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588 PART 441—PENEM ANTIBIOTIC DRUGS Subpart A—Bulk Drugs

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588 PART 441—PENEM ANTIBIOTIC DRUGS Subpart A—Bulk Drugs Pt. 441 21 CFR Ch. I (4±1±98 Edition) PART 441ÐPENEM ANTIBIOTIC (ii) Samples, if required by the Direc- DRUGS tor, Center for Drug Evaluation and Research: Subpart AÐBulk Drugs (a) For all tests except sterility: 10 packages, each containing approxi- Sec. mately 500 milligrams. 441.20a Sterile imipenem monohydrate. (b) For sterility testing: 20 packages, Subpart B [Reserved] each containing equal portions of ap- proximately 300 milligrams. Subpart CÐInjectable Dosage Forms (b) Tests and methods of assayÐ(1) Po- tency. Proceed as directed in § 436.216 of 441.220 Imipenem monohydrate-cilastatin this chapter, using a column heater sodium injectable dosage forms. ° 441.220a Sterile imipenem monohydrate- which will maintain a 50 C column cilastatin sodium. temperature, and ultraviolet detection 441.220b Imipenem monohydrate-cilastatin system operating at a wavelength of sodium for injection. 254 nanometers, a column packed with microparticulate (3 to 10 micrometers AUTHORITY: 21 U.S.C. 357. in diameter) reversed phase packing material such as octyl or octadecyl hy- Subpart AÐBulk Drugs drocarbon bonded silicas, a flow rate of § 441.20a Sterile imipenem 2.0 milliliters per minute, and a known monohydrate. injection volume of 10 microliters. Re- agents, working standard and sample (a) Requirements for certificationÐ(1) solutions, system suitability require- Standards of identity, strength, quality, ments, and calculations are as follows: and purity. Imipenem monohydrate is the monohydrate form of [5R-[5α, 6α, (i) ReagentsÐ(a) Phosphate buffer, (R*)]]-6-(1-hydroxyethyl)-3-[[2- 0.001M. Dissolve 272 milligrams of [(iminomethyl) amino]ethyl]thio]-7- monobasic potassium phosphate in oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-car- 1,800 milliliters of deionized water. Ad- boxylic acid. It is a white to tan col- just the pH to 6.8 with 0.5N sodium hy- ored powder. It is so purified and dried droxide or dilute phosphoric acid. Di- that: lute to 2,000 milliliters with deionized (i) Its potency is not less than 900 water and filter prior to use. micrograms and not more than 1,050 (b) Mobile phase. Dissolve 2.0 grams of micrograms of imipenem per milligram 1-hexanesulfonic acid, sodium salt in on an anhydrous basis. 800 milliliters of phosphate buffer, (ii) It is sterile. 0.001M. Adjust the pH to 6.8 with 0.5N (iii) It is nonpyrogenic. sodium hydroxide or dilute phosphoric (iv) Its loss on drying is not less than acid and dilute to 1,000 milliliters with 5.0 percent and not more than 8.0 per- phosphate buffer, 0.001M. Filter and cent. degas the mobile phase just prior to its (v) Its specific rotation in an aqueous introduction into the chromatograph solution containing 5 milligrams of pumping system. imipenem per milliliter at 25 °C is ¶85° (c) 0.1 Percent bicarbonate solution. to ¶95° on an anhydrous basis. Dissolve 50 milligrams of sodium bicar- (vi) It gives a positive identity test. bonate in 40 milliliters of phosphate (vii) It is crystalline. buffer, 0.001M, and dilute to 50 milli- (2) Labeling. It shall be labeled in ac- liters with phosphate buffer, 0.001M. cordance with the requirements of (d) 0.9 Percent saline solution. Dissolve § 432.5 of this chapter. 9.0 grams of sodium chloride in 800 mil- (3) Requests for certification; samples. liliters of deionized water and dilute to In addition to complying with the re- 1.0 liter with deionized water. quirements of § 431.1 of this chapter, (ii) Preparations of working standard each such request shall contain: and sample solutionsÐ(a) Working stand- (i) Results of tests and assays on the ard solution. Accurately weigh approxi- batch for potency, sterility, pyrogens, mately 25 milligrams of the imipenem loss on drying, specific rotation, iden- working standard into a 50-milliliter tity, and crystallinity. volumetric flask. Immediately prior to 588 VerDate 09<APR>98 09:55 Apr 16, 1998 Jkt 179070 PO 00000 Frm 00582 Fmt 8010 Sfmt 8010 Y:\SGML\179070.TXT 179070-3 Food and Drug Administration, HHS § 441.220a analysis, add 10 milliliters of 0.9 per- time equal to that observed for the cent saline solution and 1 milliliter of standard); 0.1 percent bicarbonate solution. Add As=Area of the imipenem peak in the chro- phosphate buffer, 0.001M, and shake matogram of the imipenem working standard; until dissolved. Sonicate, if necessary, Ps=Anhydrous imipenem activity in the but for no longer than 1 minute. Dilute imipenem working standard solution in to volume with phosphate buffer, micrograms per milliliter; 0.001M, to obtain a solution containing Cu=Milligrams of sample per milliliter of approximately 500 micrograms of sample solution; and imipenem per milliliter. Mix well and L=Percent loss on drying of the sample. inject immediately. (2) Sterility. Proceed as directed in (b) Sample solution. Dissolve an accu- § 436.20 of this chapter, using the meth- rately weighed portion (approximately od described in paragraph (e)(1) of that 25 milligrams) of the sample with 10 section. milliliters of 0.9 percent saline solution (3) Pyrogens. Proceed as directed in and 1 milliliter of 0.1 percent bicarbon- § 436.32(a) of this chapter, using a solu- ate solution in a 50-milliliter volu- tion containing 5.0 milligrams of metric flask. Dilute the sample solu- imipenem per milliliter, except inject tion to volume with phosphate buffer, 10 milliliters per kilogram of rabbit 0.001M, to obtain a solution containing weight. 