Table 1. Allow the solution to stand for NLT 6 h at Solution C: Acetonitrile and Solution B (7:3)

Transcription

1 Acceptance Revision Bulletin Official February 1, 2013 Tacrolimus 1 Tacrolimus Capsules criteria: 930% 1050% PERFORMANCE TESTS DEFINITION Tacrolimus Capsules contain NLT 930% and NMT 1050% Change to read: of the labeled amount of tacrolimus (C 44H 69NO 12) DISSOLUTION 711 IDENTIFICATION Test 1 A The retention time of the major peak of the Sample Medium: Hydroxypropylcellulose in water (1:2 10 4); corresponds to that of the Standard as adjusted with 6% phosphoric acid to a ph of 45; obtained in the Assay 900 ml Apparatus 2: 50 rpm with sinker (see Dis ASSAY 711, Figure 2a) PROCEDURE Time: 90 min [NOTEAllow the Standard and Sample Mobile phase: Acetonitrile, methanol, water, and 6% to stand for 3 h at ambient temperature before use phosphoric acid (46:18:36:01) Protect the s from light by using low-actinic Standard stock : (L/360) mg/ml in acetoniglassware] trile, where L is the Capsule label claim in mg Standard : To 200 ml of the Standard stock Solution B: 50 g/l of polyoxyethylene (23) lauryl add 500 ml of Medium, and mix to obtain ether [NOTEPolyoxyethylene (23) lauryl ether is also s with known concentrations as indicated in called Brij-35] Table 1 Allow the to stand for NLT 6 h at Solution C: Acetonitrile and Solution B (7:3) 25 before use Mobile phase: Acetonitrile, tert-butyl methyl ether, Sample : Pass 10 ml of the under and Solution A (335:55:600) test through a G4 glass filter To 50 ml of the filtrate Standard : 50 µg/ml of USP Tacrolimus RS in add 20 ml of acetonitrile, and mix Allow the solu- Solution C tion to stand for NLT 1 h at 25 before use Sample : Equivalent to 50 µg/ml of tacrolimus, from NLT 10 Capsules, in Solution C [NOTESonicate, and stir with a magnetic stirrer] Table 1 Capsule Strength Final Concentration (See Chromatography 621, System Suitability) (µg/ml) Detector: UV 205 nm 1 08 Column: 40-mm 55-cm; 3-µm packing L1 5 4 Flow rate: 1 ml/min Injection volume: 5 µl (See Chromatography 621, System Suitability) Sample: Standard Detector: 210 nm [NOTEThe relative retention times for tacrolimus Column: 46-mm 15-cm; 5-µm packing L7 19-epimer and tacrolimus are 067 and 10, Column temperature: 50 respectively] Flow rate: Adjust the flow rate so that the retention time of tacrolimus is approximately 14 min Tailing factor: NMT 20 Injection volume: See Table 2 Relative standard deviation: NMT 30% for the sum of the tacrolimus and tacrolimus 19-epimer peaks Table 2 Capsule Strength Injection Volume Samples: Standard and Sample (µl) Calculate the percentage of tacrolimus (C 44H 69NO 12) in the portion of Capsules taken: Result = (r U/r S) (C S/C U) r U r S C S C U tacrolimus 19-epimer from the Sample tacrolimus 19-epimer from the Standard = concentration of USP Tacrolimus RS in the Standard = nominal concentration of the Sample [NOTEFor products with strengths other than those listed in Table 2, adjust the injection volume to deliver an equivalent amount of tacrolimus into the column] Sample: Standard Re: NLT 15 between tacrolimus 19-epimer and tacrolimus Tailing factor: NMT 15 Relative standard deviation: NMT 15% Samples: Standard and Sample Result = (r U/r S) C S D V (100/L) 2013 The United States Pharmacopeial Convention All Rights Reserved

