Welcome to Scribd, the world's digital library. Read, publish, and share books and documents. See more ➡
Download
Standard view
Full view
of .
Add note
Save to My Library
Sync to mobile
Look up keyword
Like this
2Activity
×
0 of .
Results for:
No results containing your search query
P. 1
Handbook of Pharmaceutical Manufacturing Formulations Second Edition Six Volume Set

Handbook of Pharmaceutical Manufacturing Formulations Second Edition Six Volume Set

Ratings: (0)|Views: 147|Likes:
Published by Himanshu Mittal

More info:

Published by: Himanshu Mittal on Jul 02, 2012
Copyright:Attribution Non-commercial

Availability:

Read on Scribd mobile: iPhone, iPad and Android.
download as PDF, TXT or read online from Scribd
See More
See less

04/15/2013

pdf

text

original

 
ProcessValidation:GeneralPrinciplesandPractices
I.INTRODUCTION
ThisguidanceoutlinesthegeneralprinciplesandapproachesthatFDAconsiderstobeappropriateelementsofprocessval-idationforthemanufactureofhumanandanimaldrugandbiologicalproducts,includingactivepharmaceuticalingredi-ents(APIordrugsubstance),collectivelyreferredtointhisguidanceasdrugsorproducts.Thisguidanceincorporatesprinciplesandapproachesthatmanufacturerscanuseinvali-datingamanufacturingprocessbasedonguidanceprincipleslistedinthereferencesattheendofthischapter.ThisguidancealignsprocessvalidationactivitieswiththeproductlifecycleconceptandwithexistingFDAguid-ance.Thelifecycleconceptlinksproductandprocessde-velopment,qualificationofthecommercialmanufacturingprocess,andmaintenanceoftheprocessinastateofcon-trolduringroutinecommercialproduction.Thisguidancepromotesmodernmanufacturingprinciples,processim-provement,innovation,andsoundscienceandappliestoalldrugs,human,veterinary,biological,finishedproducts,phar-maceuticalandbiologicalAPIbutisnotrelevantfordietarysupplements,medicaldevices,typeAmedicatedarticlesandhumantransplanttissues.Thisguidancealsodoesnotspecificallydiscusstheval-idationofautomatedprocesscontrolsystems(i.e..computerhardwareandsoftwareinterfaces),whicharecommonlyin-tegratedintomoderndrugmanufacturingequipment.Thisaspectisdiscussedelsewhereinanotherchapter.Thisguid-anceisrelevant,however,tothevalidationofprocessesthatincludeautomatedequipmentinprocessing.
II.BACKGROUND
IntheFederalRegisterofMay11,1987(52FR17638),FDAissuedanoticeannouncingtheavailabilityofaguidanceentitled"GuidelineonGeneralPrinciplesofProcessVali-dation"(the1987guidance).Thisguidanceincludesmany;changestotheoriginalconceptsofvalidationandincludesFDA'scurrentthinkingonprocessvalidationinconcordancewiththegoalsofFDA'sinitiativeentitled"PharmaceuticalCGMPsforthe21stCentury'-ARisk-BasedApp'roach,"par-ticularlywithregardtotheuseoftechnologicaladvancesinpharmaceuticalmanufacturing,aswellasimplementationofmodernriskmanagementandqualitysystemtoolsandconcepts.FDAhastheauthorityandresponsibilitytoinspectandevaluateRrocessvalidationRerformedbymanufactur-ers.Thecurrentgoodmanufacturingpractice(CGMP)regu-lationsforvalidatingpharmaceutical(drug)manufacturingrequirethatdrugproductsbeproducedwithahighdegreeofassuranceofmeetingalltheattributestheyareintendedtopossess[21CFR211.100(a)and211.110(a)].EffectiveprocessvalidationcontributessignificantlytoassuringdruggualityThebasicprincipleofqualityassuranceisthatadrugshouldbeRroducedthatisfitforitsintendeduse;thisp'rinciRlein-~_;--F~or-coRurRosesofthischaRter,processvalidationisde-finedasthecollectionandevaluationofdata,fromthepro-cessdesignstagethroughoutproduction,whichestablishesscientificevidencethataRrocessiscapableofconsistently'deliveringqualityproducts.Processvalidationinvolvesase-riesofactivitiestakingplaceoverthelifecycleoftheproductandprocess.Thisguidancedescribesthep'rocessvalidationactivitiesinthreestages.StageI-ProcessDesig:u:Thecommercialprocessisde-finedduringthisstagebasedonknowledgegainedthroughdeveloRmentandscale-upactivities.Stage2-ProcessQualification:Duringthisstage,thepro-cessdesignisconfirmedasbeingcapableofreproduciblecommercialmanufacturing_.
....,..-,--:-c::---,---..
Stage3-ContinuedProcessVerification:Ongoingassur-anceisgainedduringroutineproductionthattheprocessremainsinastateofcontroLThischapterdescribesactivitiestypicalineachstage,butinpractice,someactivitiesindifferentstagesmightoverlap.Beforeanybatchfromtheprocessiscommerciallydis-tributedforusebyconsumers,amanufacturershouldhavegainedahighdegreeofassuranceintheperformanceofthemanufacturingprocesssuchthatitwillconsistentlyproduceAPIsanddrugproductsmeetingthoseattributesrelatingtoidentity,strength,quality,purity,andpotency.Theassuranceshouldbeobtainedfromobjectiveinformationanddatafromlaboratory-,pilot-.and/orcommercial-scalestudies.Infor-mationanddatashoulddemonstratethatthecommercialmanufacturingprocessiscapableofconsistentlyproducingacceptablequalityproductswithincommercialmanufactur-ingconditions,includingthoseconditionsthatposeahighriskofprocessfailure.Asuccessfulvalidationprogramdependsuponinfor-mationandknowledgefromproductandprocessdevelop-ment.ThisknowledgeandunderstandingisthebasisforestablishinganapproachtocontrolthatisaRRropriateforthemanufacturingprocess.Manufacturersshouldunderstandthesourcesofvariation,
~--:--.....
detectthepresenceanddegreeofvariation,-'-
-;-'"7"I>
understandtheimpactofvariationontheRrocessandul-timatelyonproductattributes,andcontrolthevariationinamanner
cL.o-m-m-e-n-s-u-ra-t-e-w.....,..itCCh-troh......
riskitrep'resentstothep'rocessandp'roduct.
98
 
