A Review On Process Validation - Pharmatutor

8/11/2016
AREVIEWONPROCESSVALIDATION|PharmaTutor
AREVIEWONPROCESSVALIDATION
ABOUTAUTHORS
SuryaPratapSingh*,KailashDhaker,AbhisekNamdev,MahaveerPrasadKhinchi,SurbhiBhatnagar
1Departmentofpharmaceutics,KotaCollegeofPharmacy,
Kota,Rajasthan,India
sp.kota91@gmail.com
ABSTRACT
Process validation is the process for improving the safety and quality of the dosage form which is
manufacturedinthepharmaceuticalindustry.Basically,Processvalidationemphasizetheroleofobjective
measure and statistical tools and analyses knowledge ,detection ,and control of variability and give assurance on
consistentofquality/productivethroughoutlifecycleofproduct.ResultfromProcessvalidationmethodcanbeusedto
judge the quality and consistency of analytical result. The purpose of this review to cover need of process validation,
principleofprocessvalidation,typeofprocessvalidation,phaseofprocessvalidation,strategyforprocessvalidation.In
thisreviewarticlewediscussedabouttheimportanceandstrategyofvalidationofanalyticalprocedure.
REFERENCEID:PHARMATUTORART2451
INTRODUCTION
Validation is an act of proving that procedure, process, equipment, material, activity or system perform as expected
under given set of condition and also give the required accuracy, precision, sensitivity, ruggedness, etc. Method for
processvalidationistheprocessusedtoconfirmthattheanalyticalprocedureemployedforaspecifictestissuitablefor
itsintendeduse.Resultfrommethodvalidationcanbeusedtojudgethequalityandconsistencyofanalyticalresultitis
an integral part of good analytical practice. The process is developed in such a way that the required parameter are
achieved and it ensures that the output of the process will consistency meet required parameter during the routine
production.
Purposeofvalidation
Validationisdefinedasadocumentedprogramthatprovidesahighdegreeofassurancethataspecificprocess,method,
orsystemwillconsistentlyproducearesultmeetingpredeterminedacceptancecriteria.
The purpose of validation is to demonstrate the capability of the water treatment and air handling system to
continuouslysupplytherequiredquantityofwaterandairwiththespecifiedqualityattributes.Documentedmeansto
provide documented evidence. Validation provides the system owner with the means of assessing when a water
treatmentand/orairhandlingsystemisoperatingoutsideestablishedcontrolparameterlimitsandprovidesameansfor
bringing the system back into a state of control. It results in written operating and maintenance procedures for
personneltofollow,whichinturnhelpsensureconsistentsystemperformance.[1,2]
Methodvalidation
http://www.pharmatutor.org/articles/areviewonprocessvalidation?utm_source=feedburner&utm_medium=email&utm_campaign=Feed%3A+PharmatutorJo...
1/7
8/11/2016
Methodvalidation
Methodvalidationisvastareawhichincludesmanyvalidationparameterswithdifferentapproachesfordifferentlevelof
requirementbasedonintendeduseofanalyticalmethod,criticalityandregulatoryrequirements.Validatedmethodalso
cangivetheunpredictedorunknownproblemduringthecourseofroutineusage,becausevalidatedmethodhasalso
limitedlevelofconfidence,asmethodwasvalidatedforknownorpredictedvariableparametersoreverymethodcanfail
soonerorlater.Butstillaftermethoddevelopmentitneedstobevalidatedasperrequirementwhichgivescertainlevel
ofconfidenceforitsintendeduse.[3]
Thetypeanddegreeofvalidationdependsonthenatureofthetest.Inparticular,methodsdescribedinpharmacopeias
may not have to be validated, but those should be verified. Different test methods require different validation
parametersasdevelopmentoftheprojectprogressesandasanalyticalandproductspecificinformationisacquired,the
analytical methods evolve gradually updated. Each company has its own approach and set of acceptance criteria for
different analytical assays, but these approaches must be within the confines of their line unit quality assurance
departmentandbeinaccordancewithanyregulatoryprovisions.Inthissection,adescriptionforeachoftheparameters
tobevalidated(figuresofmerit)isdescribedindetails.[5]
Onceananalyticalmethodisdevelopedforitsintendeduse,itmustbevalidated.Theextentofvalidationevolveswith
thedrugdevelopmentphase.Usually,alimitedvalidationiscarriedouttosupportanInvestigationalNewDrug(IND)
application and a more extensive validation for New Drug Application (NDA) and Marketing Authorization Application
(MAA).TypicalparametersrecommendedbyFDA,USP,andICH.[4]
1.Specificity
2.Linearity&Range
3.Precision
(i)Methodprecision(Repeatability)
(ii)Intermediateprecision(Ruggedness)
4.Accuracy(Recovery)
5.Solutionstability
6.LimitofDetection(LOD)
7.LimitofQuantification(LOQ)
8.Robustness
Advantagesofanalyticalmethodvalidation
