No

1. 1

2. TABLE OF CONTENTS
2
Calibration
Qualification
o DesignQualification[Dq]
o InstallationQualification[Iq]
o operationalQualification[oq]
o PerformanceQualification[Pq]
 Validation
 organizationFor Validation
 ValidationMasterPlan
 ValidationProtocol

3. Typesof Validation
o ProspectiveValidation
o ConcurrentValidation
o RetrospectiveValidation
o Re-Validation
StreamliningValidationoperations
Calibrationv/sValidation
UserRequirementSpecifications
AcceptanceTesting
o FactoryAcceptanceTest
o SiteAcceptanceTest
Calibration AndPreventiveMaintenance
Calibration of AnalyticalBalance 3

4. ○ CALIBRATION
• “Calibration ofaninstrumentis theprocessofdeterminingitsaccuracy.
Theprocessinvolvesobtainingareadingfromtheinstrumentand
measuringitsvariationfromthereadingobtainedfromastandard
instrument.”
• Calibration of an instrument also involves adjusting its precision and
accuracy so that its readings come in accordance with the established
standard.
• Thisis importantforjustifyingtheprocessesofQualificationand
Validation.
• Theinstrumentorequipmentwiththeknownaccuracyis knownas
standards.All theotherinstrumentsaremeasuredagainstthisstandard.
Itis importanttoknowthatthestandardsvaryfromonecountrytothe
otherdependinguponthetypeofindustry.
• CalibrationAchieves2Mainobjectives—
a)Itcheckstheaccuracyofaninstrument
b)Itdeterminesthetraceabilityofthemeasurement
4

5. Scope/PurposeofCalibration
5
Calibrationis primarilydonetoachieve5mainpurposeswhichare:
 Tomakesurethatthereadingsofequipmentorinstrumentsareconsistent
withothermeasurementsanddisplaythecorrectreadingseverysingletime
 Todeterminetheaccuracy,precision,reliability anddeviationofthe
measurementsproducedbyall theinstruments
 Toestablishthereliability oftheinstrumentbeingusedandwhetheritcan
betrustedtodeliverrepeatableresultseachtime
 Tomapthe‘drift’ asdocumented.Instrumentshaveatendencytoproduce
inaccuratemeasurementsoveraperiodoftime,followingrepeateduse.
 Ensuringthattheindustrystandards,qualityassurancebenchmarkssuch
ascurrentgoodmanufacturingpractice(cGMP)andgovernment
regulationsareadheredto.

6. • WhatIs InstrumentCalibration?
o Instrumentcalibrationcanbedefinedastheprocessof
comparingthemeasurementsmadebytheinstrumenttobe
calibratedagainstaknownmeasurementofeitherstandards
oraninstrumentknowntobemakingmeasurementsthat
exceedtheacceptablelimitsofaccuracyandprecision.
o Usually,calibrationlabspreferastandardwith10timesthe
accuracy; however,mostregulatingorganizationsand
authoritiesalsoaccepta3:1accuracyratio.
6

7. Frequencyof InstrumentCalibration
7
• Howoftenyouconductinstrumentcalibrationmainlydepends
uponitstendencytodriftfromthetruemeasurementandhow
itimpactsthequalityoftheendproduct.Examineeach
instrumentbeingusedandstudyitsbehavior.Basedonthis
information,youcandesignacalibrationscheduleforeach
instrument.Theintervalbetweencalibrationscanvaryas:
 Weekly
 Monthlyorbi-monthly
 Quarterly,semi-annuallyorannually
 Aftereveryheavyusageoftheinstrument

8. WhenShouldTheMeasuringInstrumentsBeCalibrated?
8
Thefrequencyofcalibratingthemeasuringinstrumentsdependsonanumberof
differentfactors.Thefollowingis aguideoutliningwheninstrumentsneedtobe
calibratedasapartof GMP:
 Assoonasyoubringinanewinstrument,youshouldcalibrateit beforeyou
testitout.
 Beforeandafteryoutakecritical measurements
 Afteranyinstanceofelectrical ormechanicalshockorasimilareventthat
includesafall, bump,etc.
 Whenyoususpectthattheaccuracyofmeasurementsbeingproducedis
questionable
 If therewereanyrepairs orre-qualificationsoftheinstrument
 Asperincludedaspartofacalibrationschedule
 Dependingonthetaskandprocessesassomerequirecalibrationtobe
conductedbeforetheworkstarts
 Accordingtothemanufacturer’srecommendation

9. • CommonlyUsedCalibration MethodsandProcedures:
Therearedifferentwaysthatareusedtocalibrateaninstrument.These
methodsarechosenbasedonthedesiredresultsofthecalibrationand
regulatoryauthorities’requirements,likeFDA guidelines.Let uslookatthree
suchprocedures:
• StandardCalibration:This methodis mostlypreferredforcalibrating
instrumentsthatarenon-criticaltoqualityorarenotrequiredforaccreditation
andlicensepurposes.Usetraceablestandardsanddocumentitsperformance.
• CalibrationwithData:Proceduresforcalibrationswithdataaresimilarto
thatofaccreditedcalibration.Theonlyexceptionbeingthattheseprocedures
arenotaccreditedtotheISо standard.Moreover,theyarenotaccompaniedby
dataonmeasurementuncertainties.
• ISo 17025AccreditedCalibration:Thishastobethestrictestmethodof
calibration.Generally,it requires ameasurementreportwhichhasthedetails
ofthemeasurementsthataremadeagainstastandardof‘asfound’(before
calibrationis started)and‘as left’ (oncethecalibrationis completed).If the
calibrationis donebyacalibrationserviceprovider,theymustissuea
certificate ofthesame.
9

