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©2015 Waters Corporation 1

Update to USP <621> Chromatography: What does this mean?

USP 37 NF 32 1S – Current as of August

2014


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


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>).

1http://www.uspnf.com/uspnf/scienceFAQ.html#q4


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, 2014 - significant changes to Chapter <621> Chromatography


Current Changes to <621>

Flow rate (isocratic): F2 = F1 x [(dc22 x dp1)/(dc1

2 x dp2)]

L/dp = column length (L) to particle size (dp) ratio N = theoretical plate count (for solid-core particles)

Previous (USP36-NF31)

Isocratic & Gradient Isocratic Gradient Particle Size -50%

Column Length ±70% 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

Variable Since Aug 1, 2014 (USP37-NF32 S1) Allowable Adjustments in USP <621> Chromatography

per constant L/dp or N: -25% to +50% no changes allowed


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 Per constant L/dp or N: -25%

to +50% No changes allowed -50%, no increase No changes allowed

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

*F2=F1 x [(dc22 x dp1)/(dc1

2 x dp2)] *F2=F1 x [(L2 x d22)/(L1 x d1

2)]

L/dp = column length (L) to particle size (dp) ratio L= Column Length

N = theoretical plate count (for solid-core particles) d= Column ID

Refer to Chapter <621> of USP37-NF32 S1 for further information and details on adjustments not shown

Refer to Section <2.2.46> of EP version 8.2 for further information and details on adjustments not shown


• 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

Benefits: Isocratic USP Method Levonorgestrel/Ethinyl Estradiol

0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 0.000

0.010

0.020

0.030 HPLC XBridge C

8

0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00

AU

0.000

0.010

0.020

0.030 HPLC USP Res: 6.9

0.00 0.20 0.40 0.60 0.80 1.00

0.000

0.010

0.030

0.050

Minutes 0.00 0.20 0.40 0.60 0.80 1.00

Minutes Minutes

AU

levo

norg

estre

l ACQUITY UPLC H-Class Column: ACQUITY BEH C8, 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

Alliance 2695 HPLC Column: XBridge C8, 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

UPLC USP Res: 7.0

levo

norg

estre

l

ethi

nyl e

stra

diol

et

hiny

l est

radi

ol


0.00 5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00 50.00 55.00

HPLC Separation on Alliance HPLC System

XBridgeTM C18 4.6 x 100 mm, 3.5 µm Tailing = 1.60 Rs = 7.6

Gal

anta

min

e

1 2

4 5

Benefits: USP Gradient Method Galantamine and Related compounds

AU

0.000

0.010

0.020

0.030

0.040

0.050

0.060

0.070

0.080

0.090

0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00

UPLC Separation on ACQUITY UPLC H-Class

ACQUITY UPLC BEH C18 2.1 x 50 mm, 1.7 µm Tailing = 1.43 Rs = 7.2

Gal

anta

min

e

1 2

4 5

HPLC to UPLC Transfer: Reduce analysis time by 77% (4.3X) while preserving separation integrity Tailing and Resolution Criteria were met Assay Criteria: USP Tailing < 2.0 Rs (galantamine/impurity 4) > 4.5 Re-validation will be required under USP37-NF32 S1 (effective Aug 2014).


Empower Method Validation Manager for Verification/Validation

Improve compliance and reduce errors:

Automate testing within Empower


Reference Experts from USP37-NF32 1S (Published)


“Allowable adjustments”


Changes to Particle Size


Changes to Flow Rate


Changes to Other factors


Example provided

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