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the ointment, accurately weighed, into a high-speed glass blender. Add that quantity of alcohol U.S.P. XX which is sufficient to obtain a stock solution of convenient concentration. Blend 3 to 5 minutes. Make proper estimated dilutions of an aliquot to the reference concentration with alcohol U.S.P. XX. The content of gramicidin is satisfactory if it is not less than 90 percent and not more than 120 percent of the number of milligrams of gramicidin that it is represented to contain.

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

(39 FR 19046, May 30, 1974, as amended at 47 FR 23710, June 1, 1982]

$444.542k Neomycin sulfate-polymyxin

B sulfate-hydrocortisone acetate

cream.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Neomycin sulfate-polymyxin B sulfate-hydrocortisone acetate cream contains, in each gram, neomycin sulfate equivalent to 3.5 milligrams of neomycin, polymyxin B sulfate equivalent to 10,000 units of polymyxin B, and 5.0 milligrams of hydrocortisone acetate in a suitable and harmless vehicle. Its neomycin sulfate content is satisfactory if it is not less than 90 percent and not more than 130 percent of the number of milligrams of neomycin that it is represented to contain. Its polymyxin B sulfate content is satisfactory if it is not less than 90 percent and not more than 130 percent of the number of units of polymyxin B that it is represented to contain. The neomycin sulfate used conforms to the standards prescribed by $444.42(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 the requirements of § 431.1 of this chapter, each such request shall contain:

(1) Results of tests and assays on:

(a) The neomycin sulfate used in making the batch for potency, loss on drying, pH, and identify.

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

(c) The batch for neomycin content and polymyxin B content.

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

(a) The neomycin sulfate 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 6 immediate containers.

(b) Tests and methods of assay; potency—(1) Neomycin content. Proceed as directed in $ 436.105 of this chapter, preparing the sample for assay as follows: Transfer an accurately weighed representative portion of the sample into a high-speed glass blender jar containing 1.0 milliliter polysorbate 80 and sufficient 0.1 M potassium phosphate buffer, pH 8.0 (solution 3), to obtain a stock solution of convenient concentration. Blend for 3 to 5 minutes. Dilute an aliquot of the stock solution with solution 3 to the reference concentration of 1.0 microgram of neomycin per milliliter (estimated).

(2) Polymyxin B content. Proceed as directed in $ 436.105 of this chapter, except add to each concentration of the polymyxin B standard response line a quantity of neomycin to yield the same concentration of neomycin as that present when the sample is diluted to contain 10 units of polymyxin B per milliliter. Prepare the sample for assay as follows: Transfer an accurately weighed representative portion of the sample into a high-speed glass blender jar containing 1.0 milliliter polysorbate 80 and sufficient 10 percent potassium phosphate buffer, pH 6.0 (solution 6), to obtain a stock solution of convenient concentration. Blend for 3 to 5 minutes. Dilute an aliquot of the stock solution with solution 6 to the reference concentration of 10 units of polymyxin B per milliliter (estimated).

[50 FR 15108, Apr. 17, 1985, as amended at 55 FR 11584, Mar. 29, 1990)

8 444.5421 Neomycin sulfate-polymyxin

B sulfate cream.

(a) Requirements for certification-(1) Standards of identity, strength, quality, and purity. Neomycin sulfate-polymyxin B sulfate cream is a cream containing, in each gram, neomycin sulfate equivalent to 3.5 milligrams of neomycin and polymyxin B sulfate equivalent to 10,000 units of polymyxin B in a suitable and harmless vehicle. It may contain a suitable local anesthetic. Its neomycin sulfate content is satisfactory if it is not less than 90 percent and not more than 130 percent of the number of milligrams of neomycin that it is represented to contain. Its polymyxin B sulfate content is satisfactory if it is not less than 90 percent and not more than 130 percent of the number of units of polymyxin B that it is represented to contain. The neomycin sulfate used conforms to the standards prescribed by 8444.42(a)(1). The polymyxin B sulfate used conforms to the standards prescribed by $448.30(a)(1) of this chapter.

(2) Labeling-(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; and

(c) An expiration date that conforms to the requirements prescribed by $ 432.5(a)(3) of this chapter.

(ii) On the label of the immediate container or other labeling attached to or within the package, adequate directions under which the layman 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 neomycin sulfate used in making the batch for potency, loss on drying, pH, and identity.

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

(c) The batch for neomycin content and polymyxin B content.

