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(b) Tests and methods of assay—(1) Cefotiam potency and content. Determine both micrograms of cefotiam per milligram of sample and milligrams of cefotiam per container. Proceed as directed in $442.58a(b)(1), preparing the sample solutions and calculating the potency and content as follows:

(i) Preparation of sample solutions. Use separate containers for preparation of each sample solution as described in paragraphs (b)(1)(i) (A) and (B) of this section.

(A) Cefotiam potency (micrograms of cefotiam per milligram). Dissolve an accurately weighed sample with sufficient distilled water to obtain a solution containing approximately 1,000 micrograms of cefotiam per milliliter. Further dilute this solution with mobile phase to obtain a solution containing 50 micrograms of cefotiam activity per milliliter (estimated).

(B) Cefotiam content (milligrams of cefotiam per vial). Reconstitute the sample as directed in the labeling. Then, 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. Dilute the solution thus obtained with sufficient distilled water to obtain a solution containing 1,000 micrograms of cefotiam activity per milliliter (estimated). Further dilute this solution with mobile phase to obtain a solution containing 50 micrograms of cefotiam activity per milliliter (estimated).

(ii) Calculations—(A) Cefotiam potency (micrograms per milligram). Calculate the micrograms of cefotiam per milligram as follows:

where: Au-Area of the cefotiam peak in the chro

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

standard); Ag=Area of the cefotiam peak in the chro

matogram of the cefotiam working

standard; P =Cefotiam activity in the cefotiam work

ing standard solution in micrograms 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(g) of this chapter, using a solution containing 40

40 milligrams of cefotiam per milliliter.

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

(5) PH. Proceed as directed in 8436.202 of this chapter, using an aqueous solution containing 100 milligrams per milliliter.

(6) Sodium carbonate content. Proceed as directed in $436.357 of this chapter.

(54 FR 20786, May 15, 1989)

Micrograms of

A, XP, X100 cefotiam per

milligram Ą XC, X(100-L-S) where: Av=Area of the cefotiam peak in the chro

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

standard); Ar=Area of the cefotiam peak in the chro

matogram of the cefotiam working

standard; P =Cefotiam activity in the cefotiam work

§ 442.260 Cefpiramide sodium for in

jection. (a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Cefpiramide sodium for injection is a dry mixture of cefpiramide and sodium benzoate. It contains other buffers and preservatives.

Its cefpiramide potency is satisfactory if each milligram of cefpiramide sodium for injection contains not less than 754 micrograms and not more than 924 containing approximately 0.25 milligram of cefpiramide per milliliter (estimated).

(B) Cefpiramide content (milligrams of cefpiramide per vial). Reconstitute the sample as directed in the labeling. Then, 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, Dilute the solution thus obtained with sufficient distilled water to obtain a solution containing 1.0 milligram of cefpiramide activity per milliliter (estimated). Further dilute this solution with mobile phase to obtain a solution containing 0.25 milligram of cefpiramide activity per milliliter (estimated).

(ii) Calculations.---(A) Cefpiramide potency (micrograms per milligram). Calculate the micrograms of cefpiramide per milligram as follows:

micrograms of cefpiramide on an anhydrous basis. Its cefpiramide content is satisfactory if it contains not less than 90 percent and not more than 120 percent of the number of milligrams of cefpiramide that it is represented to contain. It is sterile. It is nonpyrogenic. Its moisture content is not more than 3.0 percent. Its pH in an aqueous solution containing 100 milligrams per milliliter is not less than 6.0 and not more than 8.0. It passes the identity test. The cefpiramide used conforms to the standards prescribed by $442.60(a)(1).

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

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

(i) Results of tests and assays on:

(A) The cefpiramide used in making the batch for potency, moisture, pH, total related substances, specific rotation, identity, and crystallinity.

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

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

(A) The cefpiramide 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) Cefpiramide potency and content. Determine both micrograms of cefpiramide per milligram of sample and milligrams of cefpiramide per container. Proceed as directed in $442.60(b)(1), preparing the sample solutions and calculating the potency and content as follows:

(i) Preparation of sample solutions. Use separate containers for preparation of each sample solution as described in paragraphs (b)(1)(1)(A) and (b)(1)(i)(B) of this section.

(A) Cefpiramide potency (micrograms of cefpiramide per milligram). Dissolve an accurately weighed sample with sufficient mobile phase to obtain a solution

Micrograms of

A, XP, x100 cefpiramide

per milligram A, XC X(100-m) where:

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

As=Area of the cefpiramide peak in the chromatogram of the cefpiramide working standard;

Po=Cefpiramide activity in the cefpiramide working standard solution in micrograms per milliliter;

C.=Milligrams of the sample per milliliter of sample solution;

m =Percent moisture content of the sample.