Eachmanufacturershouldjudgewhetherithasgainedsufficientunderstandingtoprovideahighdegreeofassur-anceinitsmanufacturingprocesstojustifycommercialdistri-butionoftheproduct.Focusingonqualificationeffortswith-outunderstandingthemanufacturingprocessmaynotleadtoadequateassuranceofquality.Afterestablishingandcon-firmingtheprocess,manufacturersmustmaintaintheprocessinastateofcontroloverthelifeoftheprocess,evenasma-terials,equipment,productionenvironment,personnel,andmanufacturingprocedureschange.
III.STATUTORYANDREGULATORYREQUIREMENTSFORPROCESSVALIDATION
Processvalidationfordrugs(finishedpharmaceuticalsandcomponents)isalegallyenforceablerequirementundersec-tion501(a)(2)(B)oftheAct,whichstatesthefollowing:
1\
drug...shallbedeemedtobeadulterated...if...themeth-odsusedin,orthefacilitiesorcontrolsusedfor,itsmanufac-tureprocessing,packing,orholdingdonotconformtoorarenotoperatedoradministeredinconformitywithcurrentgoodmanufacturingpracticetoassurethatsuchdrugmeetsthereC[uirementsofthisActastosafetyandhastheidentityandstrength,andmeetsthequalityandpuritycharacteristics,whichitpurportsorisrepresentedtopossess.
FDAregulationsdescribingCGMParep'rovidedin21CFRparts210and211.Processvalidationisrequired,inbothgeneralandspecificterms,bytheCGMPregulationsinRarts210and211.Thefoundationforprocessvalidationisprovidedin
§
211.100(a),whichstatesthat"[t]hereshallbewrittenproce-duresforproductionandprocesscontroldesignedtoassurethatthedrugproductshavetheidentity,strength,quality,andpuritytheypurp'ortorarerep'resentedtop'ossess"(em-phasisadded).Thisregulationrequiresthatmanufacturersdesignaprocessincludingoperationsandcontrolsthatwillresultinaproductmeetingtheseattributes.Productqualityinthecontextofprocessvalidationmeansthatproductper-formanceisconsistentfrombatch-to-batchandunit-to-unit.Manyproductsaresingle-sourceorinvolvecomplicatedpro-cessestomanufacture.Validationalsooffersassurancethataprocessisreasonablysafeguardedfromsourcesofvari-abilityaffectingproductionoutput,thelossofwhichcancausesupplyproblems,therebynegativelyaffectingpublichealth.
."o-_=;..,..-:-=--_-:-...,..-_-:-o:----c__.,....-----,
_~_O;;.,,'therCGMPregulationsdefinethevariousaspectsofvalidation.Section211.110(a),Samplingandtestingofin-processmaterialsanddrugproducts,requiresthatcontrolprocedures"...beestablishedtomonitortheoutputandtovalidatetheperformanceofthosemanufacturingprocessesthatmayberesponsibleforcausingvariabilityinthechar-acteristicsofin-processmaterialandthedrugRroduct"(em-phasisadded).Thisregulationestablishestherequirementthatevenwell-designedprocessesmustincludein-processcontrolprocedurestoassurefinalproductquality.CGMPregulationsrequirethatbatchsamplesrepresentthebatchunderanalysis[see,e.g.,
§
211.160(b)(3)]andthatthesamplingplanresultinstatisticalconfidence
211.165(c)and(d)]thatthebatchmeetsitspredeterminedspecifications