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

(a) The neomycin sulfate 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 six immediate containers.

(b) Tests and methods of assay; potency-(1) Neomycin content. Proceed as directed in 8 436.105 of this chapter, preparing the sample for assay as follows: Transfer an accurately weighed representative portion of the sample into a high-speed glass blender jar containing 1.0 milliliter polysorbate 80 and sufficient 0.1 M potassium phosphate buffer, pH 8.0 (solution 3), to obtain a stock solution of convenient concentration. Blend for 3 to 5 minutes. Dilute an aliquot of the stock solution with solution 3 to the reference concentration of 1.0 microgram of neomycin per milliliter (estimated).

(2) Polymyxin B content. Proceed as directed in $436.105 of this chapter, except add to each concentration of the polymyxin B standard response line a quantity of neomycin to yield the same concentration of neomycin as that present when the sample is diluted to contain 10 units of polymyxin B per milliliter. Prepare the sample for assay as follows: Transfer

accurately weighed portion of the sample into a high-speed glass blender jar containing 1.0 milliliter polysorbate 80 and sufficient 10 percent potassium phosphate buffer, pH 6.0 (solution 6), to obtain a stock solution of convenient CONcentration. Blend for 3 to 5 minutes. Dilute an aliquot of the stock solution with solution 6 to the reference concentration of 10 units of polymyxin B per milliliter (estimated).

an

(50 FR 15109, Apr. 17, 1985, as amended at 55 FR 11584, Mar. 29, 1990; 55 FR 50173, Dec. 5, 1990]

179-070 0-98-25

Subparts G[Reserved]

Subpart J-Certain Other Dosage

Forms

§ 444.942 Neomycin sulfate in certain

other dosage forms.

the batch, but in no case less than 10 such portions. Each such portion shall be collected at such intervals throughout the entire time of packaging the batch that the quantities packaged during the intervals are approximately equal.

(b) Tests and methods of assay; potency, moisture, pH, and identity. Proceed as directed in $444.42a(b) (1), (5), (6), and (7).

[39 FR 19046, May 30, 1974, as amended at 50 FR 19919, May 13, 1985; 53 FR 12658, Apr. 15, 1988; 53 FR 31837, Aug. 22, 1988)

8 444.942a Neomycin sulfate for

compounding oral products. (a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Neomycin sulfate for compounding oral products is the sulfate salt of a kind of neomycin or a mixture of two or more such salts. It is so purified and dried that:

(i) It has a potency of not less than 600 micrograms of neomycin per milligram.

(ii) [Reserved]

(iii) Its moisture content is not more than 8 percent.

(iv) Its pH is an aqueous solution containing 33 milligrams per milliliter is not less than 5.0 nor more than 7.5.

(v) It gives a positive identity test for neomycin.

(2) Packaging. The immediate container shall be of colorless, transparent glass and it shall be a tight container as defined by the U.S.P. It shall be so sealed that the contents cannot be used without destroying such seal. Each such container shall contain not less than 10 grams and not more than 100 grams of neomycin sulfate.

(3) Labeling. It shall be labeled in accordance with the requirements prescribed by $432.5(a) of this chapter. Its expiration date is 12 months.

(4) Requests for certification; samples. (i) In addition to complying with the conditions of $ 431.1 of this chapter, a person who requests certification of a batch of neomycin sulfate for compounding oral products shall submit with the request a statement showing the batch mark, the number of packages of each size in the batch, and the date on which the latest assay of the drug comprising such batch was completed. Such request shall be accompanied or followed by results of tests and assays made on the batch for potency, moisture, pH, and identity.

(ii) Such person shall submit with his request a sample consisting of a 0.5 gram portion for each 5,000 packages in

8 444.942b Sterile neomycin sulfate

and polymyxin B sulfate solution. (a) Requirements for certification (1) Standards of identity, strength, quality, and purity. Sterile neomycin sulfate and polymyxin B sulfate solution is an aqueous solution containing in each milliliter 40 milligrams of neomycin and 200,000 units of polymyxin B. If packaged in a multiple-dose container, it shall contain a suitable and harmless preservative. It is sterile. Its pH is not less than 4.5 and not more than 6.0, except that for issuance of a certificate it is not less than 5.0. The neomycin sulfate used conforms to the standards prescribed by $444.42a(a)(1) (1), (vi), and (vii). The polymyxin B sulfate used conforms to the standards prescribed by $448.30a(a)(1) (i), (vi), (vii), and (ix) of this chapter. Each other substance used, if its name is recognized in the U.S.P. or the N.F., conforms to the standards prescribed therefor by such official compendium.

