed in ceftizoxime per milligram on an anhy- § 436.20 of this chapter, using the meth- drous basis. If the ceftizoxime is od described in paragraph (e)(1) of that packaged for dispensing, its section. ceftizoxime content is not less than 850 (3) Pyrogens. Proceed as directed in micrograms and not more than 995 § 436.32(b) of this chapter, using a solu- micrograms of ceftizoxime per milli- tion containing 50 milligrams of gram on an anhydrous basis and also, ceftizoxime per milliliter. each container contains not less than (4) Moisture. Proceed as directed in 90 percent and not more than 115 per- § 436.201 of this chapter. cent of the number of milligrams of (5) pH. Proceed as directed in § 436.202 ceftizoxime that it is represented to of this chapter, using an aqueous solu- contain. tion containing 100 milligrams per mil- (ii) It is sterile. liliter. (iii) It is nonpyrogenic. (6) Identity. From the high-pressure (iv) Its moisture content is not more liquid chromatograms of the sample than 8.5 percent. and the ceftizoxime working standard (v) Its pH in an aqueous solution con- determined as directed in paragraph taining 100 milligrams per milliliter is (b)(1) of this section, calculate the ad- not less than 6.0 and not more than 8.0. justed retention times of the (vi) It gives a positive identity test. ceftizoxime in the sample and standard (vii) It is crystalline. solutions as follows: (2) Labeling. It shall be labeled in ac- Adjusted retention time of ceftizoxime=t¥t cordance with the requirements of a § 432.5 of this chapter. where: (3) Requests for certification; samples. t=Retention time measured from point of in- In addition to complying with the re- jection into the chromatograph until the maximum of the ceftizoxime sample or quirements of § 431.1 of this chapter, working standard peak appears on the each such request shall contain: chromatogram; and
(i) Results of tests and assays on the ta=Retention time measured from point of batch for ceftizoxime content, steril- injection into the chromatograph until ity, pyrogens, moisture, pH, identity, the maximum of nonretarded solute ap- and crystallinity. pears in the chromatogram. (ii) Samples, if required by the Direc- tor, Center for Drug Evaluation and The sample and the ceftizoxime work- Research: ing standard should have corresponding adjusted ceftizoxime retention times. (a) If the batch is packaged for re- packing or for use in the manufacture (7) Crystallinity. Proceed as directed of another drug: in § 436.203(a) of this chapter. (1) For all tests except sterility: 10 [48 FR 46271, Oct. 12, 1983; 48 FR 49656, Oct. 27, packages, each containing at least 500 1983, as amended at 55 FR 11583, Mar. 29, 1990] milligrams. (2) For sterility testing: 20 packages, § 442.18 Cefuroxime sodium. each containing equal portions of ap- (a) Requirements for certification—(1) proximately 300 milligrams. Standards of identity, strength, quality, (b) If the batch is packaged for dis- and purity. Cefuroxime sodium is the pensing: sodium salt of (6R,7R)-3-carbamoyloxy- (1) For all tests except sterility: A methyl-7-[(2Z)-2-(2-furyl)-2- minimum of 10 immediate containers; methoxyiminoacetamido]cepha-3-em-4- or if each container contains less than carboxylic acid. It is so purified and 1 gram of ceftizoxime, a minimum of 20 dried that: immediate containers. (i) Its potency is not less than 855 (2) For sterility testing: 20 immediate micrograms and not more than 1,000 containers, collected at regular inter- micrograms of cefuroxime activity per vals throughout each filling operation. milligram on an anhydrous basis.
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(ii) Its moisture content is not more (ii) It is sterile. than 3.5 percent. (iii) It is nonpyrogenic. (iii) The pH of an aqueous solution (iv) Its moisture content is not more containing 100 milligrams of than 3.5 percent. cefuroxime per milliliter is not less (v) Its pH in an aqueous solution is than 6.0 and not more than 8.5. not less than 6.0 and not more than 8.5. (iv) It gives a positive identity test (vi) It gives a positive identity test. for cefuroxime. (2) Labeling. It shall be labeled in ac- (2) Labeling. It shall be labeled in ac- cordance with the requirements of cordance with the requirements of § 432.5 of this chapter. § 432.5 of this chapter. (3) Requests for certification; samples. (3) Requests for certification; samples. In addition to complying with the re- In addition to complying with the re- quirements of § 431.1 of this chapter, quirements of § 431.1 of this chapter, each such request shall contain: each such request shall contain: (i) Results of tests and assays on the (i) Results of tests and assays on the batch for potency, moisture, pH, and batch for cefuroxime content, sterility, identity. pyrogens, moisture, pH, and identity. (ii) Samples, if required by the Direc- (ii) Samples, if required by the Direc- tor, Center for Drug Evaluation and tor, Center for Drug Evaluation and Research: 10 packages, each containing Research: approximately 1 gram. (a) If the batch is packaged for re- (b) Tests and methods of assay—(1) Po- packing or for use as an ingredient in tency. Proceed as directed in § 442.343. the manufacture of another drug: (2) Moisture. Proceed as directed in (1) For all tests except sterility: 10 § 436.18a(b)(4) of this chapter. packages, each containing approxi- (3) pH. Proceed as directed in § 436.202 mately 1 gram. of this chapter, using an aqueous solu- (2) For sterility testing: 20 packages, tion containing 100 milligrams of each containing approximately 1 gram. cefuroxime per milliliter. (b) If the batch is packaged for dis- (4) Identity. Proceed as directed in pensing: § 442.18a(b)(6). (1) For all tests except sterility: A [54 FR 40654, Oct. 3, 1989; 54 FR 50686, Dec. 8, minimum of 10 immediate containers. 1989] (2) For sterility testing: 20 immediate containers, collected at regular inter- § 442.18a Sterile cefuroxime sodium. vals throughout each filling operation. (a) Requirements for certification—(1) (b) Tests and methods of assay—(1) Standards of identity, strength, quality, Cefuroxime content. Proceed as directed and purity. Cefuroxime sodium is the in § 436.343 of this chapter. sodium salt of (6R, 7R )-3- (2) Sterility. Proceed as directed in carbamoyloxy-methyl-7-[(2Z )-2-(2- § 436.20 of this chapter, using the meth- furyl)-2-methoxyiminoacetamido] od described in paragraph (e)(1) of that cepha-3-em-4-carboxylic acid. It is so section. purified and dried that: (3) Pyrogens. Proceed as directed in (i) If the cefuroxime is not packaged § 436.32(b) of this chapter, using a solu- for dispensing, its cefuroxime content tion containing 50 milligrams of is not less than 855 micrograms and not cefuroxime per milliliter. more than 1,000 micrograms of (4) Moisture. Proceed as directed in cefuroxime per milligram on an anhy- § 436.201 of this chapter, using the titra- drous basis. If the cefuroxime is tion procedure described in paragraph packaged for dispensing, its cefuroxime (e)(1) of that section. content is not less than 855 micrograms (5) pH. Proceed as directed in § 436.202 and not more than 1,000 micrograms of of this chapter, using an aqueous solu- cefuroxime per milligram on an anhy- tion containing 100 milligrams per mil- drous basis and also, each container liliter. contains not less than 90 percent and (6) Identity. From the high-pressure not more than 120 percent of the num- liquid chromatograms of the sample ber of milligrams of cefuroxime that it and the cefuroxime working standard is represented to contain. determined as directed in paragraph
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(b)(1) of this section, calculate the ad- Research: 10 packages, each containing justed retention times of the approximately 500 milligrams. cefuroxime in the sample and standard (b) Tests and methods of assay—(1) Po- solutions as follows: tency. Proceed as directed in § 436.216 of this chapter, using ambient tempera- Adjusted retention time of cefuroxime=t¥ta ture, an ultraviolet detection system where: operating at a wavelength of 278 t=Retention time measured from point of in- jection into the chromatograph until the nanometers, a 25-centimeter by 4.6-mil- maximum of the cefuroxime sample or limeter column packed with methyl working standard peak appears on the silane bonded silica 5 micrometers in chromatogram; and particle size, a flow rate of 1 milliliter ta=Retention time measured from point of per minute, and a known injection vol- injection into the chromatograph until ume of 10 microliters. Reagents, work- the maximum of nonretarded solute ap- ing standard and sample solutions, sys- pears in the chromatogram. tem suitability requirements, and cal- The sample and the cefuroxime work- culations are as follows: ing standard should have corresponding (i) Reagents—(A) 0.2M Ammonium adjusted cefuroxime retention times. phosphate solution. Transfer 23.0 grams of ammonium dihydrogen phosphate to [48 FR 38461, Aug. 24, 1983, as amended at 55 a 1-liter volumetric flask. Dissolve and FR 11583, Mar. 29, 1990] dilute to volume with distilled water. § 442.19 Cefuroxime axetil. Mix well. (B) Mobile phase. Transfer 380 milli- (a) Requirements for certification—(1) liters of methanol to a 1-liter volu- Standards of identity, strength, quality, metric flask and dilute to volume with and purity. Cefuroxime axetil is an 0.2M ammonium phosphate solution. amorphous mixture of the diastereo- isomers of 5-thia-1-azabicyclo[4.2.0]oct- (C) Internal standard solution. Prepare 2-ene-2-carboxylic acid, 3- a solution containing 5.4 milligrams of [[(aminocarbonyl)oxy]methyl]-7-[[2- acetanilide per milliliter in methanol. furanyl(methoxyimino)acetyl]amino]- (D) System suitability test solution. Mix 8-oxo-, 1-(acetyloxy)ethyl ester, [6R-[6 10.0 milliliters of a solution containing alpha, 7 beta (Z)]]-. It is so purified and 1.2 milligrams of cefuroxime axetil dried that: working standard per milliliter in (i) Its potency is not less than 745 methanol with 5.0 milliliters of inter- micrograms and not more than 875 nal standard solution, 2.0 milliliters of micrograms of cefuroxime per milli- a solution containing 0.3 milligram of gram on an anhydrous basis. The ratio an authentic sample of (RS)-1- of isomer A to total isomer content is acetoxyethyl (6R, 7R)-3- not less than 0.48 and not more than carbamoyloxymethyl-7-[(2′Z)-2-(fur-2- 0.55. yl)-2-methoxy-iminoacetamido]ceph-2- (ii) Its moisture content is not more em-4-carboxylate (delta-2 isomers of than 1.5 percent. cefuroxime axetil) per milliliter in (iii) It is amorphous and not crys- methanol and 1.8 milliliters of meth- talline. anol. Dilute to 50 milliliters with 0.2M (iv) It passes the identity test. ammonium phosphate solution. (2) Labeling. It shall be labeled in ac- (ii) Preparation of working standard cordance with the requirements of and sample solutions—(A) Working stand- § 432.5 of this chapter. ard solution. Dissolve approximately 30 (3) Request for certification; samples. In milligrams of the cefuroxime axetil addition to complying with the re- working standard, accurately weighed, quirements of § 431.1 of this chapter, in methanol and dilute to 25 milliliters each such request shall contain: with methanol. Immediately transfer (i) Results of tests and assays on the 10.0 milliliters of the working standard batch for cefuroxime potency, isomer A solution to a 50-milliliter volumetric ratio, moisture, crystallinity, and iden- flask. Add 5.0 milliliters of internal tity. standard solution and 3.8 milliliters of (ii) Samples, if required by the Direc- methanol, and dilute to volume with tor, Center for Drug Evaluation and 0.2M ammonium phosphate soluton to
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obtain a solution containing 0.2 milli- (D) Coefficent of variation. The coeffi- gram of cefuroxime activity per milli- cient of variation (SRin percent) of five liter. Store the solution under refrig- replicate injections is satisfactory if it eration no more than 8 hours. is not more than 2.0 percent. If the sys- (B) Sample solution. Dissolve approxi- tem suitability requirements have been mately 30 milligrams of the sample, ac- met, then proceed as described in curately weighed, in methanol and di- § 436.216(b) of this chapter. Alternate lute to 25 milliliters with methanol. chromatographic conditions are ac- Immediately transfer 10.0 milliliters of ceptable provided reproducibility and the sample solution to a 50-milliliter resolutiona recomparable to the sys- tem. However, the sample preparation volumetric flask. Add 5.0 milliliters of described in paragraph (b)(1)(ii)(B) of internal standard solution and 3.8 mil- this section should not be changed. liliters of methanol, and dilute to vol- (iv) Calculations—(A) Calculate the ume with 0.2M ammonium phosphate micrograms of cefuroxime per milli- solution to obtain a solution contain- gram of sample as follows: ing 0.2 milligram of cefuroxime activ- ity per milliliter (estimated). Store the Micrograms of RP× ×100 solution under refrigeration no more cefuroxime per = u s than 8 hours. R× C ×()100 − m (iii) System suitability requirements— milligram s u (A) Tailing factor. The tailing factor (T) where: is satisfactory for isomer A if it is not Ru = Sum of the peak height of the cefuroxime axetil sample isomer A and more than 1.5 at 5 percent of peak isomer B peaks/Peak height of the inter- height. nal standard; (B) Efficiency of the column. The effi- Rs = Sum of the peak heights of the ciency of the column (n) is satisfactory cefuroxime axetil working standard iso- for isomer A if it is greater than 3,000 mer A and isomer B peaks/Peak height of the internal standard; theoretical plates. Ps = Cefuroxime activity in the cefuroxime (C) Resolution. The resolution (R) be- axetil working standard solution in tween isomer A and isomer B of micrograms per milliliter; cefuroxime axetil is satisfactory if it is Cu = Milligrams of sample per milliliter of not less than 1.5 and the resolution (R) sample solution; and between isomer A and the delta-2 iso- m = Percent moisture content of the sample. mers of cefuroxime axetil is satisfac- (B) Calculate the ratio of isomer A to tory if it is not less than 1.5. total isomer content as follows:
Peak height of isomer A peak Ratio of isomer A to isomer content = Peak height of isomer A peak + Peak height of isomer B peak
(2) Moisture. Proceed as directed in eral oil mull prepared as described in § 436.201 of this chapter, using the titra- paragraph (b)(2) of that section. tion procedure described in paragraph [52 FR 42432, Nov. 5, 1987; 52 FR 43966, Nov. 17, (e)(1) of that section. 1987; 52 FR 45528, Nov. 30, 1987, as amended at (3) Crystallinity. Proceed as directed 54 FR 47351, Nov. 14, 1989; 55 FR 11583, Mar. in § 436.203(a) of this chapter, except 29, 1990] that the particles do not reveal the phenomena of birefringence and extinc- § 442.20a Sterile cefonicid sodium. tion positions on revolving the micro- (a) Requirements for certification—(1) scope stage. Standards of identity, strength, quality, (4) Identity. Proceed as directed in and purity. Sterile cefonicid sodium is § 436.211 of this chapter, using the min- a white to off-white lyophilized powder. It is so purified and dried that:
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(i) If the cefonicid sodium is not § 436.350 of this chapter, using ambient packaged for dispensing, its cefonicid temperature, an ultraviolet detection content is not less than 832 micrograms system operating at a wavelength of and not more than 970 micrograms of 254 nanometers, and a column packed cefonicid per milligram on an anhy- with octadecyl silane bonded silica drous basis. If the cefonicid sodium is ranging from 3 to 30 micrometers in packaged for dispensing, its cefonicid particle size. Reagents, working stand- content is not less than 832 micrograms ard and sample solutions, system suit- and not more than 970 micrograms of ability requirements, and calculations cefonicid per milligram on an anhy- are as follows: drous basis and also, each container (i) Reagents—(a) 0.2M Ammonium phos- contains not less than 90 percent and phate solution. Transfer 23.0 grams of not more than 120 percent of the num- ammonium dihydrogen phosphate to a ber of milligrams of cefonicid that it is 1-liter volumetric flask. Dissolve and represented to contain. dilute to volume with distilled water. (ii) It is sterile. Mix well. (iii) It is nonpyrogenic. (b) Mobile phase. Mix 0.2M ammonium (iv) Its moisture content is not more phosphate solution : methyl alco- than 5.0 percent. hol : distilled water (1 : 2.5 : 16.5). Filter (v) Its pH in an aqueous solution con- through a suitable filter capable of re- taining 50 milligrams per milliliter is moving particulate matter to 0.5 mi- not less than 3.5 and not more than 6.5. cron in diameter. Degas the mobile (vi) The specific rotation in a meth- phase just prior to its introduction anol solution containing 10 milligrams into the chromatograph. of cefonicid sodium per milliliter at 25° (ii) Working standard and sample solu- C is ¥42°±5°. tions—(a) Preparation of working stand- (vii) It passes the identity test. ard solution. Prepare the working (2) Labeling. It shall be labeled in ac- standard solution fresh before injection cordance with the requirements of by dissolving an accurately weighed § 432.5 of this chapter. portion of the cefonicid working stand- (3) Requests for certification; samples. ard with sufficient mobile phase as de- In addition to complying with the re- scribed in paragraph (b)(1)(i)(b) of this quirements of § 431.1 of this chapter, section to obtain a solution containing each such request shall contain: approximately 20 micrograms of (i) Results of tests and assays on the cefonicid per milliliter. batch for cefonicid content, sterility, (b) Preparation of sample solutions—(1) pyrogens, moisture, pH, specific rota- Product not packaged for dispensing tion, and identity. (micrograms of cefonicid per milligram). (ii) Samples, if required by the Direc- Dissolve an accurately weighed portion tor, Center for Drug Evaluation and of the sample with sufficient mobile Research: phase as described in paragraph (a) If the batch is packaged for re- (b)(1)(i)(b) of this section to obtain a packing or for use as an ingredient in concentration of approximately 20 the manufacture of another drug; micrograms of cefonicid per milliliter. (1) For all tests except sterility: 10 (2) Product packaged for dispensing. packages, each containing at least 500 Determine both micrograms of milligrams. cefonicid per milligram of the sample (2) For sterility testing: 20 packages, and milligrams of cefonicid per con- each containing equal portions of ap- tainer. Use separate containers for proximately 300 milligrams. preparation of each sample solution as (b) If the batch is packaged for dis- described in paragraphs (b)(1)(ii)(b)(2) pensing: (i) and (ii) of this section. (1) For all tests except sterility: A (i) Micrograms of cefonicid per milli- minimum of 10 immediate containers. gram. Dissolve an accurately weighed (2) For sterility testing: 20 immediate portion of the sample with sufficient containers, collected at regular inter- mobile phase as described in paragraph vals throughout each filling operation. (b)(1)(i)(b) of this section to obtain a (b) Tests and methods of assay—(1) concentration of approximately 20 Cefonicid content. Proceed as directed in micrograms of cefonicid per milliliter.
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(ii) Milligrams of cefonicid per con- As=Area of the cefonicid peak in the chro- tainer. Reconstitute the sample as di- matogram of the cefonicid working rected in the labeling. Then, using a standard; suitable hypodermic needle and sy- Ps=Cefonicid activity in the cefonicid work- ing standard solution in micrograms per ringe, remove all of the withdrawable milliliter; contents if it is represented as a single- Cu=Milligrams of sample per milliliter of dose container; or, if the labeling speci- sample solution; and fies the amount of potency in a given m=Percent moisture content of the sample. volume of the resultant preparation, remove an accurately measured rep- (b) Calculate the cefonicid content of resentative portion from each con- the container as follows: tainer. Further dilute an aliquot of the solution thus obtained with sufficient Milligrams of A× P × d cefonicid per = u s mobile phase to obtain a concentration × of approximately 20 micrograms of container As 1, 000 cefonicid per milliliter. where: (iii) System suitability requirements— Au=Area of the cefonicid peak in the chro- (a) Tailing factor. The tailing factor (T) matogram of the sample (at a retention is satisfactory if it is not more than 1.3 time equal to that observed for the at 5 percent of peak height. standard); (b) Efficiency of the column. The effi- As=Area of the cefonicid peak in the chro- matogram of the cefonicid working ciency of the column (n) is satisfactory standard; if it is greater than 1,500 theoretical Ps=Cefonicid activity in the cefonicid work- plates. ing standard solution in micrograms per (c) Resolution factor. Prepare a resolu- milliliter; and tion solution containing desacetyl d=Dilution factor of the sample. cefonicid by heating a 200-microgram- (2) Sterility. Proceed as directed in per-milliliter solution of cefonicid § 436.20 of this chapter, using the meth- working standard in mobile phase de- od described in paragraph (e)(1) of that scribed in paragraph (b)(1)(i)(b) of this section. section, on a steam bath for 30 min- (3) Pyrogens. Proceed as directed in utes. Inject a known volume between 10 § 436.32(b) of this chapter, using a solu- and 20 microliters of the desacetyl tion containing 50 milligrams of cefonicid containing solution in the cefonicid per milliliter. same manner as described for the (4) Moisture. Proceed as directed in standard solution. The resolution fac- § 436.201 of this chapter. tor (R) between cefonicid and desacetyl (5) pH. Proceed as directed in § 436.202 cefonicid is satisfactory if it is not less of this chapter, using an aqueous solu- than 1.1. tion containing 50 milligrams per mil- (d) Coefficient of variation. The coeffi- liliter. cient of variation (S in percent) of five R (6) Specific rotation. Dissolve and di- replicate injections is satisfactory if it lute an accurately weighed sample is not more than 2.0 percent. with sufficient methanol to obtain a If the system suitability parameters concentration of approximately 10 mil- have been met, then proceed as de- ligrams of cefonicid sodium per milli- scribed in § 436.350(b) of this chapter. liter. Proceed as directed in § 436.210 of (iv) Calculations—(a) Calculate the this chapter, using a 1.0-decimeter po- micrograms of cefonicid per milligram larimeter tube. Calculate the specific of sample as follows: rotation on an anhydrous basis. (7) Identity. The high-performance Micrograms of AP× ×100 liquid chromatogram of the sample, de- cefonicid = u s termined as directed in paragraph per milligram A× C ×()100 − m (b)(1) of this section, compares quali- s u tatively to that of the cefonicid work- where: ing standard. Au=Area of the cefonicid peak in the chro- matogram of the sample (at a retention [49 FR 34348, Aug. 30, 1984; 49 FR 44460, Nov. time equal to that observed for the 7, 1984, as amended at 54 FR 41824, Oct. 12, standard); 1989; 55 FR 11583, Mar. 29, 1990]
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§ 442.21 Cephaloglycin dihydrate. cephaloglycin content, identity, and (a) Requirements for certification—(1) crystallinity. Standards of identity, strength, quality, (ii) Samples required: 10 packages, and purity. Cephaloglycin dihydrate is each containing approximately 500 mil- the dihydrate form of 7-(D-α-amino- ligrams. phenylacetamido) cephalosporanic (b) Tests and methods of assay—(1) Po- acid. It is a white to off-white powder. tency. Proceed as directed in § 436.105 of It is so purified and dried that: this chapter, preparing the sample for (i) Its potency is not less than 900 assay as follows: Dissolve an accu- micrograms of cephaloglycin per milli- rately weighed portion of the sample in gram on an anhydrous basis. sufficient sterile distilled water to give (ii) [Reserved] a stock solution of 100 micrograms of (iii) Its moisture is not less than 8.2 cephaloglycin per milliliter (esti- and not more than 12 percent. mated). Further dilute an aliquot of (iv) Its pH in an aqueous suspension the stock solution with 0.1M potassium containing 50 milligrams per milliliter phosphate buffer, pH 4.5 (solution 4), to is not less than 3.0 and not more than the reference concentration of 10 5.5. micrograms of cephaloglycin per milli- (v) Its cephaloglycin content is not liter (estimated). less than 95 and not more than 104 per- (2) [Reserved] cent on an anhydrous basis. (vi) It gives a positive identity test (3) Moisture. Proceed as directed in for cephaloglycin dihydrate. § 436.201 of this chapter. (vii) It is crystalline. (4) pH. Proceed as directed in § 436.202 (2) Labeling. It shall be labeled in ac- of this chapter, using an aqueous sus- cordance with the requirements of pension containing 50 milligrams per § 432.5(b) of this chapter. milliliter. (3) Requests for certification; samples. (5) Cephaloglycin content. Proceed as In addition to complying with the re- directed in § 436.213 of this chapter, quirements of § 431.1 of this chapter, using the titration procedure described each such request shall contain: in paragraph (e)(2) of that section. Cal- (i) Results of tests and assays on the culate the cephaloglycin content as batch for potency, moisture, pH, follows:
()AB− (normality of perchloric acid reagent) (405.4) (100) (100) Percent cephaloglycin content = (Weight of sample in milligrams) (100 − m)
where: § 442.22a Sterile cefmenoxime hydro- A=Milliliters of perchloric acid reagent chloride. used in titrating the sample; (a) Requirements for certification—(1) B=Milliliters of perchloric acid reagent Standards of identity, strength, quality, used in titrating the blank; and purity. Cefmenoxime hydrochloride m=Percent moisture content of the sample. is 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- (6) Identity. Proceed as directed in carboxylic acid, 7-[[(2-amino-4- § 436.211 of this chapter, using the 0.5- thiazolyl) percent potassium bromide disc pre- (methoxyimino)acetyl]amino]-3-[[(1- pared as described in paragraph (b)(1) methyl-1H-tetrazol-5-yl)thio]methyl]-8- of that section. oxo-, hydrochloride (2:1), [6R-[6α,7β(Z)]]- (7) Crystallinity. Proceed as directed . It is so purified and dried that: in § 436.203(a) of this chapter. (i) Its cefmenoxime content is not less than 869 and not more than 1,015 [39 FR 19040, May 30, 1974, as amended at 50 micrograms of cefmenoxime per milli- FR 19919, May 13, 1985] gram on an anhydrous basis. (ii) It is sterile.
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(iii) It is nonpyrogenic. (ii) Preparation of working standard (iv) Its moisture content is not more and sample solutions—(A) Working stand- than 1.5 percent. ard solution. Dissolve approximately 50 (v) It passes the identity test. milligrams of the cefmenoxime work- (vi) It is crystalline. ing standard, accurately weighed, in 10 (2) Labeling. It shall be labeled in ac- milliliters of 0.1M phosphate buffer so- cordance with the requirements of lution, pH 6.8 and dilute to 50 milli- § 432.5 of this chapter. liters with mobile phase. Transfer 4.0 (3) Requests for certification; samples. milliliters of this solution to a 50-milli- In addition to complying with the re- liter volumetric flask, add 20 milli- quirements of § 431.1 of this chapter, liters of internal standard solution and each such request shall contain: dilute to volume with mobile phase to (i) Results of tests and assays on the obtain a solution containing 80 batch for cefmenoxime content, steril- micrograms of cefmenoxime per milli- ity, pyrogens, moisture, identity, and liter. crystallinity. (B) Sample solution. Dissolve approxi- (ii) Samples, if required by the Direc- mately 50 milligrams of cefmenoxime tor, Center for Drug Evaluation and sample, accurately weighed, in 10 milli- Research: liters of 0.1M phosphate buffer solu- (A) For all tests except sterility: 10 tion, pH 6.8. Dilute to 50 milliliters packages, each containing approxi- with mobile phase. Transfer 4.0 milli- mately 500 milligrams. liters of this solution to a 50-milliliter (B) For sterility testing: 1 package volumetric flask, add 20 milliliters of containing approximately 6 grams of a internal standard solution and dilute composite sample. to volume with mobile phase. (b) Tests and methods of assay—(1) (iii) System suitability requirements— Cefmenoxime content. Proceed as di- (A) Tailing factor. The tailing factor (T) rected in § 436.363 of this chapter, using for the cefmenoxime peak is satisfac- ambient temperature, an ultraviolet detection system operating at a wave- tory if it is not more than 1.6 at 5 per- length of 254 nanometers, a column cent of peak height. packed with microparticulate (3 to 10 (B) Efficiency of the column. The effi- micrometers in diameter) reversed ciency of the column (n) is satisfactory phase packing material such as octa- if it is greater than 1,200 theoretical decyl hydrocarbon bonded silicas, a plates for the cefmenoxime peak. flow rate not to exceed 2.0 milliliters (C) Resolution. The resolution (R) be- per minute, and a known injection vol- tween the peak for cefmenoxime and ume between 10 and 20 microliters. Re- phthalimide is satisfactory if it is not agents, working standard and sample less than 2.3. solutions, system suitability require- (D) Coefficient of variation. The ments, and calculations are as follows: coefficiednt of variation (SR in percent) (i) Reagents—(A) 0.1M Phosphate buff- of 5 replicate injections is satisfactory er solution, pH 6.8. Dissolve 6.4 grams of if it is not more than 2.0 percent. If the monobasic potassium phosphate and system suitability requirements have 18.9 grams of dibasic sodium phosphate been met, then proceed as described in in 750 milliliters of water. Adjust the § 436.363(b) of this chapter. pH to 6.8 with 1N sodium hydroxide and (iv) Calculations. Calculate the dilute to 1,000 milliliters. micrograms of cefmenoxime per milli- (B) Internal standard solution. Dis- gram of sample as follows: solve and dilute 0.15 gram of phthal- imide in methanol to 100 milliliters. Micrograms of RP× ×100 (C) Mobile phase. Mix cefmenoxime per = u s water:acetonitrile:glacial acetic acid × × − (50:10:1). Filter through a suitable filter milligram Rs C u ()100 m capable of removing particulate matter where:
to 0.5 micron in diameter. Degas the Ru=Area of cefmenoxime peak in the chro- mobile phase just prior to its introduc- matogram of the sample/Area of internal tion into the chromatograph. standard peak;
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Rs=Area of the cefmenoxime peak in the § 442.23a Sterile cephaloridine. chromatogram of the cefmenoxime work- ing standard/Area of internal standard (a) Requirements for certification—(1) peak; Standards of identity, strength, quality, α Ps=Cefmenoxime activity in the and purity. Cephaloridine is 7-[ -(2- cefmenoxime working standard solution thienyl)-acetamido]-3-(1-pyridyl-meth- in micrograms per milliliter; yl)-3-cephem-4-carboxylic acid betaine. Cu=Milligrams of sample per milliliter of It is a white to off-white powder. It is sample solution; and so purified and dried that: m=Percent moisture content of the sample. (i) Its potency is not less than 900 (2) Sterility. Proceed as directed in micrograms of cephaloridine per milli- § 436.20 of this chapter, using the meth- gram. If it is packaged for dispensing, od described in paragraph (e)(1) of that its potency is satisfactory if it is not section, except in lieu of diluting fluid less than 90 percent and not more than A use diluting fluid H. 115 percent of the number of milli- grams of cephaloridine that it is rep- (3) Pyrogens. Proceed as directed in resented to contain. § 436.32(i) of this chapter, using a solu- (ii) It is sterile. tion containing 60 milligrams per mil- (iii) It is nonpyrogenic. liliter. (iv) [Reserved] (4) Moisture. Proceed as directed in (v) Its loss on drying is not more § 436.201 of this chapter, using the sam- than 2.5 percent. ple preparation described in paragraph (vi) Its pH in an aqueous solution is (d)(4) of that section and the titration not less than 3.5 and not more than 6. procedure described in paragraph (e)(3) (vii) The specific rotation in an aque- of that section, except: ous solution containing 10 milligrams (i) In lieu of 3 milliliters of anhy- of cephaloridine per milliliter at 25° C. drous methanol solution, inject 20 mil- is ∂48°±4°. liliters of a formamide:methanol solu- (viii) It is crystalline. tion (2:1) into the container and shake (ix) The ultraviolet absorption spec- to dissolve the contents (prior to use in trum between the wavelengths of 220 preparation of the form- and 310 nanometers compares quali- amide:methanol solution, dry 500 tatively to that of the cephaloridine grams of formamide over 20 grams of working standard. The ratio of the anhydrous sodium sulfate for 24 hours); absorbance of the maximum at the (ii) Rinse the syringe, needle, and im- wavelength of 240 nanometers to that mediate container with two separate 5- of the shoulder at 255 nanometers is milliliter portions of anhydrous meth- not less than 1.05 and not more than anol, in lieu of one 3-milliliter portion 1.17. of anhydrous methanol; and (2) Labeling. It shall be labeled in ac- (iii) In § 436.201(e)(3) of this chapter, cordance with the requirements pre- add a sufficient volume of the form- scribed by § 432.5 of this chapter. amide:methanol solution (2:1) to cover (3) Requests for certification; samples. the electrodes in the dry titrating ves- In addition to the requirements of sel, in lieu of 20 milliliters of solvent A § 431.1 of this chapter, each such re- before starting the titration. quest shall contain: (5) Identity. Using a 0.0025-percent so- (i) Results of tests and assays on the lution of the sample in 0.1M phosphate batch for potency, sterility, pyrogens, buffer, pH 6.8 and a suitable loss on drying, pH, specific rotation, spectrophotometer, record the ultra- crystallinity, and identity. violet absorption spectrum from 220 to (ii) Samples of the batch: ( ) If the batch is packaged for re- 310 nanometers. The spectrum com- a packing or for use as an ingredient in pares qualitatively to that of the the manufacture of another drug: cefmenoxime working standard simi- (1) For all tests except sterility: 10 larly tested. packages, each containing at least 500 (6) Crystallinity. Proceed as directed milligrams. in § 436.203(a) of this chapter. (2) For sterility testing: 20 packages, [53 FR 13402, Apr. 25, 1988; 53 FR 19368, May each containing equal portions of ap- 27, 1988] proximately 300 milligrams.
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(b) If the batch is packaged for dis- (c) Hydroxylamine colorimetric assay. pensing: Proceed as directed in § 436.205 of this (1) For all tests except sterility: A chapter. minimum of 13 immediate containers (2) Sterility. Proceed as directed in of the batch. § 436.20 of this chapter, using the meth- (2) For sterility testing: 20 immediate od described in paragraph (e)(1) of that containers collected at regular inter- section. (3) Pyrogens. Proceed as directed in vals throughout each filling operation. § 436.32(b) of this chapter, using a solu- (b) Tests and methods of assay—(1) Po- tion containing 50 milligrams of tency—(i) Sample preparation. Dissolve cephaloridine per milliliter. an accurately weighed sample in suffi- (4) [Reserved] cient 1.0 percent potassium phosphate (5) Loss on drying. Proceed as directed buffer, pH 6.0 (solution 1), for the in § 436.200(b) of this chapter. microbiological agar diffusion assay, (6) pH. Proceed as directed in § 436.202 distilled water for the iodometric assay of this chapter, using an aqueous solu- or hydroxylamine colorimetric assay, tion containing 250 milligrams of to give a stock solution of convenient cephaloridine per milliliter. If it is concentration; also if it is packaged for packaged for dispensing, however, use dispensing, reconstitute as directed in the solution obtained after reconstitut- the labeling. Then using a suitable ing the drug as directed in the labeling. hypodermic needle and syringe, remove (7) Specific rotation. Dilute an accu- all of the withdrawable contents if it is rately weighed sample with sufficient represented as a single-dose container; distilled water to give a concentration or, if the labeling specifies the amount of approximately 10 milligrams of of potency in a given volume of the re- cephaloridine per milliliter. Proceed as sultant preparation, remove an accu- directed in § 436.210 of this chapter rately measured representative portion using a 2.0-decimeter polarimeter tube. from each container. Dilute with either (8) Crystallinity. Proceed as directed solution 1 or distilled water as speci- in § 436.203(a) of this chapter. (9) Identity. Using a 0.0025-percent so- fied above to give a stock solution of lution of the sample in water and a convenient concentration. suitable spectrophotometer, record the (ii) Assay procedures. Use any of the ultraviolet absorption spectrum from following methods; however, the re- 220 to 310 nanometers. The spectrum sults obtained from the micro- compares qualitatively to that of the biological agar diffusion assay shall be cephaloridine working standard simi- conclusive. larly tested. (a) Microbiological agar diffusion assay. Proceed as directed in § 436.105 of [39 FR 19040, May 30, 1974, as amended at 43 FR 9800, Mar. 10, 1978; 50 FR 19919, May 13, this chapter, diluting an aliquot of the 1985] stock solution with solution 1 to the reference concentration of 1.0 § 442.25a Sterile cephalothin sodium. microgram of cephaloridine per milli- (a) Requirements for certification—(1) liter (estimated). Standards of identity, strength, quality, (b) Iodometric assay. Proceed as di- and purity. Sterile cephalothin sodium rected in § 436.204 of this chapter. If it is the sodium salt of the compound is packaged for dispensing, dilute an al- formed by reaction of thiophene-2-ace- iquot of the stock solution with dis- tic acid with 7-amino-cephalosporanic tilled water to the prescribed con- acid. The 7-amino-cephalosporanic acid centration. is obtained from a kind of cephalosporin. It is so purified and NOTE: The 10 milliliters of 0.01N iodine dried that: must be added within 20 seconds after the ad- dition of the 2.0 milliliters of 1.2N HCl, and (i) Its potency is not less than 850 the assay should be completed within 1 hour micrograms of cephalothin per milli- after the sample and standard are first put gram on an anhydrous basis. If it is into solution. The working standard should packaged for dispensing, its potency is be dried as described in § 436.200(a) of this satisfactory if it is not less than 90 per- chapter. cent and not more than 115 percent of
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the number of milligrams of (2) For sterility testing: 20 immediate cephalothin that it is represented to containers collected at regular inter- contain. vals throughout each filling operation. (ii) It is sterile. (b) Tests and methods of assay—(1) Po- (iii) It is nonpyrogenic. tency—(i) Sample preparation. Dissolve (iv) [Reserved] an accurately weighed sample in suffi- (v) Its loss on drying is not more cient 1.0 percent potassium phosphate than 1.5 percent. buffer, pH 6.0 (solution 1), for the (vi) Its pH in an aqueous solution is microbiological agar diffusion assay, not less than 4.5 and not more than 7.0. distilled water for the iodometric assay (vii) The specific rotation in an aque- or hydroxylamine colorimetric assay, ous solution containing 50 milligrams to give a stock solution of convenient of cephalothin sodium per milliliter at concentration; also if it is packaged for 25° C is ∂129°±5°. dispensing, reconstitute as directed in (viii) It gives a positive identity test. the labeling. Then, using a suitable (ix) It is crystalline. hypodermic needle and syringe, remove (2) Packaging. In addition to the re- all of the withdrawable contents if it is quirements of § 432.1 of this chapter, if represented as a single-dose container; it is packaged for dispensing and is in- or, if the labeling specifies the amount tended for both intravenous and of potency in a given volume of the re- intramuscular use, each vial shall con- sultant preparation, remove an accu- tain the equivalent of 1 gram of rately measured representative portion cephalothin; except that if it is from each container. Dilute with either packaged for dispensing and is intended solution 1 or distilled water as speci- solely for intravenous use, each vial fied above to give a stock solution of shall contain the equivalent of 4 grams convenient concentration. of cephalothin. (ii) Assay procedures. Use any of the (3) Labeling. In addition to the label- following methods; however, the re- ing requirements prescribed by § 432.5 sults obtained from the micro- of this chapter, if it is packaged for dis- biological agar diffusion assay shall be pensing, each package shall bear on its conclusive. label and labeling, the following state- (a) Microbiological agar diffusion ment: ‘‘After reconstitution, store in a assay. Proceed as directed in § 436.105 of refrigerator and use within 48 hours. If this chapter, diluting an aliquot of the kept at room temperature, use within 6 stock solution with solution 1 to the hours.’’ reference concentration of 1.0 (4) Requests for certification; samples. microgram of cephalothin per milli- In addition to the requirements of liter (estimated). § 431.1 of this chapter, each such re- (b) Iodometric assay. Proceed as di- quest shall contain: rected in § 436.204 of this chapter. If it (i) Results of test and assay on the is packaged for dispensing, dilute an al- batch for potency, sterility, pyrogens, iquot of the stock solution with dis- loss on drying, pH, specific rotation, tilled water to the prescribed con- crystallinity, and identity. centration. (ii) Samples of the batch: NOTE: The 10 milliliters of 0.01N iodine (a) If the batch is packaged for re- must be added within 20 seconds after the ad- packing or for use as an ingredient in dition of the 2.0 milliliters of 1.2N HCl, and the manufacture of another drug: the assay should be completed within 1 hour (1) For all tests except sterility: 10 after the sample and standard are first put packages, each containing equal por- into solution. The working standard should tions of approximately 500 milligrams. be dried as described in § 436.200(a) of this (2) For sterility testing: 20 packages, chapter. each containing equal portions of ap- (c) Hydroxylamine colorimetric assay. proximately 300 milligrams. Proceed as directed in § 436.205 of this (b) If the batch is packaged for dis- chapter. pensing: (2) Sterility. Proceed as directed in (1) For all tests except sterility: A § 436.20 of this chapter, using the meth- minimum of 10 immediate containers od described in paragraph (e)(1) of that of the batch. section.
