Current Trends and Changing USP Updates in Pharmaceutical Industri

Current Trends and Changing USP Updates in Pharmaceutical Industry
Doug McCabe
May 2018
©2018 Waters Corporation COMPANY CONFIDENTIAL 1

Agenda
 Overview of USP and Chapter <621>

– Current allowable changes as compared with European Pharmacopeia (EP)
– Pending changes in upcoming stage 4 harmonized chapter
 Method Transfer Example

– Current USP <621> Guidelines
 Harmonization & Proposed USP <621> Updates
 Practical System Considerations for Method Modernization

What is the USP?
 The United States Pharmacopeia (USP) is a pharmacopeia (compendium

of drug information) for the United States
– Published annually by the United States Pharmacopeial Convention, a nonprofit organization that owns the
trademark and copyright.
– The USP is published in a combined volume with the National Formulary (a formulary) as the USP-NF.
o If a drug ingredient or drug product has an applicable USP quality standard (in the form of a USP-NF monograph),
it must conform in order to use the designation "USP" or "NF.“
– A drug or drug ingredient with a name recognized in USP-NF is deemed adulterated if it does not satisfy compendial
standards for strength, quality or purity.
– USP has no role in enforcing its standards; enforcement is the responsibility of Food and Drug Association (FDA)
and other government authorities in the U.S. and elsewhere.
 USP works closely with government agencies, ministries, and regulatory

authorities around the world to help provide standards of identity, strength,
quality, and purity that can help safeguard the global supply of medicines,
dietary supplements, and food ingredients.

USP General Chapter Chromatography <621>
 USP-NF <621> are the guidelines governing allowed adjustments to

chromatographic systems.
– It “defines the terms and procedures used in chromatography and provides general information regarding system
suitability
 USP-NF <621> initially did not provide the necessary flexibility to change the
chromatographic system (i.e., column) without revalidating the method. The
emerging new technologies were outpacing the allowed changes, which were
not able to accommodate these new options.
 In 2009, a stimuli paper was drafted that proposed changes to the isocratic
and gradient guidelines to allow for reductions in analysis time while
preserving the column performance and quality of separation.

The Beginning of A Significant Change to
Chromatography <621>
 Stimuli Article PF 35(6) [Nov-Dec 2009]

Method Validation, Verification, and Transfer
New/Interna
l Methods
USP
Methods
<621>
Compendial methods must pass the system
suitability requirement(s), and these need to be
verified with the API and/or Final drug formulation

USP Chapter <621> Chromatography
Defines “Allowable Adjustments”
“Adjustments to the specified chromatographic system may be
necessary in order to meet system suitability requirements.”
USP 40-NF35 through Second Supplement
- Official until May 1, 2018
Significant changes to General Chapter <621> Chromatography

were made in August 2014 USP 37-NF 32 (based on 2009 Stimuli
article)
Upcoming Harmonization changes to be official in USP 41-NF 36 2S

(Dec 2018) indicate further gradient method flexibility
link to PF 43(5) text
 Adjustments permitted only when:
– Suitable standards are available for all compounds used in suitability test
– Adjustments (or column change) yields results that meet all system suitability requirements specified in
official procedure.
 Must use the same L-designation of column

USP-NF <621> Guidelines
Since Aug 1, 2014

Previous (USP36-NF31)
Variable (USP37-NF32 S1)
Isocratic and Gradient Isocratic Gradient
Particle Size -50% Per constant L/dp or No changes allowed

N: -25% to +50%
Column Length ±70% No changes allowed
Column ID Any allowed Flexible if linear velocity maintained No changes allowed
Flow Rate ±50% Based on particle size and ±50% No changes allowed
Injection Volume Any reduction Any allowed
Column Temperature ±10oC ±10°C
Mobile Phase pH ±0.2 unit ±0.2 unit
Currently, changes are allowed to

isocratic methods ONLY

Points of Emphasis <621>
LC Mobile Phase Composition Allowable Changes
 pH ±0.2 units (both isocratic and gradient)

