FDA工艺验证指南Word文档下载推荐.docx

FDA工艺验证指南Word文档下载推荐.docx

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acceptableelementsofprocessvalidationforthepreparationof

humanandanimaldrugproductsandmedicaldevices.

II.SCOPE

ThisguidelineisissuedunderSection10.90（21CFR10.90）andis

applicabletothemanufactureofpharmaceuticalsandmedical

devices.Itstatesprinciplesandpracticesofgeneral

applicabilitythatarenotlegalrequirementsbutareacceptableto

theFDA.Apersonmayrelyuponthisguidelinewiththeassurance

ofitsacceptabilitytoFDA,ormayfollowdifferentprocedures.

Whendifferentproceduresareused,apersonmay,butisnot

requiredto,discussthematterinadvancewithFDAtopreventthe

expenditureofmoneyandeffortonactivitiesthatmaylaterbe

determinedtobeunacceptable.Inshort,thisguidelinelists

principlesandpracticeswhichareacceptabletotheFDAforthe

processvalidationofdrugproductsandmedicaldevices;

itdoes

notlisttheprinciplesandpracticesthatmust,inallinstances,

beusedtocomplywithlaw.

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Thisguidelinemaybeamendedfromtimetotime.Interested

personsareinvitedtosubmitcommentsonthisdocumentandany

subsequentrevisions.Writtencommentsshouldbesubmittedtothe

DocketsManagementBranch（HFA-305）,FoodandDrugAdministration,

Room4-62,5600FishersLane,Rockville,Maryland20857.Received

commentsmaybeseeninthatofficebetween9\a.m.and4\p.m.,

MondaythroughFriday.

III.INTRODUCTION

ProcessvalidationisarequirementoftheCurrentGood

ManufacturingPracticesRegulationsforFinishedPharmaceuticals,

21CFRParts210and211,andoftheGoodManufacturingPractice

RegulationsforMedicalDevices,21CFRPart820,andtherefore,is

applicabletothemanufactureofpharamaceuticalsandmedical

devices.

SeveralfirmshaveaskedFDAforspecificguidanceonwhatFDA

expectsfirmstodotoassurecompliancewiththerequirementsfor

processvalidation.Thisguidelinediscussesprocessvalidation

elementsandconceptsthatareconsideredbyFDAasacceptable

partsofavalidationprogram.Theconstituentsofvalidation

presentedinthisdocumentarenotintendedtobeall-inclusive.

FDArecognizesthat,becauseofthegreatvarietyofmedical

products（drugproductsandmedicaldevices）,processesand

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manufacturingfacilities,itisnotpossibletostateinone

documentallofthespecificvalidationelementsthatare

applicable.Severalbroadconcepts,however,havegeneral

applicabilitywhichmanufacturerscanusesuccessfullyasaguide

invalidatingamanufacturingprocess.Althoughtheparticular

requirementsofprocessvalidationwillvaryaccordingtosuch

factorsasthenatureofthemedicalproduct（e.g.,sterilevs

non-sterile）andthecomplexityoftheprocess,thebroadconcepts

statedinthisdocumenthavegeneralapplicabilityandprovidean

acceptableframeworkforbuildingacomprehensiveapproachto

processvalidation.

Definitions

Installationqualification-Establishingconfidencethatprocess

equipmentandancillarysystemsarecapableofconsistently

operatingwithinestablishedlimitsandtolerances.

Processperformancequalification-Establishingconfidencethat

theprocessiseffectiveandreproducible.

Productperformancequalification-Establishingconfidencethrough

appropriatetestingthatthefinishedproductproducedbya

specifiedprocessmeetsallreleaserequirementsforfunctionality

andsafety.

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Prospectivevalidation-Validationconductedpriortothe

distributionofeitheranewproduct,orproductmadeundera

revisedmanufacturingprocess,wheretherevisionsmayaffectthe

product'

scharacteristics.

Retrospectivevalidation-Validationofaprocessforaproduct

alreadyindistributionbaseduponaccumulatedproduction,testing

andcontroldata.

Validation-Establishingdocumentedevidencewhichprovidesahigh

degreeofassurancethataspecificprocesswillconsistently

produceaproductmeetingitspre-determinedspecificationsand

qualityattributes.

Validationprotocol-Awrittenplanstatinghowvalidationwillbe

conducted,includingtestparameters,productcharacteristics,

productionequipment,anddecisionpointsonwhatconstitutes

acceptabletestresults.

Worstcase-Asetofconditionsencompassingupperandlower

processinglimitsandcircumstances,includingthosewithin

standardoperatingprocedures,whichposethegreatestchanceof

processorproductfailurewhencomparedtoidealconditions.Such

conditionsdonotnecessarilyinduceproductorprocessfailure.