10. ImportanceofRegularCalibration:
10
• Calibrationis responsiblefordefiningtheaccuracyofanymeasurement
anditsqualitythatis recordedbyanyinstrument.
Whenyoustartworkingwithanyinstrument,itmustbecalibrated
well,thusassuringyouofaccurateresults.However,overaperiodof
timeyouwill startobservinga‘drift’. Calibrationminimizessuch
uncertaintiesbyassuringtheaccuracyofthetestequipment.
• Whenyouregularlycalibrateyourequipment,youcaneliminatethedrift
atitsbuddingstageinsteadofallowingittogrowtill itaffectsthe
measurementsinsignificantways.
• Calibrationhelpsinquantifyingandcontrollingerrorsanduncertainties
withinvariousmeasurementprocessestoanacceptablelevel.
• Further,ithelpsinimprovingtheaccuracyofthemeasuringdevice,
whichinturnimprovesthequalityoftheendproduct.
• In short,regularcalibrationallowspharmaceuticalcompaniestohave
confidenceintheirresultswhichtheycanrecord,monitorandcontrol.

11. QUALIFIcATIoN
11
• It referstoactivitiesundertakentodemonstratethatutilities
andequipmentaresuitablefortheirintendeduseand
performproperly.
• It is theactionofprovingthatanyequipmentorprocess
workscorrectlyandconsistentlyandproducestheexpected
results.
• “It is theactionofprovinganddocumentingthatequipment
orancillary systemsareproperlyinstalled,workcorrectly,
andactuallyleadtotheexpectedresults.”
• Qualificationis partofvalidation,buttheindividual
qualificationstepsalonedonotconstituteprocess
validation.

12. • Qualification ofanalytical instrumentationis essentialfor
accurateandprecisemeasurementofanalyticaldata.If the
instrumentationis notqualified,ensuringthattheresults
indicatedaretrustworthy,all otherworkbasedupontheuse
ofthatinstrumentationis suspect.
• Qualificationofinstrumentsis notasingle,continuous
processbutinsteadresultsfrommanydiscreteactivities.For
convenience,theseactivitieshavebeengroupedinto4phases
ofqualification.Thesephasesaredescribedbelow:
DesignQualification(DQ)
Installation Qualification (IQ)
operationalQualification(oQ)
PerformanceQualification(PQ)
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13. DesignQualification (DQ):
• It is thedocumentedverificationthattheproposeddesignof
thefacilities,systemsandequipmentis suitableforthe
intendedpurpose.
• DQshouldbeperformedwhennewequipmentis being
purchased,orwhenexistingequipmentis beingusedfora
newapplication.DQservesastheprecursortodefiningthe
equipmentInstallationQualification(IQ) andoQ protocols.
• Thepurposeis toensurethatall therequirementsforthefinal
systemshavebeenclearlydefinedatthestart.
Inotherwords,
“Hasitbeendesignedandselectedcorrectly?”
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14. • DQcheckitems:
GMPsandregulatoryrequirements
Performancecriteria
Reliability andefficiency
Commissioningrequirements
Constructability andinstallationofequipment
Safetyandenvironmentimpact
Descriptionoftheintendeduseoftheequipment
Preliminaryselectionofthesupplier
Final selectionoftheequipment
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15. InstallationQualification(IQ):
• It is documentedevidencethatthepremises,supportingutilities,the
equipmenthavebeenbuiltandinstalledincompliancewithdesign
specifications
• Itverifiesthattheequipmenthasbeeninstalledinaccordancewith
manufacturersrecommendationinapropermannerandplacedinan
environmentsuitableforitsintendedpurpose.
• It involvestheco-ordinateeffortsofthevendor,theoperatingdepartment
andtheprojectteam.
• ThepurposeofI.Q is tochecktheinstallationsite/environment,confirms
equipmentspecificationsandverifiestheconditionofinstalledequipment;
andalsotoensurethatall aspects(staticattributes)ofthefacilityor
equipmentareinstalledcorrectlyandcomplywiththeoriginaldesign.
In otherwords,
“Hasitbeenbuiltorinstalledcorrectly?”
• InI.Q, connecteachunit(Electricalsystem,Flowlinesystem)andconfirm
thattheconnectionsarecorrect. 15