211.165(a)].Section211.110(b)providestwoprinciplestofollowwhenestablishingin-processspecifications.Thefirstprincipleisthat"...in-processspecificationsforsuchchar-acteristics(ofin-processmaterialandthedrugproduct)shall
Process
Validation:GeneralPrinciplesandPractices
99
beconsistentwithdrugproductfinalspecifications...."Ac-cordingly,in-processmaterialshouldbecontrolledtoassurethatthefinaldrugproductwillmeetitsqualityrequire-ments.Thesecondprincipleinthisregulationfurtherrequiresthatin-processspecifications"...shallbederivedfrompre-viousacceptableprocessaverageandprocessvariabilityes-timateswherepossibleanddeterminedbytheapplicationofsuitablestatisticalprocedureswhereappropriate."Thisre-quirement,inpart,establishestheneedformanufacturerstoanalyzeprocessperformanceandcontrolbatch-to-batchvariability.TheCGMPregulationsalsodescribeanddefineactivi-tiesconnectedwithprocessdesign,development,andmain-tenance.Section211.180(e)requiresthatinformationanddataaboutproductperformanceandmanufacturingexperiencebeperiodicallyreviewedtodeterminewhetheranychangestotheestablishedprocessarewarranted.Ongoingfeedbackaboutproductperformanceisanessentialfeatureofprocessmaintenance.Inaddition,theCGMPregulationsrequirethatfacil-itiesinwhichdrugsaremanufacturedbeofsuitablesize,construction,andlocationtofacilitateproperoperations(21CFR211.42).Equipmentmustbeofappropriatedesign,ad-equatesize,andsuitablylocatedtofacilitateoperationsforitsintendeduse(21CFR211.63).Automated,mechanical,andelectronicequipmentmustbecalibrated,inspected,orcheckedaccordingtoawrittenprogramdesignedtoassureproperperformance(21CFR211.68).Insummary,theCGMPregulationsrequirethatman-ufacturingprocessesbedesignedandcontrolledtoassurethatin-processmaterialsandthefinishedproductmeetpre-determinedqualityrequirementsanddosoconsistentlyandreliably.
IV.RECOMMENDATIONS
A.GeneralConsiderationsforProcessValidation
Inallstagesoftheproductlifecycle,goodprojectmanage-mentandgoodarchivingthatcapturescientificknowledgewillmaketheprocessvalidationprogrammoreeffectiveandefficient.Thesepracticesshouldensureuniformcollectionandassessmentofinformationabouttheprocess,reducethechanceforredundantinformationgatheringandanalysis,andenhancetheaccessibilityofsuchinformationlaterintheproductlifecycle.Anintegratedteamapproachisrecommendedtopro-cessvalidationthatincludesexpertisefromavarietyofdis-ciplines,includingprocessengineering,industrialpharmacy,analyticalchemistry,microbiology,statistics,manufacturing,andqualityassurance.Projectplans,alongwiththefullsup-portofseniormanagement,areessentialelementsforsuccess.Throughouttheproductlifecycle,variousstudiescanbeinitiatedtodiscover,observe,correlate,orconfirminfor-mationabouttheproductandprocess.Allstudiesshouldbeplannedandconductedaccordingtosoundscientificprin-ciples,appropriatelydocumented,andshouldbeapprovedinaccordancewiththeestablishedprocedureappropriateforthestageofthelifecycle.
B.SpecificStagesandActivitiesofProcessValidationintheProductLifecycle
Thefollowingsubsectionsdescribetherecommendedstagesandspecificactivities.
 