2 2 Tacrolimus Official February 1, 2013 r U = peak response of tacrolimus from the Sample V = volume of Medium, 900 ml Tolerances: NLT 80% (Q) of the labeled amount of r S = peak response of tacrolimus from the Standard tacrolimus (C 44H 69NO 12) is dissolved Test 3: If the product complies with this test, the label- C S = concentration of USP Tacrolimus RS in the ing indicates that it meets USP Dis Test 3 Standard Medium: 50 mg/l of hydroxypropyl cellulose in D = dilution factor of the Sample water Adjust with phosphoric acid to a ph of 45; V = volume of Medium, 900 ml 900 ml Apparatus 2 (without sinker), Time, and Sample so- Tolerances: NLT 80% (Q) of the labeled amount of lution: Proceed as directed for Test 1 tacrolimus (C 44H 69NO 12) is dissolved Buffer: 36 g/l of monobasic potassium phosphate in Test 2: If the product complies with this test, the label- water Adjust with diluted phosphoric acid to a ph of ing indicates that it meets USP Dis Test 2 25 [NOTEAllow the Standard to stand for 3 h at Mobile phase: Buffer and acetonitrile (1:1) ambient temperature before use Protect the s Standard stock : 01 mg/ml of USP from light by using low-actinic glassware] Tacrolimus RS in acetonitrile Buffer: Dissolve 6 g of sodium dodecyl sulfate and Standard : Dilute the Standard stock 828 g of monobasic sodium phosphate in 6000 ml with Medium to obtain a final concentration of of water Adjust with 2 N sodium hydroxide to a ph (L/900) mg/ml, where L is the Capsule label claim of 70 Sample : Pass a portion of the under Medium: Buffer; 900 ml test through a suitable filter Apparatus 2: 50 rpm, with sinkers Time: 60 min (See Chromatography 621, System Suitability) Standard stock : 02 mg/ml of USP Tacrolimus RS in alcohol and Medium (3:7) [NOTE Detector: UV 210 nm Dissolve USP Tacrolimus RS in alcohol using 30% of Column: 46-mm 10-cm; 5-µm packing L1 the final volume Sonicate until dissolved, and dilute with Medium to volume] Flow rate: 13 ml/min Standard : Dilute the Standard stock Injection volume: 100 µl with Medium to obtain a final concentration of 5 µg/ ml Sample: Standard Sample : Pass a portion of the under [NOTEThe relative retention times for tacrolimus test through a suitable filter 19-epimer, tacrolimus open ring, and tacrolimus are 067, 079, and 10, respectively] Mobile phase: Acetonitrile, tert-butyl methyl ether, and Solution A (335:50:600) Tailing factor: NMT 20 Relative standard deviation: NMT 20% (See Chromatography 621, System Suitability) Samples: Standard and Sample Detector: UV 205 nm Column: 40-mm 55-cm; 3-µm packing L1 Flow rate: 12 ml/min Injection volume: 100 µl r U = sum of the peak responses of tacrolimus, Sample: Standard tacrolimus 19-epimer, and tacrolimus open [NOTEThe relative retention times for tacrolimus ring from the Sample 19-epimer and tacrolimus are 067 and 10, r S = sum of the peak responses of tacrolimus, respectively] tacrolimus 19-epimer, and tacrolimus open ring from the Standard Tailing factor: NMT 20 C S = concentration of the Standard Relative standard deviation: NMT 50% for the sum of the areas of tacrolimus and tacrolimus 19-epimer V = volume of Medium, 900 ml Tolerances: NLT 75% (Q) of the labeled amount of Samples: Standard and Sample tacrolimus (C 44H 69NO 12) is dissolved Test 4: If the product complies with this test, the labeling indicates that it meets USP Dis Test 4 Medium: Hydroxypropylcellulose in water (1 in 20,000) adjusted with phosphoric acid to a ph of 45 See Table 3 for the volume r U r S tacrolimus 19-epimer from the Sample Table 3 Capsule Strength Volume of Medium tacrolimus 19-epimer from the Standard (ml) C S = concentration of the Standard The United States Pharmacopeial Convention All Rights Reserved

