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further dilute to 1 milligram of cephradine per milliliter (estimated).

(e) Procedure. Use the standard and sample solutions prepared as indicated in paragraph (b)(1)(ii) (c) and (d) of this section respectively. The arrangement

of the apparatus and flow of samples and reagents are shown in the manifold diagram set forth in this paragraph (b)(1)(ii)(e). The sampler rate is usually 40 per hour, but may be varied.

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where:

Ar=Absorbance of sample solution;
Pg=Potency of working standard solution

in micrograms, per milliliter; A3=Absorbance of working standard solu

tion; Wu=Milligrams of sample per milliliter of

sample solution; m=Percent moisture in sample.

(iii)
High-pressure

liquid chromatographic assay. Proceed as directed in § 436.337 of this chapter, preparing the sample as described in paragraph (e)(3)(i) of that section.

(2) [Reserved)

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

(4) PH. Proceed as directed in $436.202 of this chapter, using an aqueous solution containing 10 milligrams per milliliter.

(5) Cephalexin content. Proceed as directed in $ 436.337 of this chapter.

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

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

(vi) Its pH in an aqueous solution containing 10 milligrams per milliliter is not less than 3.5 and not more than 6.0.

(vii) Its cephalexin content is not more than 5 percent on an anhydrous basis.

(viii) It passes the identity test. (ix) It is crystalline.

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

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

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

(ii) Samples required:

(a) If the batch is packaged for repacking or for manufacturing use:

(1) For all tests except sterility: 10 packages, each containing approximately 500 milligrams.

(2) For sterility testing: 1 package containing approximately 6 grams of a composite sample.

(6) If the batch is packaged for dispensing:

(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 any of the following methods; however, the results obtained from the microbiological agar

diffusion assay shall be conclusive.

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

accurately weighed sample in sufficient 1 percent potassium phosphate buffer, pH 6.0 (80lution 1), to give a stock solution containing 1.0 milligram of cephradine per milliliter (estimated); also, if it is packaged for dispensing, reconstitute the sample as directed in the labeling, except use distilled water in lieu of reconstituting fluid. Then using a suitable hypodermic needle and syringe, remove an accurately measured representative portion from each container. Dilute with solution 1 to give a

[40 FR 26270, June 23, 1975, as amended at 45 FR 16474, Mar. 14, 1980; 46 FR 25608, May 8, 1981; 48 FR 51293, Nov. 8, 1983; 49 FR 47485, Dec. 5, 1984; 50 FR 19919, May 13, 1985)

an

$ 442.40a Sterile cephradine.

(a) Requirements for certification (1) Standards of identity, strength, quality, and purity. Cephradine is 7-[D-2 - amino -2- (1,4 cyclohexadien 1 -yl) acetamido] - 3 - methyl - 8 - OXO - 5-thia - 1- azabicyclo[4.2.0]oct -2 ene-2-carboxylic acid. It is so purified and dried that:

(1) Its potency is not less than 900 and not more than 1,050 micrograms of cephradine per milligram on the anhydrous basis. If it is packaged for dispensing, its cephradine content is satisfactory if it is not less than 90 percent and not more than 115 percent of the number of milligrams of cephradine that it is represented to contain.

(ii) It is sterile.
(iii) It is nonpyrogenic.
(iv) [Reserved]

(v) Its moisture content is not more than 6.0 percent.

stock solution of convenient concentration. Further dilute an aliquot of the stock solution with solution 1 to the reference concentration of 10 micrograms of cephradine per milliliter (estimated).

(ii) Hydroxylamine colorimetric assay. Proceed as directed in $ 442.40(b)(1)(ii). If packaged for dispensing, reconstitute the sample as directed in the labeling using distilled water instead of the reconstituting fluid. Further dilute an aliquot of this solution with distilled water to 1 milligram of cephradine per milliliter (estimated). (iii) High-pressure

liquid chromatographic assay. Proceed as directed in $436.337 of this chapter.

(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 80 milligrams of cephradine per milliliter.

(4) [Reserved]

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

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

(7) Cephalexin content. Proceed as directed in $ 442.40(b)(5).

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

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

(ii) (Reserved]

(iii) Its moisture content is not less than 8.5 percent and not more than 10.5 percent.

(iv) Its pH in an aqueous solution containing 10 milligrams per milliliter is not less than 3.5 and not more than 6.0.