16. • IQ checkitems:
Equipmentdesignfeatures(i.e. materialofconstructioncleanability,
etc.)
Installationconditions(wiring, utility, functionality, etc.)
Calibration, preventativemaintenance,cleaningschedules.
Safetyfeatures.
Supplierdocumentation,prints,drawingsandmanuals.
Softwaredocumented.
Sparepartslist.
Environmentalconditions(suchascleanroomrequirements,
temperature,andhumidity).
• AnyproblemsidentifiedinI.Q mustbeinvestigatedandappropriate
actionsmustbetaken.All suchactionsmustbedocumentedand
approvedbyhigherauthority.
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17. operationalQualification(oQ):
• It referstoestablishingbyobjectiveevidenceprocesscontrollimits
andactionlevelswhichresultinproductthatall predetermined
requirements.
• oQ is theprocessofdemonstratingthataninstrumentwillfunction
accordingtoitsoperationalspecificationintheselectedenvironment.
• Thepurposeis toensurethatall thedynamicattributescomplywith
theoriginal design.
In otherwords,
“Doesitworkcorrectly?”
• Prior toimplementingo.Q, checkthesystemconfiguration,determine
theitemstobeevaluatedandrecordthemino.Q recordandhave
themapproved.
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18. • oQ checкitems:
Processcontrol limits(time,temperature,pressure,linespeed,setup
conditions, etc.)
Softwareparameters.
Rawmaterialspecifications
Processoperatingprocedures.
Materialhandlingrequirements.
Processchangecontrol.
Training.
Potentialfailuremodes,actionlevelsandworst-caseconditions.
Theuseofstatisticallyvalidtechniquessuchasscreeningexperimentsto
optimizetheprocesscanbeusedduringthisphase.
• Anyproblemsidentifiedino.Q mustbeinvestigatedand
appropriateactionsmustbetaken.All suchactionsmustbe
documentedandapprovedbyhigherauthority.
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19. Performancequalification:
• AftertheIQ andoQ havebeenperformed,theinstrument’scontinued
suitabilityforitsintendeduseis provedthroughperformance
qualification.
• Itreferstoestablishingbyobjectiveevidencethattheprocess,under
anticipatedconditions,consistentlyproducesaproductwhichmeetsall
predeterminedrequirements.
• PQ shouldalwaysbeperformedunderconditionsthataresimilar to
routinesampleanalysis.PQ shouldbeperformedonadaily basisor
whenevertheequipmentis beingused.
• PQconsiderationsinclude:
 Actualproductandprocessparametersandproceduresestablishedin oQ.
 Acceptability oftheproduct.
 AssuranceofprocesscapabilityasestablishedinoQ.
 Process repeatability, longtermprocessstability.
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20. • Theobjectiveis toensurethattheinstrumentis performingwithin
specifiedlimits.ThePQ representsthefinalqualificationofequipment
orsystem.
• It isusedtoestablishandorconfirm;
1.Definitionofperformancecriteria andtestprocedures.
2.Selectionofcritical parameters,withpredefinedspecifications.
3.Determinationofthetestintervals,e.g.,
(a)- Everyday.
(b)- Everytimethesystemis used.
(c) - Before,betweenandafteraseriesofruns.
4.Definecorrectiveactionsonwhattodoif thesystemdoesnotmeet
theestablishedcriteria.
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21. Re–Qualification:
• Modificationto,orrelocationofequipmentshouldfollowsatisfactory
reviewandauthorizationofthedocumentedchangeproposalthrough
thechangecontrolprocedure.Thisformalreviewshouldinclude
considerationofre-qualificationoftheequipment.
• Minorchangesorchangeshavingnodirectimpactonfinalorin-
processproductqualityshouldbehandledthroughthedocumentation
systemofthepreventivemaintenanceprogram.
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22. ScopeofPerformanceQualification.
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• Accordingtoregulatorydocuments,like FDA guidelines,thescopeofPQ
is somewhatlimited.Whileequipmentvalidationteststheability
individuallyforeachpieceofequipment,PQ verifiestheperformanceof
equipment,systemsandfacilitiesasawhole.
• Itrepresentsthefinalqualification,includinganyrequalificationofthe
systemandequipmentthatyouuseinyourbusiness.
• Typically,thescopeofPQextendstoincludethefollowingscenarios:
Newsystemsbeingdeliveredandoperatedforthefirst time
Existing systemsinuse(aspartofaregularmaintenanceschedule)
Systemsthathavebeenmodifiedtoanydegree
Equipment/systemswhichhavebeenusedmorethantheynormally
wouldbe
Afterasystemhasbeenexpandedinordertoincreaseitscapacity

23. FrequencyofPerformingPerformance
Qualification
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• TheobjectiveofPQ is toprovidequalityassurancethatthesystemis
capableofbeingsubsequentlyvalidated.GMPandothersuch
guidelinesmightnotspecifythefrequencyofperformingPQ,sothe
scheduleorfrequencyyouchoosedependsonalotoffactors.
• Thiswill typicallybeoneormoreofthefollowing:
•Everyday
•Eachtimetheequipmentorsystemis used
•Before,after,orevenduring,aseriesofoperations
•otherperiodicschedule,orasneeded

24. VALIDATIoN:
24
• Validationis anintegralpartofqualityassurance;it involvesthe
systematicstudyofsystems,facilities andprocessesaimedat
determiningwhethertheyperformtheirintendedfunctions
adequatelyandconsistentlyasspecified.
• Avalidatedprocessis onewhichhasbeendemonstratedtoprovide
ahighdegreeofassurancethatuniformbatcheswill beproduced
thatmeettherequiredspecifications andhasthereforebeen
formallyapproved.
• Validationin itselfdoesnotimproveprocessesbutconfirmsthat
theprocesseshavebeenproperlydevelopedandareundercontrol.

