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or more suitable preservatives and anesthetic agents, and with or without one or more suitable solubilizers and stabilizers. Its potency is satisfactory if it contains not less than 90 percent and not more than 115 percent of the number of milligrams of tetracycline hydrochloride that it is represented to contain. It is sterile. It is nonpyrogenic. Its loss on drying is not more than 5 percent. Its pH in an aqueous solution containing 10 milligrams per milliliter is not less than 2.0 and not more than 3.0.

Its 4epianhydrotetracycline content is not more than 3.0 percent. The tetracycline phosphate complex conforms to the standards prescribed by $446.82(a)(1), and it contains no depressor substance.

(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 tetracycline phosphate complex used in making the batch for potency, moisture, pH, depressor substances, absorptivity,

4epianhydrotetracycline content, identity, and crystallinity.

(6) The batch for potency, sterility, pyrogens, loss on drying, pH, and 4epianhydrotetracycline content.

(ii) Samples required:

(a) The tetracycline phosphate complex used in making the batch: 10 packages, each containing approximately 300 milligrams, and one package containing approximately 1 gram.

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

(b) Tests and methods of assay—(1) POtency. Reconstitute the sample as directed in the labeling. Then, using a suitable hypodermic needle and syringe, remove all the withdrawable contents if it is represented as a singledose 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 the sample thus obtained with sufficient 0.1N hydrochloric acid to obtain a stock solution of convenient concentration containing not less

than 150 micrograms of tetracycline hydrochloride per milliliter (estimated). Further dilute an aliquot of the stock solution with sterile distilled water to the reference concentration of 0.24 microgram of tetracycline hydrochloride 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 of sample.

(3) Pyrogens. Proceed as directed in § 436.32(b) of this chapter, using a solution containing 5.0 milligrams of tetracycline hydrochloride per milliliter.

(4) Loss on drying. Proceed as directed in $ 436.200(b) of this chapter.

(5) PH. Proceed as directed in $436.202 of this chapter, using an aqueous solution containing 10 milligrams per milliliter.

(6) Depressor substances in the tetracycline phosphate compler used in making the batch. Proceed as directed in § 436.35 of this chapter. Prepare the test solution by dissolving 40 milligrams of sample in 2.0 milliliters of 0.1N hydrochloric acid and diluting with sterile distilled water (diluent 3) to the prescribed concentration.

(7) 4-Epianhydrotetracycline. Proceed as directed in $436.309 of this chapter.

[43 FR 11168, Mar. 17, 1978, as amended at 46 FR 60568, Dec. 11, 1981; 50 FR 19920, May 13, 1985)

Subpart D-Ophthalmic Dosage

Forms

$ 446.310 Chlortetracycline hydro

chloride ophthalmic ointment. (a) Requirements for certification (1) Standards of identity, strength, quality, and purity. Chlortetracycline hydrochloride ophthalmic ointment contains chlortetracycline hydrochloride in a suitable and harmless ointment base. Each gram contains 10 milligrams of chlortetracycline hydrochloride. Its potency is satisfactory if it contains not less than 90 percent and not more than 125 percent of the number of milligrams of chlortetracycline hydrochloride that it is represented to contain. It is sterile. Its moisture content is not more than 0.5 percent. It passes

the test for metal particles. The chlor- (4) Metal particles. Proceed as directed tetracycline hydrochloride used con- in $436.206 of this chapter. forms to the standards prescribed by

(43 FR 11169, Mar. 17, 1978, as amended at 50 $ 446.10a(a)(1).

