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than 130 percent of the number of milligrams of tetracycline hydrochloride per milliliter that it is represented to contain. The 4-epitetracycline hydrochloride content is satisfactory if it contains not less than 135 percent and not more than 165 percent of the amount of tetracycline hydrochloride in the reconstituted solution at the time of reconstitution. The loss on drying of the dry mixture is not more than 5.0 percent. When reconstituted as directed in the labeling, its pH is not less than 1.9 and not more than 3.5. The tetracycline hydrochloride used conforms to the standards prescribed by $ 446.81a, except sterility, pyrogens, and histamine. The 4-epitetracycline hydrochloride used conforms to the following standards: It gives a positive identity test for 4-epitetracycline hydrochloride; its 4-epitetracycline content is not less than 70 percent; its total anhydrotetracycline

and

4epianhydrotetracycline content is not more than 2.0 percent; its loss on drying is not more than 6.0 percent; its pH in an aqueous solution containing 10 milligrams per milliliter is not less than 2.3 and not more than 4.0.

(2) Labeling. It shall be labeled in accordance with the requirements of 8 432.5 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, and crystallinity.

(b) The 4-epitetracycline hydrochloride used in making the batch for 4-epitetracycline content and identity, total anhydrotetracycline and 4epianhydrotetracycline content, loss on drying, and pH.

(c) The batch for tetracycline hydrochloride content, 4-epitetracycline hydrochloride content, loss on drying, and pH.

(ii) Samples required:

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

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

(b) Tests and methods of assay of the tetracycline hydrochloride for topical solution—(1) Tetracycline hydrochloride content and 4-epitetracycline hydrochloride content. Proceed as directed in $ 436.340 of this chapter.

(2) Loss on drying. Proceed as directed in $436.200(a) of this chapter, except use the contents of one immediate container.

(3) PH. Proceed as directed in 8436.202 of this chapter, using the solution obtained when reconstituted as directed in the labeling.

(c) Tests and methods of assay of the 4epitetracycline hydrochloride used in making the batch-(1) 4-epitetracycline content and identity. Proceed as directed in paragraph (b)(1) of this section, except in lieu of $ 446.5816(b)(1)(iv) prepare the sample by weighing accurately 20 milligrams 15 milligrams of 4epitetracycline hydrochloride bulk powder and transfer to a 25-milliliter volumetric flask. Dissolve with 1.0 milliliter of methyl alcohol and dilute to volume with the buffer solution. Pipet a 2.0-milliliter aliquot to a 10-milliliter volumetric flask and dilute to volume with the buffer solution. Place the column in a suitable support. Place a 100milliliter graduate under the column. Open the column stopcock, pipet 2.0 milliliters of solution from the 10-milliliter volumetric flask onto the column packing and allow the sample to permeate the column packing. Place a solvent reservoir containing 20 milliliters of benzene on top of the column and begin to collect the eluate (at flow rate of approximately 1 milliliter per minute). When the benzene level reaches the top of the column packing, replace the empty solvent reservoir with a second solvent reservoir containing 60 milliliters of chloroform and continue elution. When the chloroform level reaches the top of the column packing, replace second empty solvent reservoir with a third solvent reservoir containing 50-milliliters of the n-butanol:chloroform mixture and replace the 100-milliliter graduate with a 10-milliliter graduate. Collect 8.0 milliliters of eluate. Replace the 10-milliliter graduate with a 50-milliliter low-actinic volumetric flask and continue collecting the eluate

eluate containing the 4epitetracycline fraction until the column runs dry. Determine the absorbance of the 4-epitetracycline eluate as described in paragraph (b)(1)(v) of this section.

179-070 0-98%-27

Calculate the 4-epitetracycline hydrochloride content of the 4epitetracycline hydrochloride bulk powder as follows:

by

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The identity of the 4-epitetracycline hydrochloride is confirmed if the absorbance of the sample after column elution is such that the 4epitetracycline hydrochloride content is greater than 70 percent by weight.

(2) Total anhydrotetracycline and 4epianhydrotetracycline content. Proceed as directed in $436.309 of this chapter.

