Lapas attēli
PDF
ePub

PART 441-PENEM ANTIBIOTIC

DRUGS

Subpart A-Bulk Drugs

Sec. 441.20a Sterile imipenem monohydrate.

Subpart B [Reserved)

Subpart C-Injectable Dosage Forms

441.220 Imipenem monohydrate-cilastatin

sodium injectable dosage forms. 441.220a Sterile imipenem monohydrate

cilastatin sodium. 441.220b Imipenem monohydrate-cilastatin

sodium for injection.

AUTHORITY: 21 U.S.C. 357.

Subpart A-Bulk Drugs

8 441.20a Sterile

imipenem monohydrate. (a) Requirements for certification (1) Standards of identity, strength, quality, and purity. Imipenem monohydrate is the monohydrate form of [5R-[50, 6a, (R*)]]-6-(1-hydroxyethyl)-3-[[2[(iminomethyl) amino)ethyl]thio]-7oxo-1-azabicyclo[3.2.0)-hept-2-ene-2-carboxylic acid. It is a white to tan colored powder. It is so purified and dried that:

(i) Its potency is not less than 900 micrograms and not more than 1,050 micrograms of imipenem per milligram on an anhydrous basis.

(ii) It is sterile.
(iii) It is nonpyrogenic.

(iv) Its loss on drying is not less than 5.0 percent and not more than 8.0 percent.

(v) Its specific rotation in an aqueous solution containing 5 milligrams of imipenem per milliliter at 25 °C is +85° to +95° on an anhydrous basis.

(vi) It gives a positive identity test. (vii) 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, sterility, pyrogens, loss on drying, specific rotation, identity, and crystallinity.

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

(a) For all tests except sterility: 10 packages, each containing approximately 500 milligrams.

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

(b) Tests and methods of assay-(1) Potency. Proceed as directed in $ 436.216 of this chapter, using a column heater which will maintain a 50 °C column temperature, and ultraviolet detection system operating at a wavelength of 254 nanometers, a column packed with microparticulate (3 to 10 micrometers in diameter) reversed phase packing material such as octyl or octadecyl hydrocarbon bonded silicas, a flow rate of 2.0 milliliters per minute, and a known injection volume of 10 microliters. Reagents, working standard and sample solutions, system suitability requirements, and calculations are as follows:

(i) Reagentsa) Phosphate buffer, 0.001M. Dissolve 272 milligrams of monobasic potassium phosphate in 1,800 milliliters of deionized water. Adjust the pH to 6.8 with 0.5N sodium hydroxide or dilute phosphoric acid. Dilute to 2,000 milliliters with deionized water and filter prior to use.

(6) Mobile phase. Dissolve 2.0 grams of 1-hexanesulfonic acid, sodium salt in 800 milliliters of phosphate buffer, 0.001M. Adjust the pH to 6.8 with 0.5N sodium hydroxide or dilute phosphoric acid and dilute to 1,000 milliliters with phosphate buffer, 0.001M. Filter and degas the mobile phase just prior to its introduction into the chromatograph pumping system.

(c) 0.1 Percent bicarbonate solution. Dissolve 50 milligrams of sodium bicarbonate in 40 milliliters of phosphate buffer, 0.001M, and dilute to 50 milliliters with phosphate buffer, 0.001M.

(d) 0.9 Percent saline solution. Dissolve 9.0 grams of sodium chloride in 800 milliliters of deionized water and dilute to 1.0 liter with deionized water.

(ii) Preparations of working standard and sample solutions-(a) Working standard solution. Accurately weigh approximately 25 milligrams of the imipenem working standard into a 50-milliliter volumetric flask. Immediately prior to

time equal to that observed for the

standard); As=Area of the imipenem peak in the chro

matogram of the imipenem working

standard; P=Anhydrous Imipenem activity in the

imipenem working standard solution in

micrograms per milliliter; Cw=Milligrams of sample per milliliter of

sample solution; and L=Percent loss on drying of the sample.

analysis, add 10 milliliters of 0.9 percent saline solution and 1 milliliter of 0.1 percent bicarbonate solution. Add phosphate buffer, 0.001M, and shake until dissolved. Sonicate, if necessary, but for no longer than 1 minute. Dilute to volume with phosphate buffer, 0.001M, to obtain a solution containing approximately 500 micrograms of imipenem per milliliter. Mix well and inject immediately.

