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standard; Ps=Loracarbef activity in the loracarbef

working standard solution in

micrograms per milliliter; and d = Dilution factor of the sample.

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

(3) Dissolution test. Proceed as directed in $ 436.215 of this chapter. The quantity Q, the amount of loracarbef activity dissolved, is 75 percent within 30 minutes.

(4) Identity. The retention time of the loracarbef response in the high-performance liquid chromatographic procedure described in paragraph (b)(1) of this section as applied to the sample solution compares qualitatively to that of the loracarbef reference standard.

8 443.120b Loracarbef for oral suspen

sion.

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 the loracarbef content as follows:

(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.

Milligrams of loracarbef_Au XP, xd per capsule

Ą, R1,000 where: Av=Area of the loracarbef peak in the chro

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

standard); AssArea of the loracarbef peak in the chro

matogram of the loracarbef working

(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)(1)) to obtain a concentration of 0.2 milligram loracarbef activity per milliliter (estimated).

(ii) Calculations. Calculate the loracarbef content as follows:

444.7 Amikacin sulfate. 444.10a Dihydrostreptomycin sulfate, crys

talline dihydrostreptomycin sulfate, di

hydrostreptomycin hydrochloride. 444.20 Gentamicin sulfate. 444.20a Sterile gentamicin sulfate. 444.30 Kanamycin sulfate. 444.30a Sterile kanamycin sulfate. 444.42 Neomycin sulfate. 444.42a Sterile neomycin sulfate. . 444.46 Netilmicin sulfate. 444.50 Paromomycin sulfate. 444.62 Sisomicin sulfate. 444.70a Sterile streptomycin sulfate. 444.80 Tobramycin. 444.81a Sterile tobramycin sulfate.

Subpart B-Oral Dosage Forms

of

444.130 Kanamycin sulfate capsules. 444.142 Neomycin sulfate oral dosage forms. 444.142a Neomycin sulfate tablets. 444.142b Neomycin sulfate oral solution. 444.150 Paromomycin sulfate oral dosage

forms. 444.150a Paromomycin sulfate capsules. 444.150b Paromomycin sulfate sirup.

Subpart C-Injectable Dosage Forms

Milligrams of loracarbef A, XP, xd per 5 milliliters of sample

Ą, X1,000 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; and d Dilution factor of the sample.

444.206 Amikacin sulfate injection. 444.220 Gentamicin sulfate injection. 444.230 Kanamycin sulfate injection. 444.246 Netilmicin sulfate injection. 444.262 Sisomicin sulfate injection. 444.270 Streptomycin sulfate injectable dos

age forms. 444.270a Sterile streptomycin sulfate. 444.270b Streptomycin sulfate injection. 444.280 Tobramycin sulfate injection. 444.281 Sterile tobramycin sulfate.

Subpart D-Ophthalmic Dosage Forms

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

(3) pH. Proceed as directed in $436.202 of this chapter, using the drug constituted as directed in the labeling.

(4) Identity. The retention time of the loracarbef response in the high-performance liquid chromatographic procedure described in paragraph (b)(1) of this section as applied to the sample solution compares qualitatively to that of the loracarbef reference standard.

444.320 Gentamicin sulfate ophthalmic dos

age forms. 444.320a Gentamicin sulfate ophthalmic so

lution. 444.320b Gentamicin sulfate ophthalmic

ointment. 444.320c Gentamicin sulfate-prednisolone

acetate ophthalmic suspension. 444.320d Gentamicin sulfate-prednisolone

acetate ophthalmic ointment. 444.342 Neomycin sulfate ophthalmic dosage

forms. 444.342a Neomycin sulfate

ophthalmic suspension; neomycin sulfate

ophthalmic solution (the blanks being filled in with the established name(s) of the other active ingredient(s) present in accordance with para

graph (a)(1) of this section). 444.342b Neomycin sulfate-polymyxin B sul

fate-gramicidin ophthalmic solution. 444.3420 Neomycin sulfate- gramicidin

PART 444-OLIGOSACCHARIDE

ANTIBIOTIC DRUGS

Subpart A-Bulk Drugs

Sec. 444.6 Amikacin.

Subpart F-Dermatologic Dosage Forms

ophthalmic solution; neomycin 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 sec

tion). 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 para

graph (a)(1) of this section). 444.342e Neomycin sulfate ointment; neomycin sulfate

ointment (the blank being filled in with the established name(s) of certain other active ingredi

ent(s)). 444.342f Neomycin sulfate-gramicidin topi

cal ointment; neomycin sulfate-gramicidin-triamcinolone acetonide ointment; neomycin

sulfate-gramicidinfludrocortisone acetate ointment. 444.342g Neomycin sulfate-hydrocortisone

acetate ophthalmic suspension; neomycin sulfate-prednisolone acetate ophthal

mic suspension. 444.342h Neomycin sulfate-polymyxin B sul

fate ophthalmic ointment. 444.3421 Neomycin sulfate-polymyxin B sul

fate ophthalmic solution. 444.342j Neomycin sulfate-polymyxin B sul

fate-dexamethasone ophthalmic suspen

sion. 444.342k Neomycin sulfate-polymyxin B sul

fate-dexamethasone ophthalmic oint

ment. 444.380 Tobramycin ophthalmic dosage

forms. 444.380a Tobramycin ophthalmic solution. 444.380b Tobramycin ophthalmic ointment. 444.380c Tobramycin-dexamethasone oph

thalmic suspension. 444.380d Tobramycin-dexamethasone oph

thalmic ointment. 444.380e Tobramycin-fluorometholone ace

tate ophthalmic suspension.

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 dos

age forms. 444.542a Neomycin sulfate ointment; neomycin sulfate

ointment (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

10tion (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). 444.542d (Reserved] 444.542e Neomycin sulfate-polymyxin B sul

fate ointment. 444.542f Neomycin sulfate-gramicidin topi

cal ointment; neomycin sulfate-gramicidin-triamcinolone acetonide ointment; neomycin

sulfate-gramicidinfludrocortisone acetate ointment. 444.542g Neomycin sulfate-gramicidin

triamcinolone acetonide cream. 444.542h Neomycin sulfate-gramicidin-tri

amcinolone acetonide lotion; neomycin sulfate-gramicidin-fludrocortisone ace

tate lotion. 444.5421 [Reserved] 444.542) Neomycin sulfate-polymyxin B sul

fate-gramicidin-benzocaine ointment. 444.542k Neomycin sulfate-polymyxin B sul

fate-hydrocortisone acetate cream. 444.5421 Neomycin sulfate-polymyxin B sul

fate cream.

Subpart E-Otic Dosage Forms

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Subpart A-Bulk Drugs

8 444.6 Amikacin.

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(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]

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Amikacin is A-3-amino-3deoxy-A-D-glucopyranosyl (1-6) - A - [6 amino - 6 - deoxy

deoxy - A A - D glucopyranosyl (14)] - N1 - [(s) 4 amino - 2 - hydroxy - 1 - oxobutyl) - 2 - deoxy - D - streptamine. It is so purified and dried that:

(i) Its potency is not less than 900 micrograms per milligram on an anhydrous basis.

(ii) [Reserved]

(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 +97o and not more than +105°.

(viii) It is crystalline.

(2) Labeling. It shall be labeled in accordance with the requirements of 8432.5 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.

$ 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)-0-16amino-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 +84o 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. Dissolve 1.0

gram

of 2,4,6trinitrobenzenesulphonic acid in 100 milliliters of distilled water.

(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.

(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 of 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 (hr) 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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