Risk-Based Strategies for Analytical Method Qualification ...c.ymcdn.com/sites/ · PDF fileRisk-Based Strategies for Analytical Method Qualification/Validation Studies ... Transfer

Risk-Based Strategies for Analytical

Method Qualification/Validation Studies

to Support Accelerated

Product Development

Stephan Krause

Principal Scientist, MedImmune

27 January 2014

CASSS CMC Strategy Forum

Washington, DC

2

Outline

Review of Strategic Opportunities to Reduce Analytical Method Lifecycle

Steps for Accelerated Programs for:

– Analytical Platform Technology (APT) methods

– Product and Process Characterization methods

– Product-Specific (‘New”) methods

– Compendial methods

Understand how analytical platform technology concepts can greatly

support accelerated development programs.

Understand how parallel (versus sequential) analytical method lifecycle

steps can further support these programs.

Presentation to Focus on Late-Stage Development Opportunities:

– Mostly Risk(s) to Manufacturer/Sponsor

2 Krause/PDA TR 57 (2012)

3

CQA Development, CMC Changes, and Specifications

FTIH POC BLA

Tox StudiesPhase 1

Phase 2Phase 3

Clinical Resupply

Mfg/Formulation Change(s)

Specifications

Revision(s)

Target Quality Criteria

Commercial

Specifications

Negotiations, Final

Commercial Specifications

QTPP

Final CQAs &

Control Strategy ApprovalPotential CQAs

Product & Process

Design

Life-Cycle

ManagementPOST-APPROVAL

CHANGESPHASE 3PHASE 1/2Pre-IND

CQ

A D

ev

elo

pm

en

t

(Qb

D P

roc

es

s)

Sp

ec

s L

ife

Cy

cle

Mg

mt

CM

C a

nd

Te

ch

Tra

ns

fer

Pro

ce

ss

Analytical

Manufacturing

Strategic or

Tactical Changes

Method

qualification

Dose

change

Delivery

Device

PQ lots

Setting of Initial

SpecificationsSpecifications

Review/Confirmation

Mfg

Transfer

Method

validation

Method

transfer

Formulation

ChangeProcess Verification

Method

Maintenance

Global

Supply

Krause/WCBP January 2013

4

Accelerated CQA Development, CMC Changes, and Specifications

FTIH POC BLA

Tox StudiesPhase 1

Phase 3

Clinical Resupply

Mfg/Formulation Change(s)

Specifications

Revision(s)

Commercial

Specifications

Negotiations, Final

Commercial Specifications

QTPP

Final CQAs &

Control Strategy Approval Potential CQAs

Product & Process

Design

Life-Cycle

ManagementPOST-APPROVAL

CHANGESPIVOTAL PHASE (3)PHASE 1 Pre-IND

CQ

A D

ev

elo

pm

en

t

(Qb

D P

roc

es

s)

Sp

ec

s L

ife

Cy

cle

Mg

mt

CM

C a

nd

Te

ch

Tra

ns

fer

Pro

ce

ss

Analytical

Manufacturing

Strategic or

Tactical Changes

Method

qualification

Dose

change

Delivery

Device

PQ

lots

Setting of Initial

SpecificationsSpecifications

Review/Confirmation

Mfg

Transfer

Method

validation

Method

transfer

Formulation

ChangeProcess Verification

Method Maintenance

Global

Supply

Method

Change

Accelerated Development

5

Analytical Method Lifecycle – Intended Use

Analytical Method

Selection

Pharmaceutical Development Supporting Studies:

Process characterization

Product characterization

Process validation

Routine Testing (registered methods):

Raw materials

In-process

Release

Stability

Intended Use

(defined)

AMD

Studies

AMD

Studies

AMQ ReportAMQ ReportIntended Use

(re-defined)

AMV Report

Identity

Safety

Purity

Quality

Potency

Quality Target Product Profile (QTPP)

Critical Quality Attributes (CQA)

Critical Process Parameters (CPP)

Krause/PDA TR 57 (2012)

6

Retrospective and Prospective Use of Data for AMV Studies from

other Processes Prior to AMV – New Method

Krause/PDA Workshop (2013)

7

Retrospective and Prospective Use of Data for AMV Studies from

other Processes Prior to AMV – Analytical Platform Method

Method

Qualification

(AMQ)

Method Validation

(AMV)

Method Transfer

(AMT)

(Less)

AMQ

Studies

“Verification”

Focus on:

Accuracy,

Specificity

PVFTIH BLA

Historical

Data - SU

Assay

Control

Tech

Transfer

(Less)

Interm.