3 Official February 1, 2013 Tacrolimus 3 Apparatus 2: 50 rpm, with sinkers IMPURITIES Time: 120 min Diluent: 1 mg/ml of hydroxypropylcellulose in water Sonicate as needed to dissolve Change to read: Buffer: To a of 1 g/l of sodium 1-hexanesulfonate in water add 01 ml/l of trifluroacetic ORGANIC IMPURITIES, PROCEDURE 1 acid [NOTEUse Organic Impurities, Procedure 1 when the im- Mobile phase: Acetonitrile, methanol, and Buffer purity profile includes tacrolimus diene and tacrolimus (550:50:400) regioisomer It is suggested that new columns be con- Standard stock : Dissolve USP Tacrolimus RS ditioned with about 500 ml of ethanol before use to in acetonitrile See Table 4 for the concentrations (L is meet the re criterion] the Capsule label claim in mg) Mobile phase: Hexane, n-butyl chloride, and acetoni- trile (7:2:1) Add n-butyl chloride to hexane, and mix Table 4 well before adding acetonitrile After adding acetonitrile, mix the Mobile phase for 2 h to get a clear Any deviations from the ratio of components in Capsule Strength Concentration the Mobile phase and the order of mixing will result in 05 L/25 a two-phase : 01 mg/ml each of USP 1 L/45 Tacrolimus RS and USP Tacrolimus Related Compound 5 L/45 A RS in Mobile phase Standard : Dilute the Standard stock Sample : Transfer the contents of a suitable with Diluent See Table 5 for the concentrations (L is number of Capsules (equivalent to about 5 mg of the Capsule label claim in mg) tacrolimus for 05-mg Capsules or 10 mg of tacrolimus for 1-mg and 5-mg Capsules) into a centrifuge tube Add 15 ml of a mixture of n-butyl chloride and aceto- Table 5 nitrile (2:1), sonicate in an ultrasonic bath for 2 min, Capsule Strength Concentration add 35 ml of n-hexane, and mix Centrifuge this solu- tion, and collect the supernatant or pass the 05 L/500 through a 05-µm membrane filter Use the within 30 min of preparation 1 L/900 5 L/900 (See Chromatography 621, System Suitability) Sample : Pass a portion of the under Detector: UV 225 nm test through a suitable filter Columns: Two 46-mm 25-cm columns; 5-µm pack- ing L20 (See Chromatography 621, System Suitability) Column temperature: 28 ± 2 Flow rate: 15 ml/min [NOTEAdjust the flow rate Detector: UV 210 nm so that the retention time of tacrolimus is approxi- Column: 46-mm 15-cm; 5-µm packing L1 mately 15 min] Injection volume: 20 µl Flow rate: 1 ml/min Run time: 3 times the retention time of tacrolimus Injection volume: 100 µl Sample: Sample: Standard Re: NLT 11 between tacrolimus and Tailing factor: NMT 20 tacrolimus related compound A Relative standard deviation: NMT 30% Tailing factor: NMT 15 Relative standard deviation: NMT 20% Samples: Standard and Sample Sample: Sample Calculate the percentage of each impurity in the portion of Capsules taken: r U = peak response from the Sample Result = (r U/F i) [1/Σ(r U/F i)] 100 r S = peak response from the Standard r U = peak response of each impurity in the Sample C S = concentration of USP Tacrolimus RS in the Standard F i = relative response factor for each corresponding impurity (see Table 6 (RB V = volume of Medium (ml) (see Table 3) 1-Feb-2013)) Acceptance criteria: See Table 6 (RB 1-Feb-2013) Disre- Tolerances: NLT 75% (Q) of the labeled amount of gard peaks due to the solvent tacrolimus (C 44H 69NO 12) is dissolved (RB 1-Feb-2013) UNIFORMITY OF DOSAGE UNITS 905 : Meet the requirements 2013 The United States Pharmacopeial Convention All Rights Reserved

4 4 Tacrolimus Official February 1, 2013 Table 6 (RB 1-Feb-2013) Table 7 (RB 1-Feb-2013) (Continued) Relative Relative Acceptance Time Solution C Solution D Retention Response Criteria, (min) (%) (%) Name Time Factor NMT (%) Tacrolimus diene a Tacrolimus regioisomer b Tacrolimus impurity 1 c Tacrolimus related Solution E: 50 g/l polyoxyethylene (23) lauryl ether in compound A 096 Solution A [NOTEPolyoxyethylene (23) lauryl ether is Tacrolimus 10 also called Brij-35] Diluent: Acetonitrile and Solution E (7:3) Tacrolimus 19- : 15 mg/ml of USP epimer, e 11 Tacrolimus System Suitability Mixture RS in Diluent d Tacrolimus open ring, f 13 Standard : 75 µg/ml of USP Tacrolimus RS in d Any individual unspecified impurity