1.Theadvantagesoftheanalyticalmethodvalidationareasfollow:
2.Thebiggestadvantageofmethodvalidationisthatitbuildsadegreeofconfidence,notonlyforthedeveloperbut
alsototheuser.
3.Although the validation exercise may appear costly and time consuming, it results inexpensive, eliminates
frustratingrepetitionsandleadstobettertimemanagementintheend.
4.Minorchangesintheconditionssuchasreagentsupplierorgrade,analyticalsetupareunavoidableduetoobvious
reasonsbutthemethodvalidationabsorbstheshockofsuchconditionsandpaysformorethaninvestedonthe
process.[6,7]
IMPORTANCEOFVALIDATION
PlanningforValidation
All validation activities should be planned. The key elements of a validation programme should be clearly defined and
documentedinavalidationmasterplan(VMP)orequivalentdocuments.
TheVMPshouldbeasummarydocument,whichisbrief,conciseandclear.TheVMPshouldcontaindataonatleastthe
following:
1.Validationpolicy.
2.Organizationalstructureofvalidationactivities.
3.Summaryoffacilities,systems,equipmentandprocessestobevalidated.
4.Documentationformat:Theformattobeusedforprotocolsandreports.
5.Planningandscheduling.
6.Changecontrol.
7.Referencetoexistingdocument.
8.Incaseoflargeprojects,itmaybenecessarytocreateseparatevalidationmasterplans.
Documentation
A written protocol should be established that specifies how qualification and validation will be conducted. The protocol
shouldbereviewedandapproved.Theprotocolshouldspecifycriticalstepsandacceptancecriteria.Areportthatcross
references the qualification and /or validation protocol should be prepared, summarizing the results obtained,
commenting on any deviations observed, and drawing the necessary conclusions, including recommending changes2/7
8/11/2016
commenting on any deviations observed, and drawing the necessary conclusions, including recommending changes
necessarytocorrectdeficiencies.
Validationsetup
Toestablishthedesiredattributes.Theseattributesincludephysicalaswellaschemicalcharacteristics.Inthecaseof
parenterals, these absence of pyrogens, and freedom from visible particles. Acceptance specifications for the product
shouldbeestablishedinordertoattainuniformityandconsistentlythedesiredproductattributes,andthespecifications
shouldbederivedfromtestingandchallengeofthesystemonsoundstatisticalbasisduringtheinitialdevelopmentand
productionphasesandcontinuingthroughsubsequentroutineproduction.
The process and equipment should be selected to achieve the product specification. For example design engineers
productionandqualityassurancepeoplemayallbeinvolved.Theprocessshouldbedefinedwithagreatdealofspecificity
andeachstepoftheprocessshouldbechallengedtodetermineitsadequacy.Theseaspectsareimportantinorderto
assureproductsofuniformquality,purityandperformance.[8]
1.Assuranceofquality.
2.Timebound.
3.Processoptimization.
4.Reductionofqualitycost.
5.Nominalmixups,andbottlenecks.
6.Minimalbatchfailures,improvedefficientlyandproductivity.
7.Reductioninrejections.
8.Increasedoutput.
9.Avoidanceofcapitalexpenditures.
10.Fewercomplaintsaboutprocessrelatedfailures.
11.Reducedtestinginprocessandinfinishedgoods.
12.Morerapidandreliablestartupofnewequipments.
13.Easierscaleupformdevelopmentwork.
14.Easiermaintenanceofequipment.
15.Improvedemployeeawarenessofprocesses.
16. Government regulation (Compliance with validation requirements is necessary for obtaining Approval to
manufactureandtointroducenewproduct).
TYPEOFPROCESSVALIDATION
ProspectiveValidation
ConcurrentValidation
RetrospectiveValidation
ProcessReValidation
ProspectiveValidation
Thisvalidationusuallycarriedoutpriortodistributioneitherofanewproductoraproductmadeunderarevised
manufacturing process. It is a preplanned scientific approach and includes the initial stages of formulation
development, process development, setting of process sampling plans, designing of batch records, defining raw
materialspecifications,completionofpilotruns,transferoftechnologyfromscaleupbatchestocommercialsize
batches, listing major process is executed and environmental controls. In Prospective Validation, the validation
protocolisexecutedbeforetheprocessisputintocommercialuse.Aseriesofexperimentshouldbedesignedto
determinethecriticalityofthesefactors.
EachexperimentshouldbeplannedandDocumentedfullyinanauthorizedprotocol.Allequipment,production
environment and the analytical testing methods to be used should have been fully validated. Master batch
documents can be prepared only after the critical parameters of the process have been identified and machine
settings, component specifications and environmental conditions have been determined. Using this defined
process a series of batches should be produced. In theory, the number of process runs carried out and
