Determine the end-point potentiometrically using a glass calomel combination electrode. Each milliliter of 0.1N sulfuric acid is equivalent to 8.401 milligrams of sodium bicarbonate.

(8) Identity. Using a 0.0025-percent solution of the sample in water and a suitable spectrophotometer, record the ultraviolet absorption spectrum from 220 to 310 nanometers. The spectrum compares qualitatively to that of the working standard similarly tested.

[40 FR 5355, Feb. 5, 1975, as amended at 46 FR 38503, July 28, 1981; 48 FR 51293, Nov. 8, 1983; 49 FR 5097, Feb. 10, 1984; 50 FR 19919, May 13, 1985]

§ 442.229 Sterile cephapirin sodium.

The requirements for certification and the tests and methods of assay for sterile cephapirin sodium packaged for dispensing are described in § 442.29a.

§ 442.240 Cephradine injectable dosage forms.

§ 442.240a Cephradine for injection.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Cephradine for injection is a dry mixture of cephradine and one or more suitable and harmless solubilizing and buffering agents. Its potency is satisfactory if it contains not less than 90 percent and not more than 115 percent of the number of milligrams of cephradine that it is represented to contain. It is sterile. It is nonpyrogenic. Its loss on drying is not more than 5.0 percent. Its pH in an aqueous solution containing 10 milligrams per milliliter is not less than 8.0 and not more than 9.6. The cephradine used conforms to the standards prescribed by § 442.40a(a)(1).

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

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

(i) Results of tests and assays on:

(a) The sterile cephradine used in making the batch for potency, moisture, pH, cephalexin content, identity, and crystallinity.

(b) The batch for potency, sterility, pyrogens, loss on drying, and pH.

(ii) Samples required:

(a) The cephradine used in making the batch: 10 packages, each containing approximately 500 milligrams.

(b) The batch:

(1) For all tests except sterility: A minimum of 10 immediate containers.

(2) For sterility testing: 20 immediate containers, collected at regular intervals throughout each filling operation.

(b) Tests and methods of assay—(1) Potency. Use either of the following methods; however, the results obtained from the microbiological agar diffusion assay shall be conclusive.

(i) Microbiological agar diffusion assay. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Reconstitute the sample as directed in the labeling for intramuscular use. Using a suitable hypodermic needle and syringe, remove all of the withdrawable contents if it is represented as a single dose container; or if the labeling specifies the amount of potency in a given volume of the resultant preparation, remove an accurately measured representative portion from each container. Further dilute an aliquot of this solution with solution 1 to the reference concentration of 10.0 micrograms of cephradine per milliliter (estimated).

(ii) Hydroxylamine colorimetric assay. Proceed as directed in § 442.40(b)(1)(ii), preparing the sample as follows: Reconstitute the sample as directed in the labeling for intramuscular use. Using a suitable hypodermic needle and syringe, remove all of the withdrawable contents if it is represented as a single dose container; or if the labeling specifies the amount of potency in a given volume of the resultant preparation, remove an accurately measured representative portion from each container. Further dilute an aliquot of this solution with distilled water to 1 milligram of cephradine per milliliter (estimated)

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

(3) Pyrogens. Proceed as directed in § 436.32(b) of this chapter, using a solution containing 80 milligrams of cephradine per milliliter.

(4) [Reserved]

(5) Loss on drying. Proceed as directed in § 436.200(b) of this chapter.

(6) pH. Proceed as directed in § 436.202 of this chapter, using an aqueous solution containing 10 milligrams per milliliter.

[40 FR 51626, Nov. 6, 1975. Redesignated at 43 FR 14646, Apr. 7, 1978; 50 FR 19919, May 13, 1985]

§ 442.240b Sterile cephradine.

The requirements for certification and the tests and methods of assay for sterile cephradine packaged for dispensing are described in § 442.40a.

[43 FR 14646, Apr. 7, 1978]

§ 442.250 Ceforanide for injection.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Ceforanide for injection is a dry mixture of ceforanide and L-lysine. Each milligram of ceforanide for injection contains not less than 900 micrograms and not more than 1,050 micrograms of ceforanide when corrected for L-lysine content. Its ceforanide content is satisfactory if it contains not less than 90 percent and not more than 115 percent of the number of milligrams of ceforanide that it is represented to contain. It is sterile. It is nonpyrogenic. Its moisture content is not more than 3.0 percent. When reconstituted as directed in the labeling, its pH is not less than 5.5 and not more than 8.5. The ceforanide used conforms to the standards prescribed by § 442.50a(a)(1).

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

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

(i) Results of tests and assays on: (a) The sterile ceforanide used in making the batch for ceforanide content, moisture, pH, and identity.

(b) The batch for ceforanide content, sterility, pyrogens, moisture, and pH.

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

(a) The ceforanide used in making the batch: 10 packages, each containing approximately 500 milligrams.

(b) The batch:

(1) For all tests except sterility: A minimum of 10 immediate containers.

(2) For sterility testing: 20 immediate containers, collected at regular intervals throughout each filling operation.

