CPV Acceptance Criteria and Conditions SK09Aug16

Stephan Krause
Director, QA Technology
AstraZeneca Biologics
BioProcessing Summit
17-18 August 2016
Boston, MA
CPV Acceptance Criteria and
Conditions

Outline
CPV/Commercial acceptance criteria - non-microbiological CQAs
- Control strategy development
- CPV conditions/rules
- “QA process”
CPV/Commercial acceptance criteria – microbiological CQAs
- Risk assessment process
- Alert and action level examples
The content and views expressed by the author/presenter are
not necessarily the views of the organization he represents.

3
Typical 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

Accelerated CQA Development, CMC Changes, and Specifications
4
FTIH POC BLA
Tox Studies
Phase 1
Phase 3
Clinical Resupply
Specifications
Revision(s)
Commercial
Specifications
Negotiations, Final
and/or Post-BLA
commitmens
QTPP
Final CQAs &
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
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
5
From: Krause, S., CaSSS CMC Strategy Forum, 27Jan14, Washington, DC.
FTIH POC BLA
Tox Studies
Phase 1
Phase 3
Clinical Resupply
Specifications
Revision(s)
Commercial
Specifications
QTPP
Final CQAs &
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
Method Maintenance
Global
Supply
Method
Change
Accelerated Development
Comp
Lots
PQ lots
Comp
Lots=

6
Typical 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
Specifications
Revision(s)
Negotiations, Final
QTPP
Final CQAs &
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
Method Maintenance
Global
Supply
Commercial
Specifications
Formal CPV

S. Krause, PDA Annual Meeting - Las Vegas 17March15

Risk Assessment Process During Product Development
Overall Risk Assessment
(ex., FMEA) Scoring
Severity Score
Probability
Score
Detectability
ScoreControl
Strategy
(p)CQA
(Prior to PV
Stage 2)
X
CQA
(at/after PV
Stage 2)
X

Assessing Product Quality and/or Process Consistency Impact
Critical Process Parameter (CPP): A process
parameter whose variability has an impact on a critical
quality attribute and therefore should be monitored or
controlled to ensure the process produces the desired
quality (ICH Q8 (R2))8.
Non-Critical Process Parameters are process
parameters whose variability has no practically
significant impact on critical quality attributes. Non-
critical process parameters fall into two categories, Key
Process Parameters and Non-Key Process
Parameters.
Key Process Parameter (KPP): A non-critical process
parameter whose variability has a practically significant
impact on process performance or process consistency.
Non-Key Process Parameter (NKPP): A non-key
process parameter is a non-critical process (control)
parameter that has no practically significant impact on
process performance or process consistency.
Courtesy of Gisela Ferreira, MedImmune

Output
Measurement
Impact Type of Criterion / Limit
In-Process
Control (IPC)
Determinant of
product quality
Acceptance Criteria:
“Numerical limits, ranges, or
other suitable measures for
acceptance of the results of
analytical procedures which
the drug substance or drug
product or materials at other
stages of their manufacture
should meet.” (ICH Q6B9)
Performance
Attribute (PA)
Used to indicate
that the process
performed as
expected; may
include quality
measurements that
do not directly
determine final
product quality
Action Limit:
“An internal (in-house) value
used to assess the
consistency of the process at
less critical steps.” (ICH
Q6B9)
Assessing Product Quality and/or Process Consistency Impact
Courtesy of Gisela Ferreira, MedImmune

Considerations for CPV (Limits)
Data Transformation of Non-Normal Distributions
15
Original-scaled data
Log-scaled data
Data are not symmetric around center:
 mean and standard deviation not appropriate metrics.
Courtesy of Steven Novick, MedImmune

16
From: Responses to Signals from a Continued Process Verification System in the Biopharmaceutical
Industry

17
How many lots before we move the center of CLs ?
From: Responses to Signals from a Continued Process Verification System in the Biopharmaceutical
Industry

Understanding Campaign Differences and Batch
Differences Within a Campaign
A 95% upper confidence limit for a
standard deviation is K * s, where K is
given in the table and s = sample standard
deviation.
There is high uncertainty in the estimate of
campaign-to-campaign variability when the
data set contains only two campaigns; the
true standard deviation might be 15.9x
greater than the existing data.
Courtesy of Steven Novick, MedImmune
# of campaigns K
2 15.9
3 4.4
4 2.9
5 2.4
6 2.1
10 1.6
25 1.3
30 1.3
100 1.1