(6) Sample solution. Dissolve an accurately weighed portion (approximately 25 milligrams) of the sample with 10 milliliters of 0.9 percent saline solution and 1 milliliter of 0.1 percent bicarbonate solution in a 50-milliliter volumetric flask. Dilute the sample solution to volume with phosphate buffer, 0.001M, to obtain a solution containing 500 micrograms of imipenem per milliliter (estimated).

(iii) System suitability requirements

(a) Tailing factor. The tailing factor (T) is satisfactory if it is not more than 1.5 at 10 percent of peak height in lieu of 5 percent of peak height.

(6) Efficiency of the column. The efficiency of the column (n) is satisfactory if it is greater than 600 theoretical plates for a 30-centimeter column.

(c) Resolution. The resolution (R) between the peaks for thienamycin and imipenem is satisfactory if it is not less than 2.0.

(d) Coefficient of variation (relative standard deviation). The coefficient of variation (Srinpercent) of 5 replicate injections is satisfactory if it is not more than 2.0 percent. If the system suitability requirements have been met, then proceed as described in $ 436.216(b) of this chapter. Alternate chromatographic conditions are acceptable provided reproducibility and resolution are comparable to the system. However, the sample preparation described in paragraph (b)(1)(ii)(6) of this section should not be changed.

(iv) Calculations. Calculate the micrograms of imipenem per milligram of sample as follows:

(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 5.0 milligrams of imipenem per milliliter, except inject 10 milliliters per kilogram of rabbit weight.

(4) Loss on drying. Proceed as directed in $436.200(1) of this chapter.

(5) Specific rotation. Dilute an accurately weighed sample with sufficient pH 7.0 phosphate buffer to give a concentration of approximately 5.0 milligrams of imipenem per milliliter. Proceed as directed in § 436.210 of this chap ter, using a 1.0-decimeter polarimeter tube. To prepare the pH 7.0 phosphate buffer, transfer 5 grams of monobasic potassium phosphate and 11 grams of dibasic potassium phosphate to a 1.0liter volumetric flask. Dissolve and dilute to volume with distilled water.

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

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

(51 FR 11573, Apr. 4, 1986; 51 FR 16517, May 5, 1986, as amended at 55 FR 11582, Mar. 29, 1990; 59 FR 8133, Feb. 18, 1994]

Subpart B-[Reserved]

Subpart C-Injectable Dosage

Forms

8 441.220 Imipenem monohydrate

cilastatin sodium injectable dosag forms.

Micrograms of

A, XP, X100 imipenem per =

milligram A, C, X(100-L) where: Ax=Area of the Imipenem peak in the chro

matogram of the sample (at a retention

$ 441.220a Sterile

imipenem monohydrate-cilastatin sodium. (a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Imipenem monohydratecilastatin sodium is a dry mixture of imipenem monohydrate and cilastatin sodium packaged for dispensing. Its potency is satisfactory if it contains not less than 400 micrograms of imipenem and not less than 400 micrograms of cilastatin per milligram. Its imipenem content is satisfactory if it is not less than 90 percent and not more than 115 percent of the number of milligrams of imipenem that it is represented to contain. Its cilastatin content is satisfactory if it is not less than 90 percent and not more than 115 percent of the number of milligrams of cilastatin that it is represented to contain. It is sterile. It is nonpyrogenic. Its loss on drying is not more than 3.5 percent. When reconstituted as directed in the labeling, its pH is not less than 6.0 and not more than 7.5. The imipenem monohydrate used conforms to the standards prescribed by $441.20a(a)(1).

(2) Labeling. It shall be labeled in accordance with the requirements of 8 432.5 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 imipenem monohydrate used in making the batch for potency, sterility, pyrogens, loss on drying, specific rotation, identity, and crystallinity.

(B) The batch for imipenem potency, cilastatin potency, imipenem content, cilastatin content, sterility, pyrogens, loss on drying, and pH.

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

(A) The imipenem monohydrate used in making the batch: 10 packages, each containing approximately 500 milligrams.

(B) The batch:

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

(2) For sterility testing: 20 immediate containers, collected at regular intervals throughout each filling operation.