(b) Tests and methods of assay—(1) Ceforanide content. Determine both micrograms of ceforanide per milligram of sample and milligrams of ceforanide per container. Proceed as directed in §436.348 of this chapter, preparing the sample solution and calculating the ceforanide content as follows:

(i) Preparation of sample solution. Use separate containers for preparation of each sample solution as described in paragraph (b)(1)(i) (a) and (b) of this section.

(a) Micrograms of ceforanide per milligram. Prepare a solution containing 1.0 milligrams per milliliter in mobile phase. Inject each sample within 5 minutes after dissolution.

(b) Milligrams of ceforanide per container. Reconstitute the sample with distilled water as directed in the labeling. Using a suitable hypodermic needle and syringe, remove all of the withdrawable contents if it is represented as a single-dose container; or, if the labeling specifies the amount of ceforanide content in a given volume of the resultant preparation, remove an accurately measured representative portion from each container. Dilute with mobile phase to obtain a stock solution containing 10.0 milligrams per milliliter (estimated). Immediately dilute an aliquot of the stock solution with mobile phase to a concentration of 1.0 milligrams of ceforanide per milliliter (estimated). Inject within 5 minutes, after preparation.

(ii) Calculations—(a) Micrograms of ceforanide per milligram. Calculate the micrograms of ceforanide per milligram of sample as follows:

(2) Sterility. Proceed as directed in § 436.20 of this chapter, using the method described in paragraph (e)(1) of that section, except reconstitute the vials with approximately 3.0 milliliters of diluting fluid A per each gram of antibiotic activity. Transfer approximately 1 milliliter from each of 20 vials into a sterile 500-milliliter Erlenmeyer flask containing 200 milliliters of diluting fluid A. Filter as described in paragraph (e)(1)(ii) of this section, except in lieu of filtering with three 100-milliliter quantities of diluting fluid A, rinse the filter membrane with three 100-milliliter portions of diluting fluid D followed by a final rinse with 100 milliliters of diluting fluid A.

(3) Pyrogens. Proceed as directed in § 436.32(b) of this chapter, using a solution containing 50 milligrams of ceforanide per milliliter.

(4) Moisture. Proceed as directed in § 436.201 of this chapter.

(5) pH. Proceed as directed in §436.202 of this chapter, using the solution obtained when the product is reconstituted as directed in the labeling.

[49 FR 25848, June 25, 1984; 49 FR 34347, Aug. 30, 1984; 49 FR 40006, Oct. 12, 1984, as amended at 55 FR 11583, Mar. 29, 1990]

§ 442.253 Cefotetan injectable dosage forms.

§ 442.253a Sterile cefotetan disodium.

The requirements for certification and the tests and methods of assay for sterile cefotetan disodium packaged for dispensing are described in § 442.53a.

[51 FR 20264, June 4, 1986. Redesignated at 59 FR 26941, May 25, 1994]

§ 442.253b Cefotetan sodium injection.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Cefotetan sodium injection is a frozen, aqueous, iso-osmotic solution of cefotetan and sodium bicarbonate. It contains one or more suitable and harmless buffer substances and a tonicity adjusting agent. Each milliliter contains cefotetan disodium equivalent to 20 milligrams or 40 milligrams of cefotetan per milliliter. Its cefotetan content is satisfactory if it is not less than 90 percent and not more than 120 percent of the number of milligrams of cefotetan that it is represented to contain. It is sterile. It contains not more than 0.17 endotoxin units per milligram of cefotetan. Its pH is not less than 4.0 and not more than 6.5. It passes the identity test. The cefotetan used conforms to the standards prescribed by § 442.52(a)(1).

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

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

(i) Results of tests and assays on: (A) The cefotetan used in making the batch for cefotetan potency, moisture, and identity.

(B) The batch for cefotetan potency, sterility, bacterial endotoxins, pH, and identity.

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

(A) The cefotetan used in making the batch: 10 packages, each containing approximately 500 milligrams.

(B) The batch:

(1) For all tests except sterility: A minimum of 12 immediate containers.

(2) For sterility testing: 20 immediate containers, collected at regular intervals throughout each filling operation.

(b) Tests and methods of assay. Thaw the sample as directed in the labeling. The sample solution used for testing must be at room temperature.

(1) Cefotetan potency. Proceed as directed in §442.52(b)(1), except prepare the sample solution and calculate the cefotetan content as follows:

(1) Preparation of sample solution. Using a suitable hypodermic needle and syringe, remove an accurately measured portion from each container immediately after thawing and reaching room temperature and dilute with mobile phase to obtain a solution containing 200 micrograms of cefotetan per milliliter (estimated). Prepare the sample solution just prior to its introduction into the chromatograph.

(ii) Calculation. Calculate the milligrams of cefotetan per milliliter of sample as follows:

Au-Area of the cefotetan peak in the chromatogram of the sample (at a retention time equal to that observed for the standard);

As-Area of the cefotetan peak in the chromatogram of the cefotetan working standard;

P-Cefotetan activity in the cefotetan work

ing standard solution in micrograms per milliliter;

Cu-Milligrams of sample per milliliter of sample solution; and

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

(3) Bacterial endotoxins. Proceed as directed in the U.S. Pharmacopeia bacterial endotoxins test.

