CASSS CMC Strategy Forum Slides for 27Jan14 - SK21Jan14

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

2Krause/PDA TR 57 (2012)

3

CQA Development, CMC Changes, and Specifications

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

h

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

Krause/WCBP January 2013

4

Accelerated CQA Development, CMC Changes, and Specifications

FTIH POC BLA

Tox StudiesPhase 1

Phase 3

Clinical ResupplyMfg/Formulation Change(s)

Specifications Revision(s)

Commercial Specifications

Negotiations, Final Commercial Specifications

QTPP

Final CQAs & Control Strategy Approval

Potential CQAsProduct & Process Design

Life-CycleManagement

POST-APPROVALCHANGES

PIVOTAL PHASE (3)PHASE 1 Pre-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

h

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 Change

Accelerated Development

5

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

IdentitySafetyPurity

QualityPotency

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/DPSpecificationTest 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 Studies

Master Plan

AMT Studies

(QC-Dev. & QC-Comm.)

SOP-specific Min/Max Method

Conditions (for PB Design)


Not Parallel Step

Process Color Legend:

Method Qualified

(SOP Lock)

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

9


for New Method


QCDev.

AMVStudies

(QC-Comm.)


Completed

In progress

Not started

AMV completed


Robustness Studies

Master Plan

AMT Studies





Not Parallel Step


Method Qualified

(SOP Lock)


10


for New Method


QCDev.

AMVStudies

(QC-Comm.)


Completed

In progress

Not started

AMV completed


Robustness Studies

Master Plan

AMT Studies





Not Parallel Step


Method Qualified

(SOP Lock)


11


for New Method


QCDev.

AMVStudies

(QC-Comm.)


Completed

In progress

Not started

AMV completed


Robustness Studies

Master Plan

AMT Studies





Not Parallel Step


Method Qualified

(SOP Lock)

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

12


for New Method


QCDev.

AMVStudies

(QC-Comm.)


Completed

In progress

Not started

AMV completed


Robustness Studies

Master Plan

AMT Studies





Not Parallel Step


Method Qualified

(SOP Lock)

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

13


for New Method


QCDev.

AMVStudies

(QC-Comm.)


Completed

In progress

Not started

AMV completed


Robustness Studies

Master Plan

AMT Studies





Not Parallel Step


Method Qualified

(SOP Lock)

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

14


for New Method


QCDev.

AMVStudies

(QC-Comm.)

PQ Lots Mfg

Completed

In progress

Not started

AMV completed


Robustness Studies

Master Plan

AMT Studies





Not Parallel Step


Method Qualified

(SOP Lock)

Analytical Method Lifecycle APT Opportunities following AMV Study Completion

15

DS/DPSpecification

Test Methods for Same SOP andNew Product


QCDev.

AMVStudies

(QC-Comm.)

PQ Lots Mfg

Completed

In progress

Not started

AMV completed

MaintenanceAMM

(QC-Comm.)

Robustness Studies

Master Plan

AMT Studies





Not Parallel Step

APT MethodAMV and AMM

(QC)

Analytical Platform Technology

APT Method

Robustness and AMT


Method Qualified

(SOP Lock)

APT Method

AMQ

Analytical Method Lifecycle for Accelerated ProgramsAPT Opportunities following prior AMV Study Completion

16

DS/DP Specification

APT Test Methods (not compendial)

APT Transfer (feasibility only, no formal AMT)

Partial AMV StudyExecution

Start PV Stage 2

(PQ Lots)

APT Maintenance

VMP Analytical Methods

APT Qualification

Studies


APT Robustness

(QC-Dev.)

Feasibility Testing

(QC-Comm.)

Simultaneous ?

Simultaneous ?

Completed

In progress

Not started

AMV completed

Not Parallel Step



Analytical Method Lifecycle for Accelerated ProgramsAdditional 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


Qualify (as relevant):A. Accuracy/MatchingB. Precision/Reliability

C. SpecificityD. 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 Method Lifecycle for Accelerated ProgramsLimited APT Opportunities

18

DS/DPSpecificationTest MethodsCompendial

Representative DS/DP Samples (from QC-Dev. or QC-Comm.)

Execution Reqs: 1. IOQ Instrument2. Analyst Training

3. Qualified Material4. Final SOP version


Completed

In progress

Not started

AMV completed

Verify (as relevant):A. Accuracy/MatchingB. Precision/Reliability

C. SpecificityD. DL or QL

Verification Report(s)

Method Verification Master Plan


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 4-5Full

Qualification

Full Robustness

Studies

Full AMT studies

Full Validation

B NewOld

(Validated)

3-4(1)

Full Qualification Plus AMC(2)

Studies

Full Robustness

Studies

Full AMT Studies

Full Validation Plus AMC(2)

Studies

CAnalytical Platform

TechnologyNew 1-2 Qualification

Robustness Studies

AMT Studies Validation

D Compendial New 1-2Verification

per USP <1226>

N/A N/AVerification

per USP <1226>

EProduct/Process Charaterization

TestsNew 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 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) 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



(QC-Dev.)