(3) Loss on drying. Proceed as directed in $ 436.200(a) of this chapter.

(4) pH. Proceed as directed in $436.202 of this chapter, using a solution containing 10 milligrams per milliliter.

standards prescribed by $446.81(a)(1), except 4-epianhydrotetracycline content.

(2) Labeling. In addition to the labeling requirements prescribed $ 432.5(a)(3) of this chapter, each package shall bear on its label or labeling as hereinafter indicated, the following:

(i) On the label of the immediate container and on the outside wrapper or container, if any:

(a) The batch mark.

(6) The name and quantity of each active ingredient contained in the drug.

(ii) On the label of the immediate container or other labeling attached to or inserted within the package: Adequate directions under which the layperson can use the drug safely and efficaciously.

(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 and moisture.

(ii) Samples required:

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

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

(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 three more 20- to 25-milliliter quantities of 0.1N hydrochloric acid. Combine the acid 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

[42 FR 59066, Nov. 15, 1977; 43 FR 3705, Jan. 27, 1978, as amended at 48 FR 51291, Nov. 8, 1983; 50 FR 19920, May 13, 1985)

$ 446.581d Tetracycline hydrochloride

ointment. (a) Requirements for certification-(1) Standards of identity, strength, quality, and purity. Tetracycline hydrochloride ointment contains tetracycline hydrochloride in a suitable and harmless ointment base. Each gram contains 30 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. Its moisture content is not more than 1 percent. The tetracycline hydrochloride used conforms to the

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

[43 FR 11174, Mar. 17, 1978 as amended at 44 FR 30333, May 25, 1979. Redesignated at 45 FR 16472, Mar. 14, 1980, and amended at 50 FR 19920, May 13, 1985)

Subpart G-Vaginal Dosage

Forms

§ 446.667 Oxytetracycline hydro

chloride-polymyxin B sulfate vagi

nal tablets. (a) Requirements for certification-(1) Standards of identity, strength, quality, and purity. Oxytetracycline hydrochloride-polymyxin B sulfate vaginal tablets are tablets composed of oxytetracycline hydrochloride and polymyxin B sulfate with one or more suitable diluents, binders, lubricants, and preservatives. Each tablet contains oxytetracycline hydrochloride equivalent to 100 milligrams of oxytetracycline and polymyxin B sulfate equivalent to 100,000 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 120 percent of the number of units of polymyxin B that it is represented to contain. The loss on drying is not more than 3.0 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.

(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, identity, and crystallinity.

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

(c) The batch for oxytetracycline content, polymyxin B content, and loss on drying.

(ii) Samples required:

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

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

(c) The batch: A minimum of 30 tablets.

(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 a representative number of tablets into a high-speed glass blender jar containing 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. Remove an aliquot of the stock solution and further dilute 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: Grind a representative number of tablets into a fine powder and place this powder, accurately weighed, into a filter funnel with a solvent-resistant membrane filter of 1.0 micrometer porosity. Wash the powder with five 20milliliter portions of acetone or until the yellow color has disappeared. Remove the filter and soak in 400 milliliters of 10 percent potassium phosphate buffer, pH 6.0 (solution 6), and blend. Quantitatively transfer to a 500milliliter volumetric flask and adjust to volume with solution 6. Further dilute an aliquot with solution 6 to the reference concentration of 10 units of polymyxin B per milliliter (estimated).

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PART 448—PEPTIDE ANTIBIOTIC

DRUGS

Subpart A-Bulk Drugs

Sec. 448.10 Bacitracin. 448.10a Sterile bacitracin, 448.13 Bacitracin zinc. 448.13a. Sterile bacitracin zinc. 448.15a Sterile capreomycin sulfate. 448.20a Sterile colistimethate sodium. 448.21 Colistin sulfate. 448.23 Cyclosporine. 448.25 Gramicidin. 448.30 Polymyxin B sulfate. 448.30a Sterile polymyxin B sulfate. 448.75 Tyrothricin.

