1. Stephan O. Krause, PhD
BioProcessing Summit, Boston MA
Strictly Confidential
18-19 August 2016
CPV Acceptance Criteria and Conditions

2. Outline
CPV/Commercial acceptance criteria - non-microbiological CQAs
– Control strategy development
– CPV conditions/rules
– “QA process”
CPV/Commercial acceptance criteria - microbiological CQAs
– Not presented here but available via ShareSlide
The content and views expressed by the author/presenter are not necessarily
the views of the organization he represents.

3. 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

4. Accelerated CQA Development, CMC Changes, and Specifications
4
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.

5. 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
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=

6. 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
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
Formal CPV

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

8. CPV

9. CPV

10. CPV

11. CPV
QA Process

12. 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
S. Krause, PDA Annual Meeting - Las Vegas 17March15

13. 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

14. 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

15. 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. Considerations for CPV (Limits)
Data Transformation of Non-Normal Distributions
16
From: Mark DiMartino et al. on behalf of BioPhorum Operations Group, Responses to Signals from a Continued
Process Verification System in the Biopharmaceutical Industry (to be submitted to an Autumn 2016 edition of
theISPE Journal of Pharmaceutical Engineering).

17. Considerations for CPV (Limits)
Data Transformation of Non-Normal Distributions
17
How many lots before we move the center of CLs ?
From: Mark DiMartino et al. on behalf of BioPhorum Operations Group, Responses to Signals from a Continued
Process Verification System in the Biopharmaceutical Industry (to be submitted to an Autumn 2016 edition of
theISPE Journal of Pharmaceutical Engineering).

18. 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.
# 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

19. 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%

20. Example: Drug Substance Specifications and CPV Limit(s)
Statistical Release Conditions
SK 22Feb16
HPSEC
(%Monomer)
100.0%
98.5%
DS Release NLT 98.0%
OOC Limit 99.2% (Stat: One-Sided 99.85% based on 3 SDs)
Future DS Release
Result (n=1)
DS EOSL NLT 97.0% (= DP Release)
99.5%
99.0%
98.0%
97.0%

21. Example: Drug Substance Specifications and CPV Limit(s)
“Practical” Alert/Action Conditions (based on non-stats DS
release specs)
SK 22Feb16
HPSEC
(%Monomer)
100.0%
98.5%
DS Release NLT 98.0%
Alert/Action Limit NMT 98.8%
Future DS Release
Result (n=1)
DS EOSL NLT 97.0% (= DP Release)
99.5%
99.0%
98.0%
97.0%

22. Example: Drug Substance Specifications and CPV Limit(s)
OOT Release Conditions for Sequential Batches
SK 22Feb16
HPSEC
(%Monomer)
100.0%
98.5%
DS Release NLT 98.0%
OOC Limit 99.2% (Stat: One-Sided 99.85% based on 3 SDs)
Future DS Release
Result (lot 31-32)
DS EOSL NLT 97.0% (= DP Release)
99.5%
99.0%
98.0%
97.0%
Alert/Action Limit NMT 98.8%
Future DS Release
Result (lot 31-37)

23. Example: Drug Substance Specifications and CPV Limit(s)
OOT Stability Conditions (OOT at 18M for 20-25ºC)
HPSEC
(%Monomer)
1 2 3 4
100.0%
98.5%
DS Release NLT 98.0%
DS EOSL NLT 97.0% (= DP Release)
99.5%
99.0%
98.0%
97.0%
OOT
?

24. Example: Drug Substance Specifications and CPV Limit(s)
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)

25. 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

26. PPQ Specifications, CPV Acceptance Criteria, and Non-Conformance Conditions

27. PPQ Specifications, CPV Acceptance Criteria, and Non-Conformance Conditions

28. PPQ Specifications, CPV Acceptance Criteria, and Non-Conformance Conditions

29. PPQ Specifications, CPV Acceptance Criteria, and Non-Conformance Conditions

30. Reference
CPV/Commercial acceptance criteria – microbiological
CQAs
– Risk assessment process
– Alert and action level examples
(Krause, S., “Alert, Action, and Specification Limits for Bioburden and Endotoxin”, PDA Annual
Meeting, 2015)

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