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

[42 FR 27238, May 27, 1977, as amended at 50 FR 19920, May 13, 1985)

$ 448.930 Polymyxin B sulfate in cer

tain other dosage forms.

(v) The statement "Expiration date

the blank being filled in with the date that is 12 months after the month during which the batch was certified, unless use of a longer dating period has been approved in accordance with the provisions of $ 432.5(a)(3) of this chapter.

(vi) The statement, "The potency of this drug cannot be assured for longer than 60 days after the container is first opened for compounding a prescription".

(vii) The statements, “For use only in

extemporaneous prescription compounding. Not for manufacturing use”.

(4) 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 the batch for potency, loss on drying, pH, zinc content, and identity.

(ii) Samples required: A 0.5-gram portion for each 5,000 packages in 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-(1) POtency. Proceed as directed in $436.105 of this chapter, preparing the sample for assay as follows: Dissolve an

accurately weighed sample (usually 25 to 35 milligrams) in sufficient 0.01N hydrochloric acid to give a bacitracin concentration of 100 units per milliliter (estimated). Further dilute an aliquot with solution 1 to the reference concentration of 1.0 unit of bacitracin per milliliter (estimated).

§ 448.930a Polymyxin B sulfate for pre

scription compounding. (a) Requirements for certification (1) Standards of identity, strength, quality, and purity. Polymyxin B sulfate for prescription compounding is the sulfate salt of a kind of polymyxin or a mixture of two or more such salts intended for use in the extemporaneous compounding of prescriptions by practicing pharmacists. It is a white to buff-colored powder. It is so purified and dried that:

(1) Its potency is not less than 6,000 units of polymyxin B per milligram, on an anhydrous basis.

(ii) [Reserved)

(iii) Its loss on drying is not more than 7.0 percent.

(iv) Its pH in an aqueous solution containing 5 milligrams per milliliter is not less than 5.0. and not more than 7.5.

(v) Its residue on ignition is not more than 5 percent.

(vi) It gives positive color identity tests for polymyxin.

(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 100 million units of polymyxin B.

(3) Labeling. In addition to the requirements of $ 432.5(a)(3) of this chapter, each package shall bear on its outside wrapper or container and on the immediate container the following:

(i) The statement "Caution: Federal law prohibits dispensing without prescription”.

(ii) The statement "Not sterile". (iii) The batch mark.

(iv) The number of units of polymyxin B activity in each milligram of the polymyxin B sulfate and the number of grams of polymyxin B sulfate in the immediate container.

NOTE: The final sample solution must contain the same amount of hydrochloric acid as the reference concentration of the working standard.

(2) (Reserved]

(3) Loss on drying. Proceed as directed in 8436.200(b) of this chapter.

(4) PH. Proceed as directed in 8436.202 of this chapter, using a saturated solution (approximately 100 milligrams of the sample per milliliter).

(5) Zinc content. Proceed as directed in $436.312 of this chapter.

fate solution (1:100) mixing after the addition of each drop; a reddish-violet color is produced.

(39 FR 19115, May 30, 1974, as amended at 46 FR 16684, Mar. 13, 1981; 50 FR 19920, May 13, 1985]

or

(v) The statement, “The potency of this drug cannot be assured for longer than 60 days after the container is first opened for compounding a prescription”.

(vi) The statements, "For use only in extemporaneous

prescription compounding. Not for manufacturing use''.

(4) 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, residue on ignition, and identity.

(ii) Samples required: A 0.5-gram portion for each 5,000 packages in 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-(1) Potency. Proceed as directed in $ 436.105 of this chapter, preparing the sample for assay as follows: Dissolve an accurately weighed sample in 2 milliliters of sterile distilled water for each 5 milligrams of weighed sample. Further dilute an aliquot with sufficient 10 percent potassium phosphate buffer, pH 6.0 (solution 6), to give a stock solution of convenient concentration. Further dilute an aliquot of the stock solution with solution 6 to the reference concentration of 10 units of polymyxin B per milliliter (estimated).

(2) [Reserved]

(3) Loss on drying. Proceed as directed in 8436.200(b) of this chapter.

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

(5) Residue on ignition. Proceed as directed in 8436.207(a) of this chapter.