448.510 Bacitracin dermatologic dosage

forms. 448.510a Bacitracin ointment. 448.510b-448.510c (Reserved] 448.510d Bacitracin-neomycin sulfate oint

ment. 448.510e Bacitracin-neomycin sulfate-poly

myxin B sulfate ointment. 448.510f Bacitracin-polymyxin B sulfate top

ical aerosol. 448,513 Bacitracin zinc dermatologic dosage

forms. 448.513a Bacitracin zinc-polymyxin B sul

fate ointment, 448.513b Bacitracin zinc-neomycin sulfate

ointment. 448.513C Bacitracin zinc-neomycin sulfate

polymyxin B sulfate ointment; bacitracin zinc-neomycin sulfate-polymyxin

B sulfate hydrocortisone ointment. 448.513d Bacitracin zinc-polymyxin B sul

fate topical powder. 448.513e Bacitracin zinc-polymyxin B sul

fate topical aerosol. 448.513f Bacitracin zinc ointment.

Subpart B-Oral Dosage Forms

448.121 Colistin sulfate for oral suspension. 448.123 Cyclosporine oral dosage forms. 448.123a Cyclosporine oral solution. 448.123b Cyclosporine capsules.

Subpart C-Injectable Dosage Forms

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Subpart A-Bulk Drugs

8 448.10 Bacitracin.

(a) Requirements for certification-(1) Standards of identity, strength, quality, and purity. Bacitracin is a white to brown, neutral

water-soluble polypeptide. It is so purified and dried that:

(i) Its potency is not less than 40 units of bacitracin per milligram.

(ii) [Reserved]

(iii) Its loss on drying is not more than 5 percent.

(iv) Its pH in an aqueous solution containing 10,000 units per milliliter is not less than 5.5 and not more than 7.5.

(v) It passes the identity test.

(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:

(1) Results of tests and assays on the batch for potency, loss on drying, pH, and identity.

(ii) Samples required: 10 packages, each containing approximately 1.0 gram.

(b) Tests and methods of assay-(1) Potency. Proceed as directed for bacitracin zinc in $ 436.105 of this chapter, preparing the sample for assay as follows: Dissolve an accurately weighed sample in sufficient 1.0 percent potassium phosphate buffer, pH 6.0 (solution 1), to obtain a stock solution of convenient concentration. Remove an ali

uot of the stock solution, add sufficient hydrochloric acid so that the amount of acid in the final solution will be the same as in the reference concentration of the working standard and further dilute with solution 1 to the reference concentration of 1.0 unit of bacitracin per milliliter (estimated).

(2) [Reserved]

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

(4) pH. Proceed as directed in $436.202 of this chapter, using an aqueous solution containing 10,000 units per milliliter.

(5) Identity. Proceed as directed in $ 436.319 of this chapter.

8 448.10a Sterile bacitracin.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Bacitracin is a white to brown, neutral

water-soluble polypeptide. It is so purified and dried that:

(1) Its potency is not less than 50 units per milligram. If it is packaged for dispensing, its content is satisfactory if it is not less than 90 percent and not more than 115 percent of the number of units of bacitracin that it is represented to contain.

(ii) It is sterile.
(iii) [Reserved]
(iv) It is nonpyrogenic.

(v) Its loss on drying is not more than 5 percent.

(vi) Its pH in an aqueous solution containing 10,000 units per milliliter is not less than 5.5 and not more than 7.5.

(vii) Its residue on ignition is not more than 3.0 percent.

(viii) It passes the identity test.

(ix) Its heavy metals content is not more than 30 parts per million.

(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, sterility, pyrogens, loss on drying, pH, residue on ignition, identity, and heavy metals.

(ii) Samples required:

(a) If the batch is packaged for repacking or for use in the manufacture of another drug:

(1) For all tests except sterility: 10 packages, each containing approximately 1 gram.

(2) For sterility testing: 1 package, containing approximately 12 grams.

(6) If the batch is packaged for dispensing:

(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 ands methods of assay-(1) POtency. Proceed as directed for bacitracin zinc in $436.105 of this chapter, preparing the sample for assay as follows: Dissolve an accurately weighed

[42 FR 27229, May 27, 1977, as amended at 50 FR 19920, May 13, 1985)

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