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 441—PENEM ANTIBIOTIC tity, and crystallinity. DRUGS (ii) Samples, if required by the Direc- tor, Center for Drug Evaluation and Subpart A—Bulk Drugs Research: (a) For all tests except sterility: 10 Sec. 441.20a Sterile imipenem monohydrate. packages, each containing approxi- mately 500 milligrams. Subpart B—[Reserved] (b) For sterility testing: 20 packages, each containing equal portions of ap- Subpart C—Injectable Dosage Forms proximately 300 milligrams. 441.220 Imipenem monohydrate-cilastatin (b) Tests and methods of assay—(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 A—Bulk 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 certification—(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) Reagents—(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.
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(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 solutions—(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 requirements— 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.
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(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 B—[Reserved] grams. (B) The batch: Subpart C—Injectable 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 assay—(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 certification—(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. Its imipenem (i) Cilastatin reference standard. Accu- content is satisfactory if it is not less rately weigh approximately 25 milli- than 90 percent and not more than 115 grams of the cilastatin reference stand- percent of the number of milligrams of ard into a 50-milliliter volumetric imipenem that it is represented to con- flask. Immediately prior to analysis, tain. Its cilastatin content is satisfac- add 10 milliliters of a 0.9 percent saline tory if it is not less than 90 percent and solution and 1.0 milliliter of a 0.1 per- not more than 115 percent of the num- cent bicarbonate solution. Add phos- ber of milligrams of cilastatin that it phate buffer, 0.001M, and shake until is represented to contain. It is sterile. dissolved. Sonicate, if necessary, but It is nonpyrogenic. Its loss on drying is no longer than 1 minute. Dilute to vol- not more than 3.5 percent. When recon- ume with phosphate buffer, 0.001M, to stituted as directed in the labeling, its obtain a solution containing approxi- pH is not less than 6.0 and not more mately 500 micrograms of cilastatin than 7.5. The imipenem monohydrate per milliliter. Mix well and inject im- used conforms to the standards pre- mediately. scribed by § 441.20a(a)(1). (ii) Preparation of sample solutions— (2) Labeling. It shall be labeled in ac- (A) Imipenem and cilastatin potency cordance with the requirements of (micrograms of imipenem and cilastatin § 432.5 of this chapter. per milligram). Remove the metal seal (3) Requests for certification; samples. from each of 10 containers and deter- In addition to complying with the re- mine the gross weight in grams. Dis- quirements of § 431.1 of this chapter, solve and wash out the entire contents each such request shall contain: of each container with a 0.9 percent sa- (i) Results of tests and assays on: line solution into an appropriate size (A) The imipenem monohydrate used volumetric flask to give a concentra- in making the batch for potency, ste- tion of 5 milligrams per milliliter each rility, pyrogens, loss on drying, specific of imipenem and cilastatin. Further di- rotation, identity, and crystallinity. lute with phosphate buffer, 0.001M, to (B) The batch for imipenem potency, obtain a solution containing 500 cilastatin potency, imipenem content, micrograms each of imipenem and cilastatin content, sterility, pyrogens, cilastatin per milliliter (estimated). loss on drying, and pH. Wash each stopper and container with
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small quantities of acetone or meth- anol three times being careful not to Milligrams of imipen em × × AUS P d wet the container labeling. Allow the or cilastatin per = × containers to air dry about 3 hours or milligram AS 1, 000 to constant weight. Weigh each con- where: tainer and stopper to determine tare AU=Area of the imipenem or cilastatin peak weight in grams. in the chromatogram of the sample (at a (B) Imipenem and cilastatin content retention time equal to that observed for (milligrams of imipenem and cilastatin per the standard); container). Reconstitute the sample as AS=Area of the imipenem or cilastatin peak directed in the labeling, except use a in the chromatogram of the imipenem or 0.9 percent saline solution as the recon- cilastatin working standard; stituting fluid. Then, using a suitable PS=Anhydrous imipenem or cilastatin activ- hypodermic needle and syringe, remove ity in the imipenem or cilastatin work- ing standard solution in micrograms per all of the withdrawable contents if it is milliliter; and represented as a single-dose container; d=Dilution factor of the sample. or, if the labeling specifies the amount of potency in a given volume of the re- (2) Sterility. Proceed as directed in sultant preparation, remove an accu- § 436.20 of this chapter, using the meth- rately measured representative portion od described in § 436.20(e)(1). from