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P-Hetacillin content of the hetacillin working standard in percent.

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

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

[39 FR 18976, May 30, 1974, as amended at 42 FR 59857, Nov. 22, 1977; 44 FR 10379, Feb. 20, 1979; 50 FR 19918, May 13, 1985]

§ 440.29 Hetacillin potassium.

(a) Requirements for certification—(1) Standards of identity, strength, quality and purity. Hetacillin potassium is the potassium salt of hetacillin. It occurs as a fine, white to light buff powder. It is so purified and dried that:

(1) Its potency is not less than 735 micrograms of ampicillin per milligram.

(ii) [Reserved]

(iii) Its moisture content is not more than 1.0 percent.

(iv) Its pH in an aqueous solution containing 10 milligrams per milliliter is not less than 7.0 and not more than 9.0.

(v) Its hetacillin content is not less than 82 percent and not more than 95.5 percent.

(vi) It gives a positive identity test for hetacillin potassium.

(vii) It is crystalline.

(2) Labeling. It shall be labeled in accordance with the requirements of § 432.5(b) 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, hetacillin content, identity, and crystallinity.

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

(b) Tests and methods of assay—(1) Potency. Proceed as directed for ampicillin in § 436.105 of this chapter, using the ampicillin working standard as the standard of comparison and preparing the sample for assay as follows: Dissolve an accurately weighed sample in sufficient 0.1M potassium phosphate buffer pH 8.0 (solution 3), to give a

stock solution of convenient concentration. Further dilute the stock solution with solution 3 to the reference concentration of 0.1 microgram of ampicillin per milliliter (estimated). (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) Hetacillin content. Proceed as directed in § 440.25(b)(5), except use about 110 milligrams of sample and calculate the hetacillin content as follows:

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C=Concentration in milligrams of hetacillin per milliliter of the final solution of the sample obtained from the standard response line.

P-Hetacillin content of the hetacillin working standard in percent.

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

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

[39 FR 18976, May 30, 1974, as amended at 42 FR 59857, Nov. 22, 1977; 44 FR 10379, Feb. 20, 1979; 50 FR 19918, May 13, 1985]

§ 440.29a Sterile hetacillin potassium.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Hetacillin potassium is the potassium salt of hetacillin. It occurs as a fine, white to light buff powder. It is so purified and dried that:

(i) Its potency is not less than 735 micrograms of ampicillin per milligram. If it is packaged for dispensing, its potency is satisfactory if it contains not less than 90 percent and not more than 120 percent of the number of milligrams of ampicillin that it is represented to contain.

(ii) It is sterile.

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

(v) Its moisture content is not more than 1.0 percent.

(vi) Its pH in an aqueous solution containing 10 milligrams per milliliter (or when reconstituted as directed in the labeling, if it is packaged for dispensing) is not less than 7.0 and not more than 9.0.

(vii) Its hetacillin content is not less than 82 percent and not more than 95.5 percent.

(viii) It gives a positive identity test for hetacillin potassium.

(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, hetacillin content, identity, and crystallinity.

(ii) Samples required:

(a) If the batch is packaged for repacking or for use in the manufacture of another drug:

(1) For all tests except sterility: 10 packages, each containing approximately 300 milligrams.

(2) For sterility testing: 20 packages, each containing approximately 300 milligrams.

(b) If the batch is packaged for dispensing:

(1) For all tests except sterility: A minimum of 10 immediate containers, except if each contains less than 450 milligrams, a minimum of 16 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. Proceed as directed for ampicillin in §436.105 of this chapter, using the ampicillin working standard as the standard of comparison and preparing the sample for assay as follows: Dissolve an accurately weighed sample in sufficient 0.1M potassium phosphate buffer, pH 8.0 (solution 3), to give a stock solution of convenient concentration; and also if it is packaged for dispensing, reconstitute as directed in the labeling. Then, using a suitable hypodermic needle and syringe, remove the withdrawable contents from each container represented as a single-dose

container; or if the labeling specifies the amount of potency in a given volume of the resultant preparation, withdraw an accurately measured representative portion from each container. Dilute the sample thus obtained with sufficient solution 3 to give a stock solution of convenient concentration. Further dilute the stock solution with solution 3 to the reference concentration of 0.1 microgram of ampicillin 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(a) of this chapter using a solution containing the equivalent of 18 milligrams of ampicillin 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 (or using a solution reconstituted as directed in the labeling, if it is packaged for dispensing).

(7) Hetacillin content. Proceed as directed in § 440.25(b)(5), except use about 110 milligrams of sample and calculate the potassium hetacillin content as follows:

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C=Concentration in milligrams of hetacillin per milliliter of the final solution of the sample obtained from the standard response line.

P=Hetacillin content of the hetacillin working standard in percent.

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

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

[39 FR 19876, May 30, 1974, as amended at 42 FR 59857, Nov. 22, 1977; 43 FR 2393, Jan. 17, 1978; 44 FR 10379, Feb. 20, 1979; 50 FR 19918, May 13, 1985]

§ 440.36a Sterile methicillin sodium monohydrate.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Methicillin sodium monohydrate is the monohydrated sodium salt of (2,6-dimethoxyphenyl) penicillin. It is so purified and dried that:

(i) It contains not less than 815 micrograms of methicillin per milligram.

(ii) It is sterile.

(iii) It is nonpyrogenic.

(iv) [Reserved]

(v) Its moisture content is not less than 3 percent and not more than 6 percent.