100
HandbookofPharmaceuticalManufacturingFormulations:UncompressedSolidProducts
1.
StageL-ProcessDesign
a.BuildingandCapturingProcessKnowledgeandUnderstandingProcessdesignistheactivityofdefiningthecommercialman-ufacturingprocessthatwillbereflectedinthemasterproduc-tionandcontrolrecords.Thegoalofthisstageistodesignaprocesssuitableforroutinecommercialmanufacturingthatcanconsistentlydeliveraproductthatmeetsitscriticalqual-ityattributes.Generally,earlyprocessdesignexperimentsdonotneedtobeperformedunderCGMPconditions.Theyshould,however,beconductedinaccordancewithsoundscientificmethodsandprinciples,includinggooddocumentationprac-tices.ThisrecommendationisconsistentwithICHguidanceforindustry,QlOPharmaceuticalQualitySystem.Decisionsandjustificationofthecontrolsshouldbesufficientlydoc-umentedandinternallyreviewedtoverifyandpreservetheirvalueforuselaterinthelifecycleoftheprocessandproduct.Thereareexceptions,however.Forexample,viralandimpurityclearancestudieshaveadirectimpactondrugsafetyandshouldbeperformedunderCGMPconditions,evenwhenperformedatsmallscale.Thequalityunitshouldbeinvolvedwiththesestudiesasistypicalduringcommer-cialproduction.Product-developmentactivitiesprovidekeyinputstothedesignstage,suchastheintendeddosageform,thequal-ityattributes,andageneralmanufacturingpathway.Processinformationavailablefromtheproduct-developmentstagecanbeleveragedintheprocess-designstage.However,thefullspectrumofinputvariabilitytypicalofcommercialpro-ductionisnotgenerallyknownatthisstage.Thefunctional-ityandlimitationsofcommercialmanufacturingequipmentshouldbeconsidered,aswellasthecontributionsofvariabil-itybydifferentcomponentlots,productionoperators,envi-ronmentalconditions,andmeasurementsystemsinthepro-ductionsetting.Laboratoryorpilot-scalemodelsdesignedtoberepresentativeofthecommercialprocesscanbeusedtoestimatevariability.However,itisnotaregulatoryexpecta-tionthattheprocessbedevelopedandtesteduntilitfails,butratherthataprocessbecontrolledwithincommercialmanufacturingconditions,includingthosecombinationsofconditionsposingahighriskofprocessfailure.Designinganefficientprocesswithaneffectiveprocesscontrolapproachisdependentontheprocessknowledgeandunderstandingobtained.DesignofExperiment(DOE)stud-iescanhelpdevelopprocessknowledgebyrevealingrela-tionships,includingmultifactorialinteractions,betweenthevariableinputs(e.g.,componentcharacteristicsorprocessingparameters)andtheresultingoutputs(e.g.,in-processmate-rial,intermediates,orthefinalproduct).RiskanalysistoolscanbeusedtoscreenpotentialvariablesforDOEstudiestominimizethetotalnumberofexperimentsconductedwhilemaximizingknowledgegained.TheresultsofDOEstudiescanprovidejustificationforestablishingrangesofincomingcomponentquality,equipmentparameters,andin-processmaterialqualityattributes.Otheractivities,suchasexperimentsordemonstra-tionsatlaboratoryorpilotscale,allowevaluationofcertainconditionsandpredictionofperformanceofthecommer-cialprocess.Theseactivitiesalsoprovideinformationthatcanbeusedtomodelorsimulatethecommercialprocess.Computer-basedorvirtualsimulationsofcertainunitoper-ationsordynamicscanprovideprocessunderstandingandavoidproblemsatcommercialscale.
It
