Food and Drug Administration, HHS § 441.20a (6) pH. Proceed as directed in § 436.202 imipenem per milliliter at 25 °C is ¶85° of this chapter, using an aqueous solu- to ¶95° on an anhydrous basis. tion containing 60 milligrams per mil- (vi) It gives a positive identity test. liliter. (vii) It is crystalline. (7) Penicillin G content. Proceed as di- (2) Labeling. It shall be labeled in ac- rected in § 436.316 of this chapter. cordance with the requirements of (8) Crystallinity. Proceed as directed § 432.5 of this chapter. in § 436.203(a) of this chapter. (3) Requests for certification; samples. (9) Heat stability. Proceed as directed In addition to complying with the re- in § 436.214 of this chapter. quirements of § 431.1 of this chapter, [42 FR 59873, Nov. 22, 1977; 43 FR 2393, Jan. 17, each such request shall contain: 1978, as amended at 45 FR 22922, Apr. 4, 1980; (i) Results of tests and assays on the 50 FR 19918, 19919, May 13, 1985] batch for potency, sterility, pyrogens, loss on drying, specific rotation, iden- PART 441ÐPENEM ANTIBIOTIC tity, and crystallinity. DRUGS (ii) Samples, if required by the Direc- tor, Center for Drug Evaluation and Subpart AÐBulk Drugs Research: (a) For all tests except sterility: 10 Sec. 441.20a Sterile imipenem monohydrate. packages, each containing approxi- mately 500 milligrams. Subpart BÐ[Reserved] (b) For sterility testing: 20 packages, each containing equal portions of ap- Subpart CÐInjectable Dosage Forms proximately 300 milligrams. 441.220 Imipenem monohydrate-cilastatin (b) Tests and methods of assayÐ(1) Po- sodium injectable dosage forms. tency. Proceed as directed in § 436.216 of 441.220a Sterile imipenem monohydrate- this chapter, using a column heater cilastatin sodium. which will maintain a 50 °C column 441.220b Imipenem monohydrate-cilastatin temperature, and ultraviolet detection sodium for injection. system operating at a wavelength of AUTHORITY: Sec. 507 of the Federal Food, 254 nanometers, a column packed with Drug, and Cosmetic Act (21 U.S.C. 357). microparticulate (3 to 10 micrometers in diameter) reversed phase packing Subpart AÐBulk Drugs material such as octyl or octadecyl hy- 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- (a) Requirements for certificationÐ(1) agents, working standard and sample Standards of identity, strength, quality, solutions, system suitability require- and purity. Imipenem monohydrate is ments, and calculations are as follows: 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. 595 VerDate 17<JUL>96 11:55 Jul 29, 1996 Jkt 167069 PO 00000 Frm 00590 Fmt 8010 Sfmt 8010 C:\CFR\21V5.001 pfrm13 § 441.20a 21 CFR Ch. I (4±1±96 Edition) (c) 0.1 Percent bicarbonate solution. Alternate chromatographic conditions Dissolve 50 milligrams of sodium bicar- are acceptable provided reproducibility bonate in 40 milliliters of phosphate and resolution are comparable to the buffer, 0.001M, and dilute to 50 milli- system. However, the sample prepara- liters with phosphate buffer, 0.001M. tion described in paragraph (b)(1)(ii)(b) (d) 0.9 Percent saline solution. Dissolve of this section should not be changed. 9.0 grams of sodium chloride in 800 mil- (iv) Calculations. Calculate the liliters of deionized water and dilute to micrograms of imipenem per milligram 1.0 liter with deionized water. of sample as follows: (ii) Preparations of working standard and sample solutionsÐ(a) Working stand- ard solution. Accurately weigh approxi- Micrograms of AP× ×100 imipenem per = u s mately 25 milligrams of the imipenem × × − working standard into a 50-milliliter milligram ACLs u ()100 volumetric flask. Immediately prior to where: analysis, add 10 milliliters of 0.9 per- Au=Area of the imipenem peak in the chro- cent saline solution and 1 milliliter of matogram of the sample (at a retention 0.1 percent bicarbonate solution. Add time equal to that observed for the phosphate buffer, 0.001M, and shake standard); until dissolved. Sonicate, if necessary, As=Area of the imipenem peak in the chro- but for no longer than 1 minute. Dilute