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ProcessValidation:
PracticalAspects
of
the
NewFDAGuidance
ISPEBostonChapterMeeting
April18,2013
Rusty
MorrisonCommissioningAgents,Inc.
Objectives/Summary
WhatisProcessValidation?
RegulatoryBasisandGuidanceDocuments
Definitions
ReviewoftheFDA2011PVGuidance
ApplyingNewGuidancetoOldProducts
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RegulatoryBasis
21CFR211.110a:
... control procedures shall be established
to monitor the output and to validate the
performance of those manufacturing
processes that may be responsible for
causing variability in the characteristics of
inprocess material and the drug product.
3
ProcessValidation OldDefinition
Process validation is establishing documented
evidence which provides a high degree of
assurance that a specific process will
consistently produce a product meeting its
predetermined specifications and quality
characteristics.
GuidelinesonGeneralPrinciplesofProcessValidation,FDA(1987)
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NewFDAProcessValidationGuidance
InJanuary,
2011FDA
issuednew
guidancefor
industry
regarding
process
validation
5
ProcessValidationToday
NewFDAguidancefocusedonproductqualitythroughprocessunderstandingandcontrol:
Process validation is defined as the collection andevaluation of data, from the process design stagethrough commercial production which establishesscientific evidence that a process is capable ofconsistently delivering quality product.
(emphasisadded)
GuidelinesforIndustry ProcessValidation:GeneralPrinciplesandPracticesFDA(January2011)
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ProcessValidationToday
Summaryof
significant
changes:
Addemphasistoprocessdesign
Includesdiscussionofrisk
Involveactivitiesoverentireprocesslifecycle(ongoing
program,inthreedefinedstages)
Emphasizesroleofobjectivemeasuresandstatisticaltools
Emphasizesknowledge,detectionandcontrolofvariability
Asalways,newguidancewilltaketimetoworkits
waydowntotraditionalprocessvalidation
Howto
apply
new
guidance
for
legacy
products?
7
EMADraftProcessValidationGuidance
InMarch2012
FDAissueda
draftguideline
forprocess
validation
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USFDAvs.EMA
Significantdifferencesexistbetweentheissued
FDAguidanceanddraftEMAguideline
Theremainderofthispresentationwillbebased
ontheFDAguidance.
9
Definitions
ManufacturingProcess Thesequenceofactivities,people,andsystemsinvolved
incarryingoutsomebusinessorachievingsomedesired
result.
Process
INPUTS OUTPUTS
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Definitions
ProcessParameters(akaOperatingParameters) Theconditionsunderwhichaprocessisperformed
Canbephysicalorchemical
pH,temperature,pressure,agitatorrpm,flowrate,etc.
Processparametersareusuallycontrolledwithindefined
operatingrangestosetpointvalues
Process
INPUTS OUTPUTS
Process
Parameters
11
Definitions
CriticalQualityAttributes(CQAs) Aphysical,chemical,biological,ormicrobiologicalproperty
orcharacteristicthatshouldbewithinanappropriatelimit,
range,ordistributiontoensurethedesiredproduct
quality.(ICHQ8)
NotalloutputsareCQAs
Process
INPUTS OUTPUTS
Process
Parameters
CQAs
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Definitions
CriticalQualityAttributes(CQAs) Acronymsforappropriatelimit,range,ordistribution
AcceptanceCriterion(plural:Criteria)
Specification
Process
INPUTS OUTPUTS
Process
Parameters
CQAs
13
Definitions
Critical(orKey)ProcessParameters (CPPs) Aprocessparameterwhosevariabilityhasanimpactona
criticalqualityattributeandthereforeshouldbemonitoredorcontrolledtoensuretheprocessproducesthedesiredquality(ICHQ8)
Example:pHduringionexchangechromatographysteps
Process
INPUTS OUTPUTS
Process
Parameters
CQAs
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Definitions
NonCritical/NonKeyProcessParametersThoseprocessparameterswhichdonothaveadirect
impactonproductquality
Example:Flowrateduringbioreactorinoculation
Process
INPUTS OUTPUTS
Process
Parameters
CQAs
15
16
CPPsandCQAs
CPPs CQAs
Typically, setpoint with an
operating range
Acceptance Criteria /
Specifications
Inputs Outputs
Controlled to achieve consistent,
repeatable, reliable results
Used to demonstrate process
control, repeatability, and reliability
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ProcessValidation NewGuidance
KeyConcepts:
Understandthesourcesofvariation
Detectandmeasuresourcesofvariation
Understandtheimpactofvariationontheprocess
andfinalproductattributes
Controlthesourcesofvariationcommensuratewith
therisktheyrepresenttotheprocessandfinal
productattributes