(vi) Its pH in an aqueous solution containing 10 milligrams per milliliter is not less than 5.0 and not more than 7.5.

(vii) Its methicillin content is not less than 81.5 percent.

(viii) It is crystalline.

(ix) It passes the identity test.

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

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

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

(ii) Samples required:

content,

(a) For all tests except sterility: 10 packages, each containing approximately 300 milligrams, plus one package containing approximately 2 grams.

(b) For sterility testing: 20 packages, each containing approximately 600 milligrams.

(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.

(i) Microbiological agar diffusion assay. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Dissolve an accurately

weighed portion of the sample in sufficient 1 percent potassium phosphate buffer, pH 6.0 (solution 1), to give a stock solution of convenient concentration. Further dilute an aliquot of the stock solution with solution 1 to the reference concentration of 10 micrograms of methicillin per milliliter (estimated).

(ii) Iodometric assay. Proceed as directed in § 436.204 of this subchapter.

(iii) Hydroxylamine colorimetric assay. Proceed as directed in § 436.205 of this subchapter.

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

(3) Pyrogens. Proceed as directed in § 436.32(a) of this chapter, using a solution containing 60 milligrams of methicillin per milliliter.

(4) [Reserved]

(5) Moisture. Proceed as directed in § 436.201 of this subchapter.

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

(7) Methicillin content. Dissolve an accurately weighed portion of the sample in a sufficient accurately measured volume of distilled water to obtain a concentration of 0.2 milligram of methicillin per milliliter (estimated). Treat a portion of the methicillin working standard in the same manner. Using a suitable spectrophotometer equipped with a 1-centimeter quartz cell and distilled water as the blank, determine the absorbance at 280 nanometers. If a recording spectrophotometer is used, record the ultraviolet absorption spectrum from 250 nanometers to 300 nanometers. If a nonrecording spectrophotometer is used, determine the absorbance (on a solution containing 10 milligrams per 100 milliliters) at the 280-nanometer absorption peak. (The exact position of the peak should be determined for the particular instrument used.) Calculate as follows:

Percent methicillin

Absorbance of sample x weight of working standard x volume of sample solution percent methicillin in working standard Absorbance of standard × weight of sample xvolume of standard solution

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of mezlocillin per milliliter at 25° C is 185°+10°.

(viii) It gives a positive identity test for mezlocillin.

(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, specific rotation, and identity.

(ii) Samples required:

(a) If it is packaged for repacking or for use in the manufacture of another drug:

(1) For all tests except sterility: 10 packages, each containing approximately 300 milligrams; and 5 packages, each containing approximately 1 gram.

(2) For sterility testing: 20 packages, each containing approximately 300 milligrams.

(b) If it is packaged for dispensing:

(1) For all tests except sterility: A minimum of 15 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 hydroxylamine colorimetric assay shall be conclusive.

(i) Hydroxylamine colorimetric assay. Proceed as directed in §442.40(b)(1)(ii) of this chapter, except:

(a) Buffer. In lieu of the buffer described in § 442.40(b)(1)(ii)(b)(2) of this chapter, use the buffer prepared as follows: Dissolve 200 grams of primary standard tris (hydroxymethyl) aminomethane in sufficient distilled water to make 1 liter. Filter before use. (b) Preparation of working standard solution. Dissolve and dilute an accurately weighed portion of the

Milligrams of mezlocillin

of

per multiple-dose vial

mezlocillin working standard with sufficient distilled water to obtain a concentration of 2.0 milligrams mezlocillin per milliliter.

(c) Preparation of sample solution. Dissolve an accurately weighed portion of the sample with sufficient distilled water to obtain a stock solution of convenient concentration; also, if packaged for dispensing, reconstitute as directed in the labeling using distilled water in lieu of the reconstituting fluid. 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 with distilled water to obtain a stock solution of convenient concentration. Further dilute an aliquot of the stock solution with distilled water to a concentration of 2.0 milligrams of mezlocillin per milliliter (estimated).

(d) Calculations-(1) Calculate the mezlocillin content in micrograms per milligram as follows:

Micrograms of mezlocillin per Au XP milligram of sample

where:

a

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Au-Absorbance of sample solution; Pa-Potency of working standard solution in micrograms per milliliter;

A, Absorbance of working standard solution;

d=Dilution factor of the sample;

n=Volume of sample solution assayed.

(ii) Iodometric assay. Proceed as directed in § 436.204 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(b) of this chapter, using a solution containing 100 milligrams of mezlocillin 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 100 milligrams of mezlocillin per milliliter.

(7) Specific rotation. Dilute an accurately weighed sample with sufficient distilled water to obtain a concentration of approximately 10 milligrams of mezlocillin per milliliter. Proceed as directed in §436.210 of this chapter, using a 1-decimeter polarimeter tube.

(8) Identity. Proceed as directed in

§ 436.311 of this chapter, diluting the sample with distilled water to a concentration of 4 milligrams of mezlocillin per milliliter, except:

(i) Use the mezlocillin working standard and dilute with distilled water to a concentration of 4 milligrams of mezlocillin per milligram;

(ii) In lieu of the ninhydrin spray solution, after the plate is dried with a current of warm air, expose the plate to iodine vapors for about 30 seconds; and

(iii) Mezlocillin has an Rƒ value of about 0.67.

[46 FR 58298, Dec. 1, 1981, as amended at 50 FR 19918, 19919, May 13, 1985]

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