matogram of the imipenem working to volume with phosphate buffer, standard; 0.001M, to obtain a solution containing Ps=Anhydrous imipenem activity in the approximately 500 micrograms of imipenem working standard solution in micrograms per milliliter; imipenem per milliliter. Mix well and Cu=Milligrams of sample per milliliter of inject immediately. sample solution; and (b) Sample solution. Dissolve an accu- L=Percent loss on drying of the sample. rately weighed portion (approximately 25 milligrams) of the sample with 10 (2) Sterility. Proceed as directed in milliliters of 0.9 percent saline solution § 436.20 of this chapter, using the meth- and 1 milliliter of 0.1 percent bicarbon- od described in paragraph (e)(1) of that ate solution in a 50-milliliter volu- section. metric flask. Dilute the sample solu- (3) Pyrogens. Proceed as directed in tion to volume with phosphate buffer, § 436.32(a) of this chapter, using a solu- 0.001M, to obtain a solution containing tion containing 5.0 milligrams of 500 micrograms of imipenem per milli- imipenem per milliliter, except inject liter (estimated). 10 milliliters per kilogram of rabbit (iii) System suitability requirementsÐ weight. (a) Tailing factor. The tailing factor (4) Loss on drying. Proceed as directed (T) is satisfactory if it is not more than in § 436.200(i) of this chapter. 1.5 at 10 percent of peak height in lieu of 5 percent of peak height. (5) Specific rotation. Dilute an accu- (b) Efficiency of the column. The effi- rately weighed sample with sufficient ciency of the column (n) is satisfactory pH 7.0 phosphate buffer to give a con- if it is greater than 600 theoretical centration of approximately 5.0 milli- plates for a 30-centimeter column. grams of imipenem per milliliter. Pro- (c) Resolution. The resolution (R) be- ceed as directed in § 436.210 of this chap- tween the peaks for thienamycin and ter, using a 1.0-decimeter polarimeter imipenem is satisfactory if it is not tube. To prepare the pH 7.0 phosphate less than 2.0. buffer, transfer 5 grams of monobasic (d) Coefficient of variation (relative potassium phosphate and 11 grams of standard deviation). The coefficient of dibasic potassium phosphate to a 1.0- variation (SRinpercent) of 5 replicate liter volumetric flask. Dissolve and di- injections is satisfactory if it is not lute to volume with distilled water. more than 2.0 percent. (6) Identity. Proceed as directed in If the system suitability requirements § 436.211 of this chapter, using the sam- have been met, then proceed as de- ple preparation described in paragraph scribed in § 436.216(b) of this chapter. (b)(2) of that section. 596 VerDate 17<JUL>96 11:55 Jul 29, 1996 Jkt 167069 PO 00000 Frm 00591 Fmt 8010 Sfmt 8010 C:\CFR\21V5.001 pfrm13 Food and Drug Administration, HHS § 441.220a (7) Crystallinity. Proceed as directed (ii) Samples, if required by the Direc- in § 436.203(a) of this chapter. tor, Center for Drug Evaluation and [51 FR 11573, Apr. 4, 1986; 51 FR 16517, May 5, Research: 1986, as amended at 55 FR 11582, Mar. 29, 1990; (A) The imipenem monohydrate used 59 FR 8133, Feb. 18, 1994] in making the batch: 10 packages, each containing approximately 500 milli- Subpart BÐ[Reserved] grams. (B) The batch: Subpart CÐInjectable Dosage (1) For all tests except sterility: A Forms minimum of 20 immediate containers. (2) For sterility testing: 20 immediate § 441.220 Imipenem monohydrate- containers, collected at regular inter- cilastatin sodium injectable dosage vals throughout each filling operation. forms. (b) Tests and methods of assayÐ(1) § 441.220a Sterile imipenem Imipenem and cilastatin potency and con- monohydrate-cilastatin sodium. tent. Determine the potency of the sample in micrograms per milligram of (a) Requirements for certificationÐ(1) both imipenem and cilastatin and the Standards of identity, strength, quality, milligrams of both imipenem and and purity. Imipenem monohydrate- cilastatin per container. Proceed as di- 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 cilastatin per milligram.