25. • Definitions :
• AccordingtoISo:
“Validationis theconfirmationbyexaminationandtheprovisionof
objectiveevidencethattheparticularrequirementsforaspecificintended
usearefulfilled.”
• AccordingtotheUS FoodandDrugAdministration(FDA), thegoalof
validationis to:
“Establishdocumentedevidencewhichprovidesahighdegreeof
assurancethataspecificprocesswill consistentlyproduceaproduct
meetingitspredeterminedspecificationsandqualityattributes.”
• AccordingtoEuropeancommission:
“ActionprovidinginaccordancewiththeprinciplesofGMP,thatany
procedure,process,equipment,material,activityorsystemactuallylead
totheexpectedresults.”
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26. Adequatevalidationis beneficialtothemanufacturerin manyways:
• Itdeepenstheunderstandingofprocesses;decreasestherisk of
preventingproblemsandthusassuresthesmoothrunningoftheprocess.
• Itdecreasestheriskofdefectcosts.
• It decreasestherisk ofregulatorynoncompliance.
• Afullyvalidatedprocessmayrequirelessin-processcontrolsandend
producttesting.
Validationshouldthusbeconsideredin thefollowingsituations:
• Totallynewprocess;
• Newequipment;
• Processandequipmentwhichhavebeenalteredtosuitchanging
priorities; and
• Processwheretheend-producttestis poorandanunreliableindicatorof
productquality. 27

27. Scopeofvalidation
• Validationrequiresanappropriateandsufficientinfrastructureincluding:
– organization,documentation,personnelandfinances
• Involvementofmanagementandqualityassurancepersonnel
• Personnelwithappropriatequalificationsandexperience
• Extensivepreparationandplanningbeforevalidationis performed
• Validationshouldbeperformed:
– fornewpremises,equipment,utilitiesandsystems,andprocessesandprocedures;
– atperiodicintervals;and
– whenmajorchangeshavebeenmade.
• Validationinaccordancewithwrittenprotocols.
• Validationoveraperiodoftime,e.g.atleastthreeconsecutivebatches(full
productionscale)todemonstrateconsistency.(Worstcasesituationsshouldbe
considered.)
• Significantchanges(facilities,equipment,processes)- shouldbevalidated
• Risk assessmentapproachusedtodeterminethescopeandextentofvalidation
needed 28

28. ImportanceofValidation
1.Assuranceofquality
2.Timebound
3.Process optimization
4.Reductionofqualitycost.
5.Minimalbatchfailures,improvedefficientlyandproductivity.
6.Reductionin rejections.
7.Increasedoutput.
8.Fewercomplaintsaboutprocessrelatedfailures.
9.Reducedtestingin processandin finishedgoods.
10. Morerapidandreliable start-upofnewequipments
11. Easiermaintenanceofequipment.
12. Improvedemployeeawarenessofprocesses.
13. Morerapidautomation.
14.Governmentregulation(Compliancewithvalidationrequirementsis
necessaryforobtainingapprovaltomanufactureandtointroducenew
products) 29

29. oRGANIZATIoN FoR VALIDATIoN
29
Validationorganizationcanbedividedintothreebasicareas;
1.Establishingtheorganization.
2.operatingit fromaqualityandcosteffectivenessbasis.
3.Maintainingafunctioningorganization.
• Establishingtheorganization
Formulatingadepartmentmissionis necessarysothat,not
onlyprocessvalidationstaffmembersunderstandthebreadth
oftheirjob,butalsotheothercorporategroupswithwhom
thereis interaction,canalsounderstand.

30. • Departmentsresponsible
o Site validationcommittee:- Developsitemastervalidationplan.
o Manufacturingdepartment:- Preparesthebatchesasthoughtheir
routineproductionbatches.
o Qualityassurance:- Ensurecomplianceandthatdocumentation,
proceduresarein place.Approvesprotocolsandreports.
o Qualitycontrols:- Performtestingcontractsvalidationtestingand
reviewsprotocolandreportasneeded.
o Researchanddevelopment:- Dealswithproductdesign.
o Engineeringdepartment:- Installation, qualityandcertifyplant,
facilities, equipmentandsupportsystems.
30

31. • Validationteam
Amultidisciplinaryteamis primarilyresponsibleforconductingand
supervisingvalidationstudies.Personnelqualifiedbytrainingand
experienceinarelevantdisciplinemayconductsuchstudies.
• Responsibilitiesofvalidationteam
 Createsupdatesandreviews/approvesindividualprojectvalidation
plansandvalidationdeliverables.
 Ensuresvalidationcompliancewiththecompanyvalidationmasterplan
andprojectvalidationplan.
 Coordinates,implements,verifyelementsofVMP.
 Consults on,evaluatesandapproveschanges.
 ReviewsandapprovesIQ/oQ/PQ proceduresandplans.
 Reviewstestresultsandmakesrecommendationsregardingrelease.
 Assessrisksanddevelopscontingencyplan.
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32. oRGANIzATIoN FoR VALIDATIoN
32