(2) Labeling. In addition to being labeled in accordance with the requirements of $432.5 of this chapter, the labeling shall include a statement to the effect that the drug is to be diluted for use as a urinary bladder irrigant and is not for injection. Its expiration date is 12 months.

(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 neomycin sulfate used in making the batch for potency, pH, and identity.

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

PART 446-TETRACYCLINE

ANTIBIOTIC DRUGS

Subpart A-Bulk Drugs

Sec. 446.10 Chlortetracycline hydrochloride. 446.10a Sterile chlortetracycline hydro

chloride. 446.15 Demeclocycline. 446.16 Demeclocycline hydrochloride. 446.20 Doxycycline hyclate. 446.20a Sterile doxycycline hyclate. 446.21 Doxycycline monohydrate. 446.42 Meclocycline sulfosalicylate. 446.50 Methacycline hydrochloride. 446.60 Minocycline hydrochloride. 446.65 Oxytetracycline. 446.65a Sterile oxytetracycline. 446.66 Oxytetracycline calcium. 446.67 Oxytetracycline hydrochloride. 446.67a Sterile oxytetracycline hydro

chloride. 446.75a Sterile rolitetracycline. 446.76a Sterile rolltetracycline nitrate. 446.80 Tetracycline. 446.81 Tetracycline hydrochloride. 446.81a Sterile tetracycline hydrochloride. 446.82 Tetracycline phosphate complex.

Subpart B-Oral Dosage Forms

(c) The batch for neomycin content, polymyxin B content, pH, and sterility.

(11) Samples required:

(a) The neomycin sulfate used in making the batch: Ten packages, each containing approximately 300 milligrams.

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

(c) The batch:

(1) For all tests except sterility: A minimum of six immediate containers.

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

(b) Tests and methods of assay—(1) POtency-(i) Neomycin content. Proceed as directed in $444.42a(b)(1), except prepare the sample as follows: Remove an accurately measured portion and dilute with 0.1M potassium phosphate buffer, pH 8.0, to the proper prescribed reference concentration. The neomycin content is satisfactory if it is not less than 90 percent nor more than 130 percent of the number of milligrams of neomycin that it is represented to contain.

(ii) Polymyxin B content. Remove an accurately measured portion and dilute with 10-percent potassium phosphate buffer, pH 6.0, to a reference concentration of 10 units of polymyxin B per milliliter. Proceed as directed in $448.30a(b)(1) of this chapter, except add to each concentration of the polymyxin B standard curve a quantity of neomycin to yield the same concentration of neomycin as that present when the sample is diluted to contain 10 units of polymyxin B per milliliter. The polymyxin B content is satisfactory if it is not less than 90 percent nor more than 130 percent of the number of units of polymyxin B that it is represented to contain.

(2) Sterility. Proceed as directed in $ 436.20 of this chapter, using the method described in paragraph (e)(1) of that section.

(3) PH. Proceed as directed in $ 440.80a(b)(5)(ii) of this chapter, using the undiluted sample.

446.110 Chlortetracycline hydrochloride cap

sules. 446.115 Demeclocycline oral dosage forms. 446.115a Demeclocycline oral suspension. 446.115b Demeclocycline for oral suspension. 446.116 Demeclocyline hydrochloride oral

dosage forms. 446.116a Demeclocycline hydrochloride tab

lets. 446.116b (Reserved] 446.116c Demeclocycline hydrochloride cap

sules. 446.120 Doxycycline hyclate oral dosage

forms. 446.120a Doxycycline hyclate capsules. 446.120b Doxycycline calcium oral suspen

sion. 446.120c Doxycycline hyclate tablets. 446.120d Doxycycline hyclate pellet-filled

capsules. 446.121 Doxycycline monohydrate oral dos

age forms. 446.121a Doxycycline monohydrate for oral

suspension 446.121b Doxycycline monohydrate capsules. 446.150 Methacycline hydrochloride oral

dosage forms. 446.150a Methacycline hydrochloride cap

sules. 446.150b Methacycline hydrochloride oral

suspension. 446.160 Minocycline hydrochloride oral dos

age forms. 446.160a Minocycline hydrochloride tablets.