(6) Identity. (i) To a solution of 2 milligrams of polymyxin B sulfate in 5 milliliters of water, add 0.5 milliliter of triketohydrindene solution (1:1,000) and 2 drops of pyridine, boil for 1 minute, and cool; a blue color develops; and

(ii) To a solution of 2 milligrams of polymyxin B sulfate in 5 milliliters of water, add 5 milliliters of sodium hydroxide solution (1:10), mix well, and add, dropwise, 5 drops of a cupric sul

$ 448.930b Sterile polymyxin B sulfate

benzalkonium chloride urethral lu

bricant. (a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Sterile polymyxin B sulfate-benzalkonium chloride urethral lubricant is polymyxin B sulfate and benzalkonium chloride, with one more suitable and harmless suspending agents, in a suitable and harmless base. It contains, in each gram, 5,000 units of polymyxin B and 330 micrograms of benzalkonium chloride. Its content of polymyxin B is satisfactory if it contains 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. It is sterile. Its pH is not less than 4.0 and not more than 5.5. The polymyxin B sulfate used conforms to the standards prescribed by $ 448.30a(a)(1), except sterility, pyrogens, and 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:

(1) Results of tests and assays on:

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

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

(ii) Samples required:

(a) The polymyxin B sulfate 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 § 436.105 of Subpart C-Injectable Dosage Forms

449.204 Amphotericin B for injection.

Subpart D-Ophthalmic Dosage Forms

449.340 Natamycin ophthalmic suspension.

Subpart E (Reserved)

Subpart F-Dermatologic Dosage Forms

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 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. Further dilute an aliquot of the stock solution with solution 6 to the reference concentration of 10 units of polymyxin B per milliliter (estimated).

(2) Sterility. Proceed as directed in $ 436.20(e)(1) of this chapter, except dissolve

the

ointment as follows: Aseptically transfer a portion of 0.25 gram from each of 10 immediate containers of the drug to 400 milliliters of diluting fluid D in an Erlenmeyer flask. Repeat the procedure on another 10 immediate containers. Swirl the flasks to dissolve the ointment.

(3) pH. Proceed as directed in $ 436.202 of this chapter, using the undiluted sample.

449.504 Amphotericin B dermatologic dosage

forms. 449.504a Amphotericin B ointment. 449.504b Amphotericin B cream. 449.504c Amphotericin B lotion. 449.550 Nystatin dermatologic dosage forms. 449.550a Nystatin ointment. 449.550b Nystatin-iodochlorhydroxyquin

ointment. 449.550c Nystatin-neomycin sulfate-grami

cidin-triamcinolone acetonide ointment; nystatin-neomycin sulfate-gramicidin

fludrocortisone acetate ointment. 449.550d Nystatin cream. 449.550e Nystatin-neomycin sulfate-grami

cidin-triamcinolone acetonide cream. 449.550f Nystatin topical powder. 449.550g Nystatin-neomycin sulfate-grami

cidin topical powder. 449.550h Nystatin lotion.

[blocks in formation]

on

(ii) It contains not more than 15 percent of amphotericin A.

(iii) [Reserved]

(iv) Its loss on drying is not more than 5.0 percent.

(v) It contains not more than 3.0 percent residue on ignition.

(vi) It passes the identity test.

(2) Labeling. In addition to the labeling prescribed by $ 432.5(b) of this chapter, each package shall bear on its label the statements "Store below 10° C.” and “Protect from light and moisture".

(3) Requests for certification; samples. In addition to the requirements of $431.1 of this chapter, each such request shall contain:

(i) Results of test and assays on the batch for potency, amphotericin A content, loss

drying, residue on iginition, and identity.

(ii) Samples required on the batch: 10 packages, each containing not less than 500 milligrams.

(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 accurately weighed sample in sufficient dimethylsulfoxide to give a stock solution of convenient concentration. Further dilute

aliquot with dimethylsulfoxide to a concentration of 20 micrograms of amphotericin B per milliliter (estimated). Remove an allquot; 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) Amphotericin A content-(i) Amphotericin A. Dry approximately 20 milligrams of the nystatin working standard as described in $436.200(a) of this chapter. Accurately weigh the dried working standard and quantitatively transfer into a 200

milliliter volumetric flask. Add exactly 40.0 mil

liliters of dimethylsulfoxide and dissolve. Make to mark with methyl alcohol and mix thoroughly. Pipette 4.0 milliliters of this solution into a 50milliliter volumetric flask. Add methyl alcohol to mark and mix thoroughly.

(ii) Amphotericin B. Dry approximately 50 milligrams of the amphotericin B working standard as described in § 436.200(a) of this chapter. Accurately weigh the dried working standard and quantitatively transfer into a 50-milliliter volumetric flask. Add 10 milliliters of dimethylsulfoxide and dissolve. Make to mark with methyl alcohol and mix thoroughly. Pipette 4.0 milliliters of this solution into a 50milliliter volumetric flask. Add methyl alcohol to mark and mix thoroughly. The standard solution should be used for 1 day only.