FR 19920, May 13, 1985) (2) Labeling. It shall be labeled in accordance with the requirements of 8 446.367 Oxytetracycline hydro$ 432.5 of this chapter.

chloride ophthalmic dosage forms. (3) Requests for certification; samples. In addition to complying with the re

8 446.367c Oxytetracycline hydro

chloride-hydrocortisone quirements of $431.1 of this chapter,

acetate

ophthalmic suspension. each such request shall contain: (i) Results of tests and assays on:

(a) Requirements for certification (1) (a) The chlortetracycline hydro

Standards of identity, strength, quality, chloride used in making the batch for

and purity. Oxytetracycline hydropotency, loss on drying, pH, crystallin

chloride-hydrocortisone acetate oph

thalmic suspension is oxytetracycline ity, and identity.

hydrochloride and hydrocortisone ace(6) The batch for potency, sterility,

tate in a suitable and harmless oil base moisture, and metal particles.

containing aluminum tristearate. Each (ii) Samples required:

milliliter contains oxytetracycline hy(a) The chlortetracycline hydro

drochloride equivalent to 5 milligrams chloride used in making the batch: 10

of oxytetracycline and 15 milligrams of packages, each containing approxi

hydrocortisone acetate. Its potency is mately 300 milligrams.

satisfactory if it contains not less than (6) The batch:

90 percent and not more than 115 per(1) For all tests except sterility: A cent of the number of milligrams of oxminimum of 15 immediate containers. ytetracycline that it is represented to

(2) For sterility testing: 20 immediate contain. It is sterile. Its moisture concontainers, collected at regular inter- tent is not more than 1 percent. The vals throughout each filling operation. oxytetracycline hydrochloride used (b) Tests and methods of assay—(1) Po

conforms to the standards prescribed tency. Proceed as directed in $ 436.106 of by $446.67a (a)(1). this chapter, preparing the sample for

(2) Labeling. It shall be labeled in acassay as follows: Place an accurately cordance with the requirements of weighed representative portion of the $ 432.5 of this chapter. sample into a separatory funnel con- (3) Requests for certification; samples. taining approximately 50 milliliters of In addition to complying with the reperoxide-free ether. Shake the sample quirements of $431.1 of this chapter, and ether until homogeneous. Add 20 to

each such request shall contain: 25 milliliters of 0.01N hydrochloric acid

(i) Results of tests and assays on: and shake well. Allow the layers to (a) The oxytetracycline hydroseparate. Remove the acid layer and re- chloride used in making the batch for peat the extraction procedure with potency, loss on drying, pH, absorptiveach of three more 20- to 25-milliliter ity, crystallinity, and identity. quantities of 0.01N hydrochloric acid. (6) The batch for potency, sterility, Combine the extractives in a suitable and moisture. volumetric flask and dilute to volume (ii) Samples required: with 0.01N hydrochloric acid. Further (a) The oxytetracycline hydrodilute an aliquot with sterile distilled chloride used in making the batch: 10 water to the reference concentration of packages, each containing approxi0.06 microgram of chlortetracycline hy- mately 300 milligrams. drochloride per milliliter (estimated). (b) The batch:

(2) Sterility. Proceed as directed in (1) For all tests except sterility: A $ 436.20 of this chapter, using the meth- minimum of five immediate containod described in paragraph (e)(3) of that section.

(2) For sterility testing: 20 immediate (3) Moisture. Proceed as directed in containers collected at regular inter$ 436.201 of this chapter.

vals throughout each filling operation.

ers.

(b) Tests and methods of assay-(1) POtency. Proceed as directed in 8436.106 of this chapter, preparing the sample for assay as follows: Place an accurately measured, representative portion of the sample into a high-speed glass blender jar containing 1.0 milliliter of polysorbate 80 and sufficient 0.1N hydrochloric acid to obtain a stock solution of convenient concentration containing not less than 150 micrograms of oxytetracycline per milliliter (estimated). Blend for 3 to 5 minutes. Further dilute an aliquot with sterile distilled water to the reference concentration of 0.24 microgram of oxytetracycline per milliliter (estimated).

(2) Sterility. Proceed as directed in 8 436.20 of this chapter, using the method described in paragraph (e)(2) of that section, except use 0.25 milliliter of the sample in lieu of 1.0 milliliter.

