1. Stephan Krause
Director, QA Technology
AstraZeneca Biologics
Bioprocess Summit - Keynote
03-04 August 2015
Boston, MA
Analytical Methods and
Specification Revisions during
the Product Lifecycle

2. 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

3. Risk Assessment(s) and Control Strategy Elements During Product Development
3
FTIH POC BLAQTPP
Final CQAs &
Control Strategy Approval
Potential CQAs
Product & Process
Design
Life-Cycle
Management
POST-APPROVAL
CHANGES
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-assessed
Re-assessed
In-Process
Testing
Characterization
Testing

4. 4
CQA Development, CMC Changes, and Specifications
From: Krause, S., WCBP, 30Jan13, Washington, DC.
FTIH POC BLA
Tox Studies
Phase 1
Phase 2
Phase 3
Clinical Resupply
Mfg/Formulation Change(s)
Specifications
Revision(s)
Negotiations, Final
Commercial Specifications
QTPP
Final CQAs &
Control Strategy Approval
Potential CQAs
Product & Process
Design
Life-Cycle
Management
POST-APPROVAL
CHANGES
PHASE 3PHASE 1/2Pre-IND
CQADevelopment
(QbDProcess)
SpecsLifeCycle
Mgmt
CMCandTech
TransferProcess
Analytical
Manufacturing
Strategic or
Tactical Changes
Method
qualification
Dose
change
Delivery
Device
PQ lots
Setting of Initial
Specifications
Specifications
Revision(s)
Mfg
Transfer
Method
validation
Method
transfer
Formulation
Change
Process Verification
Method Maintenance
Global
Supply
Commercial
Specifications

5. Accelerated CQA Development, CMC Changes, and Specifications
5
FTIH POC BLA
Tox Studies
Phase 1
Phase 3
Clinical Resupply
Mfg/Formulation Change(s)
Specifications
Revision(s)
Commercial
Specifications
Negotiations, Final
Commercial Specifications
and/or Post-BLA
commitmens
QTPP
Final CQAs &
Control Strategy Approval
Potential CQAs
Product & Process
Design
Life-Cycle
Management
POST-APPROVAL
CHANGES
PIVOTAL PHASE (3)PHASE 1Pre-IND
CQADevelopment
(QbDProcess)
SpecsLifeCycle
Mgmt
CMCandTech
TransferProcess
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
Method
Change
Accelerated Development
From: Krause, S., CaSSS CMC Strategy Forum, 27Jan14, Washington, DC.

6. Accelerated CQA Development, CMC Changes, and Specifications
6
From: Krause, S., CaSSS CMC Strategy Forum, 27Jan14, Washington, DC.
FTIH POC BLA
Tox Studies
Phase 1
Phase 3
Clinical Resupply
Mfg/Formulation Change(s)
Specifications
Revision(s)
Commercial
Specifications
QTPP
Final CQAs &
Control Strategy Approval
Potential CQAs
Product & Process
Design
Life-Cycle
Management
POST-APPROVAL
CHANGES
PIVOTAL PHASE (3)PHASE 1Pre-IND
CQADevelopment
(QbDProcess)
SpecsLifeCycle
Mgmt
CMCandTech
TransferProcess
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
Method
Change
Accelerated Development
Comp
Lots
PQ lots
Comp
Lots=

7. PQ Lots = Comparability Lots
7
FTIH POC BLA
Tox Studies
Phase 1
Phase 3
Clinical Resupply
Mfg/Formulation Change(s)
Specifications
Revision(s)
Commercial
Specifications
QTPP
Final CQAs &
Control Strategy Approval
Potential CQAs
Product & Process
Design
Life-Cycle
Management
POST-APPROVAL
CHANGES
PIVOTAL PHASE (3)PHASE 1Pre-IND
CQADevelopment
(QbDProcess)
SpecsLifeCycle
Mgmt
CMCandTech
TransferProcess
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
Method
Change
Accelerated Development
Comp
Lots
PQ lots
Comp
Lots=
How to manage two sets of acceptance
criteria (commercial specifications vs.
equivalence/non-inferiority limits) for
same sets of results ?

8. Typical Analytical Method and Specification Lifecycle(s)
8
AMV
Studies
Start PV
Stage 2
(PQ Lots)
Maintenance
(continuous
AMV)
AMT
Studies
Commercial
Specifications
Method
Qualified
Pivotal/Phase 3
Specifications
Phase 1/2
Specifications
SpecscoveredinAMV?From: Krause, S., PDA Journal of Pharmaceutical Science and Technology, Sep/Oct 2015.

9. 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.