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(3) Pyrogens. Proceed as directed in of the cephalexin standard similarly § 436.32(b) of this chapter, using a solu- treated and corrected for potency. tion containing 50 milligrams of (vi) It gives a positive identity test. cephalothin per milliliter. (vii) It is crystalline. (4) [Reserved] (2) Labeling. It shall be labeled in ac- (5) Loss on drying. Proceed as directed cordance with the requirements of in § 436.200(b) of this chapter. § 432.5 of this chapter. (6) pH. Proceed as directed in § 436.202 (3) Requests for certification; samples. of this chapter, using an aqueous solu- In addition to complying with the re- tion containing 250 milligrams per mil- quirements of § 431.1 of this chapter, liliter; however, if it is packaged for each such request shall contain: dispensing, use the solution obtained (i) Results of tests and assays on the after reconstituting the drug as di- batch for potency, moisture, pH, ab- rected in the labeling. sorptivity, identity, and crystallinity. (7) Specific rotation. Dilute an accu- (ii) Samples required: 10 packages, rately weighed sample with sufficient each containing approximately 300 mil- distilled water to give a concentration ligrams. of approximately 50 milligrams per (b) Tests and methods of assay—(1) Po- milliliter. Proceed as directed in tency. Use either of the following meth- § 436.210 of this chapter, using a 1.0-dec- ods; however, the results obtained from imeter polarimeter tube and calculate the microbiological agar diffusion the specific rotation on an anhydrous assay shall be conclusive. basis. (i) Microbiological agar diffusion assay. Proceed as directed in § 436.105 of this (8) Crystallinity. Proceed as directed chapter, preparing the sample for assay in § 436.203(a) of this chapter. as follows: Dissolve an accurately (9) Identity. Using a 0.0025-percent so- weighed sample in sufficient 1 percent lution of the sample in water and a potassium phosphate buffer, pH 6.0 (so- suitable spectrophotometer, record the lution 1), to give a stock solution con- ultraviolet absorption spectrum from taining 1.0 milligram per milliliter (es- 220 to 310 nanometers. The spectrum timated). Further dilute an aliquot of compares qualitatively to that of the the stock solution with solution 1 to cephalothin working standard simi- the reference concentration of 20 larly tested. micrograms of cephaxelin per milliliter [39 FR 19040, May 30, 1974, as amended at 46 (estimated). FR 46312, Sept. 18, 1981; 48 FR 11427, Mar. 18, (ii) Iodometric assay. Proceed as di- 1983; 50 FR 19919, May 13, 1985] rected in § 436.204 of this chapter. § 442.27 Cephalexin monohydrate. NOTE: The 10 milliliters of 0.01N iodine must be added within 20 seconds after the ad- (a) Requirements for certification—(1) dition of the 2.0 milliliters of 1.2N hydro- Standards of identity, strength, quality, chloric acid, and the assay should be com- and purity. Cephalexin monohydrate is pleted within 1 hour after the sample and the monohydrate form of 7-(D-alpha- standard are first put into solution. amino-alpha- phenylacetamido)-3- (2) [Reserved] methyl-3-cephem-4-carboxylic acid. It (3) Moisture. Proceed as directed in is so purified and dried that: § 436.201 of this chapter. (i) Its potency is not less than 900 (4) pH. Proceed as directed in § 436.202 micrograms of cephalexin per milli- of this chapter, using an aqueous sus- gram on an anhydrous basis. pension containing 50 milligrams per (ii) [Reserved] milliliter. (iii) Its moisture content is not less (5) Absorptivity. Determine the than 4.0 nor more than 8.0 percent. absorbance of the sample and standard (iv) Its pH in an aqueous solution solutions in the following manner: Dis- containing 50 milligrams per milliliter solve accurately weighed portions of is not less than 3.0 nor more than 5.5. approximately 50 milligrams each of (v) When calculated on an anhydrous the sample and standard in 250 milli- basis, its absorptivity at 262 liters of distilled water. Transfer a 10- nanometers is not less than 95 percent milliliter aliquot to a 100-milliliter vol- and not more than 104 percent of that umetric flask and dilute to volume
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with distilled water. Using a suitable termine the percent absorptivity of the spectrophotometer and distilled water sample relative to the absorptivity of as the blank, determine the absorbance the standard using the following cal- of each solution at 262 nanometers. De- culations:
Absorbance Milligrams Percent relative =of sample ×of standard ×Potency of standard in × 10 absorptivity Absorbance Milligrams micrograms per milligram 100 − m of standard of sample
where m=percent moisture in the sample. Research: 10 packages, each containing (6) Identity. Proceed as directed in approximately 500 milligrams. § 436.211 of this chapter, using the 0.5 (b) Tests and methods of assay—(1) percent potassium bromide disc pre- Cephalexin potency. Proceed as directed pared as described in paragraph (b)(1) in § 442.40(b)(1)(ii), except that of that section. ‘‘cephalexin’’ is substituted at each oc- (7) Crystallinity. Proceed as directed currence of ‘‘cephradine’’. in § 436.203 of this chapter. (2) Moisture. Proceed as directed in § 436.201 of this chapter. [39 FR 19040, May 30, 1974, as amended at 50 (3) pH. Proceed as directed in § 436.202 FR 19919, May 13, 1985; 52 FR 35912, Sept. 24, 1987] of this chapter, using an aqueous solu- tion containing 10 milligrams per mil- § 442.28 Cephalexin hydrochloride liliter. monohydrate. (4) Identity. Proceed as directed in (a) Requirements for certification—(1) § 436.367 of this chapter. Standards of identity, strength, quality, (5) Crystallinity. Proceed as directed and purity. Cephalexin hydrochloride in § 436.203(a) of this chapter. monohydrate is the hydrochloride salt [54 FR 48860, Nov. 28, 1989] of 7-(D-alpha- amino-alpha- phenylacetamido)-3-methyl-3-cephem- § 442.29a Sterile cephapirin sodium. 4-carboxylic acid monohydrate. It is so purified and dried that: (a) Requirements for certification—(1) (i) Its potency is not less than 800 Standards of identity, strength, quality, micrograms and not more than 880 and purity. Sterile cephapirin sodium is α micrograms of cephalexin per milli- the sodium salt of 7-[ (4-pyridylthio) - gram on an ‘‘as is’’ basis. acetamido]-cephalosporanic acid. It is (ii) Its moisture content is not less a white to off-white powder. It is so pu- than 3.0 nor more than 6.5 percent. rified and dried that: (iii) The pH of an aqueous solution (i) Its potency is not less than 855 containing 10 milligrams per milliliter micrograms and not more than 1,000 is not less than 1.5 nor more than 3.0. micrograms of cephapirin per milli- (iv) It gives a positive identity test. gram on an ‘‘as is’’ basis. If it is (v) It is crystalline. packaged for dispensing, its content is (2) Labeling. It shall be labeled in ac- satisfactory if it contains not less than cordance with the requirements of 90 percent and not more than 115 per- § 432.5 of this chapter. cent of the number of milligrams of (3) Requests for certification; samples. cephapirin that it is represented to In addition to complying with the re- contain. quirements of § 431.1 of this chapter, (ii) It is sterile. each such request shall contain: (iii) It is nonpyrogenic. (i) Results of tests and assays on the (iv) [Reserved] batch for cephalexin potency, mois- (v) Its moisture content is not more ture, pH, identity, and crystallinity. than 2.0 percent. (ii) Samples, if required by the Direc- (vi) Its pH in an aqueous solution tor, Center for Drug Evaluation and containing 10 milligrams of cephapirin
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per milliliter is not less than 6.5 and fies the amount of potency in a given not more than 8.5. volume of the resultant preparation, (vii) Its cephapirin content is not less remove an accurately measured rep- than 92 percent and not more than 105 resentative portion from each con- percent on an anhydrous basis. tainer. Dilute with solution 1 to give a (viii) It gives a positive identity test stock solution of convenient con- for sodium cephapirin. centration. Further dilute an aliquot of (ix) It is crystalline. the stock solution with solution 1 to (2) Labeling. It shall be labeled in ac- the reference concentration of 1.0 cordance with the requirements of microgram of cephapirin per milliliter § 432.5 of this chapter. (estimated). (3) Requests for certification; samples. (ii) Iodometric assay. Proceed as di- In addition to complying with the re- rected in § 436.204 of this chapter. In ad- quirements of § 431.1 of this chapter, dition if it is packaged for dispensing, each such request shall contain: reconstitute as directed in the labeling. (i) Results of tests and assays on the Then using a suitable hypodermic nee- batch for potency, sterility, pyrogens, dle and syringe, remove all of the moisture, pH, cephapirin content, iden- withdrawable contents if it is rep- tity, and crystallinity. resented as a single-dose container; or, (ii) Samples required: if the labeling specifies the amount of (a) If the batch is packaged for re- potency in a given volume of the re- packing or for use in the manufacture sultant preparation, remove an accu- of another drug: rately measured representative portion (1) For all tests except sterility: 9 from each container. Dilute with dis- packages, each containing approxi- tilled water to the prescribed con- mately 500 milligrams, and 1 package centration. containing approximately 5 grams. (iii) Hydroxylamine colorimetric assay. (2) For sterility testing: 20 packages, Proceed as directed in § 436.205 of this each containing approximately 300 mil- chapter. In addition, if it is packaged ligrams. for dispensing, reconstitute as directed (b) If the batch is packaged for dis- in the labeling. Then using a suitable pensing: hypodermic needle and syringe, remove (1) For all tests except sterility: A all of the withdrawable contents if it is minimum of 14 immediate containers, represented as a single-dose container; except if each contains less than 1 or, if the labeling specifies the amount gram, a minimum of 19 immediate con- of potency in a given volume of the re- tainers. sultant preparation, remove an accu- (2) For sterility testing: 20 immediate rately measured representative portion containers, collected at regular inter- from each container. Dilute with dis- vals throughout each filling operation. tilled water to the prescribed con- (b) Tests and methods of assay—(1) Po- centration. tency. Use any of the following meth- (2) Sterility. Proceed as directed in ods; however, the results obtained from § 436.20 of this chapter, using the meth- the microbiological agar diffusion od described in paragraph (e)(1) of that assay shall be conclusive. section. (i) Microbiological agar diffusion assay. (3) Pyrogens. Proceed as directed in Proceed as directed in § 436.105 of this § 436.32(b) of this chapter, using a solu- chapter, preparing the sample for assay tion containing 100 milligrams of as follows: Dissolve an accurately cephapirin per milliliter. weighed sample in sufficient 1 percent (4) [Reserved] potassium phosphate buffer, pH 6.0 (so- (5) Moisture. Proceed as directed in lution 1), to give a stock solution of § 436.201 of this chapter. convenient concentration; also, if it is (6) pH. Proceed as directed in § 436.202 packaged for dispensing, reconstitute of this chapter, using an aqueous solu- as directed in the labeling. Then using tion containing 10 milligrams per mil- a suitable hypodermic needle and sy- liliter. ringe, remove all of the withdrawable (7) Cephapirin content. Proceed as di- contents if it is represented as a single– rected in § 436.213 of this chapter, using dose container; or, if the labeling speci- the titration procedure described in
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paragraph (e)(2) of that section. Cal- culate the cephapirin content as fol- lows:
()AB− (normality of perchloric acid reagent) (222 .7) (100) (100) Percent cephapirin content = (Weight of sample in milligrams) (100 − m)
where: (i) Results of tests and assays on the A=Milliliters of perchloric acid reagent batch for potency, moisture, pH, used in titrating the sample. cephalexin content, identity, and crys- B=Milliliters of perchloric acid reagent used in titrating the blank. tallinity. m=Percent moisture content of the sample. (ii) Samples required: 10 packages, each containing approximately 500 mil- (8) Identity. Proceed as directed in ligrams. § 436.211 of this chapter, using a 1.0 per- (b) Tests and methods of assay—(1) Po- cent potassium bromide disc prepared tency. Use any of the following meth- as directed in paragraph (b)(1) of that ods; however, the results obtained from section. the microbiological agar diffusion (9) Crystallinity. Proceed as directed assay shall be conclusive. in § 436.203(a) of this chapter. (i) Microbiological agar diffusion assay. [39 FR 19040, May 30, 1974, as amended at 40 Proceed as directed in § 436.105 of this FR 23725, June 2, 1975; 50 FR 19919, May 13, chapter, preparing the sample for assay 1985] as follows: Dissolve an accurately § 442.40 Cephradine. weighed sample in sufficient 1 percent potassium phosphate buffer, pH 6.0 (so- (a) Requirements of certification—(1) lution 1), to give a stock solution con- Standards of identity, strength, quality, taining 1.0 milligram of cephradine per . Cephradine is (6 , 7 )-7- and purity R R milliliter (estimated). Further dilute [(R)-2-amino-2-(1,4-cyclohexadien-1-yl) an aliquot of the stock solution with acetamido]-3-methyl-8-oxo-5-thia-1- solution 1 to the reference concentra- azabicyclo [4.2.0]oct-2-ene-2-carboxylic tion of 10 micrograms of cephradine per acid. It is so purified and dried that: milliliter (estimated). (i) Its potency is not less than 900 micrograms and not more than 1,050 (ii) Hydroxylamine colorimetric assay micrograms of cephradine per milli- for cephradine—(a) Typical equipment. gram on an anhydrous basis. Use automated equipment capable of (ii) [Reserved] performing the following functions: In- (iii) Its moisture content is not more troduction of sample into reaction ves- than 6.0 percent. sels, addition of reagents to the sam- (iv) Its pH in an aqueous solution ples to form reaction mixtures, incuba- containing 10 milligrams per milliliter tion of the reaction mixtures, colori- is not less than 3.5 and not more than metric determination of the reaction 6.0. product at 480 nanometers using a 1- (v) Its cephalexin content is not more centimeter tubular flow cuvette, and than 5 percent on an anhydrous basis. documentation of the results with a (vi) It passes the identity test. strip chart recorder. A suitable system (vii) It is crystalline. is the Auto Analyzer II equipment con- (2) Labeling. It shall be labeled in ac- sisting of a Solid or Liquid Sampler II, cordance with the requirements of a twenty channel Pump III, a colorim- § 432.5 of this chapter. eter equipped with a 1-centimeter tubu- (3) Requests for certification; samples. lar flow cuvette and light filters pro- In addition to complying with the re- ducing incident light at 480 quirements of § 431.1 of this chapter, nanometers, and a strip chart recorder each such request shall contain: with scale expander.
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(b) Reagents—(1) Hydroxylamine hydro- (c) Preparation of working standard so- chloride solution. Dissolve 20 grams of lutions. Dissolve and dilute an accu- hydroxylamine hydrochloride and 5 rately weighed portion of the milliliters of emulsifying stock solu- cephradine working standard in suffi- tion (prepared to contain 100 milli- cient distilled water to obtain a con- grams of polyoxyethylene fatty alcohol centration of 1 milligram of cephradine ether, such as Brij-35 or equivalent, per per milliliter. 100 milliliters distilled water) in suffi- (d) Preparation of sample solutions. cient distilled water to make 1 liter. Dissolve an accurately weighed portion (2) Buffer. Dissolve 173 grams of so- of the sample in distilled water and dium hydroxide and 20.6 grams of so- dium acetate in sufficient distilled further dilute to 1 milligram of water to make 1 liter. Dilute 75 milli- cephradine per milliliter (estimated). liters of this solution with distilled (e) Procedure. Use the standard and water to 500 milliliters. sample solutions prepared as indicated (3) 3.3N Sulfuric acid. Dilute 91 milli- in paragraph (b)(1)(ii) (c) and (d) of this liters of concentrated sulfuric acid to 1 section respectively. The arrangement liter with distilled water. of the apparatus and flow of samples (4) Ferric nitrate solution. Dissolve 300 and reagents are shown in the manifold grams of ferric nitrate nonahydrate diagram set forth in this paragraph (9H2O) in a mixture of 2.8 milliliters of (b)(1)(ii)(e). The sampler rate is usually concentrated sulfuric acid and suffi- 40 per hour, but may be varied. cient distilled water to make 1 liter.
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(f) Calculate the potency of the sam- cephradine that it is represented to ple in micrograms per milligram as fol- contain. lows: (ii) It is sterile. (iii) It is nonpyrogenic. Micrograms of AP× ×100 (iv) [Reserved] cephradine per = u s (v) Its moisture content is not more milligram of sample A× W ×()100 − m than 6.0 percent. s u (vi) Its pH in an aqueous solution where: A =Absorbance of sample solution; containing 10 milligrams per milliliter u is not less than 3.5 and not more than Ps=Potency of working standard solution in micrograms, per milliliter; 6.0. As=Absorbance of working standard solu- (vii) Its cephalexin content is not tion; more than 5 percent on an anhydrous Wu=Milligrams of sample per milliliter of basis. sample solution; (viii) It passes the identity test. m=Percent moisture in sample. (ix) It is crystalline. (iii) High-pressure liquid (2) Labeling. It shall be labeled in ac- chromatographic assay. Proceed as di- cordance with the requirements of rected in § 436.337 of this chapter, pre- § 432.5 of this chapter. paring the sample as described in para- (3) Requests for certification; samples. graph (e)(3)(i) of that section. In addition to complying with the re- (2) [Reserved] quirements of § 431.1 of this chapter, (3) Moisture. Proceed as directed in each such request shall contain: § 436.201 of this chapter. (i) Results of tests and assays on the (4) pH. Proceed as directed in § 436.202 batch for potency, sterility, pyrogens, of this chapter, using an aqueous solu- moisture, pH, cephalexin content, iden- tion containing 10 milligrams per mil- tity, and crystallinity. liliter. (ii) Samples required: (5) Cephalexin content. Proceed as di- (a) If the batch is packaged for re- rected in § 436.337 of this chapter. packing or for manufacturing use: (6) Identity. Proceed as directed in (1) For all tests except sterility: 10 § 436.211 of this chapter, using the 1 per- packages, each containing approxi- cent potassium bromide disc prepared mately 500 milligrams. as described in paragraph (b)(1) of that (2) For sterility testing: 1 package section. containing approximately 6 grams of a (7) Crystallinity. Proceed as directed composite sample. in § 436.203(a) of this chapter. (b) If the batch is packaged for dis- [40 FR 26270, June 23, 1975, as amended at 45 pensing: FR 16474, Mar. 14, 1980; 46 FR 25608, May 8, (1) For all tests except sterility: A 1981; 48 FR 51293, Nov. 8, 1983; 49 FR 47485, minimum of 10 immediate containers. Dec. 5, 1984; 50 FR 19919, May 13, 1985] (2) For sterility testing: 20 immediate containers, collected at regular inter- § 442.40a Sterile cephradine. vals throughout each filling operation. (a) Requirements for certification—(1) (b) Tests and methods of assay—(1) Po- Standards of identity, strength, quality, tency. Use any of the following meth- and purity. Cephradine is 7-[D-2 - amino ods; however, the results obtained from -2- (1,4 - cyclohexadien - 1 -yl) the microbiological agar diffusion acetamido] - 3 - methyl - 8 - oxo - 5-thia assay shall be conclusive. - 1- azabicyclo[4.2.0]oct -2 - ene-2-car- (i) Microbiological agar diffusion assay. boxylic acid. It is so purified and dried Proceed as directed in § 436.105 of this that: chapter, preparing the sample for assay (i) Its potency is not less than 900 and as follows: Dissolve an accurately not more than 1,050 micrograms of weighed sample in sufficient 1 percent cephradine per milligram on the anhy- potassium phosphate buffer, pH 6.0 (so- drous basis. If it is packaged for dis- lution 1), to give a stock solution con- pensing, its cephradine content is sat- taining 1.0 milligram of cephradine per isfactory if it is not less than 90 per- milliliter (estimated); also, if it is cent and not more than 115 percent of packaged for dispensing, reconstitute the number of milligrams of the sample as directed in the labeling,
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except use distilled water in lieu of re- azabicyclo[4.2.0]oct-2-ene-2-carboxylic constituting fluid. Then using a suit- acid. It is so purified and dried that: able hypodermic needle and syringe, (i) Its potency is not less than 900 remove an accurately measured rep- micrograms and not more than 1,050 resentative portion from each con- micrograms of cephradine per milli- tainer. Dilute with solution 1 to give a gram on an anhydrous basis. stock solution of convenient con- (ii) [Reserved] centration. Further dilute an aliquot of (iii) Its moisture content is not less the stock solution with solution 1 to than 8.5 percent and not more than 10.5 the reference concentration of 10 percent. micrograms of cephradine per milli- (iv) Its pH in an aqueous solution liter (estimated). containing 10 milligrams per milliliter (ii) Hydroxylamine colorimetric assay. is not less than 3.5 and not more than Proceed as directed in § 442.40(b)(1)(ii). 6.0. If packaged for dispensing, reconstitute (v) Its cephalexin content is not more the sample as directed in the labeling than 5 percent on an anhydrous basis. using distilled water instead of the re- (vi) It passes the identity test. constituting fluid. Further dilute an (vii) It is crystalline. aliquot of this solution with distilled water to 1 milligram of cephradine per (2) Labeling. It shall be labeled in ac- milliliter (estimated). cordance with the requirements of (iii) High-pressure liquid § 432.5 of this chapter. chromatographic assay. Proceed as di- (3) Requests for certification; samples. rected in § 436.337 of this chapter. In addition to complying with the re- (2) Sterility. Proceed as directed in quirements of § 431.1 of this chapter, § 436.20 of this chapter, using the meth- each such request shall contain: od described in paragraph (e)(1) of that (i) Results of tests and assays on the section. batch for potency, moisture, pH, (3) Pyrogens. Proceed as directed in cephalexin content, identity, and crys- § 436.32(g) of this chapter, using a solu- tallinity. tion containing 80 milligrams of (ii) Samples required: 10 packages, cephradine per milliliter. each containing approximately 500 mil- (4) [Reserved] ligrams. (5) Moisture. Proceed as directed in (b) Tests and methods of assay—(1) Po- § 436.201 of this chapter. tency. Use any of the following meth- (6) pH. Proceed as directed in § 436.202 ods; however, the results obtained from of this chapter, using an aqueous solu- the hydroxylamine colorimetric assay tion containing 10 milligrams per mil- shall be conclusive. liliter. (i) Microbiological agar diffusion assay. (7) Cephalexin content. Proceed as di- Proceed as directed in § 436.105 of this rected in § 442.40(b)(5). chapter, preparing the sample for assay (8) Identity. Proceed as directed in as follows: Dissolve an accurately § 436.211 of this chapter, using the 1 per- weighed sample in sufficient 1 percent cent potassium bromide disc prepared potassium phosphate buffer, pH 6.0 (so- as described in paragraph (b)(1) of that lution 1), to obtain a stock solution of section. convenient concentration. Further di- (9) Crystallinity. Proceed as directed lute an aliquot of the stock solution in § 436.203(a) of this chapter. with solution 1 to the reference con- [40 FR 51626, Nov. 6, 1975, as amended at 43 centration of 10.0 micrograms of FR 14646, Apr. 7, 1978; 49 FR 47485, Dec. 5, cephradine per milliliter (estimated). 1984; 50 FR 19919, May 13, 1985] (ii) Hydroxylamine colorimetric assay for cephradine. Proceed as directed in § 442.41 Cephradine dihydrate. § 442.40(b)(1)(ii). (a) Requirements for certification—(1) (iii) High-pressure liquid Standards of identity, strength, quality, chromatographic assay. Proceed as di- and purity. Cephradine dihydrate is the rected in § 436.337 of this chapter, pre- dihydrate form of (6R,7R)-7-[(R)-2- paring the sample as described in para- amino-2-(1,4-cyclohexadien-1- graph (e)(3)(i) of that section. yl)acetamido]-3-methyl-8-oxo-5-thia-1- (2) [Reserved]
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(3) Moisture. Proceed as directed in (b) For sterility testing: One package § 436.201 of thichapter. containing approximately 6 grams of a (4) pH. Proceed as directed in § 436.202 composite sample. of this chapter, using an aqueous solu- (b) Tests and methods of assay—(1) tion containing 10 milligrams per mil- Ceforanide content. Proceed as directed liliter. in § 436.348 of this chapter, preparing (5) Cephalexin content. Proceed as di- the sample and calculating the rected in § 436.337 of this chapter. ceforanide content as follows: (6) Identity. Proceed as directed in (i) Preparation of sample solution. Pre- § 436.211 of this chapter, using the 1 per- pare a solution containing 1.0 milli- cent potassium bromide disc prepared gram per milliliter in mobile phase. In- as described in paragraph (b)(1) of that ject each sample within 5 minutes after section. dissolution. (7) Crystallinity. Proceed as directed (ii) Calculations. Calculate the in § 436.203(a) of this chapter. micrograms of ceforanide per milli- [47 FR 11856, Mar. 19, 1982, as amended at 49 gram of sample as follows: FR 47485, Dec. 5, 1984; 50 FR 19919, May 13, 1985] Micrograms of AP× ceforanide = u s § 442.50a Sterile ceforanide. × per milligram ACs u (a) Requirements for certification—(1) where: Standards of identity, strength, quality, Au = Area of the ceforanide peak in the chro- and purity. Ceforanide is 5-thia-1- matogram of the sample (at a retention azabicyclo[4.2.0]oct-2-ene-2-carboxylic time equal to that observed for the acid, 7-[[[2-(amino-meth- standard); yl)phenyl]acetyl]amino]-3-[[[1- As = Area of the ceforanide peak in the chro- (carboxymethyl)-1H-tetrazol-5-yl]- matogram of the ceforanide working thio]methyl]-8-oxo-,(6R-trans)-. It is a standard; white to off-white powder. It is so puri- Ps = Ceforanide activity in the ceforanide fied and dried that: working standard solution in micrograms per milliliter; and (i) Its ceforanide content is not less Cu = Milligrams of sample per milliliter of than 900 micrograms and not more sample solution. than 1,050 micrograms of ceforanide per milligram. (2) Sterility. Proceed as directed in (ii) It is sterile. § 436.20 of this chapter, using the meth- (iii) It is nonpyrogenic. od described in paragraph (e)(1) of that (iv) Its moisture content is not more section, except: than 5.0 percent. (i) In paragraph (e)(1)(i)(a) of that (v) Its pH in an aqueous suspension section, use diluting fluid G in lieu of containing 50 milligrams per milliliter diluting fluid A; and is not less than 2.5 and not more than (ii) In lieu of three 100-milliliter 4.5. quantities of diluting fluid A in para- (vi) It passes the identity test. graph (e)(2) of that section, filter three (2) Labeling. It shall be labeled in ac- 100-milliliter quantities of diluting cordance with the requirements of fluid D followed by a 100-milliliter § 432.5 of this chapter. quantity of diluting fluid A. (3) Requests for certification; samples. (3) Pyrogens. Proceed as directed in In addition to complying with the re- § 436.32(b) of this chapter, except sus- quirements of § 431.1 of this chapter, pend 1 gram of sterile ceforanide in 12.5 each such request shall contain: milliliters of pyrogen-free water (dilu- (i) Results of tests and assays on the ent 1). Add 320 milligrams of pyrogen- batch for ceforanide content, sterility, free L-lysine base, shake to dissolve pyrogens, moisture, pH, and identity. the mixture. If the mixture is not dis- (ii) Samples, if required by the Direc- solved, add an amount of L-lysine nec- tor, Center for Drug Evaluation and essary to obtain a solution. The test Research: sample should contain not more than a (a) For all tests except sterility: 10 total of 340 milligrams of L-lysine. Di- packages, each containing approxi- lute the resulting solution to 20 milli- mately 500 milligrams. liters. Use a test dose of 1 milliliter of
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the 50 milligrams per milliliter test so- decyl hydrocarbon bonded silicas, a lution per kilogram of rabbit weight. flow rate not exceeding 2.0 milliliters (4) Moisture. Proceed as directed in per minute, and a known injection vol- § 436.201 of this chapter. ume of between 10 and 20 microliters. (5) pH. Proceed as directed in § 436.202 Reagents, working standard solution, of this chapter, using an aqueous sus- sample solution, resolution test solu- pension containing 50 milligrams per tion, system suitability requirements, milliliter. and calculations are as follows: (6) Identity. Proceed as directed in (i) Reagents—(A) Diluting solution. § 436.211 of this chapter, using the sam- Mix water:methanol:acetonitrile ple preparation as described in para- (90:5:5). graph (b)(2) of that section. (B) Mobile phase. Mix 0.1M phosphoric [49 FR 25847, June 25, 1984; 49 FR 40006, Oct. acid:glacial acetic 12, 1984, as amended at 55 FR 11583, Mar. 29, acid:methanol:acetonitrile 1990] (1700:100:105:105). Filter through a suit- able filter capable of removing particu- § 442.52 Cefotetan. late matter greater than 0.5 micron in (a) Requirements for certification—(1) diameter. Degas the mobile phase just Standards of identity, strength, quality, prior to its introduction into the chro- and purity. Cefotetan is (6R,7S)-4-[[2- matograph. carboxy-7-methoxy-3-[[(1-methyl-1H- (ii) Preparation of working standard, tetrazol-5-yl)thio]methyl]-8-oxo-5-thia- sample, and resolution test solutions—(A) 1-azabicyclo[4.2.0]oct-2-ene-7-yl]-car- Working standard solution. Accurately α bamoyl]-1,3-dithietane-∆2, -malonamic weigh approximately 50 milligrams of acid. It is so purified and dried that: the cefotetan working standard into a (i) Its potency is not less than 950 250-milliliter volumetric flask contain- micrograms and not more than 1,030 ing 12.5 milliliters of methanol. Swirl micrograms of cefotetan activity per the flask for several minutes, then add milligram on the anhydrous basis. 12.5 milliliters of acetonitrile. Swirl (ii) Its moisture content is not more the flask until the cefotetan is dis- than 2.5 percent. solved. Dilute to volume with water to (iii) It gives a positive identity test obtain a solution containing approxi- for cefotetan. mately 200 micrograms of cefotetan per (2) Labeling. It shall be labeled in ac- milliliter. Mix well. Protect the work- cordance with the requirements of ing standard solution from light. § 432.5 of this chapter. (B) Sample solution. Dissolve an accu- (3) Requests for certification; samples. rately weighed portion of the sample In addition to complying with the re- with sufficient diluting solution de- quirements of § 431.1 of this chapter, scribed in paragraph (b)(1)(i)(A) of this each such request shall contain: section to obtain a concentration of ap- (i) Results of tests and assays on the proximately 200 micrograms of batch for potency, moisture, and iden- cefotetan per milliliter. tity. (C) Resolution test solution. Place 10 (ii) Samples, if required by the Direc- milliliters of the working standard so- tor, Center for Drug Evaluation and lution in a stoppered flask containing a Research: 10 packages each containing few milligrams of magnesium carbon- approximately 500 milligrams. ate. Close the flask and sonicate for 10 (b) Tests and methods of assay—(1) Po- minutes. If the solution is not slightly tency. Proceed as directed in § 436.216 of turbid, add more magnesium carbonate this chapter, except use the resolution and repeat sonication. Filter the turbid test solution to determine resolution solution through a 0.5-micron filter and in lieu of the working standard solu- use within 2 hours. As this solution tion. Perform the assay at ambient stands, the tautomer concentration in- temperature, using an ultraviolet de- creases. tection system operating at a wave- (iii) System suitability requirements— length of 254 nanometers, a column (A) Tailing factor. The tailing factor (T) packed with microparticulate (3 to 10 is satisfactory if it is not more than 1.3 micrometers in diameter) reversed at 10 percent of peak height in lieu of phase packing material such as octa- 5 percent of peak height.