each container. Accurately dilute (3) Pyrogens. Proceed as directed in the solution thus obtained in a suitable § 436.32(a) of this chapter, using a solu- volumetric flask with sufficient 0.9 per- tion containing 5.0 milligrams of cent saline solution to obtain a stock imipenem per milliliter except inject 10 solution containing about 2,500 milliliters per kilogram of rabbit micrograms of imipenem and 2,500 weight. micrograms of cilastatin per milliliter. (4) Loss on drying. Proceed as directed Transfer a 10-milliliter aliquot of this in § 436.200(a) of this chapter. solution to a 50-milliliter volumetric (5) pH. Proceed as directed in § 436.202 flask and dilute to volume with phos- of this chapter. phate buffer, 0.001M, to obtain a solu- [58 FR 26670, May 4, 1993] tion containing 500 micrograms of imipenem and 500 micrograms of § 441.220b Imipenem monohydrate- cilastatin per milliliter (estimated). cilastatin sodium for injection. (iii) Calculations—(A) Imipenem and (a) Requirements for certification—(1) cilastatin potency. Calculate the Standards of identity, strength, quality, micrograms of imipenem and cilastatin and purity. Imipenem monohydrate- per milligram as follows: cilastatin sodium is a dry mixture of imipenem monohydrate, cilastatin so- Milligrams of × × dium, and sodium bicarbonate AUS P d imipenem or cilastatin = packaged for dispensing. Its potency is × × per milligram AWSS1, 000 satisfactory if it contains not less than where: 400 micrograms of imipenem and not AU=Area of the imipenem or cilastatin peak less than 400 micrograms of cilastatin in the chromatogram of the sample (at a per milligram. Its imipenem content is retention time equal to that observed for satisfactory if it is not less than 90 per- the standard); cent and not more than 115 percent of AS=Area of the imipenem or cilastatin peak the number of milligrams of imipenem in the chromatogram of the imipenem or that it is represented to contain. Its cilastatin working standard; cilastatin content is satisfactory if it PS=Anhydrous imipenem or cilastatin activ- ity in the respective working standard is not less than 90 percent and not solution in micrograms per milliliter; more than 115 percent of the number of d=Dilution factor of the 10 samples; and milligrams of cilastatin that it is rep- WS=Net contents of 10 containers in grams resented to contain. It is sterile. It is (gross weight of 10 containers in grams— nonpyrogenic. Its loss on drying is not tare weight of 10 containers in grams). more than 3.5 percent. When reconsti- (B) Imipenem and cilastatin content. tuted as directed in the labeling, its pH Calculate the imipenem or cilastatin is not less than 6.5 and not more than content of the container as follows: 8.5. The imipenem monohydrate used
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conforms to the standards prescribed per milliliter. Mix well and inject im- by § 441.20a(a)(1). mediately. (2) Labeling. It shall be labeled in ac- (ii) Preparation of sample solutions—(a) cordance with the requirements of Imipenem and cilastatin potency § 432.5 of this chapter. (micrograms of imipenem and cilastatin (3) Requests for certification; samples. per milligram). Remove the metal seal In addition to complying with the re- from each of 10 containers and deter- quirements of § 431.1 of this chapter, mine gross weight in grams. Dissolve each such request shall contain: and wash out the entire contents of (i) Results of tests and assays on: each container with 0.9 percent saline (a) The imipenem monohydrate used into an appropriate size volumetric in making the batch for potency, ste- flask to give a concentration of 5 milli- rility, pyrogens, loss on drying, specific grams per milliliter each of imipenem rotation, identity, and crystallinity. and cilastatin. Further dilute with (b) The batch for imipenem potency, phosphate buffer, 0.001 M, to obtain a cilastatin potency, imipenem content, cilastatin content, sterility, pyrogens, solution containing 500 micrograms loss on drying, and pH. each of imipenem and cilastatin per (ii) Samples, if required by the Direc- milliliter (estimated). Wash each stop- tor, Center for Drug Evaluation and per and container with small quan- Research tities of acetone or methanol three (a) The imipenem used in making the times being careful not to wet the con- batch: 10 packages, each containing ap- tainer labeling. Allow the containers to proximately 500 milligrams. air dry about 3 hours or to constant (b) The batch: weight. Weigh each container and stop- (1) For all tests except sterility: A per to determine tare weight in grams. minimum of 20 immediate containers. (b) Imipenem and cilastatin content (2) For sterility testing: 20 immediate (milligrams of imipenem and cilastatin per containers, collected at regular inter- container). Reconstitute the sample as vals throughout each filling operation. directed in the labeling, except use 0.9 (b) Tests and methods of assay—(1) percent saline solution as the recon- Imipenem and cilastatin potency and con- stituting fluid. Then, using a suitable tent. Determine the potency of the hypodermic needle and syringe, remove sample in micrograms per milligram of all of the withdrawable contents if it is both imipenem and cilastatin and the represented as a single-dose