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conforms to the standards prescribed by § 443.20(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 loracarbef used in making the batch for potency, moisture, pH, specific rotation, crystallinity, and identity.

(B) The batch for content, moisture, dissolution, and identity.

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

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

(B) The batch: A minimum of 100 capsules.

(b) Tests and methods of assay-(1) Loracarbef content. Proceed as directed in §443.20(b)(1), preparing the sample solution and calculating the loracarbef content as follows:

(i) Preparation of sample solution. Place one intact capsule in a 200-milliliter volumetric flask containing 150 milliliters of distilled water. Shake the mixture vigorously to aid disruption of the capsule. Sonicate the mixture briefly (5 minutes). Dilute the contents to volume with distilled water. Mix well and immediately transfer a suitable aliquot to a volumetric flask of appropriate size to obtain a solution containing 0.2 milligram per milliliter (estimated) of loracarbef when diluted to volume with mobile phase (described in §443.20(b)(1)(i)). Filter this solution through a 0.45-micron membrane filter before injecting it into the chromatograph.

(ii) Calculations. Calculate loracarbef content as follows:

Milligrams of loracarbef Au XP, per capsule

where:

the

xd

A ̧ ×1,000

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

As Area of the loracarbef peak in the chromatogram of the loracarbef working

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§ 443.120b Loracarbef for oral suspension.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Loracarbef for oral suspension is loracarbef with one or more suitable and harmless preservatives, sweeteners, suspending agents, colorings, antifoaming agents, and flavorings. When constituted as directed in the labeling, each milliliter contains the equivalent of either 20 or 40 milligrams loracarbef activity. Its loracarbef content is satisfactory if it is not less than 90 percent and not more than 115 percent of the number of milligrams of loracarbef that it is represented to contain. Its moisture content is not more than 2.0 percent. When constituted as described in the labeling, the pH of the suspension is not less than 3.5 and not more than 6.0. It passes the identity test. The loracarbef used conforms to the standards prescribed by § 443.20(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) Resuits of tests and assays on:

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

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

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

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

(B) The batch: A minimum of 10 immediate containers.

(b) Tests and methods of assay-(1) Loracarbef content. Proceed as directed in §443.20(b)(1), preparing the sample solution and calculating the loracarbef content as follows:

(i) Preparation of sample solution. Constitute as directed in the labeling. Transfer a 5.0-milliliter portion of the suspension into an appropriately sized volumetric flask and quantitatively dilute stepwise with mobile phase (described in §443.20(b)(1)(i)) to obtain a concentration of 0.2 milligram of loracarbef activity per milliliter (estimated).

(ii) Calculations. Calculate loracarbef content as follows:

the

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ophthalmic solution; neomy

cin sulfate-gramicidin ophthalmic suspension (the blanks being filled in with the established name(s) of the other ingredient(s) present in accordance with paragraph (a)(1) of this section). 444.342d Neomycin sulfate-polymyxin B sulfate ophthalmic suspension

(the blank being filled in with the established name(s) of the other active ingredient(s) present in accordance with paragraph (a)(1) of this section). 444.342e Neomycin sulfate ointment; neomycin sulfateointment (the

blank being filled in with the established name(s) of certain other active ingredient(s)).

444.342f Neomycin sulfate-gramicidin topical ointment; neomycin sulfate-gramicidin-triamcinolone acetonide ointment;

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Subpart F-Dermatologic Dosage Forms

444.520 Gentamicin sulfate dermatologic dosage forms.

444.520a Gentamicin sulfate ointment. 444.520b Gentamicin sulfate cream. 444.540 Neomycin palmitate dermatologic dosage forms.

444.542 Neomycin sulfate dermatologic dosage forms.

444.542a Neomycin sulfate ointment; neomycin sulfateointment (the

blank being filled in with the established name(s) of the other active ingredient(s) present in accordance with paragraph (a)(1) of this section).

444.542b Neomycin sulfate cream; neomycin sulfate cream (the blank being filled in with the established name(s) of the other active ingredient(s) present in accordance with paragraph (a)(1) of this section).

444.542c Neomycin sulfate

10

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oph

444.5421

oph

ace

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[Reserved]

ace

444.542j Neomycin sulfate-polymyxin B sulfate-gramicidin-benzocaine ointment. 444.542k Neomycin sulfate-polymyxin B sulfate-hydrocortisone acetate cream.

444.5421 Neomycin sulfate-polymyxin B sulfate cream.

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

(iv) Its pH in an aqueous solution containing 10 milligrams per milliliter is not less than 9.5 and not more than 11.5.

(v) It gives a positive identity test for amikacin.

(vi) Its residue on ignition is not more than 1.0 percent.

(vii) Its specific rotation is not less than +97° and not more than +105°.

(viii) 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, safety, moisture, pH, identity, residue on ignition, specific rotation, and crystallinity.

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

(b) Tests and methods of assay—(1) Potency. Proceed as directed in § 436.106 of this chapter, preparing the sample for assay as follows: Dissolve an accurately weighed sample in sufficient sterile distilled water to obtain a stock solution of convenient concentration. Further dilute an aliquot of the stock solution with distilled water to the reference concentration of

10.0

micrograms of amikacin 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) Identity. Proceed as directed in § 436.318 of this chapter.

(6) Residue on ignition. Proceed as directed in § 436.207(a) of this chapter.