 Salt concentration in buffer ± 10% adjustment, if permitted pH
variation is met
 Ratio of components in mobile phase
– Minor components of mobile phase (≤50%) can be adjusted ±30% relative, but must meet
permitted absolute 10% change for any component.
– Adjustment can be made to one minor component in a ternary mixture
– Ternary mixtures
60:35:5 (30% of 35) 10.5% absolute, exceeds allowable – 2nd component may be
adjusted within 25 – 45% absolute; 3rd component (30% of 5) 1.5% absolute
– Binary mixtures
50:50 30% of 50 is 15% absolute, exceeds allowable – permitted 40:60 – 60:40
2:98 30% of 2 is 0.6% absolute – maximum range 1.4 – 2.6

Points of Emphasis <621> Other Allowable
Considerations
 UV Wavelength
– Deviation from specified wavelength not permitted
o Vendor calibration wavelength error, at most ±3 nm
 Column temperature ±10ºC

– Column thermostatting is recommended to improve retention time reproducibility
 Columns
– Same L designation in monograph
– Column inner diameter (HPLC): Can be adjusted if the linear velocity is kept constant
– Particle size
 Injection volume (HPLC)
– Can be adjusted, must meet accepted precision, linearity, and detection limit
o Excessive injection volume can reduce N and resolution
 Flow rate
– Particle size change requires flow adjustment, to higher linear velocity
• F2 = F1 × [(dc2 2 × dp1 )/(dc1 2 × dp2 )]
• Isocratic flow rate adjustment ± 50% with equivalent N

Point of Emphasis
System Suitability
 Verify that the chromatographic system is adequate for the

intended analysis
– Replicate injections of a standard preparation or other standard solutions are compared to
ascertain whether requirements for precision are met.
o *Data from 5 replicate injections of the analyte are used to calculate the relative standard
deviation (RSD), if the requirement is ≤ 2.0%; data from six replicate injections are used if the
RSD requirement is >2.0%.General Assay Repeatability
(Does not apply to related substance tests)
B is the difference between upper limit given in individual monograph and 100%
e.g. monograph 98 – 102% → B = 2.0. If 5 injections made, % RSD must be < 0.73% unless
specified otherwise in monograph
*Unless specified in individual monograph

USP-NF FAQs: <621> Chromatography
 1. To what degree can a chromatographic procedure be modified and still
be in compliance? Can column length, internal diameter, mobile phase
composition be modified?
– Chromatography General Chapter <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.
 2. What brand of HPLC/GC column was used in the development and/or
validation of a particular test? Is there an alternative chromatographic
column for a particular test?
– The most updated information on the brand name of the column used to validate any chromatographic procedure in
USP—NF, together with possible alternatives, where applicable are available at the
following www.uspchromcolumns.com.
 3. How much deviation is allowed from a relative retention time prescribed
in a monograph?
– From <621>, the deviations of relative retention time values measured for the test substance from the values
obtained for the reference compound and mixture should not exceed the reliability estimates determined statistically
from replicate assays of the reference compound. Also, relative retention times may be provided in monographs for
informational purposes only, to aid in peak identification. There are no acceptance criteria applied to relative retention
1http://www.usp.org/frequently-asked-questions/chromatography
times.

How to Best Utilize Allowable Changes in
Chapter <621>
 Isocratic methods:
– Scale methods to columns that are packed with smaller particles, without re-validation
o Increase laboratory throughput
o Decrease solvent usage = cost savings
 Gradient methods:
– Currently, any changes to gradient methods will require re-validation
 Systems
– ACQUITY H-Class for ultimate separation performance and throughput
o Columns with sub-2-µm particles and 2.1 mm internal diameters
– ACQUITY Arc for HPLC and/or U(H)PLC separations (future-proof your lab)
o Existing HPLC column formats, and/or 2.x µm particles packed in 3.0 mm internal diameters

Method Modernization Example Within
Current USP Guidelines

Revisiting USP-NF <621> Guidelines
Since Aug 1, 2014


N: -25% to +50%
Currently, changes are allowed to

isocratic methods ONLY

What do these changes mean for our isocratic methods?
1. We can now use any particle size and column dimensions as long as the column
meets equivalent L/dp or N within -25% to +50% of the original column.
– This means we can use 1.7 µm particle sizes in place of 5 µm particles.
– This means we can use shorter columns for faster analysis times.
2. We can also now scale the flow rate to the particle size and ±50% provided that
N does not decrease by more than 20%.
𝑭𝟐 = 𝑭𝟏 𝒙 [(𝒅𝒄𝟐𝟐 𝒙 𝒅𝒑𝟏 )/(𝒅𝒄𝟏𝟐 𝒙 𝒅𝒑𝟐 )]

"F1 and F2 are the flow rates for the original and modified conditions, respectively; dc1 and
dc2 are the respective column diameters; and dp1 and dp2 are the particle sizes.”
– This means that we can potentially use faster flow rates for faster analysis times.
– Flow rates can be scaled using method calculators such as the ACQUITY UPLC Columns Calculator.
3. Because of the changes, we can use newer (smaller or solid-core) particle

technologies.

