1

Risk-Based Analytical Method Validation and Maintenance Strategies

Stephan O. Krause, Ph.D.

Principal Scientist, Regulatory Science, Development

MedImmune

PDA/PCMO Task Force Leader for Analytical Methods and IMP Specifications

2

The Late-Stage Analytical Method Lifecycle: Risk-based Validation and Maintenance Strategies

Agenda:

Part 1 AMV - Readiness Assessment Process Risk-Based AMV Study Designs and Acceptance Criteria

Parts 2-3 Analytical Method Replacement (AMR) Analytical Method Maintenance (AMM)

Part 3 The Analytical Method Transfer (AMT) Process

Krause/PDA, 2012

3

The Analytical Method Life Cycle

Krause/PDA, 2012

An

aly

tica

l Me

tho

d D

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pm

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t

A

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lytic

al M

eth

od

V

alid

atio

n

(Po

st-V

alid

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n) L

ife

Cy

cle

Ste

ps

Select and Design – Establish Intended Use of Analytical Procedure

Development and Optimization

Performance Review, Qualification

Validation Acceptance Criteria

Validation

Post-Validation Life Cycle Steps

Transfer of Methods

Validation Prerequisites Assessment

IdentityImpurity

LimitImpurity Quantity

Assay / Potency

Tech Transfer

Resource Assessment

Standards and Controls

StabilityVerify Product Specifications

Maintenance TransferComparability

StudyOOS/Valiation

Failures

4

SpecificityPrecisionAccuracy

QL/DLLinearityRange

Robustness Data

Regulatory Requirements

Validation Risk Assessment that method meets intended use

StandardsControls

Stability of Reagents, Samples

Existing Knowledge

(Product and Process)

AMV Protocol

No

Is Method ready for

Validation?

Collect more data

and/or optimize method

AMV Acceptance Criteria

Specification to meet

Documented Summary of

Method Performance

Characteristics (Handover Package,

Development Report)

Yes

Documented Intended Use

Example of Assessment Process of AMV Readiness

Krause/PDA, 2012

5

General AMV Risk Assessment Strategy

The purpose of risk assessment(s) for AMV studies is to provide measurable results for:

1) The desired amount of formal validation studies to be executed.

2) The level of method performance needed as manifested in the AMV protocol acceptance criteria.

Krause/PDA, 2012

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Points to Consider in Overall Risk Assessment for Analytical Methods

Points to Consider Examples Expected Potential Risk/Impact

Method type and intended use (Identity, Safety, Purity, Quality, Potency, and Stability)

a. Safety test: Sterility test using new rapid microbial method.b. Quality test: Excipient concentration at final production stage.a. Purity/Stability test: Degradation products during storage.

a. Potential risk to patients and firm is high if sterility test provides false negative results.b. Potential risk to patients is relatively low if the quality test provides inaccurate results as excipient is quantitatively added during production.c. Potential risk to patients is high if stability test is incapable to measure all degradation products.

Surrogate and/or complementary method is routinely used

Purity/Safety test: A HPSEC method is used for quantitation of protein aggregate levels. A second electrophoresis method provides similar results for aggregate levels.

If second method routinely supports the results of the primary method, the risk to patients may be lower if the primary method provides inaccurate results.

Production Process Stage

Purity Test: Fermentation impurities are measured before purification and after purification.

Early-stage inaccurate impurity results from less reliable test method are lower risk to patients if late-stage testing provides more accurate results.

Analytical Platform Technology (APT)

Purity test: APT HPSEC method is used to test in-process samples.

Current QC experience with this method performance should lower the risk to patient and/or firm if the effect of different sample types is insignificant.

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The Six General AMQ Classes and Prospective AMQ Studies

AMQ Class DescriptionTypical Risk /

Uncertainty Level (1=Low, 5=High)

Suggested Prospective AMQ StudiesAMQ

Class No.Analytical Method

Product / Process Sample

A New New 4-5 Full Qualification

B New Old 3-4Full Qualification Plus

Bridging Studies

CAnalytical Platform

Technology (not qualified “as run”)

New 2-3 Partial Qualification

DAnalytical Platform

Technology (qualified)

New 1-2Partial Qualification or

Verification

EAnalytical Platform

Technology (qualified)

Modified(Formulation,

Conc.)1-2 Verification

F Compendial New 1-2Verification per USP

<1226>

8

The Five General AMV Classes and Prospective AMV Studies

AMV Class Description Typical Risk /

Uncertainty Level (1=Low, 5=High)

Suggested Prospective AMV Studies

AMV Class No.