Example: Drug Substance Specifications and CPV Limit(s)
SK 22Feb16
Time (years)
HPSEC
(%Monomer)
1 2 3 4
100.0%
98.5%
DS Release NLT 98.0%
Historical DS Release
(n=25)
DS EOSL NLT 97.0% (= DP Release)
99.5%
99.0%
98.0%
97.0%

Statistical Release Conditions
SK 22Feb16
HPSEC
(%Monomer)
100.0%
98.5%
OOC Limit 99.2% (Stat: One-Sided 99.85% based on 3 SDs)
Future DS Release
Result (n=1)
99.5%
99.0%
98.0%
97.0%

“Practical” Alert/Action Conditions (based on non-stats DS release specs)
SK 22Feb16
HPSEC
(%Monomer)
100.0%
98.5%
Alert/Action Limit NMT 98.8%
Future DS Release
Result (n=1)
99.5%
99.0%
98.0%
97.0%

OOT Release Conditions for Sequential Batches
SK 22Feb16
HPSEC
(%Monomer)
100.0%
98.5%
OOC Limit 99.2% (Stat: One-Sided 99.85% based on 3 SDs)
Future DS Release
Result (lot 31-32)
99.5%
99.0%
98.0%
97.0%
Alert/Action Limit NMT 98.8%
Future DS Release
Result (lot 31-37)

OOT Stability Conditions (OOT at 18M)
HPSEC
(%Monomer)
1 2 3 4
100.0%
98.5%
99.5%
99.0%
98.0%
97.0%
OOT
?

OOT Stability Conditions (OOT for 2-8C at 18M)
Time (years)
HPSEC
(%Monomer)
1 2 3 4
100.0%
98.5%
DS EOSL NLT 97.0%
99.5%
99.0%
98.0%
97.0%
Avg of n=5 DS lots (R -EOSL = 0.5%)
OOT(R)
OOT(S)
OOS
Assay Variation +
Slope Uncertainty
(n=5 DS)

PPQ Specifications, CPV Acceptance Criteria, and Non-Conformance Conditions
Comparability
CQA Result
“OOA”
CPP Result
“OOR”
KPP Result
“OOR”
NKPP Result
“OOR”
(Potential) Failed
Comparability
Study
Product Impact
No Product
Impact but
Process Impact
No Product and/
or Process Impact
CSD Approved
Discoverant CPV
Tool Available for
Real-Time
Monitoring
NC and CAPA
NC and CAPA
Event and
Possible CAPA
Event only
(Trended)
PPQ
Specification
“OOS”
(Potential)
Unacceptable
Product Quality
and Failed PPQ
Study
(Potential) Batch
Rejection/Recall
N=2 Sets of CQA Acceptance Criteria
(PPQ Specifications = PPQ Protocol Acceptance Criteria;
Comparability Protocol Acceptance Criteria)
N=3 Sets of Out-of-Range (OOR) Conditions
IncreasingSeverityofProcess/Product/QualityImpact
Biostats
report and JOS
final

PPQ Specifications, CPV Acceptance Criteria, and Non-Conformance Conditions
CPP Result
“OOR”
KPP Result
“OOR”
NKPP Result
“OOR”
Product Impact
No Product
Impact but
Process Impact
No Product and/
or Process Impact
Control Strategy
Document =>
CPV Protocol
NC and CAPA
Event and
Possible CAPA
Event only
(Trended)
N=3 Sets of Out-of-Range (OOR) Conditions KPIs in Quality Matrics
Manage
Individual Events
Manage Repeat
Events
Trend Repeat
Events

Outline
CPV/Commercial acceptance criteria - non-microbiological CQAs
- Control strategy development
- CPV conditions/rules
- “QA process”
CPV/Commercial acceptance criteria – microbiological CQAs
- Risk assessment process
- Alert and action level examples
The content and views expressed in this presentation expressed by the author/presenter
are not necessarily the views of the organization he represents.