How did these changes to isocratic methods come about?
Since Aug 1, 2014


N: -25% to +50%
 How did the two ways to modernize an isocratic method using

“Equivalent L/dp” and “Equivalent N” come about??

How “Equivalent L/dp” and “Equivalent N” Work with
Efficiency
 “Equivalent L/dp” is based on the reduced plate height

equation:
 Assuming h ≈ constant and h ≈ 2 for fully porous particles,

the method can be scaled by L/dp to get an equivalent plate
count N when transferring to fully porous stationary phases
 If using solid-core particles, h decreases to ≈ 1.4 – 1.6

(solid-core), which increases efficiency. Thus, “Equivalent
N” may be used to scale the method. Plate count
measurements must be taken on all columns using:
Example USP Method Modernization: Dofetilide
 Dofetilide:
– Prescription pharmaceutical to treat patients with irregular heartbeats
– Class III antiarrhythmic agent that specifically blocks potassium channels
– Manufactured by Pfizer under the brand name TIKOSYN®
– Generic dofetilide was approved for manufacturing and marketing by the FDA in 2016
 USP Assay Method
– Isocratic method
– Analyzes both dofetilide and its related desmethyl compound
1
Dofetilide
2
Dofetilide Related Compound A

Dofetilide: USP Assay Requirements
Column
 The method requires an L7 (C8) column and was originally run
with a Waters Nova-Pak® C8 4 µm, 3.9 x 150 mm column
– L/dp = 37,500
System Suitability Requirements

 Resolution: NLT 8.0 between dofetilide and dofetilide related
compound A
 Relative Standard Deviation: NMT 2.0% (or, %RSD for

Retention Time in min must be NMT 2.0%)

Dofetilide: Original Method Conditions
 System: Alliance® HPLC System with PDA

 Column(s): Nova-Pak C8 4 µm, 3.9 x 150 mm
 Mobile Phase: Acetonitrile:Buffer Solution (1:3)
 Buffer Solution: 1.36 g monobasic potassium phosphate and 5 mg
ascorbic acid in 1 L water, adjusted with potassium
hydroxide solution to pH 7.0
 KOH Solution: 0.56 g/mL KOH in water
 Separation Technique: Isocratic
 Flow Rate: 1.00 mL/min
 Column Temperature: 30°C
 Detection: UV at 230 nm
 Sampling Rate: 20 points/sec
 Injection volume: 50 µL
 Sample Diluent: Mobile Phase
 Sample Preparation: 25 µg/mL dofetilide, 0.5 µg/mL dofetilide related compound A

Dofetilide: Original Method Results
1
3.9 x 150 mm
Nova-Pak C8 4 µm 7.04 min
1
0.25
1.00 mL/min Dofetilide
0.20
0.15
AU
2
Dofetilide Related Compound A
0.10
0.05
2
3.61 min
0.00
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5
Minutes
%RSD
USP Plate Count
Resolution Retention Time (min) USP Plate Count
Column L/dp (N)
NLT 8.0 NMT 2.0 (N) Compound 2
Compound 1
Compound 1
Nova-Pak C8
4 µm 37,500 13.08 0.17 7,535 4,296
3.9 x 150 mm

Dofetilide Modernized Method Conditions: Requirements
Column
 L7 (C8) column that meets either:
L/dp Requirement Plate Count (N) Requirement
Original: 37,500 Original (Dofetilide): Original (Related

OR 7,535 Compound): 4,296
Min: 28,125 (-25%)
Max: 56,250 (+50%) Min: 5,651 (-25%) Min: 3,222 (-25%)
Max: 11,302 (+50%) Max: 6,444 (+50%)
System Suitability Requirements