33. • Departmentinteraction:
once the validation team has been constituted and mission
have been formalized, the team will interact with different
departmentswhichare:
Researchanddevelopmentdepartment
Engineering department,
Productiondepartment,
Maintenancedepartment,
Qualitycontroldepartment,
Qualityassurancedepartment.
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34. VALIDATIoN MASTER PLAN
34
• Thevalidationmasterplanshouldprovideanoverviewoftheentire
validationoperation,itsorganizationalstructure,itscontentand
planning.
• Themainelementsofitbeingthemlist/inventoryoftheitemstobe
validatedandtheplanningschedule.
• All validationactivitiesrelatingtocritical technicaloperations,relevant
toproductandprocesscontrolswithinafirmshouldbeincludedinthe
validationmasterplan.
Itshouldcompriseall prospective,concurrentandretrospective
validationsaswellasrevalidation.
• TheValidationMasterPlanshouldbeasummarydocumentandshould
thereforebebrief,conciseandclear.
• Itshouldnotrepeatinformationdocumentedelsewherebutshouldrefer
toexistingdocumentssuchaspolicydocuments,SoP’s andvalidation
protocolsandreports.

35. • Theformatandcontentshouldinclude:
 Introduction:validationpolicy, scope,locationandschedule.
 organizationalstructure: personnelresponsibilities.
 Plant/process/productdescription:rationalforinclusions or
exclusionsandextentofvalidation.
 Specific processconsiderationsthatarecritical andthose
requiringextraattention.
Keyacceptancecriteria.
Documentationformat.
ReferencetotherequiredSoPs.
Timeplansofeachvalidationprojectandsub-project.
List ofproducts/processes/systemstobevalidated,summarizedin
amatrixformat,validationapproach.
Re-validationactivities,actualstatusandfutureplanning
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36. VALIDATIoN PRoTocoL
36
• Awrittenplanstatinghowvalidationwillbeconducted,includingtest
parameters,productcharacteristics,productionandpackaging
equipment,anddecisionpointsonwhatconstitutesacceptabletest
results.
• This document should give details of critical steps of the manufacturing
process that should b
e measured, the allowable range of variability and
themannerinwhichthesystemwillbetested.
• Thevalidationprotocolprovidesasynopsisofwhatis hopedtobe
accomplished.
• Theprotocolshouldlist theselectedprocessandcontrolparameters,
statethenumberofbatchestobeincludedinthestudy,andspecifyhow
thedata,onceassembled,will betreatedforrelevance.Thedateof
approvalbythevalidationteamshouldalsobenoted.
• Inthecasewhereaprotocolis alteredormodifiedafteritsapproval,
appropriatereasoningforsuchachangemustbedocumented.

37. • Thevalidationprotocolshouldbenumbered,signedand
dated,andshouldcontainasaminimumthefollowing
information:
objectives,scopeofcoverageofthevalidationstudy
validationteammembership,theirqualificationsand
responsibilities
typeofvalidation:prospective,concurrent,retrospective,re-
validation
numberandselectionofbatchestobeonthevalidationstudy
alist ofall equipmenttobeused;theirnormalandworstcase
operatingparameters
outcomeofIQ, oQ forcritical equipment
37

38. requirementsforcalibrationofall measuringdevices
critical processparametersandtheirrespectivetolerances
descriptionoftheprocessingsteps:copyofthemaster
documentsfortheproduct
samplingpoints,stagesofsampling,methodsofsampling,
samplingplans
statisticaltoolstobeusedintheanalysisofdata
trainingrequirementsfortheprocessingoperators
validatedtestmethodstobeusedinin-processtestingandfor
thefinishedproduct
specifications forrawandpackagingmaterialsandtest
methods formsandchartstobeusedfordocumentingresults
38

39. TYPES oF VALIDATIoN
39
Prospectivevalidation
• Itis definedastheestablisheddocumentedevidencethatasystemdoes
whatitpurportstodobasedonapre-plannedprotocol.
• Thisvalidationusuallycarriedoutpriortodistributioneitherofanew
productoraproductmadeunderarevisedmanufacturingprocess.
• Performedonatleastthreesuccessiveproduction-size (Consecutive
batches).
• Theobjectiveoftheprospectivevalidationis toproveordemonstratethat
theprocesswillworkinaccordancewithvalidationprotocolprepared
forthepilotproductiontrials.Prospectivevalidationshouldnormallybe
completedpriortothedistributionandsaleofthemedicinalproduct.
• InProspectiveValidation,thevalidationprotocolis executedbeforethe
processis putintocommercialuse.