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(B) Efficiency of the column. The effi- (i) If the cefotetan disodium is not ciency of the column (n) is satisfactory packaged for dispensing, its potency is if it is greater than 1,500 theoretical not less than 830 micrograms and not plates. more than 970 micrograms of cefotetan (C) Resolution. The resolution (R) be- per milligram on the anhydrous basis. tween the peak for cefotetan and its If the cefotetan disodium is packaged tautomer is satisfactory if it is not less for dispensing, its potency is not less than 2.0. than 830 micrograms and not more (D) Coefficient of variation. The coeffi- than 970 micrograms of cefotetan per cient of variation (Srin percent) of five milligram on the anhydrous basis and replicate injections is satisfactory if it also, each container contains not less is not more than 2.0 percent. If the sys- than 90 percent and not more than 120 tem suitability requirements have been percent of the number of milligrams of met, then proceed as described in cefotetan that it is represented to con- § 436.216 (b) of this chapter. Alternate tain. chromatographic conditions are ac- (ii) It is sterile. ceptable provided comparable system (iii) It is nonpyrogenic. suitability requirements are met. How- (iv) Its moisture content is not more ever, the sample preparation described than 1.5 percent. in paragraph (b)(1)(ii)(B) of this section (v) Its pH in an aqueous solution con- should not be changed. taining 100 milligrams of cefotetan (iv) Calculation. Calculate the disodium per milliliter is not less than micrograms of cefotetan per milligram 4.0 and not more than 6.5. of sample as follows: (vi) It gives a positive identity test for cefotetan. Micrograms of APV× × ×1, 000 (2) Labeling. It shall be labeled in ac- cefotetan per = US f × cordance with the requirements of milligram AVS s § 432.5 of this chapter. where: (3) Requests for certification; samples. AU = Area of the cefotetan peak in the chro- In addition to complying with the re- matogram of the sample (at a retention quirements of § 431.1 of this chapter, time equal to that observed for the each such request shall contain: standard); (i) Results of tests and assays on the AS = Area of the cefotetan peak in the chro- matogram of the cefotetan working batch for potency, sterility, pyrogens, standard; moisture, pH, and identity. PS = Cefotetan activity in the cefotetan (ii) Samples, if required by the Direc- working standard solution in tor, Center for Drug Evaluation and micrograms per milliliter; Research: Vf = Volume of flask used to dilute standard; (a) If the batch is packaged for re- and packing or for use in the manufacture V = Volume of sample diluted. s of another drug: (2) Moisture. Proceed as directed in (1) For all tests except sterility: 10 § 436.201 of this chapter. packages, each containing approxi- (3) Identity. Proceed as directed in mately 500 milligrams. § 436.211 of this chapter using the potas- (2) For sterility testing: 20 packages, sium bromide discs prepared as de- each containing approximately 300 mil- scribed in § 436.211(b)(1) of this chapter ligrams. or the mineral oil mull prepared as de- (b) If the batch is packaged for dis- scribed in § 436.211(b)(2) of this chapter. pensing: [59 FR 26940, May 25, 1994, as amended at 60 (1) For all tests except sterility: A FR 33712, June 29, 1995] minimum of 10 immediate containers. (2) For sterility testing: 20 immediate § 442.53a Sterile cefotetan disodium. containers, collected at regular inter- (a) Requirements for certification—(1) vals throughout each filling operation. Standards of identity, strength, quality, (b) Tests and methods of assay—(1) Po- and purity. Sterile cefotetan disodium tency. Proceed as directed in § 436.216 of is a white to off-white lyophilized pow- this chapter, except use the resolution der. It is so purified and dried that: test solution to determine resolution
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in lieu of the working standard solu- (i) Micrograms of cefotetan per milli- tion. Perform the assay at ambient gram. Dissolve an accurately weighed temperature, using an ultraviolet de- portion of the sample with sufficient tection system operating at a wave- diluting solution described in para- length of 254 nanometers, a column graph (b)(1)(i)(a) of this section, to ob- packed with microparticulate (3 to 10 tain a concentration of approximately micrometers in diameter) reversed 200 micrograms of cefotetan per milli- phase packing material such as octa- liter. decyl hydrocarbon bonded silicas, a (ii) Milligrams of cefotetan per con- flow rate not exceeding 2.0 milliliters tainer. Reconstitute the sample as di- per minute, and a known injection vol- rected in the labeling. Then, using a ume of between 10 and 20 microliters. suitable hypodermic needle and sy- Reagents, working standard solution, ringe, remove all of the withdrawable sample solution, resolution test solu- contents if it is represented as a single- tion, system suitability requirements, dose container; or, if the labeling speci- and calculations are as follows: fies the amount of potency in a given (i) Reagents—(a) Diluting solution. Mix volume of the resultant preparation, water:methanol:acetonitrile (90:5:5). remove an accurately measured rep- (b) Mobile phase. Mix 0.1M phosphoric resentative portion from each con- acid:glacial acetic tainer. Further dilute an aliquot of the acid:methanol:acetonitrile solution thus obtained with sufficient (1700:100:105:105). Filter through a suit- diluting solution described in para- able filter capable of removing particu- graph (b)(1)(i)(a) of this section, to ob- late matter greater than 0.5 micron in tain a concentration of approximately diameter. Degas the mobile phase just 200 micrograms of cefotetan per milli- prior to its introduction into the chro- liter. matograph. (c) Resolution test solution. Place 10 (ii) Preparation of working standard, milliliters of the working standard so- sample, and resolution test solutions—(a) lution in a stoppered flask containing a Working standard solution. Accurately few milligrams of magnesium carbon- weigh approximately 50 milligrams of ate. Close the flask and sonicate for 10 the cefotetan working standard into a minutes. If the solution is not slightly 250-milliliter volumetric flask contain- turbid, add more magnesium carbonate ing 12.5 milliliters of methanol. Swirl and repeat sonication. Filter the turbid the flask for several minutes, then add solution through a 0.5-micron filter and 12.5 milliliters of acetonitrile. Swirl use within 2 hours. As this solution the flask until the cefotetan is dis- stands, the tautomer concentration in- solved. Dilute to volume with water to creases. obtain a solution containing approxi- (iii) System suitability requirements— mately 200 micrograms of cefotetan per (a) Tailing factor. The tailing factor (T) milliliter. Mix well. Protect the work- is satisfactory if it is not more than 1.3 ing standard solution from light. at 10 percent of peak height in lieu of (b) Sample solutions—(1) Product not 5 percent of peak height. packaged for dispensing (micrograms of (b) Efficiency of the column. The effi- cefotetan per milligram). Dissolve an ac- ciency of the column (n) is satisfactory curately weighed portion of the sample if it is greater than 1,500 theoretical with sufficient diluting solution de- plates. scribed in paragraph (b)(1)(i)(a) of this (c) Resolution. The resolution (R) be- section, to obtain a concentration of tween the peak for cefotetan and its approximately 200 micrograms of tautomer is satisfactory if it is not less cefotetan per milliliter. than 2.0. (2) Product packaged for dispensing. (d) Coefficient of variation. The coeffi- Determine both micrograms of cient of variation (SR in percent) of five cefotetan per milligram of the sample replicate injections is satisfactory if it and milligrams of cefotetan per con- is not more than 2.0 percent. tainer. Use separate containers for If the system suitability requirements preparation of each sample solution as have been met, then proceed as de- described in paragraphs (b)(1)(ii)(b)(2) scribed in § 436.216(b) of this chapter. (i) and (ii) of this section. Alternate chromatographic conditions
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are acceptable provided comparable tatively to that of the cefotetan work- system suitability requirements are ing standard. met. However, the sample preparation [51 FR 20263, June 4, 1986, as amended at 52 described in paragraph (b)(1)(ii)(b) of FR 35912, Sept. 24, 1987; 55 FR 11583, Mar. 29, this section should not be changed. 1990] (iv) Calculations—(a) Calculate the micrograms of cefotetan per milligram § 442.54 Cefpodoxime proxetil. of sample as follows: (a) Requirements for certification—(1) Standards of identity, strength, quality, Micrograms of × × ± APu s 100 and purity. Cefpodoxime proxetil is ( )- cefotetan = 1-hydroxyethyl(∂)-(6R,7R)-7-[2-(2- × × − per milligram As C u ()100 m amino-4-thiazolyl)glyoxylamido]-3- where: (methoxymethyl)-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2- Au=Area of the cefotetan peak in the chro- matogram of the sample (at a retention time carboxylate,72-(Z)-(O-methyloxime), equal to that observed for the standard); isopropyl carbonate (ester). It is so pu- As=Area of the cefotetan peak in the chro- rified and dried that: matogram of the cefotetan working stand- (i) Its potency is not less than 690 ard; micrograms and not more than 804 Ps=Cefotetan activity in the cefotetan micrograms of cefpodoxime activity working standard solution in micrograms per milliliter; per milligram, on an anhydrous basis. (ii) The ratio of its R-epimer to total Cu=Milligrams of sample per milliliter of sample solution; and cefpodoxime is not less than 0.5 and not m=Percent moisture content of the sample. more than 0.6. (b) Calculate the cefotetan content of (iii) Its moisture content is not more the container as follows: than 3 percent. (iv) It gives a positive identity test. A× P × d (2) Labeling. It shall be labeled in ac- Milligrams of = u s cordance with the requirements of cefotetan per container A ×1, 000 § 432.5 of this chapter. s (3) Requests for certification; samples. where: In addition to complying with the re- Au=Area of the cefotetan peak in the chro- quirements of § 431.1 of this chapter, matogram of the sample (at a retention time each such request shall contain: equal to that observed for the standard); (i) Results of tests and assays on the As=Area of the cefotetan peak in the chro- matogram of the cefotetan working stand- batch for cefpodoxime potency, isomer ard; ratio, moisture, and identity. Ps=Cefotetan activity in the cefotetan (ii) Samples, if required by the Direc- working standard solution in micrograms tor, Center for Drug Evaluation and per milliliter; and Research: 10 packages, each containing d=Dilution factor of the sample. approximately 500 milligrams. (2) Sterility. Proceed as directed in (b) Tests and methods of assay—(1) Po- § 436.20 of this chapter, using the meth- tency. Proceed as directed in § 436.216 of od described in paragraph (e)(1) of that this chapter, using a suitable section. thermostatted column heating mecha- (3) Pyrogens. Proceed as directed in nism to maintain a column tempera- § 436.32(b) of this chapter, using a solu- ture of 40 °C, an ultraviolet detection tion containing 50 milligrams of system operating at a wavelength of cefotetan per milliliter. 254 nanometers, a 15 centimeter X 4.6 (4) Moisture. Proceed as directed in millimeter (i.d.) column packed with § 436.201 of this chapter. microparticulate (5 micrometers in di- (5) pH. Proceed as directed in § 436.202 ameter) reversed phase packing mate- of this chapter, using an aqueous solu- rial such as octadecyl silane bonded to tion containing 100 milligrams of silicas, a flow rate of 0.8 milliliter per cefotetan disodium per milliliter. minute, and a known injection volume (6) Identity. The high-performance of 2 microliters. The retention time for liquid chromatogram of the sample de- the S-epimer is approximately 22 min- termined as directed in paragraph utes and the retention time for R- (b)(1) of this section, compares quali- epimer is approximately 28 minutes.
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The internal standard (propylparaben) standard add 3 milliliters of internal has a retention time of 34 minutes. Mo- standard solution and 25 milliliters of bile phase, dilution solvent, resolution dilution solvent. The standard solution solution, internal standard solution, is stable for at least 48 hours. Refrig- working standard and sample solu- eration is not recommended. tions, system suitability requirements, (vi) Sample solution. Accurately weigh and calculations are as follows: approximately 42 milligrams of the (i) Mobile phase. The mobile phase sample, add 3 milliliters of internal consists of 420 milliliters of methanol, standard and 25 milliliters of dilution 580 milliliters of deionized water, and solvent. The sample solution is stable 230 milligrams of L-histidine hydro- for at least 48 hours. Refrigeration is chloride. The pH is adjusted to 2.5±0.1 not recommended. using 2N sulfuric acid. The mobile (vii) System suitability requirements— phase must be at room temperature for (A) Asymmetry factor.The asymmetry a correct pH measurement. The meth- factor (As) is satisfactory if it is not anol concentration may be adjusted to less than 0.8 and not more than 1.1 for achieve comparable retention times the R-epimer of cefpodoxime peak. from column to column. Increasing (B) Efficiency of the column. The abso- methanol reduces retention times. Fil- lute efficiency (hr) is satisfactory if it ter the mobile phase through a suitable is not more than 5 for the R-epimer filter capable of removing particulate peak. matter 0.5 micron in diameter and (C) Resolution factor. The resolution degas it just before its introduction factor (R) between the peak for ANTI– into the chromatograph. A and the peak for the R-epimer is sat- (ii) Dilution solvent. Prepare a solvent for dilution by thoroughly mixing 495 isfactory if it is not less than 1.3. Al- milliliters of deionized water, 495 milli- ternately, the resolution factor (R) be- liters of acetonitrile, and 10 milliliters tween the peak for the R-epimer and of acetic acid in an appropriate con- the peak for the S-epimer of tainer. cefpodoxime is not less than 11. (iii) Resolution solution. Prepare a 1 (D) Coefficient of variation (Relative milligram per milliliter solution of any standard deviation). The coefficient of bulk containing ANTI–A in dilution variation (SRin percent of 5 replicate solvent. Use this solution to determine injections) is satisfactory if it is not the resolution between ANTI–A and the more than 2 percent. later-eluting drug epimer (R-epimer). (E) Capacity factor (k’). The capacity Alternately, the resolution factor can factor (k’) for the R-epimer of be determined between the R and S iso- cefpodoxime is satisfactory if it is not mers. less than 10.4 and not more than 15.6. (iv) Internal standard solution. Pre- (F) If the system suitability param- pare a solution of propylparaben in di- eters in this paragraph (b)(1)(iv) have lution solvent at a concentration of 10 been met, then proceed as described in milligrams per milliliter. § 436.216(b) of this chapter. (v) Preparation of working standard so- (viii) Calculations. Calculate the lutions. Accurately weigh approxi- micrograms of cefpodoxime proxetil mately 42 milligrams of the per milligram of sample on an anhy- cefpodoxime proxetil working reference drous basis as follows:
RP× ×100 Micrograms of cefpodoxime proxetil per milligram = u s × × − Rs C u (100 m)
where: Rs = Ratio of cefpodoxime proxetil peaks Ru = Ratio of cefpodoxime proxetil peaks area (sum of both epimers) to the inter- area (sum of both epimers) to the inter- nal standard peak response in the work- nal standard peak response in the sample ing standard solution; solution;
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Ps = Cefpodoxime proxetil activity of the (3) Requests for certification; samples. working standard solution in In addition to complying with the re- micrograms per milliliter; quirements of § 431.1 of this chapter, Cu = Milligrams of sample per milliliter of sample solution; and each such request shall contain: m = Percent moisture content of the sample. (i) Results of tests and assays on the batch for ceftriaxone potency, mois- (2) Isomer ratio. Using the procedure ture, pH, crystallinity, and identity. described in paragraph (b)(1) of this (ii) Samples, if required by the Direc- section, calculate the ratio of the R- tor, Center for Drug Evaluation and epimer (Ab) to the sum of the S-epimer and R-epimer (Aa and Ab), by the equa- Research: 10 packages, each containing tion approximately 500 milligrams. (b) Tests and methods of assay—(1) Isomer Ratio = Ab/(Aa ∂ Ab) Ceftriaxone potency. Proceed as directed where: in § 442.55a(b)(1) of this chapter, except Aa = Area of the early eluting S-epimer prepare the sample solution and cal- peak; and culate the micrograms of ceftriaxone Ab = Area of the late eluting R-epimer free acid per milligram as follows: peak. (i) Preparation of sample solution. Dis- (3) Moisture. Proceed as directed in solve an accurately weighed portion of § 436.201 of this chapter, except use 30 the sample with sufficient water to ob- milliliters of solvent C instead of 20 tain a concentration of 180 micrograms milliliters of solvent A. of ceftriaxone activity per milliliter. (4) Identity. Proceed as directed in Prepare the sample solution just prior § 436.211 of this chapter, using the min- to its introduction into the chro- eral oil mull prepared as described in matograph. paragraph (b)(2) of that section. (ii) Calculation. Calculate the [60 FR 58231, Nov. 27, 1995] micrograms of ceftriaxone anhydrous free acid per milligram as follows: § 442.55 Ceftriaxone sodium. Micrograms of (a) Requirements for certification—(1) AP× ceftriaxone anhydrous = u s Standards of identity, strength, quality, × and purity. Ceftriaxone sodium is the 5- free acid per milligram ACs u thia-1-azabicyclo[4.2.0]oct-2-ene-2-car- Where:
boxylic acid, 7-[[(2-amino-4-thiazolyl) Au=Area of the ceftriaxone peak in the (methoxyimino)acetyl]amino]-8-oxo-3- chromatogam of the sample (at a reten- [[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo- tion time equal to that observed for the 1,2,4-triazin-3-yl)thio]methyl]- standard); ,disodium salt, [6R-[6alpha, 7beta(Z)]]-. As=Area of the ceftriaxone peak in the chro- It is so purified and dried that: matogram of the ceftriaxone working standard; (i) Its ceftriaxone potency is not less Ps=Ceftriaxone activity in the ceftriaxone than 795 micrograms of ceftriaxone per working standard solution in milligram on an anhydrous free acid micrograms of anhydrous free acid per basis. milliliter; and
(ii) Its moisture content is not less Cu=Milligrams of sample per milliliter of than 8 percent and not more than 11 sample solution. percent. (2) Moisture. Proceed as directed in (iii) The pH of an aqueous solution § 436.201 of this chapter. containing the equivalent of 100.0 mil- (3) pH. Proceed as directed in § 436.202 ligrams per milliliter is not less than of this chapter, using an aqueous solu- 6.0 and not more than 8.0. tion containing 100 milligrams per mil- (iv) It is crystalline. liliter. (v) It gives a positive identity test (4) Crystallinity. Proceed as directed for ceftriaxone. in § 436.203(a) of this chapter. (2) Labeling. It shall be labeled in ac- cordance with the requirements of § 432.5 of this chapter.
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(5) Identity. Proceed as directed in moisture, pH, crystallinity, and iden- § 436.211 of this chapter, using a potas- tity. sium bromide disc containing 1.3 milli- (ii) Samples, if required by the Direc- grams of ceftriaxone sodium in 300 mil- tor, Center for Drug Evaluation and ligrams of potassium bromide, pre- Research: pared as described in paragraph (b)(1) (a) If the batch is packaged for re- of that section. packing or for manufacturing use: [52 FR 44860, Nov. 23, 1987, as amended at 55 (1) For all tests except sterility: 10 FR 11583, Mar. 29, 1990] packages, each containing approxi- mately 500 milligrams. § 442.55a Sterile ceftriaxone sodium. (2) For sterility testing: 20 packages, (a) Requirements for certification—(1) each containing equal portions of ap- Standards of identity, strength, quality, proximately 300 milligrams. and purity. Ceftriaxone sodium is 5- (b) If the batch is packaged for dis- thia-1-azabicyclo[4.2.0]oct-2-ene-2-car- pensing: boxylic acid, 7-[[(2-amino-4-thiazolyl) (1) For all tests except sterility: A (methoxyimino)acetyl]amino]-8-oxo-3- minimum of 10 immediate containers. [[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo- 1,2,4-triazin-3-yl)thio]methyl]-, (2) For sterility testing: 20 immediate disodium salt, [6R-[6α,7β(Z)]]-. It is so containers, collected at regular inter- purified and dried that: vals throughout each filling operation. (i) If the ceftriaxone sodium is not (b) Tests and methods of assay—(1) packaged for dispensing, its Ceftriaxone potency and container con- ceftriaxone potency is not less than 795 tent. Proceed as directed in § 436.354 of micrograms of ceftriaxone per milli- this chapter, using ambient tempera- gram on an anhydrous free acid basis. ture, an ultraviolet detection system If the ceftriaxone sodium is packaged operating at a wavelength of 270 for dispensing, its ceftriaxone potency nonometers (or 254 nanometers fixed is not less than 776 micrograms of mercury source), and a column packed ceftriaxone per milligram on an anhy- with a five-micron octadecyl reverse drous free acid basis and also, each phase packing or equivalent; and also, container contains not less than 90 per- using the following system suitability cent and not more than 115 percent of requirements, reagents, working stand- the number of milligrams of ard, test and sample solutions, and cal- ceftriaxone that it is represented to culations: contain. (i) System suitability requirements—(a) (ii) It is sterile. Capacity factor. The capacity factor (k) (iii) It is nonpyrogenic. for the ceftriaxone peak is satisfactory (iv) Its moisture content is not less if it is not less than 2 and not more than 8 percent and not more than 11 than 5. percent. (b) Resolution. The resolution (R) be- (v) Its pH in an aqueous solution con- tween the peak for ceftriaxone E-iso- taining the equivalent of 100.0 milli- mer and ceftriaxone is satisfactory if it grams per milliliter is not less than 6.0 is not less than 3.0. and not more than 8.0. (vi) It is crystalline. (c) Asymmetry factor. The asymmetry (vii) It gives a positive identity test factor (As) is satisfactory if it is not for ceftriaxone. more than 1.6 at 10 percent of the peak (2) Labeling. It shall be labeled in ac- height. cordance with the requirements of (d) Efficiency of the column. The effi- § 432.5 of this chapter. ciency of the column (hr) is satisfac- (3) Requests for certification; samples. tory if it is less than 20 (equivalent to In addition to complying with the re- a value of 1,500 or greater theoretical quirements of § 431.1 of this chapter, plates when using a 15-centimeter col- each such request shall contain: umn with 5-micrometer-size particles). (i) Results of tests and assays on the (e) Coefficient of variation. The coeffi- batch for ceftriaxone potency, and if cient of variation (SR in percent) of five packaged for dispensing, potency and replicate injections is satisfactory if it container content, sterility, pyrogens, is less than 2.0 percent.
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If the system suitability parameters acid per milligram). Dissolve an accu- have been met, then proceed as de- rately weighed portion of the sample scribed in § 436.354(b) of this chapter. with sufficient water to obtain a con- (ii) Reagents—(a) pH 7.0 phosphate centration of 180 micrograms of buffer. Dissolve 13.6 grams of dibasic ceftriaxone activity per milliliter. potassium phosphate and 4.0 grams of (2) Product packaged for dispensing. monobasic potassium phosphate in suf- Determine both potency (micrograms ficient water to make 1,000 milliliters. of ceftriaxone anhydrous free acid per Adjust to pH 7.0 ±0.1 with 18N phos- milligram of the sample) and container phoric acid or 10N potassium hydrox- content (milligrams of anhydrous free ide. acid ceftriaxone per container). Use (b) pH 5.0 citrate buffer. Dissolve 25.8 separate containers for preparation of grams of sodium citrate in 500 milli- each sample solution as described in liters of water. Adjust the pH to 5.0±0.1 paragraph (b)(1)(iii)(b)(2) (i) and (ii) of with 20 percent aqueous citric acid, and this section. dilute to 1,000 milliliters with water. (i) Micrograms of ceftriaxone anhydrous (c) Mobile phase. Dissolve 4.0 grams of free acid per milligram. Dissolve an accu- tetraheptylammonium bromide with rately weighed portion of the sample 500 milliliters of acetonitrile. Add 440 with sufficient water to obtain a con- milliliters of water, 55 milliliters of pH centration of approximately 180 7.0 phosphate buffer, and 5 milliliters of micrograms of ceftriaxone activity per pH 5.0 citrate buffer. Mix and dilute 800 milliliter. milliliters of this solution with 200 mil- (ii) Milligrams of ceftriaxone per con- liliters of distilled water. Filter the tainer. Reconstitute the sample as di- mobile phase through a suitable glass rected in the labeling. Then, using a fiber filter or equivalent which is capa- suitable hypodermic needle and sy- ble of removing particulate contamina- ringe, remove all of the withdrawable tion greater than 0.5 micron in diame- contents if it is represented as a single- ter. Degas the mobile phase just prior dose container; or, if the labeling speci- to its introduction into the chro- fies the potency contained in a given matograph. volume of the resulting preparation, (iii) Working standard and sample so- remove an accurately measured rep- lutions—(a) Preparation of working resentative portion from each con- standard solution. Dissolve an accu- tainer. Dilute the aliquot of the solu- rately weighed portion of the tion thus obtained with sufficient ceftriaxone working standard with suf- water to obtain a concentration of ap- ficient water to obtain a solution con- proximately 180 micrograms of taining approximately 180 micrograms ceftriaxone activity per milliliter. of ceftriaxone activity per milliliter. (iv) Calculations. (a) Calculate the Prepare the working standard solution micrograms of ceftriaxone anhydrous just prior to its introduction into the free acid per milligram as follows: chromatograph. (b) Preparation of test solution. Dis- Micrograms of AP× solve together accurately weighed por- ceftriaxone anhydrous = u s tions of the ceftriaxone working stand- × ard and the ceftriaxone sodium E-iso- free acid per milligram AsC u mer reference standard with sufficient where:
water to obtain a solution containing Au=Area of the ceftriaxone peak in the chro- approximately 160 micrograms of matogram of the sample (at a retention ceftriaxone activity per milliliter of time equal to that observed for the each standard. Prepare the test solu- standard); tion just prior to its introduction into As=Area of the ceftriaxone peak in the chro- the chromatograph. matogram of the ceftriaxone working standard; (c) Preparation of sample solution. Pre- Ps=Ceftriaxone activity in the ceftriaxone pare the sample solution just prior to working standard solution in its introduction into the chro- micrograms of anhydrous free acid per matograph. milliliter; and
(1) Product not packaged for dispensing Cu=Milligrams of sample per milliliter of (micrograms of ceftriaxone anhydrous free sample solution.
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(b) Calculate the ceftriaxone anhy- (i) Its potency is not less than 790 and drous free acid content of the container not more than 925 micrograms of as follows: cefotiam per milligram on an anhy- drous basis. Milligrams of A× P × d (ii) It is sterile. ceftriaxone anhydrous = u s (iii) It is nonpyrogenic. × free acid per container As 1, 000 (iv) Its moisture content is not more where: than 7.0 percent. Au=Area of the ceftriaxone peak in the chro- (v) It passes the identity test. matogram of the sample (at a retention (vi) It is crystalline. time equal to that observed for the (2) Labeling. It shall be labeled in ac- standard); cordance with the requirements of As=Area of the ceftriaxone peak in the chro- § 432.5 of this chapter. matogram of the ceftriaxone working standard; (3) Requests for certification; samples. Ps=Ceftriaxone activity in the ceftriaxone In addition to complying with the re- working standard solution in quirements of § 431.1 of this chapter, micrograms of anhydrous free acid per each such request shall contain: milliliter; and (i) Results of tests and assays on the d=Dilution factor of the sample. batch for potency, sterility, pyrogens, (2) Sterility. Proceed as directed in moisture, identity, and crystallinity. § 436.20 of this chapter, using the meth- (ii) Samples, if required by the Direc- od described in paragraph (e)(1) of that tor, Center for Drug Evaluation and section. Research: (3) Pyrogens. Proceed as directed in (A) For all tests except sterility: 10 § 436.32(h) of this chapter, using a solu- packages, each containing approxi- tion containing 20 milligrams of mately 500 milligrams. ceftriaxone per milliliter. (B) For sterility testing: One package (4) Moisture. Proceed as directed in containing approximately 6 grams of a § 436.201 of this chapter. composite sample. (5) pH. Proceed as directed in § 436.202 (b) Tests and methods of assay—(1) Po- of this chapter, using an aqueous solu- tency. Proceed as directed in § 436.216 of tion containing 100 milligrams per mil- this chapter, using ambient tempera- liliter. ture, an ultraviolet detection system (6) Crystallinity. Proceed as directed operating at a wavelength of 254 in § 436.203(a) of this chapter. nanometers, a column packed with (7) Identity. Proceed as directed in microparticulate (3 to 10 micrometers § 436.211 of this chapter, using a potas- in diameter) reversed phase packing sium bromide disc containing 1.3 milli- material such as octadecyl hydro- grams of ceftriaxone sodium in 300 mil- carbon bonded silicas, a flow rate not ligrams of potassium bromide, pre- to exceed 2.0 milliliters per minute, pared as described in paragraph (b)(1) and a known injection volume of be- of that section. tween 10 and 20 microliters. Mobile [50 FR 9999, Mar. 13, 1985; 50 FR 11690, Mar. 25, phase, working standard and sample 1985; 50 FR 18243, Apr. 30, 1985, as amended at solutions, resolution test solution, sys- 55 FR 11583, Mar. 29, 1990] tem suitability requirements, and cal- culations are as follows: § 442.58a Sterile cefotiam (i) Mobile phase. Dissolve 13.1 grams dihydrochloride. of ammonium sulfate in 850 milliliters (a) Requirements for certification—(1) of water. Adjust the pH to 6.5 with di- Standards of identity, strength, quality, lute aqueous ammonia. Add 150 milli- and purity. Cefotiam dihydrochloride is liters of acetonitrile. Filter through a 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-car- suitable filter capable of removing par- boxylic acid, 7-[[(2-amino-4- ticulate matter to 0.5 micron in diame- thiazolyl)acetyl]-amino-3[[[1-[2- ter. Degas the mobile phase just prior (dimethylamino)ethyl]-1H-tetrazol-5- to its introduction into the chro- yl]-thio]methyl]-8-oxo-, matograph. dihydrochloride, (6R-trans)-. It is so pu- (ii) Preparation of working standard, rified and dried that: sample, and resolution test solutions—(A)
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Working standard solution. Dissolve ap- As=Area of the cefotiam peak in the chro- proximately 100 milligrams of the matogram of the cefotiam working cefotiam working standard, accurately standard; weighed, in water and dilute to 100 mil- Ps=Cefotiam activity in the cefotiam work- ing standard solution in micrograms per liliters. Further dilute with mobile milliliter; phase to obtain a solution containing Cu=Milligrams of the sample per milliliter of 50 micrograms of cefotiam activity per sample solution; and milliliter. m=Percent moisture content of the sample. (B) Sample solution. Dissolve approxi- mately 100 milligrams of the sample, (2) Sterility. Proceed as directed in accurately weighed, in water and dilute § 436.20 of this chapter, using the meth- to 100 milliliters. Further dilute with od described in paragraph (e)(1) of that mobile phase to obtain a solution con- section. taining 50 micrograms of cefotiam ac- (3) Pyrogens. Proceed as directed in tivity per milliliter (estimated). § 436.32(g) of this chapter, using a solu- (C) Resolution test solution. Dissolve tion containing 40 milligrams per mil- an accurately weighed portion of liliter. cefotiam working standard in water to (4) Moisture. Proceed as directed in obtain a solution containing approxi- § 436.201 of this chapter, using the sam- mately 1.0 milligram of cefotiam activ- ple preparation described in paragraph ity per milliliter. Heat this solution at (d)(4) of that section and the titration 95 °C for 15 minutes. This procedure al- procedure described in paragraph (e)(3) lows cefotiam lactone to be produced. of that section, except: Dilute 1.0 milliliter of this solution to (i) In lieu of 3 milliliters of anhy- 100 milliliters with mobile phase. drous methanol solution, inject 20 mil- (iii) System suitability requirements— liliters of a formamide:methanol solu- (A) Tailing factor. The tailing factor (T) tion (2:1) into the container and shake for the cefotiam peak is satisfactory if to dissolve the contents (prior to use in it is not more than 1.76 at 5 percent of preparation of the form- peak height. amide:methanol solution, dry 500 (B) Efficiency of the column. The effi- grams of formamide over 20 grams of ciency of the column (n) is satisfactory anhydrous sodium sulfate for 24 hours); if it is greater than 1985 theoretical (ii) Rinse the syringe, needle, and im- plates for the cefotiam peak. mediate container with two separate 5- (C) Resolution factor. The resolution milliliter portions of anhydrous meth- factor (R) between the peak for cefotiam and the peak for cefotiam anol, in lieu of one 3-milliliter portion lactone (generated in situ) is satisfac- of anhydrous methanol; and tory if it is not less than 4.0. (iii) In paragraph (e)(3) of that sec- (D) Coefficient of variation. The coeffi- tion, add a sufficient volume of the formamide:methanol solution (2:1) to cient of variation (SR in percent) of 5 replicate injections is satisfactory if it cover the electrodes in the dry is not more than 1.0 percent. If the sys- titrating vessel, in lieu of 20 milliliters tem suitability parameters have been of solvent A before starting the titra- met, then proceed as described in tion. § 436.216(b) of this chapter. (5) Identity. Using a solution contain- (iv) Calculations. Calculate the ing 20 micrograms per milliliter of micrograms of cefotiam per milligram water and a suitable of sample as follows: spectrophotometer, record the ultra- violet absorption spectrum from 220 to Micrograms of AP× ×100 310 nanometers. The spectrum com- cefotiam = u s pares qualitatively to that of the × × − per milligram As C u ()100 m cefotiam working standard similarly where: tested. (6) Crystallinity. Proceed as directed Au=Area of the cefotiam peak in the chro- matogram of the sample (at a retention in § 436.203(a) of this chapter. time equal to that observed for the standard); [54 FR 20785, May 15, 1989]
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§ 442.60 Cefpiramide. and a known injection volume of be- (a) Requirements for certification—(1) tween 10 and 20 microliters. Reagents, Standards of identity, strength, quality, working standard and sample solu- and purity. Cefpiramide is (6R, 7R)-7- tions, resolution test solution, system [(R)-2-(4-hydroxy-6-methyl- suitability requirements, and calcula- nicotinamido)-2-(p- tions are as follows: hydroxyphenyl)acetamido]-3-[[(1-meth- (i) Reagents—(A) 0.01M phosphate buff- Dissolve 1.36 grams of monobasic po- yl-1H-tetrazol-5-yl)thio]methyl]-8-oxo- er. 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-car- tassium phosphate in 900 milliliters of boxylic acid. It is so purified and dried water. Adjust the pH to 6.8 with 1N so- that: dium hydroxide and dilute to 1,000 mil- (i) Its potency is not less than 974 liliters with water. micrograms of cefpiramide activity per (B) Mobile phase. Mix 0.01M phosphate milligram on an anhydrous basis. buffer: acetonitrile: tetrahydrofuran: (ii) Its moisture content is not more methanol (880:40:40:40). Filter through a than 9.0 percent. suitable filter capable of removing par- (iii) Its pH in an aqueous suspension ticulate matter to 0.5 micron in diame- containing 5 milligrams per milliliter ter. Degas the mobile phase just prior is not less than 3.0 and not more than to its introduction into the chro- 5.0. matograph. (iv) Its total related substances con- (ii) Preparation of working standard, tent by high performance liquid chro- sample, and resolution test solutions—(A) matography is not more than 2.0 per- Working standard solution. Dissolve and cent. No individual impurity is more dilute an accurately weighed portion of than 0.7 percent. the cefpiramide working standard in (v) The specific rotation in sufficient mobile phase to obtain a so- dimethylformamide solution contain- lution containing 0.25 milligram of ing 10 milligrams of cefpiramide per cefpiramide activity per milliliter. milliliter is ¥106 ± 6 °C calculated on (B) Sample solution. Dissolve an accu- an anhydrous basis. rately weighed portion of the sample in (vi) It passes the identity test. mobile phase and further dilute to 0.25 (vii) It is crystalline. milligram of cefpiramide per milliliter (2) Labeling. It shall be labeled in ac- (estimated). cordance with the requirements of (C) Resolution test solution. Dissolve § 432.5 of this chapter. an accurately weighed portion of (3) Requests for certification; samples. cefpiramide working standard in 0.01N In addition to complying with the re- sodium hydroxide to obtain a solution quirements of § 431.1 of this chapter, containing approximately 1.0 milli- each such request shall contain: gram of cefpiramide activity per milli- (i) Results of tests and assays on the liter. Heat this solution at 95 °C for 10 batch for potency, moisture, pH, total minutes. This procedure allows related substances, specific rotation, cefpiramide lactone to be produced. Di- identity, and crystallinity. lute 1.0 milliliter of this solution to 20 (ii) Samples, if required by the Cen- milliliters with mobile phase. ter for Drug Evaluation and Research: (iii) System suitability requirements)— 10 packages each containing approxi- (A) Asymmetry factor. Calculate the mately 500 milligrams. asymmetry factor (As), measured at a (b) Tests and methods of assay—(1) Po- point 5 percent of the peak height from tency. Proceed as directed in § 436.216 of the baseline as follows: this chapter, using ambient tempera- a+b ture, an ultraviolet detection system A = operating to a wavelength of 254 s nanometers, a 15- to 30-centimeter X 4- 2a where: millimeter (inside diameter) column a=Horizontal distance from point of ascent packed with microparticulate (5 to 10 to point of maximum peak height; and micrometers in diameter) reversed b=Horizontal distance from the point of phase packing material such as maximum peak height to point of descent.
octylsilane bonded to silica, a flow rate The asymmetry factor (As) is satisfactory if not to exceed 2.0 milliliters per minute, it is not less than 0.95 and not more than 1.4.
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(B) Efficiency of the column. From the number of theoretical plates (n) cal- Micrograms of × × APu s 100 culated as described in § 436.216(c)(2) of cefpiramide = × × − this chapter calculate the reduced per milligram As C u ()100 m plate height (hr) as follows: where: (L )(10 , 000 ) Au=Area of the cefpiramide peak in the = chromatogram of the sample (at a retention hr time equal to that observed for the stand- (n)( d p ) ard); where: As=Area of the cefpiramide peak in the L=Length of the column in centimeters; chromatogram of the cefpiramide working standard; n=Number of theoretical plates; and P =Cefpiramide activity in the cefpiramide d =Average diameter of the particles in the s p working standard solution in micrograms analytical column packing in micrometers. per milliliter; The absolute efficiency (h ) is satisfac- Cu=Milligrams of cefpiramide sample per r milliliter of sample solution; and tory if it is not more than 12.5 for the m=Percent moisture content of the sample. cefpiramide peak. (C) Resolution factor. The resolution (2) Moisture. Proceed as directed in factor (R) between the peak for § 436.201 of this chapter. cefpiramide and the peak for (3) pH. Proceed as directed in § 436.202 cefpiramide lactone (generated in situ) of this chapter, using an aqueous sus- is satisfactory if it is not less than 6.0. pension containing 5 milligrams of (D) Coefficient of variation (relative cefpiramide per milliliter. standard deviation). The coefficient of (4) Total related substances. Proceed as variation (Sr in percent of 5 replicate directed in paragraph (b)(1) of this sec- injections is satisfactory if it is not tion except use the following reagents, more than 2.0 percent. standard and sample solutions, and cal- (E) Capacity factor (k′). Calculate the culations: capacity (k′) for cefpiramide as follows: (i) Reagents—(A) 0.03M phosphate buff- er. Dissolve 4.08 grams of monobasic t− t k©= r o potasssium phosphate in 800 milliliters t of water. Adjust the pH to 7.5 with 1N o sodium hydroxide and dilute to 1,000 where: milliliters with water. tr=Retention time of cefpiramide in min- (B) Mobile phase. Mix 0.03M phosphate utes; and buffer: methanol (750:250). Filter t =Column dead time in minutes, which is o through a suitable filter capable of re- estimated from the following equation: moving particulate matter to 0.5 mi- (31416 . )(DL2 )( )( 0 . 75 ) cron in diameter. Degas the mobile = phase just prior to its introduction to 4F into the chromatograph. where: (ii) Preparation of working standard D=Column diameter in centimeters; and sample solutions. L=Column length in centimeters; (A) Working standard solution. Trans- 0.75=Average total column porosity; and fer about 12.5 milligrams of 5-mer- F=Flow rate in milliliters per minute. capto-1-methyl-1H-tetrazole (MMT) and an amount of cefpiramide working The capacity factor (k′) for cefpiramide standard equivalent to about 25 milli- is satisfactory if it is not less than 2.0 grams of cefpiramide activity, both ac- and not more than 3.0. If the system curately weighed, to a 100-milliliter suitability parameters have been met, volumetric flask. Dissolve and dilute then proceed as described in § 436.216(b) to volume with 0.03M phosphate buffer. of this chapter. Further dilute 2.0 milliliters of this so- (iv) Calculations. Calculate the lution to 100 milliliters with mobile micrograms of cefpiramide per milli- phase. gram of sample as follows:
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(B) Sample solution. Transfer about 25 (iii) Calculations. Calculate the per- milligrams of the test material, accu- centages, individually, of MMT and any rately weighed, to a 50-milliliter volu- other compounds detected as follows: metric flask. Dissolve and dilute to volume with mobile phase.
