Code of Federal Regulations: Containing a Codification of Documents of ...

buffer, pH 8.0 (solution 3), and shake well. Allow the layers to separate. Remove the buffer layer and repeat the extraction procedure with each of three more 20- to 25- milliliter quantities of solution 3. Combine the buffer extractives in a suitable volumetric flask and dilute to volume with solution 3. Remove an aliquot and further dilute with solution 3 to the reference concentration of 1.0 microgram of neomycin per milliliter (estimated).

(b) If the ointment is water miscible. Place an accurately weighed representative portion of the sample into a highspeed glass blender jar containing 1.0 milliliter of polysorbate 80 and sufficient 0.1M potassium phosphate buffer, pH 8.0 (solution 3), to give a stock solution of convenient concentration. Blend for 3 to 5 minutes. Remove an aliquot and further dilute with solution 3 to the reference concentration of 1.0 microgram of neomycin per milliliter (estimated).

(iii) 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:

(a) If the ointment is not water miscible. 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 10 percent potassium phosphate buffer, pH 6.0 (solution 6), and shake well. Allow the layers to separate. Remove the buffer layer and repeat the extraction procedure with each of three more 20- to 25-milliliter quantities of solution 6. Combine the buffer extractives in a suitable volumetric flask and dilute to volume with solution 6. Remove an aliquot and further dilute with solution 6 to the reference concentration of 10 units of polymyxin B per milliliter (estimated).

(b) If the ointment is water miscible. Place an accurately weighed representative portion of the sample into a highspeed glass blender jar containing 1.0

milliliter polysorbate 80 and sufficient 10 percent potassium phosphate buffer, pH 6.0 (solution 6), to give a stock solution of convenient concentration. Blend for 3 to 5 minutes. Remove an aliquot and further dilute with solution 6 to the reference concentration of 10 units of polymyxin B per milliliter (estimated).

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

[42 FR 27235, May 27, 1977, as amended at 55 FR 50173, Dec. 5, 1990]

§ 448.513d Bacitracin zinc-polymyxin B sulfate topical powder.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Bacitracin zinc-polymyxin B sulfate topical powder contains bacitracin zinc and polymyxin B sulfate in a suitable and harmless base. Each gram contains 500 units of bacitracin and 10,000 units of polymyxin B. Its bacitracin content is satisfactory if it is not less than 90 percent and not more than 120 percent of the number of units of bacitracin 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. Its moisture content is not more than 7.0 percent. It contains not more than an average of 10 microoganisms per gram. The bacitracin zinc used conforms to the standards prescribed by § 448.13(a)(1). The polymyxin B sulfate used conforms to the standards prescribed by § 448.30(a)(1).

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

(a) The batch mark.

(b) 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 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 test and assays on:

(a) The bacitracin zinc used in making the batch for potency, loss on drying, pH, zinc content, and identity.

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

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

(a) The bacitracin zinc used in making the batch: 10 packages, each containing approximately 1.0 gram.

(b) The polymyxin B sulfate used in making the batch: 10 packages, each containing approximately 1.0 gram.

(b) Tests and methods of assay-(1) Potency—(1) Bacitracin content. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Wash an accurately weighed sample (usually 2 grams) into a 100-milliliter volumetric flask with 0.01N hydrochloric acid. Dilute to volume with 0.01N hydrochloric acid. Further dilute an aliquot with solution 1 to the reference concentration of 1.0 unit of bacitracin per milliliter (estimated).

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

(ii) Polymyxin B content. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Dissolve an accurately weighed representative portion of the sample (usually 1 gram) in 20 milliliters of sterile distilled water. Wash into an appropriate-sized volumetric flask with 10 percent potassium phosphate buffer, pH 6.0 (solution 6). Further dilute with solution 6 to the reference concentration of 10 units of polymyxin B per milliliter (estimated).

