(a) The nystatin used in making the batch: 10 packages, each containing approximately 300 milligrams. (b) The batch: A minimum of 36 pastilles. (b) Tests and methods of assay—(1) Potency. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Place a representative number of pastilles into a high-speed glass blender jar containing 100 milliliters of sterile distilled water. Blend for 18 to 20 minutes. Add 400 milliliters of dimethylformamide and continue blending for an additional 10 minutes. Remove an aliquot and add sufficient 80 percent dimethylformamide so that upon final dilution with 10 percent potassium phosphate buffer, pH 6.0 (solution 6), to the reference concentration of 20 units of nystatin per milliliter, the concentration of dimethylformamide will be 4 percent. (2) pH. Dissolve 1 pastille in 100 milliliters of distilled water at 37 °C, cool, and proceed as directed in § 436.202 of this chapter. (3) Disintegration time. Proceed as directed in § 436.212 of this chapter, using the method described in paragraph (e)(4) of that section. [52 FR 4617, Feb. 13, 1987; 52 FR 7741, Mar. 12, 1987, as amended at 55 FR 11584, Mar. 29, 1990] Subpart C-Injectable Dosage Forms § 449.204 Amphotericin B for injection. (a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Amphotericin B for injection is a dry mixture containing in each immediate container 50 milligrams of amphotericin B, 41 milligrams of sodium desoxycholate, and suitable buffering substances. Its potency is satisfactory if it is not less than 90 percent and not more than 120 percent of the number of milligrams of amphotericin B that it is represented to contain. It is sterile. It is nonpyrogenic. Its loss on drying is not more than 8.0 percent. Its pH in an aqueous solution containing 10 milligrams of amphotericin B per milliliter is not less than 7.2 and not more than 8.0. The amphotericin B used conforms (2) Labeling. In addition to the labeling requirements prescribed by § 432.5 of this chapter, each package shall bear on its label and labeling the following statement: "For intravenous infusion in hospitals only". (3) Requests for certification; samples. In addition to the requirements of § 431.1 of this chapter, each such request shall contain: (i) Results of tests and assays on: (a) The amphotericin B used in making the batch for potency, amphotericin A content, loss on drying, pH, residue on ignition, and identity. (b) The batch for potency, sterility, pyrogens, loss on drying, and pH. (ii) Samples required: (a) Amphotericin B used in making the batch: 10 packages, each containing approximately equal portions of not less than 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) Potency. Proceed as directed in §436.105 of this chapter, preparing the sample for assay as follows: Reconstitute as directed in the labeling. Then using a suitable syringe and hypodermic needle, remove all of the withdrawable contents if the container 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 sufficient dimethylsulfoxide to give a stock solution of convenient concentration. Further dilute an aliquot of the stock solution with dimethylsulfoxide to a concentration of 20 micrograms of amphotericin B per milliliter (estimated). Remove an aliquot of this solution and dilute with 0.2M potassium phosphate buffer, pH 10.5 (solution 10), to the reference concentration of 1.0 microgram of amphotericin B 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, except use 50 milligrams in lieu of 300 milligrams. (3) [Reserved] (4) Pyrogens. Proceed as directed in § 436.32(e) of this chapter, using a solution containing 2 milligrams of amphotericin B per milliliter, except in lieu of paragraph (a)(3), if no rabbit shows an individual rise in temperature of 1.1° C. or more above its respective control temperature, and if the sum of the three temperature rises does not exceed 3° C., the sample meets the requirements for absence of pyrogen. If one or two rabbits show a temperature rise of 1.1° C. or more, or if the sum of temperature rises exceeds 3o C., repeat the test using five other rabbits. If not more than three of the eight rabbits show a temperature rise of 1.1° C. or more, and if the sum of the temperature rises does not exceed 8° C. the sample meets the requirements for absence of pyrogens. (5) Loss on drying. Proceed as directed in § 436.200(b) of this chapter. (6) pH. Proceed as directed in § 436.202 of this chapter