 Resolution: NLT 8.0 between dofetilide and dofetilide related compound A
 Relative Standard Deviation: NMT 2.0% (or, %RSD for Retention Time in min must be NMT 2.0%)

Dofetilide: Modernized Method Conditions
Only changes are listed
 System: ACQUITY UPLC® H-Class System

 Column(s): CORTECS C8 2.7 µm, 3.0 x 100 mm (meets L/dp guideline)
CORTECS C8 2.7 µm, 3.0 x 75 mm
CORTECS C8 2.7 µm, 3.0 x 50 mm
CORTECS UPLC C8 1.6 µm, 3.0 x 50 mm (meets L/dp guideline)
CORTECS UPLC C8 1.6 µm, 3.0 x 30 mm
 Flow Rate: 0.88 mL/min (2.7 µm columns)
1.30 mL/min (1.6 µm columns)
Scaled using the relationship (±50%):
𝑭𝟐 = 𝑭𝟏 𝒙 [(𝒅𝒄𝟐𝟐 𝒙 𝒅𝒑𝟏 )/(𝒅𝒄𝟏𝟐 𝒙 𝒅𝒑𝟐 )]
 Injection volume:
19.8 µL (3.0 x 100 mm columns)
Scaled using the relationship:
𝑵𝒆𝒘 𝑪𝒐𝒍𝒖𝒎𝒏 𝑽𝒐𝒍𝒖𝒎𝒆
𝑵𝒆𝒘 𝑰𝒏𝒋𝒆𝒄𝒕𝒊𝒐𝒏 𝑽𝒐𝒍𝒖𝒎𝒆 = 𝑶𝒓𝒊𝒈𝒊𝒏𝒂𝒍 𝑰𝒏𝒋𝒆𝒄𝒕𝒊𝒐𝒏 𝑽𝒐𝒍𝒖𝒎𝒆 𝒙
𝑶𝒓𝒊𝒈𝒊𝒏𝒂𝒍 𝑪𝒐𝒍𝒖𝒎𝒏 𝑽𝒐𝒍𝒖𝒎𝒆

Dofetilide: Modernized Method Conditions using
“Equivalent L/dp” Isocratic Separation
Original Compendial Chromatogram 3.9 x 150 mm 7.04
Nova-Pak C8 4 µm
FULLY POROUS 1.00 mL/min
3.61
2.33 3.0 x 100 mm
1.01 CORTECS C8 2.7 µm SOLID-CORE
0.88 mL/min
0.88 3.0 x 50 mm
CORTECS UPLC C8 1.6 µm SOLID-CORE
0.38 1.30 mL/min
%RSD
L/dp
Resolution Retention Time (min) USP Plate Count USP Plate Count
Column must be between 28,125 (-
NLT 8.0 NMT 2.0 (N) Compound 1 (N) Compound 2
25%) and 56,250 (+50)
Compound 1
Nova-Pak C8
4 µm 37,500 13.08 0.17 7,535 4,296
3.9 x 150 mm
CORTECS C8
2.7 µm 37,037 24.90 0.03 17,813 12,798
3.0 x 100 mm
CORTECS UPLC C8
1.6 µm 31,250 20.67 0.00 13,075 7,057
3.0 x 50 mm

Dofetilide: Modernized Method Conditions using
“Equivalent N” Isocratic Separation
%RSD
Resolution Retention Time (min) USP Plate Count (N)* USP Plate Count (N)*
Column L/dp*
NLT 8.0 NMT 2.0 Compound 1 Compound 2
Compound 1
Nova-Pak C8 4 µm
37,500 13.08 0.17 7,535 4,296
3.9 x 150 mm
CORTECS C8 2.7 µm
27,778
3.0 x 75 mm
CORTECS C8 2.7 µm
18,519
3.0 x 50 mm
CORTECS C8 1.6 µm
18,750
3.0 x 30 mm
*L/dp must be between 28,125 (-25%) and 56,250 (+50%) to successfully

modernize the original method using the “Equivalent L/dp” allowed change.
 Since the shorter columns we want to use do not meet “equivalent L/dp” guidelines, we will
see if they meet “equivalent N” guidelines in order to modernize the method instead.
 That means N must be between 5,651 (-25%) and 11,302 (+50%) for dofetilide and 3,222
(-25%) to 6,444 (+50%) for its related compound to successfully modernize the original
method using the “Equivalent N” allowed change.