(4) pH. Proceed as directed in §436.202 of this chapter, using the undiluted solution.

(5) Identity. The high-performance liquid chromatogram of the sample determined as directed in paragraph (b)(1) of this section compares quali

tatively to that of the cefotetan working standard.

[59 FR 26941, May 25, 1994]

§ 442.255 Ceftriaxone injectable dosage forms.

§ 442.255a Sterile ceftriaxone sodium.

The requirements for certification and the tests and methods of assay for sterile ceftriaxone sodium packaged for dispensing as described in § 442.55a.

[50 FR 10001, Mar. 13, 1985. Redesignated at 52 FR 44860, Nov. 23, 1987]

§ 442.255b Ceftriaxone sodium injection.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Ceftriaxone sodium injection is a frozen aqueous iso-osmotic solution of ceftriaxone sodium which may contain one or more suitable and harmless buffer substances. Each milliliter contains ceftriaxone sodium equivalent to 10, 20, or 40 milligrams of ceftriaxone per milliliter. Its ceftriaxone content is satisfactory if it is not less than 90 percent and not more than 115 percent of the number of milligrams of ceftriaxone that it is represented to contain. It is sterile. It is nonpyrogenic. Its pH is not less than 6.0 and not more than 8.0. It passes the identity test. The ceftriaxone sodium used conforms to the standards prescribed by § 442.55(a)(1).

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

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

(i) Results of tests and assays on:

(A) The ceftriaxone sodium used in making the batch for potency, moisture, pH, crystallinity, and identity.

(B) The batch for content, sterility, pyrogens, pH, and identity.

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

(A) The ceftriaxone sodium used in making the batch: 10 packages, each containing 500 milligrams.

(B) The batch:

(1) For all tests except sterility: A minimum of 10 immediate containers.

(2) For sterility testing: 20 immediate containers, collected at regular intervals throughout each filling operation.

(b) Tests and methods of assay. Thaw the sample as directed in the labeling. The sample solution used for testing must be at room temperature.

(1) Ceftriaxone content. Proceed as directed in §442.55a(b)(1) of this chapter, except prepare the sample solution and calculate the ceftriaxone content as follows:

(i) Preparation of sample solution. Using a suitable hypodermic needle and syringe, remove an accurately measured representative portion from each container immediately after thawing and reaching room temperature and dilute with mobile phase to obtain a solution containing 180 micrograms of ceftriaxone per milliliter (estimated). Prepare the sample solution just prior to its introduction into the chromatograph.

(ii) Calculation. Calculate the milligrams of ceftriaxone anhydrous free acid per milliliter of sample as follows:

Milligrams of ceftriaxone anhydrous free acid per milliliter

where:

A x P x d

น

A, × 1,000

A=Area of the ceftriaxone peak in the chromatogram of the sample (at a retention time equal to that observed for the standard);

A,=Area of the ceftriaxone peak in the chromatogram of the ceftriaxone working standard;

P,=Ceftriaxone activity in the ceftriaxone working standard solution in micrograms of anhydrous free acid per milliliter; and

d=Dilution factor of the sample.

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

(3) Pyrogens. Proceed as directed in § 436.32(a) of this chapter, except inject a sufficient volume of the undiluted solution to deliver 40 milligrams of ceftriaxone per kilogram.

(4) pH. Proceed as directed in §436.202 of this chapter, using the undiluted solution.

(5) Identify. The high-performance liquid chromatogram of the sample determined as directed in paragraph (b)(1) of this section compares quali

tatively to that of the ceftriaxone working standard.

[52 FR 44860, Nov. 23, 1987, as amended at 55 FR 11583, Mar. 29, 1990]

§442.258 Cefotiam dihydrochloride for injection.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Cefotiam dehydrochloride for injection is a dry mixture of cefotiam dihydrochloride and sodium carbonate. Its cefotiam potency is satisfactory if each milligram of cefotiam dihydrochloride for injection contains not less than 790 micrograms and not more than 925 micrograms of cefotiam on an anhydrous basis, when corrected for sodium carbonate content. Its cefotiam content is satisfactory if it contains not less than 90 percent and not more than 120 percent of the number of milligrams of cefotiam that it is represented to contain. It is sterile. It is nonpyrogenic. Its loss on drying is not more than 6.0 percent. The pH of an aqueous solution containing 100 milligrams per milliliter is not less than 5.7 and not more than 7.2. The cefotiam dihydrochloride used conforms to the standards prescribed by § 442.58a(a)(1).

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

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

(1) Results of tests and assays on: (A) The cefotiam dihydrochloride used in making the batch for potency, moisture, identity, and crystallinity.

(B) The batch for cefotiam potency, cefotiam content, sterility, pyrogens, loss on drying, pH, and sodium carbonate content.

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

(A) The cefotiam dihydrochloride used in making the batch: 10 packages, each containing approximately 500 milligrams.

(B) The batch:

(1) For all tests except sterility: A minimum of 10 immediate containers. (2) For sterility testing: 20 immediate containers, collected at regular intervals throughout each filling operation.