(B) Cefpiramide content (milligrams of cefpiramide per vial). Calculate the cefpiramide content of the vial as follows:

Milligrams of cefpiramide A, XP, xd per vial

Ą, X1,000

where:

Ar=Area of the cefpiramide peak in the chromatogram of the sample (a ta retention time equal to that observed for the standards);

Ag-Area of the cefpiramide peak in the chromatogram of the cefpiramide working standard;

Pg=Cefpiramide activity in the cefpiramide working standard solution in micrograms 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 8 436.20(e)(1).

(3) Pyrogens. Proceed as directed in 8 436.32(b) of this chapter, using a solution containing 50 milligrams of cefpiramide 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 an aqueous solution containing 100 milligrams per milliliter.

(6) Identify. The high-performance liquid chromatogram of the sample determined directed in paragraph (b)(1) of this section compares qualitatively to that of the cefpiramide working standard.

as

passes

the identity test. The cefmetazole used conforms to

to the standards prescribed by $442.69(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 cefmetazole used in making the batch for potency, moisture, and identity.

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

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

(A) The cefmetazole 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) Cefmetazole potency. Proceed as directed in $442.70a(b)(1), except prepare the sample solution and calculate the cefmetazole content as follows:

(i) 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 500 micrograms of cefmetazole per milliliter (estimated). Prepare the sample solution just prior to its introduction into the chromatograph.

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

(55 FR 14242, Apr. 17, 1990)

§ 442.270 Cefmetazole injectable dos

age forms.

8442.270a Sterile cefmetazole sodium.

The requirements for certification and the tests and methods of assay for sterile cefmetazole sodium packaged for dispensing are described in 442.70a.

(55 FR 6636, Feb. 26, 1990]

$ 442.270b Cefmetazole sodium injec

tion. (a) Requirements for certification (1) Standards of identity, strength, quality, and purity. Cefmetazole sodium injection is a frozen, aqueous, iso-osmotic solution of cefmetazole and sodium citrate. It contains one or more suitable and harmless buffer substances and a tonicity adjusting agent. Each milliliter contains cefmetazole sodium equivalent to 20 milligrams or 40 milligrams of cefmetazole per milliliter. Its cefmetazole content is satisfactory if it is not less than 90 percent and not more than 120 percent of the number of milligrams of cefmetazole that it is represented to contain. It is sterile. It contains not more than 0.2 endotoxin units per milligram. Its pH is not less than 4.2 and not more than 6.2. It

Milligrams of cefmetazole _ A, XP, xd per milliliter

A x1,000

where:

Au=Area of the cefmetazole peak in the chro

matogram of the - sample (at a retention time equal to that observed for the standard);

179 070 0498—--23

As=Area of the cefmetazole peak in the chro

matogram of the cefmetazole working

standard; Ps=Cefmetazole activity in the cefmetazole

working standard solution in

micrograms 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) Bacterial endotoxins. Proceed as directed in the United States 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

directed in paragraph (b)(1) of this section compares qualitatively to that of the cefmetazole working standard.

as

(59 FR 12546, Mar. 17, 1994]

PART 443-CARBACEPHEM

ANTIBIOTIC DRUGS

(ii) Its moisture content is not less than 3.5 percent and not more than 6.0 percent.

(iii) The pH of an aqueous slurry containing 100 milligrams per milliliter is not less than 3.5 and not more than 5.5.

(iv) Its specific rotation in an 0.1 N HCl solution containing 10 milligrams of loracarbef per milliliter at 25° C is +27°to +33° on an anhydrous basis.

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

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

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

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

(ii) Samples, if required by the Director, Center for Drug Evaluation and Research: 10 packages, each containing approximately 500 milligrams.

(b) Tests and methods of assay—(1) Potency. Proceed as directed in $436.216 of this chapter, using ambient temperature, an ultraviolet detection system operating at wavelength of 265 nanometers, a 25-centimeter by 4.6-millimeter (inside

diameter) column packed with microparticulate (5 micrometers in diameter) reversed phase packing material such as octadecyl silane bonded to silicas, a flow rate of 1.5 milliliters per minute, and a known injection volume between 10 and 20 microliters. The retention time for loracarbef is between 10 and 13 minutes. Mobile phase, working standard, sample and resolution test solutions, system suitability requirements, and calculations are as follows:

(i) Mobile phase. Dissolve 2.0 grams of pentanesulfonic acid sodium salt monohydrate in 1,560 milliliters of water. Add 20 milliliters of triethylamine. Adjust the pH to 2.5 with phosphoric acid. Add 440 milliliters of methanol and mix. Filter the mobile phase through a suitable filter capable of removing particulate matter 0.5 micron in diameter and degas it just prior to its introduction into the chromatograph.