Dofetilide: Modernization Results using “Equivalent N”
%RSD USP Plate Count (N)* USP Plate Count ( N)*
Resolution Retention Time (min) Compound 1 must be Compound 2 must be
Column L/dp
NLT 8.0 NMT 2.0 between 5,651 (-25%) between 3,222 (-25%)
Compound 1 and 11,302 (+50) and 6,444 (+50)
Nova-Pak C8 4 µm
37,500 13.08 0.17 7,535 4,296
3.9 x 150 mm
CORTECS C8 2.7 µm
27,778 20.89 0.06 13,261 7,375
3.0 x 75 mm Over the upper efficiency limit!
CORTECS C8 2.7 µm
18,519 16.84 0.09 9,484 5,251
3.0 x 50 mm
CORTECS C8 1.6 µm
18,750 14.84 0.00 7,094 4,469
3.0 x 30 mm
Original Compendial Chromatogram 3.9 x 150 mm

FULLY POROUS Nova-Pak C8 4 µm
1.00 mL/min
3.0 x 75 mm
Modernization Using "Equivalent N“CORTECS C8 2.7 µm SOLID-CORE
Does not meet USP Requirements 0.88 mL/min
3.0 x 50 mm
CORTECS C8 2.7 µm
0.88 mL/min SOLID-CORE
3.0 x 30 mm
CORTECS C8 1.6 µm
1.30 mL/min
SOLID-CORE

Dofetilide: Modernized USP Method
Using Equivalent L/dp and Equivalent N
3.9 x 150 mm 7.04
Original Compendial Chromatogram Nova-Pak C8 4 µm
3.61 1.00 mL/min
3.0 x 100 mm
2.33
CORTECS C8 2.7 µm
1.01 Modernization Using "Equivalent L/dp" 0.88 mL/min
92%
decrease in
1.80 3.0 x 75 mm
Modernization Using "Equivalent N“ CORTECS C8 2.7 µm sample
0.77 0.88 mL/min analysis
Does not meet USP Requirements
AU
1.22 3.0 x 50 mm time

CORTECS C8 2.7 µm
0.54 Modernization Using "Equivalent N"
0.88 mL/min
90%
0.88 3.0 x 50 mm
reduction in
CORTECS UPLC C8 1.6 µm
0.38 Modernization Using "Equivalent L/dp"
1.30 mL/min solvent
0.55 3.0 x 30 mm consumption
CORTECS UPLC C8 1.6 µm
0.24 Modernization Using "Equivalent N"
1.30 mL/min
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5
Minutes
By using “equivalent N”, smaller columns can be used to decrease sample

analysis times and solvent costs.

USP <621> Updates and Harmonization
(USP 41-NF36 2S)
Anticipated official date:
December 1, 2018

Comparison of Current USP and EP Guidelines for
Allowable Method Changes – Limited Gradient Changes
USP <621> Guidelines (as of Aug 1, 2014)
Guidelines are Currently

EP <2.2.46> V8.2 Guidelines
Isocratic Gradient Isocratic Gradient
Stationary phase
Particle Size
not Aligned
No change to the “L” designation of the stationary phase
Per constant L/dp or

No changes allowed
No change in the identity of substituent of stationary phase (e.g. no replacement of C8 for C18)
-50%, no increase No changes allowed

N: -25% to +50%
Column Length No changes allowed ±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 if linear velocity maintained No changes allowed ±25%
Injection Volume Flexible as long as consistent with accepted precision, linearity, and detection limits Decrease only, if proper detection and repeatability met; No increase permitted
Column Temperature ±10°C ±10°C ±5°C