[39 FR 19045, May 30, 1974, as amended at 41 FR 56307, Dec. 28, 1976; 42 FR 18059, Apr. 5, 1977; 50 FR 19919, May 13, 1985)

mic dosage forms. 446.381a Tetracycline hydrochloride

hydrochloride ophthalmic ointment. 446.381b Tetracycline hydrochloride oph

thalmic suspension.

Subpart E-Otic Dosage Forms

446.467 Oxytetracycline hydrochloride-poly

myxin B sulfate otic ointment.

446.160b Minocycline hydrochloride cap

sules. 446.160C Minocycline hydrochloride oral sus

pension. 446.165 Oxytetracycline oral dosage forms. 446.165a Oxytetracycline tablets. 446.1656446.165c (Reserved) 446.165d Oxytetracycline for oral suspen

sion. 446.166 Oxytetracycline calcium oral sus

pension. 446.167 Oxytetracycline hydrochloride cap

sules. 446.180 Tetracycline oral dosage forms. 446.180a-446.180b (Reserved) 446.180c Tetracycline oral suspension. 446.181 Tetracycline hydrochloride oral dos

age forms, 446.181a-446.1810 [Reserved] 446.181d Tetracycline hydrochloride tablets. 446.181e Tetracycline hydrochloride cap

sules. 446.182 Tetracycline phosphate complex

capsules.

Subpart F-Dermatologic Dosage Forms

446.510 Chlortetracycline hydrochloride

ointment. 446.542 Meclocycline sulfosalicylate cream. 446.567 Oxytetracycline hydrochloride der

matologic dosage forms. 446.567a (Reserved) 446.567b Oxytetracycline hydrochloride

polymyxin B sulfate topical ointment. 446.567c Oxytetracycline hydrochloride

polymyxin B sulfate topical powder. 446.581 Tetracycline hydrochloride dermato

logic dosage forms. 446.581a-446.581b [Reserved) 446.5810 Tetracycline hydrochloride for top

ical solution. 446.581d Tetracycline hydrochloride oint

ment.

Subpart C-injectable Dosage Forms

Subpart G-Vaginal Dosage Forms

446.667 Oxytetracycline hydrochloride-poly

myxin B sulfate vaginal tablets.

Subpart H-Rectal Dosage Forms

[Reserved)

446.220 Doxycycline hyclate for injection. 446.260 Sterile minocycline hydrochloride. 446.265 Oxytetracycline injection. 446.267 Oxytetracycline hydrochloride for

injection. 446.275 Rolltetracycline injectable dosage

forms. 446.275a Rolitetracycline for intravenous

use. 446.275b Rolitetracycline for intramuscular

use. 446.276 Rolitetracycline nitrate injectable

dosage forms. 446.276a Rolitetracycline nitrate for intra

venous use. 446.276b Rolitetracycline nitrate for

intramuscular use. 446.281 Tetracycline

hydrochloride injectable dosage forms. 446.281a Sterile tetracycline hydrochloride. 446.2816 Tetracycline hydrochloride for

intramuscular use. 446.281d Tetracycline hydrochloride for in

travenous use. 446.282 Tetracycline phosphate complex for

injection.

Subpart I [Reserved]

Subpart J-Certain Other Dosage Forms

[Reserved]

AUTHORITY: 21 U.S.C. 357.

SOURCE: 39 FR 19076, May 30, 1974, unless otherwise noted.

Subpart D-Ophthalmic Dosage Forms

446.310 Chlortetracycline hydrochloride

ophthalmic ointment. 446.367 Oxytetracycline hydrochloride oph

thalmic dosage forms. 446.367c Oxytetracycline hydrochloride-hy

drocortisone acetate ophthalmic suspen

sion. 446.367e Oxytetracycline hydrochloride

polymyxin B sulfate ophthalmic oint

ment. 446.381 Tetracycline hydrochloride ophthal

Subpart A-Bulk Drugs 8 446.10 Chlortetracycline hydro

chloride. (a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Chlortetracycline hydrochloride is [4S - (4a, 4aa,5aa,6p, 12aa] - 7

chloro 4 (dimethylamino) - 1,4, 4a,5,5a,6,11,12a - octahydro 3,6,10,12, 12a - pentahydroxy - 6 - methyl - 1,11 dioxo

2 naphthacenecarboxamidemonohydrochloride. Chlortetracycline is produced by the growth of Streptomyces

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