Examples for Clinical and Process Qualification (PV Stage 2) Drug
Substance Specifications for Bioburden and Endotoxin
Test /
Specification
IMP Phase 1-2
IMP Pivotal or
Phase 3
PQ Lots
(PV Stage 2)
Reported
Results
Example
Bioburden
NMT 10 CFU per
100 mL
NMT 1 CFU per
10 mL
NMT 1 CFU per
10 mL
0 CFU per
10 mL (1)
Endotoxin
(LAL)
NMT 1.75 EU/mg
protein
NMT 1.75 EU/mg
protein
NMT 0.50
EU/mg protein
0.01 EU/mg
protein
Bioburden: Specification for this critical safety quality attribute is compendia-based and an industry
standard. Specification can remain unchanged as it is already tightly controlled for early-stage clinical
studies. The use of a 10 mL sample volume was validated and justified with spiked DS samples.
(1) The 100 mL sample volume may be required, if a volume smaller than 100 mL cannot be validated
(equivalent) or upon request of a regulatory agency.
Endotoxin (LAL): A specification suggested in USP <85> for the Bacterial Endotoxins Test (by LAL; NMT
5.0 EU/kg body weight) can be used for early and late-stage clinical studies. Calculation: 5.0 EU/kg x 35
kg/100 mg = 1.75 EU/mg (not changed as 1.7549 EU/mg = 5.014 (5.0 EU/kg)). For PQ lots, the DS
specification is tightened, based on plant-specific manufacturing experience.

Possible IPC Alert/Action levels of Upstream/Downstream and DS
Specification Lifecycle Strategy - Endotoxin
DS Endotoxin Specification:
• For PQ and/or when extensive plant-specific experience exists, tighten DS specifications.
• Use statistically calculated limits and/or use justified limits (ex., clinical experience, maximum
patient exposure).
IPC Alert/Action Levels:
• For clinical and/or limited plant-specific historical experience, use QRM tools (ex., modified FMEA)
to establish risk-based IPC alert/action limits.
• Use three levels (high, medium, low) for each IPC sample based the QRM risk priority numbers.
• For commercial and/or when extensive plant-specific experience exists,
• Use calculated worse-case limits based on microbial proliferation opportunity. The primary
factors that affect the risk of microbial proliferation during hold times are the growth-
promoting properties of the in-process materials, initial bioburden level, and storage
conditions.
• Or, set statistically calculated limits (ex., based on plant-specific process capability.)
• Or, use a combination between the two as data may not be continuous (most results
reported as: < Alert Level (DL/QL) and/or therefore not normally distributed.

Possible IPC Alert/Action levels of Upstream/Downstream and DS
Specification Lifecycle Strategy - Bioburden
DS Bioburden Specification:
• Specification for this critical safety quality attribute is compendia-based and an industry standard.
• Specification can remain unchanged as it is already tightly controlled for early-stage clinical
studies.
• The use of less than 100 mL sample volume (ex., 10 mL) should be validated and justified with
spiked DS samples. Some regulatory agencies may require a 100 mL sample volume.
IPC Alert/Action Levels:
• For clinical and/or limited plant-specific historical experience, use QRM tools (ex., modified FMEA)
to establish risk-based IPC alert/action limits.
• Use three levels (high, medium, low) for each IPC sample based the QRM risk priority numbers.
• For commercial and/or when extensive plant-specific experience exists,
• Use calculated worse-case limits based on microbial proliferation opportunity. The primary
factors that affect the risk of microbial proliferation during hold times are the growth-promoting
properties of the in-process materials, initial bioburden level, and storage conditions.
• Or, set statistically calculated limits (ex., based on plant-specific process capability.)
• Or, use a combination between the two as data may not be continuous and/or normally
distributed. S. Krause, PDA Annual Meeting - Las Vegas 17March15

General Considerations for Bioburden and Endotoxin
IPC for Downstream
• IPC action and alert limits for bioburden and endotoxin are narrower
towards the end of the downstream process.
• Bioburden and endotoxin IPC limits are narrower at/after Virus Filtration.
• The alert limit is further tightened to ≤ 0 CFU/10 mL at the final step(s) so
that any presence of bioburden is investigated.
• Proliferation Opportunity (time, temperature, replicability – link to
endotoxin)
• Endotoxin limits for in-process intermediates are determined based on
the following factors:
• Quantitation Limit of 0.005 EU/mL
• Maximum valid dilution (MVD) – Dilution Factor used
• Expected clearance through the purification unit operations
• Proliferation Opportunity (time, temperature, replicability – link to
bioburden)