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

(3) Microorganism count—(i) Conduct of test for bacteria. Using approximately 200 milligrams of powder from each of

five separate immediate containers, proceed as directed in § 436.20(e)(1) of this chapter, except after the three washings transfer the entire filter membrane to the surface of medium N as described in § 436.20(c)(14) of this chapter. Incubate the plate for 7 days at 30° C. to 32° C. Count the number of colonies appearing on the filter pad and calculate therefrom the number of viable microorganisms per gram of powder.

(ii) Conduct of test for molds and yeasts. Proceed as directed § 436.20(e)(1) of this chapter, using approximately 200 milligrams from each of the five containers tested, except transfer the entire filter membrane to the surface of medium N as described in § 436.20(c)(14) of this chapter, and incubate at 22° C. to 25° C. for 7 days. Count the number of colonies appearing on the filter pad and calculate therefrom the number of viable microorganisms per gram of powder.

[42 FR 27236, May 27, 1977, as amended at 50 FR 15110, Apr. 17, 1985; 55 FR 11584, Mar. 29, 1990]

§ 448.513e Bacitracin zinc-polymyxin B sulfate topical aerosol.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Bacitracin zinc-polymyxin B sulfate topical aerosol is bacitarcin zinc, polymyxin B sulfate in a suitable and harmless vehicle, packaged in a pressurized container with suitable and harmless inert gases. Each gram contains 120 units of bacitracin and 2,350 units of polymyxin B. Its bacitracin content is satisfactory if it is not less than 90 percent and not more than 130 percent of the number of units of bacitracin that it is represented to contain. Its polymyxin B 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. Its moisture content is not more than 0.5 percent. It contains not more than an average of 10 microorganisms per container. The bacitracin zinc used conforms to the standards prescribed by §448.13(a)(1). The polymyxin B sulfate used conforms to the standards prescribed by

§ 448.30(a)(1).

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

(a) The batch mark.

(b) 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 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 bacitracin zinc used in making the batch for potency, loss on drying, pH, zinc content, and identity.

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

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

(a) The bacitracin zinc used in making the batch: 10 packages, each containing approximately 1.0 gram.

(b) The polymyxin B sulfate used in making the batch: 10 packages, each containing approximately 1.0 gram.

(b) Tests and methods of assay-(1) Potency—(1) Sample preparation. Spray, as directed in the labeling, the entire contents of each container to be tested into separate 2-liter Erlenmeyer flask, held in a horizontal position. Add 500 milliliters of 0.01N hydrochloric acid and shake to dissolve the contents. Immediately remove aliquots of this sample solution and proceed as directed paragraph (b)(1)(1)(a) and (b) of this section for each antibiotic to be tested.

(a) Bacitracin content. Proceed as directed in § 436.105 of this chapter, diluting an aliquot of the sample solution with 1 percent potassium phosphate buffer, pH 6.0 (solution 1), to the ref

erence concentration of 1.0 unit of bacitracin per milliliter (estimated).

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

(b) Polymyxin B content. Proceed as directed in §436.105 of this chapter, diluting an aliquot of the sample solution with 10 percent potassium phosphate buffer, pH 6.0 (solution 6), to the reference concentration of 10.0 units of polymyxin B per milliliter (estimated). (ii) [Reserved]

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

(3) Microorganism count―(i) Conduct of test for bacteria. Thoroughly cleanse the valve of each container to be tested with a suitable disinfectant. Into an empty, sterile Erlenmeyer flask, stoppered with a cotton plug, spray about one-half of the contents of each of five separate immediate containers by removing the cotton plug temporarily and using aseptic technique. Allow the propellant to evaporate. To the dry residue, which should not exceed 1 gram, add 500 milliliters of diluting fluid C as described in §436.20(d)(3) of this chapter. Stopper the flask and swirl to dissolve the drug. As soon as the sample has completely dissolved, proceed as directed in §436.20(e)(1)(ii) of this chapter, except after the three washings transfer the entire filter membrane to the surface of medium N as described in §436.20(c)(14) of this chapter. Incubate the plate for 7 days at 30° C. to 32° C. Count the number of colonies appearing on the filter pad and calculate therefrom the number of viable microorganisms per gram of powder.