observations made should be sufficient to allow the normal extent of variation and trends to be established to
provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs
withinthefinallyagreedparameters,givingproductofthedesiredqualitywouldconstituteapropervalidationof
theprocess.Inpractice,itmaytakesomeconsiderabletimetoaccumulatethesedata.
Prospectivevalidationshouldinclude,butnotbelimitedtothefollowing:
Shortdescriptionoftheprocess.[12]
Summaryofthecriticalprocessingstepstobeinvestigated.
Listoftheequipment/facilitiestobeused(includingmeasuring,monitoring/recordingequipment)togetherwith
itscalibrationstatus.
Finishedproductspecificationsforrelease.
Listofanalyticalmethods,asappropriate.
Proposedinprocesscontrolswithacceptancecriteria.
3/7
8/11/2016
Proposedinprocesscontrolswithacceptancecriteria.
Additionaltestingtobecarriedout,withacceptancecriteriaandanalyticalvalidation,asappropriate.
Samplingplan.
Methodsforrecordingandevaluatingresults.
Functionsandresponsibilities.
Proposedtimetable.
ConcurrentValidation
Aprocesswherecurrentproductionbatchesareusedtomonitorprocessingparameters.Itgivesofthepresent
batchbeingstudied,andofferslimitedassuranceregardingconsistencyofqualityfrombatchtobatch.Concurrent
Validationmaybethepracticalapproachundercertaincircumstances.Examplesofthesemaybewhen:
Apreviousvalidatedprocessisbeingtransferredtoathirdpartycontractmanufacturerortoanothersite.
The product is a different strength of a previously validated product with the same ratio of active/inactive
ingredients.
The number of lots evaluated under the Retrospective Validation were not sufficient to obtain a high degree of
assurancedemonstratingthattheprocessisfullyundercontrol.
Thenumberofbatchesproducedarelimited.
Processwithlowproductionvolumeperbatchandmarketdemand.
RetrospectiveValidation
Conductedfiraproductalreadybeingmarked,andisbasedonextensivedataaccumulatedoverseverallotsandover
time.RetrospectiveValidationmaybeusedforolderproductswhichwerenotvalidatedbythefabricatoratthetimethat
theywerefirstmarketed,andwhicharenowtobevalidatedtoconfirmtotherequirementsofdivisionoftheRegulation
tobeFoodandDrugsAct.
This is achieved by the review of the historical manufacturing testing data to prove that the process has always
remainedincontrol.Thistypeofvalidationofaprocessforaproductalreadyindistribution .[13]
SomeoftheessentialelementsforRetrospectiveValidationare:
Batchesmanufacturedforadefinedperiod(minimumof10lastconsecutivebatches).
Numberoflotsreleasedperyear.
Batchsize/strength/manufacturer/year/period.
Mastermanufacturing/packagingdocuments.
Currentspecificationsforactivematerials/finishedproducts.
Listofprocessdeviations,correctiveactionsandchangestomanufacturingdocuments.
Dataforstabilitytestingforseveralbatches.
Changecontrol
Writtenproceduresshouldbeinplacetodescribetheactionstobetakenifchangeisproposedtothestartingmaterial,
productcomponent,processequipment,processenvironment(orsite),methodofproductionoranyotherchangethat
may affect product quality or reproducibility of the process. Change control procedure should ensure that sufficient
support data are generated to demonstrate that the revised process will result in a product of the desired quality,
consistentwiththeapprovedspecifications.
ProcessReValidation:
Required when there is a change in any of the critical process parameters, formulation, primary packaging
components, raw material fabricator, major equipment or premises. Failure to meet product and process
specificationsinbatcheswouldalsorequireprocessrevalidation.
ReValidationbecomesnecessaryincertainsituations.Thefollowingareexamplesof
someoftheplannedorunplannedchangesthatmayrequirerevalidation:
Changesinrawmaterials(physicalpropertiessuchasdensity,viscosity,particle
distribution,andmoisture,etc.,thatmayaffecttheprocessorproduct).
Changes in the source of active raw material manufacturer. Changes in packaging material (primary
container/closuresystem).
Changesintheprocess(e.g.,mixingtime,dryingtemperaturesandbatchsize).
Changesintheequipment(e.g.additionofautomaticdetectionsystem).
Changesofequipmentwhichinvolvethereplacementofequipmentonalikeforlike
basiswouldnotnormallyrequirearevalidationexceptthatthisnewequipment
Changesintheplant/facility.
ReValidationbecomesnecessaryincertainsituations.
PRINCIPLEFORPROCESSVALIDATION
InstallationQualification(IQ):
It is establishing by objective evidence that all key aspects of the process equipment and ancillary system
installationadheretothemanufacturersapprovedspecificationandthattherecommendationofthe
supplierofthe*equipmentaresuitablyconsidered.
IQconsiderationsare:
Equipmentdesignfeatures(i.e.materialofconstructioncleanability,etc.)