Analytical MethodProduct /

Process Sample

A New New 4-5 Full Validation

B New Old (Validated) 3-4(1) Full Validation Plus AMR(2) Studies

CAnalytical Platform

Technology (not validated “as run”)

New 2-3 Partial Validation

D Old (Validated) New 1-2Partial Validation or

Verification

E Compendial New 1-2Verification per USP

<1226>

(1) If a new analytical method (forced method replacement) is needed due to supply reasons, the risk level can be generally considered higherbecause no other option may exist. Unforced test method replacements can be considered to be a lower risk level as more time may be availableto optimize the method performance.

(2) AMR = Analytical Method Replacement. A study to confirm that a new analytical method can perform equally or better than the existing one.

From Krause, PDA/DHI 2007.

99

FACenter for Biologics Evaluation & ResearchCenter for Biologics Evaluation & ResearchFDAFDA

SafetyMethodsValidated

Qualified Methods

SafetyMethodsValidated

Qualified Methods

ValidatedMethods

ValidatedMethods

Re-Validation(as needed)

Replacement(Supplement)

Re-Validation(as needed)

Replacement(Supplement)

SelectionDesign

Development Optimization

SelectionDesign

Development Optimization

Life Cycle of Analytical MethodsLife Cycle of Analytical MethodsLife Cycle of Analytical MethodsLife Cycle of Analytical Methods

Phase 1Phase 1 Phase 2Phase 2Discovery/Pre-clinicalDiscovery/Pre-clinical Phase 3Phase 3 BLA BLA Post-LicensurePost-Licensure

PerformanceCharacteristics

Robustness

PerformanceCharacteristics

Robustness

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CQA Development, CMC Changes, Specifications

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FTIH POC BLA

Tox StudiesPhase 1

Phase 2Phase 3

Clinical ResupplyMfg/Formulation Change(s)

Specifications Revision(s)

Target Quality CriteriaCommercial

Specifications

Negotiations, Final Commercial Specifications

QTPP

Final CQAs & Control Strategy Approval

Potential CQAsProduct & Process Design

Life-CycleManagement

POST-APPROVALCHANGES

PHASE 3PHASE 1/2Pre-IND

CQ

A D

evel

op

men

t(Q

bD

Pro

cess

)S

pec

s L

ife

Cyc

le

Mg

mt

CM

C a

nd

Tec

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Tra

nsf

er P

roce

ss Analytical

Manufacturing

Strategic or Tactical Changes

Method qualification

Dose change

Delivery Device

PQ lots

Setting of Initial Specifications

Specifications Review/Confirmation

Mfg Transfer

Method validation

Method transfer

Formulation Change

Process Verification

Method Maintenance

Global Supply

Method transfer

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Analytical Method Lifecycle – Intended Use

Analytical Method Selection

Pharmaceutical Development Supporting Studies:Process characterizationProduct characterizationProcess validation

Routine Testing (registered methods):Raw materialsIn-process Release Stability

Intended Use (defined)

AMD Studies

AMD Studies

AMQ ReportAMQ ReportIntended Use (re-defined)

AMV Report

IdentitySafetyPurityQualityPotency

Quality Target Product Profile (QTPP)Critical Quality Attributes (CQA)

Critical Process Parameters (CPP)

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Risk-Based AMV Protocol Acceptance Criteria

Specifications

Consider Type of

Specifications

Acceptance Criteria

Existing Knowledge

One-Sided Specifications(NMT, NLT, LT)

Two-Sided Specifications

(Range)

Regulatory Requirements

Historical Method

Performance

Historical Data from this

Product and Process

Knowledge from Similar Product and

Process

Krause/PDA, 2012

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Analytical Method Replacement (AMR) Categories from ICH E9 (and USP <1033> for Equivalence)

Equivalence

Non-inferiority

Superiority

Krause/PDA, 2012

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Analytical Method Replacement Suggested Performance Comparison Characteristics and Statistics

ICH Q2(R1) Category

Identification Test

(Qualitative)

Limit Test (Qualitative)

Limit Test (Quantitative)

Potency or Content (Purity

or Range) (Quantitative)

Accuracy Not Required Not Required TOST; Some Data could be at QL level

TOST

Intermediate Precision

Not Required Not Required ANOVA, mixed linear model, or other variance component analysis

ANOVA, mixed linear model, or other variance component analysis

Specificity Probability and/or Chi-Squared for Number of Correct Observations

Probability and/or Chi-Squared for Number of Correct Observations

Not Required Not Required

Detection Limit

Not Required Depends on how DL was established. Probability calculations may be used

Not Required Not Required

Krause/PDA, 2012

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Demonstrating Equivalence

Equ

ival

ence

Lim

it

-90

% C

I

- Delta 0 + Delta

+90

% C

I New Method

“Lower Results”New Method

“Higher Results”