(ii) Conduct of test for molds and yeasts. Proceed as directed in paragraph (b)(3)(1) of this section, except transfer the entire filter membrane to the surface of medium N as described in §436.20(c)(14) of this chapter, and incubate at 25° C. for 7 days.

[42 FR 27237, May 27, 1977, as amended at 50 FR 15110, Apr. 17, 1985; 55 FR 11584, Mar. 29, 1990; 55 FR 40381, Oct. 3, 1990]

§ 448.513f Bacitracin zinc ointment. (a) Requirements for certification—(1) Standards of identity, strength, quality,

and purity. Bacitracin zinc ointment is composed of 500 units of bacitracin zinc per gram in a suitable ointment base. Its potency is satisfactory if it is not less than 90 percent and not more than 140 percent of the number of units of bacitracin that it is represented to contain. Its moisture content is not more than 0.5 percent. The bacitracin zinc used conforms to the standards prescribed by § 448.13(a)(1).

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

(a) The batch mark.

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

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 bacitracin zinc used in making the batch for potency, loss on drying, pH, zinc content, and identity.

(b) The batch for potency and moisture.

(ii) Samples required:

(a) The bacitracin zinc used in making the batch: 10 packages, each containing 1.0 gram.

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

(b) Tests and methods of assay—(1) Potency. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Place an accurately weighed representative portion of the sample into a separtory funnel containing approximately 50 milliliters of peroxide-free ether. Shake the sample and ether until homogeneous. Add 20 to 25 milliliters of 0.01N hydrochloric acid and shake well. Allow the layers to separate. Remove the aid layer and repeat the extraction procedure with each of three more 20- to 25-milliliter quantities of 0.01N hydrochloric acid. Combine the acid extractives in a suitable volumetric flask and dilute to vol

ume with 0.01N hydrochloric acid. (If the bacitracin content is less than 100 units per milliliter in 0.01N hydrochloric acid, add sufficient additional hydrochloic acid to each concentration of the standard response line so that each standard solution contains the same amout of acid as the 1.0 unit per milliliter sample solution.) Remove an aliquot and further dilute with 1.0 percent potassium phosphate buffer, pH 6.0 (solution 1), to the reference concentration of 1.0 unit of bacitracin per milliliter (estimated).

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

[42 FR 27237, May 27, 1977, as amended at 50 FR 19920, May 13, 1985]

(1) Its potency is not less than 40 units of bacitracin per milligram. (ii) [Reserved]

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

(iv) Its pH in an aqueous solution containing 10,000 units per millilter is not less than 5.5 and not more than 7.5. (v) It passes the identity test.

(2) Packaging. The immediate container shall be of colorless, transparent glass, and it shall be a tight container as defined by the United States Pharmacopeia (U.S.P.). It shall be so sealed that the contents cannot be used without destroying such seal. Each such container shall contain 500,000 or 5 million units of bacitracin.

(3) Labeling. Each package shall bear on its outside wrapper or container and

on the immediate container the following:

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

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

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

(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 the use of a longer dating period has been approved in accordance with § 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 § 432.1 of this chapter, each request shall contain:

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

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

§ 448.913 Bacitracin zinc for prescription compounding.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Bacitracin zinc for prescription compounding is the zinc salt of a kind of bacitracin or a mixture of two or more such salts intended for use in the extemporaneous compounding of prescriptions by practicing pharmacists. 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 5.0 percent.

(iv) Its pH in a saturated aqueous solution is not less than 6.0 and not more than 7.5.

(v) Its zinc content is not more than 10 percent by weight on a moisture-free basis.

(vi) It passes the identity test.

(2) Packaging. The immediate container shall be of colorless, transparent glass and it shall be a tight container as defined by the United States Pharmacopeia (U.S.P.). It shall be so sealed that the contents cannot be used without destroying such seal. Each such container shall contain 500,000 or 5 million units of bacitracin.

(3) Labeling. 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 bacitracin activity in each milligram of the bacitracin zinc, and the number of grams of bacitracin zinc in the immediate container.

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