No changes permitted to specified wavelength; vendor or other validated procedure
UV Detector wavelength No changes permitted
used to ensure ± 3 nm error
Salt: No adjustment permitted
Salt: ± 10%,
Salt: ± 10%, if pH met Adjustment of minor component and gradient
Minor component ± 30% relative, ± 2%
Mobile Phase Composition Minor component ± 30% relative, ± 10% absolute; adjustment to one minor acceptable if SST met, principle peaks elute ±
absolute; no other component altered by >
component in ternary mixture 15% of indicated RT and final composition isn’t
10% absolute
weaker in elution power than prescribed
Aqueous component ±0.2 unit or ± 1.0 unit
Mobile Phase pH ±0.2 unit No changes allowed
when non-ionizable substances examined
2 2 2 2
*F2=F1 x [(dc2 x dp1)/(dc1 x dp2)] *F2=F1 x [(L2 x d2 )/(L1 x d1 )]
L/dp = column length (L) to particle size (dp) ratio L= Column Length; d= Column ID
Adjustment of isocratic hold permitted at start of gradient to account for dwell volume
N = theoretical plate count (for porous to solid-core particles)
differences

Pharmacopeia Harmonization

The Basis for Harmonization Chromatography Chapters
ICH Q6A:
“Wherever they are appropriate, pharmacopoeial procedures should be
utilized……To signify the harmonized status of these procedures, the
pharmacopoeias have agreed to include a statement in their respective texts
which indicates that the procedures and acceptance criteria from all three
pharmacopoeias are considered equivalent and are, therefore, interchangeable.”
 Q4 Expert Working Group (EWG Nov 2003)

– 11 compendial general test chapters discussed during development of the ICH Q6A Guideline.
– Further expanded scope in 2008 to include 5 additional compendial general test chapters
o The harmonization of these chapters was deemed essential to obtain full utility of the
ICH Q6A Guideline.
ICH – International Conference on Harmonization http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html

Proposed Changes USP <621> Chapter; December 1, 2018
USP <621> Guidelines (as of Aug 1, 2014) Proposed USP <621> Guidelines (as of Dec 1, 2018)
Variable (USP37-NF32 S1) (USP41-NF36 S2)
Isocratic Gradient Isocratic Gradient
Stationary phase No change to the “L” designation of the stationary phase No change of the physio-chemical characteristics of the stationary phase permitted
Particle Size Constant L/dp or -25%~+50% prescribed L/dp

No changes allowed superficially porous particles: N -25% to +50%
Per constant L/dp or
L/dp = column length (L) to particle size (dp) ratio; N = theoretical plate count (for solid-core
Column Length N: -25% to +50%
No changes allowed particles
Meet SST criteria, same elution order
Gradient time segment adjusted for column volume
Column ID Flexible if linear velocity maintained No changes allowed tG2 = tG1 X (F1 / F2)[(L2 x dc22)/(L1 X dC12)]
L x dc2 = column volume
*Based on particle size and ± 50%
*F2 = F1 X [(dc22 X dp1)]/[(dc12 X dp2)]
Flow Rate *Based on particle size and ±50% No changes allowed
tG2 = tG1 X (F1 / F2)[(L2 x dc22)/(L1 X dC12)]
Vinj2 = Vinj1(L2dc22)/((L1dc12)
Injection Volume Flexible Vinj2, Vinj2: Injection volume L Column length, d, Column ID,
except for changes from totally porous particles to superficially porous particles
Column Temperature ±10°C ±10°C
Meet SST criteria

±0.2 unit
Composition:± 30 % relative or ± 2 % absolute the principal peak(s) elute(s) within ± 15 %
Mobile Phase Composition and Salt: ± 10%, if pH met
pH : ± 0.2 pH units the final composition of the mobile phase is not
pH Minor component ± 30% relative, ± 10% absolute; adjustment to one minor
Concentration of salts : ± 10 weaker in elution
component in ternary mixture
power than the prescribed composition
No adjustment permitted,
Detector wavelength No adjustment permitted
vendor UV startup calibration at most ± 3nm
t0 = t = (D-D0) / F
Dwell volume NA NA
D:Dwell volume, F: Flow rate

Proposed Harmonized Chromatography Chapter
Variable Isocratic Gradient
Stationary phase No change of the physio-chemical characteristics of the stationary phase permitted (i.e. chromatographic support, surface modification and
extent of chemical modification must be the same)
Particle size Constant L/dp or -25%~+50% prescribed L/dp

