bioprocess summit - 03aug15 - final sk27jul15

Stephan KrauseDirector, QA TechnologyAstraZeneca Biologics

Bioprocess Summit - Keynote03-04 August 2015 Boston, MA

Analytical Methods and Specification Revisions during

the Product Lifecycle

2

Outline

• Review of Specifications and CMC Processes: Opportunities and Considerations

• Specification Setting/Revision Process, Rationale, and Case Study

• Review of Strategic Opportunities to Reduce Analytical Method Lifecycle Steps

Specifically for Accelerated Programs

- Analytical Platform Technology (APT) methods- Product and Process Characterization methods- Product-Specific (“New”) 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

Risk Assessment(s) and Control Strategy Elements During Product Development

3

FTIH POC BLAQTPP

Final CQAs & Control Strategy Approval

Potential CQAsProduct & Process Design

Life-CycleManagement

POST-APPROVALCHANGES

PHASE 3PHASE 1/2Pre-IND

CQA

Patient Impact Severity

Assessed(Safety and

Efficacy)

Overall Risk Assessment (ex., FMEA)

Final Assessment

Uncertainty

Detectability

Occurrence

Control Strategy

Procedural Control

Process Validation

Lot Release Testing

Raw Material Control

Stability Testing

Operational Parameters

Risk(s)

Control(s)

Re-a

sse

ssed

Re

-ass

ess

ed

In-Process Testing

Characterization Testing

4

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





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

5

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.

Accelerated CQA Development, CMC Changes, and Specifications

6

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

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, Sep/Oct 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 Revision Process - Purity by HPSEC

10

HPSEC Specification Revision Process – Comparability, Manufacturing, and Clinical Experience

11

95.0

96.0

97.0

98.0

99.0

100.0

NLT 95.0%

Phase 2 => Phase 3

Re l

eas e

an

d S

tab

il ity

Sp

ecs

Re

visi

on

N=1

Tox => Phase 1 (FTIH)

Phase 1 => Phase 2

T=2M

N=2

T=3M

N=3

T=6M

N=4

T=12M

N=6

T=24MT=36M

N=10 N=15

T=48M

(Pre-) Commercial (PV Stage 2)

Historical DP Release Results (T=0M)

DP Stability Results – Accelerated Condition

DP Stability Results – Recommended Temperature

Process Change(s): Comparability Demonstrated

Co

mm

erci

al

Rel

ease

an

d

Sta

bili

ty S

pec

s

HPSEC DP Specification Revision Process for Phase 3/Pivotal Studies and PQ Lots

12

95.0

96.0

97.0

98.0

99.0

100.0

NLT 95.0% (S)

Tig

hte

n D

P S

hel

f-L

ife

Lim

it

Representative Degradation for 3-years

N=12 DP batches (clinical phase 2

and 3)



Statistical Tolerance Limit

Mean Purity Level

Estimated Degradation Uncertainty

NLT 97.0% (S)

NLT 98.3% (R)

Tig

ht e

n D

P R

elea

se L

i mit

Analytical Method Variation (long-term)Analytical Capability

NLT 96.0% (R)

Tig

hte

n D

P

Rel

ease

Lim

it

NLT 95.0% (R + S)

Specs Revision for Phase 3

Specs Revision for PQ Lots

HPSEC DS Specification (and Release Target) Revision Process for Phase 3/Pivotal Studies and PQ Lots

13

95.0

96.0

97.0

98.0

99.0

100.0

NLT 98.3% (DS Release) Representative Degradation for Desired 1-Year DS Hold and Post-Thaw

Handling

Estimated Degradation Uncertainty

NLT 98.7% (DS Mfg Target)

NLT 96.0%

Tigh

ten

DS

/DP

Rel

ease

Lim

it

Specs Revision for

Phase 3

Specs Revision for

PQ Lots

Tigh

ten

DS

/DP

R

elea

se L

imit

NLT 95.0%

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

14


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


and 3)



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)

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

15


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)



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)

Difference Acceptable ?

16

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

Krause/PDA Workshop (2013)

17

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)

18

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)

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)


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)


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 Preparing for PQ (at Commercial Plant)

22


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)

23


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)

24


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 and MA Approval

25

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 ProgramsAdditional APT Opportunities

26

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 Platform Technology


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 Characterization

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

• Setting specifications for late-stage/commercial products is

challenging.

• Opportunities exist to reduce typical analytical method

lifecycle steps for accelerated programs.

• Use of (analytical) platform technology can greatly support

accelerated development programs.

References:

1. Krause et al., PDA TR 57, Analytical Method Validation and Transfer for Biotechnology

Products, August 2012.

2. Krause, Setting Specifications of Biological IMPs, PDA J. Pharm. Sci. Tech., Sep/Oct 2015.

28

bioprocess summit - 03aug15 - final sk27jul15

Documents

cmc changes

product development

sequential analytical

accelerated cqa development

product lifecycle

control strategy elements

ftih poc bla tox studies

ma analytical methods