The requirements for certification and the tests and methods of assay for sterile erythromycin gluceptate packaged for dispensing are described in § 452.30a.

[46 FR 16685, Mar. 13, 1981]

§ 452.232 Erythromycin lactobionate injectable dosage forms.

§ 452.232a Erythromycin lactobionate for injection.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Erythromycin lactobionate for injection is a dry mixture of erythromycin lactobionate and a suitable preservative. It contains the equivalent of 300 milligrams, 500 milligrams, or 1 gram of erythromycin per vial. Its potency is satisfactory if it is not less than 90 percent and not more than 120 percent of the number of milligrams of erythromycin that it is represented to contain. It is sterile. It is nonpyrogenic. Its moisture content is not more than 5 percent. Its pH is not less than 6.5 and not more than 7.5. The erythromycin used conforms to the standards prescribed by § 452.10(a)(1) (i), (iii), (iv), (v), (vi), (vii), and (viii).

(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 erythromycin used in making the batch for potency, pH, moisture, residue on ignition, heavy metals, and crystallinity.

(b) The batch for potency, sterility, pyrogens, moisture, pH, and identity. (ii) Samples required:

(a) The erythromycin used in making the batch: 10 containers, each consisting of not less than 500 milligrams.

(b) The batch:

(1) For all tests except sterility: A minimum of 12 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. Using a suitable hypodermic needle and syringe, remove the total withdrawable contents from each container represented as a singledose container; or if the labeling specifies the amount of potency in a given volume of the preparation, withdraw an accurately measured volume from each container. Dilute with sterile distilled water to obtain a concentration of 10 milligrams of erythromycin base per milliliter (estimated). Further dilute with 0.1M potassium phosphate buffer, pH 8.0 (solution 3), to the reference concentration of 1.0 microgram of erythromycin base 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(b) of this chapter, using a solution containing 30 milligrams of erythromycin 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 a concentration of 50 milligrams of erythromycin per milliliter.

(7) Identity. Proceed as directed in $436.211 of this chapter, using the sample preparation method described in paragraph (b)(2) of that section.

[39 FR 19149, May 30, 1974, as amended at 50 FR 19920, 19921, May 13, 1985. Redesignated at 51 FR 35216, Oct. 2, 1986]

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Erythromycin ophthalmic ointment is erythromycin in a suitable and harmless ointment base. Each gram of ointment contains 5 milligrams of erythromycin. Its potency is satisfactory if it is not less than 90 percent and not more than 120 percent of the number of milligrams of erythromycin that it is represented to contain. It is sterile. The moisture content is not more than 1 percent. The erythromycin used conforms to the standards prescribed by §452.10(a)(1) (i), (iii), (iv), (v), (vii), and (viii).

(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 erythromycin used in making the batch for potency, pH, moisture, residue on ignition, crystallinity, and identity.

(b) The batch for potency, sterility, and moisture.

(ii) Samples required:

(a) The erythromycin used in making the batch: 10 packages, each containing 500 milligrams.

(b) The batch:

(1) For all tests except sterility: A minimum of five immediate contain

ers.

(2) For sterility testing: Twenty immediate containers, collected at regular intervals throughout each filling operation.

(b)(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 ointment in a separatory funnel containing 50 milliliters of reagent-grade petroleum ether. Shake until dissolved. Wash with four separate washings of a 4:1 mixture of methyl alcohol and distilled water. Combine the washings and bring to volume with the methyl alcohol-water solution in a

volumetric flask. Further dilute with 0.1M potassium phosphate buffer, pH 8.0 (solution 3), to the reference concentration of 1.0 microgram of erythromycin base per milliliter (estimated).

(2) Sterility. Proceed as directed in § 436.20 of this chapter, using the method described in paragraph (e)(3) of that section.

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

[39 FR 19149, May 30, 1974, as amended at 49 FR 5097, Feb. 10, 1984; 50 FR 19921, May 13, 1985]

Subpart E [Reserved]

Subpart F-Dermatologic Dosage Forms

§ 452.510 Erythromycin dermatologic dosage forms.

§ 452.510a Erythromycin ointment.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Erythromycin ointment is erythromycin in a suitable and harmless ointment base. It may contain suitable preservatives. Each gram of ointment contains 20 milligrams of erythromycin. Its potency is satisfactory if it is not less than 90 percent and not more than 125 percent of the number of milligrams of erythromycin that it is represented to contain. The moisture content is not more than 1.0 percent. The erythromycin used conforms to the standards prescribed by

§ 452.10(a)(1) (i), (iii), (iv), (v), (vii), and (viii).