(v) Its cephalexin content is not more than 5 percent on an anhydrous basis.

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

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

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

(i) Results of tests and assays on the batch for potency, moisture,

PH, cephalexin content, identity, and crystallinity.

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

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

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

follows: Dissolve an accurately weighed sample in sufficient 1 percent potassium phosphate buffer, pH 6.0 (solution 1), to obtain a stock solution of convenient concentration. Further dilute an aliquot of the stock solution with solution 1 to the reference concentration of 10.0 micrograms of cephradine per milliliter (estimated).

(ii) Hydroxylamine colorimetric assay for cephtadine. Proceed as directed in $ 442.40(b)(1)(ii). (iii) High-pressure

liquid chromatographic assay. Proceed as directed in $ 436.337 of this chapter, preparing the sample as described in paragraph (e)(3)(i) of that section.

(2) (Reserved]

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

(4) PH. Proceed as directed in $436.202 of this chapter, using an aqueous solution containing 10 milligrams per milliliter.

as

[40 FR 51626, Nov. 6, 1975, as amended at 43 FR 14646, Apr. 7, 1978; 49 FR 47485, Dec. 5, 1984; 50 FR 19919, May 13, 1985)

$ 442.41 Cephradine dihydrate.

(a) Requirements for certification-(1) Standards of identity, strength, quality, and purity. Cephradine dihydrate is the dihydrate form of (6R,7R)-7-[(R)-2amino-2-(1,4-cyclohexadien-1yl)acetamido)-3-methyl-8-oxo-5-thia-1azabicyclo(4.2.0]oct-2-ene-2-carboxylic acid. It is so purified and dried that:

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

179 070 0-98-21

(5) Cephalexin content. Proceed as directed in 436.337 of this chapter.

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

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

the sample and calculating the ceforanide content as follows:

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

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

[47 FR 11856, Mar. 19, 1982, as amended at 49 FR 47485, Dec. 5, 1984; 50 FR 19919, May 13, 1985)

Micrograms of

A, XP, ceforanide

per milligram A, XC where: As = Area of the ceforanide peak in the chro

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

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

matogram of the ceforanide working

standard; Ps = Ceforanide activity in the ceforanide

working standard solution in

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

sample solution.

$ 442.50a Sterile ceforanide.

(a) Requirements for certification-(1) Standards of identity, strength, quality, and purity. Ceforanide is 5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,

7-[[[2-amino-methyl)phenyljacetyl)amino]-3-[[[1(carboxymethyl)-1H-tetrazol-5-yl)thio]methyl)-8-oxo-,(6R-trans)-. It is a white to off-white powder. It is so purified and dried that:

(i) Its ceforanide content is not less than 900 micrograms and not more than 1,050 micrograms of ceforanide per milligram.

(ii) It is sterile.
(iii) It is nonpyrogenic.

(iv) Its moisture content is not more than 5.0 percent.

(v) Its pH in an aqueous suspension containing 50 milligrams per milliliter is not less than 2.5 and not more than 4.5.

(vi) It passes the 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 ceforanide content, sterility, pyrogens, moisture, pH, and identity.

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

(a) For all tests except sterility: 10 packages, each containing approximately 500 milligrams.

(6) For sterility testing: One package containing approximately 6 grams of a composite sample.

(b) Tests and methods of assay-(1) Ceforanide content. Proceed as directed in $436.348 of this chapter, preparing

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

(i) In paragraph (e)(1)(1)(a) of that section, use diluting fluid G in lieu of diluting fluid A; and

(ii) In lieu of three 100-milliliter quantities of diluting fluid A in paragraph (e)(2) of that section, filter three 100-milliliter quantities of diluting fluid D followed by a 100-milliliter quantity of diluting fluid A.

(3) Pyrogens. Proceed as directed in $ 436.32(b) of this chapter, except suspend 1 gram of sterile ceforanide in 12.5 milliliters of pyrogen-free water (diluent 1). Add 320 milligrams of pyrogenfree L-lysine base, shake to dissolve the mixture. If the mixture is not dissolved, add an amount of L-lysine necessary to obtain a solution. The test sample should contain not more than a total of 340 milligrams of L-lysine. Dilute the resulting solution to 20 milliliters. Use a test dose of 1 milliliter of the 50 milligrams per milliliter test solution per kilogram of rabbit weight.

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

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