Installationconditions(wiring,utility,functionality,etc.)
Calibration,preventativemaintenance,cleaningschedules.
Safetyfeatures.
Supplierdocumentation,prints,drawingsandmanuals.
4/7
8/11/2016
Supplierdocumentation,prints,drawingsandmanuals.
Softwaredocumented.
Sparepartslist.
Environmentalconditions(suchascleanroomrequirements,temperature,andhumidity
OperationalQualification(OQ):
It is establishing by objective evidence process control limits and action levels which result in product that all
predeterminerequirements.
OQconsiderationsinclude:
Processcontrollimits(time,temperature,pressure,linespeed,setupconditions,etc.)
Softwareparameters.
Rawmaterialspecifications
Processoperatingprocedures.
Materialhandlingrequirements.
Processchangecontrol.
Training.
Shorttermstabilityandcapabilityoftheprocess,(latitudestudiesorcontrolcharts).
Potentialfailuremodes,actionlevelsandworstcaseconditions.
Theuseofstatisticallyvalidtechniquessuchasscreeningexperimentstooptimizetheprocesscanbeusedduring
thisphase.
PerformanceQualification(PQ):
It is establishing by objective evidence that the process, under anticipated conditions, consistently produces a
productwhichmeetsallpredeterminedrequirements.
PQconsiderationsinclude:
ActualproductandprocessparametersandproceduresestablishedinOQ.
Acceptabilityoftheproduct.
AssuranceofprocesscapabilityasestablishedinOQ.
Processrepeatability,longtermprocessstability.[13]
STAGESOFPROCESSVALIDATION
ProcessValidationisdefinedasthecollectionandevaluationofdata,fromtheprocessdesignstagethroughcommercial
production,whichestablishesscientificevidencethataprocessiscapableofconsistentlydeliveringqualityproduct.[15]
ThefollowingstageswereperformedinProcessValidation
Stage1ProcessDesign:
Focusingexclusivelyonqualificationeffortswithoutalsounderstandingthemanufacturingprocessisdefinedduringthis
stagebasedonknowledgegainedthroughdevelopmentandscaleupactivities.Itcoversallactivitiesrelatingtoproduct
researchanddevelopment,formulation,pilotbatchstudies,scaleupstudies,transferoftechnologytocommercialscale
batches, establishing stability conditions, storage and handling of inprocess and finished dosage forms, equipment
qualification, installation qualification, master production documents ,operational qualification, process capability. Also
this is the stage in which the establishment of a strategy for process control is taking place using accumulation
knowledgeandunderstandingoftheprocess.
Stage2ProcessQualification:
During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial
manufacturing. It confirm that all established limits of the Critical Process Parameters are valid and that satisfactory
productscanbeproducedevenunderworstcaseconditions.GMPcompliantproceduresmustbefollowedinthisstage
andsuccessfulcompletionofthisstageisnecessarybeforecommercialdistributionofaproduct.
Therearetwoaspectofprocessqualification
(a)Designoffacilitiesandqualificationofequipmentandutilities
Properdesignofmanufacturingfacilityisdesiredunder21CFRpart211,subpartC,of
theCGMPregulationonBuildingsandFacilities.
Activities performed to assure proper facility design and that the equipment and utilities are suitable for their
intendeduseandperformproperly.
(b)ProcessPerformancequalification
Criteriaandprocessperformanceindicatorsthatallowforascienceandriskbaseddecisionabouttheabilityof
theprocesstoconsistentlyproducequalityproducts.
Partoftheplanningforstage2involvesdefiningperformancecriteriaanddecidingwhatdatatocollectwhen,how
muchdata,andappropriateanalysisofthedata.
Likelyconsistofplannedcomparisonsandevaluationsofsomecombinationofprocess
measuresaswellasinprocessandtrialproductattributes.
Manufacturermustscientificallydeterminesuitablecriteriaandjustifyit.
Objectivemeasures,wherepossible.
Maybepossibletoleverageearlierstudydataifrelevanttothecommercialscale.
Stage3ContinuedProcessVerification:
On going assurance is gained during routine production that the process remains in a state of control. The validation
maintenancestagerequiresfrequentreviewofallprocessrelateddocuments,includingvalidationauditreportstoassure
thattherehavebeennochanges,deviations,failures,modificationstotheproductionprocess,andthatallSOPshave
been followed, including change control procedures. A successful validation program depends on the knowledge and5/7
8/11/2016
been followed, including change control procedures. A successful validation program depends on the knowledge and
understandingandtheapproachtocontrolmanufacturingprocesses.Theseincludethesourceofvariation,thelimitation
ofthedetectionofthevariation,andtheattributessusceptibleofthevariation .[16]
Table 1 :
Verification
Continued
Process
Stage
Intent
Typicalactivities
A combination of product and

