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potency is satisfactory if it is not less than 90 percent and not more than 140 percent of the number of milligrams of candicidin that it is represented to contain. Its moisture content is not more than 0.1 percent. The candicidin used conforms to the requirements of $ 449.10(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 the requirements of $ 431.1 of this chapter, each such request shall contain:

(i) Results of tests and assays on:

(a) The candicidin used in making the batch for potency, loss on drying, PH, and identity.

(b) The batch for potency and moisture.

(ii) Samples required:

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

(6) The batch: A minimum of five 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 n- hexane (containing 0.1 percent butylated hydroxyanisole). Shake the sample and n- hexane until homogeneous.

Add 15 milliliters of dimethylsulfoxide (containing 0.1 percent butylated hydroxyanisole) and shake well. Allow the layers to separate. Remove the bottom layer and repeat the extraction procedure with a second 15-milliliter portion of dimethylsulfoxide (containing 0.1 percent butylated hydroxyanisole). Combine the extractives in a suitable volumetric flask and fill to volume with sterile distilled water. Further dilute an aliquot with sterile distilled water to the reference concentration of 0.06 microgram of candicidin per milliliter (estimated).

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

$ 449.610b Candicidin vaginal tablets.

(a) Requirements for certification (1) Standards of identity, strength, quality, and purity. Candicidin vaginal tablets are tablets composed of candicidin with suitable binders, diluents, and lubricants. Each tablet contains 3 milligrams of candicidin. Its potency is satisfactory if it is not less than 90 percent and not more than 150 percent of the number of milligrams of candicidin that it is represented to contain, except that for the issuance of a certificate for each batch, the candicidin content must be not less than 115 percent and not more than 150 percent of the number of milligrams of candiçidin that it is represented to contain. The tablets shall disintegrate within 30 minutes. The loss on drying is not more than 1 percent. The candicidin used in making the batch conforms to the standards of 8 449.10(a)(1).

(2) Labeling. The drug shall be labeied 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 candicidin used in making the batch for potency, loss on drying, pH, and identity.

(6) The batch for potency, loss on drying, and disintegration time.

(ii) Samples required. (a) The candicidin used in making the batch: 10 packages, each consisting of approximately 300 milligrams.

(6) The batch: A minimum of 56 tablets.

(b) Tests and methods of assay—(1) Potency. Proceed as directed in $436.106 of this chapter, preparing the sample for assay as follows: Weigh a pool of five tablets and grind in a mortar to a very fine powder. Suspend an accurately weighed aliquot (of approximately 2 grams) in 10 milliliters of dimethylsulfoxide. Centrifuge for 5 minutes at 2,000 revolutions per minute. Carefully decant the supernatant solution into a sterile 250-milliliter volumetric flask. Wash the residue three times with 5-milliliter portions

of

dimethylsulfoxide, centrifuging each time. Add the washes to the 250-milliliter volumetric flask

(39 FR 19134, May 30, 1974, as amended at 40 FR 15089, Apr. 4, 1975]

and fill to volume with sterile distilled water. Using sterile distilled water, further dilute to the reference concentration of 0.06 microgram of candicidin per milliliter (estimated).

(2) Disintegration time. Proceed as directed in $ 436.212 of this chapter, using the method described in paragraph (e)(1) of that section, except use distilled water as the immersion fluid.

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

(containing 0.1 percent butylated hydroxyanisole). Add the washes to the separatory funnel. Shake the sample and n- hexane until homogeneous. Add 15 milliliters of dimethylsulfoxide (containing 0.1 percent butylated hydroxyanisole) and shake well. Allow the layers to separate. Remove the bottom layer and repeat the extraction procedure with a second 15-milliliter portion of dimethylsulfoxide (containing 0.1 percent butylated hydroxyanisole). Combine the extractives in a suitable volumetric flask and fill to volume with sterile distilled water. Further dilute an aliquot with sterile distilled water to the reference concentration of 0.06 microgram of candicidin per milliliter (estimated).

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

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8 449.610c Candicidin vaginal capsules.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Candicidin vaginal capsules are gelatin capsules containing 3 milligrams of candicidin in a suitable and harmless ointment. The candicidin content is satisfactory if it is not less than 90 percent and not more than 150 percent of the number of milligrams of candicidin that it is represented to contain. The moisture content is not more than 0.1 percent. The candicidin used conforms to the requirements of $ 449.10(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 candicidin used in making the batch for potency, loss on drying, pH, and identity.

(6) The batch for potency and moisture.

(ii) Samples required:

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

(6) The batch: A minimum of 20 capsules.