ACP× × ×100 T = Percent MMT (tetrazole) = u s s 1 × × ACs u 1, 000 RCP× × ×100 T = Percent related compound = u s s 2 × × RCs u 1, 000 LCP× × ×100 L = Percent largest related compound = u s s × × RCs u 1, 000
where: [(cyanomethyl)thio]acetamido]-7- Au=Area of the tetrazole sample peak; methoxy-3-[[(1-methyl-1H-tetrazol-5- As=Area of the tetrazole working standard yl)thio]methyl]-8-oxo-5-thia-1- peak; azabicyclo[4.2.0]oct-2-ene-2-carboxylic Cs=Concentration of the working standard in milligrams per milliliter; acid. It is so purified and dried that: Ps=Potency of the working standard in (i) Its potency is not less than 970 micograms per milligram; micrograms of cefmetazole activity per Cu=Concentration of the sample solutions milligram. in milligrams per milliliter; (ii) Its moisture content is not more Ru=Sum of peak areas of other compounds, excepting MMT and cefpiramide, detected in than 0.5 percent. the sample chromatogram. (iii) It gives a positive identity test Rs=Area of the cefpiramide working stand- for cefmetazole. ard peak; and (2) Labeling. It shall be labeled in ac- Lu=Area of the largest related peak, except cordance with the requirements of MMT. § 432.5 of this chapter. T=Percent total related compounds=T ∂T . 1 2 (3) Requests for certification; samples. (5) Specific rotation. Dilute an accu- In addition to complying with the re- rately weighed sample with sufficient quirements of § 431.1 of this chapter, dimethylformamide to obtain a con- each such request shall contain: centration of approximately 10 milli- (i) Results of tests and assays on the grams of cefpiramide per milliliter. batch for potency, moisture, and iden- Proceed as directed in § 436.210 of this tity. chapter, using a 1-decimeter polarim- (ii) Samples, if required by the Direc- eter tube. Calculate the specific rota- tor, Center for Drug Evaluation and tion on the anhydrous basis. (6) Identify. Proceed as directed in Research: 10 packages each containing § 436.211 of this chapter using a 1-per- approximately 500 milligrams. cent potassium bromide disc prepared (b) Tests and methods of assay—(1) Po- as directed in § 436.211(b)(1). tency. Proceed as directed in (7) Chrystallinity. Proceed as directed § 442.70a(b)(1). in § 436.203(a) of this chapter. (2) Moisture. Proceed as directed in § 436.201 of this chapter. [55 FR 14240, Apr. 17, 1990] (3) Identity. Proceed as directed in § 442.69 Cefmetazole. § 436.211 of this chapter using a mineral oil mull prepared as described in para- (a) Requirements for certification—(1) graph (b)(2) of that section. Standards of identity, strength, quality, and purity. Cefmetazole is (6R,7S)-7-[2- [59 FR 12546, Mar. 17, 1994]
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§ 442.70a Sterile cefmetazole sodium. (2) For sterility testing: 20 packages, each containing equal portions of ap- (a) Requirements for certification—(1) proximately 300 milligrams. Standards of identity, strength, quality, (B) If the batch is packaged for dis- and purity. Sterile cefmetazole sodium pensing: is the sodium salt of (6R-cis)-7- [[[cyanomethyl)thio]acetyl]amino]-7- (1) For all tests except sterility: A methoxy-3-[[(1-methyl-1H-tetrazol-5- minimum of 10 immediate containers yl)thio]methyl]-8-oxo-5-thia-1- of the batch. azabicyclo[4.2.0]oct-2-ene-2-carboxylic (2) For sterility testing: 20 immediate acid. It is a lyophilized powder. It is so containers collected at regular inter- purified and dried that: vals throughout each filling operation. (i) If the cefmetazole sodium is not (b) Tests and methods of assay—(1) Po- packaged for dispensing, its tency. Proceed as directed in § 436.216 of cefmetazole potency is not less than this chapter, using ambient tempera- 860 micrograms and not more than 1,003 ture, an ultraviolet detection system micrograms of cefmetazole activity per operating at a wavelength of 214 milligram on an anhydrous basis. If the nanometers, a 25-centimeter X 4.0- or cefmetazole sodium is packaged for dis- 4.6-millimeter (inside diameter) col- pensing, its cefmetazole potency is not umn packed with microparticulate (5 less than 860 micrograms and not more micrometers in diameter) reversed than 1,003 micrograms of cefmetazole phase packing material such as octa- activity per milligram on an anhydrous decyl silane bonded to silicas, a flow basis and also, each container contains rate of not more than 2.0 milliliters per not less than 90 percent and not more minute, and a known injection volume than 120 percent of the number of milli- of between 10 and 20 microliters. Mo- grams of cefmetazole that it is rep- bile phase, working standard and sam- resented to contain. ple solutions, resolution test solution, (ii) It is sterile. system suitability requirements, and (iii) It contains not more than 0.2 calculations are as follows: endotoxin units per milligram. (i) Mobile phase. Transfer 5.75 grams (iv) Its moisture content is not more of ammonium dihydrogen phosphate to than 0.5 percent. a 1-liter container. Add 700 milliliters of deionized water and agitate to aid (v) The pH of an aqueous solution dissolution. Transfer 3.2 milliliters of containing 100 milligrams per milliliter 40 percent tetrabutylammonium hy- is not less than 4.2 and not more than droxide (TBAH) in distilled water to 6.2. the solution and shake. Add 280 milli- (vi) It gives a positive identity test. liters of methanol and a range 20 to 30 (2) Labeling. It shall be labeled in ac- milliliters of tetrahydrofuran and mix cordance with the requirements of well. Adjust the pH to 4.5±0.1 with § 432.5 of this chapter. phosphoric acid. The mobile phase is (3) Requests for certification; samples. 0.05M ammonium dihydrogen phos- In addition to complying with the re- phate: methanol: tetrahydrofuran quirements of § 431.1 of this chapter, (700:280:20–30). It is 0.005M with respect each such request shall contain: to TBAH. Filter the mobile phase (i) Results of tests and assays on the through a suitable filter capable of re- batch for cefmetazole potenty and con- moving particulate matter to 0.5 mi- tent (if packaged for dispensing), ste- cron in diameter and degas it just prior rility, bacterial endotoxins, moisture, to its introduction into the chro- pH, and identity. matograph. (ii) Samples, if required by the Cen- (ii) Preparation of working standard, ter for Drug Evaluation and Research: sample, and resolution test solutions—(A) (A) If the batch is packaged for re- Working standard solution. Dissolve and packing or for use as an ingredient in dilute and accurately weighed portion the manufacture of another drug: of the cefmetazole working standard in (1) For all tests except sterility: 10 sufficient mobile phase to obtain a so- packages, each containing approxi- lution containing 0.2 milligram of mately 500 milligrams. cefmetazole activity per milliliter.
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Analyze this solution within 10 min- (iii) System suitability requirements— utes. (A) Asymmetry factor. Calculate the (B) Sample solutions—(1) Product not asymmetry factor (A s), measured at a packaged for dispensing (micrograms of point 10 percent of the peak height cefmetazole per milligram). Dissolve an from the baseline as follows: accurately weighed sample with suffi- cient mobile phase to obtain a solution = a+b containing approximately 0.2 milli- As gram of cefmetazole per milliliter (es- 2a timated). Analyze this solution within where: 10 minutes. a=Horizontal distance from point of ascent (2) Product packaged for dispensing. to point of maximum peak height; and Determine both micrograms of b=Horizontal distance from point of maxi- mum peak height to point of descent. cefmetazole per milligram of sample and milligrams of cefmetazole per con- The asymmetry factor (As) is satisfac- tainer. Use separate containers for tory if it is not less than 0.94 and not preparation of each sample solution as more than 1.6. described in paragraphs (B) Efficiency of the column. From the (b)(1)(ii)(B)(2)(i) and (ii) of this section. number of theoretical plates (n) cal- (i) Micrograms of cefmetazole per milli- culated as described in § 436.216(c)(2) of gram. Dissolve an accurately weighed this chapter calculate the reduced sample with sufficient mobile phase to plate height (hr) as follows: obtain a solution containing approxi- mately 0.2 milligram of cefmetazole = (L )(10,000) per milliliter (estimated). Analyze this hr solution within 10 minutes. (n )( d p ) (ii) Milligrams of cefmetazole per con- where: tainer. Reconstitute the sample as di- rected in the labeling. Then, using a L = Length of the column in centimeters; suitable hypodermic needle and sy- n = Number of theoretical plates; and dp = Average diameter of the particles in the ringe, remove all of the withdrawable analytical column packing in microm- contents if it is represented as a single- eters. dose container; or, if the labeling speci-
fies the amount of potency in a given The absolute efficiency (hr) is satisfac- volume of the resultant preparation, tory if it is not more than 20 for the remove an accurately measured rep- cefmetazole peak. resentative portion from each con- (C) Resolution factor. The resolution tainer. Dilute the solution thus ob- factor (R) between the peak for tained with sufficient distilled water to cefmetazole and the peak for obtain a solution containing 1,000 cefmetazole lactone (generated in situ) micrograms of cefmetazole activity per is satisfactory if it is not less than 3.0. milliliter (estimated). Further dilute (D) Coefficient of variation (relative this solution with mobile phase to ob- standard deviation). The coefficient of tain a solution containing 0.2 milli- variation (SR in percent of 5 replicate gram of cefmetazole activity per milli- injections) is satisfactory if it is not liter (estimated). Analyze this solution more than 2.0 percent. within 10 minutes. (E) Capacity factor (k′). Calculate the (C) Resolution test solution. Dissolve capacity factor (k′) for cefmetazole as an accurately weighed portion of follows: cefmetazole working standard in 0.01N − sodium hydroxide to obtain a solution tr t o containing approximately 1.0 milli- k©= gram of cefmetazole activity per milli- to liter. Heat this solution at 95 °C for 10 where: minutes. This procedure generates tr=Retention time of cefmetazole in minutes; cefmetazole lactone. Dilute 1.0 milli- and liter of this solution to 20 milliliters to=Column dead time in minutes, which is es- with mobile phase. timated from the following equation:
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(2) Sterility. Proceed as directed in 2 § 436.20 of this chapter, using the meth- = (31416 . )(DL )( )( 0 . 75 ) to od described in § 436.20(e)(1). 4F (3) Bacterial endotoxins. Proceed as di- where: rected in the United States Pharma- D=Column diameter in centimeters; copeia bacterial endotoxins test. L=Column length in centimeters; (4) Moisture. Proceed as directed in 0.75=Average total column porosity; and § 436.201 of this chapter. F=Flow rate in milliliters per minute. (5) pH. Proceed as directed in § 436.202 of this chapter, using an aqueous solu- The capacity factor (k′) for cefmetazole tion containing 100 milligrams per mil- is satisfactory if it is not less than 2.0 liliter. (6) Identity. Proceed as directed in and not more than 8.0. If the system § 436.211 of this chapter using a mineral suitability parameters have been met, oil mull prepared as described in then proceed as described in § 436.216(b) § 436.211(b)(2). of this chapter. (iv) Calculations—(A) Cefmetazole po- [55 FR 6634, Feb. 26, 1990] tency (micrograms of cefmetazole per mil- § 442.80 Cefprozil. ligram). Calculate the micrograms of cefmetazole per milligram of sample as (a) Requirements for certification—(1) follows: Standards of identity, strength, quality, and purity. Cefprozil is an approximate Micrograms of 9:1 mixture of the Z (cis) and the E AP× ×100 (trans) isomers, respectively, of cefmetazole = u s × × − (6R,7R)-7-[(R)-2-amino-2-(p- per milligram As C u ()100 m hydroxyphenyl)acetamido]8-oxo-3-pro- where: penyl-5-thia-1-azabicyclo[4.2.0]oct-2- ene-2-carboxylic acid. It is so purified Au=Area of the cefmetazole peak in the chro- matogram of the sample (at a retention and dried that: time equal to that observed for the (i) Its potency is not less than 900 standard); micrograms nor more than 1,050
As=Area of the cefmetazole peak in the chro- micrograms of cefprozil activity per matogram of the cefmetazole working milligram, on an anhydrous basis. standard; (ii) The ratio of its (E) isomer to Ps=Cefmetazole activity in the cefmetazole total cefprozil is not less than 0.06 nor working standard solution in more than 0.11. micrograms per milliliter; (iii) Its moisture content is not less Cu=Milligrams of cefmetazole sample per than 3.5 percent nor more than 6.5 per- milliliter of sample solution; and m=Percent moisture content of the sample. cent. (B) Cefmetazole content (milligrams of (iv) The pH of an aqueous solution cefmetazole per container). Calculate the containing 5 milligrams per milliliter cefmetazole content of the container as is not less than 3.5 nor more than 6.5. follows: (v) It is crystalline. (vi) It gives positive identity tests. Milligrams of cefmetazole A× P × d (2) Labeling. It shall be labeled in ac- = u s per container × cordance with the requirements of As 1, 000 § 432.5 of this chapter. where: (3) Requests for certification; samples. In addition to complying with the re- Au=Area of the cefmetazole peak in the chro- matogram of the sample (at a retention quirements of § 431.1 of this chapter, time equal to that observed for the each such request shall contain: standard); (i) Results of tests and assays on the
As=Area of the cefmetazole peak in the chro- batch for cefprozil potency, E isomer to matogram of the cefmetazole working total cefprozil ratio, moisture, pH, standard; crystallinity, and identity. Ps=Cefmetazole activity in the cefmetazole (ii) Samples, if required by the Direc- working standard solution in tor, Center for Drug Evaluation and micrograms per milliliter; and Research: 10 packages, each containing d=Dilution factor of the sample. approximately 500 milligrams.
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(b) Tests and methods of assay—(1) Po- volume with water and mix thor- tency. Proceed as directed in § 436.216 of oughly. Use this solution within 6 this chapter, using ambient tempera- hours. ture, an ultraviolet detection system (iii) Sample solution. Accurately operating at a wavelength of 280 weigh approximately 15 milligrams of nanometers, a 25 centimeter × 3.9 to 4.6 sample into a 50-milliliter volumetric millimeter (id) column packed with flask. Dilute to volume with water and microparticulate (5 to 10 micrometers shake the flask vigorously until the in diameter) reversed phase packing solute dissolves completely. Use this material such as octadecyl silane bond- solution within 6 hours. ed to silicas, a flow rate of 1.0 milliliter (iv) System suitability requirements— per minute, and a known injection vol- (A) Asymmetry factor. The asymmetry ume of 10 microliters. The retention factor (AS)is satisfactory if it is not time for cefprozil (Z) is between 4 and less than 0.9 and not more than 1.1 for 6 minutes and the retention time for the cefprozil (Z) response. cefprozil (E) is between 6 and 8 min- (B) Efficiency of the column. The abso- utes. Mobile phase, working standard lute efficiency (hr) is satisfactory if it and sample solutions, system suit- is not more than 10 for the cefprozil (Z) ability requirements, and calculations response. are as follows: (C) Resolution factor. The resolution (i) . Dissolve 20.7 grams Mobile phase factor (R) between the response for of ammonium phosphate, monobasic in cefprozil (Z) and the response for 1,800 milliliters of water and adjust the cefprozil (E) is satisfactory if it is not pH to 4.4 with phosphoric acid, if nec- less than 2.5. essary. Add 200 milliliters of acetoni- (D) Coefficient of variation (Relative trile and mix. Filter the mobile phase standard deviation). The coefficient of through a suitable filter capable of re- variation (S of 5 replicate injections of moving particulate matter 0.5 micron R the cefprozil (Z) reference solution re- in diameter and degas it just prior to sponse) is satisfactory if it is not more its introduction into the chro- than 2.0 percent. matograph. The proportion of acetoni- trile may be modified in the range of 6 (E) Capacity factor (k’). The capacity to 14 percent to obtain the desired re- factor (k’) for cefprozil (Z) is satisfac- tention times. Increasing the amount tory if it is not less than 0.7 and not of acetonitrile will decrease both the more than 1.1. If the system suitability retention times and the separation be- parameters have been met, then pro- tween the isomers, whereas, decreasing ceed as described in § 436.216(b) of this the amount of acetonitrile will in- chapter. crease retention times and the separa- (v) Calculations. Calculate the tion between the isomers. micrograms of cefprozil per milligram (ii) Preparation of working standard of sample on an anhydrous basis as fol- solutions—(A) Cefprozil (Z) working lows: standard solution. Accurately weigh ap- proximately 12.5 milligrams of the Micrograms of cefprozil AP× (Z) or cefprozil (E) = u s cefprozil (Z) working standard into a AC× 50-milliliter volumetric flask. Dilute to per milligram (as is) s u volume with water and shake the flask cefprozil (Z) Micrograms of cefprozil vigorously until the solute dissolves = + completely. Use this solution within 6 per milligram (as is) cefprozil (E) hours. (B) Cefprozil (E) working standard so- cefprozil lution. Accurately weigh approximately potency × 12.5 milligrams of the cefprozil (E) Micrograms of cefprozil = (as is) 100 working standard into a 50-milliliter per milligram (Anhydrous) ()100 − m volumetric flask. Dilute to volume where: with water and shake the flask vigor- AU = Area of the cefprozil (Z) or cefprozil (E) ously until the solute dissolves com- response in the chromatogram of the pletely. Pipet 5 milliliters into a 50- sample (at a retention time equal to that milliliter volumetric flask, dilute to observed for the standard);
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AS = Area of the cefprozil (Z) or cefprozil (E) percent and not more than 120 percent response in the chromatogram of the of the number of milligrams of cefaclor cefprozil (Z) or the cefprozil (E) working that it is represented to contain. Its standard ; moisture content is not more than 8.0 PS = Cefprozil (Z) or cefprozil (E) activity in the cefprozil (Z) or the cefprozil (E) percent. The cefaclor monohydrate working standard solution in used conforms to the standards pre- micrograms per milliliter; scribed by § 442.4(a)(1). CU = Milligrams of sample per milliliter of (2) Labeling. It shall be labeled in ac- sample solution; and cordance with the requirements of m = Percent moisture content of the sample. § 432.5 of this chapter. (2) Cefprozil (E)/cefprozil ratio. Using (3) Requests for certification; samples. the procedure described in paragraph In addition to complying with the re- (b)(1) of this section calculate the quirements of § 431.1 of this chapter, cefprozil (E)/cefprozil ratio as follows: each such request shall contain: (i) Results of tests and assays on: cefprozil (E) (mcg/mg, as is) (a) The cefaclor monohydrate used in Trans ratio = cefprozil (mcg/mg, as is) Total making the batch for potency, mois- ture, pH, identity, and crystallinity. (3) Moisture. Proceed as directed in (b) The batch for potency and mois- § 436.201 of this chapter. ture. (4) pH. Proceed as directed in § 436.202 (ii) Samples required: of this chapter, using a carbon dioxide (a) The cefaclor monohydrate used in free aqueous solution containing 5 mil- making the batch: 10 packages, each ligrams of cefprozil per milliliter. containing approximately 300 milli- (5) Crystallinity. Proceed as directed grams. in § 436.203(a) of this chapter. (b) The batch: A minimum of 30 cap- (6) Identity—(i) Infrared. Proceed as sules. directed in § 436.211 of this chapter, (b) Tests and methods of assay—(1) Po- using a 1.0 percent potassium bromide tency. Proceed as directed in disc prepared as described in paragraph § 442.40(b)(1)(ii) of this chapter, except (b)(1) of that section. prepare the working standard and sam- (ii) High performance liquid chroma- ple solutions and calculate the potency tography (HPLC). The HPLC retention of the sample as follows: times for the responses of the cefprozil (i) Preparation of working standard so- isomers in the assay preparation of the lution. Dissolve and dilute an accu- sample must be within 2 percent of the rately weighed portion of the cefaclor HPLC retention times of the responses working standard in sufficient 0.1M po- of the corresponding cefprozil working tassium phosphate buffer, pH 4.5 (as de- standards. scribed in § 436.101(a)(4) of this chapter) [58 FR 26660, May 4, 1993] to obtain a concentration of 1 milli- gram of cefaclor per milliliter. Subpart B—Oral Dosage Forms (ii) Preparation of sample solution. Place one capsule into a high-speed § 442.104 Cefaclor monohydrate oral glass blender jar containing sufficient dosage forms. 0.1M potassium phosphate buffer, pH 4.5 (as described in § 436.101(a)(4) of this § 442.104a Cefaclor monohydrate cap- chapter) to obtain a concentration of 1 sules. milligram of cefaclor per milliliter. (a) Requirements for certification—(1) Filter a portion to be used through a Standards of identity, strength, quality, 10-micron filter. and purity. Cefaclor monohydrate cap- (iii) Calculations. Calculate the sules are composed of cefaclor cefaclor content in milligrams per cap- monohydrate and one or more suitable sule as follows: and harmless lubricants and diluents enclosed in a gelatin capsule. Each cap- Milligrams of × × = Au P a d sule contains cefaclor monohydrate × equivalent to either 250 milligrams or cefaclor per capsule As 1, 000 500 milligrams of cefaclor. Its potency where:
is satisfactory if it is not less than 90 Au = Absorbance of sample solution; 655
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Pa = Potency of working standard in ple solutions and calculate the potency micrograms per milliliter; of the sample as follows: As = Absorbance of working standard solu- (i) Preparation of working standard so- tion; lution. Dissolve and dilute an accu- d= Dilution factor of the sample. rately weighed portion of the cefaclor (2) Moisture. Proceed as directed in working standard in sufficient 0.1M po- § 436.201 of this chapter. tassium phosphate buffer, pH 4.5 (as de- [46 FR 3833, Jan. 16, 1981; 46 FR 21360, Apr. 10, scribed in § 436.101(a)(4) of this chapter) 1981] to obtain a concentration of 1 milli- gram of cefaclor per milliliter. § 442.104b Cefaclor monohydrate for (ii) Preparation of sample solution. Re- oral suspension. constitute the sample as directed in (a) Requirements for certification—(1) the labeling. Transfer a 5.0-milliliter Standards of identity, strength, quality, portion into an appropriate-sized volu- and purity. Cefaclor monohydrate for metric flask and dilute to volume with oral suspension is cefaclor 0.1M potassium phosphate buffer, pH monohydrate with one or more suitable 4.5 (as described in § 436.101(a)(4) of this and harmless diluents, buffer sub- chapter) to obtain a concentration of 1 stances, colorings and flavorings. When milligram of cefaclor per milliliter. reconstituted as directed in the label- (iii) Calculations. Calculate the ing, each milliliter contains cefaclor cefaclor content as follows: monohydrate equivalent to 25 milli- × × grams, 37.5 milligrams, 50 milligrams, Milligrams of cefaclor = Au P a d or 75 milligrams of cefaclor. Its po- for 5 milliliters of sample × As 1, 000 tency is satisfactory if it is not less than 90 percent and not more than 120 where: percent of the number of milligrams of Au=Absorbance of sample solution; cefaclor that it is represented to con- Pa=Potency of working standard in tain. Its moisture content is not more micrograms per milliliter; than 2.0 percent. When reconstituted as As=Absorbance of working standard solution; directed in the labeling, its pH is not d=Dilution factor of the sample. less than 2.5 and not more than 5.0. The (2) Moisture. Proceed as directed in cefaclor monohydrate used conforms to § 436.201 of this chapter. the standards prescribed by § 442.4(a)(1). (3) pH. Proceed as directed in § 436.202 (2) Labeling. It shall be labeled in ac- of this chapter, using the drug recon- cordance with the requirements of stituted as directed in the labeling. § 432.5 of this chapter. (3) Requests for certification; samples. [46 FR 3833, Jan. 16, 1981; 46 FR 21360, Apr. 10, 1981, as amended at 47 FR 22515, May 25, 1982; In addition to complying with the re- 54 FR 41824, Oct. 12, 1989] quirements of § 431.1 of this chapter, each such request shall contain: § 442.106 Cefadroxil monohydrate oral (i) Results of tests and assays on: dosage forms. (a) The cefaclor monohydrate used in making the batch for potency, mois- § 442.106a Cefadroxil monohydrate ture, pH, identity, and crystallinity. capsules. (b) The batch for potency, moisture, (a) Requirements for certification—(1) and pH. Standards of identity, strength, quality, (ii) Samples required: and purity. Cefadroxil monohydrate (a) The cefaclor monohydrate used in capsules are composed of cefadroxil making the batch: 10 packages, each monohydrate and one or more suitable containing approximately 300 milli- and harmless lubricants and diluents grams. enclosed in a gelatin capsule. Each cap- (b) The batch: A minimum of six im- sule contains either 250 or 500 milli- mediate containers. grams of cefadroxil. Its moisture con- (b) Tests and methods of assay—(1) Po- tent is not more than 7.0 percent. The tency. Proceed as directed in cefadroxil monohydrate used conforms § 442.40(b)(1)(ii) of this chapter, except to the standards prescribed by prepare the working standard and sam- § 442.6(a)(1).
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(2) Labeling. It shall be labeled in ac- § 442.106b Cefadroxil monohydrate cordance with the requirements of tablets. § 432.5 of this chapter. (a) Requirements for certification—(1) (3) Requests for certification; samples. Standards of identity, strength, quality, In addition to complying with the re- and purity. Cefadroxil monohydrate quirements of § 431.1 of this chapter, tablets are composed of cefadroxil each such request shall contain: monohydrate and one or more suitable (i) Results of tests and assays on: and harmless binders and lubricants, (a) The cefadroxil monohydrate used and with or without coloring and film- in making the batch for potency, mois- coating substances. Each tablet con- ture, pH, absorptivity, identity, and tains cefadroxil monohydrate equiva- crystallinity. lent to 1,000 milligrams of cefadroxil. (b) The batch for potency and mois- Its potency is satisfactory if it is not ture. less than 90 percent and not more than (ii) Samples required: 120 percent of the number of milli- (a) The cefadroxil monohydrate used grams of cefadroxil that it is rep- in making the batch: 10 packages, each resented to contain. Its moisture con- containing approximately 500 milli- tent is not more than 8.0 percent. The grams. tablets disintegrate within 15 minutes. (b) The batch: A minimum of 30 cap- The cefadroxil monohydrate used con- sules. forms to the standards prescribed by (b) Tests and methods of assay—(1) Po- § 442.6(a)(1). tency. Use either of the following meth- (2) Labeling. It shall be labeled in ac- ods; however, the results obtained from cordance with the requirements of the hydroxylamine colorimetric assay § 432.5 of this chapter. shall be conclusive. (3) Requests for certification; samples. (i) Microbiological agar diffusion assay. In addition to complying with the re- Proceed as directed in § 436.105 of this quirements of § 431.1 of this chapter, chapter, preparing the sample for assay each such request shall contain: as follows: Place a representative num- (i) Results of tests and assays on: ber of capsules into a high-speed glass blender jar containing sufficient 1 per- (a) The cefadroxil monohydrate used cent potassium phosphate buffer, pH 6.0 in making the batch for potency, mois- (solution 1), to give a stock solution of ture, pH, absorptivity, identity, and convenient concentration. Blend for 3 crystallinity. to 5 minutes. Remove an aliquot and (b) The batch for potency, moisture, further dilute with solution 1 to the and disintegration time. reference concentration of 20.0 (ii) Samples required: micrograms of cefadroxil per milliliter (a) The cefadroxil monohydrate used (estimated). in making the batch: 10 packages, each (ii) Hydroxylamine colorimetric assay. containing approximately 500 milli- Proceed as directed in § 442.40(b)(1)(ii) grams. of this chapter, preparing the sample (b) The batch: A minimum of 36 tab- as follows: Blend a representative num- lets. ber of capsules in a high-speed glass (b) Tests and methods of assay—(1) Po- blender jar with sufficient distilled tency. Use either of the following meth- water to give a stock solution of con- ods; however, the results obtained from venient concentration. Further dilute the hydroxylamine colorimetric assay an aliquot of this solution with dis- shall be conclusive. tilled water to a concentration of 1 (i) Microbiological agar diffusion assay. milligram of cefadroxil per milliliter Proceed as directed in § 436.105 of this (estimated). chapter, preparing the sample for assay (2) Moisture. Proceed as directed in as follows: Place a representative num- § 436.201 of this chapter. ber of tablets into a high-speed glass [43 FR 20978, May 16, 1978; 43 FR 27180, June blender jar containing sufficient 1 per- 23, 1978; 45 FR 16472, Mar. 14, 1980. Redesig- cent potassium phosphate buffer, pH 6.0 nated and amended at 46 FR 2992, Jan. 13, (solution 1), to obtain a stock solution 1981; 50 FR 19919, May 13, 1985] of convenient concentration. Blend for
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3 to 5 minutes. Further dilute an ali- and harmless preservatives, suspending quot of the stock solution with solu- agents, surfactants, binders, and tion 1 to the reference concentration of flavorings. When reconstituted as di- 20 micrograms of cefadroxil per milli- rected in the labeling, each milliliter liter (estimated). contains cefadroxil monohydrate (ii) Hydroxylamine colorimetric assay. equivalent to either 25, 50, or 100 milli- Proceed as directed in § 442.40(b)(1)(ii) grams of cefadroxil. Its potency is sat- of this chapter, except prepare the isfactory if it is not less than 90 per- working standard and sample solutions cent and not more than 120 percent of and calculate the cefadroxil content as the number of milligrams of cefadroxil follows: that it is represented to contain. Its (a) Preparation of working standard so- moisture content is not more than 2.0 lution. Dissolve and dilute an accu- percent. When reconstituted as di- rately weighed portion of the rected in the labeling, its pH is not less cefadroxil working standard in suffi- than 4.5 and not more than 6.0. The cient distilled water to a final con- cefadroxil monohydrate used conforms centration of 1 milligram of cefadroxil to the standards prescribed by per milliliter. § 442.6(a)(1). (b) Preparation of sample solution. (2) Labeling. It shall be labeled in ac- Blend a representative number of tab- cordance with the requirements of lets in a high-speed glass blender jar § 432.5 of this chapter. with sufficient distilled water to obtain (3) Requests for certification; samples. a stock solution of convenient con- In addition to complying with the re- centration. Further dilute an aliquot of quirements of § 431.1 of this chapter, this solution with distilled water to a each such request shall contain: concentration of 1 milligram of (i) Results of tests and assays on: cefadroxil per milliliter (estimated). (a) The cefadroxil monohydrate used (c) Calculations. Calculate the in making the batch for potency, mois- cefadroxil content as follows: ture, pH, absorptivity, identity, and A× P × d crystallinity. Milligrams per tablet = u s (b) The batch for potency, moisture, × × and pH. As 1, 000 n (ii) Samples required: where: (a) The cefadroxil monohydrate used A =Absorbance of sample solution; u in making the batch: 10 packages, each Ps=Potency of working standard in micrograms per milligram; containing approximately 300 milli- d=Dilution factor for sample; grams. As=Absorbance of working standard solu- (b) The batch: A minimum of six im- tion; mediate containers. n=Number of tablets in the sample as- (b) Tests and methods of assay—(1) Po- sayed. tency. Use either of the following meth- (2) Moisture. Proceed as directed in ods; however, the results obtained from § 436.201 of this chapter. the hydroxylamine colorimetric assay (3) Disintegration time. Proceed as di- shall be conclusive. rected in § 436.212 of this chapter, using (i) Microbiological agar diffusion assay. the procedure described in paragraph Proceed as directed in § 436.105 of this (e)(1) of that section. chapter, preparing the sample for assay [46 FR 2992, Jan. 13, 1981; 46 FR 15880, Mar. 10, as follows: Reconstitute the sample as 1981, as amended at 50 FR 19919, May 13, 1985; directed in the labeling. Transfer an 54 FR 47352, Nov. 14, 1989] accurately measured representative portion of the suspension into an ap- § 442.106c Cefadroxil monohydrate for propriate-sized volumetric flask and di- oral suspension. lute to volume with 1 percent potas- (a) Requirements for certification—(1) sium phosphate buffer, pH 6.0 (solution Standards of identity, strength, quality, 1). Further dilute an aliquot of this so- and purity. Cefadroxil monohydrate for lution with solution 1 to the reference oral suspension is cefadroxil concentration of 20.0 micrograms of monohydrate with one or more suitable cefadroxil per milliliter (estimated).
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(ii) Hydroxylamine colorimetric assay. cent and not more than 120 percent of Proceed as directed in § 442.40(b)(1)(ii) the number of milligrams of cefadroxil of this chapter, except prepare the that it is represented to contain. Its working standard and sample solutions moisture content is not more than 7.0 and calculate the cefadroxil content as percent. It passes the dissolution test. follows: The cefadroxil hemihydrate used con- (a) Preparation of working standard so- forms to the standards prescribed in lution. Dissolve and dilute an accu- § 442.7(a)(1). rately weighed portion of the (2) Labeling. It shall be labeled in ac- cefadroxil working standard in suffi- cordance with the requirements of cient distilled water to a final con- § 432.5 of this chapter. centration of 1 milligram of cefadroxil (3) Requests for certification; samples. per milliliter. In addition to complying with the re- (b) Preparation of sample solution. Re- quirements of § 431.1 of this chapter, constitute the sample as directed in each such request shall contain: the labeling. Transfer an accurately (i) Results of tests and assays on: measured representative portion to a (A) The cefadroxil hemihydrate used volumetric flask and bring to volume in making the batch for potency, mois- with distilled water to give a stock so- ture, pH, absorptivity, identity, and lution of convenient concentration. crystallinity. Further dilute an aliquot of this solu- (B) The batch for content, moisture, tion with distilled water to a con- and dissolution. centration of 1 milligram of cefadroxil (ii) Samples, if required by the Direc- per milliliter (estimated). tor, Center for Drug Evaluation and (c) Calculations. Calculate the Research: cefadroxil content as follows: (A) The cefadroxil hemihydrate used in making the batch: 10 packages, each A× P × d Milligrams per dose = u s containing approximately 500 milli- × As 1, 000 grams. where: (B) The batch: A minimum of 100 cap- Au=Absorbance of sample solution; sules. Ps=Potency of working standard in (b) Tests and methods of assay—(1) micrograms per milligram; Cefadroxil content. Use either of the fol- d=Dilution factor for sample; lowing methods; however, the results As=Absorbance of working standard solution. obtained from the hydroxylamine col- (2) Moisture. Proceed as directed in orimetric assay shall be conclusive. § 436.201 of this chapter. (i) Microbiological agar diffusion assay. (3) pH. Proceed as directed in § 436.202 Proceed as directed in § 436.105 of this of this chapter, using the drug recon- chapter, preparing the sample for assay stituted as directed in the labeling. as follows: Place a representative num- ber of capsules into a high-speed glass [46 FR 16679, Mar. 13, 1981, as amended at 50 FR 19919, May 13, 1985] blender jar containing sufficient 1 per- cent potassium phosphate buffer, pH 6.0 § 442.107 Cefadroxil hemihydrate oral (solution 1), to give a stock solution of dosage forms. convenient concentration. Blend for 3 to 5 minutes. Remove an aliquot and § 442.107a Cefadroxil hemihydrate cap- further dilute with solution 1 to the sules. reference concentration of 20 (a) Requirements for certification—(1) micrograms of cefadroxil per milliliter Standards of identity, strength, quality, (estimated). and purity. Cefadroxil hemihydrate (ii) Hydroxylamine colorimetric assay capsules are composed of cefadroxil for cefadroxil. Proceed as directed in hemihydrate and one or more suitable § 442.40(b)(1)(ii), except prepare the and harmless lubricants and diluents working standard and sample solutions enclosed in a gelatin capsule. Each cap- and calculate the potency of the sam- sule contains cefadroxil hemihydrate ple as follows: equivalent to 500 milligrams of (A) Preparation of working standard cefadroxil. Its cefadroxil content is sat- solutions. Dissolve and dilute an accu- isfactory if it is not less than 90 per- rately weighed portion of the
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cefadroxil working standard in suffi- to the standards prescribed in cient distilled water to obtain a stock § 442.7(a)(1). solution of convenient concentration. (2) Labeling. It shall be labeled in ac- Further dilute an aliquot of this solu- cordance with the requirements of tion with distilled water to a con- § 432.5 of this chapter. centration of 1 milligram of cefadroxil (3) Requests for certification; samples. per milliliter. In addition to complying with the re- (B) Preparation of sample solutions. quirements of § 431.1 of this chapter, Blend a representative number of cap- each such request shall contain: sules in a high-speed glass blender jar (i) Results of tests and assays on: with sufficient distilled water to obtain a stock solution of convenient con- (A) The cefadroxil hemihydrate used centration. Further dilute an aliquot of in making the batch for potency, mois- this solution with distilled water to a ture, pH, absorptivity, identity, and concentration of 1 milligram of crystallinity. cefadroxil per milliliter (estimated). (B) The batch for content, moisture, (C) Calculations. Calculate the and dissolution. cefadroxil content as follows: (ii) Samples, if required by the Direc- tor, Center for Drug Evaluation and × × Milligrams of = Au P s d Research: cefadroxil per capsule × × (A) The cefadroxil hemihydrate used As 1, 000 n in making the batch: 10 packages, each where: containing approximately 500 milli- A = Absorbance of sample solution; U grams. AS = Absorbance of working standard solu- tion; (B) The batch: A minimum of 100 tab- PS = Potency of working standard solution in lets. micrograms per milliliter; (b) Tests and methods of assay—(1) d = Dilution factor of the sample; Cefadroxil content. Use either of the fol- n = Number of capsules in the sample as- sayed. lowing methods; however, the results obtained from the hydroxylamine col- (2) Moisture. Proceed as directed in orimetric assay shall be conclusive. § 436.201 of this chapter. (i) Microbiological agar diffusion assay. (3) Dissolution. Proceed as directed in Proceed as directed in § 436.105 of this § 436.215 of this chapter. The quantity Q chapter, preparing the sample for assay (the amount of cefadroxil dissolved) is as follows: Place a representative num- 75 percent within 45 minutes. ber of tablets into a high-speed glass [59 FR 8857, Feb. 24, 1994] blender jar containing sufficient 1 per- cent potassium phosphate buffer, pH 6.0 § 442.107b Cefadroxil hemihydrate tab- (solution 1), to give a stock solution of lets. convenient concentration. Blend for 3 (a) Requirements for certification—(1) to 5 minutes. Remove an aliquot and Standards of identity, strength, quality, further dilute with solution 1 to the and purity. Cefadroxil hemihydrate tab- reference concentration of 20 lets are composed of cefadroxil micrograms of cefadroxil per milliliter hemihydrate and one or more suitable (estimated). and harmless binders and lubricants, (ii) Hydroxylamine colorimetric assay with or without coloring and film-coat- for cefadroxil. Proceed as directed in ing substances. Each tablet contains § 442.40(b)(1)(ii), except prepare the cefadroxil hemihydrate equivalent to 1,000 milligrams of cefadroxil. Its working standard and sample solutions cefadroxil content is satisfactory if it and calculate the potency of the sam- is not less than 90 percent and not ple as follows: more than 120 percent of the number of (A) Preparation of working standard milligrams of cefadroxil that it is rep- solutions. Dissolve and dilute an accu- resented to contain. Its moisture con- rately weighed portion of the tent is not more than 8.0 percent. It cefadroxil working standard in suffi- passes the dissolution test. The cient distilled water to obtain a stock cefadroxil hemihydrate used conforms solution of convenient concentration.