40. concurrent validation
• It is aprocesswherecurrentproductionbatchesareusedtomonitor
processingparameters.
• ConcurrentValidationmeansestablishingdocumentedevidencea
processdoeswhatitis supposedtobasedondatageneratedduring
actualimplementationoftheprocess.
• Itis importantinthesecaseswhenthesystemsandequipmenttobe
usedhavebeenfullyvalidatedpreviously.
• It is similartoprospective,excepttheoperatingfirmwill sell the
productduringthequalificationruns,tothepublicatitsmarketprice,
andalsosimilartoretrospectivevalidation.
• This validationinvolves in-processmonitoringofcritical processing
stepsandproducttesting.Thishelpstogenerateanddocumented
evidencetoshowthattheproductionprocessis inastateofcontrol.
40

41. Retrospectivevalidation
• Itis definedastheestablisheddocumentedevidencethatasystem
doeswhatitpurportstodoonthereviewandanalysisof
historicalinformation.Thistypeofvalidationofaprocessis fora
productalreadyindistribution.
• Retrospectivevalidationis onlyacceptableforwell-established
processesandwill beinappropriatewheretherehavebeenrecent
changesinthecompositionoftheproduct,operatingprocedures
orequipment.
• Validationofsuchprocessesshouldbebasedonhistoricaldata.
• For retrospectivevalidation,generallydatafromtentothirty
consecutivebatchesshouldbeexaminedtoaccessprocess
consistency,butfewerbatchesmaybeexaminedif justified.
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42. Revalidation
• Re-validationprovidestheevidencethatchangesinaprocessand/orthe
processenvironmentthatareintroduceddonotadverselyaffectprocess
characteristicsandproductquality.Documentationrequirementswill bethe
sameasfortheinitial validationoftheprocess.
• Re-validationbecomesnecessaryin certainsituations.Someofthechanges
thatrequirevalidationareasfollows:
Changesinrawmaterials(physical propertiessuchasdensity,viscosity,
particlesizedistribution etc.,thatmayaffecttheprocessorproduct).
Changesinthesourceofactiverawmaterialmanufacturer.
Changesin packagingmaterial(primarycontainer/closuresystem)
Changesintheprocess(e.g.,mixingtime,dryingtemperaturesand
batchsize)
Changesintheequipment(e.g.,additionofautomaticdetectionsystem).
Changesintheplant/facility.
42

43. sTREAMLINING VALIDATIoN oPERATIoNs
43
• Thebestapproachtoavoidingneedlessandexpensivetechnicaldelays
is toworkinparallel. Thekeyelementsatthisimportantstageofthe
overallprocessaretheAPI, analyticaltestmethods,andthedrug
product(pharmaceuticaldosageform).Anintegratedandparallelway
ofgettingthesethreevitallyimportantfunctionstoworktogetheris
depictedin Figurebelow.
• Figureshowsthattheuseofasingleanalyticalmethodstesting
functionis animportanttechnicalbridgebetweentheAPI andthedrug
productdevelopmentfunctionsasthelattertwomovethroughthe
variousstagesofdevelopment,clinicalstudy,processdevelopment,
andprocessvalidationandintoproduction.

44. 44

45. cALIBRATIoN v/sVALIDATIoN
45
• Calibrationandvalidationaretwoprocessesin manufacturingto
guaranteethequalityoftheproductorrelatedapparatus.
• Withthecalibration,themeasurementsarecomparedwithanaccepted
referencemeasurement,toassuretheconsideredmeasurements
complywiththerequirements.
• Withthevalidation,theperformance,quality,andotheroperating
parametersofasystemaretestedtoverifythattheycomplywiththe
requirements.

46. cALIBRATIoN v/sVALIDATIoN
cALIBRATIoN
• calibrationis ademonstration
that,aparticular Instrumentor
deviceproducesresultswithin
specifiedlimitsbycomparisons
withthoseproducedbyareference
ortraceablestandardoveran
appropriaterangeof
measurements.
• In calibrationperformanceofan
instrumentordeviceis comparing
againstareference standard.
46
VALIDATIoN
• Validationis adocumented
programthatprovideshighdegree
ofassurancethataspecific
process, equipment,methodor
systemconsistently producesa
resultmeetingpre-determined
acceptancecriteria.
• Nosuchreference standardsare
usinginvalidation program.

47. cALIBRATIoN v/sVALIDATIoN
cALIBRATIoN
• Calibrationensuresthatinstrument
ormeasuringdevicesproducing
accurateresults.
• Shall b
e performed periodically, to
identify the ‘drift’ of the measuring
device or equipment and make them
accurate.
• Shall b
e performed as per calibration
SoP.
VALIDATIoN
• Validationprovidesdocumented
evidencethataprocess, equipment,
methodorsystemproducesconsistent
results(in otherwords,itensuresthat
uniformsbatchesareproduced).
• Nosuchrequirements.Shall be
performedwhenchangesor
modificationshappentotheexisting
systemoroncerevalidationperiodis
reached.
• Shall beperformedaspervalidation
protocol.
47

48. UserRequirementsspecification(URs).
• This focusesonthe‘‘what’’ratherthanthe‘‘how.’’
48
• TheUserRequirementsSpecificationdescribesthebusinessneedsforwhat
usersrequirefromthesystem.
• UserRequirementsSpecificationsarewrittenearlyinthevalidationprocess,
typicallybeforethesystemis created.Theyarewrittenbythesystemownerand
end-users,withinputfromQualityAssurance.
• RequirementsoutlinedintheURSareusuallytestedinthePerformance
QualificationorUser AcceptanceTesting.
• UserRequirementsSpecificationsarenotintendedtobeatechnicaldocument;
readerswithonlyageneralknowledgeofthesystemshouldbeableto
understandtherequirementsoutlinedintheURS.
• AURSdefinesclearly andprecisely, whatthecustomer(i.e.you)wantsthe
systemtodo,andshouldbeunderstoodbyboththecustomerandthe
instrumentvendor.
• TheURSis alivingdocument,andmustbekeptupdated,viaachangecontrol
procedure.