(b) Tests and methods of assay-(1) POtency. Proceed as directed in 436.106 of this chapter, preparing the sample for assay as follows: Remove the tips from two capsules and express the ointment from each capsule into a separatory funnel containing approximately 50 milliliters of no hexane (containing 0.1 percent butylated hydroxyanisole). Wash out the capsules at least two times with 2- to 3-milliliter portions of warm (approximately 50° C) n- hexane

$ 449.650a Nystatin vaginal tablets.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Nystatin vaginal tablets are tablets composed of nystatin and suitable and harmless diluents, binders, and lubricants. Each tablet contains 100,000 units of nystatin. Its potency is satisfactory if it is not less than 90 percent and not more than 140 percent of the number of units of nystatin that it is represented to contain. The loss on drying is not more than 5 percent. The disintegration time is not more than 1 hour. The nystatin used conforms to the standards prescribed therefor by $ 449.50(a)(1) (i), (iii), (iv), and (v).

(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 nystatin used in making the batch for potency, loss on drying, pH, and identity.

(6) The batch for nystatin content, loss on drying, and disintegration time.

(ii) Samples required:

(a) The nystatin used in making the batch: 10 immediate containers of approximately 300 milligrams each.

(6) The batch: A minimum of 36 tablets.

(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 tablets for 3 to 5 minutes in a high-speed glass blender with sufficient dimethylformamide to give a convenient concentration. Dilute an aliquot with

sufficient dimethylformamide to give a stock solution containing 400 units of nystatin per milliliter (estimated). Further dilute the stock solution with 10 percent potassium phosphate buffer, pH 6.0 (solution 6), to the reference concentration of 20 units of nystatin per milliliter (estimated).

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

(3) Disintegration time. Proceed as directed in $436.212 of this chapter, using the procedure described in paragraph (e)(1) of that section, except use distilled water in lieu of gastric fluid.

(6) The batch for potency and moisture.

(ii) Samples required:

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

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

(b) Tests and methods of assay—(1) Potency. Proceed as directed in 8 436.105 of this chapter, preparing the sample for assay as follows: Place a representative number of suppositories into a highspeed glass blender jar containing sufficient dimethylformamide to give a convenient concentration. Blend for 3 to 5 minutes. Dilute an aliquot with sufficient dimethylformamide to obtain a concentration of 400 units of nystatin per milliliter (estimated). Further dilute an aliquot with 10 percent potassium phosphate buffer, pH 6.0 (solution 6), to the reference concentration of 20 units of nystatin per milliliter (estimated).

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

(43 FR 43458, Sept. 26, 1978, as amended at 50 FR 19920, May 13, 1985)

(39 FR 19134, May 30, 1974. Redesignated at 43 FR 43458, Sept. 26, 1978]

PART 450-ANTITUMOR ANTIBIOTIC

DRUGS

Subpart A-Bulk Drugs

Sec. 450.10a Sterile bleomycin sulfate. 450.20 Dactinomycin. 450.22 Daunorubicin hydrochloride. 450.24 Doxorubicin hydrochloride. 450.30 Idarubicin hydrochloride. 450.40 Plicamycin. 450.45 Mitomycin.

Subpart B [Reserved)

$ 449.650b Nystatin vaginal supposi

tories. (a) Requirements for certification (1) Standards of identity, strength, quality, and purity. Nystatin vaginal suppositories contain in each suppository 100,000 units of nystatin in a suitable and harmless water soluble base. Its potency is satisfactory if it is not less than 90 percent and not more than 130 percent of the number of units of nystatin that it is represented to contain. Its moisture content is not more than 1.5 percent. The nystatin used conforms to the standards prescribed by $ 449.50(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 nystatin used in making the batch for potency, loss on drying, pH, and identity.

Subpart C-Injectable Dosage Forms

450.210 Sterile bleomycin sulfate. 450.220 Dactinomycin for injection. 450.222 Daunorubicin hydrochloride for in

jection. 450.224 Doxorubicin

hydrochloride injectable dosage forms. 450.224a Doxorubicin hydrochloride for in

jection. 450.224b Doxorubicin hydrochloride injec

tion. 450.230 Idarubicin hydrochloride for injec

tion. 450.240 Plicamycin for injection. 450.245 Mitomycin for injection.

AUTHORITY: 21 U.S.C. 357. .

Subpart A-Bulk Drugs

remove

8 450.10a Sterile bleomycin sulfate.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Sterile bleomycin sulfate is the amorphous sulfate salt of bleomycin. Bleomycin has been separated into several similar glyco-peptide molecules. It is a cream-colored powder that is so purified and dried that:

(i) Its potency is not less than 1.5 units and not more than 2.0 units of bleomycin per milligram. If it is packaged for dispensing, the content of the ampoule or vial is not less than 90 percent and not more than 120 percent of the number of units of bleomycin that it is represented to contain.

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

(v) It contains no depressor substances.

(vi) Its loss on drying is not more than 6.0 percent.

(vii) Its pH in an aqueous solution containing 10 units per milliliter is not less than 4.5 and not more than 6.0.

(viii) Its copper content is not greater than 0.1 percent.

(ix) Its content of various bleomycins is as follows: Bleomycin A2 is not less than 55 percent and not more than 70 percent; bleomycin B2 is not less than 25 percent and not more than 32 percent; bleomycin B4 is not more than 1 percent. Bleomycins A2 and B2 should comprise not less than 85 percent of the total bleomycins.