process design (Quality by Design
QBD).
Process
Design
Todefinethecommercialprocess
onknowledgegainedthrough
developmentandscaleup
activities.
Experiments to determine process

parameters,
variability
and
necessarycontrol.
Riskassessments
Other activities required to define
thecommercialProcess.
Designorexperimenttesting
Facilitydesign.Equipment&utilities
qualification.
Performancequalification(PQ).
Process
Qualification
To confirm the process design as capable of reproducible

commercialmanufacturing.
Strong emphasis on the use of

statisticalanalysisofprocessdatato
understandprocessconsistencyand
Performance.
Procedurelaseddatacollectionfrom
everybatch.
Data trending and
analysisproductreview.
statistical
6/7
8/11/2016
Continued
Process
Verification
To provide ongoing assurance that the process remains in a

state of control during routine production through quality
procedures through quality procedures and continuous
improvementinitiatives.
Equipmentandfacilitymaintenance
calibration.
Managementreviewandproduction
stafffeedback.
Improvement initiative
processexperience.
through
7/7

A Review On Process Validation - Pharmatutor

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

A Review On Process Validation - Pharmatutor

Uploaded by

Copyright:

Available Formats

8/11/2016

A combination of product and

Experiments to determine process

To confirm the process design as capable of reproducible

Strong emphasis on the use of

To provide ongoing assurance that the process remains in a

You might also like