Diluent Sensitivity : 15 µg/ml of USP Tacrolimus RS Total impurities g 10 in Diluent from Standard (14E,18E)-17-Allyl-1-hydroxy-12-[(E)-2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa- Sample : Equivalent to 15 mg/ml of tacrolimus in Diluent [NOTEShake the mixture on a a 4-azatricyclo[ ,9 ] octacosa-14,18-diene-2,3,10,16-tetrone mechanical shaker for 30 min, and pass through a suitb (4E,11E)-10-Allyl-7,8,10,13,14,15,16,17,18,19,20,21,26,22,28,28a-hex- able filter] adecahydro-7,21-dihydroxy-3-(4-hydroxy-3-methoxycyclohexyl)-16,18- dimethoxy-4,6,12,14,20-pentamethyl-17,21-epoxy-3h-pyrido[2,1-c] [1,4]oxaazacyclopentacosine-1,9,22,23(6H,25H)-tetrone (See Chromatography 621, System Suitability) c Tacrolimus impurity 1 is a specified, unidentified impurity Detector: UV 220 nm d For information only Not to be reported Column: 46-mm 15-cm; 3-µm packing L1 e (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19S,26aS)-8-Allyl- methylvinyl}-14,16-dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-3h- Flow rate: 15 ml/min pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4h,23h)-tetrone Injection volume: 40 µl (3S,4R,5S,8R,12S,14S,15R,16S,18R,26aS,E)-8-Allyl- f 5,6,11,12,13,14,15,16,17,18,24,25,26,26a-tetradecahydro-5,15,20,20- Samples:, Standard, tetrahydroxy-3-{(e)-2-[(1r,3r,4r)-4-hydroxy-3-methoxycyclohexyl]-1- and Sensitivity methylvinyl}-14,16-dimethoxy-4,10,12,18-tetramethyl-3h-pyrido[2,1-c] [1,4]oxaazacyclotricosine-1,7,19,21(4H,8H,20H,23H)-tetrone Signal-to-noise ratio: NLT 100, Sensitivity g Total impurities limit does not include tacrolimus open ring and tacrolimus 19-epimer Re: NLT 30 between tacrolimus and asco- mycin, Change to read: Relative standard deviation: NMT 100% for the sum of the responses of tacrolimus and tacrolimus ORGANIC IMPURITIES, PROCEDURE 2 19-epimer, Standard [NOTEUse Organic Impurities, Procedure 2 when the im- purity profile includes tacrolimus 21-carboxylic acid Samples: Standard and Sample and tacrolimus 8-epimer It is suggested to equilibrate Calculate the percentage of each impurity in the porthe column overnight with a mixture of Solution C and tion of Capsules taken: Solution D (17:3) before performing this procedure Allow the, Standard, Result = (r U/r S) (C S/C U) P 100 and Sample to stand for 3 h at ambient temr U = peak response of each impurity from the perature before use Protect the s from light by using low-actinic glassware] Sample r S = sum of the peak responses for tacrolimus Solution B: Acetonitrile and tert-butyl methyl ether 19-epimer and tacrolimus from the Standard (81:19) [NOTEThe ratio of acetonitrile to tert-butyl methyl ether is critical] C S = concentration of USP Tacrolimus RS in the Solution C: Solution A and Solution B (4:1) Standard Solution D: Solution A and Solution B (1:4) C U = nominal concentration of tacrolimus in the Mobile phase: See Table Sample 7 (RB 1-Feb-2013) P = potency of tacrolimus in USP Tacrolimus RS (mg/mg) Table 7 (RB 1-Feb-2013) Acceptance criteria: See Table 8 (RB 1-Feb-2013) Disre- Time Solution C Solution D gard peaks that are smaller than the tacrolimus peak in (min) (%) (%) the Sensitivity The United States Pharmacopeial Convention All Rights Reserved

