process validation - practicle aspects - ISPE.pdf

8/14/2019 process validation - practicle aspects - ISPE.pdf

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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

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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.

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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

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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

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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

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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.


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HowmanyPPQruns? Considerationsforthedurationoftheheightened

samplingandmonitoringperiod:

volumeofproduction

processcomplexity

levelofprocessunderstanding

experiencewithsimilarproductsandprocesses

Morevariabilitymoreruns

Moreuncertaintymoreruns


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PPQProtocol

Manufacturingconditions

Datacollectionandevaluation

Testing,includingacceptancecriteria

Samplingplan

Intraandinterbatchquality

PPQReport

Summarizedata/resultsfromPPQruns

Stateaclearconclusionregardingstateofcontrol


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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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Howisthisaccomplished? System(s)fordetectingunplanneddepartures

fromtheprocessasdesigned

Ongoingprogramtocollectandanalyzeproduct

andprocessdatathatrelatetoproductquality

Processtrends

Inprocessmaterial

Finishedproducts

Statisticaltrending

with

review

StatisticianorpersonwithSPCtraining31


Othermeanstodetectvariation

Deviations/nonconformances

OutofSpecificationresults

Batchrecords

Defectcomplaints

Adverseeventreports

etc.

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FDArecommends

continued

monitoring

and

samplingofprocessparametersandqualityattributesatthelevelestablishedduringPPQuntilsufficientdataisavailabletogeneratevariabilityestimates.

Theseestimatescanprovidethebasisforestablishinglevelsandfrequencyofroutinesamplingandmonitoringfortheparticularproductandprocess.

Monitoringcanthenbeadjustedtoastatistically

appropriateand

representative

level.

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ProcessValidationSampling

34

0

2

4

6

8

10

12

1 6 11 16 21 26

AmountofSampling

LotNumber


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Approvedproduct

implies

that

Stages

1and

2

complete

HowtoimplementStage3

Thegoalofthethirdvalidationstageiscontinual

assurancethattheprocessremainsinastateofcontrol

(thevalidatedstate)duringcommercialmanufacture.

Asystemorsystemsfordetectingunplanned

departuresfromtheprocessasdesignedisessentialto

accomplishthis

goal.

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Theory:Continuetogainknowledgethroughout

productlifecycle

Manufacturingexperienceshouldyieldincreased

knowledgeandprocessimprovements

Lackofprocessimprovementsindicateslackof

processunderstandingandfailuretolearn(implement

learning)

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Practice:Dont

fix

it

if

its

not

broke

Traditionallymanufacturersarereluctanttochangea

processoncevalidated

Reluctancetolookbackwardatreleasedlots(what

willwefind?)

Analysis,trending,andassessingvariabilityare

typicallyadhoc

Onlyimpetusforchangeweredeviations/OOS

results

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Challenge:IdentifyingCPPsandCQAs

Sources:

Originalprocessvalidation

Specifications

Batchrecords/SOPs

Deviations/CAPAs/ChangeControls

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Challenge:Obtaining

Data

Executedbatchrecords

Annualproductreview

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Challenge:EstablishingaCPVProgram

Howwilltheprogrambesetup?

Whowillimplementit?

Whataretherequiredqualifications?

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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


Recommendations

SmallSteps

Obtaindata,eitherretrospectivelyorprospectively

Plotdatawithspecificationlimits

Lookforobviousissues:

Trends

Visualmeanvalueoffsetfromtargetor

specificationcenterline

Bimodalresults

Insufficientresolution(pHonlyrecordedto0.1unit)

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RecommendationsSmallSteps,continued

Assessnormalityofdata

Establishcontrollimits(2030datapointsneeded)

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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

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Challenges:Artifactsarefoundindatareview:BimodalResults

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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

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