using an aqueous solution containing 10 milligrams of amphotericin B per milliliter. [39 FR 19134, May 30, 1974, as amended at 45 FR 16472, Mar. 14, 1980; 50 FR 19920, May 13, 1985] Subpart D-Ophthalmic Dosage Forms § 449.340 Natamycin ophthalmic suspension. (a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Natamycin ophthalmic suspension contains natamycin with one or more suitable and harmless preservatives in a suitable and harmless aqueous vehicle. Each milliliter contains 50 milligrams of natamycin. Its potency is satisfactory if it is not less than 90 percent and not more than 125 percent of the number of milligrams of natamycin that it is represented to contain. It is sterile. Its pH is not less than 5.0 and not more than 7.5. The natamycin used conforms to the standards prescribed by § 449.40(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 natamycin used in making the batch for potency, moisture, pH, identity, and crystallinity. (b) The batch for potency, sterility, and pH. (ii) Samples required: (a) The natamycin used in making the batch: 10 packages, each containing not less than 500 milligrams. (b) The batch: (1) For all tests except sterility: A minimum of five immediate contain ers. (2) For sterility testing: 20 immediate containers, collected at regular intervals throughout each filling operation. (b) Tests and methods of assay. Dilute solutions of natamycin are very sensitive to light and should be kept in the dark as much as possible or substantial decomposition will take place. (1) Potency. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Dilute an accurately measured representative portion of the sample with sufficient dimethylsulfoxide to give a stock solution of convenient concentration. Further dilute an aliquot of the stock solution with dimethylsulfoxide to a concentration of 100 micrograms of natamycin per milliliter (estimated). Further dilute an aliquot with 0.2M potassium phosphate buffer, pH 10.5 (solution 10), to the reference concentration of 5.0 micrograms of natamycin per milliliter (estimated). (2) Sterility. Proceed as directed in § 436.20 of this chapter, using the method described in paragraph (e)(2) of that section, except use 0.25 milliliter of sample in lieu of 1.0 milliliter. (3) pH. Proceed as directed in §436.202 of this chapter, using the undiluted suspension. [43 FR 55384, Nov. 28, 1978, as amended at 48 FR 51293, Nov. 8, 1983] Subpart E [Reserved] Subpart F-Dermatologic Dosage Forms § 449.504 Amphotericin B dermatologic dosage forms. § 449.504a Amphotericin B ointment. (a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Amphotericin B ointment is composed of amphotericin B in a suitable and harmless ointment base. It may contain suitable and harmless coloring agents and protectants. It contains 30 milligrams of amphotericin B in each gram. Its potency is satisfactory if it is not less than 90 percent and not more than 125 percent of the number of milligrams of amphotericin B that it is represented to contain. Its moisture content is not more than 1.0 percent. The amphotericin B used conforms to the standards prescribed by § 449.4(a)(1) (i), (ii), (v), (vi), and (vii). (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 the requirements of § 431.1 of this chapter, each such request shall contain: (i) Results of tests and assays on: (a) The amphotericin B used in making the batch for potency, amphotericin A content, pH, residue on ignition, and identity. (b) The batch for potency and moisture. (ii) Samples required: (a) Amphotericin B used in making the batch: 10 packages, each containing not less than 500 milligrams. (b) The batch: A minimum of 5 immediate containers. (b) Tests and methods of assay—(1) Potency. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Place an accurately weighed representative portion of the sample (usually 1 gram) into an appropriate-sized Erlenmeyer flask with 10 milliliters of ethyl ether. Allow to dissolve for 1 hour with the intermittent manual shaking. Add a measured amount of dimethylsulfoxide to the flask and place on a shaker for 10 minutes. Further dilute with dimethylsulfoxide to a concentration of 20 micrograms of amphotericin B per milliliter (estimated). Remove an aliquot and dilute with 0.2M potassium phosphate buffer, pH 10.5 (solution 10), to the reference concentration of 1.0 microgram of amphotericin B per milliliter (estimated). (2) Moisture. Proceed as