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Further dilute an aliquot of this solu- cefixime moiety. The cefixime tri- tion with distilled water to a con- hydrate used conforms to the standards centration of 1 milligram of cefadroxil prescribed by § 442.15(a)(1) of this part. per milliliter. (2) Labeling. It shall be labeled in ac- (B) Preparation of sample solutions. cordance with the requirements of Blend a representative number of tab- § 436.5 of this chapter. lets in a high-speed glass blender jar (3) Requests for certification; samples. with sufficient distilled water to obtain In addition to complying with the re- a stock solution of convenient con- quirements of § 431.1 of this chapter, centration. Further dilute an aliquot of each such request shall contain: this solution with distilled water to a (i) Results of tests and assays on: concentration of 1 milligram of (A) The cefixime trihydrate used in cefadroxil per milliliter (estimated). making the batch, for potency, mois- (C) Calculations. Calculate the ture, pH, crystallinity, specific rota- cefadroxil content as follows: tion, and identity. (B) The batch, for content, moisture, Milligrams of cefadroxil A× P × d pH, and identity. = u s per tablet A×1, 000 × n (ii) Samples, if required by the Direc- s tor, Center for Drug Evaluation and where: Research. A = Absorbance of sample solution; U (A) The cefixime used in making the AS = Absorbance of working standard solu- tion; batch: 10 packages, each containing ap- PS = Potency of working standard solution in proximately 500 milligrams. micrograms per milliliter; (B) The batch: A minimum of 10 im- d = Dilution factor of the sample; and mediate containers. n = Number of tablets in the sample assayed. (b) Tests and methods of assay—(1) (2) Moisture. Proceed as directed in Content. Proceed as directed in § 436.201 of this chapter. § 442.15(b)(1) of this part, preparing the (3) Dissolution. Proceed as directed in sample solution and calculating the § 436.215 of this chapter. The quantity Q cefixime content as follows: (the amount of cefadroxil dissolved) is (i) Preparation of the sample solution. 75 percent within 30 minutes. Reconstitute as directed in the label- ing. Transfer a 5.0-milliliter portion of [59 FR 8857, Feb. 24, 1994] the suspension into an appropriately § 442.115 Cefixime trihydrate oral dos- sized volumetric flask and quan- age forms. titatively dilute stepwise with 0.1M phosphate buffer, pH 7.0, to obtain a § 442.115a Cefixime trihydrate for oral concentration of 0.2 milligram of suspension. cefixime activity per milliliter (esti- (a) Requirements for certification—(1) mated). Standards of identity, strength, quality, (ii) Calculations. Calculate the and purity. Cefixime trihydrate for oral cefixime content as follows: suspension is cefixime trihydrate with A× P × d one or more suitable and harmless pre- Milligrams of cefixime per = u s servatives, suspending agents, diluents, 5 milliliters of sample × and flavorings. When reconstituted as As 1, 000 directed in the labeling, each milliliter contains the equivalent of 20 milli- Au = Area of the cefixime peak in the chro- grams of cefixime. Its cefixime tri- matogram of the sample (at a retention time equal to that observed for the hydrate potency is satisfactory if it is standard); not less than 90 percent and not more As = Area of the cefixime peak in the chro- than 120 percent of the number of milli- matogram of the cefixime working grams of cefixime that it is represented standard. to contain. Its moisture content is not Ps = Cefixime activity in the cefixime work- more than 2.0 percent. When reconsti- ing standard solution in micrograms per tuted as described in labeling, the pH milliliter; and of the suspension is not less than 2.5 d = Dilution factor of the sample. and not more than 4.5. It passes the (2) Moisture. Proceed as directed in identity test for the presence of the § 436.201 of this chapter.
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(3) pH. Proceed as directed in § 436.202 sample solution and calculating the of this chapter, using the drug recon- cefixime content as follows: stituted as directed in the labeling. (i) Preparation of sample solution. (4) Identity. The high performance Grind one or a known number of tab- liquid chromatogram of the sample de- lets using a mortar and pestle. Quan- termined as directed in paragraph titatively transfer the ground tablet(s) (b)(1) of this section, compares quali- into a suitable volumetric flask, tatively to that of the cefixime work- sonicate and dilute with 0.1M phos- ing standard. phate buffer, pH 7.0 to a concentration of 4 milligrams per milliliter. Cen- [53 FR 24259, June 28, 1988] trifuge the sample at 3,000 revolutions § 442.115b Cefixime trihydrate tablets. per minute for 10 minutes. Take an ali- quot of the supernatant and quali- (a) Requirements for certification—(1) tatively dilute to a concentration of 0.2 Standards of identity, strength, quality, milligram of cefixime activity per mil- and purity. Cefixime trihydrate tablets liliter in 0.1M phosphate buffer, pH 7.0 are composed of cefixime trihydrate (estimated). and one or more suitable and harmless (ii) Calculations. Calculate the diluents, binders, lubricants, colorings, cefixime content as follows: and coating substances. Each tablet contains cefixime trihydrate equiva- Milligrams of cefixime A× P × d lent to either 200 milligrams or 400 mil- = u s ligrams of cefixime. Its cefixime tri- per tablet A× n hydrate content is satisfactory if it is s not less than 90 percent and not more Au = Area of the cefixime peak in the chro- than 110 percent of the number of milli- matogram of the sample (at a retention grams of cefixime that it is represented time equal to that observed for the to contain. Its moisture content is not standard); more than 10.0 percent. It passes the As = Area of the cefixime peak in the chro- dissolution test. It passes the identity matogram of the cefixime working test for the presence of the cefixime standard. moiety. The cefixime used conforms to Ps = Cefixime activity in the cefixime work- the standards prescribed by ing standard solution in micrograms per § 442.15(a)(1) of this part. milliliter; d = Dilution factor of the sample; and (2) Labeling. It shall be labeled in ac- n = Number of tablets in the sample. cordance with the requirements of § 432.5 of this chapter. (2) Moisture. Proceed as directed in (3) Requests for certification; samples. § 436.201 of this chapter. In addition to complying with the re- (3) Dissolution test. Proceed as di- quirements of § 431.1 of this chapter, rected in § 436.215 of this chapter. The each such request shall contain: quantity Q (the amount of cefixime dis- (i) Results of tests and assays on: solved) is 75 percent within 45 minutes. (A) The cefixime used in making the (4) Identity. The high-performance batch for potency, moisture, pH, crys- liquid chromatogram of the sample de- tallinity, specific rotation, and iden- termined as directed in paragraph tity. (b)(1) of this section compares quali- (B) The batch, for content, moisture, tatively to that of the cefixime work- dissolution, and identity. ing standard. (ii) Samples, if required by the Direc- [53 FR 24259, June 28, 1988] tor, Center for Drug Evaluation and Research. § 442.119 Cefuroxime axetil oral dos- (A) The cefixime used in making the age forms. batch: 10 packages, each containing ap- proximately 500 milligrams. § 442.119a Cefuroxime axetil tablets. (B) The batch: A minimum of 10 im- (a) Requirements for certification—(1) mediate containers. Standards of identity, strength, quality, (b) Tests and methods of assay—(1) and purity. Cefuroxime axetil tablets Content. Proceed as directed in are composed of cefuroxime axetil and § 442.15(b)(1) of this part, preparing the one or more suitable and harmless
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diluents, binders, lubricants, and color- obtain a stock solution containing 0.24 ings. Each tablet contains 125 milli- milligram of cefuroxime axetil per mil- grams, 250 milligrams, or 500 milli- liliter. Store the stock solution under grams of cefuroxime activity. Its po- refrigeration no more than 8 hours. tency is satisfactory if it is not less (B) Sample solution. Grind a rep- than 90 percent and not more than 110 resentative number of tablets in a mor- percent of the number of milligrams of tar and pestle. Immediately swirl the cefuroxime activity that it is rep- ground tablets in a volumetric flask resented to contain. Its moisture con- containing methanol and shake for 10 tent is not more than 2.0 percent at the minutes to dissolve the ground time of certification and not more than cefuroxime axetil. Dilute with meth- 6.0 percent at the time of expiry. It anol to give a stock solution of conven- passes the dissolution test. It passes the film-coat rupture test. It passes the ient concentration. Filter the stock so- identity test. The cefuroxime axetil lution. Transfer 5.0 milliliters of fil- used conforms to the standards pre- trate to a 50-milliliter volumetric scribed by § 442.19(a)(1). flask. Add 5.0 milliliters of internal (2) Labeling. It shall be labeled in ac- standard solution and 8.8 milliliters of cordance with the requirements of methanol. Dilute to volume with 0.2M § 432.5 of this chapter. ammonium phosphate solution. Store (3) Requests for certification; samples. in a refrigerator and use within 8 In addition to complying with the re- hours. quirements of § 431.1 of this chapter, (ii) System suitability requirements—(A) each such request shall contain: Tailing factor. The tailing factor (T) is (i) Results of tests and assays on: satisfactory for isomer A if it is not (A) The cefuroxime axetil used in more than 1.5 at 5 percent of peak making the batch for potency, isomer height. A ratio, moisture, crystallinity, and (B) Efficiency of the column. The effi- identity. ciency of the column (n) is satisfactory (B) The batch for potency, moisture, for isomer A if it is greater than 3,000 dissolution, film-coat rupture, and theoretical plates. identity. (C) Resolution. The resolution (R) be- (ii) Samples, if required by the Direc- tween isomer A and isomer B of tor, Center for Drug Evaluation and Research: cefuroxime axetil is satisfactory if it is (A) The cefuroxime axetil used in not less than 1.5 and the resolution (R) making the batch: 10 packages, each between isomer A and the delta-2 iso- containing approximately 500 milli- mers of cefuroxime axetil is satisfac- grams. tory if it is not less than 1.5. (B) The batch: A minimum of 100 tab- (D) Coefficient of variation. The coeffi- lets. cient of variation (SR in percent) of five (b) Tests and methods of assay—(1) Po- replicate injections is not more than tency. Proceed as directed in 2.0 percent. If the system suitability § 442.19(b)(1). Working standard and requirements have been met, then pro- sample solutions, system suitability ceed as described in § 436.216(b) of this requirements, and calculations are as chapter. Alternate chromatographic follows: conditions are acceptable provided re- (i) Preparation of working standard producibility and resolution are com- and sample solutions—(A) Working stand- parable to the system. However, the ard solution. Dissolve approximately 30 sample preparation described in para- milligrams of the cefuroxime axetil graph (b)(1)(i)(B) of this section should working standard, accurately weighed, not be changed. in methanol and dilute to 25 milliliters. (iii) Calculations. Calculate the Transfer 10.0 milliliters of the working cefuroxime content as follows: standard solution to a 50-milliliter vol- umetric flask. Add 5.0 milliliters of in- Milligrams of cefuroxime R× P × d = u s ternal standard solution, 3.8 milliliters per tablet × of methanol, and dilute to volume with Rs n 0.2M ammonium phosphate solution to where:
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Ru=Sum of the peak heights of the the standards prescribed by cefuroxime axetil sample isomer A and § 442.19(a)(1). isomer B peaks/Peak height of the inter- (2) Labeling. It shall be labeled in ac- nal standard; cordance with the requirements of Rs=Sum of the peak heights of the § 432.5 of this chapter. cefuroxime axetil working standard iso- mer A and isomer B peaks/Peak height of (3) Requests for certification; samples. the internal standard; In addition to complying with the re-
Ps=Potency of the cefuroxime axetil working quirements of § 431.1 of this chapter, standard in milligrams of cefuroxime ac- each such request shall contain: tivity per milliliter; (i) Results of tests and assays on: d=Dilution factor of the sample; and (A) The cefuroxime axetil used in n=Number of tablets in the sample assayed. making the batch for potency, isomer A ratio, moisture, crystallinity, and (2) Moisture. Proceed as directed in identity. § 436.201 of this chapter, using the titra- (B) The batch for cefuroxime po- tion procedure described in paragraph tency, dissolution, moisture, pH of con- (e)(1) of that section. stituted suspension, and identity. (3) Dissolution. Proceed as directed in (ii) Samples, if required by the Direc- § 436.215 of this chapter. The quantity Q tor, Center for Drug Evaluation and (the amount of cefuroxime activity dis- Research: solved) is 60 percent at 15 minutes and (A) The cefuroxime axetil used in 75 percent at 45 minutes. making the batch: 10 packages, each (4) Film-coat rupture test. Proceed as containing approximately 500 milli- directed in § 436.217 of this chapter. grams. (5) Identity. The high-performance (B) The batch: A minimum of 12 im- liquid chromatogram of the sample so- mediate containers. lution determined as directed in para- (b) Tests and methods of assay—(1) Po- graph (b)(1) of this section compares tency. Proceed as directed in qualitatively to that of the cefuroxime § 442.19(b)(1). Working standard and axetil working standard solution. sample solutions and calculations are [52 FR 42433, Nov. 5, 1987; 52 FR 45528, Nov. 30, as follows: 1987, as amended at 54 FR 47352, Nov. 14, 1989; (i) Preparation of working standard so- 54 FR 50472, Dec. 6, 1989; 55 FR 11583, Mar. 29, lution. Dissolve approximately 15 milli- 1990. Redesignated at 60 FR 27222, May 23, grams of the cefuroxime axetil working 1995] standard, accurately weighed, in 20.0 milliliters of methanol in a 50-milli- § 442.119b Cefuroxime axetil for oral liter volumetric flask. Dilute to vol- suspension. ume with deionized water, and swirl to (a) Requirements for certification—(1) mix. Store for no more than 8 hours Standards of identity, strength, quality, under refrigeration and protected from and purity. Cefuroxime axetil for oral light. suspension is cefuroxime axetil with (ii) Preparation of sample solution. Re- one or more suitable and harmless constitute the sample as directed in diluents, suspending and sweetening the labeling. Transfer an accurately agents, and flavorings. When reconsti- measured representative portion of the tuted as directed in the labeling, it suspension equivalent to one dose into contains cefuroxime axetil equivalent a 200-milliliter volumetric flask. Add 10 to 25 milligrams of cefuroxime per mil- milliliters of methanol and disperse limeter. Its potency is satisfactory if it the sample. Dilute to volume with is not less than 90 percent and not methanol. Dilute 20.0 milliliters of this more than 115 percent of the number of solution to volume in a 50-milliliter milligrams of cefuroxime that it is rep- volumetric flask with deionized water, resented to contain. It passes the dis- swirl to mix, and allow to stand for 10 solution test. Its moisture content is minutes. (Note: A white turbidity is not more than 0.2 percent. When recon- formed.) Filter this solution via a suit- stituted as directed in the labeling, its able disposable filter unit, discarding pH is not less than 3.5 and not more the first 5 milliliters. Store for no more than 5.5. It passes the identity test. than 8 hours under refrigeration and The cefuroxime axetil used conforms to protect from light.
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(iii) Calculations. Calculate the milli- (3) Requests for certification; samples. grams of cefuroxime per dose (5 milli- In addition to the requirements of liters) as follows: § 431.1 of this chapter, each such re- quest shall contain: × × Milligrams of cefuroxime AUS P d (i) Results of tests and assays on: = (a) The cephaloglycin dihydrate used per 5 milliliters of sample × AS 1, 000 in making the batch for potency, mois- where: ture, pH, cephaloglycin content, iden- AU = Sum of the areas of the cefuroxime tity, and crystallinity. axetil sample isomer A and isomer B (b) The batch for potency and mois- peaks; ture. AS = Sum of the peak areas of the cefuroxime (ii) Samples required: axetil working standard isomer A and (a) The cephaloglycin dihydrate used isomer B peaks; in making the batch: 10 packages, each PS = Cefuroxime activity in the cefuroxime containing approximately 300 milli- axetil working standard solution in micrograms per milliliter; and grams. d = Dilution factor of the sample. (b) The batch: A minimum of 30 cap- sules. (2) Dissolution. Proceed as directed in (b) Tests and methods of assay—(1) Po- § 436.215 of this chapter. The quantity Q tency. Proceed as directed in § 436.105 of (the amount of cefuroxime activity dis- this chapter, preparing the sample for solved) is 60 percent at 30 minutes. assay as follows: Place a representative (3) Moisture. Proceed as directed in number of capsules into a high-speed § 436.201 of this chapter. glass blender jar with sufficient 0.1M (4) . Reconstitute as directed in pH potassium phosphate buffer, pH 4.5 (so- the labeling and proceed as directed in lution 4), to give a stock solution of § 436.202 of this chapter. convenient concentration. Blend for 3 (5) Identity. The high-performance to 5 minutes. Remove an aliquot and liquid chromatogram of the sample de- further dilute with solution 4 to the termined as directed in paragraph reference concentration of 10 (b)(1) of this section compares quali- micrograms of cephaloglycin per milli- tatively to that of the cefuroxime liter (estimated). axetil working standard. (2) Moisture. Proceed as directed in [60 FR 27222, May 23, 1995] § 436.201 of this chapter. § 442.121 Cephaloglycin dihydrate oral [39 FR 19040, May 30, 1974, as amended at 50 dosage forms. FR 19919, May 13, 1985] § 442.121a Cephaloglycin dihydrate § 442.121b Cephaloglycin dihydrate for capsules. oral suspension. (a) Requirements for certification—(1) (a) Requirements for certification—(1) Standards of identity, strength, quality, Standards of identity, strength, quality, and purity. Cephaloglycin dihydrate and purity. Cephaloglycin dihydrate for capsules are composed of cephaloglycin oral suspension is cephaloglycin dihydrate and one or more suitable lu- dihydrate with one or more suitable bricants and diluents enclosed in a diluents, buffer substances, colorings, gelatin capsule. Each capsule contains and flavorings. When reconstituted as cephaloglycin dihydrate equivalent to directed in the labeling, each milliliter 250 milligrams of cephaloglycin. Its po- contains cephaloglycin dihydrate tency is satisfactory if it is not less equivalent to 50 milligrams of than 90 percent and not more than 120 cephaloglycin. Its potency is satisfac- percent of the number of milligrams of tory if it is not less than 90 percent and cephaloglycin that it is represented to not more than 120 percent of the num- contain. Its moisture content is not ber of milligrams of cephaloglycin that more than 9 percent. The cephaloglycin it is represented to contain. Its mois- used conforms to the standards pre- ture content is not more than 2 per- scribed by § 442.21(a)(1). cent. When reconstituted as directed in (2) Labeling. It shall be labeled in ac- the labeling, its pH is not less than 3.0 cordance with the requirements of and not more than 5.0. It passes the § 432.5 of this chapter. identity test for the presence of the
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cephaloglycin moiety. The violet absorption spectrum of this solu- cephaloglycin dihydrate used conforms tion from 230 to 320 nanometers. The to the standards prescribed by spectrum compares qualitatively to § 442.21(a)(1). that of the cephaloglycin working (2) Labeling. It shall be labeled in ac- standard similarly treated. cordance with the requirements of [39 FR 19040, May 30, 1974, as amended at 50 § 432.5 of this chapter. FR 19919, May 13, 1985] (3) Requests for certification; samples. In addition to complying with the re- § 442.127 Cephalexin monohydrate quirements of § 431.1 of this chapter, oral dosage forms. each such request shall contain: (i) Results of tests and assays on: § 442.127a Cephalexin monohydrate (a) The cephaloglycin dihydrate used tablets. in making the batch for potency, mois- (a) Requirements for certification—(1) ture, pH, cephaloglycin content, iden- Standards of identity, strength, quality, tity, and crystallinity. and purity. Cephalexin monohydrate (b) The batch for potency, moisture, tablets are composed of cephalexin pH, and identity. monohydrate and one or more suitable (ii) Samples required: and harmless diluents, binders, lubri- (a) The cephaloglycin dihydrate used cants, colorings, and coating sub- in making the batch: 10 packages, each stances. Each tablet contains containing approximately 500 milli- cephalexin monohydrate equivalent to grams. 250, 500, or 1,000 milligrams of (b) The batch: A minimum of six im- cephalexin. Its potency is satisfactory mediate containers. if it is not less than 90 percent and not (b) Tests and methods of assay—(1) Po- more than 120 percent of the number of tency. Proceed as directed in § 436.105 of milligrams of cephalexin that it is rep- this chapter, preparing the sample for resented to contain. Its moisture con- assay as follows: Reconstitute as di- tent is not more than 9 percent. The rected in the labeling. Place an accu- tablets disintegrate within 30 minutes. rately measured representative portion The cephalexin monohydrate used con- of the suspension into an appropriate- forms to the standards prescribed by sized volumetric flask and dilute to § 442.27(a)(1). volume with 0.1M potassium phosphate (2) Labeling. It shall be labeled in ac- buffer, pH 4.5 (solution 4). Further di- cordance with the requirements of lute an aliquot of the stock solution § 432.5 of this chapter. with solution 4 to the reference con- (3) Requests for certification; samples. centration of 10 micrograms of In addition to complying with the re- cephaloglycin per milliliter (esti- quirements of § 431.1 of this chapter, mated). each such request shall contain: (2) Moisture. Proceed as directed in (i) Results of tests and assays on: § 436.201 of this chapter. (a) The cephalexin monohydrate used (3) pH. Proceed as directed in § 436.202 in making the batch for potency, mois- of this chapter, using the drug recon- ture, pH, absorptivity, identity, and stituted as directed in the labeling. crystallinity. (4) Identity. Dilute a representative (b) The batch for potency, moisture, portion of the sample with sufficient and disintegration time. distilled water to give a concentration (ii) Samples required: of 2.5 milligrams of cephaloglycin per (a) The cephalexin monohydrate used milliliter (estimated). Shake vigor- in making the batch: 10 packages, each ously on a mechanical shaker for 30 containing approximately 300 milli- minutes. Filter through Whatman No. grams. 1 filter paper, discarding the first few (b) The batch: A minimum of 36 tab- milliliters of filtrate. Further dilute an lets. aliquot of the filtrate with sufficient (b) Tests and methods of assay—(1) Po- distilled water to give a concentration tency. Use either of the following meth- of 0.05 milligram of cephaloglycin per ods; however, the results obtained from milliliter (estimated). Using a suitable the microbiological agar diffusion spectrophotometer, record the ultra- assay shall be conclusive.
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(i) Microbiological agar diffusion assay. (2) Labeling. It shall be labeled in ac- Proceed as directed in § 436.105 of this cordance with the requirements of chapter, preparing the sample for assay § 432.5 of this chapter. as follows: Place a representative num- (3) Requests for certification; samples. ber of tablets into a high-speed glass In addition to complying with the re- blender jar containing sufficient 1 per- quirements of § 431.1 of this chapter, cent potassium phosphate buffer, pH 6.0 each such request shall contain: (solution 1), to give a stock solution of (i) Results of tests and assays on: convenient concentration. Blend for 3 (a) The cephalexin monohydrate used to 5 minutes. Further dilute with solu- in making the batch for potency, mois- tion 1 to the reference concentration of ture, pH, absorptivity, identity, and 20.0 micrograms of cephalexin per mil- crystallinity. liliter (estimated). (b) The batch for potency and mois- (ii) Iodometric assay. Proceed as di- ture. rected in § 436.204 of this chapter, pre- (ii) Samples required: paring the sample as follows: Blend a (a) The cephalexin monohydrate used representative number of tablets in a in making the batch: 10 packages, each high-speed glass blender with sufficient containing approximately 300 milli- distilled water to give a stock solution grams. of convenient concentration. Further (b) The batch: A minimum of 30 cap- dilute with distilled water to the pre- sules. scribed concentration of cephalexin. (b) Tests and methods of assay—(1) Po- tency. Use either of the following meth- NOTE: The 10.0 milliliters of 0.01N iodine ods; however, the results obtained from must be added within 20 seconds after the ad- the microbiological agar diffusion dition of the 2.0 milliliters of 1.2N hydro- assay shall be conclusive. chloric acid, and the assay should be com- (i) Microbiological agar diffusion assay. pleted within 1 hour after the sample and Proceed as directed in § 436.105 of this standard are first put into solution. chapter, preparing the sample for assay (2) Moisture. Proceed as directed in as follows: Place a representative num- § 436.201 of this chapter. ber of capsules into a high-speed glass (3) Disintegration time. Proceed as di- blender jar with sufficient 1 percent po- rected in § 436.212 of this chapter, using tassium phosphate buffer, pH 6.0 (solu- the procedure described in paragraph tion 1), to give a stock solution of con- (e)(1) of that section. venient concentration. Blend for 3 to 5 minutes. Remove an aliquot and fur- [39 FR 19040, May 30, 1974, as amended at 40 ther dilute with solution 1 to the ref- FR 49083, Oct. 21, 1975; 50 FR 19919, May 13, 1985; 52 FR 20710, June 3, 1987] erence concentration of 20.0 micrograms of cephalexin per milliliter § 442.127b Cephalexin monohydrate (estimated). capsules. (ii) Iodometric assay. Proceed as di- rected in § 436.204 of this chapter, pre- (a) Requirements for certification—(1) paring the sample as follows: Blend a Standards of identity, strength, quality, representative number of capsules in a and purity. Cephalexin monohydrate high-speed glass blender with sufficient capsules are composed of cephalexin distilled water to give a stock solution monohydrate and one or more suitable of convenient concentration. Further and harmless lubricants and diluents dilute with distilled water to the pre- enclosed in a gelatin capsule. Each cap- scribed concentration of cephalexin. sule contains cephalexin monohydrate equivalent to either 125, 250, or 500 mil- NOTE: The 10.0 milliliters of 0.01N iodine ligrams of cephalexin. Its potency is must be added within 20 seconds after the ad- satisfactory if it is not less than 90 per- dition of the 2.0 milliliters of 1.2N hydro- chloric acid, and the assay should be com- cent and not more than 120 percent of pleted within 1 hour after the sample and the number of milligrams of cephalexin standard are first put into solution. that it is represented to contain. Its moisture content is not more than 10 (2) Moisture. Proceed as directed in percent. The cephalexin monohydrate § 436.201 of this chapter. used conforms to the standards pre- [39 FR 19040, May 30, 1974, as amended at 50 scribed by § 442.27(a)(1). FR 19919, May 13, 1985]
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§ 442.127c Cephalexin monohydrate for sium phosphate buffer, pH 6.0 (solution oral suspension. 1). Further dilute an aliquot of this so- (a) Requirements for certification—(1) lution with solution 1 to the reference Standards of identity, strength, quality, concentration of 20.0 micrograms of and purity. Cephalexin monohydrate for cephalexin per milliliter (estimated). oral suspension is cephalexin (ii) Iodometric assay. Proceed as di- monohydrate with one or more suitable rected in § 436.204 of this chapter, pre- and harmless diluents, buffer sub- paring the sample as follows: Reconsti- stances, colorings, and flavorings. tute the sample as directed in the la- When reconstituted as directed in the beling. Transfer an accurately meas- labeling, each milliliter contains ured representative portion to a volu- cephalexin monohydrate equivalent to metric flask and bring to volume with 25 milligrams, 50 milligrams, or 100 distilled water. Further dilute an ali- milligrams of cephalexin. Its potency quot of this solution with distilled is satisfactory if it is not less than 90 water to the prescribed concentration percent and not more than 120 percent of cephalexin.
of the number of milligrams of NOTE: The 10 milliliters of 0.01N iodine cephalexin that it is represented to must be added within 20 seconds after the ad- contain. Its moisture content is not dition of the 2.0 milliliters of 1.2N hydro- more than 2 percent. When reconsti- chloric acid, and the assay should be com- tuted as directed in the labeling, its pH pleted within 1 hour after the sample and is not less than 3.0 and not more than standard are first put into solution. 6.0. The cephalexin used conforms to (2) Moisture. Proceed as directed in the standards prescribed by § 436.201 of this chapter. § 442.27(a)(1). (3) pH. Proceed as directed in § 436.202 (2) Labeling. It shall be labeled in ac- of this chapter, using the drug recon- cordance with the requirements of stituted as directed in the labeling. § 432.5 of this chapter. (3) Requests for certification; samples. [39 FR 19040, May 30, 1974, as amended at 45 In addition to complying with the re- FR 16472, Mar. 14, 1980; 50 FR 19919, May 13, quirements of § 431.1 of this chapter, 1985] each such request shall contain: (i) Results of tests and assays on: § 442.128 Cephalexin hydrochloride monohydrate tablets. (a) The cephalexin used in making the batch for potency, moisture, pH, (a) Requirements for certification—(1) absorptivity, identity, and crystallin- Standards of identity, strength, quality, ity. and purity. Cephalexin hydrochloride (b) The batch for potency, moisture, monohydrate tablets are composed of and pH. cephalexin hydrochloride monohydrate (ii) Samples required: and one or more suitable and harmless (a) The cephalexin used in making lubricants, colorings and coating sub- the batch: 10 packages, each containing stances. Each tablet contains approximately 300 milligrams. cephalexin hydrochloride monohydrate (b) The batch: A minimum of six im- equivalent to 250 milligrams, 333 milli- mediate containers. grams or 500 milligrams of cephalexin. (b) Tests and methods of assay—(1) Po- Its cephalexin content is satisfactory if tency. Use either of the following meth- it is not less than 90 percent and not ods; however, the results obtained from more than 120 percent of the number of the microbiological agar diffusion milligrams of cephalexin that it is rep- assay shall be conclusive. resented to contain. Its moisture con- (i) Microbiological agar diffusion assay. tent is not more than 8.0 percent. The Proceed as directed in § 436.105 of this tablets pass the dissolution test. It chapter, preparing the sample for assay passes the identity test. The as follows: Reconstitute the sample as cephalexin hydrochloride monohydrate directed in the labeling. Transfer an used conforms to the standards pre- accurately measured representative scribed by § 442.28(a)(1). portion of the suspension into an ap- (2) Labeling. It shall be labeled in ac- propriate-sized volumetric flask and di- cordance with the requirements of lute to volume with 1-percent potas- § 432.5 of this chapter.
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(3) Requests for certification; samples. (2) Labeling. It shall be labeled in ac- In addition to complying with the re- cordance with the requirements of quirements of § 431.1 of this chapter, § 432.5 of this chapter. each such request shall contain: (3) Requests for certification; samples. (i) Results of tests and assays on: In addition to complying with the re- (A) The cephalexin hydrochloride quirements of § 431.1 of this chapter, monohydrate used in making the batch each such request shall contain: for cephalexin potency, moisture, pH, (i) Results of tests and assays on: identity, and crystallinity. (a) The cephradine used in making (B) The batch for cephalexin content, the batch for potency, moisture, pH, moisture, dissolution, and identity. cephalexin content, identity, and crys- (ii) Samples, if required by the Direc- tallinity. tor, Center for Drug Evaluation and (b) The batch for potency, moisture, Research. and pH. (A) The cephalexin hydrochloride (ii) Samples required: monohydrate used in making the (a) The cephradine used in making batch: 10 packages, each containing ap- the batch: 10 packages, each containing proximately 500 milligrams. 500 milligrams. (B) The batch: A minimum of 36 tab- (b) The batch: A minimum of six im- lets. mediate containers. (b) Tests and methods of assay—(1) (b) Tests and methods of assay—(1) Po- Cephalexin content. Proceed as directed tency. Use either of the following meth- in § 442.140c(b)(1)(ii), except that ods; however, the results obtained from ‘‘cephalexin’’ is substituted at each oc- currence of ‘‘cephradine’’. the microbiological agar diffusion assay shall be conclusive. (2) Moisture. Proceed as directed in § 436.201 of this chapter. (i) Microbiological agar diffusion assay. Proceed as directed in § 436.105 of this (3) Dissolution. Proceed as directed in § 436.215 of this chapter. The quantity Q chapter, preparing the sample for assay (the amount of cephalexin dissolved) is as follows: Reconstitute the sample as not less than 75 percent at 45 minutes. directed in the labeling. Transfer an (4) Identity. Proceed as directed in accurately measured representative § 436.367 of this chapter. portion of the suspension into an ap- propriate-sized volumetric flask and di- [54 FR 48860, Nov. 28, 1989] lute to volume with 1 percent potas- sium phosphate buffer, pH 6.0 (solution § 442.140a Cephradine for oral suspen- 1), to obtain a stock solution of con- sion. venient concentration. Further dilute (a) Requirements for certification—(1) an aliquot of the stock solution with Standards of identity, strength, quality, solution 1 to the reference concentra- and purity. Cephradine for oral suspen- tion of 10.0 micrograms of cephradine sion is cephradine with one or more per milliliter (estimated). suitable and harmless diluents, buffer (ii) Hydroxylamine colorimetric assay. substances, colorings, and flavorings. Proceed as directed in § 442.40(b)(1)(ii) When reconstituted as directed in the of this chapter, preparing the sample labeling, each milliliter contains 25 as follows: Reconstitute the sample as milligrams or 50 milligrams of directed in the labeling. Transfer an cephradine. Its potency is satisfactory accurately measured representative if it is not less than 90 percent and not more than 125 percent of the number of portion to a volumetric flask and bring milligrams of cephradine that it is rep- to volume with distilled water. Further resented to contain. Its moisture con- dilute an aliquot of this solution with tent is not more than 1.5 percent. When distilled water to 1 milligram of reconstituted as directed in the label- cephradine per milliliter (estimated). ing, its pH is not less than 3.5 and not (2) Moisture. Proceed as directed in more than 6.0. The cephradine used § 436.201 of this chapter. conforms to the standards prescribed by § 442.40(a)(1).
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(3) pH. Proceed as directed in § 436.202 further dilute with solution 1 to the of this chapter, using the drug recon- reference concentration of 10.0 stituted as directed in the labeling. micrograms of cephradine per milli- [40 FR 26272, June 23, 1975, as amended at 45 liter (estimated). FR 16476, Mar. 14, 1980; 50 FR 19919, May 13, (ii) Hydroxylamine colorimetric assay. 1985] Proceed as directed in § 442.40(b)(1)(ii) of this chapter, preparing the sample § 442.140b Cephradine capsules. as follows: Blend a representative num- (a) Requirements for certification—(1) ber of capsules in a high-speed glass Standards of identity, strength, quality, blender jar with sufficient distilled and purity. Cephradine capsules are water to give a stock solution of con- composed of cephradine and one or venient concentration. Further dilute more suitable and harmless lubricants an aliquot of this solution with dis- and diluents enclosed in a gelatin cap- tilled water to 1 milligrams of sule. Each capsule contains 250 milli- cephradine per milliliter (estimated). grams or 500 milligrams of cephradine. (2) Loss on drying. Proceed as directed Its potency is satisfactory if it is not in § 436.200(b) of this chapter. less than 90 percent and not more than 120 percent of the number of milli- [40 FR 26272, June 23, 1975, as amended at 50 grams of cephradine that it is rep- FR 19919, May 13, 1985] resented to contain. Its loss on drying § 442.140c Cephradine tablets. is not more than 7.0 percent. The cephradine used conforms to the stand- (a) Requirements for certification—(1) ards prescribed by § 442.40(a)(1). Standards of identity, strength, quality, (2) Labeling. It shall be labeled in ac- and purity. Cephradine tablets are com- cordance with the requirements of posed of cephradine and one or more § 432.5 of this chapter. suitable and harmless diluents, bind- (3) Requests for certification; samples. ers, lubricants, and colorings. Each In addition to complying with the re- tablet contains 1,000 milligrams of quirements of § 431.1 of this chapter, cephradine. Its potency is satisfactory each such request shall contain: if it is not less than 90 percent and not (i) Results of tests and assays on: more than 120 percent of the number of (a) The cephradine used in making milligrams of cephradine that it is rep- the batch for potency, moisture, pH, resented to contain. Its moisture con- cephalexin content, identity, and crys- tent is not more than 6.0 percent. It tallinity. disintegrates within 30 minutes. The (b) The batch for potency and loss on cephradine used conforms to the stand- drying. ards prescribed by § 442.40(a)(1). (ii) Samples required: (2) Labeling. It shall be labeled in ac- (a) The cephradine used in making cordance with the requirements of the batch: 10 packages, each containing § 432.5 of this chapter. approximately 500 milligrams. (3) Requests for certification; samples. (b) the batch: A minimum of 30 cap- In addition to complying with the re- sules. quirements of § 431.1 of this chapter, (b) Tests and methods of assay—(1) Po- each such request shall contain: tency. Use either of the following meth- (i) Results of tests and assays on: ods; however, the results obtained from the microbiological agar diffusion (a) The cephradine used in making assay shall be conclusive. the batch for potency, moisture, pH, (i) Microbiological agar diffusion assay. cephalexin content, identity, and crys- Proceed as directed in § 436.105 of this tallinity. chapter, preparing the sample for assay (b) The batch for potency, moisture, as follows: Place a representative num- and disintegration time. ber of capsules into a high-speed glass (ii) Samples required: blender jar containing sufficient 1 per- (a) The cephradine used in making cent potassium phosphate buffer, pH 6.0 the batch: 10 packages, each containing (solution 1), to give a stock solution of approximately 500 milligrams. convenient concentration. Blend for 3 (b) The batch: A minimum of 36 tab- to 5 minutes. Remove an aliquot and lets.
