module 5 general chapters 621 update

7/21/2019 Module 5 General Chapters 621 Update

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Waters Executive UPLC Forum17-18 May 2012

,

Ravi Ravichandran, Ph.D.

,

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Topics

Proposed Revisions to Chromatography

- -

revision proposal in PF 37(3) MayJune 2011 revision proposal in PF 38(2) Mar-Apr 2012

Harmonization of Chromatography with EP & JP

Validation Verification Method Transfer Chapters

Definitions

Equivalent or Better concept

Transfer of Analytical Procedures

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Main points

Chromatography describes in detail the range of

adjustments allowed in the system when the suitability

test failed What if the prescribed column is no longer available

or a more rap separa on can e o a ne w ano er

column. Both these situations currently require

revalidation

Ideal scenario allows the flexibility to change column

dimensions or particle size as long as equivalent or

e er co umn per ormance s ma n a ne

USP published a Stimuli article in PF35(6)Nov-Dec

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Stimuli article PF 35(6)

Transfer of HPLC Procedures to Suitable Columns of

Reduced Dimensions and Particle Sizes

Uwe D. Neue, Doug McCabe, Vijaya Ramesh, Horacio Pappa, Jim

DeMuth

ABSTRACT This Stimuli article contains proposals to help

the analyst adjust HPLC column length and particle size toachieve separation power at least equivalent to that used in

the original procedure, markedly increasing the range of

o tions currentl allowed in Chromato ra h . The

article presents the scientific rationale for application of these

proposals to isocratic procedures and follows with gradient

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Examples

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PF 37(3) May-Jun-2011 proposal

Based on stimuli article Transfer of HPLC Procedures to Suitable

Columns of Reduced Dimensions and Particle Sizes ublished in

PF 35(6) [Nov.Dec. 2009], pages 16221626.A more flexible approach to select HPLC column dimensions

particle size to achieve separation power equivalent to that obtained

using the prescribed column.Approach increases the range of options currently allowed in the

chapter.

Hel s reducin solvent consum tion

Reduces time of the analysis,

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PF 37(3) May-Jun-2011

Particle Size (HPLC): The particle size and/or the length of the column

may be modified provided that the ratio of length (L) to particle size (dp)

remains constant or varies not more than 25% with respect to the ratio

obtained with the column prescribed in the monograph. When particlesize is not mentioned in the monograph, the ratio must be calculated

column.

,

require adjustment:

F2 = F1 (dc22 dp1) / (dc1

2 dp2)

Where F1 and F2 are the flow rates for the original and modifiedconditions, respectively; dc1 and dc2 are the respective column

diameters, and d 1 and d 2 are the particle sizes.

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PF 37(3) May-Jun 2011

1

2

2

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dpdcFF

=

Relative Values

21 pc

L, mm dc, mm dp, m L/dp F N Pressure Time

250 4.6 10 25,000 0.5 0.8 0.2 3.3

150 4.6 5 30,000 1.0 1.0 1.0 1.0

150 2.1 5 30,000 0.2 1.0 1.0 1.0

. . , . . . .

100 2.1 3.5 28,600 0.3 1.0 1.9 0.5

75 4.6 2.5 30,000 2.0 1.0 4.0 0.3

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75 2.1 2.5 30,000 0.4 1.0 4.0 0.3

50 4.6 1.7 29,400 2.9 1.0 8.5 0.1


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PF 38(2) Mar-Apr 2012

The proposal for particle size allowances was amended

Additional changes are added:

Allowing the use of a guard column even when it is

not prescribed in the individual monograph.

Under System suitability, it is indicated what type of

.

Allowances to modify the particle size in liquid

chromatography are being modify.

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PF 38(2) Particle size changes

or socra c separa ons, e par c e s ze an or e

length of the column may be modified provided that the

ratio of the column len th L to the article size d

remains constant or into the range between -25% to

+50% of the prescribed L/dp ratio. Alternatively, other

number of theoretical plates (N) is within -25% to +50%,

relative to the prescribed column.