Precision

& Reprod.

Historical

Data - RU

Assay

Control

“Approved”

Method

Krause/PDA Workshop (2013)

Ideal Analytical Method Lifecycle Clinical Phase 1-2 (prior to transfer from Pilot to Commercial Plant)

8

DS/DP

Specification

Test Methods

for New Method

Robustness

Studies Execution

QCDev.

AMVStudies

(QC-Comm.)

Start PV

Stage 2(PQ Lots)

Completed

In progress

Not started

AMV completed

Maintenance

(QC-Comm.)

Robustness

StudiesMaster Plan

AMT Studies

(QC-Dev. &

QC-Comm.)

SOP-specific

Min/Max Method

Conditions

(for PB Design)

Commercial

Specifications

Not Parallel Step

Process Color

Legend:

Method Qualified

(SOP Lock)

Ideal Analytical Method Lifecycle Preparing for Tech Transfer (Pilot to Commercial Plant)

9

DS/DP

Specification

Test Methods

for New Method

Robustness

Studies Execution

QCDev.

AMVStudies

(QC-Comm.)

Start PV

Stage 2(PQ Lots)

Completed

In progress

Not started

AMV completed

Maintenance

(QC-Comm.)

Robustness

StudiesMaster Plan

AMT Studies

(QC-Dev. &

QC-Comm.)

SOP-specific

Min/Max Method

Conditions

(for PB Design)

Commercial

Specifications

Not Parallel Step

Process Color

Legend:

Method Qualified

(SOP Lock)


10

DS/DP

Specification

Test Methods

for New Method

Robustness

Studies Execution

QCDev.

AMVStudies

(QC-Comm.)

Start PV

Stage 2(PQ Lots)

Completed

In progress

Not started

AMV completed

Maintenance

(QC-Comm.)

Robustness

StudiesMaster Plan

AMT Studies

(QC-Dev. &

QC-Comm.)

SOP-specific

Min/Max Method

Conditions

(for PB Design)

Commercial

Specifications

Not Parallel Step

Process Color

Legend:

Method Qualified

(SOP Lock)


11

DS/DP

Specification

Test Methods

for New Method

Robustness

Studies Execution

QCDev.

AMVStudies

(QC-Comm.)

Start PV

Stage 2(PQ Lots)

Completed

In progress

Not started

AMV completed

Maintenance

(QC-Comm.)

Robustness

StudiesMaster Plan

AMT Studies

(QC-Dev. &

QC-Comm.)

SOP-specific

Min/Max Method

Conditions

(for PB Design)

Commercial

Specifications

Not Parallel Step

Process Color

Legend:

Method Qualified

(SOP Lock)

Ideal Analytical Method Lifecycle Preparing for PQ (at Commercial Plant)

12

DS/DP

Specification

Test Methods

for New Method

Robustness

Studies Execution

QCDev.

AMVStudies

(QC-Comm.)

Start PV

Stage 2(PQ Lots)

Completed

In progress

Not started

AMV completed

Maintenance

(QC-Comm.)

Robustness

StudiesMaster Plan

AMT Studies

(QC-Dev. &

QC-Comm.)

SOP-specific

Min/Max Method

Conditions

(for PB Design)

Commercial

Specifications

Not Parallel Step

Process Color

Legend:

Method Qualified

(SOP Lock)

Ideal Analytical Method Lifecycle Preparing for PQ (at Commercial Plant)

13

DS/DP

Specification

Test Methods

for New Method

Robustness

Studies Execution

QCDev.

AMVStudies

(QC-Comm.)

Start PV

Stage 2(PQ Lots)

Completed

In progress

Not started

AMV completed

Maintenance

(QC-Comm.)

Robustness

StudiesMaster Plan

AMT Studies

(QC-Dev. &

QC-Comm.)

SOP-specific

Min/Max Method

Conditions

(for PB Design)

Commercial

Specifications

Not Parallel Step

Process Color

Legend:

Method Qualified

(SOP Lock)

Ideal Analytical Method Lifecycle Executing PQ Studies (at Commercial Plant)

14

DS/DP

Specification

Test Methods

for New Method

Robustness

Studies Execution

QCDev.

AMVStudies

(QC-Comm.)

PQ Lots

Mfg

Completed

In progress

Not started

AMV completed

Maintenance

(QC-Comm.)