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(b) Tests and methods of assay—(1) Po- § 442.141 Cephradine dihydrate cap- tency. Use either of the following meth- sules. ods; however, the results obtained from (a) Requirements for certification—(1) the hydroxylamine colorimetric assay Standards of identity, strength, quality, shall be conclusive. and purity. Cephradine dihydrate cap- (i) Microbiological agar diffusion assay. sules are composed of cephradine Proceed as directed in § 436.105 of this dihydrate and one or more suitable and chapter, preparing the sample for assay harmless lubricants and diluents en- as follows: Place a representative num- closed in a gelatin capsule. Each cap- ber of tablets into a high-speed glass sule contains 250 milligrams or 500 mil- blender jar containing sufficient 1 per- ligrams of cephradine. Its potency is cent potassium phosphate buffer, pH 6.0 satisfactory if it is not less than 90 per- (solution 1), to give a stock solution of cent and not more than 120 percent of convenient concentration. Blend for 3 the number of milligrams of to 5 minutes. Remove an aliquot and cephradine that it is represented to contain. Its moisture content is not further dilute with solution 1 to the more than 11.0 percent. It passes the reference concentration of 10.0 dissolution test if the quantity Q is 85 micrograms of cephradine per milli- percent at 60 minutes. The cephradine liter (estimated). dihydrate used conforms to the stand- (ii) Hydroxylamine colorimetric assay. ards prescribed by § 442.41(a)(1). Proceed as directed in § 442.40(b)(1)(ii), (2) Labeling. It shall be labeled in ac- except prepare the sample and cal- cordance with the requirements of culate the cephradine content as fol- § 432.5 of this chapter. lows: (3) Requests for certification; samples. (a) Preparation of sample. Blend a rep- In addition to complying with the re- resentative number of tablets in a quirements of § 431.1 of this chapter, high-speed glass blender jar with suffi- each such request shall contain: cient distilled water to give a stock so- (i) Results of tests and assays on: lution of convenient concentration. (a) The cephradine dihydrate used in Further dilute an aliquot of this solu- making the batch for potency, mois- tion with distilled water to 1 milligram ture, pH, cephalexin content, identity, of cephradine per milliliter (esti- and crystallinity. mated). (b) The batch for potency, moisture, and dissolution. ( ) Calculate the b Calculations. (ii) Samples required: cephradine content as follows: (a) The cephradine dihydrate used in A× P × d making the batch: 10 packages, each Milligrams per tablet = u a containing approximately 500 milli- × × As 1, 000 n grams. where: (b) The batch: A minimum of 100 cap- sules. A =Absorbance of sample solution; u (b) Tests and methods of assay—(1) Po- P =Potency of working standard in s tency. Use either of the following meth- micrograms per milligram; d=Dilution factor for sample; ods; however, the results obtained from the hydroxylamine colorimetric assay As=Absorbance of working standard solu- tion; shall be conclusive. n=Number of tablets in the sample as- (i) Microbiological agar diffusion assay. sayed. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay (2) Moisture. Proceed as directed in as follows: Place a representative num- § 436.201 of this chapter. ber of capsules into a high-speed glass (3) Disintegration time. Proceed as di- blender jar containing sufficient 1 per- rected in § 436.212 of this chapter, using cent potassium phosphate buffer, pH 6.0 the procedure described in paragraph (solution 1), to obtain a stock solution (e)(1) of that section. of convenient concentration. Blend for 3 to 5 minutes. Further dilute and ali- [45 FR 22919, Apr. 4, 1980, as amended at 50 quot of the stock solution with solu- FR 19919, May 13, 1985] tion 1 to the reference concentration of
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10.0 micrograms of cephradine per mil- colorings, and coating substances. liliter (estimated). Each tablet contains cefpodoxime (ii) Hydroxylamine colorimetric assay. proxetil equivalent to either 100 milli- Proceed as directed in § 442.40(b)(1)(ii), grams or 200 milligrams of except prepare the sample solution and cefpodoxime. Its cefpodoxime proxetil calculate the cephradine content as content is satisfactory if it is not less follows: than 90 percent and not more than 110 (a) Preparation of sample solution. percent of the number of milligrams of Blend a representative number of cap- cefpodoxime that it is represented to sules in a high-speed glass blender jar contain. Its loss on drying is not more with sufficient distilled water to obtain than 5 percent. It passes the dissolu- a stock solution of convenient con- tion test. It passes the identity test. centration. Further dilute an aliquot of The cefpodoxime proxetil used con- this solution with distilled water to a forms to the standards prescribed by concentration of 1 milligram of § 442.54(a)(1). cephradine per milliliter (estimated). (2) Labeling. It shall be labeled in ac- (b) Calculations. Calculate the cordance with the requirements of cephradine content as follows: § 432.5 of this chapter. (3) Requests for certification; samples. A× P × d Milligrams per capsule = u a In addition to complying with the re- A×1, 000 × n quirements of § 431.1 of this chapter, s each such request shall contain: where: A =Absorbance of sample solution; (i) Results of tests and assays on: u (A) The cefpodoxime proxetil used in Ps=Potency of working standard in micrograms per milligram; making the batch for potency, isomer d=Dilution factor for sample; ratio, moisture, and identity. As=Absorbance of working standard solu- (B) The batch for content, loss on tion; drying, dissolution, and identity. n=Number of capsules in the sample as- (ii) Samples, if required by the Direc- sayed. tor, Center for Drug Evaluation and (2) Moisture. Proceed as directed in Research: § 436.201 of this chapter. (A) The cefpodoxime proxetil used in (3) Dissolution. Proceed as directed in making the batch: 10 packages, each § 436.541 of this chapter, except: containing approximately 500 milli- (i) A distance of 2.5±0.2 centimeters grams. should be maintained between the (B) The batch: A minimum of 100 tab- lower edge of the stirring blade and the lets. lowest inner surface of the vessel dur- (b) Tests and methods of assay—(1) ing test rather than 4.5±0.5 centimeters Cefpodoxime content. Proceed as di- as specified in paragraph (a) of that rected in § 442.54(b)(1), preparing the section; and sample solution and calculating the (ii) In lieu of paragraph (d) of that cefpodoxime content as follows: section, use the interpretation de- (i) Preparation of sample solution. Ob- scribed in the United States Pharma- tain the average tablet weight of at copeia XX dissolution test. least 20 tablets. Grind the tablets using a mortar and pestle. Weigh approxi- [47 FR 11857, Mar. 19, 1982, as amended at 50 FR 19919, May 13, 1985] mately 660 milligrams into a suitable container. Add 30 milliliters of internal § 442.154 Cefpodoxime proxetil oral standard solution. Shake for 30 min- dosage forms. utes using a horizontal platform shak- er or equivalent. Centrifuge for about § 442.154a Cefpodoxime proxetil tab- 10 minutes at 3,000 revolutions per lets. minute until the particulate matter (a) Requirements for certification—(1) has settled. Withdraw a 1 milliliter ali- Standards of identity, strength, quality, quot of the supernatant and dilute with and purity. Cefpodoxime proxetil tab- 9 milliliters of dilution solvent. The lets are composed of cefpodoxime sample solutions are stable for at least proxetil and one or more suitable and 48 hours. Refrigeration is not rec- harmless diluents, binders, lubricants, ommended.
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(ii) Calculations. Calculate the cefpodoxime content as follows:
Milligrams of cefpodoxime = ()RRWWFFFFP///× () × () × × × per tablet sam std std sam 1 3 2 4
where: harmless preservatives, sweeteners, Rsam = Ratio of cefpodoxime proxetil peaks suspending agents, buffers, and area (sum of both epimers) to the inter- flavorings. When constituted as di- nal standard peak area in the sample rected in the labeling, each milliliter preparation; contains the equivalent of either 10 or Rstd = Ratio of cefpodoxime proxetil peaks area (sum of both epimers) to the inter- 20 milligrams cefpodoxime activity. Its nal standard peak area in the standard cefpodoxime proxetil content is satis- preparation; factory if it is not less than 90 percent Wstd = Weight of cefpodoxime proxetil ref- and not more than 110 percent of the erence standard, in milligrams; number of milligrams of cefpodoxime Wsam = Weight of sample, in milligrams; that it is represented to contain. Its F1 = Volume of internal standard used in the sample preparation, in milliliters; loss on drying is not more than 0.5 per- cent. When constituted as described in F2 = 0.766; The ratio of molecular weight for free-acid cefpodoxime over the molecular the labeling, the pH of the suspension weight of cefpodoxime proxetil (427.46/ is not less than 4 and not more than 557.61); 5.5. It passes the identity test. The F3 = Volume of internal standard used in the cefpodoxime proxetil used conforms to standard preparation, in milliliters; the standards prescribed by F4 = Average tablet weight, i.e., weight of § 442.54(a)(1). tablets used in sample preparation di- vided by the number of tablets; and (2) Labeling. It shall be labeled in ac- P = Purity of the cefpodoxime proxetil ref- cordance with the requirements of erence standard, expressed as a decimal. § 432.5 of this chapter. (3) Requests for certification samples. In (2) Loss on drying. Proceed as directed addition to complying with the re- in § 436.200(a) of this chapter, except quirements of § 431.1 of this chapter, dry the sample at a temperature of 80° each such request shall contain: C and a pressure of 5 millimeters of (i) Results of tests and assays on: mercury or less for 16 hours. (A) The cefpodoxime proxetil used in (3) Dissolution test. Proceed as di- making the batch for potency, isomer rected in § 436.215 of this chapter. The ratio, moisture, and identity. quantity Q (the amount of cefpodoxime (B) The batch for content, loss on activity dissolved) is 70 percent within drying, pH, and identity. 30 minutes. (ii) Samples, if required by the Direc- (4) Identity. Using the high-perform- tor, Center for Drug Evaluation and ance liquid chromatographic procedure Research: described in paragraph (b)(1) of this (A) The cefpodoxime proxetil used in section, the retention times for the making the batch: 10 packages, each peaks of the active ingredients must be containing approximately 500 milli- within 2 percent of the retention times grams. for the peaks of the corresponding ref- (B) The batch: A minimum of 10 in- erence standards. termediate containers. [60 FR 58232, Nov. 27, 1995] (b) Tests and methods of assay—(1) Cefpodoxime content. Proceed as di- § 442.154b Cefpodoxime proxetil gran- rected in § 442.54(b)(1), preparing the ules for oral suspension. sample solution and calculating the (a) Requirements for certification—(1) cefpodoxime content as follows: Standards of identity, strength, quality, (i) Preparation of sample solution. Re- and purity. Cefpodoxime proxetil gran- constitute as directed in the labeling. ules for oral suspension is cefpodoxime Immediately before sampling the sus- proxetil and one or more suitable and pension, shake vigorously for several
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seconds. Into a suitable container, ac- tions per minute until the particulate curately weigh out 6 grams of the 50 matter has settled. Withdraw a 1 milli- milligrams per 5 milliliters suspension, liter aliquot of the supernatant and di- or 3 grams of the 100 milligrams per 5 lute with 1 milliliter of dilution sol- milliliters suspension. Add 5 milliliters vent. The sample solutions are stable of internal standard solution and 25 for at least 48 hours. Refrigeration is milliliters of dilution solvent. Shake not recommended. for 30 minutes using a horizontal plat- (ii) Calculations. Calculate the form shaker or equivalent. Centrifuge cefpodoxime content as follows: for about 10 minutes at 3,000 revolu-
Milligrams of cefpodoxime = ()RRWWFFFFFP////× () × () × () × × per5 millilitersof suspension sam std std sam 1 3 2 4 5
where: for the peaks of the corresponding ref- Rsam = Ratio of cefpodoxime proxetil peaks erence standards. area (sum of both epimers) to the inter- nal standard peak area in the sample [60 FR 58233, Nov. 27, 1995] preparation; § 442.180 Cefprozil oral dosage forms. Rstd = Ratio of cefpodoxime proxetil peaks area (sum of both epimers) to the inter- nal standard peak area in the standard § 442.180a Cefprozil tablets. preparation; (a) Requirements for certification—(1) Wstd = Weight of cefpodoxime proxetil ref- Standards of identity, strength, quality, erence standard, in milligrams; and purity. Cefprozil tablets are com- Wsam = Weight of sample, in grams; posed of cefprozil and one or more suit- F1 = Volume of internal standard used in the able and harmless diluents, binders, lu- sample; preparation, in milliliters; bricants, colorings, and coating sub- F2 = 0.766; The ratio of molecular weight for stances. Each tablet contains cefprozil free-acid cefpodoxime over the molecular equivalent to either 250 milligrams or weight of cefpodoxime proxetil (427.46/ 557.61); 500 milligrams of anhydrous cefprozil. The cefprozil content of the tablets is F3 = Volume of internal standard used in the standard preparation, in milliliters; satisfactory if it is not less than 90 per- cent nor more than 120 percent of the F4 = 0.2; Factor to convert to 5 milliliters; number of milligrams of anhydrous F5 = Specific gravity of suspension for milli- gram per 5 milliliter calculated on the cefprozil that it is represented to con- air-free basis (specific gravity is deter- tain. The moisture content of the tab- mined on a sample of suspension that has lets is not more than 7 percent. The been shaken gently on a platform shaker tablets pass the dissolution test. The under vacuum for 2 hours); and tablets pass the identity tests. The P = Purity of the cefpodoxime proxetil ref- cefprozil used conforms to the stand- erence standard, expressed as a decimal. ards prescribed by § 442.80(a)(1) of this (2) Loss on drying. Proceed as directed part. in § 436.200(a) of this chapter, except (2) Labeling. It shall be labeled in ac- dry the sample at a temperature of 80° cordance with the requirements of C and a pressure of 5 millimeters of § 432.5 of this chapter. mercury or less for 16 hours. (3) Requests for certification; samples. In addition to complying with the re- (3) pH. Proceed as directed in § 436.202 quirements of § 431.1 of this chapter, of this chapter, using the drug con- each such request shall contain: stituted as directed in the labeling. (i) Results of tests and assays on: (4) Identity. Using the high-perform- (A) The cefprozil used in making the ance liquid chromatographic procedure batch for potency, E-isomer ratio, described in paragraph (b)(1) of this moisture, pH, crystallinity, and iden- section, the retention times for the tity. peaks of the active ingredients must be (B) The batch for content, moisture, within 2 percent of the retention times dissolution, and identity.
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(ii) Samples, if required by the Direc- quantity Q (the amount of cefprozil ac- tor, Center for Drug Evaluation and tivity dissolved) is 75 percent at 45 Research: minutes. (A) The cefprozil used in making the (4) Identity—(i) High performance liq- batch: 10 packages, each containing ap- uid chromatography. Using the high per- proximately 500 milligrams. formance liquid chromatographic pro- (B) The batch: A minimum of 100 tab- cedure described in paragraph (b)(1) of lets. this section, the retention times for (b) Tests and methods of assay—(1) the responses of the active ingredients Cefprozil content. Proceed as directed in must be within 2 percent of the reten- § 442.80(b)(1) of this part, preparing the tion times for the responses of the cor- sample solution and calculating the responding reference standards. cefprozil content as follows: (ii) Thin layer chromatography. Pro- (i) Preparation of sample solution. ceed as directed in § 436.368 of this chap- Place one or a known number of intact ter. tablets into a 250-milliliter volumetric [58 FR 26661, May 4, 1993] flask containing about 180 milliliters of distilled water. Allow the tablet(s) to § 442.180b Cefprozil for oral suspen- disintegrate as aided by swirling and sion. brief ultrasonication. Dilute the con- (a) Requirements for certification—(1) tents to volume with distilled water Standards of identity, strength, quality, and mix thoroughly. Transfer an ali- and purity. Cefprozil for oral suspension quot of this solution to a volumetric is cefprozil with one or more suitable flask of suitable size to obtain a solu- and harmless preservatives, sweeten- tion containing 0.3 milligram per milli- ers, suspending agents, buffers, and liter of cefprozil (estimated) when di- flavorings. The cefprozil content of the luted to volume with water. Filter oral suspension is satisfactory if it is through a 0.45 micron filter prior to in- not less than 90 percent nor more than jection into the chromatographic sys- 120 percent of the number of milli- tem. grams of anhydrous cefprozil that it is (ii) Calculations. Calculate the represented to contain. When con- cefprozil content as follows: stituted as directed in the labeling, × × each milliliter contains the equivalent Milligrams of cefprozil (Z) = Au P s d of either 25 or 50 milligrams anhydrous or cefprozil (E) per tablet × × cefprozil activity. Its moisture content As 1, 000 n is not more than 3 percent. When con- Milligrams of cefprozil stituted as described in the labeling, (Z) per tablet Milligrams of the pH of the suspension is not less = + cefprozil per tablet than 4.0 nor more than 6.0. It passes the Milligrams of cefprozil identity tests. The cefprozil used con- (E) per tablet forms to the standards prescribed by where: § 442.80(a)(1) of this part. AU=Area of the cefprozil (Z) or cefprozil (E) (2) Labeling. It shall be labeled in ac- response in the chromatogram of the cordance with the requirements of sample (at a retention time equal to that § 432.5 of this chapter. observed for the standard); (3) Requests for certification samples. In AS=Area of the cefprozil (Z) or cefprozil (E) response in the chromatogram of the addition to complying with the re- cefprozil (Z) or the cefprozil (E) working quirements of § 431.1 of this chapter, standard; each such request shall contain: PS=Cefprozil (Z) or cefprozil (E) activity in (i) Results of tests and assays on: the cefprozil (Z) or the cefprozil (E) (A) The cefprozil used in making the working standard solution in batch for potency, E-isomer ratio, micrograms per milliliter; moisture, pH, crystallinity, and iden- d = Dilution factor of the sample; and tity. n = Number of tablets taken in the sample. (B) The batch for content, moisture, (2) Moisture. Proceed as directed in pH, and identity. § 436.201 of this chapter. (ii) Samples, if required by the Direc- (3) Dissolution test. Proceed as di- tor, Center for Drug Evaluation and rected in § 436.215 of this chapter. The Research:
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(A) The cefprozil used in making the formance liquid chromatographic pro- batch: 10 packages, each containing ap- cedure described in paragraph (b)(1) of proximately 500 milligrams. this section, the retention times for (B) The batch: A minimum of 10 in- the responses of the active ingredients termediate containers. must be within 2 percent of the reten- (b) Tests and methods of assay—(1) tion times for the responses of the cor- Cefprozil content. Proceed as directed in responding reference standards. § 442.80(b)(1), preparing the sample solu- (ii) Thin layer chromatography. Pro- tion and calculating the cefprozil con- ceed as directed in § 436.368 of this chap- tent as follows: ter. (i) Preparation of sample solution. Con- stitute as directed in the labeling. [58 FR 26661, May 4, 1993] Transfer a portion of the suspension containing 250 milligrams (estimated) Subpart C—Injectable Dosage of cefprozil into a 250-milliliter volu- Forms metric flask using a glass syringe and a 13-gauge needle. Dilute to volume § 442.208 Cefamandole nafate for injec- with water, ultrasonicate briefly to tion. dissolve and mix well. Transfer a 15- (a) Requirements for certification—(1) milliliter aliquot of this solution to a Standards of identity, strength, quality, 50-milliliter volumetric flask and di- and purity. Cefamandole nafate for in- lute to volume with water to obtain a jection is a dry mixture of cefamandole solution containing 0.3 milligram per nafate and one or more suitable and milliliter of cefprozil (estimated). Fil- harmless buffering agents. The ter through a 0.45 micron filter prior to cefamandole nafate may be isolated in injection into the chromatographic the manufacture of cefamandole nafate system. for injection. Its cefamandole content (ii) Calculations. Calculate the is satisfactory if it is not less than 90 cefprozil content as follows: percent and not more than 115 percent of the number of milligrams of Milligrams of cefprozil (Z) A× P × d × 5 cefamandole that it is represented to or cefprozil (E) per 5 = u s × × contain. It is sterile. It is milliliters of sample AVs 1, 000 nonpyrogenic. Its moisture content is Milligrams of cefprozil not more than 3.0 percent. Its pH is not Milligrams of cefprozil (Z)/5 mL sample less than 6.0 and not more than 8.0. If = + per 5 mL of sample Milligrams of cefprozil isolated, the cefamandole nafate used (E)/5 mL sample conforms to the standards prescribed where: by § 442.8a(a)(1). If the cefamandole nafate is not isolated, the potency of AU=Area of the cefprozil (Z) or cefprozil (E) response in the chromatogram of the the dry mixture is not less than 810 sample (at a retention time equal to that micrograms and not more than 1,000 observed for the standard); micrograms of cefamandole per milli- AS=Area of the cefprozil (Z) or cefprozil (E) gram on an anhydrous basis when cor- response in the chromatogram of the rected for sodium carbonate; and the cefprozil (Z) or the cefprozil (E) working dry mixture gives a positive identity standard; test. PS=Cefprozil (Z) or cefprozil (E) activity in the cefprozil (Z) or the cefprozil (E) (2) Labeling. It shall be labeled in ac- working standard solution in cordance with the requirements of micrograms per milliliter; § 432.5 of this chapter. d = Dilution factor of the sample; and (3) Requests for certification; samples. V = Volume of sample taken in milliliters. In addition to complying with the re- (2) Moisture. Proceed as directed in quirements of § 431.1 of this chapter, § 436.201 of this chapter. each such request shall contain: (3) pH. Proceed as directed in § 436.202 (i) Results of tests and assays on: of this chapter, using the drug con- (a) If isolated, the cefamandole stituted as directed in the labeling. nafate used in making the batch for (4) Identity—(i) High Performance liq- cefamandole content, moisture, pH, uid chromatography. Using the high-per- and identity.
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(b) The batch for cefamandole con- content in a given volume of the re- tent, sterility, pyrogens, moisture, and sultant preparation, remove an accu- pH. In addition, if the cefamandole rately measured representative portion nafate is not isolated, results of tests from each container. Further dilute an and assays on the dry mixture for po- aliquot of this solution with distilled tency and identity. water to obtain a concentration of 2.0 (ii) Samples required: milligrams of cefamandole per milli- (a) For all tests except sterility: A liter (estimated). Transfer 5 milliliters minimum of 10 immediate containers, of this solution to a 50-milliliter volu- unless the cefamandole nafate is not metric flask, add 30 milliliters of pH 2.3 isolated, a minimum of 15 immediate buffer, dilute to volume with distilled containers. water, and mix. In addition, if the (b) For sterility testing: 20 imme- cefamandole nafate is not isolated, pre- diate containers, collected at regular pare the sample solution as described intervals throughout each filling oper- in § 436.324(d) of this chapter. Deter- ation. mine the sodium carbonate content as (b) Tests and methods of assay—(1) follows: Dissolve an accurately weighed Cefamandole content. Proceed as di- portion of the dry mixture, approxi- rected in § 436.324 of this chapter, pre- mately 1.0 gram, with approximately paring the sample solution and cal- 100 milliliters of distilled water. Ti- culating the cefamandole content as trate with 0.2N hydrochloric acid. De- follows: termine the end-point (i) Sample preparation. Reconstitute potentiometrically to the first equiva- the sample as directed in the labeling. lent using a glass calomel combination If it is represented as a single dose con- electrode. Each milliliter of 0.2N hy- tainer, remove all of the withdrawable drochloric acid is equivalent to 21.2 contents with a suitable hypodermic milligrams of sodium carbonate. needle and syringe. If the labeling (ii) Calculations—(a) Calculate the specifies the amount of cefamandole cefamandole content as follows:
Potency of working A×Milligrams of ×standard in micrograms × f working standard. per milligram Milligrams of cefamandole = B×50 × 1, 000
where: od described in paragraph (e)(1) of that A=The peak height of the sample; section. B=The peak height of the working (3) Pyrogens. Proceed as directed in standard; and § 436.32(b) of this chapter, using a solu- f=The dilution factor of the sample. tion containing 50 milligrams of (b) If the cefamandole nafate is not cefamandole per milliliter. isolated in the manufacture of (4) [Reserved] cefamandole nafate for injection, cal- (5) Moisture. Proceed as directed in culate the micrograms of cefamandole § 436.201 of this chapter. per milligram of sample as described in (6) pH. Proceed as directed in § 436.202 § 436.324(f) of this chapter. The of this chapter, using an aqueous solu- micrograms per milligram of tion containing 100 milligrams per mil- cefamandole is corrected for sodium liliter, except determine the pH 30 min- carbonate content and moisture con- utes after preparation of the sample so- tent. lution. (2) Sterility. Proceed as directed in § 436.20 of this chapter, using the meth-
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(7) Identity. Proceed as directed in (ii) Samples required: § 436.323 of this chapter. (a) The cefamandole sodium used in [44 FR 20665, Apr. 6, 1979, as amended at 47 making the batch: 10 packages, each FR 42099, Sept. 24, 1982; 50 FR 19919, May 13, containing approximately 500 milli- 1985] grams. (b) The batch: § 442.209 Cefamandole sodium for in- (1) For all tests except sterility: A jection. minimum of 10 immediate containers. (a) Requirements for certification—(1) (2) For sterility testing: 20 immediate Standards of identity, strength, quality, containers, collected at regular inter- and purity. Cefamandole sodium for in- vals throughout each filling operation. jection is a dry mixture of cefamandole (b) Tests and methods of assay—(1) sodium and one or more suitable and Cefamandole content. Proceed as di- harmless buffering agents. Its rected in § 436.324 of this chapter, pre- cefamandole content is satisfactory if paring the sample solution and cal- it is not less than 90 percent and not culating the cefamandole content as more than 115 percent of the number of follows: milligrams of cefamandole that it is represented to contain. It is sterile. It (i) Sample solution. Reconstitute the is nonpyrogenic. Its moisture content sample as directed in the labeling. If it is not more than 3.0 percent. Its pH is is represented as a single-dose con- not less than 6.0 and not more than 8.5. tainer, remove all the withdrawable The cefamandole sodium used conforms contents with a suitable hypodermic to the standards prescribed by needle and syringe. If the labeling § 442.9a(a)(1). specifies the amount of potency in a (2) Labeling. It shall be labeled in ac- given volume of the resultant prepara- cordance with the requirements of tion, remove an accurately measured § 432.5 of this chapter. representative portion from each con- (3) Requests for certification; samples. tainer. Further dilute an aliquot of In addition to complying with the re- this solution with distilled water to ob- quirements of § 431.1 of this chapter, tain a concentration of 2.0 milligrams each such request shall contain: of cefamandole per milliliter (esti- (i) Results of tests and assays on: mated). Transfer 5 milliliters of this (a) The cefamandole sodium used in solution to a 50-milliliter volumetric making the batch for cefamandole con- flask, add 30 milliliters of pH 2.3 buffer, tent, moisture, pH, and identity. dilute to volume with distilled water, (b) The batch for cefamandole con- and mix. tent, sterility, pyrogens, moisture, and (ii) Calculations. Calculate the pH. cefamandole content as follows:
Potency of working A×Milligrams of ×standard in micrograms × f working standard. per milligram Milligrams of cefamandole = B×50 × 1, 000
where: od described in paragraph (e)(1) of that A=The peak height of the sample; section. B=The peak height of the working stand- (3) Pyrogens. Proceed as directed in ard; § 436.32(b) of this chapter, using a solu- f=The dilution factor of the sample. tion containing 50 milligrams of (2) Sterility. Proceed as directed in cefamandole per milliliter. § 436.20 of this chapter, using the meth- (4) [Reserved]
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(5) Moisture. Proceed as directed in (2) Labeling. It shall be labeled in ac- § 436.201 of this chapter. cordance with the requirements of (6) pH. Proceed as directed in § 436.202 § 432.5 of this chapter. of this chapter, using an aqueous solu- (3) Requests for certification; samples. tion containing 100 milligrams per mil- In addition to complying with the re- liliter. quirements of § 431.1 of this chapter, each such request shall contain: [47 FR 20756, May 14, 1982, as amended at 50 FR 19919, May 13, 1985] (i) Requests of tests and assays on: (a) The cefazolin used in making the § 442.211 Cefazolin sodium injectable batch for cefazolin content, moisture, dosage forms. heavy metals, and identity. (b) The batch for cefazolin content, § 442.211a Sterile cefazolin sodium. sterility, pyrogens, pH, and identity. The requirements for certification (ii) Samples, if required by the Direc- and the tests and methods of assay for tor, Center for Drug Evaluation and sterile cefazolin sodium packaged for Research: dispensing are described in § 442.11a, ex- (a) The cefazolin used in making the cept for the following additional re- batch: 10 packages, each containing ap- quirements if it is packaged with lido- proximately 500 milligrams. caine hydrochloride injection 0.5 per- (b) The batch: cent U.S.P.: (1) For all tests except sterility: A (a) The pH, when reconstituted and minimum of 10 immediate containers. diluted to 100 milligrams per milliliter (2) For sterility testing: 20 immediate with lidocaine hydrochloride injection containers, collected at regular inter- 0.5 percent U.S.P., is not less than 5.5 vals throughout each filling operation. and not more than 7.0. (b) Tests and methods of assay—(1) (b) In addition to the information re- Cefazolin content. Proceed as directed in quired by § 442.11a (a)(3)(i), the follow- § 436.342 of this chapter, preparing the ing shall be submitted: sample solution and calculating the (1) The pH on the batch reconstituted cefazolin content as follows: with lidocaine hydrochloride injection (i) Preparation of sample solution. 0.5 percent U.S.P.; and Using a suitable hypodermic needle and (2) Results of tests and assays on the syringe, transfer an accurately meas- lidocaine hydrochloride injection 0.5 ured representative portion from each percent to show conformance with container, equivalent to 40 milligrams U.S.P. requirements. of cefazolin, to a 100-milliliter volu- [42 FR 18059, Apr. 5, 1977. Redesignated at 48 metric flask. Dilute to volume with FR 33479, July 22, 1983] buffer solution, pH 7.0, and mix. Trans- fer 10.0 milliliters of this solution to a § 442.211b Cefazolin sodium injection. 200-milliliter volumetric flask, add 5.0 (a) Requirements for certification—(1) milliliters of internal standard solu- Standards of identity, strength, quality, tion, dilute to volume with buffer solu- and purity. Cefazolin sodium injection tion, pH 7.0, and mix is a frozen aqueous solution of (ii) Calculation. Calculate the milli- cefazolin sodium in an isoosmotic dilu- grams of cefazolin per milliliter of ent. Each milliliter contains cefazolin sample as follows: sodium equivalent to either 10 milli- Milligrams of cefazolin R× P × d grams or 20 milligrams of cefazolin per = u s milliliter. Its cefazolin content is satis- per milliliter R ×1, 000 factory if it is not less than 90 percent s and not more than 115 percent of the number of milligrams of cefazolin that Ru=Area of the cefazolin peak in the chro- it is represented to contain. It is ster- matogram of the sample (at a retention time equal to that observed for the ile. It is nonpyrogenic. Its pH is not standard) /Area of internal standard less than 4.5 and not more than 7.0. It peak; passes the identity test. The cefazolin Rs=Area of cefazolin peak in the chromato- used conforms to the standards pre- gram of the cefazolin working standard scribed by § 442.10(a)(1). /Area of internal standard peak;
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Ps=Cefazolin activity in the cefazolin work- used conforms to the standards pre- ing standard solution in micrograms per scribed by § 442.12(a)(1). milliliter; and (2) Labeling. It shall be labeled in ac- d=Dilution factor of the sample. cordance with the requirements of (2) Sterility. Proceed as directed in § 432.5 of this chapter. § 436.20 of this chapter, using the meth- (3) Requests for certification; samples. od described in paragraph (e)(1) of that In addition to complying with the re- section. quirements of § 431.1 of this chapter, (3) Pyrogens. Proceed as directed in each such request shall contain: § 436.32(a) of this chapter, except inject (i) Results of tests and assays on: a sufficient volume of the undiluted so- (a) The cefoperazone sodium used in lution to deliver 50 milligrams of making the batch for potency, mois- cefazolin per kilogram. ture, pH, and identity. (4) pH. Proceed as directed in § 436.202 (b) The batch for potency, sterility, of this chapter, using the undiluted so- pyrogens, pH, and identity. lution. (ii) Samples, if required by the Direc- (5) Identity. The high-pressure liquid tor, Center for Drug Evaluation and chromatogram of the sample deter- Research: mined as directed in paragraph (b)(1) of (a) The cefoperazone sodium used in this section compares qualitatively to making the batch: 10 packages, each that of the cefazolin working standard. containing approximately 500 milli- [48 FR 33479, July 22, 1983; 48 FR 40516, Sept. grams. 8, 1983; 49 FR 48184, Dec. 11, 1984, as amended (b) The batch: at 55 FR 11583, Mar. 29, 1990] (1) For all tests except sterility: A minimum of 10 immediate containers. § 442.212 Cefoperazone injectable dos- age forms. (2) For sterility testing: 20 immediate containers collected at regular inter- § 442.212a Sterile cefoperazone so- vals throughout each filling operation. dium. (b) Tests and methods of assay. Thaw The requirements for certification the sample as directed in the labeling. and the tests and methods of assay for The sample solution used for testing sterile cefoperazone sodium packaged must be at room temperature. for dispensing are described in § 442.12a. (1) Potency. Proceed as directed in § 436.338 of this chapter, preparing the [48 FR 790, Jan. 7, 1983. Redesignated at 51 sample solution and calculating the FR 36688, Oct. 15, 1986] cefoperazone content as follows: (i) Sample solution. Using a suitable § 442.212b Cefoperazone sodium injec- tion. hypodermic needle and syringe, remove an accurately measured representative (a) Requirements for certification—(1) portion from each container and dilute Standards of identity, strength, quality, with mobile phase to obtain a solution and purity. Cefoperazone sodium injec- containing 160 micrograms per milli- tion is a frozen aqueous iso-osmotic so- liter (estimated). lution of cefoperazone sodium which (ii) Calculations. Calculate the milli- may contain one or more suitable and grams of cefoperazone per milliliter of harmless buffer substances in a dilu- sample as follows: ent. Each milliliter contains cefoperazone sodium equivalent to ei- Milligrams of A× P × d ther 20 milligrams or 40 milligrams of = u s cefoperazone per milliliter. Its cefoperazone per milliliter A ×1, 000 cefoperazone content is satisfactory if s it is not less than 90 percent and not more than 120 percent of the number of Au=Area of the cefoperazone peak in the chromatogram of the sample (at a reten- milligrams of cefoperazone that it is tion time equal to that observed for the represented to contain. It is sterile. It standard); is nonpyrogenic. Its pH is not less than As=Area of the cefoperazone peak in the 4.5 and not more than 6.5. It passes the chromatogram of the cefoperazone work- identity test. The cefoperazone sodium ing standard;
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Ps=Cefoperazone activity in the cefoperazone (2) Labeling. It shall be labeled in ac- working standard solution in cordance with the requirements of micrograms per milliliter; and § 432.5 of this chapter. d=Dilution factor of the sample. (3) Requests for certification; samples. (2) Sterility. Proceed as directed in In addition to complying with the re- § 436.20 of this chapter, using the meth- quirements of § 431.1 of this chapter, od described in paragraph (e)(1) of that each such request shall contain: section. (i) Results of tests and assays on: (3) Pyrogens. Proceed as directed in (a) The cefotaxime sodium used in § 436.32(a) of this chapter, except inject making the batch for potency, mois- a sufficient volume of the undiluted so- ture, pH, and identity. lution to deliver 10 milligrams of (b) The batch for potency, sterility, cefoperazone per kilogram. pyrogens, pH, and identity. (4) pH. Proceed as directed in § 436.202 (ii) Samples, if required by the Direc- of this chapter, using the undiluted so- tor, Center for Drug Evaluation and lution. (5) Identity. The high-performance Research: liquid chromatogram of the sample de- (a) The cefotaxime sodium used in termined as directed in paragraph making the batch: 10 packages, each (b)(1) of this section compares quali- containing approximately 500 milli- tatively to that of the cefoperazone grams. working standard. (b) The batch: (1) For all tests except sterility: A [51 FR 36688, Oct. 15, 1986, as amended at 54 minimum of 10 immediate containers. FR 47352, Nov. 14, 1989; 55 FR 11583, Mar. 29, 1990] (2) For sterility testing: 20 immediate containers, collected at regular inter- § 442.213 Cefotaxime injectable dosage vals throughout each filling operation. forms. (b) Tests and methods of assay. Thaw the sample as directed in the labeling. § 442.213a Sterile cefotaxime sodium. The sample solution used for testing The requirements for certification must be at room temperature. and the tests and methods of assay for (1) Potency. Use either of the follow- sterile cefotaxime sodium packaged for ing methods; however, the results ob- dispensing are described in §442.13a. tained from the hydroxylamine colori- [46 FR 25607, May 8, 1981. Redesignated at 50 metric assay shall be conclusive. FR 45109, Oct. 30, 1985] (i) Microbiological agar diffusion assay. Proceed as directed in § 436.105 of this § 442.213b Cefotaxime sodium injec- chapter, preparing the sample for assay tion. as follows: Using a suitable hypodermic (a) Requirements for certification—(1) needle and syringe, remove an accu- Standards of identity, strength, quality, rately measured representative portion and purity. Cefotaxime sodium injec- from each container and dilute with tion is a frozen aqueous solution of sufficient 1 percent potassium phos- cefotaxime sodium with one or more phate buffer, pH 6.0 (solution 1), to give suitable and harmless buffer sub- a stock solution of convenient con- stances in an isosmotic diluent. Each centration. Further dilute an aliquot of milliliter contains cefotaxime sodium the stock solution with solution 1 to equivalent to either 20 milligrams or 40 the reference concentration of 2.0 milligrams of cefotaxime per milliliter. micrograms of cefotaxime per milli- Its cefotaxime content is satisfactory liter (estimated). if it is not less than 90 percent and not (ii) Hydroxylamine colorimetric assay. more than 110 percent of the number of Proceed as directed in § 436.205 of this milligrams of cefotaxime that it is rep- chapter, preparing the sample as fol- resented to contain. It is sterile. It is lows: Using a suitable hypodermic nee- nonpyrogenic. Its pH is not less than dle and syringe, remove an accurately 5.0 and not more than 7.5. It passes the measured representative portion from identity test. The cefotaxime sodium each container and dilute with distilled used conforms to the standards pre- water to give a stock solution of con- scribed by § 442.13(a)(1). venient concentration. Further dilute
