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

(39 FR 19149, May 30, 1974, as amended at 50 FR 19921, May 13, 1985)

than 90 days after the container is first opened for compounding a prescription."

(vi) The statements “For use only in extemporaneous

prescription compounding. Not for manufacturing

Subpart I [Reserved]

use.»;

Subpart J-Certain Other Dosage

Forms

$452.910 Erythromycin for prescrip

tion compounding. (a) Requirements for certification–(1) Standards of identity, strength, quality, and purity. Erythromycin for prescription compounding is the odorless, white to grayish-white or slightly yellow compound of a kind of erythromycin or a mixture of two or more such compounds. It is so purified and dried that:

(i) It contains not less than 850 micrograms of erythromycin per milligram calculated on an anhydrous basis.

(ii) Its moisture content is not more than 10 percent.

(iii) Its pH is not less than 8.0 nor more than 10.5.

(iv) Its residue on ignition is not more than 2.0 percent.

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

(vi) It is crystalline.

(2) Packaging. The immediate container shall be a tight container as defined by the United States Pharmacopeia XXI. It shall be so sealed that the contents cannot be used without destroying such seal. Each such container shall contain 10 grams, 25 grams, or 100 grams of erythromycin.

(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 micrograms of erythromycin activity in each milligram of erythromycin and the number of grams of erythromycin in the immediate container.

(v) The statement “The potency of this drug cannot be assured for longer

(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, moisture, pH, residue on ignition, identity, and crystallinity.

(ii) Samples, if required by the Director, Center for Drug Evaluation and Research: 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 methyl alcohol to obtain a concentration of 10 milligrams of erythromycin base per milliliter (estimated). Dilute this solution further with sufficient 0.1M potassium phosphate buffer, pH 8.0 (solution 3), to obtain a stock solution containing 1.0 milligram of erythromycin base per

milliliter (estimated). Further dilute an aliquot of the stock solution with solution 3 to the reference concentration of 1.0 microgram of erythromycin base per milliliter (estimated).

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

(3) pH. Proceed as directed in $436.202 of this chapter, except standardize the pH meter with pH 7.0 and pH 10.0 buffers and prepare the sample as follows: Dissolve 200 milligrams of sample in 5 milliliters of reagent grade methyl alcohol. Add 95 milliliters of water and mix. Record the pH when an equilibrium value has been reached.

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

(5) Identity test. Proceed as directed in $ 436.211 of this chapter, using the sample preparation method described in paragraph (b)(3) of that section.

(6) Crystallinity. Proceed as directed in $ 436.203(a) of this chapter.

(51 FR 35213, Oct. 2, 1986, as amended at 55 FR 11584, Mar. 29, 1990; 55 FR 25392, June 21, 1990)

PART 453-LINCOMYCIN

ANTIBIOTIC DRUGS

Subpart A-Bulk Drugs

Sec. 453.20 Clindamycin hydrochloride hydrate. 453.21 Clindamycin palmitate hydro

chloride. 453.22 Clindamycin phosphate. 453.22a Sterile clindamycin phosphate. 453.30 Lincomycin

hydrochloride monohydrate. 453.30a Sterile lincomycin hydrochloride

monohydrate.

Subpart B-Oral Dosage Forms

453.120 Clindamycin hydrochloride hydrate

capsules. 453.121 Clindamycin palmitate hydro

chloride oral dosage forms. 453.121a Clindamycin palmitate hydro

chloride for oral suspension. 453.121b Clindamycin palmitate hydro

chloride for oral solution. 453.130 Lincomycin hydrochloride oral dos

age forms. 453.130a Lincomycin

hydrochloride monohydrate capsules. 453.130b Lincomycin hydrochloride syrup.

(ii) Its microbiological activity is not less than 800

micrograms of clindamycin per milligram.

(iii) (Reserved]

(iv) Its moisture content is not less than 3.0 percent and not more than 6.0 percent.

(v) Its pH in an aqueous solution containing 100 milligrams per milliliter is not less than 3.0 and not more than 5.5.

(vi) It is crystalline.

(vii) It passes the identity test for clindamycin hydrochloride hydrate.

