Continuous Process Verification for a f T t i S F t d L PL ......Maint Check Process Maint Check...
Transcript of Continuous Process Verification for a f T t i S F t d L PL ......Maint Check Process Maint Check...
Continuous Process Verification for a Continuous Process Verification for a L P d t F Sit T f L P d t F Sit T f Legacy Product; From Site Transfer Legacy Product; From Site Transfer Through Post Marketing ChangesThrough Post Marketing Changes
Richard SchichoRichard SchichoJanuary 28, 2013
AgendaAgenda
Process Development/Manufacturing History
Site Transfer to “Paperless” Plant
Tech Transfer and Process Performance Qualification
Continuous Process Verification and Qualification of Post Marketing Changesg g
Process Development/Manufacturing HistoryProcess Development/Manufacturing Historyp g yp g yCommercial process developed at launch site > 10 years ago with limited DOE process> 10 years ago with limited DOE process characterizationProcess transferred to two CMO’s post-approvalProcess transferred to two CMO s post approval to support commercial demandTech Transfers included facility-fit and other minor changes, supported with analytical, non-clinical and clinical PK comparability studiesT h T f t l l t i l d dTech Transfer to paperless plant included facility-fit changes, supported with analytical comparability and enhanced process data package
Tech Transfer to Paperless PlantTech Transfer to Paperless PlantppGreenfield plant designed with highly automated and integrated electronic systemsand integrated electronic systemsElectronic batch records and QC laboratory methods integrated with business systemsg yBatch context database system with > 4500 points configuredSix production bioreactors with a single downstream trainIQ/OQ/PQ studies, kla studies and non-GMP engineering runsC bi d d t k t t i l fCombined data package to support equivalence of bioreactors and N=3 PPQ study
Paperless Plant Components
ERP
rtal
genc
e P
or
Mfg EngineBatch Query/
ReportsKPI Dashboards
LIMS
Methods Execution
urin
g In
telli Mfg Engine Reports
eBatch RcdEnterprise Data Historian
Enterprise Reporting
Maintenance & Calibration
Doc. Mgmt
Man
ufac
tu Batch Engine(S88 Recipe)
Common Data
Training Records
Advanced Analytics
Ent
erpr
ise
Plant Floor (DCS/PLC, BAS, PAT
System/Devices)
DataHistorian QMS/CAPA
eChange Control
E
Plant Execution and Transactional
Mfg Operations Analysis & Reporting
Supporting Business Systems
Interface Interface -- MES/ERPMES/ERP
Interface Interface –– MES/LIMS/Lab NotebookMES/LIMS/Lab NotebookMES LIMS Lab Notebook
Start Recipe Execution
Generate Sample ID’s
Start
Initiate LIMS Job
R t S l ID
Collect Sample
Processing
Record LIMS Sample and
Send ID
Request Sample ID
Return Sample ID
Start Assay Preparation
Send SampleReceive Test
RequestTest Request
Conduct Assay & Approve
Results
Continue Processing
Return Results if Required
If Material
Send Test ResultsResults
Update Genealogy
Consumption Send
GenealogyProcess Order
Complete PFD for Process Unit
Maint Check
ProcessMaint Check Maint
CheckMaint Check
Room Check
Condition Checks Material Checks
Check
HygienicPreparation
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HygienicPreparation
HygienicPreparation
Process
Preparation
Process
Process HygienicPost
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H i i
Process
HygienicProcess
Process
HygienicPost
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Identifying Resuable ‘Patterns’
Process Performance QualificationProcess Performance QualificationQQThree PPQ runs operated in a single production bioreactorbioreactorProcessing from vial thaw through to drug substance fill under protocol, including media gand buffer preparationDesignated Validation Parameters throughout ththe processExtended characterization testing of drug substance including side by side testing ofsubstance, including side-by-side testing of comparator lots from approved siteLong term, intermediate and acceleratedLong term, intermediate and accelerated stability studies
Continuous Process Verification and Continuous Process Verification and Qualification of PostQualification of Post--marketing Changesmarketing ChangesQQ g gg gQuality Systems
Complaints and Adverse Event ReportingOOS, Market life stability studies, process d i ti (i l di i ld i ti )deviations (including process yield variation)Facility/equipment maintenance and calibration programscalibration programs
Statistical Process Control ProgramN l ti it iNear real-time process monitoringAbility to perform ad hoc queries to investigate statistical trends shifts or outliersstatistical trends shifts or outliers
Statistical Process Control ProgramStatistical Process Control ProgramggEncompasses in-process, release test data and release test method performance parametersp pDevelopment of >400 control charts, PPs, CPPs, CQAs, system suitability and KPIs
Temporary limits set after 10 lots and permanent limits set after 30 lots; Process Capability
A d d i f l h i h ilAutomated updating of control charts with email notification of statistical alertsInvestigation of outliers shifts and trends toInvestigation of outliers, shifts and trends to identify special cause variationCompilation of data for annual reports andCompilation of data for annual reports and assessment of validated state of the process
Statistical Process Control ProgramStatistical Process Control ProgramggCross-funtional team including Mfg Technology, Mfg QC QE Validation and AutomationMfg, QC, QE, Validation and AutomationWeekly meetings for review of data trending; investigation of statistical alert eventsinvestigation of statistical alert eventsDevelopment of CAPA and continuous improvement opportunities
Potential changes to reduce process variability are evaluated via Change Control
t di th d f dditi lsystem regarding the need for additional Process Characterization and/or Qualification
Process HierarchyProcess HierarchyProcess HierarchyProcess Hierarchy
Chromatography NodeChromatography Node
Bioreactor NodeBioreactor Node
Data Model Capabilities Data Model Capabilities –– Control Charts Control Charts
Control Charting of all Critical Process Parameters with automated e-mail alerts for excursionsOver 400 charts refresh on a daily basis and generate alerts via e-mail including Upstream, Downstream and Drug Substance data
Data Model Capabilities Leveraged Data Model Capabilities Leveraged –– Transition Transition AnalysisAnalysis
Data Model Capabilities Leveraged Data Model Capabilities Leveraged –– Raw Materials Raw Materials AnalysisAnalysis
Due to small groupings of batches that utilize the same raw material lot Segmented chart shows raw material high and low performance within one lot of the raw material This demonstrates that this raw
Segmented chart shows also highlighted raw materials that had a potential impact on the bioreactor performanceg p g
numbers, segmented charts were used in the analysis.
The raw materials analysis eliminated many of the raw materials that were not
within one lot of the raw material. This demonstrates that this raw material is not the main contributing factor for the performance.
potential impact on the bioreactor performance.
y ythe primary factor effecting the production bioreactor performance.
In the initial stages of the investigation, some raw materials were identified as g g ,a potential root cause of the performance shift. Changes in the planned raw materials for future batches were made to mitigate the potential impact of the identified raw materials.
Qualification of PostQualification of Post--approval Changesapproval ChangesQQ pp gpp gReview and approval of proposed changeIdentification of key parameters related to potential impact of process changeP d ti f “t t” ith hProduction of “test” runs with process changeStatistical analysis of impact of process change including assessment of Process control chartsincluding assessment of Process control charts
Qualification of PostQualification of Post--approval Changesapproval ChangesQQ pp gpp g
ConclusionsConclusionsHighly integrated electronic systems
Ensure control of process and analytical method executionEnable the collection of data in real timeEnable the use of sophisticated analytical tools f ti it ifor continuous process monitoring, process change qualification and periodic assessment of the validated state of the process
AcknowledgementsAcknowledgementsgg
Joe ShiminskyPete Mikkonen