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ProcessValidation NewGuidance
Processvalidationinvolvesaseriesofactivities
takingplaceoverthelifecycleoftheproduct:
Stage1:ProcessDesign
Stage2:ProcessQualification
Stage3:ContinuedProcessVerification
Manyactivitiesoccurinmorethanonestage
(thinklifecycle)
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Stage1:ProcessDesign
Thecommercial
manufacturing
process
is
defined
duringthisstagebasedonknowledgegained
throughdevelopmentandscaleupactivities
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Stage1:ProcessDesignElement1:Building/CapturingProcessKnowledge
QualityTargetProductProfile(ICHQ8)
Intendeddosageform
Routeofadministration
Expecteddrugproductqualityattributes
Generalmanufacturingpathway
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Activities(Characterization)
DesignofExperiments
DesignSpace/ControlSpace
RiskAssessments
Laborpilotscaleexperiments
Computermodeling
Documentationofresultsisessential
Stage1:ProcessDesignElement1:Building/CapturingProcessKnowledge
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Stage1:ProcessDesignElement2:EstablishProcessControlStrategy
Controlsourcesofvariation
Reduceinputvariation
Adjustforinputvariationduringmanufacturing
Combinationofboth
ProcessAnalyticalTechnology(PAT)
implementation
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Stage2:ProcessQualification
Theprocess
design
is
evaluated
to
determine
if
the
processiscapableofreproduciblecommercial
manufacturing
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Stage2:ProcessQualificationElement1:Utility/EquipmentQualification
Demonstrationthatutilitiesandequipmentare
suitablefortheirintendeduse,andperform
properly.
InstallationQualification(IQ)
OperationalQualification(OQ)
PerformanceQualification(PQ)
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Stage2:ProcessQualificationElement2:ProcessPerformanceQualification(PPQ)
Thisstagehastraditionallybeenknownas
conformancerunsordemonstrationbatches
AmanufacturermustsuccessfullycompletePPQ
beforecommencingcommercialdistributionof
thedrugproduct
ApproachtoPPQshouldbebasedon
Overallproduct&processunderstanding
Demonstrationofcontrol
Useofobjectivemeasures(statistics)toprovide
assuranceofcontrol25
Inmostcases,PPQwillhaveahigherlevelof
sampling,additionaltesting,andgreaterscrutinyof
processperformancethanwouldbetypicalof
routinecommercialproduction
Theincreasedlevelofscrutiny,testing,andsampling
shouldcontinuethroughtheprocessverification
stageas
appropriate,
to
establish
levels
and
frequencyofroutinesamplingandmonitoringfor
theparticularproductandprocess.
Stage2:ProcessQualificationElement2:ProcessPerformanceQualification(PPQ)
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HowmanyPPQruns? Considerationsforthedurationoftheheightened
samplingandmonitoringperiod:
volumeofproduction
processcomplexity
levelofprocessunderstanding
experiencewithsimilarproductsandprocesses
Morevariabilitymoreruns
Moreuncertaintymoreruns
Stage2:ProcessQualificationElement2:ProcessPerformanceQualification(PPQ)
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PPQProtocol
Manufacturingconditions
Datacollectionandevaluation
Testing,includingacceptancecriteria
Samplingplan
Intraandinterbatchquality
PPQReport
Summarizedata/resultsfromPPQruns
Stateaclearconclusionregardingstateofcontrol
Stage2:ProcessQualificationElement2:ProcessPerformanceQualification(PPQ)
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Stage2:ProcessQualificationElement2:ProcessPerformanceQualification(PPQ)
ReleaseofPPQBatches Normally,completionofallPPQbatchesand
approvalofPPQreportsisrequiredfor
commercialdistributionofaproduct
Underspecialcircumstances,concurrentrelease
ofPPQbatchesmaybeacceptable
Infrequentlymanufactured(orphandrugs)
Shorthalf
lives
Drugshortage
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Stage3:ContinuedProcessVerification(CPV)
GoalofCPV:Continualassurancethattheprocess
remainsinastateofcontrol(thevalidatedstate)
duringcommercialmanufacture
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Stage3:ContinuedProcessVerification(CPV)
Howisthisaccomplished? System(s)fordetectingunplanneddepartures
fromtheprocessasdesigned
Ongoingprogramtocollectandanalyzeproduct
andprocessdatathatrelatetoproductquality
Processtrends
Inprocessmaterial
Finishedproducts
Statisticaltrending
with
review
StatisticianorpersonwithSPCtraining31
Stage3:ContinuedProcessVerification(CPV)
Othermeanstodetectvariation
Deviations/nonconformances
OutofSpecificationresults
Batchrecords
Defectcomplaints
Adverseeventreports
etc.