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

(43 FR 11169, Mar. 17, 1978, as amended at 50 FR 19920, May 13, 1985]

$ 446.367e Oxytetracycline hydro

chloride-polymyxin B sulfate opb

thalmic ointment. (a) Requirements for certification (1) Standards of identity, strength, quality, and purity. Oxytetracycline hydrochloride-polymyxin B sulfate ophthalmic ointment is oxytetracycline hydrochloride and polymyxin B sulfate in a suitable and harmless ointment base. Each gram contains oxytetracycline hydrochloride equivalent to 5 milligrams of oxytetracycline and polymyxin B sulfate equivalent to 10,000 units of polymyxin B. Its oxytetracycline content is satisfactory if it is not less than 90 percent and not more than 120 percent of the number of milligrams of oxytetracycline that it is represented to contain. Its polymyxin B content is satisfactory if it is not less than 90 percent and not more than 125 percent of the number of units of polymyxin B that it is represented to contain. It is sterile. Its moisture content is not more than 1 percent. It passes the test for metal particles. The oxytetracycline hydrochloride used conforms to the standards prescribed by $ 446.67a (a)(1). The polymyxin B sulfate used conforms to the standards prescribed by $448.30a(a)(1) of this chapter.

(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 oxytetracycline hydrochloride used in making the batch for potency, loss on drying, pH, absorptivity, crystallinity, and identity.

(0) The polymyxin B sulfate used in making the batch for potency, pH, loss on drying, residue on ignition, and identity.

(c) The batch for oxytetracycline content, polymyxin B content, sterility, moisture, and metal particles.

(ii) Samples required:

(a) The oxytetracycline hydrochloride used in making the batch: 10 packages, each containing approximately 300 milligrams.

(0) The polymyxin B sulfate used in making the batch: 10 packages, each containing approximately 300 milligrams.

(c) The batch:

(1) For all tests except sterility: 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-(i) Oxytetracycline content. Proceed as directed in $ 436.106 of this chapter, preparing the sample for assay as follows: Place an accurately weighed representative portion of the sample into a separatory funnel containing approximately 50 milliliters of peroxidefree ether. Shake the ointment and ether until homogeneous. Add 20 to 25 milliliters of 0.1N hydrochloric acid and shake well. Allow the layers to separate. Remove the acid layer and repeat the extraction procedure with each of three more 20- to 25-milliliter quantities of 0.1N hydrochloric acid. Combine the acid extractives in a suitable volumetric flask and dilute to volume with 0.1N hydrochloric acid to obtain a stock solution of convenient concentration containing not less than 150 micrograms of oxytetracycline per milliliter (estimated). Further dilute an aliquot of the stock solution with sterile distilled water to the reference concentration of 0.24 microgram of oxytetracycline per

milliliter (estimated).

(ii) Polymyxin B content. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Weigh accurately 0.5 to 1 gram of the ointment and place into a 15-milliliter centrifuge tube. Add 10 milliliters of peroxide-free ether. Stir until contents are homogeneous and centrifuge for 10 minutes at 3,000 revolutions

per minute. Decant the supernatant ether. Repeat washing and centrifugation steps once more. Add 10 milliliters of acetone, stir until contents are homogeneous, and centrifuge for 10 minutes at 3,000 revolutions per minute. Decant the supernatant acetone. Repeat acetone wash and centrifugation once more. Continue acetone washings until the yellow color in the residue disappears. Add 3 to 4 drops of polysorbate 80 to the residue and mix well. Gently wash the residue into a 100-milliliter volumetric flask with 10 percent potassium phosphate buffer, pH 6.0 (solution 6), and further dilute with solution 6 to the reference concentration of 10 units of polymyxin B 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.

(4) Metal particles. Proceed as directed in $ 436.206 of this chapter.

cycline hydrochloride that it is represented to contain. It is sterile. Its moisture content is not more than 0.5 percent. It passes the test for metal particles. The tetracycline hydrochloride used conforms to the standards prescribed by $ 446.81a(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 tetracycline hydrochloride used in making the batch for potency, loss on drying, pH, absorptivity, crystallinity, and identity.

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

(ii) Samples required:

(a) The tetracycline hydrochloride used in making the batch: 10 packages, each containing approximately 300 milligrams.