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PF 38(2) Mar-Apr 2012 : Use of Guard column

In LC procedures, a guard column may be used with the

following requirements, unless otherwise is indicated in

e n v ua monograp :

(a) the length of the guard column must be NMT 15%

of the length of the analytical column, and

analytical column (e.g., silica) and contain the same

bonded phase (e.g., C18).

In any case, all system suitability requirements specified

in the official procedure must be met with the guard

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column installed


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PF 38(2)Mar-Apr 22012: Isocratic vs gradient

Ad ustments to chromato ra hic conditions: Isocratic vs

gradient

gradient elution may cause changes in selectivity and

should be made with caution. If adjustments arenecessary, c ange n co umn pac ng ma n a n ng e

same chemistry), the duration of an initial isocratic hold

when rescribed , and/or dwell volume ad ustments are

allowed. Additional allowances for gradient adjustmentare noted in the text below.

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PF 38(2)Mar-Apr2012: Isocratic vs gradient

Adjustment Isocratic Gradient

pH of Mobile Phase Allowed Allowed

Concentration of Salts in Buffer Allowed Allowed

Ratio of Components in Mobile

Phase

Allowed Not allowed

Column dimensions (length,

diameter)Allowed Not allowed

Particle size Allowed Not allowed

Flow rate Allowed Not allowed

Injection volume Allowed Not allowed

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Additional Committee activities on

Stimuli article to be published in PF 38(3) May-

June 2012: Signal-to-Noise Measurements from

Chromatographic Data by John V. Hinshaw and John

W. Dolan

The article discuss the correlation between manual

and electronic (root-mean-square, RMS)

Currently in USP: S/N = 2H/h

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Stimuli article published in PF 38(3) [May-June 2012]:Signal-to-Noise Measurements from Chromatographic Data

Recommendations:

Definition of S/N: S/N = S/Np-p

The signal should be measured from the best estimate of the

center of the noise band to the highest point on the peak.

the noise measurement should be taken over an interval of 5

half-height peak widths or 30 s, whichever is larger.

RMS noise should not be used as the primary definition of S/N

The use a conversion factor to convert p-p noise

measurements to RMS ones or vice versa, is discouraged as

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Harmonization activities under the PDG initiated

EP is the leading pharmacopeia for this chapter

At this time pharmacopeias are evaluating Stage 3 draft

Some sections are easy to harmonize, others not so easy

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Comparison USP and EP

Parameter USP EP

Requirement after Chrom system Verification Meeting SS

a us men necessary requ remen s

adequate

Particle Size L/dp = constant 50% reduction

Internal diameter Change allowed as

long as linear

velocit is ke t

+ 25%

constant

Injection volume Decrease or

increase

Only decrease

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(proposed)


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Topics

Proposed Revisions to Chromatography

- -

revision proposal in PF 37(3) MayJune 2011 revision proposal in PF 38(2) Mar-Apr 2012

Harmonization of Chromatography with EP & JP

Validation Verification Method Transfer Chapters

DefinitionsEquivalent or Better concept


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Validation - Verification - Transfer

Validation of Compendial ProceduresValidation will be required when

an analytical procedure is used to test a non-official article.

an official article is tested using an alternative procedure (seeUSP General Notices 6.30).

Verification of Compendial Procedures

Verification will be required the first time an official article is testedusing a USP procedure.

Transfer of Anal tical Procedures

Transfer will applies when a non-compendial procedure is movedfrom one lab to another.

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Definitions for Validation & Verification

Validation of Compendial Procedures:

users of analytical methods described in the USP-NF arenot required to validate accuracy and reliability of these,

conditions of use. [21 CFR 211.194(a)(2)]

< > er ca on o ompen a roce ures:Verification consists of assessing selected analyticalperformance characteristics, such as those that are

escr e n c ap er < >, o genera e appropr a e,relevant data rather than repeating the validation process.