Column length superficially porous particles: -25% to +50%
L/dp = column length (L) to particle size (dp) ratio New!
N = theoretical plate count (for solid-core particles)
Meet SST criteria, same elution order
Gradient
Flow rate *Based on particle size and ± 50%
adjustment
*F2 = F1 X [(dc22 X dp1)]/[(dc12 X dp2)] flexibility
tG2 = tG1 X (F1 / F2)[(L2 x dc22)/(L1 X dC12)]
Injection volume Vinj2 = Vinj1(L2dc22)/((L1dc12)

Vinj2, Vinj2: Injection volume L Column length, d, Column ID,
except for changes from totally porous particles to superficially porous particles
Column
temperature ± 10ºC
Mobile phase Composition:± 30 % relative or ± 2 % absolute, whichever is Meet SST criteria

composition and larger Principal peak elutes within ± 15%
pH : ± 0.2 pH units Not weaker in final composition elution power than prescribed
pH
Concentration of salts : ± 10% composition
Detector No adjustment permitted

wavelength
Dwell volume N/A t0 = t = (D-D0) / F D:Dwell volume, F: Flow rate

Summary
 USP Chapter <621> provides the chromatography guidelines

for allowable method changes
– These can be used to modernize existing methods
– This is for both compendial and inhouse created methods
 Current <621> guidelines allow changes in particle size, column

configuration, temperature, and flow rate are allowed only for
isocratic separations
 Expected updates to Chapter <621> will provide guidelines for

allowable changes to gradinet methods
– Expected time frame for approval is December 1, 2018

Thank You for Your Time and Attention

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Current Trends and Changing USP Updates in Pharmaceutical Industry

©2018 Waters Corporation COMPANY CONFIDENTIAL 1

 Overview of USP and Chapter <621>

 Method Transfer Example

 Harmonization & Proposed USP <621> Updates

 Practical System Considerations for Method Modernization

©2018 Waters Corporation COMPANY CONFIDENTIAL 2

 The United States Pharmacopeia (USP) is a pharmacopeia (compendium

 USP works closely with government agencies, ministries, and regulatory

©2018 Waters Corporation COMPANY CONFIDENTIAL 3

 USP-NF <621> are the guidelines governing allowed adjustments to

©2018 Waters Corporation COMPANY CONFIDENTIAL 4

 Stimuli Article PF 35(6) [Nov-Dec 2009]

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Significant changes to General Chapter <621> Chromatography

Upcoming Harmonization changes to be official in USP 41-NF 36 2S

 Must use the same L-designation of column

©2018 Waters Corporation COMPANY CONFIDENTIAL 7

Since Aug 1, 2014

Particle Size -50% Per constant L/dp or No changes allowed

Currently, changes are allowed to

©2018 Waters Corporation COMPANY CONFIDENTIAL 8

 pH ±0.2 units (both isocratic and gradient)

©2018 Waters Corporation COMPANY CONFIDENTIAL 9

 Column temperature ±10ºC

©2018 Waters Corporation COMPANY CONFIDENTIAL 10

 Verify that the chromatographic system is adequate for the

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Since Aug 1, 2014

Particle Size -50% Per constant L/dp or No changes allowed

Currently, changes are allowed to

©2018 Waters Corporation COMPANY CONFIDENTIAL 15

𝑭𝟐 = 𝑭𝟏 𝒙 [(𝒅𝒄𝟐𝟐 𝒙 𝒅𝒑𝟏 )/(𝒅𝒄𝟏𝟐 𝒙 𝒅𝒑𝟐 )]

3. Because of the changes, we can use newer (smaller or solid-core) particle

©2018 Waters Corporation COMPANY CONFIDENTIAL 16

Since Aug 1, 2014

Particle Size -50% Per constant L/dp or No changes allowed

 How did the two ways to modernize an isocratic method using

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 “Equivalent L/dp” is based on the reduced plate height

 Assuming h ≈ constant and h ≈ 2 for fully porous particles,

 If using solid-core particles, h decreases to ≈ 1.4 – 1.6

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System Suitability Requirements

 Relative Standard Deviation: NMT 2.0% (or, %RSD for

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 System: Alliance® HPLC System with PDA

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L/dp Requirement Plate Count (N) Requirement

Original: 37,500 Original (Dofetilide): Original (Related

System Suitability Requirements

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 System: ACQUITY UPLC® H-Class System

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*L/dp must be between 28,125 (-25%) and 56,250 (+50%) to successfully

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Original Compendial Chromatogram 3.9 x 150 mm