(6) The batch:

(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. Proceed as directed in $ 436.106 of this chapter, preparing the sample for assay as follows: Place an accurately weighed representative portion of the sample into a separatory funnel containing approximately 50 milliliters of peroxide-free ether. Shake the sample and ether until homogeneous. Add 20 to 25 milliliters of 0.1N hydrochloric acid and shake well. Allow the layers to separate. Remove the acid layer and repeat the extraction procedure with each of 3 more 20- to 25-milliliter quantities of 0.1N hydrochloric acid. Combine the extractives in a suitable volumetric flask and fill to volume with 0.1N hydrochloric acid to obtain a stock solution of convenient concentration containing not less than 150 micrograms of tetracycline hydrochloride per milliliter (estimated). Further dilute an aliquot with sterile distilled water to the reference concentration of 0.24 micrograms of tetracycline hydrochloride per

milliliter (estimated).

[43 FR 11170, Mar. 17, 1978; 43 FR 34457, Aug. 4, 1978, as amended at 50 FR 19920, May 13, 1985)

$ 446.381 Tetracycline hydrochloride

ophthalmic dosage forms.

8446.381a Tetracycline hydrochloride

ophthalmic ointment. (a) Requirements for certification-(1) Standards of identity, strength, quality, and purity. Tetracycline hydrochloride ophthalmic ointment contains tetracycline hydrochloride in a suitable and harmless ointment base. Each gram contains 10 milligrams of tetracycline hydrochloride. Its potency is satisfactory if it contains not less than 90 percent and not more than 125 percent of the number of milligrams of tetra

(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.

(4) Metal particles. Proceed as directed in $ 436.206 of this chapter.

(43 FR 11170, Mar. 17, 1978, as amended at 50 FR 19920, May 13, 1985)

assay as follows: Place an accurately measured representative portion of the sample into a high-speed glass blender jar with 1 milliliter polysorbate 80 and sufficient 0.1N hydrochloric acid to give a stock solution of convenient concentration containing not less that 150 micrograms of tetracycline hydrochloride per milliliter (estimated). Blend for 3 to 5 minutes. Remove an aliquot and further dilute with sterile distilled water to the reference concentration of 0.24 microgram of tetracycline hydrochloride 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.

(43 FR 11171, Mar. 17, 1978, as amended at 46 FR 46313, Sept. 18, 1981; 50 FR 19920, May 13, 1985]

Subpart E-Otic Dosage Forms

8 446.381b Tetracycline hydrochloride

ophthalmic suspension. (a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Tetracycline hydrochloride ophthalmic suspension contains tetracycline hydrochloride in a suitable and harmless oily base. Each milliliter contains 10 milligrams of tetracycline hydrochloride. Its potency is satisfactory if it contains not less than 90 percent and not more than 125 percent of the number of milligrams of tetracycline hydrochloride that it is represented to contain. It is sterile. Its moisture content is not more than 0.5 percent. The tetracycline hydrochloride used conforms to the standards prescribed by $ 446.81a(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 tetracycline hydrochloride used in making the batch for potency, loss on drying, pH, absorptivity, crystallinity, and identity.

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

(ii) Samples required:

(a) The tetracycline hydrochloride used in making the batch: 10 packages, each containing approximately 300 milligrams.

(6) The batch:

(1) For all tests except sterility: A minimum of five 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 8436.106 of this chapter, preparing the sample for

$ 446.467 Oxytetracycline hydro

chloride-polymyxin B sulfate otic

ointment. (a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Oxytetracycline hydrochloride-polymyxin B sulfate otic ointment is oxytetracycline hydrochloride and polymyxin B sulfate in a suitable and harmless ointment base. Each gram of ointment contains oxytetracycline hydrochloride equivalent to 5 milligrams of oxytetracycline and polymyxin B sulfate equivalent to 10,000 units of polymyxin B. Its oxytetracycline hydrochloride content is satisfactory if it contains not less than 90 percent and not more than 120 percent of the number of milligrams of oxytetracycline that it is represented to contain. Its polymyxin B sulfate content is satisfactory if it contains not less than 90 percent and not more than 125 percent of the number of units of polymyxin B that it is represented to contain. Its moisture content is not more than 1 percent. The oxytetracycline hydrochloride used conforms to the standards prescribed by $ 446.67(a)(1). The polymyxin B sulfate used conforms to the

standards prescribed by $ 448.30(a)(1) of this chapter.

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