directed in § 436.201 of this chapter. § 449.504b Amphotericin B cream. (a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Amphotericin B cream is composed of amphotericin B, with or without one or more suitable and harmless emollients, perfumes, dispersants, and preservatives, in a suitable and harmless cream base. It contains 30 milligrams of amphotericin B in each gram. Its potency is satisfactory if it is not less than 90 percent and not more than 125 percent of the number of milligrams of amphotericin B per gram that it is represented to contain. The amphotericin B used conforms to the standards prescribed by § 449.4(a)(1) (i), (ii), (v), (vi), and (vii). (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 the requirements of § 431.1 of this chapter, each such request shall contain: (i) Results of tests and assays on: (a) The amphotericin B used in making the batch for potency, amphotericin A content, pH, residue on ignition, and identity. (b) The batch for potency. (li) Samples required: (a) Amphotericin B used in making the batch: 10 packages, each containing not less than 500 milligrams. (b) The batch: A minimum of 5 immediate containers. (b) Tests and methods of assay; potency. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: With the aid of a high-speed glass blender, dissolve an accurately weighed sample in sufficient dimethylsulfoxide to give a stock solution of convenient concentration. Further dilute with dimethylsulfoxide to a concentration of 20 micrograms of amphotericin B per milliliter (estimated). Remove an aliquot and dilute with 0.2M potassium phosphate buffer, pH 10.5 (solution 10), to the reference concentration of 1.0 microgram of amphotericin B per milliliter (estimated). § 449.504c Amphotericin B lotion. (a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Amphotericin B lotion is composed of amphotericin B in a suitable and harmless lotion vehicle. It contains suitable and harmless emollients, emulsifiers, coloring agents, diluents, preservatives, and perfumes. It contains 30 milligrams of amphotericin B per milliliter. Its potency is satisfactory if it is not less than 90 percent and not more than 125 percent of the number of milligrams of amphotericin B per milliliter that it is represented to contain. Its pH is not less than 5.0 and not more than 7.0. The amphotericin B used conforms to the standards prescribed by § 449.4(a)(1) (i), (ii), (v), (vi), and (vii). (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 the requirements of § 431.1 of this chapter, each such request shall contain: (i) Results of tests and assays on: (a) The amphotericin B used in making the batch for potency, amphotericin A content, pH, residue on ignition, and identity. (b) The batch for potency and pH. (ii) Samples required: (a) The amphotericin B used in making the batch: 10 packages, each containing not less than 500 milligrams. (b) The batch: A minimum of 5 immediate containers. (b) Tests and methods of assay—(1) Potency. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Dissolve an aliquot in sufficient dimethylsulfoxide to give a stock solution of convenient concentration. Further dilute the stock solution with dimethylsulfoxide to a concentration of 20 micrograms of amphotericin B per milliliter (estimated). Remove an aliquot and dilute with 0.2M potassium phosphate buffer, pH 10.5 (solution 10), to the reference concentration of 1.0 microgram of amphotericin B per milliliter (estimated). (2) pH. Proceed as directed in § 436.202 of this chapter, using the undiluted lotion. § 449.550 Nystatin dermatologic dosage forms. § 449.550a Nystatin ointment. (a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Nystatin ointment is composed of nystatin and a suitable and harmless ointment base. Each gram contains 100,000 units of nystatin. Its potency is satisfactory if it is not less than 90 percent and not more than 130 percent of the number of units of nystatin that it is represented to contain. The moisture content is not more than 0.5 percent. The nystatin used conforms to the standards prescribed by § 449.50(a)(1) (i), (iii), (iv), and (v). (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 the requirements of § 431.1 of this chapter, each such request shall contain: (1) Results of tests and assays on: (a) The nystatin used in making the batch for potency, loss on drying, pH, and identity. (b) The batch for potency and moisture. (ii) Samples