(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 erythromycin used in making the batch for potency, pH, moisture, residue on ignition, crystallinity, and identity.

(b) The batch for potency and moisture.

(ii) Samples required:

(a) The erythromycin 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 ointment in a separatory funnel containing 50 milliliters of reagent-grade petroleum ether. Shake until dissolved. Wash with four separate washings of a 4:1 mixture of methyl alcohol and distilled water. Combine the washings and bring to volume with the methyl alcohol-water solution in a volumetric flask. Further dilute with 0.1M potassium phosphate buffer, pH 8.0 (solution 3), to the reference concentration of 1.0 microgram of erythromycin base per milliliter (estimated).

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

[39 FR 19149, May 30, 1974, as amended at 49 FR 5097, Feb. 10, 1984; 49 FR 47829, Dec. 7, 1984; 50 FR 47214, Nov. 15, 1985]

§ 452.510b Erythromycin topical solution.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Erythromycin topical solution contains in each milliliter 15.0 or 20.0 milligrams of erythromycin. It may also contain one or more suitable and harmless solvents, surfactants, buffer substances, diluents, and perfumes. Its potency is satisfactory if it is not less than 90 percent and not more than 125 percent of the number of milligrams of erythromycin that it is represented to contain. If it contains 15.0 milligrams of erythromycin per milliliter, its moisture content is not more than 5.0 percent. If it contains 20.0 milligrams of erythromycin per milliliter, its moisture content is not more than 8.0 percent, except if it contains acetone, its moisture content is not more than 2.0 percent. The erythromycin used conforms to the standards prescribed by § 452.10(a)(1), heavy metals.

except

(2) Packaging. In addition to the requirements of § 432.1 of this chapter, it may either be dispensed on individually packaged pledgets, each individual pledget containing 0.8 milliliter of

erythromycin topical solution, or in a jar containing 60 pledgets. The jar contains 0.8 milliliter of erythromycin topical solution per pledget. Although the pledgets in the jar are not individually packaged, the drug is uniformly distributed throughout the pledgets. The erythromycin topical solution used on the pledgets contains 20 milligrams of erythromycin per milliliter.

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

(4) 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 erythromycin used in making the batch for potency, moisture, pH, residue on ignition, identity, and crystallinity.

(b) The batch for potency and moisture.

(ii) Samples required:

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

(b) The batch: A minimum of 6 immediate containers.

(b) Tests and methods of assay. If the erythromycin topical solution is dispensed on a pledget, express the contents of a representative number of pledgets into a suitable container to obtain a volume of sample adequate to perform each assay described in paragraph (b)(1) and (2) of this section.

(1) Potency. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Using a suitable hypodermic needle and syringe, remove an accurately measured representative portion of the sample and dilute with 0.1M potassium phosphate buffer, pH 8.0 (solution 3), to obtain a stock solution of convenient concentration. Further dilute an aliquot of the stock solution with solution 3 to the reference concentration of 1.0 microgram of erythromycin base per milliliter (estimated).

(2) Moisture. Proceed as directed in § 436.201 of this chapter, except if the

sample contains acetone, in lieu of Solvent A, use a mixture of pyridine and methanol (1:1).

[46 FR 2995, Jan. 13, 1981, as amended at 48 FR 51293, Nov. 8, 1983; 49 FR 374, Jan. 4, 1984; 50 FR 1504, Jan. 11, 1985; 50 FR 19921, May 13, 1985; 50 FR 20204, May 15, 1985; 54 FR 47352, Nov. 14, 1989; 54 FR 50472, Dec. 6, 1989]

§ 452.510d Erythromycin-benzoyl peroxide topical gel.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Erythromycin-benzoyl peroxide topical gel is erythromycin packaged in combination with a suitable and harmless gel containing benzoyl peroxide and one or more suitable dispersants, stabilizing agents, perfumes, and wetting agents. When reconstituted as directed in the labeling, each gram contains 30 milligrams of erythromycin and 50 milligrams of benzoyl peroxide. The erythromycin content is satisfactory if it contains not less than 90 percent and not more than 125 percent of the number of milligrams of erythromycin that it is represented to contain. The benzoyl peroxide content is satisfactory if it contains not less than 90 percent and not more than 115 percent of the milligrams of benzoyl peroxide that it is represented to contain. The erythromycin used conforms to the standards prescribed by §452.10(a)(1), except with respect to heavy metals.

(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 erythromycin used in making the batch for potency, moisture, pH, residue on ignition, identity, and crystallinity.

(b) The batch for erythromycin content and benzoyl peroxide content.