Subpart A-Bulk Drugs

Sec. 443.20 Loracarbef.

а.

Subpart B-Oral Dosage Forms

443.120 Loracarbef oral dosage forms. 443.120a Loracarbef capsules. 443.120b Loracarbef for oral suspension.

AUTHORITY: 21 U.S.C. 357.

SOURCE: 58 FR 26667, May 4, 1993, unless otherwise noted.

Subpart A-Bulk Drugs

$ 443.20 Loracarbef.

(a) Requirements for certification (1) Standards of identity, strength, quality, and purity. Loracarbef is the monohydrate form of (6R,7S)-7-[(R)-2amino-2-phenylacetamido)-3-chloro-8oxo-1-azabicyclo[4.2.O]oct-2-ene-2-carboxylic acid. It is so purified and dried that:

(i) Its potency is not less than 960 micrograms and not more than 1,020 micrograms of loracarbef activity per milligram, on an anhydrous basis.

а.

where: Au=Area of the loracarbef peak in the chro

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

standard); As=Area of the loracarbef peak in the chro

matogram of the loracarbef working

standard; Ps=Loracarbef activity in the loracarbef

working standard solution in

micrograms per milliliter; Cu=Milligrams of sample per milliliter of

sample solution; and m = Percent moisture content of the sample.

(ii) Preparation of working standard, sample, and resolution test solutions—(A) Working standard solution. Accurately weigh approximately 10 milligrams of the loracarbef working reference standard into 50-milliliter volumetric flask. Dissolve and dilute to volume with mobile phase. Brief sonication may be required to obtain complete dissolution of the material.

(B) Sample solution. Accurately weigh approximately 10 milligrams of sample into a 50-milliliter volumetric flask. Dissolve and dilute to volume with mobile phase. Brief sonication may be required to obtain complete dissolution of the material.

(C) Resolution test solution. Prepare a resolution test solution containing approximately 0.2 milligram per milliliter each of loracarbef and loracarbef L-isomer in the mobile phase.

(iii) System suitability requirements(A) Asymmetry factor. The asymmetry factor (As) at 5 percent peak height is satisfactory if it is not less than 0.8 and not more than 1.3 for the loracarbef peak.

(B) Efficiency of the column. The absolute efficiency (hr) is satisfactory if it is not more than 20 for the loracarbef peak.

(C) Resolution factor. The resolution factor (R) (R) between the

peak for loracarbef and the peak for the resolution standard loracarbef L-isomer in the resolution test solution is satisfactory if it is not less than 6.0.

(D) Coefficient of variation (relative standard deviation). The coefficient of variation (Sr in percent of 5 replicate injections) is satisfactory if it is not more than 2.0 percent.

(E) Capacity factor (k'). The capacity factor (k') for loracarbef is satisfactory if it is not less than 5 and not more than 8. If the system suitability parameters have been met, then proceed as described in 8436.216(b) of this chapter.

(iv) Calculations. Calculate the micrograms of loracarbef per milligram of sample on an anhydrous basis as follows:

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

(3) PH. Proceed as directed in $ 436.202 of this chapter, using an aqueous suspension containing 100 milligrams per milliliter.

(4) Specific rotation. Dissolve and dilute an accurately weighed sample with sufficient 0.1 N HCl to obtain a concentration of approximately 10 milligrams of loracarbef activity per milliliter. Proceed as directed in $436.210 of this chapter, using a 1.0-decimeter polarimeter tube. Calculate the specific rotation on the anhydrous basis.

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

(6) Identity. Proceed as directed in $436.211 of this chapter, using the 1.0 percent potassium bromide disc prepared as described in $436.211(b)(1).

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or

8 443.120a Loracarbef capsules.

(a) Requirements for certification-(1) Standards of identity, strength, quality, and purity. Loracarbef capsules are composed of loracarbef and one more suitable and harmless lubricants and diluents enclosed in a gelatin capsule. Each capsule contains loracarbef equivalent to either 200 milligrams or 400 milligrams of loracarbef. Its loracarbef content is satisfactory if it is not less than 90 percent and not more than 110 percent of the number of milligrams of loracarbef that it is represented to contain. Its moisture content is not more than 8.5 percent. It passes the dissolution test. It passes the identity test. The loracarbef used

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