Robustness

StudiesMaster Plan

AMT Studies

(QC-Dev. &

QC-Comm.)

SOP-specific

Min/Max Method

Conditions

(for PB Design)

Commercial

Specifications

Not Parallel Step

Process Color

Legend:

Method Qualified

(SOP Lock)

Analytical Method Lifecycle APT Opportunities following AMV Study Completion

15

DS/DP

Specification

Test Methods for

Same SOP and

New Product

Robustness

Studies Execution

QCDev.

AMVStudies

(QC-Comm.)

PQ Lots

Mfg

Completed

In progress

Not started

AMV completed

Maintenance

AMM

(QC-Comm.)

Robustness

StudiesMaster Plan

AMT Studies

(QC-Dev. &

QC-Comm.)

SOP-specific

Min/Max Method

Conditions

(for PB Design)

Commercial

Specifications

Not Parallel Step

APT MethodAMV and AMM

(QC)

Analytical Platform

Technology

APT

Method Robustness

and AMT

Process Color

Legend:

Method Qualified

(SOP Lock)

APT

Method AMQ

Analytical Method Lifecycle for Accelerated Programs APT Opportunities following prior AMV Study Completion

16

DS/DP

Specification

APT Test Methods

(not compendial)

APT Transfer

(feasibility only,

no formal AMT)

Partial

AMV Study

Execution

Start PV Stage 2

(PQ Lots)

APT

Maintenance

VMP Analytical

Methods

APT

Qualification

Studies

Commercial

Specifications

APT

Robustness(QC-Dev.)

Feasibility

Testing

(QC-Comm.)

Simultaneous ?

Simultaneous ?

Completed

In progress

Not started

AMV completed

Not Parallel Step

Analytical Platform

Technology

Process Color

Legend:

Analytical Method Lifecycle for Accelerated Programs Additional APT Opportunities

17

Qualification of

Test Methods

Process and/or

Product

Characterization

Representative

Samples

Available (Dev.)

Execution Reqs: (1. IOQ Instrument)

(2. Analyst Training)

3. Final SOP version

QC Dev. or

QC Comm.

Confirm

Method

Suitability

Start PV

Stage 2(PQ Lots)

Qualify (as relevant):A. Accuracy/Matching

B. Precision/Reliability

C. Specificity

D. DL or QL

Qualification

Report(s)

Method

Qualification

Master Plan

Final PV Process Ranges and/or

Analytical Control Strategy

APT (Reduced)

Qualification

Opportunity

Completed

In progress

Not started

AMV completed

Not Parallel Step

Analytical Platform

Technology

Process Color

Legend:

Analytical Method Lifecycle for Accelerated Programs Limited APT Opportunities

18

DS/DP

Specification

Test Methods

Compendial

Representative

DS/DP Samples

(from QC-Dev.

or QC-Comm.)

Execution Reqs: 1. IOQ Instrument

2. Analyst Training

3. Qualified Material

4. Final SOP version

Start PV

Stage 2(PQ Lots)

Completed

In progress

Not started

AMV

completed

Verify (as relevant):A. Accuracy/Matching

B. Precision/Reliability

C. Specificity

D. DL or QL

Verification

Report(s)

Method

Verification

Master Plan

Commercial

Specifications

Not Parallel Step

Process Visual Legend:

QC

Comm.

Risk/Uncertainty Levels and Risk-Based Opportunities (Typical) (Analytical Method Lifecycle Steps in Typical Order)

19

AMQ-Robustness-AMT-AMV

Class Description Typical

Risk /

Uncertainty

Level

(1=Low,

5=High)

Suggested

Prospective

AMQ Studies

(QC-Dev.)

Suggested

Prospective

Robustness

Studies

(QC-Dev.)

Suggested

Prospective

AMT Studies

(QC-Dev./ QC-

Comm.)

Suggested

Prospective

AMV Studies

(QC Comm.) No. Analytical

Method

Product /

Process

Sample

A New New 4-5 Full

Qualification

Full

Robustness

Studies

Full AMT

studies Full Validation

B New Old

(Validated) 3-4(1)

Full

Qualification

Plus AMC(2)

Studies

Full

Robustness

Studies

Full AMT

Studies

Full Validation

Plus AMC(2)

Studies

C

Analytical

Platform

Technology

New 1-2 Qualification Robustness

Studies AMT Studies Validation

D Compendial New 1-2

Verification

per USP

<1226>

N/A N/A

Verification

per USP

<1226>

E

Product/Process

Charaterization

Tests

New 2-3 Qualification N/A N/A N/A

(1) If a new analytical method (forced method replacement) is needed due to supply reasons, the risk level can be generally considered higher

because no other option may exist. Unforced test method replacements can be considered to be a lower risk level as more time may be available

to optimize the method performance.