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with distilled water to the prescribed (2) Labeling. It shall be labeled in ac- concentration. cordance with the requirements of (2) Sterility. Proceed as directed in § 432.5 of this chapter. § 436.20 of this chapter, using the meth- (3) Requests for certification; samples. od described in paragraph (e)(1) of that In addition to complying with the re- section. quirements of § 431.1 of this chapter, (3) Pyrogens. Proceed as directed in each such request shall contain: § 436.32(a) of this chapter, except inject (i) Results of tests and assays on: a sufficient volume of the undiluted so- (a) The cefoxitin sodium used in making the batch for cefoxitin content, lution to deliver 50 milligrams of moisture, pH, identity, and crystallin- cefotaxime per kilogram. ity. (4) pH. Proceed as directed in § 436.202 (b) The batch for cefoxitin content, of this chapter, using the undiluted so- sterility, pyrogens, pH, and identity. lution. (ii) Samples, if required by the Direc- (5) Identity. Proceed as directed in tor, Center for Drug Evaluation and § 436.323 of this chapter, except prepare Research: spotting solutions as follows: Prepare (a) The cefoxitin sodium used in solutions of the sample and working making the batch: 10 packages, each standard, each containing 1 milligram containing approximately 500 milli- of cefotaxime per milliliter in distilled grams. water. (b) The batch: (1) For all tests except sterility: A [50 FR 45109, Oct. 30, 1985; 50 FR 48078, Nov. minimum of 10 immediate containers. 21, 1985, as amended at 55 FR 11583, Mar. 29, 1990] (2) For sterility testing: 20 immediate containers, collected at regular inter- § 442.214 Cefoxitin injectable dosage vals throughout each filling operation. forms. (b) Tests and methods of assay. Thaw the sample as directed in the labeling. § 442.214a Sterile cefoxitin sodium. The sample solution used for testing must be at room temperature. The requirements for certification (1) Cefoxitin content. Proceed as di- and the tests and methods of assay for rected in § 436.347 of this chapter, pre- sterile cefoxitin packaged for dispens- paring the working standard and sam- ing are described in § 442.14a. ple solutions and calculating the [44 FR 10376, Feb. 20, 1979. Redesignated at 49 cefoxitin content as follows: FR 47827, Dec. 7, 1984] (i) Working standard solution. Dissolve an accurately weighed portion of the § 442.214b Cefoxitin sodium injection. cefoxitin working standard with water (a) Requirements for certification—(1) to obtain a solution containing 200 Standards of identity, strength, quality, micrograms of cefoxitin per milliliter. and purity. Cefoxitin sodium injection (ii) Sample solution. Using a suitable is a frozen aqueous solution of hypodermic needle and syringe, remove cefoxitin sodium with one or more suit- an accurately measured representative able and harmless buffer substances in portion from each container and dilute with sufficient water to obtain a solu- an isotonic diluent. Each milliliter tion containing 200 micrograms of contains cefoxitin sodium equivalent cefoxitin per milliliter (estimated). to either 20 or 40 milligrams of (iii) Calculations. Calculate the milli- cefoxitin. Its cefoxitin content is satis- grams of cefoxitin per milliliter of factory if it contains not less than 90 sample as follows: percent and not more than 120 percent of the number of milligrams of A× P × d cefoxitin that it is represented to con- Milligrams of = u s tain. It is sterile. It is nonpyrogenic. cefoxitin per milliliter A ×1, 000 Its pH is not less than 4.5 and not more s where: than 8.0. It passes the identity test. Au=Area of the cefoxitin peak in the chro- The cefoxitin sodium used conforms to matogram of the sample (at a retention the standards prescribed by time equal to that observed for the § 442.14(a)(1). standard);
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As=Area of the cefoxitin peak in the chro- cent, except that for the issuance of a matogram of the cefoxitin working certificate for each batch of the sodium standard; carbonate formulation, the pyridine Ps=Cefoxitin activity in the cefoxitin work- content is not more than 0.12 percent. ing standard solution in micrograms per milliliter; and Its pyridine content, if it contains L- d=Dilution factor of the sample. arginine, is not more than 0.3 percent, except that for the issuance of a cer- (2) Sterility. Proceed as directed in tificate, the pyridine content of the L- § 436.20 of this chapter, using the meth- arginine formulation is not more than od described in paragraph (e)(1) of that 0.10 percent. The ceftazidime section. pentahydrate conforms to the standard (3) Pyrogens. Proceed as directed in prescribed by § 442.16a(a)(1). § 436.32(a) of this chapter, except inject a sufficient volume of the undiluted so- (2) Labeling. In addition to the re- lution to deliver 50 milligrams of quirements of § 432.5 of this chapter, cefoxitin per kilogram. each package of the L-arginine formu- (4) pH. Proceed as directed in § 436.202 lation shall bear on its outside wrapper of this chapter, using the undiluted so- or container and on the immediate con- lution. tainer the statement ‘‘For Patients 12 (5) Identity. The high-pressure liquid years and Older’’. chromatogram of the sample deter- (3) Requests for certification; samples. mined as directed in paragraph (b)(1) of In addition to complying with the re- this section compares qualitatively to quirements of § 431.1 of this chapter, that of the cefoxitin working standard. each such request shall contain: (i) Results of tests and assays on: [49 FR 47827, Dec. 7, 1984, as amended at 55 FR 11583, Mar. 29, 1990] (a) The ceftazidime pentahydrate used in making the batch for potency, § 442.216 Ceftazidime injectable dos- loss on drying, pH, crystallinity, iden- age forms. tity, and high molecular weight poly- mer content. § 442.216a Ceftazidime pentahydrate (b) The batch for ceftazidime po- for injection. tency, ceftazidime content, sterility, (a) Requirements of certification—(1) pyrogens, loss on drying, pH, and pyri- Standards of identity, strength, quality, dine content. and purity. Ceftazidime pentahydrate (ii) Samples, if required by the Direc- for injection is a dry mixture of tor, Center for Drug Evaluation and ceftazidime pentahydrate and sodium Research: carbonate or L-arginine. Its (a) The ceftazidime pentahydrate ceftazidime potency is satisfactory if used in making the batch: 10 packages, each milligram of ceftazidime each containing approximately 500 mil- pentahydrate for injection contains not ligrams. less than 900 micrograms and not more (b) The batch: than 1,050 micrograms of cefazidime ac- tivity when corrected for both loss on (1) For all tests except sterility: A drying and its sodium carbonate or L- minimum of 10 immediate containers. arginine content, as appropriate for the (2) For sterility testing: 20 immediate formulation. Its ceftazidime content is containers, collected at regular inter- satisfactory if it is not less than 90 per- vals throughout each filling operation. cent and not more than 120 percent of (b) Tests and methods of assay—(1) the number of milligrams of Ceftazidime potency and content. Deter- ceftazidime that it is represented to mine both micrograms of ceftazidime contain. It is sterile. It is per milligram of sample and milli- nonpyrogenic. Its loss on drying is not grams of ceftazidime per container. more than 12.5 percent if it contains L- Proceed as directed in § 442.16a(b)(1), arginine and not more than 13.5 per- preparing the sample solutions and cal- cent if it contains sodium carbonate. culating the potency and content as The pH of its aqueous solution is not follows: less than 5.0 and not more than 7.5. Its (i) Preparation of sample solutions. Use pyridine content, if it contains sodium separate containers for preparation of carbonate, is not more than 0.4 per- each sample solution as described in
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paragraphs (b)(1)(i) (a) and (b) of this m = Percent loss on drying (determined as di- section. rected in § 436.200(h) of this chapter if the (a) Ceftazidime potency (micrograms of formulation contains sodium carbonate and determined as directed in § 436.200(g) ceftazidime per milligram). Accurately of this chapter if the formulation con- weigh and dissolve approximately 350 tains L-arginine); milligrams of ceftazidime sample in S = Percent sodium carbonate content of the distilled water and dilute to volume in sample (determined as directed in § 436.357 of a 250-milliliter volumetric flask to ob- this chapter); and A = Percent L-arginine content of the sample tain a stock solution containing ap- (determined as directed in § 455.204 of this proximately 1,000 micrograms of chapter, except use ceftazidime instead of ceftazidime per milliliter. Mix well. aztreonam in the working standard solution Immediately prior to chromatography, and use water instead of mobile phase). Pre- further dilute 5 milliliters of stock so- pare the sample solution by diluting an accu- rately weighed portion of the contents of a lution to 50 milliliters with water to vial with water to 0.2 milligram per milli- obtain a solution containing 100 liter (estimated). The resolution between the micrograms of ceftazidime activity per ceftazidime peak and the arginine peak is milliliter (estimated). not less than 6.0, the asymmetry factor for (b) Ceftazidime content (milligrams of the arginine peak is not more than 4.0). ceftazidime per vial). Reconstitute the (b) Ceftazidime content (milligrams of sample as directed in the labeling. ceftazidime per vial). Calculate the Then, using a suitable hypodermic nee- ceftazidime content of the vial as fol- dle and syringe, remove all of the lows: withdrawable contents if it is rep- A× P × d resented as a single-dose container; or, Milligrams of ceftazidime = u s if the labeling specifies the amount of per vial A ×1, 000 potency in a given volume of the re- s sultant preparation, remove an accu- rately measured representative portion Au=Area of the ceftazidime peak in the chro- matogram of the sample (at a retention from each container. Further dilute an time equal to that observed for the aliquot of this solution with distilled standard); water to obtain a concentration of 1.0 As=Area of the ceftazidime peak in the chro- milligram per milliliter (estimated). matogram of the ceftazidime working Immediately prior to chromatography, standard; Ps=Ceftazidime activity in the ceftazidime dilute 5.0 milliliters of the sample solu- working standard solution in tion to 50 milliliters with water. micrograms per milliliter; and (ii) Calculations—(a) Ceftazidime po- d=Dilution factor of the sample. tency (micrograms per milligram). Cal- (2) Sterility. Proceed as directed in culate the micrograms of ceftazidime § 436.20 of this chapter, using the meth- per milligram as follows: od described in paragraph (e)(1) of that section. Micrograms × × (3) Pyrogens. Proceed as directed in APu s 100 of ceftazidime = § 436.32(b) of this chapter, using a solu- × × − − − per milligram As C u ()100 m SA tion containing 80 milligrams of ceftazidime per milliliter. (4) Loss on drying. Proceed as directed Au = Area of the ceftazidime peak in the in § 436.200(h) of this chapter if the for- chromatogram of the sample (at a reten- mulation contains sodium carbonate tion time equal to that observed for the and as directed in § 436.200(g) of this standard); chapter if the formulation contains L- As = Area of the ceftazidime peak in the chromatogram of the ceftazidime work- arginine. ing standard; (5) pH. Proceed as directed in § 436.202 of this chapter, preparing the sample Ps = Ceftazidime activity in the ceftazidime working standard solution in solution as follows: reconstitute the micrograms per milliliter; sample in the sealed container to give
Cu = Milligrams of sample per milliliter of an aqueous solution containing ap- sample solution; proximately 100 milligrams per milli- liter, relieving the pressure inside the
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container if necessary during the re- stock solution containing approxi- constitution. mately 2,500 micrograms of pyridine (6) Pyridine content. Proceed as di- per milliliter. Mix well. Immediately rected in § 436.358 of this chapter, using prior to chromatography, further di- a temperature of 40 °C, an ultraviolet lute 2.0 milliliters of stock solution to detection system operating at a wave- 200 milliliters with phosphate buffer, length of 254 nanometers, a column pH 7.0, to obtain a solution containing packed with microparticulate (5 mi- 25 micrograms of pyridine per milli- crometers in diameter) reversed phase liter. packing material such as octadecyl hy- (b) Sample solution. Accurately weigh drocarbon bonded silicas, a flow rate of approximately 660 milligrams of the 1.6 milliliters per minute, and a known sample into a 100-milliliter volumetric injection volume from 10 to 20 micro- flask and add 50 milliliters of phos- liters. Reagents, working standard and phate buffer, pH 7.0. Shake until dis- sample solutions, system suitability solved and dilute to volume with phos- requirements, and calculations are as phate buffer, pH 7.0. Mix well. Store follows: the solution at a temperature below 15 (i) —( ) Reagents a Phosphate buffer, pH °C and inject into the chromatograph 7.0. Dissolve 5.68 grams of sodium phos- within 1 hour of preparation. phate, dibasic, anhydrous and 3.63 grams of potassium phosphate, (iii) System suitability requirements— monobasic, in water and dilute to 1,000 (a) Tailing factor. The tailing factor (T) milliliters. is satisfactory if it is not more than 2.5 (b) Mobile phase. Mix 300 milliliters of at 5 percent of peak height. acetonitrile and 100 milliliters of 0.25M (b) Resolution. The resolution (R) be- ammonium phosphate, monobasic, di- tween the peak for pyridine and the lute to 1,000 milliliters with water and peak for t-butyl ceftazidime is satisfac- add sufficient 10M ammonia solution to tory if it is not less than 3. give a pH of 7.0±0.1. Filter the mobile (c) Coefficient of variation. The coeffi- phase through a suitable glass fiber fil- cient of variation (SR in percent) of five ter or equivalent that is capable of re- replicate injections is satisfactory if it moving particulate contamination to 1 is not more than 3 percent. micron in diameter. Degas the mobile If the system suitability requirements phase just prior to its introduction have been met, then proceed as de- into the chromatograph pumping sys- scribed in § 436.358(b) of this chapter. tem. Alternate chromatographic conditions (c) System suitability test solution. Pre- are acceptable provided reproducibility pare a solution in phosphate buffer, pH and resolution are comparable to the 7.0, containing 25 micrograms of pyri- system. However, the sample prepara- dine and 25 micrograms of an authentic tion described in paragraph (b)(6)(ii)(b) sample of (6R, 7R)-7-[(Z)-2-(2- of this section should not be changed. Aminothiazol-4-yl)-2-(2-t- butoxy- carbonylprop-2-yloxyimino) (iv) Calculations. Calculate the pyri- acetamido]-3-(1-pyridiniummethyl) dine content in percent of the sample ceph-3-em-4-carboxylate (t-butyl as follows: ceftazidime) per milliliter. Note, if no HP× ×0. 1 t-butyl ceftazidime is present in the Pyridine content in percent = u s sample solution, the working standard HC× solution may be substituted for the s u system suitability test solution and the system suitability requirement for Hu=Height of the pyridine peak in the chro- resolution for t-butyl ceftazidime is matogram of the sample (at a retention omitted. time equal to that observed for the standard); (ii) Preparation of working standard Hs=Height of the pyridine peak in the chro- and sample solutions—(a) Working stand- matogram of the pyridine working stand- ard solution. Accurately weigh approxi- ard; mately 250 milligrams of pyridine into Ps=Pyridine content of the pyridine working a 100-milliliter volumetric flask and di- standard solution in micrograms per mil- lute to volume with water to obtain a liliter; and
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Cu=Milligrams of sample per milliliter of (b) Tests and methods of assay. Thaw sample solution. the sample as directed in the labeling. [50 FR 48400, Nov. 25, 1985; 50 FR 52917, Dec. The sample solution used for testing 27, 1985; 50 FR 53308, Dec. 31, 1985; 51 FR 2478, must be at room temperature. Jan. 17, 1986. Redesignated at 54 FR 40652, (1) Ceftazidime content. Proceed as di- Oct. 3, 1989, and amended at 55 FR 11583, Mar. 29, 1990; 56 FR 484, Jan. 7, 1991; 59 FR 8398, rected in § 442.216(b)(1), except prepare Feb. 22, 1994] the sample solution and calculate the ceftazidime content as follows: § 442.216b Ceftazidime sodium injec- (i) Preparation of sample solution. Re- tion. move an accurately measured rep- (a) Requirements for certification—(1) resentative portion from each con- Standards of identity, strength, quality, tainer immediately after thawing and and purity. Ceftazidime sodium injec- reaching room temperature and dilute tion is a frozen, aqueous, iso-osmotic with mobile phase to obtain a solution solution of ceftazidime sodium which containing 100 micrograms of may contain one or more suitable and ceftazidime per milliliter (estimated). harmless buffer substances and a tonic- Prepare the sample solution just prior ity adjusting agent. Each milliliter to its introduction into the chro- contains ceftazidime sodium equiva- matograph. lent to 10, 20, or 40 milligrams of (ii) Calculation. Calculate the milli- ceftazidime per milliliter. Its grams of ceftazidime per milliliter of ceftazidime content is satisfactory if it is not less than 90 percent and not sample as follows: more than 120 percent of the number of A× P × d milligrams of ceftazidime that it is Milligrams of ceftazidime = u s represented to contain. It is sterile. It per milliliter A ×1, 000 is nonpyrogenic. Its pH is not less than s 5.0 and not more than 7.5 It passes the where: identity test. The ceftazidime Au=Area of the ceftazidime peak in the chro- pentahydrate conforms to the stand- matogram of the sample (at a retention ards prescribed by § 442.16(a)(1). time equal to that observed for the standard); (2) Labeling. It shall be labeled in ac- As=Area of the ceftazidime peak in the chro- cordance with the requirements of matogram of the ceftazidime working § 432.5 of this chapter. standard; (3) Requests for certification; samples. Ps=Ceftazidime activity in the ceftazidime In addition to complying with the re- working standard solution in quirements of § 431.1 of this chapter, micrograms per milliliter; and each such request shall contain: d=Dilution factor of the sample. (i) Results of tests and assays on: (A) The ceftazidime pentahydrate (2) Sterility. Proceed as directed in used in making the batch for potency, § 436.20 of this chapter, using the meth- loss on drying, pH, crystallinity, iden- od described in paragraph (e)(1) of that tity, and high molecular weight poly- section. mer content. (3) Pyrogens. Proceed as directed in (B) The batch for ceftazidime con- § 436.32(b) of this chapter, except inject tent, sterility, pyrogens, pH, and iden- a sufficient volume of the diluted solu- tity. tion to deliver 80 milligrams of (ii) Samples, if required by the Direc- ceftazidime per kilogram. tor, Center for Drug Evaluation and (4) pH. Proceed as directed in § 436.202 Research; of this chapter, using the undiluted so- (A) The ceftazidime pentahydrate lution. used in making the batch: 10 packages, (5) Identify. The high performance each containing 500 milligrams. liquid chromatogram of the sample de- (B) The batch: termined as directed in paragraph (1) For all tests except sterility: A (b)(1) of this section compares quali- minimum of 10 immediate containers. tatively to that of the ceftazidime (2) For sterility testing: 20 immediate working standard. containers, collected at regular inter- vals throughout each filling operation. [54 FR 40652, Oct. 3, 1989]
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§ 442.217 Ceftizoxime injectable dosage (2) For sterility testing: 20 immediate forms. containers, collected at regular inter- vals throughout each filling operation. § 442.217a Sterile ceftizoxime sodium. (b) Tests and methods of assays. Thaw The requirements for certification the sample as directed in the labeling. and the tests and methods of assay for The sample solution used for testing sterile ceftizoxime sodium packaged must be at room temperature. for dispensing are described in § 442.17a. (1) Ceftizoxime content. Proceed as di- [48 FR 46272, Oct. 12, 1983. Redesignated at 49 rected in § 436.345 of this chapter, ex- FR 49286, Dec. 19, 1984] cept prepare the sample solution and calculate the ceftizoxime content as § 442.217b Ceftizoxime sodium injec- follows: tion. (i) Sample solution. Using a suitable (a) Requirements for certification—(1) hypodermic needle and syringe, trans- Standards of identity, strength, quality, fer an accurately measured representa- and purity. Ceftizoxime sodium injec- tive portion from each container, tion is a frozen aqueous solution of equivalent to 40 milligrams of ceftizoxime sodium with one or more ceftizoxime, to a 100-milliliter volu- suitable and harmless buffer sub- metric flask. Dilute to volume with pH stances in an isoosmotic diluent. Each 7.0 buffer solution and mix. Transfer milliliter contains ceftizoxime sodium 10.0 milliliters of this solution to a 200- equivalent to either 20 milligrams or 40 milliliter volumetric flask, add 5.0 mil- milligrams of ceftizoxime per milli- liliters of internal standard solution, liter. Ceftizoxime content is satisfac- dilute to volume with pH 7.0 buffer so- tory if it is not less than 90 percent and lution, and mix. not more than 115 percent of the rep- (ii) Calculations. Calculate the milli- resented number of milligrams of grams of ceftizoxime per milliliter of ceftizoxime. It is sterile. It is sample as follows: nonpyrogenic. Its pH is not less than 5.5 and not more than 8.0. It passes the × × Milligrams of ceftizoxime Ru P s d identity test. The ceftizoxime sodium = per milliliter × used conforms to the standards pre- Rs 1, 000 scribed by § 442.17(a)(1). where: (2) Labeling. It shall be labeled in ac- cordance with the requirements of Ru=Area of the ceftizoxime peak in the chro- matogram of the sample (at a retention § 432.5 of this chapter. time equal to that observed for the (3) Requests for certification; samples. standard)/Area of the internal standard In addition to complying with the re- peak;
quirements of §431.1 of this chapter, Rs=Area of the ceftizoxime peak in the chro- each such request shall contain: matogram of the ceftizoxime working (i) Results of tests and assays on: standard/Area of the internal standard (a) The ceftizoxime sodium used in peak; making the batch for ceftizoxime con- Ps=Ceftizoxime activity in the ceftizoxime working standard solution in tent, moisture, pH, identity, and crys- micrograms per milliliter; and tallinity. d=Dilution factor of the sample. (b) The batch for ceftizoxime con- tent, sterility, pyrogens, pH, and iden- (2) Sterility. Proceed as directed in tity. § 436.20 of this chapter, using the meth- (ii) Samples, if required by the Direc- od described in paragraph (e)(1) of that tor, Center for Drug Evaluation and section. Research, of: (3) Pyrogens. Proceed as directed in (a) The ceftizoxime sodium used in § 436.32(a) of this chapter, except inject making the batch: 10 packages, each a sufficient volume of the undiluted so- containing approximately 500 milli- lution to deliver 50 milligrams of grams. ceftizoxime per kilogram. (b) The batch: (4) pH. Proceed as directed in §436.202 (1) For all tests except sterility: A of this chapter, using the undiluted so- minimum of 10 immediate containers. lution.
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(5) Identity. The high-pressure liquid (A) The cefuroxime sodium used in chromatogram of the sample deter- making the batch: 10 packages, each mined as directed in paragraph (b)(1) of containing 1 gram. this section compares qualitatively to (B) The batch: that of the ceftizoxime working stand- (1) For all tests except sterility: A ard. minimum of 10 immediate containers. [49 FR 49286, Dec. 19, 1984; 50 FR 253, Jan. 3, (2) For sterility testing: 20 immediate 1985, as amended at 55 FR 11583, Mar. 29, 1990] containers, collected at regular inter- vals throughout each filling operation. § 442.218 Cefuroxime injectable dosage (b) Tests and methods of assay—Thaw forms. the sample as directed in the labeling. The sample solution used for testing § 442.218a Sterile cefuroxime sodium. must be at room temperature. The requirements for certification (1) Cefuroxime content. Proceed as di- and the tests and methods of assay for rected in § 436.343 of this chapter, ex- sterile cefuroxime sodium packaged for cept prepare the sample solution and dispensing are described in § 442.18a. calculate the cefuroxime content as [48 FR 38461, Aug. 24, 1983. Redesignated at 54 follows: FR 40654, Oct. 3, 1989] (i) Preparation of sample solution. Re- move an accurately measured rep- § 442.218b Cefuroxime sodium injec- resentative portion from each con- tion. tainer immediately after thawing and (a) Requirements for certification—(1) reaching room temperature and dilute Standards of identity, strength, quality, with water to obtain a solution con- and purity. Cefuroxime sodium injec- taining 50 micrograms of cefuroxime tion is a frozen, aqueous, iso-osmotic per milliliter (estimated). Prepare the solution of cefuroxime sodium which sample solution just prior to its intro- may contain one or more suitable and duction in the chromatograph. harmless buffer substances and a tonic- (ii) Calculation. Calculate the milli- ity adjusting agent. Each milliliter grams of cefuroxime per milliliter of contains cefuroxime sodium equivalent sample as follows: to 15 or 30 milligrams of cefuroxime per × × milliliter. Its cefuroxime content is Milligrams of cefuroxime Au P s d satisfactory if it is not less than 90 per- = per milliliter × cent and not more than 120 percent of As 1, 000 the number of milligrams of where: cefuroxime that it is represented to Au=Area of the cefuroxime peak in the chro- contain. It is sterile. It is matogram of the sample (at a retention nonpyrogenic. Its pH is not less than time equal to that observed for the 5.0 and not more than 7.5. It passes the standard); identity test. The cefuroxime sodium As=Area of the cefuroxime peak in the chro- used conforms to the standards pre- matogram of the cefuroxime working scribed by § 442.18(a)(1). standard; (2) Labeling. It shall be labeled in ac- Ps=Cefuroxime activity in the cefuroxime cordance with the requirements of working standard solution in micrograms per milliliter; and § 432.5 of this chapter. d=Dilution factor of the sample. (3) Requests for certification; samples. In addition to complying with the re- (2) Sterility. Proceed as directed in quirements of § 431.1 of this chapter, § 436.20 of this chapter, using the meth- each such request shall contain: od described in paragraph (e)(1) of that (i) Results of tests and assays on: section. (A) The cefuroxime sodium used in (3) Pyrogens. Proceed as directed in making the batch for potency, mois- § 436.32(b) this chapter, except inject a ture, pH, and identity. sufficient volume of the undiluted solu- (B) The batch for cefuroxime content, tion to deliver 50 milligrams of sterility, pyrogens, pH, and identity. cefuroxime per kilogram. (ii) Samples, if required by the Direc- (4) pH. Proceed as directed in § 436.202 tor, Center for Drug Evaluation and of this chapter, using the undiluted so- Research: lution.
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(5) Identity. The high performance (ii) Samples, if required by the Direc- liquid chromatogram of the sample de- tor, Center for Drug Evaluation and termined as directed in paragraph Research: (b)(1) of this section compares quali- (A) The cefmenoxime hydrochloride tatively to that of the cefuroxime used in making the batch: 10 packages, working standard. each containing approximately 500 mil- ligrams. [54 FR 40654, Oct. 3, 1989] (B) The batch: (1) For all tests except sterility: A § 442.220 Sterile cefonicid sodium. minimum of 10 immediate containers. The requirements for certification (2) For sterility testing: 20 immediate and the tests and methods of assay for containers, collected at regular inter- sterile cefonicid sodium packaged for vals throughout each filling operation. dispensing are described in § 442.20a. (b) Tests and methods of assay—(1) Cefmenoxime content. Proceed as di- [49 FR 34349, Aug. 30, 1984] rected in § 436.363 of this chapter, using ambient temperature, an ultraviolet § 442.222 Cefmenoxime hydrochloride detection system operating at a wave- for injection. length of 254 nanometers, a column (a) Requirements for certification—(1) packed with microparticulate (3 to 10 Standards of identity, strength, quality, micrometers in diameter) reversed and purity. Cefmenoxime hydrochloride phase packing material such as octa- for injection is a dry mixture of decyl hydrocarbon bonded silicas, a cefmenoxime hydrochloride and so- flow rate not to exceed 2.0 milliliters dium carbonate. Each milligram of per minute, and a known injection vol- cefmenoxime hydrochloride for injec- ume between 10 and 20 microliters. Re- tion contains not less than 869 and not agents, working standard and sample more than 1,015 micrograms of solutions, system suitability require- cefmenoxime on an anhydrous and so- ments, and calculations are as follows: dium carbonate-free basis. Its (i) Reagents—(A) 0.1M Phosphate buff- cefmenoxime content is satisfactory if er solution, pH 6.8. Dissolve 6.4 grams of it contains not less than 90 percent and monobasic potassium phosphate and not more than 115 percent of the num- 18.9 grams of dibasic sodium phosphate ber of milligrams of cefmenoxime that in 750 milliliters of water. Adjust the it is represented to contain. It is ster- pH to 6.8 with 1N sodium hydroxide and ile. It is nonpyrogenic. Its loss on dry- dilute to 1,000 milliliters. ing is not more than 1.5 percent. Its pH (B) Internal standard solution. Dis- in an aqueous solution containing 100 solve and dilute 0.15 gram of phthal- milligrams per milliliter is not less imide in methanol to 100 milliliters. than 6.4 and not more than 7.9. The (C) Mobile phase. Mix cefmenoxime hydrochloride used con- water:acetonitrile:glacial acetic acid forms to the standards prescribed by (50:10:1). Filter through a suitable filter § 442.22a(a)(1) of this chapter. capable of removing particulate matter (2) Labeling. It shall be labeled in ac- to 0.5 micron in diameter. Degas the cordance with the requirements of mobile phase just prior to its introduc- tion into the chromatograph. § 432.5 of this chapter. (ii) Preparation of working standard (3) Requests for certification; samples. and sample solutions—(A) Working stand- In addition to complying with the re- ard solution. Dissolve approximately 50 quirements of § 431.1 of this chapter, milligrams of the cefmenoxime work- each such request shall contain: ing standard, accurately weighed, in 10 (i) Results of tests and assays on: milliliters of 0.1M phosphate buffer so- (A) The cefmenoxime hydrochloride lution, pH 6.8 and dilute to 50 milli- used in making the batch for liters with mobile phase. Transfer 4.0 cefmenoxime content, moisture, iden- milliliters of this solution to a 50-milli- tity, and crystallinity. liter volumetric flask, add 20 milli- (B) The batch for cefmenoxime con- liters of internal standard solution and tent, sterility, pyrogens, loss on dry- dilute to volume with mobile phase to ing, pH, and sodium carbonate content. obtain a solution containing 80
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micrograms of cefmenoxime per milli- (D) Coefficient of variation. The coeffi- liter. cient of variation (SR in percent) of 5 (B) Sample solutions. Determine both replicate injections is satisfactory if it micrograms of cefmenoxime per milli- is not more than 2.0 percent. If the sys- gram of the sample and milligrams of tem suitability requirements have been cefmenoxime per container. Use sepa- met, then proceed as described in rate containers for preparation of each § 436.363(b) of this chapter. sample solution as described in para- (iv) Calculations—(A) Micrograms per graphs (b)(1)(ii)(B) (1) and (2) of this milligram. Calculate the micrograms of section. cefmenoxime per milligram as follows: (1) Micrograms of cefmenoxime per milli- Micrograms of × × × gram. Dissolve the accurately weighed T3Ru P 3 100 d dry contents of a sample with suffi- cefmenoxime per = × − − cient distilled water to obtain a solu- milligram RCs u ()100 LS tion containing 1 milligram of where: cefmenoxime per milliliter (estimated). Ru=Area of the cefmenoxime peak in the Transfer 4.0 milliliters of this solution chromatogram of the sample/Area of in- to a 50-milliliter volumetric flask, add ternal standard peak; 20 milliliters of internal standard solu- Rs=Area of the cefmenoxime peak in the tion and dilute to volume with mobile chromatogram of the cefmenoxime work- phase to obtain a solution containing ing standard/Area of internal standard peak;≤ 80 micrograms of cefmenoxime per mil- Ps=Cefmenoxime activity in the liliter (estimated). cefmenoxime working standard solution (2) Milligrams of cefmenoxime per con- in micrograms per milliliter; tainer. Reconstitute the sample as di- Cu=Milligrams of sample per milliliter of rected in the labeling. Then, using a sample solution; suitable hypodermic needle and sy- d=Dilution factor of the sample; L=Percent loss on drying (determined as di- ringe, remove all of the withdrawable rected in paragraph (b)(4) of this section); contents if it is represented as a single- and dose container; or, if the labeling speci- S=Percent sodium carbonate (determined as fies the amount of potency in a given directed in paragraph (b)(6) of this sec- volume of the resultant preparation, tion). remove an accurately measured rep- (B) Milligrams of cefmenoxime per vial. resentative portion from each con- Calculate the cefmenoxime content of tainer. Dilute the solution thus ob- the vial as follows: tained with sufficient distilled water to obtain a solution containing 1 milli- × × Milligrams of Ru P s d gram of cefmenoxime per milliliter (es- = cefmenoxime per vial × timated). Transfer 4.0 milliliters of this Rs 1, 000 solution to a 50-milliliter volumetric where: flask, add 20 milliliters of internal standard solution and dilute to volume Ru=Area of the cefmenoxime peak in the chromatogram of the sample/Area of in- with mobile phase to obtain a solution ternal standard peak; containing 80 micrograms of Rs=Area of the cefmenoxime peak in the cefmenoxime per milliliter (estimated). chromatogram of the cefmenoxime work- (iii) System suitability requirements— ing standard/Area of internal standard (A) Tailing factor. The tailing factor (T) peak; for the cefmenoxime peak is satisfac- Ps=Cefmenoxime activity in the cefmenoxime working standard solution tory if it is not more than 1.6 at 5 per- in micrograms per milliliter; and cent of peak height. d=Dilution factor of the sample. (B) Efficiency of the column. The effi- (2) Sterility. Proceed as directed in ciency of the column (n) is satisfactory § 436.20 of this chapter, using the meth- if it is greater than 1,200 theoretical od described in paragraph (e)(1) of that plates for the cefmenoxime peak. section. (C) Resolution. The resolution (R) be- (3) Pyrogens. Proceed as directed in tween the peak for cefmenoxime and § 436.32(b) of this chapter, using a solu- phthalimide is satisfactory if it is not tion containing 60 milligrams of less than 2.3. cefmenoxime per milliliter.
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(4) Loss on drying. Proceed as directed quirements of § 431.1 of this chapter, in § 436.200(a) of this chapter. each such request shall contain: (5) pH. Proceed as directed in § 436.202 (i) Results of tests and assays on: of this chapter, using an aqueous solu- (a) The cephalothin sodium used in tion containing 100 milligrams per mil- making the batch for potency, loss on liliter. drying, pH, specific rotation, identity, (6) Sodium carbonate content. Proceed and crystallinity. as directed in § 436.364 of this chapter. (b) The batch for potency, sterility, [53 FR 13403, Apr. 25, 1988; 53 FR 19369, May pyrogens, and pH. 27, 1988] (ii) Samples required: (a) The cephalothin sodium used in § 442.223 Sterile cephaloridine. making the batch: 10 packages, each The requirements for certification containing approximately 500 milli- and the tests and methods of assay for grams. sterile cephaloridine packaged for dis- (b) The batch: pensing are described in § 442.23a. (1) For all tests except sterility: A minimum of 10 immediate containers. [39 FR 19040, May 30, 1974, as amended at 55 FR 11583, Mar. 29, 1990] (2) For sterility testing: 20 immediate containers, collected at regular inter- § 442.225 Cephalothin sodium vals throughout each filling operation. injectable dosage forms. (b) Tests and methods of assay. Thaw the ampoule contents as directed in the § 442.225a Sterile sodium cephalothin. labeling. The sample solution used for The requirements for certification testing must be at room temperature. and the tests and methods of assay for (1) Potency. Use either of the follow- sterile sodium cephalothin packaged ing methods; however, the results ob- for dispensing are described in § 442.25a. tained from the microbiological agar [39 FR 19040, May 30, 1974. Redesignated at 40 diffusion assay shall be conclusive. FR 11351, Mar. 11, 1975] (i) Microbiological agar diffusion assay. Proceed as directed in § 436.105 of this § 442.225b Cephalothin sodium injec- chapter, preparing the sample for assay tion. as follows: Using a suitable hypodermic (a) Requirements for certification—(1) needle and syringe, remove an accu- Standards of identity, strength, quality, rately measured representative portion and purity. Cephalothin sodium injec- from each container and dilute with tion is a frozen aqueous solution of sufficient 1 percent potassium phos- cephalothin sodium with one or more phate buffer, pH 6.0 (solution 1), to give suitable and harmless buffer sub- a stock solution of convenient con- stances. It may contain sodium chlo- centration. Further dilute an aliquot of ride or dextrose. Each milliliter con- the stock solution with solution 1 to tains cephalothin sodium equivalent to the reference concentration of 1.0 20 milligrams, 40 milligrams, or 100 microgram of cephalothin per milli- milligrams of cephalothin. Its potency liter (estimated). is satisfactory if it is not less than 90 (ii) Hydroxylamine colorimetric assay. percent and not more than 115 percent Proceed as directed in § 436.205 of this of the number of milligrams of chapter, preparing the sample as fol- cephalothin that it is represented to lows: Using a suitable hypodermic nee- contain. It is sterile. It is dle and syringe, remove an accurately nonpyrogenic. Its pH is not less than measured representative portion from 6.0 and not more than 8.5. The each container and dilute with distilled cephalothin sodium used conforms to water to give a stock solution of con- the standards prescribed by venient concentration. Further dilute § 442.25a(a)(1). with distilled water to the prescribed (2) Labeling. It shall be labeled in ac- concentration. cordance with the requirements of (2) Sterility. Proceed as directed in § 432.5 of this chapter. § 436.20 of this chapter, using the meth- (3) Requests for certification; samples. od described in paragraph (e)(1) of that In addition to complying with the re- section.