isimportanttounder-standthedegreetowhichmodelsrepresentthecommercialprocess,includinganydifferencesthatmightexist,asthismayhaveanimpactontherelevanceofinformationderivedfromthestudies.
It
isessentialthatactivitiesandstudiesresultinginproductunderstandingbedocumented.Documentationshouldreflectthebasisfordecisionsmadeaboutthepro-cess.Forexample,manufacturersshoulddocumentthevari-ablesstudiedforaunitoperationandtherationaleforthosevariablesidentifiedassignificant.Thisinformationisusefulduringtheprocessqualificationandcontinuedprocessver-ificationstages,includingwhenthedesignisrevisedorthestrategyforcontrolisrefinedorchanged.b.EstablishingaStrategyforProcessControlProcessknowledgeandunderstandingisthebasisforestab-lishinganapproachtoprocesscontrolforeachunitoperationandtheprocessoverall.Strategiesforprocesscontrolcanbedesignedtoreduceinputvariation,adjustforinputvaria-tionduringmanufacturing(andsoreduceitsimpactontheoutput),orcombinebothapproaches.Processcontrolsaddressvariabilitytoassurequalityoftheproduct.Controlscanconsistofmaterialanalysisandequipmentmonitoringatsignificantprocessingpointsde-signedtoassurethattheoperationremainsontargetandincontrolwithrespecttooutputquality.Specialattentiontocontroloftheprocessthroughoperationallimitsandin-processmonitoringisessential(1)wheretheproductattributeisnotreadilymeasurableduetolimitationsofsamplingorde-tectability(e.g.,viralclearanceormicrobialcontamination),or(2)whenintermediatesandproductscannotbehighlycharacterizedandwell-definedqualityattributescannotbeidentified.Thesecontrolsareincludedinthemasterproduc-tionandcontrolrecords[see21CFR211.186(a)and(b)(9)].Moreadvancedstrategies,suchasprocessanalyticaltechnology(PAT),usetimelyanalysisandcontrolloopstoadjusttheprocessingconditionssothattheoutputremainsconstant.Manufacturingsystemsofthistypecanprovideahigherdegreeofprocesscontrol.InthecaseofPATstrat-egy,theapproachtoprocessqualificationwillbediffer-entfromthatforotherprocessdesigns.Furtherinforma-tiononPATprocessescanbefoundinFDA'sguidanceforindustryonPAT-AFrameworkforInnovativePhar-maceuticalDevelopment,Manufacturing,andQualityAs-surance(availableontheInternetathttp://www.fda.gov/cder/guidance/index.htm).Theplannedcommercialproductionandcontrolrecords,whichcontaintheoperationallimitsandoverallstrategyforprocesscontrol,shouldbecarriedforwardtothenextstageforconfirmation.
2.Stage2-ProcessQualification
Duringtheprocessqualificationstageofprocessvalidation,theprocessdesignisconfirmedasbeingcapableofrepro-duciblecommercialmanufacture.Thisstagehastwoele-ments:(1)designofthefacilityandqualificationoftheequip-mentandutilities,and(2)performancequalification(PQ).Duringthisstage,CGMP-compliantproceduresmustbefol-lowedandsuccessfulcompletionofthisstageisnecessarybeforecommercialdistribution.Productsmanufactureddur-ingthisstage,ifacceptable,canbereleased.a.DesignofaFacilityandQualificationofUtilitiesandEquipmentProperdesignofamanufacturingfacilityisrequiredunder21CFRpart211,subpart
C,
oftheCGMPregulationsonBuild-ingsandFacilities.
It
isessentialthatactivitiesperformedto

You're Reading a Free Preview

Download
/*********** DO NOT ALTER ANYTHING BELOW THIS LINE ! ************/ var s_code=s.t();if(s_code)document.write(s_code)//-->