bioprocess summit - 03aug15 - final sk27jul15
TRANSCRIPT
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
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
Specifications Revision(s)
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
Clinical ResupplyMfg/Formulation Change(s)
Specifications Revision(s)
Commercial Specifications Negotiations, Final
Commercial Specifications and/or Post-BLA
commitmens
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
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.
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
Clinical ResupplyMfg/Formulation Change(s)
Specifications Revision(s)
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
Mfg Transfer
Method validation
Method transfer
Formulation Change
Process Verification
Method Maintenance
Global Supply
Method Change
Accelerated Development
CompLots
PQ lotsCompLots =
PQ Lots = Comparability Lots
7
FTIH POC BLA
Tox StudiesPhase 1
Phase 3
Clinical ResupplyMfg/Formulation Change(s)
Specifications Revision(s)
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
Mfg Transfer
Method validation
Method transfer
Formulation Change
Process Verification
Method Maintenance
Global Supply
Method Change
Accelerated Development
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
Commercial Specifications
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)
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)
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
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%
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)
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%
Tig
hte
n D
P S
hel
f-L
ife
Lim
i t
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
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.)
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)
Ideal Analytical Method Lifecycle Preparing for Tech Transfer (Pilot to Commercial Plant)
19
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)
Commercial Specifications
Not Parallel Step
Process Color Legend:
Method Qualified
(SOP Lock)
Ideal Analytical Method Lifecycle Preparing for Tech Transfer (Pilot to Commercial Plant)
20
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)
Commercial Specifications
Not Parallel Step
Process Color Legend:
Method Qualified
(SOP Lock)
Ideal Analytical Method Lifecycle Preparing for Tech Transfer (Pilot to Commercial Plant)
21
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)
Commercial Specifications
Not Parallel Step
Process Color Legend:
Method Qualified
(SOP Lock)
Ideal Analytical Method Lifecycle Preparing for PQ (at Commercial Plant)
22
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)
Commercial Specifications
Not Parallel Step
Process Color Legend:
Method Qualified
(SOP Lock)
Ideal Analytical Method Lifecycle Preparing for PQ (at Commercial Plant)
23
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)
Commercial Specifications
Not Parallel Step
Process Color Legend:
Method Qualified
(SOP Lock)
Ideal Analytical Method Lifecycle Executing PQ Studies (at Commercial Plant)
24
DS/DPSpecificationTest 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 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)
Analytical Method Lifecycle APT Opportunities following AMV Study Completion and MA Approval
25
DS/DPSpecification
Test Methods for Same SOP andNew Product
Robustness Studies Execution
QCDev.
AMVStudies
(QC-Comm.)
PQ Lots Mfg
Completed
In progress
Not started
AMV completed
MaintenanceAMM
(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 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 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
Start PV Stage 2(PQ Lots)
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
Process Color Legend:
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