Score Rating Overall Risk Rating (for Alert/Action Levels, exluding Occurrence)
1-27 Low The potential impact is minimal or has been minimized through effective controls
36-108 Medium
The potential impact is somewhat significant. Effective controls are in the process of being
implemented or the existing controls are not comprehensive enough to fully mitigate the risk.
162-729 High
The impact is significant. The existing controls are not effective in mitigating the risk or no controls
are in place at all.
List of Mfg
Process Steps
(Examples)
(Potential) Failure
Mode Description
Unwanted Event
Result
S
(Severity -
Patient
and/or
Firm)
O
(Previous)
Occurance
D
(Detection
Probability)
P
(Proliferation
Opportunity)
C
(Control in Place
or Risk Mitigated)
RPN (Risk Priority
Number)
Downstream
(1, 3, 9)
1=low
9=high
(patient
impact)
(1-3)
1=low
2=medium
3=high
(1-3)
1=high
2=mediu
m 3=low
Hold Time
x Temp. x
Replicabilit
y (1,3,9)
1=low
9=high
1=yes 2=not
complete
3=no
Up to 27 = green
36-108 = yellow
162-729 = red
Modified QRM FMEA for Bioburden and Endotoxin IPC
Alert/Action Levels

Modified FMEA Example for Downstream Alert/Action Levels
List of Mfg
Process
Steps
(Examples)
(Potential)
Failure Mode
Description
Unwanted Event
Result
S
(Severity -
Patient
and/or
Firm)
O
(Previous)
Occurance
D
(Detection
Probability)
P
(Proliferatio
n
Opportunity)
C
(Control in
Place or Risk
Mitigated)
RPN (Risk Priority
Number)
Downstream
(1, 3, 9)
1=low
9=high
(patient
impact)
(1-3)
1=low
2=medium
3=high
(1-3)
1=high
2=medium
3=low
Hold Time x
Temp. x
Replicability
(1,3,9) 1=low
9=high
1=yes 2=not
complete
3=no
Up to 27 = green
36-108 = yellow
162-729 = red
Formulation
Buffer
Contaminated
(bioburden) buffer
can further
contaminate the
filtered, formulated
drug
substance/bulk.
Bioburden
contamination in
DS (above Action
Level).
Unacceptable
endotoxin levels
post-filtration.
9 [1] 2 3 3 162

Is Previous Occurrence a Factor Here ?
List of Mfg
Process
Steps
(Examples)
(Potential)
Failure Mode
Description
Unwanted Event
Result
S
(Severity -
Patient
and/or
Firm)
O
(Previous
Occurrence)
D
(Detection
Probability)
P
(Proliferation
Opportunity)
C
(Control in
Place or Risk
Mitigated)
RPN (Risk Priority
Number)
Downstream
(1, 3, 9)
1=low
9=high
(patient
impact)
(1-3)
1=low
2=medium
3=high
(1-3)
1=high
2=medium
3=low
Hold Time x
Temp. x
Replicability
(1,3,9) 1=low
9=high
1=yes
2=not complete
3=no
Up to 27 = green
36-108 = yellow
162-729 = red
Formulation
Buffer
Contaminated
(bioburden) buffer
can further
contaminate the
drug
substance/bulk.
Bioburden
contamination in
DS (above Action
Level).
Unacceptable
endotoxin levels
post-filtration.
9 [1] 2 3 3 162

Can Uncertainty be a Factor ?
List of Mfg
Process
Steps
(Examples)
(Potential)
Failure Mode
Description
Unwanted Event
Result
S
(Severity -
Patient
and/or
Firm)
U
(Uncertainty)
D
(Detection
Probability)
P
(Proliferation
Opportunity)
C
(Control in
Place or Risk
Mitigated)
RPN (Risk Priority
Number)
Downstream
(1, 3, 9)
1=low
9=high
(patient
impact)
(1-3)
1=low
2=medium
3=high
(1-3)
1=high
2=medium
3=low
Hold Time x
Temp. x
Replicability
(1,3,9) 1=low
9=high
1=yes
2=not complete
3=no
Up to 27 = green
36-108 = yellow
162-729 = red
Formulation
Buffer
Contaminated
(bioburden) buffer
can further
contaminate the
drug
substance/bulk.
Bioburden
contamination in
DS (above Action
Level).
Unacceptable
endotoxin levels
post-filtration.
9 [1] 2 3 3 162