required: (a) The nystatin used in making the batch: 10 containers, each consisting of 300 milligrams. (b) The batch: A minimum of five immediate containers. (b) Tests and methods of assay—(1) Potency. Proceed as directed in §436.105 of this chapter, preparing the sample for assay as follows: Using sufficient dimethylformamide to give a concentration of 400 units of nystatin (estimated) per milliliter, blend an accurately weighed representative portion in a high-speed glass blender for 3 to 5 minutes. Further dilute with 10 percent potassium phosphate buffer, pH 6 (solution 6), to the reference concentration of 20 units of nystatin per milliliter (estimated). (2) Moisture. Proceed as directed in § 436.201 of this chapter. § 449.550b Nystatin iodochlorhydroxyquin ointment. (a) Requirements for certification—(1) Standards of identity, strength, quality, purity. and iodochlorhydroxyquin composed Nystatinointment is of nystatin and iodochlorhydroxyquin in a suitable and harmless ointment base. Each gram contains 100,000 units of nystatin and 10 milligrams of iodochlorhydroxyquin. Its nystatin content is satisfactory if it is not less than 90 percent and not more than 140 percent of the number of units of nystatin that it is represented to contain. Its iodochlorhydroxyquin content is satisfactory if it is not less than 90 percent and not more than 110 percent of the number of milligrams of iodochlorhydroxyquin that it is represented to contain. It passes the identity test for iodochlorhydroxyquin. Its moisture content is not more than 0.5 percent. The nystatin used conforms to the standards prescribed by § 449.50(a)(1). The iodochlorhydroxyquin used conforms to the standards prescribed by U.S.P. XVIII. (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 nystatin used in making the batch for potency, loss on drying, pH, and identity. (b) The iodochlorhydroxyquin used in making the batch for all U.S.P. XVIII specifications. (c) The batch for nystatin content, iodochlorhydroxyquin content, identity, and iodochlorhydroxyquin moisture. (ii) Samples required: (a) The nystatin used in making the batch: 10 packages, each containing approximately 300 milligrams. (b) The batch: A minimum of seven immediate containers. (b) Tests and methods of assay-(1) Nystatin content. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Place an accurately weighed representative portion of the sample into a high-speed glass blender jar containing sufficient dimethylformamide to give a convenient concentration. Blend for 3 to 5 minutes. Remove an aliquot and dilute with sufficient dimethylformamide to yield a stock solution containing 400 units of nystatin per milliliter (estimated). Further dilute an aliquot of the stock solution with 10 percent potassium phosphate buffer, pH 6.0 (solution 6), to the reference concentration of 20 units of nystatin per milliliter (estimated). (2) Iodochlorhydroxyquin content—(i) Reagents. (a) Ferric chloride reagent. Dissolve 1.0 gram of ferric chloride (FeCl3·6H2O) in a mixture of 1.0 milliliter of concentrated hydrochloric acid and sufficient distilled water to make 1 liter. (b) Acetone, reagent grade. (c) 2-Methoxyethanol, reagent grade. (ii) Preparation of standard solution. Dissolve an accurately weighed portion of iodochlorhydroxyquin U.S.P. reference standard in sufficient 2methoxyethanol to make a solution containing 1.0 milligram iodochlorhydroxyquin per milliliter. Transfer 5.0 milliliters of this standard solution to a 50-milliliter volumetric flask. of (iii) Preparation of sample solution. Accurately weigh a portion of the sample equivalent to 50 milligrams of iodochlorhydroxyquin into a 125-milliliter Erlenmeyer flask. Add 50 milliliters of acetone, warm on a steam bath, and shake gently. Cool to room temperature and filter contents through a pledget of glass wool into a 100-milliliter volumetric flask. Wash the Erlenmeyer flask with two 20-milliliter portions of acetone and filter the washings into the volumetric flask. Dilute to volume with acetone and mix thoroughly. Transfer a 10-milliliter aliquot of the acetone solution to a 50milliliter volumetric flask and evaporate on a steam bath. To the residue, add 20 milliliters of 2-methoxyethanol and swirl to dissolve iodochlorhydroxyquin. the (iv) Procedure. To each flask containing standard solution and sample solution, respectively, add 2.0 milliliters of ferric chloride reagent and dilute to |