(iii) Sample. Accurately weigh about 50 milligrams of the sample to be tested and quantitatively transfer into a 50-milliliter volumetric flask. Add 10 milliliters of dimethylsulfoxide and dissolve. Make to mark with methyl alcohol and mix thoroughly. Pipette 4.0 milliliters of this solution into a 50milliliter volumetric flask. Add methyl alcohol to mark and mix thoroughly.

(iv) Blank. Pipette 10 milliliters of dimethylsulfoxide into a 50-milliliter volumetric flask. Make to mark with methyl alcohol and mix. Pipette 4.0 milliliters of this solution into a 50milliliter volumetric flask. Make to mark with methyl alcohol and mix thoroughly.

(v) Procedure. Use a suitable ultraviolet spectrophotometer and l-centimeter silica celis. Adjust the instrument to zero with the blank solution. Measure the absorbances of the solutions of nystatin standard, amphotericin B standard, and the sample at 304 nanometers and at 282 nanometers. Calculate the absorptivity of each standard at both wavelengths:

an

[(BxS2)-(bxS;)]X625 Percent amphotericin A =

W *[(Bxa)-(bx A)]

where:

A=Absorptivity of nystatin standard at 282

nanometers;

B=Absorptivity of amphotericin B stand

ard at 282 nanometers; a=Absorptivity of aystatin standard at 304

nanometers; b=Absorptivity of amphotericin B standard

at 304 nanometers; Sy=Absorbance of sample at 282

nanometers; Sz=Absorbance of sample at 304

nanometers; Ws=Weight of sample in grams (on an an

hydrous basis).

(3) [Reserved)

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

(5) Residue on ignition. Proceed as directed in 436.207(a) of this chapter.

(6) Identity. Using the solutions prepared as described in paragraphs (b)(2) (ii), (iii), and (iv) of this section, record the absorption spectrum from 320 to 240 nanometers. Then dilute these solutions (1+9) with methyl alcohol and record the absorption spectrum from 400 to 320 nanometers. The sample exhibits absorption peaks at identical wavelengths with that of the amphotericin B standard. Depending on the amphotericin A content of the sample, peak may Occur

at

304 nanometers.

ter, each package shall bear on its label the statements "Store below 10° C." and "Protect from light and moisture”.

(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 the batch for potency, amphotericin A content, loss on drying, residue on ignition, and identity.

(ii) Samples required on the batch: 10 packages, each containing not less than 500 milligrams.

(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 accurately weighed sample in sufficient dimethylsulfoxide to give a stock solution of convenient concentration. Further dilute with dimethylsulfoxide to give a concentration of 20 micrograms of amphotericin B per milliliter (estimated). Dilute an aliquot 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) Amphotericin A content. Proceed as directed in $ 449.4(b)(2).

(3) [Reserved]

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

(5) Residue of ignition. Proceed as directed in $ 436.207(a) of this chapter.

(6) Identity. Proceed as directed in $ 449.4(b)(7).

a

[39 FR 19115, May 30, 1974, as amended at 46 FR 16684, Mar. 13, 1981; 49 FR 2242, Jan. 19, 1984; 50 FR 19920, May 13, 1985)

[39 FR 19134, May 30, 1974, as amended at 49 FR 2243, Jan. 19, 1984; 50 FR 19920, May 13, 1985)

$ 449.4a Amphotericin B for use in par

enteral products. (a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Amphotericin B is a yellow to golden-orange powder. It is insoluble in water at pH 6.0 to 7.0, anhydrous alcohols, esters, ethers, benzene, and toluene.

It is soluble in dimethylformamide

and dimethylsulfoxide. It is so purified and dried that:

(i) Its potency is not less than 750 micrograms of amphotericin B per milligram on an anhydrous basis.

(ii) It contains not more than 5 percent of amphotericin A.

(iii) [Reserved]

(iv) Its loss on drying is not more than 5.0 percent.

(v) It contains not more than 0.5 percent residue on ignition.

(vi) It passes the identity test.

(2) Labeling. In addition to the labeling prescribed by $432.5(b) of this chap

$ 449.10 Candicidin.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Candicidin is a brown to yellow powder. It is sparingly soluble in water; very slightly soluble in ethyl alcohol, butyl alcohol, and acetone. It is so purified and dried that:

(i) Its potency is not less than 1,000 micrograms of candicidin per milligram on an anhydrous basis.

(ii) Its loss on drying is not more than 4 percent.

(iii) Its pH is not less than 8.0 nor more than 10.0 in a 1 percent aqueous suspension.

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