(b) Tests and methods of assay-(1) Imipenem and cilastatin potency and content. Determine the potency of the sample in micrograms per milligram of both imipenem and cilastatin and the milligrams of both imipenem and cilastatin per container. Proceed as di

rected in $441.20a(b)(1), preparing the cilastatin reference standard solution, the sample solution and calculating the imipenem and cilastatin potency and content as follows:

(i) Cilastatin reference standard. Accurately weigh approximately 25 milligrams of the cilastatin reference standard into a 50-milliliter volumetric flask. Immediately prior to analysis, add 10 milliliters of a 0.9 percent saline solution and 1.0 milliliter of a 0.1 percent bicarbonate solution. Add phosphate buffer, 0.001M, and shake until dissolved. Sonicate, if necessary, but no longer than 1 minute. Dilute to volume with phosphate buffer, 0.001M, to obtain a solution containing approximately 500 micrograms of cilastatin per milliliter. Mix well and inject immediately.

(ii) Preparation of sample solutions(A) Imipenem and cilastatin potency (micrograms of imipenem and cilastatin per milligram). Remove the metal seal from each of 10 containers and determine the gross weight in grams. Dissolve and wash out the entire contents of each container with a 0.9 percent saline solution into an appropriate size volumetric flask to give a concentration of 5 milligrams per milliliter each of imipenem and cilastatin. Further dilute with phosphate buffer, 0.001M, to obtain а. solution containing 500 micrograms each of imipenem and cilastatin per milliliter (estimated). Wash each stopper and container with small quantities of acetone or methanol three times being careful not to wet the container labeling. Allow the containers to air dry about 3 hours or to constant weight. Weigh each container and stopper to determine tare weight in grams.

(B) Imipenem and cilastatin content (milligrams of imipenem and cilastatin per container). Reconstitute the sample as directed in the labeling, except use a 0.9 percent saline solution as the reconstituting fluid. Then, using a suitable hypodermic needle and syringe, remove all of 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. Accurately dilute the solution thus obtained in a suitable volumetric flask with sufficient 0.9 percent saline solution to obtain a stock solution containing about 2,500 micrograms of imipenem and 2,500 micrograms of cilastatin per milliliter. Transfer a 10-milliliter aliquot of this solution to a 50-milliliter volumetric flask and dilute to volume with phosphate buffer, 0.001M, to obtain a solution containing 500 micrograms of imipenem and 500 micrograms of cilastatin per milliliter (estimated).

(iii) Calculations—(A) Imipenem and cilastatin potency. Calculate the micrograms of imipenem and cilastatin per milligram as follows:

(3) Pyrogens. Proceed as directed in $ 436.32(a) of this chapter, using a solution containing 5.0 milligrams of imipenem per milliliter except inject 10 milliliters per kilogram of rabbit weight.

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

(5) PH. Proceed as directed in $436.202 of this chapter.

(58 FR 26670, May 4, 1993)

Milligrams of

A, XPqxd imipenem or cilastatin = per milligram As X1,000 W

S where: Au=Area of the imipenem or cilastatin peak

in the chromatogram of the sample (at a retention time equal to that observed for

the standard); As-Area of the imipenem or cilastatin peak

in the chromatogram of the imipenem or

cilastatin working standard; Ps-Anhydrous imipenem or cilastatin activ

ity in the respective working standard

solution in micrograms per milliliter; d=Dilution factor of the 10 samples; and Ws=Net contents of 10 containers in grams

(gross weight of 10 containers in grams tare weight of 10 containers in grams).

(B) Imipenem and cilastatin content. Calculate the imipenem or cilastatin content of the container as follows:

8 441.220b Imipenem monohydrate

cilastatin sodium for injection. (a) Requirements for certification (1) Standards of identity, strength, quality, and purity. Imipenem monohydratecilastatin sodium is a dry mixture of imipenem monohydrate, cilastatin sodium, and sodium bicarbonate packaged for dispensing. Its potency is satisfactory if it contains not less than 400 micrograms of imipenem and not less than 400 micrograms of cilastatin per milligram. Its imipenem content is satisfactory if it is not less than 90 percent and not more than 115 percent of the number of milligrams of imipenem that it is represented to contain. Its cilastatin content is satisfactory if it is not less than 90 percent and not more than 115 percent of the number of milligrams of cilastatin that it is represented to contain. It is sterile. It is nonpyrogenic. Its loss on drying is not more than 3.5 percent. When reconstituted as directed in the labeling, its pH is not less than 6.5 and not more than 8.5. The imipenem monohydrate used conforms to the standards prescribed by $ 441.20a(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 imipenem monohydrate used in making the batch for potency, sterility, pyrogens, loss on drying, specific rotation, identity, and crystallinity.