Up to 27 = wide limits
36-108 = medium limits
162-729 = narrow limits
Scoring Description/Justification
Current Control(s)
and/or Possible
Risk Mitigation
Recommended
Action(s)
Sampling/Testing
Bioburden
RPN-based Action(s)
Alert/Action Level(s)
Endotoxin
RPN-based
Action(s)
Alert/Action Level(s)
(Potential) high bioburden and/or endotoxin
levelscould impact product safety. Product
released with high Endotoxin levels, causing
adverse events in patients. Higher S patient
multiplier (9) used in RPN calculation. Endotoxin
levels in Formulation buffer have been below
Alert Level (1). Detectability is limited (2) due to
sampling (sample may not be representative and
real-time testing not possible). Limited
proliferation possible (3) as processing
temerature and time in manufacturign is RT and
up to 10 hours. Replicability (doubling) in
formulation buffer is not prevented. Control is
limited to bioburden filtration and not endotoxin.
High levels of bioburden would also render the
formulation buffer unacceptable.
(RPN = S (patient) [x O] x D x P x C = 9 x 1 x 2
x 3 x 3 = 162
Formulation buffer is
to be tested and
rejected prior to use
if at/above Action
Level(s).
Sample formulation
buffer no later than xx
hours prior to use.
Store formulation
buffer at 2-8 C and no
longer tha xx hours at
RT.
Narrow Limit(s):
Alert = 1 CFU/10mL;
Action = 10 CFU/10mL
Narrow Limit(s):
Alert = 0.25 EU/mL;
Action = 1.00 EU/mL

Examples of PQ (PV Stage 2) Downstream In-Process Control
Alert and Action Limits for Bioburden and Endotoxin
Test / Alert/Action
Level
Mfg Process
Step/Material
Risk Priority
Number
Alert/Action Levels
Bioburden Formulation Buffer High
Alert: 1 CFU/10mL
Action: 10 CFU/10mL
Endotoxin (LAL) Formulation Buffer High
Alert: 0.25 EU/mL
Action: 1.00 EU/mL
Bioburden
Protein A Column Wash
Buffer
Medium
Alert: 3 CFU/10mL
Action: 30 CFU/10mL
Endotoxin (LAL)
Protein A Column Wash
Buffer
Medium
Alert: 0.25 EU/mL
Action: 2.0 EU/mL
Bioburden
Combined Protein A
Column Product Pool
Low
Alert: 10 CFU/10mL
Action: 100 CFU/10mL
Endotoxin (LAL)
Combined Protein A
Column Product Pool
Low
Alert: 1.0 EU/mL
Action: 5.0 EU/mL

Examples of PQ (PV Stage 2) Upstream In-Process Control
Alert and Action Limits for Bioburden and Endotoxin
Test / Alert/Action
Level
Mfg Process
Step/Material
Risk Priority
Number
Alert/Action Levels
Bioburden
Bioreactor Pre-Transfer
Seed Sample
High Alert/Action: 1 CFU/10mL
Endotoxin (LAL)
Bioreactor Pre-Transfer
Seed Sample
High
Alert: 0.25 EU/mL
Action: 1.00 EU/mL
Bioburden
Equilibration Buffer from
Harvest Tank
Medium
Alert: 1 CFU/10mL
Action: 10 CFU/10mL
Endotoxin (LAL)
Equilibration Buffer from
Harvest Tank
Medium
Alert: 0.25 EU/mL
Action: 2.0 EU/mL
Bioburden
Post-Harvest Conditioned
Medium
Low
Alert: 10 CFU/10mL
Action: 100 CFU/10mL
Endotoxin (LAL)
Post-Harvest Conditioned
Medium
Low
Alert: 0.25 EU/mL
Action: 5.0 EU/mL

CPV Acceptance Criteria and Conditions SK09Aug16

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Viewers also liked

Viewers also liked (8)

Similar to CPV Acceptance Criteria and Conditions SK09Aug16

Similar to CPV Acceptance Criteria and Conditions SK09Aug16 (20)

CPV Acceptance Criteria and Conditions SK09Aug16

Editor's Notes