Studies(QC-Dev.)


(QC-Dev./ QC-Comm.)

Suggested Prospective AMV Studies(QC Comm.)No.

Analytical Method


A New New 4-5Full

Qualification

Full Robustness

Studies

Full AMT studies

Full Validation

B NewOld

(Validated)

3-4(1)

Full Qualification Plus AMC(2)

Studies

Full Robustness

Studies

Full AMT Studies

Full Validation Plus AMC(2)

Studies

CAnalytical Platform

TechnologyNew 1-2 Qualification

Robustness Studies

AMT Studies Validation

D Compendial New 1-2Verification

per USP <1226>

N/A N/AVerification

per USP <1226>

EProduct/Process Charaterization

TestsNew 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



(QC-Dev.)


Studies(QC-Dev.)


(QC-Dev./ QC-Comm.)

Suggested Prospective AMV Studies(QC Comm.)

Analytical Method


New New 4-5Full

Qualification

Full Robustness

Studies

Full AMT studies

Full Validation

Analytical Platform

TechnologyNew 1-2

APT(Reduced)

Qualification

APT(Reduced)

Robustness Studies

APT(Reduced)

AMT Studies

APT (Reduced) Validation

Compendial New 1-2Verification

per USP <1226>

N/A N/AVerification

per USP <1226>

Product/Process Charaterization

TestsNew 2-3

Reduced Qualification

(if APT)N/A N/A N/A




22


Risk / Uncertainty



(QC-Dev.)


Studies(QC-Dev.)


(QC-Dev./ QC-Comm.)


Analytical Method


New New 4-5Full

Qualification

Full Robustness

Studies

Full AMT studies

Full Validation

Analytical Platform

TechnologyNew 1-2

APT(Reduced)

Qualification

APT(Reduced)

Robustness Studies

APT(Reduced)

AMT Studies



per USP <1226>

N/A N/AVerification

per USP <1226>


TestsNew 2-3


(if APT)N/A N/A N/A




23


Risk / Uncertainty



(QC-Dev.)


Studies(QC-Dev.)


(QC-Dev./ QC-Comm.)


Analytical Method


New New 4-5Full

Qualification

Full Robustness

Studies

Full AMT studies

Full Validation

Analytical Platform

TechnologyNew 1-2

APT(Reduced)

Qualification

APT(Reduced)

Robustness Studies

APT(Reduced)

AMT Studies



per USP <1226>

N/A N/AVerification

per USP <1226>


TestsNew 2-3


(if APT)N/A N/A N/A




24


Risk / Uncertainty



(QC-Dev.)


Studies(QC-Dev.)


(QC-Dev./ QC-Comm.)


Analytical Method


New New 4-5Full

Qualification

Full Robustness

Studies

Full AMT studies

Full Validation

Analytical Platform

TechnologyNew 1-2

APT(Reduced)

Qualification

APT(Reduced)

Robustness Studies

APT(Reduced)

AMT Studies



per USP <1226>

N/A N/AVerification

per USP <1226>


TestsNew 2-3


(if APT)N/A N/A N/A




25


Risk / Uncertainty



(QC-Dev.)


Studies(QC-Dev.)


(QC-Dev./ QC-Comm.)


Analytical Method


New New 4-5Full

Qualification

Full Robustness

Studies

Full AMT studies

Full Validation

Analytical Platform

TechnologyNew 1-2

APT(Reduced)

Qualification

APT(Reduced)

Robustness Studies

APT(Reduced)

AMT Studies



per USP <1226>

N/A N/AVerification

per USP <1226>


TestsNew 2-3


(if APT)N/A N/A N/A



Risk-Based Opportunities for New Methods(Analytical Method Lifecycle Steps in Typical Order)

26


Risk / Uncertainty



(QC-Dev.)


Studies(QC-Dev.)


(QC-Dev./ QC-Comm.)


Analytical Method


New New 4-5Full

Qualification

Full Robustness

Studies

Full AMT studies

Full Validation

Analytical Platform

TechnologyNew 1-2

APT(Reduced)

Qualification

APT(Reduced)

Robustness Studies

APT(Reduced)

AMT Studies



per USP <1226>

N/A N/AVerification

per USP <1226>


TestsNew 2-3


(if APT)N/A N/A N/A



Risk-Based Opportunities for New Methods(Analytical Method Lifecycle Steps in Typical Order)

27


Risk / Uncertainty



(QC-Dev.)


Studies(QC-Dev.)


(QC-Dev./ QC-Comm.)


Analytical Method


New New 4-5Full

Qualification

Full Robustness

Studies

Full AMT studies

Full Validation

Analytical Platform

TechnologyNew 1-2

APT(Reduced)

Qualification

APT(Reduced)

Robustness Studies

APT(Reduced)

AMT Studies



per USP <1226>

N/A N/AVerification

per USP <1226>


TestsNew 2-3


(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

CASSS CMC Strategy Forum Slides for 27Jan14 - SK21Jan14