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Basic concepts

Validation: Challenges the analytical method using a well

Verification: Challenges the analytical environment using a

Analyst (education, training, experience)

ns rumen

Reagents

Matrix

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Analytical Performance Characteristics

Accuracy

Repeatability Intermediate precision

Re roducibilit

Specificity

Linearity

Robustness

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Verification of Compendial Procedures

Applies to drug substances, drug products, and

.

Application: titrations, chromatographic procedures,

, .

Verification is not required for basic compendial test

is an indication that the compendial procedure is not

appropriate for the article under test.

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Verification

Typical industry practices for verif ication of

compendial procedures

Specificity

Peak purity

Matrix

Accuracy: Recovery in the specification range

Precision: Repeatability in the specification range

LOD: Verification of detection at 50% of the specification

LOQ: Verification of quantitation at 50% of the specification

Usually not needed: Linearity, Range, and Robustness

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Risk-Based Approach

Complexity of the procedureComplexity of the material

Degree and extent of the verification process depends on

level of training and experience of the userthe type of procedure

associated equipment or instrumentation,

article(s) are being tested

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Allowance for alternative procedures in USP

USP 31 - NF 26 General Notices:

omp ance may e e erm ne a so y e use o a erna ve proce ures

choosen for advantages in accuracy, sensitivity, precision, selectivity, oradaptability to automation or computerized data reduction, or in others ecial circumstances. Such alternative or automated rocedure shall bevalidated.

Alternative methods and/or procedures may be used if they provideadvantages in terms of accuracy, sensitivity, precision, selectivity, orada tabilit to automation or com uterized data reduction or in other

special circumstances. Such alternative procedures and methods shallbe validated as described in the general chapter Validation ofCompendial Procedures and must be shown to give

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Equivalent or Better Concept

Option Name Demonstrating Comparison Number of

procedure

considered

1 Acceptable Procedures Acceptable No Many

2 Performance EquivalenceEquivalent or

Better

Yes Many

3 Results Equivalence EquivalentYes

One

Yes

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Reproduced fromAcceptable, equivalent or better approaches for alternatives

to official compendial procedures by W. Hauck et al. PF35(3), 2009


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Definition from the chapter:

The transfer of analytical procedures (TAP), is thedocumented process that qualifies a laboratory (the

receiving unit) to use an analytical test procedure that

,

ensuring that the receiving unit has the procedural

as intended.

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When transfer is needed?

R&D to QC labs

Site A to Site B (same company or not)

QC to Contract lab

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Transfers options

I. Comparative testing

II. Co-validation

III. Revalidation

IV. Transfer waiver

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Comparative testing

Comparative testing the common method

Performed with validated procedures

Requires analysis of a predetermined number ofsamp es o e same o y o e rans err ng an

receiving units.

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Covalidation

Transferring and Receiving units participate in

interlaborator covalidation.

Used when the procedure is not yet fully validated

enera c ap er a a on o ompen a roce ures

provides guidance about which characteristics

are appropriate for testing.

Statistical evaluation of the results may be challenging

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Revalidation

The receiving lab repeats some or all of the validation

performance characteristics

More time consuming and may be more difficult to observe

differences between different sites, operators, and

instruments.

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Transfer Waiver

New product comparable to an existing product

Receiving unit has experience in the test procedures

Analytical procedure transferred is the USP-NFVerification should a l in this case see .

Analytical procedure transferred same or similar to a

.

The personnel in charge of the development, validation

or routine analysis of the product at the sending unitmoved to the receiving unit.

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Procedure Transfer

Transfer

YESValidated?

YESCan transferTransferwaiver

NO NO

Comparative

testing

(Option I)

Is transferring

site available?

Can

comparative testing

to be done?

YES

NOYES

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eva a on

(Option III)

-

(Option II)


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Relationship between Validation / Verification/Transfer

Implementation of a

new procedure

NO

YES

Compendial? NO

YES

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Looking into the future

es a s e an xper ane o genera e

proposals for the revision of , and

New chapters under development: Critical Validation Parameters for Acceptable Procedures

Acceptable Alternative Procedures

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Contact information

Dr. Horacio Pappa

Principal Scientific Liaison, General Chapters

[email protected]

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