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micrograms of piperacillin per milligram on an anhydrous basis. If it is packaged for dispensing, it contains not less than 90.0 percent and not more than 120.0 percent of the number of grams of piperacillin that it is represented to contain.

(ii) It is sterile.

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

(v) Its moisture content is not more than 1.0 percent.

(vi) Its pH in an aqueous solution containing 400 milligrams per milliliter is not less than 5.5 and not more than 7.5.

(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 the batch for potency, sterility, pyrogens, moisture, and pH.

(ii) Samples required:

(a) If it is packaged for repacking or for use in the manufacture of another drug:

(1) For all tests except sterility: 10 packages, each containing approximately 300 milligrams; and 5 packages, each containing approximately 1 gram. (2) For sterility testing: 20 packages, each containing approximately 300 milligrams.

(b) If it is packaged for dispensing: (1) For all tests except sterility: A minimum of 15 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 § 436.334 of this chapter.

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

(3) Pyrogens. Proceed as directed in § 436.32(a) of this chapter, using a solution containing 150 milligrams of piperacillin per milliliter.

(4) [Reserved]

(5) Moisture. Proceed as directed in § 436.201 of this chapter, using the sample preparation method described in paragraph (d)(4) of that section.

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(ii) It is sterile.

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

(v) Its moisture content is not more than 6.0 percent.

(vi) Its pH in an aqueous solution containing 10 milligrams of ticarcillin per milliliter (or if packaged for dispensing after reconstitution as directed in the labeling) is not less than 6.0 and not more than 8.0.

(vii) It gives a positive identity test for ticarcillin.

(viii) Its ticarcillin content is not less than 80 percent and not more than 94 percent on an anhydrous basis.

(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 the batch for potency, sterility, pyrogens, moisture, pH, identity, and ticarcillin content.

(ii) Samples required:

(a) If it is packaged for repacking or for use in the manufacture of another drug:

(1) For all tests except sterility: 10 packages, each containing approximately 300 milligrams; and 5 packages, each containing approximately 1 gram.

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

(b) If it is packaged for dispensing: (1) For all tests except sterility: A minimum of 15 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 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 give a stock solution of convenient concentration; and also, if it is packaged for dispensing, reconstitute as directed in the labeling. Then using a suitable hypodermic needle and syringe, remove all the withdrawable contents if it is represented as a single-dose container; or if the labeling specifies the amount of potency in a given volume of the resultant preparation, remove an accurately measured representative portion from each container. If it is a singledose container, use a separate needle and syringe for each container. Dilute with sufficient solution 1 to give a stock solution of convenient concentration. Further dilute an aliquot of the stock solution with solution 1 to the reference concentration of 5.0 micrograms of ticarcillin 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.

(3) Pyrogens. Proceed as directed in § 436.32(b) of this chapter, using a solution containing 100 milligrams of ticarcillin per milliliter.

(4) [Reserved]

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

(6) pH. Proceed as directed in § 436.202 of this chapter, using an aqueous solution containing 10 milligrams of ticarcillin per milliliter (or if packaged for dispensing, use a solution prepared as directed for reconstitution in the labeling).

(7) Identity and ticarcillin content. Transfer an accurately weighed portion of approximately 40 milligrams of the sample to a 100-milliliter volumetric flask. Dissolve and dilute to volume with distilled water. Transfer 5.0 milliliters of this solution to another 100milliliter volumetric flask and dilute to volume with 0.1N methanolic hydrochloric acid (prepared by diluting 0.8 milliliter of 12N hydrochloric acid to 100 milliliters with methyl alcohol). Treat a portion of the ticarcillin standard in the same manner. Using a suitable spectrophotometer equipped with a 1.0-centimeter quartz cell and 0.1N methanolic acid as a blank, scan the absorption spectrum of the methanolic solution of the sample and the standard between the wavelengths of 300 and 200 nanometers. Determine the absorbance of each solution at the maxima, at approximately 230 nanometers. The spectrum of the samples should compare qualitatively with that of the ticarcillin working standard. Determine the percent ticarcillin as follows:

Percent ticarcillin

Absorbance of sample x Weight in milligrams of standard x Potency of standard in micrograms per milligram×10 Absorbance of standard × weight in milligrams of sample (100-m)

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(i) Its ticarcillin potency is not less than 890 micrograms of ticarcillin per milligram calculated on an anhydrous basis.

(ii) Its moisture content is not less than 4.0 and not more than 6.0 percent.

