cpv acceptance criteria and conditions sk09aug16
TRANSCRIPT
Stephan KrauseDirector, QA TechnologyAstraZeneca Biologics
BioProcessing Summit 17-18 August 2016Boston, 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 1Phase 2
Phase 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
evel
opm
ent
(QbD
Pro
cess
)Sp
ecs
Life
Cyc
le
Mgm
tC
MC
and
Tec
h Tr
ansf
er P
roce
ss 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 1Phase 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-APPROVALCHANGESPIVOTAL PHASE (3)PHASE 1 Pre-IND
CQ
A D
evel
opm
ent
(QbD
Pro
cess
)Sp
ecs
Life
Cyc
le
Mgm
tC
MC
and
Tec
h Tr
ansf
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
5From: Krause, S., CaSSS CMC Strategy Forum, 27Jan14, Washington, DC.
FTIH POC BLA
Tox Studies Phase 1Phase 3
Clinical ResupplyMfg/Formulation Change(s)
Specifications Revision(s)
Commercial Specifications
QTPP
Final CQAs & Control Strategy Approval
Potential CQAsProduct & Process Design
Life-CycleManagement
POST-APPROVALCHANGESPIVOTAL PHASE (3)PHASE 1 Pre-IND
CQ
A D
evel
opm
ent
(QbD
Pro
cess
)Sp
ecs
Life
Cyc
le
Mgm
tC
MC
and
Tec
h Tr
ansf
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 lots CompLots =
6
Typical CQA Development, CMC Changes, and Specifications
From: Krause, S., WCBP, 30Jan13, Washington, DC.
FTIH POC BLA
Tox Studies Phase 1Phase 2
Phase 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
evel
opm
ent
(QbD
Pro
cess
)Sp
ecs
Life
Cyc
le
Mgm
tC
MC
and
Tec
h Tr
ansf
er P
roce
ss 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
S. Krause, PDA Annual Meeting - Las Vegas 17March15
CPV
CPV
CPV
CPV
QA Process
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
15
Considerations for CPV (Limits)Data Transformation of Non-Normal Distributions
Original-scaled data
Log-scaled data
Data are not symmetric around center: mean and standard deviation not appropriate metrics.
Courtesy of Steven Novick, MedImmune
Considerations for CPV (Limits)Data Transformation of Non-Normal Distributions
16From: Responses to Signals from a Continued Process Verification System in the Biopharmaceutical Industry
Considerations for CPV (Limits)Data Transformation of Non-Normal Distributions
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 K2 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%
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%
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%
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)
Example: Drug Substance Specifications and CPV Limit(s)OOT Stability Conditions (OOT at 18M)
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
?
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%
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
Incr
easi
ng S
ever
ity
of P
roce
ss/P
rodu
ct/Q
ualit
y Im
pact
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
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
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
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 / Specificat
ionIMP Phase 1-2 IMP Pivotal
or Phase 3PQ 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.
S. Krause, PDA Annual Meeting - Las Vegas 17March15
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.
S. Krause, PDA Annual Meeting - Las Vegas 17March15
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
S. Krause, PDA Annual Meeting - Las Vegas 17March15
• 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 MediumThe 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 HighThe 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=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
Modified QRM FMEA for Bioburden and Endotoxin IPC Alert/Action Levels
S. Krause, PDA Annual Meeting - Las Vegas 17March15
Modified FMEA Example for Downstream Alert/Action Levels
S. Krause, PDA Annual Meeting - Las Vegas 17March15
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
Modified FMEA Example for Downstream Alert/Action LevelsIs Previous Occurrence a Factor Here ?
S. Krause, PDA Annual Meeting - Las Vegas 17March15
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 filtered, formulated drug substance/bulk.
Bioburden contamination in DS (above Action Level). Unacceptable endotoxin levels post-filtration.
9 [1] 2 3 3 162
Modified FMEA Example for Downstream Alert/Action LevelsCan Uncertainty be a Factor ?
S. Krause, PDA Annual Meeting - Las Vegas 17March15
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 filtered, formulated drug substance/bulk.
Bioburden contamination in DS (above Action Level). Unacceptable endotoxin levels post-filtration.
9 [1] 2 3 3 162
Modified FMEA Example for Downstream Alert/Action Levels
S. Krause, PDA Annual Meeting - Las Vegas 17March15
Up to 27 = wide limits 36-108 = medium limits 162-729 = narrow limits
Scoring Description/JustificationCurrent 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 HighAlert: 1 CFU/10mL
Action: 10 CFU/10mL
Endotoxin (LAL) Formulation Buffer HighAlert: 0.25 EU/mL
Action: 1.00 EU/mL
BioburdenProtein A Column Wash
BufferMedium
Alert: 3 CFU/10mL
Action: 30 CFU/10mL
Endotoxin (LAL)Protein A Column Wash
BufferMedium
Alert: 0.25 EU/mL Action: 2.0 EU/mL
BioburdenCombined Protein A
Column Product PoolLow
Alert: 10 CFU/10mL
Action: 100 CFU/10mL
Endotoxin (LAL)Combined Protein A
Column Product PoolLow
Alert: 1.0 EU/mL Action: 5.0 EU/mL
S. Krause, PDA Annual Meeting - Las Vegas 17March15
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
BioburdenBioreactor Pre-Transfer
Seed SampleHigh Alert/Action: 1 CFU/10mL
Endotoxin (LAL)Bioreactor Pre-Transfer
Seed SampleHigh
Alert: 0.25 EU/mL Action: 1.00 EU/mL
BioburdenEquilibration Buffer from
Harvest TankMedium
Alert: 1 CFU/10mL
Action: 10 CFU/10mL
Endotoxin (LAL)Equilibration Buffer from
Harvest TankMedium
Alert: 0.25 EU/mL Action: 2.0 EU/mL
BioburdenPost-Harvest Conditioned
MediumLow
Alert: 10 CFU/10mL
Action: 100 CFU/10mL
Endotoxin (LAL)Post-Harvest Conditioned
MediumLow
Alert: 0.25 EU/mL Action: 5.0 EU/mL
S. Krause, PDA Annual Meeting - Las Vegas 17March15