5 Official February 1, 2013 Tacrolimus 5 Table 8 (RB 1-Feb-2013) USP REFERENCE STANDARDS 11 USP Tacrolimus RS Relative Acceptance USP Tacrolimus Related Compound A RS Retention Criteria, (E)-8-Ethyl- Name Time NMT (%) 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hex- Tacrolimus 21-carboxylic adecahydro-5,19-dihydroxy-3-[(e)-2-(4-hydroxyacid methoxycyclohexyl)-1-methylvinyl]-14,16- a Tacrolimus open ring, c b 049 dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-3h- Ascomycin 19-epimer 052 pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21- d Tacrolimus 19-epimer, e (4H,23H)-tetrone b 062 Ascomycin, g C 43H 69NO f 084 USP Tacrolimus System Suitability Mixture RS Desmethyl tacrolimus, h f 091 It contains tacrolimus, ascomycin Tacrolimus 10 (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)- 05 (RB 1-Feb- 8-Ethyl- Tacrolimus 8-epimer ) 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hex- i Tacrolimus 8-propyl ana- adecahydro-5,19-dihydroxy-3-[(e)-2-[(1r,3r,4r)-4-hy- log, j f 130 droxy-3-methoxycyclohexyl]-1-methylvinyl]-14,16- Any individual unspeci- dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-3h- fied impurity 02 pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21- Total impurities 15 (4H,23H)-tetrone C 43H 69NO a 2-[(2R,3R,5S,6R)-6-{(1S,3S,5E,7R,10S,11R,12S,13E)-7-Allyl-10-hydroxyand tacrolimus 8-propyl analog 14-{(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl}-1-methoxy-3,5,11,13-tetramethyl-8-oxo-12-[(S)-piperidine-2-carbonyloxy]tetradeca-5,13-dienyl}- (3S,4R,5S,8S,9E,12S,14S,15R,16S,18R,19R,26aS)- 2-hydroxy-5-methoxy-3-methyltetrahydro-2H-pyran-2-yl]-2-oxoacetic ac- 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-Hexid adecahydro-5,19-dihydroxy-3-{(e)-2-[(1r,3r,4r)-4-hyb Tacrolimus open ring and tacrolimus 19-epimer are isomers of tacrolimus, which are present in equilibrium with the active ingredient droxy-3-methoxycyclohexyl]-1-methylvinyl}-14,16- They are not to be reported as degradation products dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-8-propyl-3h-pyrido[2,1-c][1,4]oxaazacyclotricosinec (3S,4R,5S,8R,12S,14S,15R,16S,18R,26aS,E)-8-Allyl- 5,6,11,12,13,14,15,16,17,18,24,25,26,26a-tetradecahydro-5,15,20,20-1,7,20,21(4H,23H)-tetrone tetrahydroxy-3-{(e)-2-[(1r,3r,4r)-4-hydroxy-3-methoxycyclohexyl]-1- C 44H 71NO methylvinyl}-14,16-dimethoxy-4,10,12,18-tetramethyl-3h-pyrido[2,1-c] [1,4]oxaazacyclotricosine-1,7,19,21(4H,8H,20H,23H)-tetrone d (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19S,26aS)-8-Ethyl- methylvinyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-3hpyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21-(4h,23h)-tetrone e (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19S,26aS)-8-Allyl- methylvinyl}-14,16-dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-3hpyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4h,23h)-tetrone f These are process impurities that are controlled in the drug substance They are not to be reported in the drug product g (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)-8-Ethyl- methylvinyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-3hpyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21-(4h,23h)-tetrone h (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)-8-Allyl- methylvinyl]-14,16-dimethoxy-4,12,18-trimethyl-15,19-epoxy-3h-pyrido [2,1-c][1,4]oxaazacyclotricosine-1,7,20,21-(4H,23H)-tetrone i (3S,4R,5S,8S,9E,12S,14S,15R,16S,18R,19R,26aS)-8-Allyl- methylvinyl}-14,16-dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-3hpyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4h,23h)-tetrone j (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)- methylvinyl}-14,16-dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-8- propyl-3h-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4h,23h)-tetrone ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Preserve in tight containers Store at controlled room temperature LABELING: If a test for Organic Impurities other than Procedure 1 is used, then the labeling states with which Organic Impurities test the article complies When more than one Dis test is given, the labeling states the Dis test used only if Test 1 is not used 2013 The United States Pharmacopeial Convention All Rights Reserved