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IV.GENERALCONCEPTS

Assuranceofproductqualityisderivedfromcarefulattentiontoa

numberoffactorsincludingselectionofqualitypartsand

materials,adequateproductandprocessdesign,controlofthe

process,andin-processandend-producttesting.Duetothe

complexityoftoday'

smedicalproducts,routineend-producttesting

aloneoftenisnotsufficienttoassureproductqualityforseveral

reasons.Someend-producttestshavelimitedsensitivity.1In

somecases,destructivetestingwouldberequiredtoshowthatthe

manufacturingprocesswasadequate,andinothersituations

end-producttestingdoesnotrevealallvariationsthatmayoccur

intheproductthatmayimpactonsafetyandeffectiveness.2

Thebasicprinciplesofqualityassurancehaveastheirgoalthe

productionofarticlesthatarefitfortheirintendeduse.These

1Forexample,USPXXIstates:

"

Nosamplingplanforapplying

sterilityteststoaspecifiedproportionofdiscreteunits

selectedfromasterilizationloadiscapableofdemonstratingwith

completeassurancethatalloftheuntestedunitsareinfact

sterile."

2Asanexample,inoneinstanceavisualinspectionfailedtodetect

adefectivestructuralweldwhichresultedinthefailureofan

infantwarmer.Thedefectcouldonlyhavebeendetectedbyusing

destructivetestingorexpensivetestequipment.

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principlesmaybestatedasfollows:

（1）quality,safety,and

effectivenessmustbedesignedandbuiltintotheproduct;

（2）

qualitycannotbeinspectedortestedintothefinishedproduct;

and（3）eachstepofthemanufacturingprocessmustbecontrolled

tomaximizetheprobabilitythatthefinishedproductmeetsall

qualityanddesignspecifications.Processvalidationisakey

elementinassuringthatthesequalityassurancegoalsaremet.

Itisthroughcarefuldesignandvalidationofboththeprocessand

processcontrolsthatamanufacturercanestablishahighdegreeof

confidencethatallmanufacturedunitsfromsuccessivelotswillbe

acceptable.Successfullyvalidatingaprocessmayreducethe

dependenceuponintensivein-processandfinishedproducttesting.

Itshouldbenotedthatinmostallcases,end-producttesting

playsamajorroleinassuringthatqualityassurancegoalsare

met;

i.e.,validationandend-producttestingarenotmutually

exclusive.

TheFDAdefinesprocessvalidationasfollows:

Processvalidationisestablishingdocumentedevidencewhich

providesahighdegreeofassurancethataspecificprocesswill

consistentlyproduceaproductmeetingitspre-determined

specificationsandqualitycharacteristics.

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Itisimportantthatthemanufacturerprepareawrittenvalidation

protocolwhichspecifiestheprocedures（andtests）tobeconducted

andthedatatobecollected.Thepurposeforwhichdataare

collectedmustbeclear,thedatamustreflectfactsandbe

collectedcarefullyandaccurately.Theprotocolshouldspecifya

sufficientnumberofreplicateprocessrunstodemonstrate

reproducibilityandprovideanaccuratemeasureofvariability

amongsuccessiveruns.Thetestconditionsfortheserunsshould

encompassupperandlowerprocessinglimitsandcircumstances,

includingthosewithinstandardoperatingprocedures,whichpose

thegreatestchanceofprocessorproductfailurecomparedtoideal

conditions;

suchconditionshavebecomewidelyknownas"

worst

case"

conditions.（Theyaresometimescalled"

mostappropriate

challenge"

conditions.）Validationdocumentationshouldinclude

evidenceofthesuitabilityofmaterialsandtheperformanceand

reliabilityofequipmentandsystems.

Keyprocessvariablesshouldbemonitoredanddocumented.Analysis

ofthedatacollectedfrommonitoringwillestablishthe

variabilityofprocessparametersforindividualrunsandwill

establishwhetherornottheequipmentandprocesscontrolsare

adequatetoassurethatproductspecificationsaremet.

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Finishedproductandin-processtestdatacanbeofvaluein

processvalidation,particularlyinthosesituationswherequality

attributesandvariabilitiescanbereadilymeasured.Where

finished（orin-process）testingcannotadequatelymeasurecertain

attributes,processvalidationshouldbederivedprimarilyfrom

qualificationofeachsystemusedinproductionandfrom

considerationoftheinteractionofthevarioussystems.

V.CGMPREGULATIONSFORFINISHEDPHARMACEUTICALS

Processvalidationisrequired,inbothgeneralandspecificterms,

bytheCurrentGoodManufacturingPracticeRegulationsforFinished

Ph