Equ

ival

ence

Lim

it

No difference

Mea

n D

iffer

enc

e

Equivalence Testing (ICH E9)Current Method = ReferenceEquivalence Demonstrated

Krause/PDA, 2012

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Demonstrating Non-Inferiority

Non

-Inf

erio

rity

Lim

it

-95

% C

I

- Delta 0

+95

% C

I

Current Method “Better Results”

New Method “Better Results”

No difference

Mea

n D

iffer

ence

Non-inferiority Testing (ICH E9)Current Method = ReferenceNon-Inferiority Demonstrated

Desirable Direction/Range

Krause/PDA, 2012

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Demonstrating Superiority

-95

% C

I

0

+95

% C

I

Current Method “Better Results”

New Method “Better Results”No difference

Mea

n D

iffer

ence

Superiority Testing (ICH E9)Current Method = Reference

Superiority Demonstrated

Sup

erio

rity

Lim

it (0

)

Desirable Direction/Range

Krause/PDA, 2012

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Demonstrating EquivalenceSimplified Case Study

Because of anticipated supply problems for critical SDS-PAGE materials, it was decided to develop and validate a capillary zone electrophoresis (CZE) method that will replace the current (licensed) electrophoretic method. The method performance characteristics for a quantitative limit test, accuracy and intermediate precision, are compared. For accuracy: A delta of plus/minus 1.0% was chosen for the equivalence category between both impurity levels. The 1.0% difference limit was set because a future result difference of 1.0% is still acceptable within the existing release and stability specifications (acceptable patient and mfger’s risks). Both methods were run simultaneously (side-by-side) for each of a total of n=30 reported results were compared by two-sided matched-paired t-test statistics with pre-specified equivalence limits of plus/minus 1.0% (% = reported percent and not relative percent).

Krause/PDA, 2012

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Demonstrating Equivalence Results

Equivalence Test Results Comparing Current Method to CZE: Sample Size (n): 30 Hypothesized Difference in Mean: 0% Minus Delta: -1.0% Plus Delta: +1.0% SDS-PAGE Mean (n=30): 3.8% CZE Mean (n=30): 5.1% 90% confidence interval of CZE results (vs. SDS-PAGE): 4.88-5.32%

Krause/PDA, 2012

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Equivalence of New Method Not Demonstrated(New method’s result are different)

Krause/PDA, 2012

Equ

ival

ence

Lim

it

- Delta 0 + Delta

New Method “Lower Results”

New Method “Higher Results”

Equ

ival

ence

Lim

it

No difference

- 9

0% C

I

+ 9

0% C

I

- 9

0% C

I

+ 9

0% C

I

- 9

0% C

I

+ 9

0% C

I

- 9

0% C

I

+ 9

0% C

I

- 9

0% C

I

+ 9

0% C

I Passes Equivalence (stat. different)

Passes Equivalence (stat. not different)

Passes Equivalence (stat. different)

Equivalence Unclear(stat. different)

Fails Equivalence (stat. different)

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Analytical Method Maintenance (AMM)

VMP for Analytical Methods

AMC AMM

AMVProcess Map Steps

Method Modifications Method Review

Critical Method Elements

Standards and Controls Critical Reagents

Software/Computer Analytical Instrumentation

Statistical Data Reduction New/Additional Operator

Emergency Reviews(OOS, many invalids)

Periodic Reviews(Short and Long Term)

Quarterly or Annual Reviews Extensive Reviews

Prospective Retrospective

Krause, 2005.

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AMM - Continuous Review Example: Combining Laboratory and Manufacturing Control Charts

88

92

96

100

104

108

112

0 10 20 30 40 50 60

Sequential Batches Tested (last n=60)

Po

ten

cy

(in

un

its

/mL

)

SPC

Assay Control

Upper Specifications

Lower Specifications

SPC Mean

(101.0 units/mL)

Assay ControlMean (99.0 units/mL)

Krause/PDA/DHI, 2007.

24

AMM - Simplified Example: Extensive Method Performance Evaluation

Krause/PDA/DHI, 2007.

AMV and Method Performance Verification Checklist Results Comments

Test Method Number/Title/Revision:

Process Step/Product Sampling Point(s):

Most Recent Validation/Verification Date:

Specifications Supported:

ICH Q2(R1) Test Method Category:

Suitable Overall Performance Demonstrated in AMV Report ?

Changes to Test System After AMV Studies ?If yes, provide more information:

Number of Valid Test Runs Over Last 12 Months

Number of Invalid Test Runs Over Last 12 Months

Calculate Invalid Rate/Percentage:

Current System Control Limits (ex., 3 Standard Deviations):

Test System in Control ?

Method Performance Acceptable ?If no, provide more information:

QC Signature:

QA Signature: