a case study of continued process verification and … case study of continued process verification...
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A Case Study of Continued Process Verification and Life Cycle Approach for a Well Characterized Insulin Analog
Warren MacKellar, PhDEli Lilly & Co.
Key Statistics• Equipment:
5,330 tanks and 6,850 pumps
• Fermentation & Purification, Distribution
• 24h Operations, 365 days/year
• 1.38 Million Square Feet (18 soccer fields)
Indianapolis Drug Substance Manufacturing
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“Good process design and development should anticipate significant sources of variability and establish appropriate detection, control, and/or mitigation strategies, as well as appropriate alert and action limits. However, a process is likely to encounter sources of variation that were not previously detected or to which the process was not previously exposed.”
CASSS CMC Forum Introduction
I’m an Expert !!
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or the Evolution of CPV
ISPE Model outlines different layers to the Control Strategy
Safety, Efficacy & Quality Business/ Operations
OperationalRequirements
OperationalParameters
Product CQAs(Critical Quality
Attributes)
Parameters, attributes and
ranges to assure Product CQAs
are met
Analytical, Facility & Engineering Control Methods
Product ControlStrategy
Operational Control Strategy
Defined and delivered by DevelopmentAligned with Registered commitmentsIndependent of site of manufacture
Details required to ensuredelivery of CPP’s, spec’s ,etcDefined at Tech Transfer to site
Leve
l 1Le
vel 2
Leve
l 3
ProcessEquipment
Analytical
People
IAPI Integrated Control Strategy (iCS)
o New Processes: iCS is documented
o Legacy Process : iCS in Progress
o Leveraging OSI Pi /Discoverant for Routine Process Monitoring
o Routine Data Reviews by Process Teams is in place
o Equipment Control Strategies ongoing
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Process Data acquisition and analysis
Historian
ManualData Entry
Analysis / Results
Read Only
LIMSSAP
Source Systems
MDI
PI SADHierarchyProcess Driven
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Science and Risk Based approach to develop comprehensive control strategy......
Control Strategy Development - Legacy Products
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Process Knowledge /
Process Understanding
Process Development
Process Characterization
Process Performance Verification
Lifecycle Management
Final Control Strategy
Quality Attributes
Process Parameters
Risk Assessment
Risk Assessment
Validation Lifecycle
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Process Validation Lifecycle
Stage 1 Stage 2 Stage 3
Development Qualification andProcess Validation
Ongoing Process Verification
Stage 2a Stage 2b Stage 3a Stage 3b
Commercial Manufacturing
Equipment Qualification(IQ,OQ,PQ)
Process Validation
Heightened Monitoring
Routine Monitoring
Validation Approach for a New Molecule
Patient Needs
Business Needs
Product Design
Process Design
Technology Transfer
Process Validation
Res
earc
h an
d cl
inic
al S
tudi
es
Commercial Manufacturing
Product Lifecycle
QTPP Process Characterization: CQAs, CPPs, PARs
Continued Process Verification: Maintaining the validated state
Process Validation (PPQ batches)
Stage 1 Stage 2 Stage 3
Increasing Process Understanding/Control Strategy Evolution
Control Strategy
Lilly’s Insulin Processes Validation Evolution
Fermentation
Precursor Isolation
Initial Purification
Drug Substance Purification
Drug Substance
Time
Validation Approach for a New Molecule
Patient Needs
Business Needs
Product Design
Process Design
Technology Transfer
Process Validation
Res
earc
h an
d cl
inic
al S
tudi
es
Commercial Manufacturing
Product Lifecycle
QTPP Process Characterization: CQAs, CPPs, PARs
Continued Process Verification: Maintaining the validated state
Process Validation (PPQ batches)
Stage 1 Stage 2 Stage 3
Increasing Process Understanding/Control Strategy Evolution
Control Strategy
Validation Evolution
Facility Expansion 1995
Product Lifecycle
Initial Registration
CPPs, PARs Defined 2005
Process Validation
Stage 1 Stage 3
Increasing Process Understanding/Control Strategy Evolution
iControlStrategy
1980s-Early 1990s
Stage 2
2011 LifecycleApproach
Process Qualification
Stage 2 Stage 2
What is our approach to CPV
8/14/2015 Company Confidential © 2015 Eli Lilly and Company 15
Periodic Evaluation
Num
ber o
f Pro
perti
es T
este
d
Product Lifecycle
2 3a 3b
270 ParametersMonitored
92 Parameters Monitored
34 AdditionalParameters MonitoredCPPs
ISOPPs
Process RemovalSpecifications
CPPsIS
Selected OPPsProcess Removal
Specification
CPPsISPR
Spec
CPPsISPR
Spec
CPPsISPR
Spec
Process Monitoring Plan
♦Focus on monitoring the effectiveness of the controls that are in place.
♦Process monitoring plan developed based on this approach is more proactive.
♦The risk assessment is used to make the final monitoring plan manageable.
♦The process monitoring plan is dynamic. It is revised as knowledge is gained during the product lifecycle.
Monitoring Plan
17Monitoring Plan identifies the who, what, when, and where.
Preventative Maintenance and CalibrationEnsures equipment and systems are maintained in a qualified state.
Annual Product ReviewMonitor, measure and analyse manufacturing processes and products,using statistical techniques, on a routine basis to evaluate trends overtime.
Change ControlAll changes proposed for a manufacturing system, equipment, method orprocess are evaluated to assess the impact on validation/ qualification.
Deviation managementProvides a structured risk-based approach to the investigation,determination of the root cause, documentation, identification andimplementation of any resultant corrective action and preventive actions(CAPAs) for all departures
Periodic Review of Facilities, Utilities, Equipment and Computer SystemsEvaluate trends, compare data with historical information to determineshifts and assess the state of control of the facility, utility, equipment andcomputer system.
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Integration within the Quality System key to maintain the
validated state
Continued Process Verification Overview
♦ Historical Legacy approach has been updated to align with current industry expectations, we are integrating learning from the last >30 years into a modern control strategy
♦ Validation program demonstrates process performance consistency for ongoing commercial manufacture
♦ CPV program and quality systems ensure process remains in state of control and continuous improvement opportunities identified and implemented appropriately
Results in a well understood and controlled process that produces high quality medicine over the lifecycle of the product
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Gregg GordonMatthew Deacon
Gerald LeisterMatthew SewardBethany Rexing
Ciaran Brady
Acknowledgements
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