casss cmc 09dec14 stephan krause

Stephan KrauseDirector, QA TechnologyAstraZeneca Biologics

CASSS CMC Strategy Forum09 December 2014 Tokyo, Japan

Risk-Based Analytical Life Cycle Steps for Accelerated Products

2

Outline

• Review of Specifications and CMC Processes: Opportunities and Considerations

• 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

• Goal: Understand how analytical platform technology and parallel (versus

sequential) analytical method and specification lifecycle steps can greatly

support accelerated development programs.

• Presentation to Focus on Late-Stage Development Opportunities:

- Mostly Risk(s) to Manufacturer/Sponsor 2

3

CQA Development, CMC Changes, and Specifications

From: Krause, S., WCBP, 30Jan13, Washington, DC.

FTIH POC BLA

Tox StudiesPhase 1

Phase 2Phase 3

Clinical ResupplyMfg/Formulation Change(s)

Specifications Revision(s)

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

eve

lop

me

nt

(Qb

D P

roc

ess

)S

pe

cs

Lif

e C

yc

le

Mg

mt

CM

C a

nd

Te

ch

T

ran

sfe

r P

roc

ess Analytical

Manufacturing

Strategic or Tactical Changes

Method qualification

Dose change

Delivery Device

PQ lots

Setting of Initial Specifications


Mfg Transfer

Method validation

Method transfer

Formulation Change

Process Verification

Method Maintenance

Global Supply

Commercial Specifications

Accelerated CQA Development, CMC Changes, and Specifications

4

FTIH POC BLA

Tox StudiesPhase 1

Phase 3



Commercial Specifications Negotiations, Final

Commercial Specifications and/or Post-BLA

commitmens

QTPP





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



Dose change

Delivery Device

PQ lots


Mfg Transfer

Method validation

Method transfer

Formulation Change


Method Maintenance

Global Supply

Method Change

Accelerated Development

From: Krause, S., CaSSS CMC Strategy Forum, 27Jan14, Washington, DC.


5


FTIH POC BLA

Tox StudiesPhase 1

Phase 3




QTPP






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



Dose change

Delivery Device

PQ lots


Mfg Transfer

Method validation

Method transfer

Formulation Change


Method Maintenance

Global Supply

Method Change


CompLots


6


FTIH POC BLA

Tox StudiesPhase 1

Phase 3




QTPP






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



Dose change

Delivery Device

PQ lots


Mfg Transfer

Method validation

Method transfer

Formulation Change


Method Maintenance

Global Supply

Method Change


CompLots

PQ lotsCompLots =

PQ Lots = Comparability Lots

7

FTIH POC BLA

Tox StudiesPhase 1

Phase 3




QTPP






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



Dose change

Delivery Device

PQ lots


Mfg Transfer

Method validation

Method transfer

Formulation Change


Method Maintenance

Global Supply

Method Change


CompLots

PQ lotsCompLots =

How to manage two sets of acceptance criteria (commercial specifications vs. equivalence/non-inferiority limits) for same sets of results ?

Typical Analytical Method and Specification Lifecycle(s)

8

AMVStudies

Start PV Stage 2(PQ Lots)

Maintenance (continuous

AMV)

AMT Studies


Method Qualified

Pivotal/Phase 3 Specifications

Phase 1/2 Specifications

Sp

ecs covered

in A

MV

?

From: Krause, S., PDA Journal of Pharmaceutical Science and Technology, Jan/Feb 2015.

9

Specification Setting Process

Acceptance Criteria

Existing Knowledge of Mfg/Analytical

Capability

Historical Data from this

specific Product and Process

Clinical Consideration

and/or Experience

“Platform” Knowledge from Similar Product

and Process

From: Krause, S., WCBP, 30Jan13, Washington, DC.

Specification Example (% Purity): Manufacturing Capability vs. Clinical Experience

10


95.0

96.0

97.0

98.0

99.0

100.0

NLT 95.0%

Tig

hte

n D

P S

hel

f-L

ife

Lim

it

N=12 DP batches (clinical phase 2

and 3)

Historical DP Release Results (T=0M)

DP Stability Results – Recommended Temperature

Estimated Clinical Purity Patient Exposure Level

(for 3-year old DP)

NLT 97.0%

NLT 97.6%

Proposed Shelf-Life Specification (3 Years) Based on Predicted

Manufacturing Capability (3 SD; n=12)


11


95.0

96.0

97.0

98.0

99.0

100.0

NLT 95.0%

Tig

hte

n D

P S

he

l f-L

ife

Lim

it


and 3)




(for 3-year old DP)

NLT 97.0%

NLT 97.6%




12


95.0

96.0

97.0

98.0

99.0

100.0

NLT 95.0%

Tig

hte

n D

P S

hel

f-L

ife

Lim

i t


and 3)




(for 3-year old DP)

NLT 97.0%

NLT 97.6%



Difference Acceptable ?

13

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 Report

Intended Use (re-defined)

AMV Report

IdentitySafetyPurity

QualityPotency

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

Critical Process Parameters (CPP)

From: Krause, S., PDA Technical Report 57, 2012.

14

Retrospective and Prospective Use of Data for AMV Studies from other Processes Prior to AMV – New Method

Krause/PDA Workshop (2013)

15

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)

16

DS/DPSpecificationTest Methods

for New Method

Robustness Studies Execution

QCDev.

AMVStudies

(QC-Comm.)


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)

17


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)


18


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)


19


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)

20


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)

21


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)

22


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

23

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

24

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

25

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

26

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)

27

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)

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

casss cmc 09dec14 stephan krause

Documents

cmc changes

sequential analytical

accelerated cqa development

ftih poc bla tox studies

analytical life cycle

cmc processes

accelerated programs

accelerated products