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(3) Pyrogens. Proceed as directed in dition, if the cephalothin sodium is not § 436.32(b) of this chapter, using a solu- isolated, results of tests and assays on tion containing 50 milligrams of the dry mixture for potency, specific cephalothin per milliliter. rotation, and identity. (4) [Reserved] (ii) Samples required: (5) pH. Proceed as directed in § 436.202 (a) For all tests except sterility: A of this chapter, using the undiluted so- minimum of 10 immediate containers, lution. unless the cephalothin sodium is not [40 FR 11351, Mar. 11, 1975, as amended at 49 isolated, a minimum of 15 immediate FR 13493, Apr. 5, 1984; 50 FR 19919, May 13, containers. 1985] (b) For sterility testing: 20 imme- diate containers, collected at regular § 442.225c Cephalothin sodium for in- intervals throughout each filling oper- jection. ation. (a) Requirements for certification—(1) (b) Tests and methods of assay—(1) Standards of identity, strength, quality, Content; potency—(i) Sample preparation. and purity. Cephalothin sodium for in- Reconstitute as directed in the label- jection is a dry mixture of cephalothin ing. Then using a suitable hypodermic sodium with one or more suitable and needle and syringe, remove all of the harmless buffer substances. The withdrawable contents if it is rep- cephalothin sodium may be isolated in resented as a single dose container; or the manufacture of cephalothin sodium if the labeling specifies the amount of for injection. Its cephalothin content is potency in a given volume of the re- satisfactory if it is not less than 90 per- sultant preparation, remove an accu- cent and not more than 115 percent of rately measured representative portion the number of milligrams of from each container. Dilute with 1 per- cephalothin that it is represented to cent potassium phosphate buffer, pH 6.0 contain. It is sterile. It is (solution 1), for the microbiological nonpyrogenic. Its loss on drying is not agar diffusion assay or distilled water more than 1.5 percent. When reconsti- for the hydroxylamine colorimetric tuted as directed in the labeling, its pH assay to obtain a stock solution of con- is not less than 6.0 and not more than venient concentration. In addition, if 8.5. If isolated, the cephalothin sodium the cephalothin sodium is not isolated, used conforms to the standards pre- dissolve an accurately weighed sample scribed by § 442.25a(a)(1). If the in sufficient 1 percent potassium phos- cephalothin sodium is not isolated: The phate buffer, pH 6.0 (solution 1), for the potency of the dry mixture is not less microbiological agar diffusion assay or than 850 micrograms of cephalothin per distilled water for the hydroxylamine milligram on an anhydrous basis when colorimetric assay to obtain a stock corrected for sodium bicarbonate; the solution of convenient concentration. specific rotation of the dry mixture in Correct the potency, micrograms of an aqueous solution containing 50 mil- cephalothin per milligram, for sodium ligrams of cephalothin per milliliter at bicarbonate content determined as de- 25° C is ∂129° ±5°; and the dry mixture scribed in paragraph (b)(7) of this sec- gives a positive identity test. tion. (2) Labeling. It shall be labeled in ac- (ii) Assay procedures. Use either of the cordance with the requirements of following methods; however, the re- § 432.5 of this chapter. sults obtained from the hydroxylamine (3) Requests for certification; samples. colorimetric assay shall be conclusive. In addition to complying with the re- (a) Microbiological agar diffusion quirements of § 431.1 of this chapter, assay. Proceed as directed in § 436.105 of each such request shall contain: this chapter, diluting an aliquot of the (i) Results of tests and assays on: stock solution with solution 1 to the (a) If isolated, the cephalothin so- reference concentration of 1.0 dium used in making the batch for po- microgram of cephalothin per milli- tency, loss on drying, pH, specific rota- liter (estimated). tion, identity, and crystallinity. (b) Hydroxylamine colorimetric assay. (b) The batch for potency, sterility, Proceed as directed in § 436.205 of this pyrogens, loss on drying, and pH. In ad- chapter.
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(2) Sterility. Proceed as directed in § 442.240 Cephradine injectable dosage § 436.20 of this chapter, using the meth- forms. od described in paragraph (e)(1) of that section. § 442.240a Cephradine for injection. (3) Pyrogens. Proceed as directed in (a) Requirements for certification—(1) § 436.32(b) of this chapter, using a solu- Standards of identity, strength, quality, tion containing 50 milligrams of and purity. Cephradine for injection is a cephalothin per milliliter. dry mixture of cephradine and one or (4) [Reserved] more suitable and harmless solubiliz- ing and buffering agents. Its potency is (5) Loss on drying. Proceed as directed satisfactory if it contains not less than in § 436.200(b) of this chapter. 90 percent and not more than 115 per- (6) pH. Proceed as directed in § 436.202 cent of the number of milligrams of of this chapter, using the drug recon- cephradine that it is represented to stituted as directed in the labeling. contain. It is sterile. It is (7) Specific rotation. Dissolve and di- nonpyrogenic. Its loss on drying is not lute an accurately weighed portion of more than 5.0 percent. Its pH in an the dry mixture with sufficient dis- aqueous solution containing 10 milli- tilled water to give a concentration of grams per milliliter is not less than 8.0 approximately 50 milligrams per milli- and not more than 9.6. The cephradine liter. Proceed as directed in § 436.210 of used conforms to the standards pre- this chapter, using a 1.0-decimeter po- scribed by § 442.40a(a)(1). larimeter tube. Calculate the specific (2) Labeling. It shall be labeled in ac- rotation on an anhydrous basis and cordance with the requirements of correct for sodium bicarbonate con- § 432.5 of this chapter. tent. Determine the sodium bicarbon- (3) Requests for certification; samples. ate content as follows: Dissolve an ac- In addition to complying with the re- curately weighed portion of the dry quirements of § 431.1 of this chapter, mixture, approximately 1.0 gram, with each such request shall contain: (i) Results of tests and assays on: approximately 50 milliliters of distilled (a) The sterile cephradine used in water. Titrate with 0.1N sulfuric acid. making the batch for potency, mois- Determine the end-point ture, pH, cephalexin content, identity, potentiometrically using a glass calo- and crystallinity. mel combination electrode. Each milli- (b) The batch for potency, sterility, liter of 0.1N sulfuric acid is equivalent pyrogens, loss on drying, and pH. to 8.401 milligrams of sodium bicarbon- (ii) Samples required: ate. (a) The cephradine used in making (8) Identity. Using a 0.0025-percent so- the batch: 10 packages, each containing lution of the sample in water and a approximately 500 milligrams. suitable spectrophotometer, record the (b) The batch: ultraviolet absorption spectrum from (1) For all tests except sterility: A 220 to 310 nanometers. The spectrum minimum of 10 immediate containers. compares qualitatively to that of the (2) For sterility testing: 20 immediate working standard similarly tested. containers, collected at regular inter- vals throughout each filling operation. [40 FR 5355, Feb. 5, 1975, as amended at 46 FR (b) Tests and methods of assay—(1) Po- 38503, July 28, 1981; 48 FR 51293, Nov. 8, 1983; tency. Use either of the following meth- 49 FR 5097, Feb. 10, 1984; 50 FR 19919, May 13, ods; however, the results obtained from 1985] the microbiological agar diffusion assay shall be conclusive. § 442.229 Sterile cephapirin sodium. (i) Microbiological agar diffusion assay. The requirements for certification Proceed as directed in § 436.105 of this and the tests and methods of assay for chapter, preparing the sample for assay sterile cephapirin sodium packaged for as follows: Reconstitute the sample as dispensing are described in § 442.29a. directed in the labeling for
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intramuscular use. Using a suitable § 442.250 Ceforanide for injection. hypodermic needle and syringe, remove (a) Requirements for certification—(1) all of the withdrawable contents if it is Standards of identity, strength, quality, represented as a single dose container; and purity. Ceforanide for injection is a or if the labeling specifies the amount dry mixture of ceforanide and L-lysine. of potency in a given volume of the re- Each milligram of ceforanide for injec- sultant preparation, remove an accu- tion contains not less than 900 rately measured representative portion micrograms and not more than 1,050 from each container. Further dilute an micrograms of ceforanide when cor- aliquot of this solution with solution 1 rected for L-lysine content. Its to the reference concentration of 10.0 ceforanide content is satisfactory if it micrograms of cephradine per milli- contains not less than 90 percent and liter (estimated). not more than 115 percent of the num- (ii) Hydroxylamine colorimetric assay. ber of milligrams of ceforanide that it Proceed as directed in § 442.40(b)(1)(ii), is represented to contain. It is sterile. It is nonpyrogenic. Its moisture con- preparing the sample as follows: Recon- tent is not more than 3.0 percent. When stitute the sample as directed in the la- reconstituted as directed in the label- beling for intramuscular use. Using a ing, its pH is not less than 5.5 and not suitable hypodermic needle and sy- more than 8.5. The ceforanide used con- ringe, remove all of the withdrawable forms to the standards prescribed by contents if it is represented as a single § 442.50a(a)(1). dose container; or if the labeling speci- (2) Labeling. It shall be labeled in ac- fies the amount of potency in a given cordance with the requirements of volume of the resultant preparation, § 432.5 of this chapter. remove an accurately measured rep- (3) Requests for certification; samples. resentative portion from each con- In addition to complying with the re- tainer. Further dilute an aliquot of quirements of § 431.1 of this chapter, this solution with distilled water to 1 each such request shall contain: milligram of cephradine per milliliter (i) Results of tests and assays on: (estimated) (a) The sterile ceforanide used in (2) Sterility. Proceed as directed in making the batch for ceforanide con- § 436.20 of this chapter, using the meth- tent, moisture, pH, and identity. od described in paragraph (e)(1) of that (b) The batch for ceforanide content, section. sterility, pyrogens, moisture, and pH. (ii) Samples, if required by the Direc- (3) Pyrogens. Proceed as directed in tor, Center for Drug Evaluation and § 436.32(b) of this chapter, using a solu- Research: tion containing 80 milligrams of (a) The ceforanide used in making cephradine per milliliter. the batch: 10 packages, each containing (4) [Reserved] approximately 500 milligrams. (5) Loss on drying. Proceed as directed (b) The batch: in § 436.200(b) of this chapter. (1) For all tests except sterility: A (6) pH. Proceed as directed in § 436.202 minimum of 10 immediate containers. of this chapter, using an aqueous solu- (2) For sterility testing: 20 immediate tion containing 10 milligrams per mil- containers, collected at regular inter- liliter. vals throughout each filling operation. (b) Tests and methods of assay—(1) [40 FR 51626, Nov. 6, 1975. Redesignated at 43 Ceforanide content. Determine both FR 14646, Apr. 7, 1978; 50 FR 19919, May 13, micrograms of ceforanide per milli- 1985] gram of sample and milligrams of ceforanide per container. Proceed as di- § 442.240b Sterile cephradine. rected in § 436.348 of this chapter, pre- The requirements for certification paring the sample solution and cal- and the tests and methods of assay for culating the ceforanide content as fol- sterile cephradine packaged for dis- lows: pensing are described in § 442.40a. (i) Preparation of sample solution. Use separate containers for preparation of [43 FR 14646, Apr. 7, 1978] each sample solution as described in
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paragraph (b)(1)(i) (a) and (b) of this Au=Area of the ceforanide sample peak (at a section. retention time equal to that observed for (a) Micrograms of ceforanide per milli- the standard); As=Area of the ceforanide peak in the chro- gram. Prepare a solution containing 1.0 matogram of the ceforanide working milligrams per milliliter in mobile standard; phase. Inject each sample within 5 min- Ps=Ceforanide activity in the ceforanide utes after dissolution. working standard solution in (b) Milligrams of ceforanide per con- micrograms per milliliter; and tainer. Reconstitute the sample with d=Dilution factor of the sample. distilled water as directed in the label- (2) Sterility. Proceed as directed in ing. Using a suitable hypodermic nee- § 436.20 of this chapter, using the meth- dle and syringe, remove all of the od described in paragraph (e)(1) of that withdrawable contents if it is rep- section, except reconstitute the vials resented as a single-dose container; or, with approximately 3.0 milliliters of di- if the labeling specifies the amount of luting fluid A per each gram of anti- ceforanide content in a given volume of biotic activity. Transfer approximately the resultant preparation, remove an 1 milliliter from each of 20 vials into a accurately measured representative sterile 500-milliliter Erlenmeyer flask portion from each container. Dilute containing 200 milliliters of diluting with mobile phase to obtain a stock so- fluid A. Filter as described in para- lution containing 10.0 milligrams per graph (e)(1)(ii) of this section, except in milliliter (estimated). Immediately di- lieu of filtering with three 100-milli- lute an aliquot of the stock solution with mobile phase to a concentration liter quantities of diluting fluid A, of 1.0 milligrams of ceforanide per mil- rinse the filter membrane with three liliter (estimated). Inject within 5 min- 100-milliliter portions of diluting fluid utes, after preparation. D followed by a final rinse with 100 mil- (ii) Calculations—(a) Micrograms of liliters of diluting fluid A. ceforanide per milligram. Calculate the (3) Pyrogens. Proceed as directed in micrograms of ceforanide per milli- § 436.32(b) of this chapter, using a solu- gram of sample as follows: tion containing 50 milligrams of ceforanide per milliliter. Micrograms of AP× ×100 (4) Moisture. Proceed as directed in ceforanide per = u s § 436.201 of this chapter. milligram ACL× ×()100 − (5) pH. Proceed as directed in § 436.202 s u of this chapter, using the solution ob- where: tained when the product is reconsti- Au=Area of the ceforanide sample peak (at a tuted as directed in the labeling. retention time equal to that observed for the standard); [49 FR 25848, June 25, 1984; 49 FR 34347, Aug. As=Area of the ceforanide peak in the chro- 30, 1984; 49 FR 40006, Oct. 12, 1984, as amended matogram of the ceforanide working at 55 FR 11583, Mar. 29, 1990] standard; Ps=Ceforanide activity in the ceforanide § 442.253 Cefotetan injectable dosage working standard solution in forms. micrograms per milliliter; Cu=Milligrams of sample per milliliter of § 442.253a Sterile cefotetan disodium. sample solution; and L=Percent lysine content of the sample. (De- The requirements for certification termined as described in § 436.349 of this and the tests and methods of assay for chapter.) sterile cefotetan disodium packaged for dispensing are described in § 442.53a. (b) Milligrams of ceforanide per vial. Calculate the ceforanide content of the [51 FR 20264, June 4, 1986. Redesignated at 59 vial as follows: FR 26941, May 25, 1994] A× P × d § 442.253b Cefotetan sodium injection. Milligrams of ceforanide = s s per vial × (a) Requirements for certification—(1) As 1, 000 Standards of identity, strength, quality, where: and purity. Cefotetan sodium injection
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is a frozen, aqueous, iso-osmotic solu- bile phase to obtain a solution contain- tion of cefotetan and sodium bicarbon- ing 200 micrograms of cefotetan per ate. It contains one or more suitable milliliter (estimated). Prepare the and harmless buffer substances and a sample solution just prior to its intro- tonicity adjusting agent. Each milli- duction into the chromatograph. liter contains cefotetan disodium (ii) Calculation. Calculate the milli- equivalent to 20 milligrams or 40 milli- grams of cefotetan per milliliter of grams of cefotetan per milliliter. Its sample as follows: cefotetan content is satisfactory if it is not less than 90 percent and not more Micrograms of AP× ×100 than 120 percent of the number of milli- cefotetan per = U s grams of cefotetan that it is rep- milligram A× C ×()100 − m resented to contain. It is sterile. It s U contains not more than 0.17 endotoxin where: AU=Area of the cefotetan peak in the chro- units per milligram of cefotetan. Its pH matogram of the sample (at a retention is not less than 4.0 and not more than time equal to that observed for the 6.5. It passes the identity test. The standard); cefotetan used conforms to the stand- AS=Area of the cefotetan peak in the chro- ards prescribed by § 442.52(a)(1). matogram of the cefotetan working (2) Labeling. It shall be labeled in ac- standard; cordance with the requirements of PS=Cefotetan activity in the cefotetan work- ing standard solution in micrograms per § 432.5 of this chapter. milliliter; (3) Requests for certification; samples. CU=Milligrams of sample per milliliter of In addition to complying with the re- sample solution; and quirements of § 431.1 of this chapter, m = Percent moisture content of the sample. each such request shall contain: (2) Sterility. Proceed as directed in (i) Results of tests and assays on: § 436.20 of this chapter, using the meth- (A) The cefotetan used in making the od described in paragraph (e)(1) of that batch for cefotetan potency, moisture, section. and identity. (3) Bacterial endotoxins. Proceed as di- (B) The batch for cefotetan potency, rected in the U.S. Pharmacopeia bac- sterility, bacterial endotoxins, pH, and terial endotoxins test. identity. (4) pH. Proceed as directed in § 436.202 (ii) Samples, if required by the Direc- of this chapter, using the undiluted so- tor, Center for Drug Evaluation and lution. Research: (5) Identity. The high-performance (A) The cefotetan used in making the liquid chromatogram of the sample de- batch: 10 packages, each containing ap- termined as directed in paragraph proximately 500 milligrams. (b)(1) of this section compares quali- (B) The batch: tatively to that of the cefotetan work- (1) For all tests except sterility: A ing standard. minimum of 12 immediate containers. (2) For sterility testing: 20 immediate [59 FR 26941, May 25, 1994] containers, collected at regular inter- vals throughout each filling operation. § 442.255 Ceftriaxone injectable dosage (b) Tests and methods of assay. Thaw forms. the sample as directed in the labeling. § 442.255a Sterile ceftriaxone sodium. The sample solution used for testing must be at room temperature. The requirements for certification (1) Cefotetan potency. Proceed as di- and the tests and methods of assay for rected in § 442.52(b)(1), except prepare sterile ceftriaxone sodium packaged for the sample solution and calculate the dispensing as described in § 442.55a. cefotetan content as follows: [50 FR 10001, Mar. 13, 1985. Redesignated at 52 (i) Preparation of sample solution. FR 44860, Nov. 23, 1987] Using a suitable hypodermic needle and syringe, remove an accurately meas- § 442.255b Ceftriaxone sodium injec- ured portion from each container im- tion. mediately after thawing and reaching (a) Requirements for certification—(1) room temperature and dilute with mo- Standards of identity, strength, quality,
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and purity. Ceftriaxone sodium injec- lution containing 180 micrograms of tion is a frozen aqueous iso-osmotic so- ceftriaxone per milliliter (estimated). lution of ceftriaxone sodium which Prepare the sample solution just prior may contain one or more suitable and to its introduction into the chro- harmless buffer substances. Each milli- matograph. liter contains ceftriaxone sodium (ii) Calculation. Calculate the milli- equivalent to 10, 20, or 40 milligrams of grams of ceftriaxone anhydrous free ceftriaxone per milliliter. Its acid per milliliter of sample as follows: ceftriaxone content is satisfactory if it is not less than 90 percent and not Milligrams of ceftriaxone A× P × d more than 115 percent of the number of anhydrous free acid = u s milligrams of ceftriaxone that it is rep- per milliliter A ×1, 000 resented to contain. It is sterile. It is s nonpyrogenic. Its pH is not less than where: Au=Area of the ceftriaxone peak in the chro- 6.0 and not more than 8.0. It passes the matogram of the sample (at a retention identity test. The ceftriaxone sodium time equal to that observed for the used conforms to the standards pre- standard); scribed by § 442.55(a)(1). As=Area of the ceftriaxone peak in the chro- (2) Labeling. It shall be labeled in ac- matogram of the ceftriaxone working cordance with the requirements of standard; § 432.5 of this chapter. Ps=Ceftriaxone activity in the ceftriaxone (3) Requests for certification; samples. working standard solution in micrograms of anhydrous free acid per In addition to complying with the re- milliliter; and quirements of § 431.1 of this chapter, d=Dilution factor of the sample. each such request shall contain: (i) Results of tests and assays on: (2) Sterility. Proceed as directed in (A) The ceftriaxone sodium used in § 436.20 of this chapter, using the meth- making the batch for potency, mois- od described in paragraph (e)(1) of that ture, pH, crystallinity, and identity. section. (B) The batch for content, sterility, (3) Pyrogens. Proceed as directed in pyrogens, pH, and identity. § 436.32(a) of this chapter, except inject (ii) Samples, if required by the Direc- a sufficient volume of the undiluted so- tor, Center for Drug Evaluation and lution to deliver 40 milligrams of Research: ceftriaxone per kilogram. (A) The ceftriaxone sodium used in (4) pH. Proceed as directed in § 436.202 making the batch: 10 packages, each of this chapter, using the undiluted so- containing 500 milligrams. lution. (B) The batch: (5) Identify. The high-performance (1) For all tests except sterility: A liquid chromatogram of the sample de- minimum of 10 immediate containers. termined as directed in paragraph (2) For sterility testing: 20 immediate (b)(1) of this section compares quali- containers, collected at regular inter- tatively to that of the ceftriaxone vals throughout each filling operation. working standard. (b) Tests and methods of assay. Thaw [52 FR 44860, Nov. 23, 1987, as amended at 55 the sample as directed in the labeling. FR 11583, Mar. 29, 1990] The sample solution used for testing must be at room temperature. § 442.258 Cefotiam dihydrochloride for (1) Ceftriaxone content. Proceed as di- injection. rected in § 442.55a(b)(1) of this chapter, (a) Requirements for certification—(1) except prepare the sample solution and Standards of identity, strength, quality, calculate the ceftriaxone content as and purity. Cefotiam dehydrochloride follows: for injection is a dry mixture of (i) Preparation of sample solution. cefotiam dihydrochloride and sodium Using a suitable hypodermic needle and carbonate. Its cefotiam potency is sat- syringe, remove an accurately meas- isfactory if each milligram of cefotiam ured representative portion from each dihydrochloride for injection contains container immediately after thawing not less than 790 micrograms and not and reaching room temperature and di- more than 925 micrograms of cefotiam lute with mobile phase to obtain a so- on an anhydrous basis, when corrected
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for sodium carbonate content. Its micrograms of cefotiam per milliliter. cefotiam content is satisfactory if it Further dilute this solution with mo- contains not less than 90 percent and bile phase to obtain a solution contain- not more than 120 percent of the num- ing 50 micrograms of cefotiam activity ber of milligrams of cefotiam that it is per milliliter (estimated). represented to contain. It is sterile. It (B) Cefotiam content (milligrams of is nonpyrogenic. Its loss on drying is cefotiam per vial). Reconstitute the not more than 6.0 percent. The pH of an sample as directed in the labeling. aqueous solution containing 100 milli- Then, using a suitable hypodermic nee- grams per milliliter is not less than 5.7 dle and syringe, remove all of the and not more than 7.2. The cefotiam withdrawable contents if it is rep- dihydrochloride used conforms to the resented as a single-dose container; or, standards prescribed by § 442.58a(a)(1). if the labeling specifies the amount of (2) Labeling. It shall be labeled in ac- potency in a given volume of the re- cordance with the requirements of sultant preparation, remove an accu- § 432.5 of this chapter. rately measured representative portion (3) Requests for certification; samples. from each container. Dilute the solu- In addition to complying with the re- tion thus obtained with sufficient dis- quirements of § 431.1 of this chapter, tilled water to obtain a solution con- each such request shall contain: taining 1,000 micrograms of cefotiam (i) Results of tests and assays on: activity per milliliter (estimated). Fur- (A) The cefotiam dihydrochloride ther dilute this solution with mobile used in making the batch for potency, phase to obtain a solution containing moisture, identity, and crystallinity. 50 micrograms of cefotiam activity per (B) The batch for cefotiam potency, milliliter (estimated). cefotiam content, sterility, pyrogens, (ii) Calculations—(A) Cefotiam potency loss on drying, pH, and sodium carbon- (micrograms per milligram). Calculate the ate content. micrograms of cefotiam per milligram (ii) Samples, if required by the Direc- as follows: tor, Center for Drug Evaluation and Research: Micrograms of AP× ×100 (A) The cefotiam dihydrochloride cefotiam per = u s used in making the batch: 10 packages, milligram AC× ×()100 −LS − each containing approximately 500 mil- s u ligrams. where: Au=Area of the cefotiam peak in the chro- (B) The batch: matogram of the sample (at a retention (1) For all tests except sterility: A time equal to that observed for the minimum of 10 immediate containers. standard); (2) For sterility testing: 20 immediate As=Area of the cefotiam peak in the chro- containers, collected at regular inter- matogram of the cefotiam working vals throughout each filling operation. standard; (b) Tests and methods of assay—(1) Ps=Cefotiam activity in the cefotiam work- Cefotiam potency and content. Deter- ing standard solution in micrograms per milliliter; mine both micrograms of cefotiam per Cu=Milligrams of the sample per milliliter of milligram of sample and milligrams of sample solution; cefotiam per container. Proceed as di- L=Percent loss on drying (determined as di- rected in § 442.58a(b)(1), preparing the rected in paragraph (b)(4) of this section); sample solutions and calculating the and potency and content as follows: S=Percent sodium carbonate (determined as (i) Preparation of sample solutions. Use directed in paragraph (b)(6) of this sec- separate containers for preparation of tion). each sample solution as described in (B) Cefotiam content (milligrams of paragraphs (b)(1)(i) (A) and (B) of this cefotiam per vial). Calculate the section. cefotiam content of the vial as follows: (A) Cefotiam potency (micrograms of cefotiam per milligram). Dissolve an ac- Milligrams of cefotiam A× P × d = u s curately weighed sample with suffi- per vial s cient distilled water to obtain a solu- A ×1, 000 tion containing approximately 1,000 where:
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Au=Area of the cefotiam peak in the chro- (3) Requests for certification; samples. matogram of the sample (at a retention In addition to complying with the re- time equal to that observed for the quirements of § 431.1 of this chapter, standard); each such request shall contain: As=Area of the cefotiam peak in the chro- matogram of the cefotiam working (i) Results of tests and assays on: standard; (A) The cefpiramide used in making Ps=Cefotiam activity in the cefotiam work- the batch for potency, moisture, pH, ing standard solution in micrograms per total related substances, specific rota- milliliter; and tion, identity, and crystallinity. d=Dilution factor of the sample. (B) The batch for cefpiramide po- (2) Sterility. Proceed as directed in tency, cefpiramide content, sterility, § 436.20 of this chapter, using the meth- pyrogens, moisture, pH, and identity. od described in paragraph (e)(1) of that (ii) Samples, if required by the Cen- section. ter for Drug Evaluation and Research: (3) Pyrogens. Proceed as directed in (A) The cefpiramide used in making § 436.32(g) of this chapter, using a solu- the batch: 10 packages, each containing tion containing 40 milligrams of approximately 500 milligrams. cefotiam per milliliter. (4) Loss on drying. Proceed as directed (B) The batch: in § 436.200(a) of this chapter. (1) For all tests except sterility: A (5) pH. Proceed as directed in § 436.202 minimum of 10 immediate containers. of this chapter, using an aqueous solu- (2) For sterility testing: 20 immediate tion containing 100 milligrams per mil- containers, collected at regular inter- liliter. vals throughout each filling operation. (6) Sodium carbonate content. Proceed (b) Tests and methods of assay—(1) as directed in § 436.357 of this chapter. Cefpiramide potency and content. Deter- mine both micrograms of cefpiramide [54 FR 20786, May 15, 1989] per milligram of sample and milli- § 442.260 Cefpiramide sodium for in- grams of cefpiramide per container. jection. Proceed as directed in § 442.60(b)(1), pre- (a) Requirements for certification—(1) paring the sample solutions and cal- Standards of identity, strength, quality, culating the potency and content as and purity. Cefpiramide sodium for in- follows: jection is a dry mixture of cefpiramide (i) Preparation of sample solutions. Use and sodium benzoate. It contains other separate containers for preparation of buffers and preservatives. Its each sample solution as described in cefpiramide potency is satisfactory if paragraphs (b)(1)(i)(A) and (b)(1)(i)(B) each milligram of cefpiramide sodium of this section. for injection contains not less than 754 (A) Cefpiramide potency (micrograms of micrograms and not more than 924 cefpiramide per milligram). Dissolve an micrograms of cefpiramide on an anhy- accurately weighed sample with suffi- drous basis. Its cefpiramide content is cient mobile phase to obtain a solution satisfactory if it contains not less than containing approximately 0.25 milli- 90 percent and not more than 120 per- gram of cefpiramide per milliliter (es- cent of the number of milligrams of timated). cefpiramide that it is represented to (B) Cefpiramide content (milligrams of contain. It is sterile. It is ). Reconstitute the nonpyrogenic. Its moisture content is cefpiramide per vial not more than 3.0 percent. Its pH in an sample as directed in the labeling. aqueous solution containing 100 milli- Then, using a suitable hypodermic nee- grams per milliliter is not less than 6.0 dle and syringe, remove all of the and not more than 8.0. It passes the withdrawable contents if it is rep- identity test. The cefpiramide used resented as a single-dose container; or, conforms to the standards prescribed if the labeling specifies the amount of by § 442.60(a)(1). potency in a given volume of the re- (2) Labeling. It shall be labeled in ac- sultant preparation, remove an accu- cordance with the requirements of rately measured representative portion § 432.5 of this chapter.
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from each container. Dilute the solu- (4) Moisture. Proceed as directed in tion thus obtained with sufficient dis- § 436.201 of this chapter. tilled water to obtain a solution con- (5) pH. Proceed as directed in § 436.202 taining 1.0 milligram of cefpiramide ac- of this chapter, using an aqueous solu- tivity per milliliter (estimated). Fur- tion containing 100 milligrams per mil- ther dilute this solution with mobile liliter. phase to obtain a solution containing (6) Identify. The high-performance 0.25 milligram of cefpiramide activity liquid chromatogram of the sample de- per milliliter (estimated). termined as directed in paragraph (ii) Calculations—(A) Cefpiramide po- (b)(1) of this section compares quali- tency (micrograms per milligram). Cal- tatively to that of the cefpiramide culate the micrograms of cefpiramide working standard. per milligram as follows: [55 FR 14242, Apr. 17, 1990]
Micrograms of AP× ×100 § 442.270 Cefmetazole injectable dos- cefpiramide = u s age forms. × × − per milligram As C u (100 m) § 442.270a Sterile cefmetazole sodium. where: The requirements for certification Au=Area of the cefpiramide peak in the and the tests and methods of assay for chromatogram of the sample (at a retention sterile cefmetazole sodium packaged time equal to that observed for the stand- for dispensing are described in § 442.70a. ard);
As=Area of the cefpiramide peak in the [55 FR 6636, Feb. 26, 1990] chromatogram of the cefpiramide working standard; § 442.270b Cefmetazole sodium injec- Ps=Cefpiramide activity in the cefpiramide tion. working standard solution in micrograms (a) Requirements for certification—(1) per milliliter; Standards of identity, strength, quality, Cu=Milligrams of the sample per milliliter and purity. Cefmetazole sodium injec- of sample solution; tion is a frozen, aqueous, iso-osmotic m =Percent moisture content of the sam- ple. solution of cefmetazole and sodium cit- rate. It contains one or more suitable (B) Cefpiramide content (milligrams of and harmless buffer substances and a cefpiramide per vial). Calculate the tonicity adjusting agent. Each milli- cefpiramide content of the vial as fol- liter contains cefmetazole sodium lows: equivalent to 20 milligrams or 40 milli- grams of cefmetazole per milliliter. Its A× P × d Milligrams of cefpiramide = u s cefmetazole content is satisfactory if it per vial × is not less than 90 percent and not As 1, 000 more than 120 percent of the number of where: milligrams of cefmetazole that it is
Au=Area of the cefpiramide peak in the represented to contain. It is sterile. It chromatogram of the sample (a ta retention contains not more than 0.2 endotoxin time equal to that observed for the stand- units per milligram. Its pH is not less ards); than 4.2 and not more than 6.2. It As=Area of the cefpiramide peak in the passes the identity test. The chromatogram of the cefpiramide working cefmetazole used conforms to the standard; standards prescribed by § 442.69(a)(1). Ps=Cefpiramide activity in the cefpiramide (2) Labeling. It shall be labeled in ac- working standard solution in micrograms per milliliter; and cordance with the requirements of d=Dilution factor of the sample. § 432.5 of this chapter. (3) Requests for certification; samples. (2) Sterility. Proceed as directed in In addition to complying with the re- § 436.20 of this chapter, using the meth- quirements of § 431.1 of this chapter, od described in § 436.20(e)(1). each such request shall contain: (3) Pyrogens. Proceed as directed in (i) Results of tests and assays on: § 436.32(b) of this chapter, using a solu- (A) The cefmetazole used in making tion containing 50 milligrams of the batch for potency, moisture, and cefpiramide per milliliter. identity.
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(B) The batch for potency, sterility, (4) pH. Proceed as directed in § 436.202 bacterial endotoxins, pH, and identity. of this chapter, using the undiluted so- (ii) Samples, if required by the Direc- lution. tor, Center for Drug Evaluation and (5) Identity. The high-performance Research: liquid chromatogram of the sample de- (A) The cefmetazole used in making termined as directed in paragraph the batch: 10 packages, each containing (b)(1) of this section compares quali- approximately 500 milligrams. tatively to that of the cefmetazole (B) The batch: working standard. (1) For all tests except sterility: A [59 FR 12546, Mar. 17, 1994] minimum of 12 immediate containers. (2) For sterility testing: 20 immediate containers, collected at regular inter- PART 443—CARBACEPHEM vals throughout each filling operation. ANTIBIOTIC DRUGS (b) Tests and methods of assay. Thaw the sample as directed in the labeling. Subpart A—Bulk Drugs The sample solution used for testing Sec. must be at room temperature. 443.20 Loracarbef. (1) Cefmetazole potency. Proceed as di- rected in § 442.70a(b)(1), except prepare Subpart B—Oral Dosage Forms the sample solution and calculate the 443.120 Loracarbef oral dosage forms. cefmetazole content as follows: 443.120a Loracarbef capsules. (i) Preparation of sample solution. 443.120b Loracarbef for oral suspension. Using a suitable hypodermic needle and AUTHORITY: Sec. 507 of the Federal Food, syringe, remove an accurately meas- Drug, and Cosmetic Act (21 U.S.C. 357). ured portion from each container im- mediately after thawing and reaching SOURCE: 58 FR 26667, May 4, 1993, unless room temperature and dilute with mo- otherwise noted. bile phase to obtain a solution contain- ing 500 micrograms of cefmetazole per Subpart A—Bulk Drugs milliliter (estimated). Prepare the sample solution just prior to its intro- § 443.20 Loracarbef. duction into the chromatograph. (a) Requirements for certification—(1) (ii) Calculation. Calculate the milli- Standards of identity, strength, quality, grams of cefmetazole per milliliter of and purity. Loracarbef is the sample as follows: monohydrate form of (6R,7S)-7-[(R)-2- amino-2-phenylacetamido]-3-chloro-8- × × oxo-1-azabicyclo[4.2.0]oct-2-ene-2-car- Milligrams of cefmetazole AU P s d = boxylic acid. It is so purified and dried per milliliter × As 1, 000 that: where: (i) Its potency is not less than 960 micrograms and not more than 1,020 AU=Area of the cefmetazole peak in the chro- micrograms of loracarbef activity per matogram of the – sample (at a retention milligram, on an anhydrous basis. time equal to that observed for the standard); (ii) Its moisture content is not less than 3.5 percent and not more than 6.0 AS=Area of the cefmetazole peak in the chro- matogram of the cefmetazole working percent. standard; (iii) The pH of an aqueous slurry con- PS=Cefmetazole activity in the cefmetazole taining 100 milligrams per milliliter is working standard solution in not less than 3.5 and not more than 5.5. micrograms per milliliter; and (iv) Its specific rotation in an 0.1 N d = Dilution factor of the sample. HCl solution containing 10 milligrams (2) Sterility. Proceed as directed in of loracarbef per milliliter at 25° C is § 436.20 of this chapter, using the meth- ∂27°to∂33° on an anhydrous basis. od described in paragraph (e)(1) of that (v) It is crystalline. section. (vi) It gives a positive identity test. (3) Bacterial endotoxins. Proceed as di- (2) Labeling. It shall be labeled in ac- rected in the United States Pharma- cordance with the requirements of copeia bacterial endotoxins test. § 432.5 of this chapter.
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