(iii) The pH of an aqueous solution containing 10 milligrams of ticarcillin per milliliter is not less than 2.5 and not more than 4.0.

(iv) It gives a positive identity test for ticarcillin.

(v) It is crystalline.

(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 the batch for potency, moisture, pH, identity, and crystallinity.

(ii) Samples, if required by the Center for Drug Evaluation and Research: 10 packages, each containing approximately 300 milligrams.

(b) Tests and methods of assay-(1) Ticarcillin potency. Determine the micrograms of ticarcillin activity per milligram of sample. Proceed as directed in §436.355 of this chapter using the equipment, conditions, reagents, and system suitability requirements as described in § 440.290b(b), except use the resolution test solution to determine resolution in lieu of the working standard solution. Prepare the working standard solution, sample solution, and resolution test solution and calculate the micrograms of ticarcillin per milligrams as follows:

(i) Preparation of working standard, sample, and resolution test solutions—(A) Working standard solution. Accurately weigh a quantity of the ticarcillin working standard containing the equivalent of approximately 90 milligrams of ticarcillin activity and transfer to a 100-milliliter volumetric flask. Dissolve and dilute to volume with diluent pH 6.4 phosphate buffer prepared as described in § 440.290b(b)(1)(i)(c).

(B) Sample solution. Dissolve an accurately weighed portion of the sample with diluent pH 6.4 buffer as prepared

in §440.290b(b)(1)(1)(c) to obtain a solution containing 0.9 milligram of ticarcillin activity per milliliter (estimated).

(C) Resolution test solution. Accurately weigh a quantity of the ticarcillin working standard containing the equivalent of approximately 90 milligrams of ticarcillin activity and transfer to a 100-milliliter volumetric flask. Prepare a solution of the clavulanic acid working standard containing the equivalent of 30 milligrams of clavulanic acid activity in a 100-milliliter volumetric flask. Dissolve and dilute to volume with diluent. Transfer 10 milliliters of this solution into the flask containing the ticarcillin standard. Dilute the combined standard solution to volume with diluent and mix. Use within 8 hours of preparation.

(ii) Calculations. Calculate the micrograms of ticarcillin per milligram as follows:

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P, Ticarcillin activity in the ticarcillin working standard solution micrograms per milliliter; C-Milligrams of ticarcillin sample per milliliter of sample solution; and m=Percent moisture content of the sample.

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

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

(4) Identity. Proceed as directed in § 440.90a(b)(7).

(5) Crystallinity. Proceed as directed in § 436.203 of this chapter.

[55 FR 5839, Feb. 20, 1990]

Subpart B-Oral Dosage Forms

§ 440.103 Amoxicillin oral dosage forms.

§ 440.103a Amoxicillin trihydrate capsules.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Amoxicillin trihydrate capsules are composed of amoxicillin trihydrate with or without one or more suitable and harmless lubricants, diluents, and drying agents, enclosed in a gelatin capsule. Each capsule contains amoxicillin trihydrate equivalent to 250 milligrams or 500 milligrams of amoxicillin. Its potency is satisfactory if it is not less than 90 percent and not more than 120 percent of the number of milligrams of amoxicillin that it is represented to contain. Its moisture content is not more than 14.5 percent. It passes the identity test. The amoxicillin trihydrate used conforms to the standards prescribed by § 440.3(a)(1).

(2) Labeling. In addition to the labeling requirements prescribed by §432.5 of this chapter, this drug shall be labeled "amoxicillin capsules".

(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 amoxicillin trihydrate used in making the batch for potency, moisture, pH, amoxicillin content, concordance, crystallinity, and identity.

(b) The batch for potency, moisture, and identity.

(ii) Samples required:

(a) The amoxicillin trihydrate used in making the batch: 12 packages, each containing approximately 300 milligrams.

(b) The batch: A minimum of 30 capsules.

(b) Tests and methods of assay—(1) Potency. Assay for potency by either of the following methods; however, the results obtained from the iodometric assay shall be conclusive:

(i) Microbiological agar diffusion assay. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Place a representative number of capsules into a high-speed glass

blender jar containing 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 0.1 microgram of amoxicillin per milliliter (estimated).

(ii) Iodometric assay. Proceed as directed in § 436.204 of this chapter, except in paragraph (d) of that section, add 3 drops of 1.2N hydrochloric acid to both the sample and working standard solutions after the addition of 0.01N iodine solution. Prepare the sample as follows: Place the contents of a representative number of capsules into a high-speed glass blender jar and add sufficient distilled water to give a convenient concentration. Blend for 3 to 5 minutes. Further dilute an aliquot with distilled water to the prescribed concentration.