(6) The batch for imipenem potency, cilastatin potency, imipenem content, cilastatin content, sterility, pyrogens, loss on drying, and pH.

Milligrams of imipenem Ay xPsxd or cilastatin per milligram

As X 1,000

where: Av=Area of the imipenem or cilastatin peak

in the chromatogram of the sample (at a retention time equal to that observed for

the standard); As=Area of the imipenem or cilastatin peak

in the chromatogram of the imipenem or

cilastatin working standard; P=Anhydrous imipenem or cilastatin activ

ity in the imipenem or cilastatin working standard solution in micrograms per

milliliter; and d=Dilution factor of the sample.

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

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

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

(6) The batch:

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

(2) For sterility testing: 20 immediate containers, collected at regular intervals throughout each filling operation.

(b) Tests and methods of assay-(1) Imipenem and cilastatin potency and content. Determine the potency of the sample in micrograms per milligram of both imipenem and cilastatin and the milligrams of both imipenem and cilastatin per container. Proceed as directed in $441.20a(b)(1) of this chapter, preparing the cilastatin reference standard solution, the sample solution and calculating the imipenem and cilastatin potency and content as follows:

(i) Cilastatin reference standard. Accurately weigh approximately 25 milligrams of the cilastatin reference standard into a 50-milliliter volumetric flask. Immediately prior to analysis, add 10 milliliters of 0.9 percent saline solution and 1 milliliter of 0.1 percent bicarbonate solution. Add phosphate buffer, 0.001M, and shake until dissolved. Sonicate, if necessary, but for no longer than 1 minute. Dilute to volume with phosphate buffer, 0.001M, to obtain a solution containing approximately 500 micrograms of cilastatin per milliliter. Mix well and inject immediately.

(ii) Preparation of sample solutions (a) Imipenem and cilastatin potency (micrograms of imipenem and cilastatin per milligram). Remove the metal seal from each of 10 containers and determine gross weight in grams. Dissolve and wash out the entire contents of each container with 0.9 percent saline into an appropriate size volumetric flask to give a concentration of 5 milligrams per milliliter each of imipenem and cilastatin. Further dilute with phosphate buffer, 0.001 M, to obtain a solution containing 500 micrograms each of imipenem and cilastatin per milliliter (estimated). Wash each stopper and container with small quantities of acetone or methanol three

times being careful not to wet the container labeling. Allow the containers to air dry about 3 hours or to constant weight. Weigh each container and stopper to determine tare weight in grams.

(6) Imipenem and cilastatin content (milligrams of imipenem and cilastatin per container). Reconstitute the sample as directed in the labeling, except use 0.9 percent saline solution as the reconstituting fluid. Then, using a suitable hypodermic needle and syringe, remove all of 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. Accurately dilute the solution thus obtained in a suitable volumetric flask with sufficient 0.9. percent saline solution to obtain a stock solution containing about 2,500 micrograms of imipenem and 2,500 micrograms of cilastatin per milliliter. Transfer a 10-milliliter aliquot of this solution to a 50-milliliter volumetric flask and dilute to volume with phosphate buffer, 0.001M, to obtain a solution containing 500 micrograms of imipenem and 500 micrograms of cilastatin per milliliter (estimated).

(iii) Calculations-(a) Calculate the micrograms of imipenem and cilastatin per milligram as follows:

Micrograms of imipenem or cilastatin =

A, XP, Xd per milligram A, X1,000 W

where: Au=Area of the imipenem or cilastatin peak

in the chromatogram of the sample (at a retention time equal to that observed for

the standard); As=Area of the imipenem or cilastatin peak

in the chromatogram of the Imipenem or

cilastatin acid working standard; Pg=Anhydrous imipenem or cilastatin activ

ity in the respective working standards

solutions in micrograms per milliliter; d=Dilution factor for the 10 samples; and Ws=Net contents of 10 containers in grams

(gross weight of 10 containers in gramstare weight of 10 containers in grams).

(6) Calculate the imipenem or cilastatin content of the container as follows:

« iepriekšējāTurpināt »