10. Specification Revision Process - Purity by HPSEC
10

11. 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
ReleaseandStabilitySpecs
Revision
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=24M
T=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
Commercial
Releaseand
StabilitySpecs

12. 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)
TightenDPShelf-LifeLimit
Representative Degradation for 3-years
N=12 DP batches
(clinical phase 2
and 3)
Historical DP Release Results (T=0M)
DP Stability Results – Recommended
Temperature
Statistical Tolerance Limit
Mean Purity Level
Estimated Degradation Uncertainty
NLT 97.0% (S)
NLT 98.3% (R)
TightenDPReleaseLimit
Analytical Method Variation (long-term)
Analytical Capability
NLT 96.0% (R)
TightenDP
ReleaseLimit
NLT 95.0% (R + S)
Specs Revision
for Phase 3
Specs Revision
for PQ Lots

13. 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%
TightenDS/DPReleaseLimit
Specs
Revision for
Phase 3
Specs
Revision for
PQ Lots
TightenDS/DP
ReleaseLimit
NLT 95.0%

14. Specification Example (% Purity): Manufacturing Capability vs. Clinical Experience
14
From: Krause, S., PDA Journal of Pharmaceutical Science and Technology, Sep/Oct 2015.
95.0
96.0
97.0
98.0
99.0
100.0
NLT 95.0%
TightenDPShelf-LifeLimit
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)

15. Specification Example (% Purity): Manufacturing Capability vs. Clinical Experience
15
From: Krause, S., PDA Journal of Pharmaceutical Science and Technology, Sep/Oct 2015.
95.0
96.0
97.0
98.0
99.0
100.0
NLT 95.0%
TightenDPShelf-LifeLimit
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)
Difference Acceptable ?

16. 16
Retrospective and Prospective Use of Data for AMV Studies from
other Processes Prior to AMV – New Method
Krause/PDA Workshop (2013)

17. 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)

18. Ideal Analytical Method Lifecycle
Clinical Phase 1-2 (prior to transfer from Pilot to Commercial Plant)
18
DS/DP
Specification
Test Methods
for New Method
Robustness
Studies
Execution
QC
Dev.
AMV
Studies
(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)
Commercial
Specifications
Not Parallel Step
Process Color
Legend:
Method
Qualified
(SOP Lock)

19. Ideal Analytical Method Lifecycle
Preparing for Tech Transfer (Pilot to Commercial Plant)
19
DS/DP
Specification
Test Methods
for New Method
Robustness
Studies
Execution
QC
Dev.
AMV
Studies
(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)
Commercial
Specifications
Not Parallel Step
Process Color
Legend:
Method
Qualified
(SOP Lock)

20. Ideal Analytical Method Lifecycle
Preparing for Tech Transfer (Pilot to Commercial Plant)
20
DS/DP
Specification
Test Methods
for New Method
Robustness
Studies
Execution
QC
Dev.
AMV
Studies
(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)
Commercial
Specifications
Not Parallel Step
Process Color
Legend:
Method
Qualified
(SOP Lock)

21. Ideal Analytical Method Lifecycle
Preparing for Tech Transfer (Pilot to Commercial Plant)
21
DS/DP
Specification
Test Methods
for New Method
Robustness
Studies
Execution
QC
Dev.
AMV
Studies
(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)
Commercial
Specifications
Not Parallel Step
Process Color
Legend:
Method
Qualified
(SOP Lock)

22. Ideal Analytical Method Lifecycle
Preparing for PQ (at Commercial Plant)
22
DS/DP
Specification
Test Methods
for New Method
Robustness
Studies
Execution
QC
Dev.
AMV
Studies
(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)
Commercial
Specifications
Not Parallel Step
Process Color
Legend:
Method
Qualified
(SOP Lock)

23. Ideal Analytical Method Lifecycle
Preparing for PQ (at Commercial Plant)
23
DS/DP
Specification
Test Methods
for New Method
Robustness
Studies
Execution
QC
Dev.
AMV
Studies
(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)
Commercial
Specifications
Not Parallel Step
Process Color
Legend:
Method
Qualified
(SOP Lock)

24. Ideal Analytical Method Lifecycle
Executing PQ Studies (at Commercial Plant)
24
DS/DP
Specification
Test Methods
for New Method
Robustness
Studies
Execution
QC
Dev.
AMV
Studies
(QC-Comm.)
PQ Lots
Mfg
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)
Commercial
Specifications
Not Parallel Step
Process Color
Legend:
Method
Qualified
(SOP Lock)

25. Analytical Method Lifecycle
APT Opportunities following AMV Study Completion and MA Approval
25
DS/DP
Specification
Test Methods for
Same SOP and
New Product
Robustness
Studies
Execution
QC
Dev.
AMV
Studies
(QC-Comm.)
PQ Lots
Mfg
Completed
In progress
Not started
AMV completed
Maintenance
AMM
(QC-Comm.)
Robustness
Studies
Master Plan
AMT
Studies
(QC-Dev. &
QC-Comm.)
SOP-specific
Min/Max Method
Conditions
(for PB Design)
Commercial
Specifications
Not Parallel Step
APT Method
AMV and AMM
(QC)
Analytical Platform
Technology
APT
Method
Robustness
and AMT
Process Color
Legend:
Method
Qualified
(SOP Lock)
APT
Method
AMQ

26. Analytical Method Lifecycle for Accelerated Programs
Additional 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
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:

27. 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 4-5
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
Characterization
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)

28. 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