container; milligrams of both imipenem and or, if the labeling specifies the amount cilastatin per container. Proceed as di- of potency in a given volume of the re- rected in § 441.20a(b)(1) of this chapter, sultant preparation, remove an accu- preparing the cilastatin reference rately measured representative portion standard solution, the sample solution from each container. Accurately dilute and calculating the imipenem and the solution thus obtained in a suitable cilastatin potency and content as fol- volumetric flask with sufficient 0.9. lows: percent saline solution to obtain a (i) Cilastatin reference standard. Accu- stock solution containing about 2,500 rately weigh approximately 25 milli- grams of the cilastatin reference stand- micrograms of imipenem and 2,500 ard into a 50–milliliter volumetric micrograms of cilastatin per milliliter. flask. Immediately prior to analysis, Transfer a 10-milliliter aliquot of this add 10 milliliters of 0.9 percent saline solution to a 50-milliliter volumetric solution and 1 milliliter of 0.1 percent flask and dilute to volume with phos- bicarbonate solution. Add phosphate phate buffer, 0.001M, to obtain a solu- buffer, 0.001M, and shake until dis- tion containing 500 micrograms of solved. Sonicate, if necessary, but for imipenem and 500 micrograms of no longer than 1 minute. Dilute to vol- cilastatin per milliliter (estimated). ume with phosphate buffer, 0.001M, to (iii) Calculations—(a) Calculate the obtain a solution containing approxi- micrograms of imipenem and cilastatin mately 500 micrograms of cilastatin per milligram as follows:
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PART 442—CEPHA ANTIBIOTIC Micrograms of A× P × d imipenem or cilastatin = u s DRUGS AW×1, 000 × per milligram s s Subpart A—Bulk Drugs where: Sec. Au=Area of the imipenem or cilastatin peak 442.4 Cefaclor monohydrate. in the chromatogram of the sample (at a 442.6 Cefadroxil monohydrate. retention time equal to that observed for 442.7 Cefadroxil hemihydrate. the standard); 442.8a Sterile cefamandole nafate. As=Area of the imipenem or cilastatin peak 442.9a Sterile cefamandole sodium. in the chromatogram of the imipenem or 442.10 Cefazolin. cilastatin acid working standard; 442.11a Sterile cefazolin sodium. Ps=Anhydrous imipenem or cilastatin activ- 442.12 Cefoperazone sodium. ity in the respective working standards 442.12a Sterile cefoperazone sodium. solutions in micrograms per milliliter; 442.13 Cefotaxime sodium. d=Dilution factor for the 10 samples; and 442.13a Sterile cefotaxime sodium. Ws=Net contents of 10 containers in grams 442.14 Cefoxitin sodium. (gross weight of 10 containers in grams– 442.14a Sterile cefoxitin sodium. tare weight of 10 containers in grams). 442.15 Cefixime trihydrate. 442.16 Ceftazidime pentahydrate. (b) Calculate the imipenem or 442.16a Sterile ceftazidime pentahydrate. cilastatin content of the container as 442.17 Ceftizoxime sodium. follows: 442.17a Sterile ceftizoxime sodium. 442.18 Cefuroxime sodium. 442.18a Sterile cefuroxime sodium. Milligrams of A× P × d imipenem or cilastatin = u s 442.19 Cefuroxime axetil. × 442.20a Sterile cefonicid sodium. per container As 1, 000 442.21 Cephaloglycin dihydrate. where: 442.22a Sterile cefmenoxime hydrochloride. 442.23a Sterile cephaloridine. A =Area of the imipenem or cilastatin peak u 442.25a Sterile cephalothin sodium. in the chromatogram of the sample (at a 442.27 Cephalexin monohydrate. retention time equal to that observed for 442.28 Cephalexin hydrochloride the standard); monohydrate. As=Area of the imipenem or cilastatin peak 442.29a Sterile cephapirin sodium. in the chromatogram of the imipenem or 442.40 Cephradine. cilastatin working standard: 442.40a Sterile cephradine. Ps=Anhydrous imipenem or cilastatin activ- 442.41 Cephradine dihydrate. ity in the imipenem or cilastatin work- 442.50a Sterile ceforanide. ing standard solution in micrograms per 442.52 Cefotetan. milliliter; and 442.53a Sterile cefotetan disodium. d=Dilution factor of the sample. 442.54 Cefpodoxime proxetil. (2) Sterility. Proceed as directed in 442.55 Ceftriaxone sodium. 442.55a Sterile ceftriaxone sodium. § 436.20 of this chapter, using the meth- 442.58a Sterile cefotiam dihydrochloride. od described in paragraph (e)(1) of that 442.60 Cefpiramide. section. 442.69 Cefmetazole. (3) Pyrogens. Proceed as directed in 442.70a Sterile cefmetazole sodium. § 436.32(a) of this chapter, using a solu- 442.80 Cefprozil. tion containing 5.0 milligrams of Subpart B—Oral Dosage Forms imipenem per milliliter except inject 10 milliliters per kilogram of rabbit 442.104 Cefaclor monohydrate oral dosage weight. forms. 442.104a Cefaclor monohydrate capsules. (4) Loss on drying. Proceed as directed 442.104b Cefaclor monohydrate for oral sus- in § 436.200(a) of this chapter. pension. (5) pH. Proceed as directed in § 436.202 442.106 Cefadroxil monohydrate oral dosage of this chapter. forms. 442.106a Cefadroxil monohydrate capsules. [51 FR 11573, Apr. 4, 1986; 51 FR 22275, June 19, 442.106b Cefadroxil monohydrate tablets. 1986, as amended at 55 FR 11582, Mar. 29, 1990. 442.106c Cefadroxil monohydrate for oral Redesignated at 58 FR 26669, May 4, 1993] suspension. 442.107 Cefadroxil hemihydrate oral dosage forms.
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