49. • Awell-writtenURs providesseveralspecificbenefits,asit:
 Servesasareferenceagainstwhichoff-the-shelfcommercialproductsareselected,
evaluatedindetail,andanyenhancementsaredefined.
 Reducesthetotalsystemeffortandcosts,sincecareful reviewofthedocument
shouldrevealomissions,misunderstandingsand/orinconsistenciesinthe
specificationandthismeansthattheycanbecorrectedeasilybeforeyoupurchase
thesystem.
 Providestheinputtouseracceptancetestspecificationsand/orqualificationofthe
system.
• TheURs shouldinclude:
o Introduction–includingthescopeofthesystem,keyobjectivesfortheproject,and
theapplicableregulatoryconcerns
o ProgramRequirements–thefunctionsandworkflowthatthesystemmustbeable
toperform
o DataRequirements–thetypeofinformationthatasystemmustbeabletoprocess
o Life cycleRequirements–includinghowthesystemwillbemaintainandusers
trained
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50. • GeneralGuidanceforWritingtheRequirements
 Thefollowingguidelinesshouldbefollowedduringtheproductionofthe
specification:
 Eachrequirementstatementshouldbeuniquelyreferencedandnolongerthan
250words.
 TheURS shouldbeconsistentandrequirementstatementsshouldnotbe
duplicatedorcontradicted.
 Specify requirementsandnotdesignsolutions.Thefocusshouldbeonwhatis
required,butnothowitis tobeachieved.
 Eachrequirementshouldbetestable.This allowstheteststobedesignedassoon
astheURSis finalised.
 Boththecustomerandthevendormustunderstandthedocument.Therefore,
jargonshouldbeavoidedwhereverpossibleandkeywordsaredefinedina
specific sectioninthedocument.
 Requirementsshouldbeprioritisedasmandatoryordesirable.
 TheURS shouldbemodifiablebutchangesshouldbeunderaformalcontrol
procedure.
 AURS is correctif everystatedrequirementhasonlyoneinterpretationandis
metbythesystem.Unfortunately,thisis veryrare.
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51. AccEPTANcE TEsTING
51
• ThequestionofwhatUSER ACCEPTANCE TESTING (UAT)is, becomesvery
importantasyoureachastateofhavingequipment/systemsdeliveredtoa
facility.
• Thesystem/equipmentis claimedtobeconstructedinamannerthathasbeen
definedbyaUserRequirement,andconstructedorfabricatedinamannerthat
meetstherequirementsoftheindustryandofyourcompanyspecifically.You
canill affordtoacceptasystemorpieceofequipmentthatdoesnotmeetthese
requirements.
• WhatisAcceptanceTesting?
UserAcceptanceTestingdefinespreciselyandclearlywhattheuserexpects
thesystemtodo.UATdocumentscontaininformationabouttheoperating
environment,therequireddataforprocessing,andthefunctionalitythatthe
systemshouldcarry out.
CompletedduringaFAT andaSAT

52. WhatisaFAT?
 AFAT orFactoryAcceptanceTestis usuallypreformedatthevendorpriorto
shippingtoaclient.Thevendorteststhesysteminaccordance withtheclients
approvedtestplansandspecificationstoshowthatsystemis atapointtobe
installedandtestedonsite.
 It’s anessentialaspectofthewholesystemlifecycle andshouldbeperformed
byexperiencedpersonnel.TimespentdoingaproperFAT willleadtofewer
problemswhentheequipmentis installed.
 summary- It is thepartialcommissioningandqualificationofequipment
and/orsystemspriortotheirshipmentfromthefabricator’ssite.
 TheFAT protocolis aninspectionthatincludes bothstaticanddynamic
exhaustivetestingofsystemsormajorsystemcomponentstosupportthe
qualificationofequipmentorasystem.Thetestsmustverifythatall
functionality detailedin theUserRequirementsSpecification(URS) is
embodiedandperformsasspecified. It is writtenbythemanufacturersand
executedbytheclientorclientrepresentative.
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53. WhatisasAT?
 sAT is SiteAcceptanceTestofasystemtoensureitis testedin
accordancetoclientapprovedtestplansandspecifications&toshow
thesystemis installedproperlyandinterfaceswithothersystemsand
peripheralsinitsworkingenvironment.
 summary- Inspectionand/ordynamictestingofthesystemsormajor
systemcomponentstosupportthequalification ofanequipment
systemconductedanddocumentedatthemanufacturingsite.
 TheSATis relatedtotheFAT andalsoentailsinspectionanddynamic
testingofsystemsormajorsystemcomponentstosupportthe
qualificationofequipment.Thisis writtenbytheclientandverifiesthat
theinstalledfunctionalityoftheequipmentmeetsorexceedsthe
operationalrequirementsasspecifiedintheequipmentURS.
 TheSATis executedoncompletionofall commissioningtasks;butprior
tothestartofInstallationQualificationexecution.
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54. cALIBRATIoN AND PREVENTIVE
MAINTENANcE
54
• Regulations of the regulatory authorities like FDA and EU require that
all the firms have program for calibration and preventive maintenance
fortestaswellasmeasurementequipments.
• Preventive maintenance program is one of the most importance aspects
forGMPinspectionasitensurestheefficientGMPoperations.
• Anyequipmentseitheritis automaticormanuallyoperatedwill
performitsfunctionsproperlyandareusedformanufacturing,
processing,packaging,labelingorholdingofdrugproducts;itis
mandatorythatitwill betimelycalibrated,inspectedandcheckedfor
errorsaccordingtothewrittenprogramwhichis speciallydesignedto
assurethebestperformanceoftheequipments.