500 micrograms of imipenem per milli- (4) Loss on drying. Proceed as directed liter (estimated). in § 436.200(i) of this chapter. (iii) System suitability requirementsÐ (5) Specific rotation. Dilute an accu- (a) Tailing factor. The tailing factor rately weighed sample with sufficient (T) is satisfactory if it is not more than pH 7.0 phosphate buffer to give a con- 1.5 at 10 percent of peak height in lieu centration of approximately 5.0 milli- of 5 percent of peak height. grams of imipenem per milliliter. Pro- (b) Efficiency of the column. The effi- ceed as directed in § 436.210 of this chap- ciency of the column (n) is satisfactory ter, using a 1.0-decimeter polarimeter if it is greater than 600 theoretical tube. To prepare the pH 7.0 phosphate plates for a 30-centimeter column. buffer, transfer 5 grams of monobasic (c) Resolution. The resolution (R) be- potassium phosphate and 11 grams of tween the peaks for thienamycin and dibasic potassium phosphate to a 1.0- imipenem is satisfactory if it is not liter volumetric flask. Dissolve and di- less than 2.0. lute to volume with distilled water. (d) Coefficient of variation (relative (6) Identity. Proceed as directed in standard deviation). The coefficient of § 436.211 of this chapter, using the sam- variation (SRinpercent) of 5 replicate ple preparation described in paragraph injections is satisfactory if it is not (b)(2) of that section. more than 2.0 percent. (7) Crystallinity. Proceed as directed If the system suitability requirements in § 436.203(a) of this chapter. have been met, then proceed as de- [51 FR 11573, Apr. 4, 1986; 51 FR 16517, May 5, scribed in § 436.216(b) of this chapter. 1986, as amended at 55 FR 11582, Mar. 29, 1990; Alternate chromatographic conditions 59 FR 8133, Feb. 18, 1994] are acceptable provided reproducibility and resolution are comparable to the Subpart BÐ Reserved system. However, the sample prepara- [ ] tion described in paragraph (b)(1)(ii)(b) of this section should not be changed. Subpart CÐInjectable Dosage (iv) Calculations. Calculate the Forms micrograms of imipenem per milligram of sample as follows: § 441.220 Imipenem monohydrate- cilastatin sodium injectable dosage forms. Micrograms of AP× ×100 imipenem per = u s § 441.220a Sterile imipenem × × − milligram ACLs u ()100 monohydrate-cilastatin sodium. where: (a) Requirements for certificationÐ(1) Au=Area of the imipenem peak in the chro- Standards of identity, strength, quality, matogram of the sample (at a retention and purity. Imipenem monohydrate- 589 VerDate 09<APR>98 09:55 Apr 16, 1998 Jkt 179070 PO 00000 Frm 00583 Fmt 8010 Sfmt 8010 Y:\SGML\179070.TXT 179070-3 § 441.220a 21 CFR Ch. I (4±1±98 Edition) cilastatin sodium is a dry mixture of rected in § 441.20a(b)(1), preparing the imipenem monohydrate and cilastatin cilastatin reference standard solution, sodium packaged for dispensing. Its po- the sample solution and calculating tency is satisfactory if it contains not the imipenem and cilastatin potency less than 400 micrograms of imipenem and content as follows: and not less than 400 micrograms of (i) Cilastatin reference standard. Accu- cilastatin per milligram. Its imipenem rately weigh approximately 25 milli- content is satisfactory if it is not less grams of the cilastatin reference stand- than 90 percent and not more than 115 ard into a 50-milliliter volumetric percent of the number of milligrams of flask. Immediately prior to analysis, imipenem that it is represented to con- add 10 milliliters of a 0.9 percent saline tain. Its cilastatin content is satisfac- solution and 1.0 milliliter of a 0.1 per- tory if it is not less than 90 percent and cent bicarbonate solution. Add phos- not more than 115 percent of the num- phate buffer, 0.001M, and shake until ber of milligrams of cilastatin that it dissolved. Sonicate, if necessary, but is represented to contain. It is sterile. no longer than 1 minute. Dilute to vol- It is nonpyrogenic. Its loss on drying is ume with phosphate buffer, 0.001M, to not more than 3.5 percent. When recon- obtain a solution containing approxi- stituted as directed in the labeling, its mately 500 micrograms of cilastatin pH is not less than 6.0 and not more per milliliter.
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