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

Krause/PDA-DHI Publications, 2007, PDA TR 57 (2012)

Risk/Uncertainty Levels and Risk-Based Opportunities (Typical) (Analytical Method Lifecycle Steps in Typical Order)

20



Risk /

Uncertainty

Level

(1=Low,

5=High)

Suggested

Prospective

AMQ Studies

(QC-Dev.)

Suggested

Prospective

Robustness

Studies

(QC-Dev.)

Suggested

Prospective

AMT Studies

(QC-Dev./ QC-

Comm.)

Suggested

Prospective

AMV Studies

(QC Comm.) No. Analytical

Method

Product /

Process

Sample

A New New 4-5 Full

Qualification

Full

Robustness

Studies

Full AMT


B New Old

(Validated) 3-4(1)

Full

Qualification

Plus AMC(2)

Studies

Full

Robustness

Studies

Full AMT

Studies

Full Validation

Plus AMC(2)

Studies

C

Analytical

Platform

Technology

New 1-2 Qualification Robustness

Studies AMT Studies Validation

D Compendial New 1-2

Verification

per USP

<1226>

N/A N/A

Verification

per USP

<1226>

E

Product/Process

Charaterization

Tests

New 2-3 Qualification N/A N/A N/A






Risk/Uncertainty Levels and Risk-Based Opportunities for APT Methods (Analytical Method Lifecycle Steps in Typical Order)

21



Risk /

Uncertainty

Level

(1=Low,

5=High)

Suggested

Prospective

AMQ Studies

(QC-Dev.)

Suggested

Prospective

Robustness

Studies

(QC-Dev.)

Suggested

Prospective

AMT Studies

(QC-Dev./ QC-

Comm.)

Suggested

Prospective

AMV Studies

(QC Comm.) Analytical

Method

Product /

Process

Sample

New New 4-5 Full

Qualification

Full

Robustness

Studies

Full AMT


Analytical

Platform

Technology

New 1-2

APT

(Reduced)

Qualification

APT

(Reduced)

Robustness

Studies

APT

(Reduced)

AMT Studies

APT

(Reduced)

Validation

Compendial New 1-2

Verification

per USP

<1226>

N/A N/A

Verification

per USP

<1226>

Product/Process

Charaterization

Tests

New 2-3

Reduced

Qualification

(if APT)

N/A N/A N/A







22



Risk /

Uncertainty

Level

(1=Low,

5=High)

Suggested

Prospective

AMQ Studies

(QC-Dev.)

Suggested

Prospective

Robustness

Studies

(QC-Dev.)

Suggested

Prospective

AMT Studies

(QC-Dev./ QC-

Comm.)

Suggested

Prospective

AMV Studies


Method

Product /

Process

Sample

New New 4-5 Full

Qualification

Full

Robustness

Studies

Full AMT


Analytical

Platform

Technology

New 1-2

APT

(Reduced)

Qualification

APT

(Reduced)

Robustness

Studies

APT

(Reduced)

AMT Studies

APT

(Reduced)

Validation

Compendial New 1-2

Verification

per USP

<1226>

N/A N/A

Verification

per USP

<1226>

Product/Process

Charaterization

Tests

New 2-3

Reduced

Qualification

(if APT)

N/A N/A N/A







23



Risk /

Uncertainty

Level

(1=Low,

5=High)

Suggested

Prospective

AMQ Studies

(QC-Dev.)

Suggested

Prospective

Robustness

Studies

(QC-Dev.)

Suggested

Prospective

AMT Studies

(QC-Dev./ QC-

Comm.)

Suggested

Prospective

AMV Studies


Method

Product /

Process

Sample

New New 4-5 Full

Qualification

Full

Robustness

Studies

Full AMT


Analytical

Platform

Technology

New 1-2

APT

(Reduced)

Qualification

APT

(Reduced)

Robustness

Studies

APT

(Reduced)

AMT Studies

APT

(Reduced)

Validation

Compendial New 1-2

Verification

per USP

<1226>

N/A N/A

Verification

per USP

<1226>

Product/Process

Charaterization

Tests

New 2-3

Reduced

Qualification

(if APT)

N/A N/A N/A







24



Risk /

Uncertainty

Level

(1=Low,

5=High)

Suggested

Prospective

AMQ Studies

(QC-Dev.)