55. INTRoDUcTIoN
55
• Definitionofcalibration:- "It is asetofoperationthatperforms
underspecificconditionstoverifythevalues/dataobtainedby
comparisonoftwoinstrumentsormeasuringdevicesoneofwhichis a
standardofknownaccuracy(Traceabletonationalstandards).It is used
todetect,correlate,reportoreliminateanyofthediscrepancyin
accuracyofinstrumentsormeasuringdeviceswhenbeingcomparedto
thestandard."
• Calibrationisonetypeofcomparisonbutitis notanadjustments.
• DefinitionofPreventiveMaintenance:"It is acareorservice
providedbypersonneltomaintaintheequipmentorfacility in
satisfactorilyworkingconditionsbyprovidinginspections,detectionand
correctionoffailuresbeforetheyoccur.Basicallytheyareconductedto
keeptheinstrumentinworkingconditionsandtoextendthelifeofthe
instrument."

56. MainadvantagesofPMare:
Improvementin thereliability ofsystem,
Decreaseinreplacementcostandtime,
Inventorymanagementsystemis alsoimproved.
RequirementsofRegulatoryAuthorities
Calibration program is required by the regulatory authority (FDA)
under section 21 CFR part 211.68 and Preventive maintenance and
calibration program is required by FDA under section 21 CFR part
211.67.
CalibrationrequirementsforLabinstrumentsundersection21
CFR part211.67are:specific directions,schedule,limitof
accuracyandprecisionremedialactionandsystemtoprevent
usageofinstrumentwhicharefailedtocalibrate.
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57. calibrationandmaintenanceprocedure(soP)
ThereshouldbeadocumentedSoP forconductingthe
calibrationandpreventivemaintenanceforeachtypeof
instrumentation.
TheSoP forcalibrationmustincludesaccuracyandprecision
limitsandwhataretheremedialactionsshouldbetakenif this
limitsdonotmeetwitheachother.Thereshouldbean
authorizeddepartmenttoperformandmonitorcalibrationand
maintenance.
TheSoP mustcontainthestepbystepcalibrationinstructions,
instrumentationmanual,propercalibrationprocedures,
provisionsforadjustments,provisionsforrecordand
documenttheactualmeasurementreadingbeforeandafter
doingadjustment.
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58. ○ softwareusedforcalibrationandPM
• LotsofsoftwareareusedforcalibrationandPMatindustrialscale.This
computerizedsystemhasmoreefficiency andguaranteedthebestresults.
○ calibrationsoftware
• QualityCalibrationManagementsystem(QCMS)is completeinstrument
anddesignedaccordingtotherequirementsof21CFR part11.This
softwareensuresregulatorycomplianceandalsotraceability.It will help
toimprovethereliabilityofplantandoptimizetheadministrativecosts.It
will helptoincreaseintheproductivityaswellasefficiency.
○ Preventivemaintenancesoftware
• RCMturbois verypopularPMsoftware.Traditionalapproachtook
yearstocompletejustonePMbutbyusingthisRCMturbo,anyonecan
quicklygoforPM.ThissoftwaredirectsusthroughEMEAprocess.But
thethingis itwillgothroughquicklyandefficiently.It is 100% reliable
andwill allowyoudorisk assessment. 59

59. cALIBRATIoN oF ANALYTIcAL BALANcE
59
Measurethepanpositionerrorofthebalance
Dailycalibration
 Themaximumandminimumweightlimitsofthebalancearetaken
anddividedintofourtofivepartsandsinglestandardweightis
selectedin thosefourorfivedifferentregionsforthepurposeof
dailycalibration.
 Thevariationallowedfromthestandardweightusedformeasuring
is NMT±0.1%ofstandardweight.
 Driftcheckfromdaytodayis carriedoutusinganyparticular
weightandthedeviationallowedshouldnotbemorethan±1%of
thatweight.

60. Monthlycalibration
• All thestandardweightsinthemaximumandminimumweighing
limitsareusedinmonthlycalibrationandthedeviationallowed
shouldnotbemorethan±0.1%ofstandardweightused.(The
standardweightsthatareusedareE1andE2weights)
Measurementofuncertainty
• For measurementofuncertaintyanysinglestandardweightis
takenandis weighedfor10timesthereadingsarenotedandthe
standarddeviationforall thereadingsis calculated.And
measurementofuncertaintycanbemeasuredusingtheformula:
• Measurementofuncertainty=
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61. 61