(7) Specific rotation. Proceed as directed in § 436.210 of this chapter, using an aqueous solution containing 20 milligrams of amikacin per milliliter and a 1.0-decimeter polarimeter tube. Calculate the specific rotation on an anhydrous basis.

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

[41 FR 49483, Nov. 9, 1976, as amended at 44 FR 10379, Feb. 20, 1979; 50 FR 19919, May 13, 1985]

§ 444.7 Amikacin sulfate.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Amikacin sulfate is the sulfate salt of D-streptamine, 0-3-amino-3deoxy-a-D-glucopyranosyl(1-6)-0-[6amino-6-deoxy-a-D-glucopyranosyl(14)]-N1-(4-amino-2-hydroxy-1-oxobutyl)2-deoxy-,(S)-. It is so purified and dried

that:

(i) Its potency is not less than 674 micrograms and not more than 786 micrograms per milligram on an anhydrous basis if the molar ratio of amikacin to sulfuric acid (H2SO4) is 1:2 and is not less than 691 micrograms and not more than 806 micrograms per milligram on an anhydrous basis if the molar ratio of amikacin to H2SO4 is 1:1.8.

(ii) Its loss on drying is not more than 13.0 percent.

(iii) The pH of an aqueous solution containing 10 milligrams of amikacin sulfate per milliliter is not less than 2.0 and not more than 4.0 if the molar ratio of amikacin to H2SO4 is 1:2 and not less than 6.0 and not more than 7.3 if the molar ratio of amikacin to H2SO4 is 1:1.8.

(iv) It gives a positive identify test for amikacin.

(v) Its residue on ignition is not more than 1.0 percent.

(vi) Its specific rotation is not less than +76° and not more than +84° on the anhydrous basis.

(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, loss on drying, pH, identity, residue on ignition, specific rotation, and crystallinity.

(ii) Samples, if required by the 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 a 25-centimeter by 4.6-millimeter column packed with irregular 5-micron octadecyl hydrocarbon bonded silica, thermostatted at 30°C, an ultraviolet detection system operating at a wavelength of 340 nanometers, a flow rate not exceeding 2.0 milliliters per minute, a chart speed of 1.0 centimeter per minute (the chart speed is increased to 5.0 centimeters per minute to obtain chromatograms used for performance parameter determinations), and a known injection volume between 15.0 and 30.0 microliters. Retention times of amikacin and kanamycin are about 10 and 15 minutes, respectively. Reagents, working standard solution, sample solution, resolution test solution, system suitability requirements, and calculations are as follows:

(i) Reagents-(A) 1.0 percent 2,4,6trinitrobenzenesulphonic acid solution. 1.0 of 2,4,6trinitrobenzenesulphonic acid in 100 milliliters of distilled water.

Dissolve

gram

(B) 0.02M potassium dihydrogen phosphate. Dissolve 2.72 grams of potassium dihydrogen phosphate in 800 milliliters of distilled water and mix to dissolve the solid. Dilute to 1,000 milliliters with distilled water and mix.

(C) Mobile phase. Mix 0.02M potassium dihydrogen phosphate and methanol, high performance liquid chromatography reagent grade (28:72 by volume). Adjust the pH to 6.5 with 0.4M potassium hydroxide. Filter the mobile phase through a suitable glass filter or equivalent which is capable of removing particulate matter contamination greater than 0.5 micron in diameter.

Degas the mobile phase just prior to its introduction into the chromatograph.

of

(ii) Preparation of working standard and sample solutions. (A) Working standard solution. Dissolve an accurately weighed portion of the amikacin working standard with sufficient distilled water to obtain a solution containing approximately 1.0 milligram amikacin activity per milliliter. This preparation is stable for 1 week. Transfer 50 microliters of this solution directly to the bottom of a 50-milliliter, glass-stoppered centrifuge tube, using an automatic micropipetter. Add 3.2 milliliters of pyridine and 2.0 milliliters of 1 percent 2,4,6trinitrobenzenesulphonic acid reagent just above the surface of the solution in the centrifuge tube. Close the tube tightly, mix and heat the tube in a water bath maintained at 75 °C±1° for 45 minutes. Remove the tube from the bath and cool it at room temperature. Filter the contents through a 0.5 micron membrane. Use the filtrate for the quantitative chromatographic determinations.

(B) Preparation of sample solution. Dissolve an accurately weighed portion of sample with sufficient distilled water to obtain a solution containing 1.0 milligram of amikacin activity per milliliter (estimated). This preparation is stable for 1 week. Proceed as directed in paragraph (b)(1)(ii)(A) of this section, beginning at "Transfer 50 microliters * * *",

(C) Resolution test solution. Prepare an aqueous solution containing about 1.0 milligram per milliliter each of amikacin and kanamycin. Proceed as directed in paragraph (b)(1)(ii)(A) of this section, beginning at "Transfer 50 microliters * * *"

(iii) System suitability requirements— (A) Asymmetry factor. The asymmetry factor (As) of the amikacin peak is satisfactory if it is not more than 1.3 at 10 percent of peak height.

(B) Efficiency of the column. The absolute efficiency (h,) is satisfactory if it is not more than 20.0 for the amikacin peak.

(C) Resolution. The resolution (R) between the amikacin peak and the kanamycin peak is satisfactory if it is not less than 5.0.

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