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

(3) Identity. Proceed as directed in § 436.311 of this chapter, preparing the sample solution as follows: Dissolve an accurately weighed portion of the amoxicillin capsule contents in 0.1N hydrochloric acid to give a solution containing 4 milligrams of amoxicillin per milliliter.

[39 FR 34033, Sept. 23, 1974, as amended at 49 FR 3458, Jan. 27, 1984; 50 FR 19919, May 13, 1985]

§ 440.103b Amoxicillin trihydrate for oral suspension.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Amoxicillin trihydrate for oral suspension is a mixture of amoxicillin trihydrate with one or more suitable and harmless colorings, flavorings, buffers, sweetening ingredients, preservatives, stabilizers, and suspending agents. When reconstituted as directed in the labeling, it contains amoxicillin trihydrate equivalent to either 25 or 50 milligrams of amoxicillin per milliliter. Its potency is satisfactory if it is not less than 90 percent and not more than 120 percent of the number of milligrams of amoxicillin that it is represented to contain. Its moisture content is not more than 3.0 percent. Its pH, when reconstituted as directed

in the labeling, is not less than 5.0 and not more than 7.5. It passes the identity test. The amoxicillin trihydrate used conforms to the standards prescribed by § 440.3(a)(1).

(2) Labeling. In addition to the labeling requirements prescribed by § 432.5 of this chapter, this drug shall be labeled "amoxicillin for oral suspension".

(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 amoxicillin trihydrate used in making the batch for potency, moisture, pH, amoxicillin content, concordance, crystallinity, and identity.

(b) The batch for potency, moisture, pH, and identity.

(ii) Samples required:

(a) The amoxicillin trihydrate used in making the batch: 12 packages, each containing approximately 300 milligrams.

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

(b) Tests and methods of assay—(1) Potency. Assay for potency by either of the following methods; however, the results obtained from the iodometric assay shall be conclusive:

(1) Microbiological agar diffusion assay. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Reconstitute the drug as directed in the labeling. Place an accurately measured representative portion of the sample into a suitable volumetric flask and dilute to volume with 0.1M potassium phosphate buffer, pH 8.0 (solution 3), to give a stock solution of convenient concentration. Mix well. Further dilute an aliquot with solution 3 to the reference concentration of 0.1 microgram of amoxicillin per milliliter (estimated).

(ii) Iodometric assay. Proceed as directed in §436.204 of this chapter, except in paragraph (d) of that section, add 3 drops of 1.2N hydrochloric acid to both the sample and working standard solutions after the addition of 0.01N iodine solution. Prepare the sample as follows: Reconstitute the drug as directed in the labeling. Place an accurately measured aliquot (usually a single dose) into an appropriately sized

volumetric flask and dilute to volume with distilled water. Mix well. Further dilute with distilled water to the prescribed concentration.

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

(3) pH. Proceed as directed in §436.202 of this chapter, using the suspension reconstituted as directed in the label

ing.

(4) Identity. Proceed as directed in § 436.311 of this chapter, preparing the sample solution as follows: From an aliquot of suspension prepared in accordance with the label, make either a 6.25:1 dilution for the 25-milligramsper-milliliter dosage; or a 12.5:1 dilution for the 50-milligrams-per-milliliter dosage, with 0.1N hydrochloric acid. The slight dilution of the acid does not have a significant effect on the test.

[39 FR 34033, Sept. 23, 1974, as amended at 49 FR 3458, Jan. 27, 1984; 50 FR 19919, May 13, 1985; 54 FR 47351, Nov. 14, 1989]

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(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Amoxicillin Amoxicillin trihydrate chewable tablets are composed of amoxicillin trihydrate with or without one or more suitable lubricants, diluents, preservatives, drying agents, flavorings, and colorings. Each tablet contains amoxicillin trihydrate equivalent to either 125 or 250 milligrams of amoxicillin. Its potency is satisfactory if it contains not less than 90 percent and not more than 120 percent of the number of milligrams of amoxicillin that it is represented to contain. Its moisture content is not more than 6.0 percent. It passes the identity test. The amoxicillin trihydrate used conforms the standards prescribed by

to

§ 440.3(a)(1).

(2) Labeling. In addition to the labeling requirements prescribed by

§ 432.5 of this chapter, this drug shall be labeled "amoxicillin tablets."

(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 assay on:

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