Update to USP <621> Chromatography: What does this mean? USP 37 NF 32 1S Current as of August 2014

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1 Update to USP <621> Chromatography: What does this mean? USP 37 NF 32 1S Current as of August Waters Corporation 1

2 What is the USP-NF? The United States Pharmacopeia National Formulary (USP-NF) is a book of pharmacopeial standards Drugs substances & preparations monographs: USP Dietary supplements & ingredients monographs: USP Excipient monographs: NF More than 4500 monographs The USP-NF is the official authority FDA-enforceable standards Enforcement of USP standards is the responsibility of FDA and other government authorities in the U.S. and elsewhere USP has no role in enforcement The U.S. Federal Food, Drug, and Cosmetics Act designates the USP NF as the official compendia for drugs marketed in the United States 2015 Waters Corporation 2

3 Why is Chromatography <621> Important? Question From CURRENT USP-NF Online FAQs1 Q. How much can I modify a chromatographic procedure and still be in compliance? Can column length, internal diameter, mobile phase composition be modified? A. Chromatography <621> contains a list of allowed adjustments to chromatographic systems. However, the user should verify the suitability of the method under the new conditions by assessing the relevant analytical performance characteristics potentially affected by the change (see section System Suitability under Chromatography <621>) Waters Corporation 3

4 USP <621> Chromatography Defines Allowable adjustments Adjustments to a USP method may be made to meet system suitability requirements Verification tests must be performed after changes Full re-validation not required Must use the same L-designation of column Isocratic hold or dwell volume adjustments are allowed USP 37 NF 32 S1 - to be official Aug. 1, significant changes to Chapter <621> Chromatography 2015 Waters Corporation 4

5 Current Changes to <621> Allowable Adjustments in USP <621> Chromatography Variable Previous (USP36-NF31) Since Aug 1, 2014 (USP37-NF32 S1) Isocratic & Gradient Isocratic Gradient Particle Size -50% per constant L/dp or N: -25% to +50% Column Length ±70% no changes allowed Flow Rate ±50% *based on particle size and ±50% no changes allowed Column ID Any allowed Any allowed no changes allowed Injection Volume Any reduction Any allowed Any allowed Column Temperature ±10 C ±10 C ±10 C Mobile Phase ph ±0.2 unit ±0.2 unit ±0.2 unit Flow rate (isocratic): F 2 = F 1 x [(dc 2 2 x dp 1 )/(dc 1 2 x dp 2 )] L/dp = column length (L) to particle size (dp) ratio N = theoretical plate count (for solid-core particles) 2015 Waters Corporation 5

6 USP and EP Variable USP <621> Guidelines as of Aug 1, 2014 (USP37-NF32 S1) Current EP <2.2.46> V8.2 Guidelines Isocratic Gradient Isocratic Gradient Particle Size -50%, no increase No changes allowed Per constant L/dp or N: -25% No changes allowed to +50% Column Length ±70% ±70% Flow Rate *Based on particle size and ±50% No changes allowed ±50%, *More if changing column dimensions *Flexible ONLY if changing column dimensions Column ID Flexible No changes allowed ±25% ±25% Injection Volume Flexible Flexible Decrease only for proper detection and repeatability Decrease only for proper detection and repeatability Column Temperature ±10 C ±10 C ±10 C ±5 C Mobile Phase ph ±0.2 unit ±0.2 unit ±0.2 unit No changes allowed *F 2 =F 1 x [(dc 2 2 x dp 1 )/(dc 1 2 x dp 2 )] *F 2 =F 1 x [(L 2 x d 2 2 )/(L 1 x d 1 2 )] L/dp = column length (L) to particle size (dp) ratio N = theoretical plate count (for solid-core particles) Refer to Chapter <621> of USP37- NF32 S1 for further information and details on adjustments not shown L= Column Length d= Column ID Refer to Section <2.2.46> of EP version 8.2 for further information and details on adjustments not shown 2015 Waters Corporation 6

7 Benefits: Isocratic USP Method Levonorgestrel/Ethinyl Estradiol HPLC HPLC AU USP XBridge Res: 6.9 C Minutes UPLC ethinyl estradiol levonorgestrel Alliance 2695 HPLC Column: XBridge C 8, 4.6 x 150mm, 5µ (L7) L/dp = 30,000 Flow Rate: 1.0 ml/min, pressure 1400 psi Mobile Phase: 35:15:45 ACN:MeOH:Water Injection Volume: 50 µl AU USP Res: 7.0 ethinyl estradiol levonorgestrel ACQUITY UPLC H-Class Column: ACQUITY BEH C 8, 2.1 x 50mm, 1.7µ (L7) L/dp = 29,400 Flow Rate: 0.61 ml/min, pressure 7700 psi Mobile Phase: 35:15:45 ACN:MeOH:Water Injection Volume: 3.5 µl Minutes Changes made within USP <621> allowable adjustments (USP37-NF32 S1, August 2014) 90% savings in runtime and 94% solvent savings per run! Re-validation not required 2015 Waters Corporation 10

8 Benefits: USP Gradient Method Galantamine and Related compounds HPLC to UPLC Transfer: HPLC Separation on Alliance HPLC System Reduce analysis time by 77% (4.3X) while preserving separation integrity Galantamine XBridge TM C x 100 mm, 3.5 µm Tailing = 1.60 Rs = 7.6 Tailing and Resolution Criteria were met Assay Criteria: UPLC Separation on ACQUITY UPLC H-Class USP Tailing < 2.0 Rs (galantamine/impurity 4) > 4.5 AU Galantamine ACQUITY UPLC BEH C x 50 mm, 1.7 µm Tailing = 1.43 Rs = 7.2 Re-validation will be required under USP37-NF32 S1 (effective Aug 2014) Waters Corporation 11

9 Empower Method Validation Manager for Verification/Validation Improve compliance and reduce errors: Automate testing within Empower 2015 Waters Corporation 12

10 Reference Experts from USP37-NF32 1S (Published) 2015 Waters Corporation 14

11 Allowable adjustments 2015 Waters Corporation 15

12 Changes to Particle Size 2015 Waters Corporation 16

13 Changes to Flow Rate 2015 Waters Corporation 17

14 Changes to Other factors 2015 Waters Corporation 18

15 Example provided 2015 Waters Corporation 19