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Stage3:ContinuedProcessVerification(CPV)
FDArecommends
continued
monitoring
and
samplingofprocessparametersandqualityattributesatthelevelestablishedduringPPQuntilsufficientdataisavailabletogeneratevariabilityestimates.
Theseestimatescanprovidethebasisforestablishinglevelsandfrequencyofroutinesamplingandmonitoringfortheparticularproductandprocess.
Monitoringcanthenbeadjustedtoastatistically
appropriateand
representative
level.
33
ProcessValidationSampling
34
0
2
4
6
8
10
12
1 6 11 16 21 26
AmountofSampling
LotNumber
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ApplyingNewGuidancetoOldProducts
Approvedproduct
implies
that
Stages
1and
2
complete
HowtoimplementStage3
Thegoalofthethirdvalidationstageiscontinual
assurancethattheprocessremainsinastateofcontrol
(thevalidatedstate)duringcommercialmanufacture.
Asystemorsystemsfordetectingunplanned
departuresfromtheprocessasdesignedisessentialto
accomplishthis
goal.
35
ApplyingNewGuidancetoOldProducts
Theory:Continuetogainknowledgethroughout
productlifecycle
Manufacturingexperienceshouldyieldincreased
knowledgeandprocessimprovements
Lackofprocessimprovementsindicateslackof
processunderstandingandfailuretolearn(implement
learning)
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ApplyingNewGuidancetoOldProducts
Practice:Dont
fix
it
if
its
not
broke
Traditionallymanufacturersarereluctanttochangea
processoncevalidated
Reluctancetolookbackwardatreleasedlots(what
willwefind?)
Analysis,trending,andassessingvariabilityare
typicallyadhoc
Onlyimpetusforchangeweredeviations/OOS
results
37
Challenge:IdentifyingCPPsandCQAs
Sources:
Originalprocessvalidation
Specifications
Batchrecords/SOPs
Deviations/CAPAs/ChangeControls
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Challenge:Obtaining
Data
Executedbatchrecords
Annualproductreview
39
ApplyingNewGuidancetoOldProducts
Challenge:EstablishingaCPVProgram
Howwilltheprogrambesetup?
Whowillimplementit?
Whataretherequiredqualifications?
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ApplyingNewGuidancetoOldProducts
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RecommendationsAssembleamultidisciplinaryteam
Validation,PD,Manufacturing,QA,QC
Getabasicprograminplace(SOPorValidation
Plan?)
Datacollection/recording
Plotting
Analysis
Responseto
out
of
control
results
ReportingFrequency(review&approval)?
Pathwayforprocessimprovements41
ApplyingNewGuidancetoOldProducts
Recommendations
SmallSteps
Obtaindata,eitherretrospectivelyorprospectively
Plotdatawithspecificationlimits
Lookforobviousissues:
Trends
Visualmeanvalueoffsetfromtargetor
specificationcenterline
Bimodalresults
Insufficientresolution(pHonlyrecordedto0.1unit)
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ApplyingNewGuidancetoOldProducts
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RecommendationsSmallSteps,continued
Assessnormalityofdata
Establishcontrollimits(2030datapointsneeded)
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ApplyingNewGuidancetoOldProducts
ApplyingNewGuidancetoOldProducts
OtherChallenges SPCassumesprocessisinastateofstatistical
control.However,noteveryelementofevery
processwillbe.
Dataisnotnormallydistributed
Observedvariationwellwithinspecificationlimits
Data
indicates
specification
limit
excursions
are
likely
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Challenges:Artifacts
are
found
in
data
review:
Trends
45
ApplyingNewGuidancetoOldProducts
Challenges:Artifactsarefoundindatareview:BimodalResults
46
ApplyingNewGuidancetoOldProducts
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References
GuidelinesforIndustry ProcessValidation:General
Principlesand
Practices FDA
(January
2011)
EMADraftGuidelineonProcessValidation(March2012)
ICHQ8:PharmaceuticalDevelopment(QBD)
ICHQ9:QualityRiskManagement
ICHQ10:PharmaceuticalQualitySystem
ASTME2500:StandardGuideforSpecification,Design,and
VerificationofPharmaceuticalandBiopharmaceutical
ManufacturingSystemsandEquipment
PDATechReport60:ProcessValidationALifecyle
Approach PDATechReport59:UtilizationofStatisticalMethodsfor
ProductionMonitoring47
OtherResources
ISPEProcessValidationDiscussionPapers
(http://www.ispe.org/publications/discussion papers)
ISPEProductQualityLifecycleImplementation(PQLI)Guides
ISPECommunitiesofPractice
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Questions/Conclusions
49
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