(x) 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:

(i) Results of tests and assays on ne batch for potency, sterility, pyrogens, depressor substances, loss on drying, pH, copper, content of various bleomycins, and identity.

(ii) Samples required:

(a) For all tests except sterility: A minimum of 20 immediate containers.

(6) 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: Dissolve an accurately weighed sample in sufficient 0.1M potassium phosphate buffer, pH 7.0 (solution 16), to provide a stock solution of convenient concentration; if it is packaged for dispensing, reconstitute as directed in the labeling. Then, using a suitable hypodermic needle and syringe,

all of the withdrawable contents. Dilute the sample thus obtained with solution 16 to provide a stock solution of convenient concentration. Further dilute an aliquot of the stock solution with solution 16 to the reference concentration of 0.04 unit of activity 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 the entire contents of each of the immediate containers tested.

(3) Pyrogens. Proceed as directed in $436.32(a) of this chapter, using a solution containing 0.5 unit of bleomycin per milliliter.

(4) [Reserved]

(5) Depressor substances. Proceed as directed in $ 436.35 of this chapter.

(6) Loss on drying. Proceed as directed in $436.200(a) of this chapter, using the total contents of 2 or 3 vials.

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

(8) Copper content-(i) Reagents. Dissolve 10 milligrams of zinc dibenzyldithiocarbamate in 100 milliliters of carbon tetrachloride.

(ii) Preparation of standard copper. solution. Accurately weigh 1.965 grams of cupric sulfate pentahydrate and transfer to a 1-liter volumetric flask. Dissolve the material in 0.1N hydrochloric acid, dilute to volume with 0.1N hydrochloric acid and mix well. Transfer 3 milliliters of this stock solution to a 1liter volumetric flask, dilute to volume with 0.1N hydrochloric acid, and mix well. This standard copper solution contains 0.0015 milligram of copper per milliliter. Transfer 10 milliliters of the standard copper solution to a 60-milliliter separatory funnel.

(iii) Preparation of the sample. Accurately weigh approximately 15 milligrams of sample into a 60-milliliter separatory funnel. Dissolve the sample in 10 milliliters of 0.1N hydrochloric acid.

(iv) Procedure. To the separatory funnels containing the sample solution and standard copper solution, add 10 milliliters

of
the

zinc

dibenzyldithiocarbamate solution and shake the funnels vigorously for 1 minute. Allow the phases to separate. Filter the carbon tetrachloride phase (lower phase) through 1 gram of anhydrous sodium sulfate to remove excess water. Using a suitable spectrophotometer equipped with 1-centimeter cells, and carbon tetrachloride as a blank, measure the absorbance of the standard copper solution and the sample solution at 435 nanometers. Calculate the percent copper as follows:

Absorbance of sample solution x 1.5 Percent copper =

Absorbance of standard copper solution

xSample weight in milligrams

(9) Content of various bleomycin fractions. Proceed as directed in $ 436.339 of this chapter.

(10) Identity test. Proceed as directed in § 436.211 of this chapter, using the method described in paragraph (b)(1) of that section, using a 1 percent mixture.

[40 FR 52005, Nov. 7, 1975; 40 FR 53998, Nov. 20, 1975, as amended at 46 FR 60568, Dec. 11, 1981; 48 FR 51913, Nov. 15, 1983; 50 FR 19920, May 13, 1985]

8 450.20 Dactinomycin.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Dactinomycin is a brightred compound that is so purified and dried that:

(i) Its dactinomycin content is not less than 900 micrograms of dactinomycin per milligram, calculated on an anhydrous basis.

(ii) Its loss on drying is not more than 15 percent.

(iii) Its absorptivity at 445 nanometers is not less than 0.95 and not more than 1.03 times that of the dactinomycin working standard at the same wavelength. Its absorbance at 240 nanometers is not less than 1.3 and not more than 1.5 times its absorbance at 445 nanometers.

(iv) It is crystalline.

(V) It passes the identity test for dactinomycin.

(2) Labeling. It shall be labeled in accordance with the requirements of

$ 432.5(b) of this chapter, and in addition each package shall bear on its label the statement “Protect from light and excessive heat."

(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 dactinomycin content, loss on drying, absorptivity, crystallinity, and identity.

(ii) Samples required: 16 packages, each containing approximately 40 milligrams. (b) Tests Tests and

and methods of assay. Dactinomycin is toxic and corrosive. It must be handled with care in the laboratory. Transfer all dry powders in a suitable hood, while wearing rubber gloves. Avoid inhaling fine particles of the powder. Do not pipette by mouth. If any of the substance contacts the skin, wash copiously with soap and water. Dispose of all waste material by dilution with large volumes of trisodium phosphate solution.

(1) Dactinomycin content. Proceed as directed in $ 436.331 of this chapter, preparing the sample and calculating the dactinomycin content as follows:

(i) Preparation of sample solution. ACcurately weigh a sufficient amount of the sample to obtain a solution containing approximately 0.25 milligram per milliliter of dactinomycin in mobile phase.

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