(2) Labeling. It shall be labeled in accordance with the requirements of $ 432.5(b) 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 clindamycin content, microbiological activity, moisture, pH, crystallinity, and identity.

(ii) Samples required: 10 packages, each containing approximately 300 milligrams.

(b) Tests and methods of assay--(1) Clindamycin content (vapor phase chromatography). Proceed as directed in $436.302 of this chapter. (2) Microbiological

activity (microbiological agar diffusion assay.) Proceed as directed in $436.105 of this chapter, preparing the sample for assay

follows: Dissolve an accurately weighed sample in sufficient sterile distilled water to give a stock solution of convenient concentration. Further dilute the stock solution with 0.1M potassium phosphate buffer, pH 8.0 (solution 3), to the reference concentration of 1.0 microgram of clindamycin per milliliter (estimated).

(3) [Reserved]

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

(5) pH. Proceed as directed in 8436.202 of this chapter, using an aqueous solution containing 100 milligrams per milliliter.

(6) Crystallinity. Proceed as directed in $ 436.203 of this chapter.

(7) Identity. Proceed as directed in $436.211 of this chapter, using the sample preparation method described in paragraph (b)(2) of that section.

Subpart C-injectable Dosage Forms

453.222 Clindamycin phosphate injection. 453.230 Lincomycin hydrochloride injection.

Subparts D-E (Reserved]

Subpart F-Dermatologic Dosage Forms

as

453.522 Clindamycin phosphate dermato

logic dosage forms. 453.522a Clindamycin phosphate topical so

lution. 453.522b Clindamycin phosphate gel. 453.522c Clindamycin phosphate lotion. 453.522d Clindamycin phosphate vaginal

cream.

AUTHORITY: 21 U.S.C. 357.

Subpart A-Bulk Drugs

8 453.20 Clindamycin hydrochloride

hydrate. (a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Clindamycin hydrochloride hydrate is the hydrated hydrochloride salt of clindamycin. It is so purified and dried that:

(i) Its clindamycin content is not less than 800 micrograms of clindamycin per milligram.

(39 FR 19161, May 30, 1974, as amended at 50 FR 19921, May 13, 1985)

8 453.21 Clindamycin palmitate hydro- phosphoric acid. It occurs as a white to chloride.

off-white powder. It is so purified and (a) Requirements for certification (1)

dried that: Standards of identity, strength, quality,

(i) Its clindamycin content is not less and purity. Clindamycin palmitate hy- than 758 micrograms of clindamycin drochloride is the white to off-white per milligram calculated on an anhyamorphous powder of the hydrochloride drous basis. salt of the palmitic acid ester of (ii) Its microbiological activity is not clindamycin. It is freely soluble in

less than 758 micrograms of water, ethanol, chloroform, and ether.

clindamycin per milligram calculated It is so purified and dried that:

on an anhydrous basis. (i) It contains not less than 540

(iii) (Reserved) micrograms of clindamycin per milli

(iv) Its moisture content is not more gram.

than 6.0 percent. (ii) [Reserved] (iii) Its moisture content is not more

(v) Its pH in an aqueous solution conthan 3.0 percent.

taining 10 milligrams per milliliter is (iv) Its pH in an aqueous solution

not less than 3.5 and not more than 4.5. containing 10 milligrams per milliliter (vi) It is crystalline. is not less than 2.8 and not more than (vii) It passes the identity test for 3.8.

clindamycin phosphate. (v) It passes the identity test for

(2) Labeling. It shall be labeled in acclindamycin palmitate hydrochloride.

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

$ 432.5 of this chapter. cordance with the requirements of

(3) Requests for certification; samples. $ 432.5 of this chapter.

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

quirements of $ 431.1 of this chapter, In addition to complying with the requirements of $431.1 of this chapter,

each such request shall contain: each such request shall contain:

(1) Results of tests and assays on the (i) Results of tests and assays on the

batch for clindamycin content, microbatch for clindamycin content, mois- biological activity, moisture, pH, crysture, pH, and identity.

tallinity, and identity. (ii) Samples required: 10 packages, (ii) Samples required: 10 packages, nine containing not less than 300 milli- nine containing approximately 300 milgrams and one package containing not ligrams and one containing 1.5 grams. less than 2 grams.

(b) Tests and methods of assay-(1) (b) Tests and methods of assay--(1)

Clindamycin content (vapor phase chroClindamycin content. Proceed as di

matography). Proceed as directed in rected in 8 436.303 of this chapter.

$ 436.304 of this chapter. (2) (Reserved]

(2) Microbiological activity (micro(3) Moisture. Proceed as directed in 8 436.201 of this chapter.

biological agar diffusion assay). Proceed (4) pH. Proceed as directed in 8436.202

as directed in $ 436.105 of this chapter, of this chapter, using an aqueous solu

preparing the sample for assay as foltion containing 10 milligrams per mil

lows: Accurately weigh approximately liliter.

12 milligrams of the clindamycin phos(5) Identity. Proceed as directed in phate sample into a 50-milliliter glass$ 436.211 of this chapter, using the sam- stoppered centrifuge tube. Pipet 25 milple preparation method described in liliters of the pH 9.0 borate buffer into paragraph (b)(2) of that section.

the centrifuge tube. Add 10 milliliters [39 FR 19161, May 30, 1974, as amended at 50

of chloroform and shake vigorously for FR 19921, May 13, 1985)

15 minutes. Centrifuge the resulting

mixture and pipet a 20-milliliter ali8453.22 Clindamycin phosphate.

quot of the aqueous phase into a 35(a) Requirements for certification—(1)

milliliter centrifuge tube. Add Standards of identity, strength, quality, weighed amount of intestinal alkaline and purity. Clindamycin phosphate is a phosphatase equivalent to 50 units of water-soluble ester of clindamycin and

a

activity and allow the solution to stand until the enzyme has completely dissolved. Place the tube into a water bath at 37° C +2° C for 2.5 hours. After the 2.5-hours hydrolysis, allow the solution to cool. Further dilute an aliquot of the solution with 0.1M potassium phosphate buffer, pH 8.0 (solution 3), to the reference concentration of 1.0 microgram of clindamycin per milliliter (estimated).

(3) (Reserved]

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

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

(6) Crystallinity. Proceed as directed in $ 436.203(a) of this chapter.

(7) Identity. Proceed as directed in $ 436.211 of this chapter, using the sample preparation method described in paragraph (b)(2) of that section, except dry the sample for 2 hours at 100o C and allow to equilibrate with the atmosphere for 1 hour.

(viii) Its pH in an aqueous solution containing 10 milligrams per milliliter is not less than 3.5 and not more than 4.5.

(ix) It is crystalline.

(x) It passes the identity test for clindamycin phosphate.

(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 clindamycin content, microbiological activity, sterility, pyrogens, depressor substances, moisture, pH, crystallinity, and identity.

(ii) Samples required:

(a) For all tests except sterility: 10 packages, nine containing approximately 300 milligrams and one containing 1.5 grams.

(6) For sterility testing: 20 packages, each containing approximately 300 milligrams.

(b) Tests and methods of assay-(1) Clindamycin content (vapor phase chromatography). Proceed as directed in $ 436.304 of this chapter. (2) Microbiological

activity (microbiological agar diffusion assay). Proceed as directed in $436.105 of this chapter, preparing the sample for assay as follows: Accurately weigh approximately 12 milligrams of the clindamycin phosphate sample into a 50-milliliter glass-stoppered centrifuge tube. Pipet 25 milliliters of the pH 9.0 borate buffer into the centrifuge tube. Add 10 milliliters of chloroform and shake vigorously for 15 minutes. Centrifuge the resulting mixture and pipet a 20-milliliter aliquot of the aqueous phase into a 35-milliliter centrifuge tube. Add a weighed amount of intestinal alkaline phosphatase equivalent to 50 units of activity1 and allow the solution to stand until the enzyme has completely dissolved. Place the tube into a water bath at 37° C.+2° C. for 2.5 hours. After the 2.5-hour hydrolysis, allow the solution to cool. Further dilute an aliquot of the solution with

(46 FR 2996, Jan. 13, 1981, as amended at 50 FR 19921, May 13, 1985)

a

8 453.22a Sterile clindamycin phos

phate. (a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Sterile clindamycin phosphate is water-soluble ester of clindamycin and phosphoric acid. It occurs as a white to off-white powder. It is so purified and dried that:

(1) Its clindamycin content is not less than 758 micrograms of clindamycin per milligram calculated on an anhydrous basis.

(ii) Its microbiological activity is not less than

758 micrograms of clindamycin per milligram calculated on an anhydrous basis.

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

(vi) It contains no depressor substances.

(vii) Its moisture content is not more than 6 percent.

1 Defined such that 50 units hydrolyzes at least 20 micromoles of a clindamycin phosphate authentic sample under the assay conditions described in this section,

1 Defined such that 50 units hydrolyzes at least 20 micromoles of a clindamycin phosphate authentic sample under the assay conditions described in this section.

179 070 0-98-31

1.0

0.1M potassium phosphate buffer, pH 8.0 (solution 3), to the reference concentration of

microgram of clindamycin per milliliter (estimated).

(3) Sterility. Proceed as directed in 8 436.20 of this chapter, using the method described in paragraph (e)(1) of that section.

(4) Pyrogens. Proceed as directed in $ 436.32(a) of this chapter, using a solution containing 24 milligrams of clindamycin per milliliter.

(5) (Reserved]

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

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

(8) pH. Proceed as directed in 8436.202 of this chapter, using an aqueous solution containing 10 milligrams per milliliter.

(9) Crystallinity. Proceed as directed in $436.203(a) of this chapter.

(10) Identity. Proceed as directed in $ 436.211 of this chapter, using the sample preparation method described in paragraph (b)(2) of that section, except dry the sample for 2 hours at 100° C. and allow to equilibrate with the atmosphere for 1 hour.

(vi) It passes the infrared identity test.

(vii) Its content of lincomycin B is not more than 5 percent.

(viii) It passes the identity test if the elution pattern of the lincomycin sample compares quantitatively to that of the lincomycin working standard under identical conditions of gas liquid chromatography

(ix) It is crystalline.

(2) Labeling. It shall be labeled in accordance with the requirements of $ 432.5(b) 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, moisture, pH, specific rotation, infrared absorption spectrum, lincomycin B content, crystallinity, and identity.

(ii) Samples of the batch: 10 packages, each containing approximately 300 milligrams.

(b) Tests and methods of assay-(1) POtency. Use either of the following methods; however, the results obtained from the gas liquid chromatography assay shall be conclusive.

(i) Microbiological turbidimetric assay. Proceed as directed in $436.106 of this chapter, preparing the sample for assay follows: Dissolve

accurately weighed sample in sufficient sterile distilled water to obtain a stock solution of convenient concentration. Further dilute an aliquot of the stock solution with sterile distilled water to the reference concentration of 0.5 microgram of lincomycin per milliliter (estimated).

(ii) Gas liquid chromatography assay. Proceed as directed in $ 436.306 of this chapter.

(2) [Reserved]

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

(4) PH. Proceed as directed in 8436.202 of this chapter, using an aqueous solution containing 100 milligrams per milliliter.

(5) Specific rotation. Accurately weigh 500 milligrams of lincomycin hydrochloride monohydrate in a 25-milliliter, glass stoppered volumetric flask and fill to volume with distilled water. Proceed as directed in $436.210 of this

[39 FR 19161, May 30, 1974, as amended at 46 FR 60568, Dec. 11, 1981; 50 FR 19921, May 13, 1985)

as

an

$ 453.30 Lincomycin hydrochloride

monohydrate. (a) Requirements for certification (1) Standards of identity, strength, quality, and purity. Lincomycin hydrochloride monohydrate is the monohydrated hydrochloride salt of lincomycin. It is freely soluble in water and soluble in acetone and dimethylformamide. It is so purified and dried that:

(i) Its potency is not less than 790 micrograms of lincomycin per milligram.

(ii) [Reserved]

(iii) Its moisture content is not less than 3.0 percent and is not more than 6.0 percent.

(iv) Its pH in an aqueous solution containing 100 milligrams per milliliter is not less than 3.0 and not more than 5.5.

(v) Its specific rotation in an aqueous solution at 25° C. is not less than + 135° and not more than + 150°.

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