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

(a) The erythromycin used in making the batch: 5 packages, each containing approximately 100 milligrams.

(b) The batch: A minimum of 8 containers.

an

(b) Tests and methods of assay-(1) Erythromycin content. Proceed as directed in §436.105 of this chapter, preparing the sample for assay as follows: Reconstitute the sample as directed in the labeling. Place accurately weighed representative portion of the constituted product into a high-speed glass blender jar containing 0.5 milliliter of polysorbate 80 and sufficient 0.1M potassium phosphate buffer, pH 8.0 (solution 3), to obtain a stock solution of convenient concentration. Blend for 3 to 5 minutes. Further dilute an aliquot of the stock solution with solution 3 to the reference concentration of 1.0 microgram of erythromycin base per milliliter (estimated).

(2) Benzoyl peroxide content. Reconstitute the sample as directed in the labeling. Place an accurately weighted representative portion 2.5 (about grams) of the constituted product into a tared 250-milliliter glass-stoppered flask. Add 50 milliliters of glacial acetic acid and 20 milliliters of methylene chloride. Stopper and shake vigorously to disperse the gel. Add 1.0 milliliter phenylsulfide, swirl, stopper, and allow to stand at room temperature for 2 minutes. Purge the flask with nitrogen for 3 seconds. Add 5 milliliters for freshly prepared saturated sodium iodide solution, stopper, and swirl to mix. Let stand in the dark for 30 minutes. Add 50 milliliters of previously boiled and cooled distilled water and titrate the liberated iodine with 0.1N sodium thiosulfate, adding starch T.S. near the endpoint. Perform a blank determination and correct the sample titer. Each milliliter of 0.1N sodium thiosulfate is equivalent to 12.11 milligrams of benzoyl peroxide. Calculate the benzoyl peroxide content as follows:

§ 452.510e Erythromycin topical gel.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Erythromycin topical gel is erythromycin in a suitable and harmless gel. Each gram contains 20 milligrams of erythromycin. The erythromycin content is satisfactory if it contains not less than 90 percent and not more than 125 percent of the number of milligrams of erythromycin that it is represented to contain. The erythromycin used conforms to the standards prescribed by § 452.10(a)(1), except with respect to heavy metals.

(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 request shall contain:

(i) Results of tests and assays on:

(A) The erythromycin used in making the batch for potency, moisture, pH, residue on ignition, identity, and crystallinity.

(B) The batch for erythromycin content.

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

(A) The erythromycin used in making the batch: 5 packages, each containing approximately 100 milligrams.

(B) The batch: A minimum of 8 containers.

(b) Tests and methods of assay; erythromycin content. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Place approximately 1 gram, accurately weighed, of the product into a highspeed glass blender jar containing 200 milliliters of 0.5 percent (volume by volume) polysorbate 80 in 0.1M potassium phosphate buffer, pH 8.0 (solution 3), to obtain a stock solution of convenient concentration. Blend for 3 to 5 minutes. Further dilute an aliquot of the stock solution with solution 3 to the reference concentration of 1.0 microgram of erythromycin base per milliliter (estimated).

[53 FR 12415, Apr. 14, 1988; 53 FR 16837, May 11, 1988]

Subpart G [Reserved]

Subpart H-Rectal Dosage Forms

§ 452.710 Erythromycin suppositories.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Erythromycin suppositories contain in each suppository 125 milligrams of erythromycin in a suitable and harmless base. The erythromycin content is satisfactory if it is not less than 90 percent nor more than 120 percent of the number of milligrams of erythromycin that it is represented to contain. The moisture content is not more than 1.0 percent. The erythromycin used conforms to the standards prescribed by § 452.10(a)(1), (i), (iii), (iv), (v), (vii), and (viii), except its moisture content is not more than 5.0 percent.

(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 erythromycin used in making the batch for potency, moisture, pH, residue on ignition, identity, and crystallinity.

(b) The batch for potency and moisture.

(ii) Samples required:

(a) The erythromycin used in making the batch: 10 packages, each containing not less than 500 milligrams.

(b) The batch: A minimum of 30 suppositories.

(b) Tests and methods of assay—(1) Potency. Proceed as directed in §436.105 of this chapter, preparing the sample for assay as follows: Blend a representative number of suppositories for 3 to 5 minutes in a high-speed glass blender with 200 milliliters of methyl alcohol. Add 300 milliliters of 0.1M potassium phosphate buffer, pH 8.0 (solution 3), and blend again for 3 to 5 minutes. Remove an aliquot and dilute with solution 3 to the reference concentration of 1.0 microgram of erythromycin base per milliliter (estimated).