Suggested

Prospective

Robustness

Studies

(QC-Dev.)

Suggested

Prospective

AMT Studies

(QC-Dev./ QC-

Comm.)

Suggested

Prospective

AMV Studies


Method

Product /

Process

Sample

New New 4-5 Full

Qualification

Full

Robustness

Studies

Full AMT


Analytical

Platform

Technology

New 1-2

APT

(Reduced)

Qualification

APT

(Reduced)

Robustness

Studies

APT

(Reduced)

AMT Studies

APT

(Reduced)

Validation

Compendial New 1-2

Verification

per USP

<1226>

N/A N/A

Verification

per USP

<1226>

Product/Process

Charaterization

Tests

New 2-3

Reduced

Qualification

(if APT)

N/A N/A N/A







25



Risk /

Uncertainty

Level

(1=Low,

5=High)

Suggested

Prospective

AMQ Studies

(QC-Dev.)

Suggested

Prospective

Robustness

Studies

(QC-Dev.)

Suggested

Prospective

AMT Studies

(QC-Dev./ QC-

Comm.)

Suggested

Prospective

AMV Studies


Method

Product /

Process

Sample

New New 4-5 Full

Qualification

Full

Robustness

Studies

Full AMT


Analytical

Platform

Technology

New 1-2

APT

(Reduced)

Qualification

APT

(Reduced)

Robustness

Studies

APT

(Reduced)

AMT Studies

APT

(Reduced)

Validation

Compendial New 1-2

Verification

per USP

<1226>

N/A N/A

Verification

per USP

<1226>

Product/Process

Charaterization

Tests

New 2-3

Reduced

Qualification

(if APT)

N/A N/A N/A






Risk-Based Opportunities for New Methods

(Analytical Method Lifecycle Steps in Typical Order)

26



Risk /

Uncertainty

Level

(1=Low,

5=High)

Suggested

Prospective

AMQ Studies

(QC-Dev.)

Suggested

Prospective

Robustness

Studies

(QC-Dev.)

Suggested

Prospective

AMT Studies

(QC-Dev./ QC-

Comm.)

Suggested

Prospective

AMV Studies


Method

Product /

Process

Sample

New New 4-5 Full

Qualification

Full

Robustness

Studies

Full AMT


Analytical

Platform

Technology

New 1-2

APT

(Reduced)

Qualification

APT

(Reduced)

Robustness

Studies

APT

(Reduced)

AMT Studies

APT

(Reduced)

Validation

Compendial New 1-2

Verification

per USP

<1226>

N/A N/A

Verification

per USP

<1226>

Product/Process

Charaterization

Tests

New 2-3

Reduced

Qualification

(if APT)

N/A N/A N/A






Risk-Based Opportunities for New Methods

(Analytical Method Lifecycle Steps in Typical Order)

27



Risk /

Uncertainty

Level

(1=Low,

5=High)

Suggested

Prospective

AMQ Studies

(QC-Dev.)

Suggested

Prospective

Robustness

Studies

(QC-Dev.)

Suggested

Prospective

AMT Studies

(QC-Dev./ QC-

Comm.)

Suggested

Prospective

AMV Studies


Method

Product /

Process

Sample

New New 4-5 Full

Qualification

Full

Robustness

Studies

Full AMT


Analytical

Platform

Technology

New 1-2

APT

(Reduced)

Qualification

APT

(Reduced)

Robustness

Studies

APT

(Reduced)

AMT Studies

APT

(Reduced)

Validation

Compendial New 1-2

Verification

per USP

<1226>

N/A N/A

Verification

per USP

<1226>

Product/Process

Charaterization

Tests

New 2-3

Reduced

Qualification

(if APT)

N/A N/A N/A






28

Summary

Opportunities exist to reduce typical analytical method lifecycle

steps for accelerated programs.

Use of (analytical) platform technology can greatly support

accelerated development programs.

Reduction and/or use of “parallel” analytical method lifecycle steps

during later-stage development (prior to PV stage 2) results in risk(s)

mostly to manufacturer/sponsor and not the patient.

28

Documents

Risk-Based Strategies for Analytical Method Qualification ...c.ymcdn.com/sites/ · PDF fileRisk-Based Strategies for Analytical Method Qualification/Validation Studies ... Transfer