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1、CONTENTRegulatoryaspectsMoistHeatSterilizationChoosing the right processValidatingasterilizationprocessCalibration of instrumentsChamber leak test“Utilities”Validation Physical issuesValidation Microbiological issuesValidatingalyophilizationprocessProcessControllerRiskAnalysisGMP & VALIDATION1972DEV
2、ENPORTINCIDENT(UK)Infusionalsolutions,producedattheDevemportHospital,causedthreepatientdeceases.TheROSENHEIMReportfoundthecausesinanotcorrectsterilizationtreatment.ExtractedfromtheROSENHEIMReportTheAIRwasnotproperlyremovedfromthechamberThedrainofthechamberwasblockedbypiecesofglassesThe lower section
3、 of the load did not reach the sterilizationtemperatureThetemperaturerecordershowedthisanomalybutpeoplethoughtitwasnotworkingproperlySterilitytestswerecarriedoutonlyontheupperlayersoftheloadGMP & VALIDATIONValidationMainconceptsPersonnelEquipmentProcess/ProductsInstrumentsDocumentsandSOPQualified,tr
4、ainedTobequalified(IQ,OQ,PQ)TobevalidatedSuitable,calibrationhastobeplannedanddocumentedUp-todate,distributed,maintainedundercontrolTerminal Moist-Heat SterilizationEngineeringEquipmentImplicationsChapter3ofEU-GMP(PremisesandEquipment)21CFRpart211.63,211.65,211.67(Equipment)Annex11UEGMP(Computerised
5、systems)21CFRpart211.68(Automatic,mechanicalandelectronicequipment)21CFRpart11(ElectronicrecordsElectronicSignatures)GAMP (GoodAutomatedManufacturingPractice)Validation21CFRparts210-211(211.100,211.110,211.213)21CFRpart820(820.75)EUGMP(Cap.5.215.24)EUGMPAnnex15:(QualificationandValidation)Compliance
6、PolicyGuideSec.490.100(ProcessValidationRequirementsforDrugProductsSubjecttoPre-MarketApproval)Terminal Moist-Heat SterilizationCONTENTRegulatoryaspectsMoistHeatSterilizationChoosing the right processValidatingasterilizationprocessCalibration of instrumentsChamber leak test“Utilities”Validation Phys
7、ical issuesValidation Microbiological issuesValidatingalyophilizationprocessProcessControllerRiskAnalysisWhat is being Sterilized?vPorousLoadsHardGoodsEquipmentPartsComponentsGlassStainlesssteelPolymericMaterialsWasteLiquidsNon-PorousLoadsFinishedProductsLaboratoryMediaIn-processFluidsWasteLiquidsPo
8、lymericMaterialsDefiningthesterilizationprocessDefining the sterilization processTemperature and Time for an effective sterilization1.CannotbedefinedbyphysicalmethodsHavetobepreliminaryinvestigatedaccordingtoamicrobiologicalapproachShouldcomplywithminimumrequirementsuchasthetraditional“Fo of 8 or mo
9、re”reportedintheProposed RulesoftheFDA(1976,Clause212.240),orthegridoftable4oftheguidelineHTM2010,Part2,Clause3.24(i.e.15minutes121-124C),reportedalsointhestandardEN285,point8.3.1.2BIOBURDENThermicresistanceoftheproductOverkillBioburdenIntegrated(Bioburden/Biologicalindicators)Validationapproaches:D
10、efining the sterilization processBalance must be MaintainedvAttainingsterilitymustnotbeaccomplishedwithlossofvproductstability.vMaintainingstabilitymustbeaccompaniedwithadequatevassuranceofsterility.DefiningthesterilizationprocessDefiningthesterilizationprocessDemonstratedPNSUDemonstratedPNSUExpecte
11、dExpected Shelf Life Shelf LifeInformationNeededInformationNeededForValidationForValidationHeatInputtoMaterialsHeatInputtoMaterialsBioburdenBioburdenMethodMethodBioburden/BIBioburden/BIMethodMethodOverkillOverkillMethodMethodCONTENTOFTHEPRESENTATIONRegulatoryaspectsMoistHeatSterilizationChoosingther
12、ightprocessCausesoffailureValidatingasterilizationprocessCalibrationofinstrumentsChamberleaktest“Utilities”ValidationPhysicalissuesValidationMicrobiologicalissuesSterilizerProcessControllerRiskAnalysisValidationWhathastobevalidated?Aprocess?Aproduct?Apieceofequipment?Letsconsiderthedefinitionof“vali
13、dation”Validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics (FDA Guideline on General Principles of Validation, 1987)Validation is a d
14、efined strategy of inter-related practices and procedures which in combination with routine production methods and quality control techniques provides documented assurance that a system is performing repetitively as intended and/or that a product conforms to its pre-determined specifications (PDA TM
15、#1 revised, Draft 13, Glossary)ValidationCommonitems:-Specify-Document-Verifytheeffectiveness-VerifythereproducibilityThescopeofvalidationistheprocessortheproduct2. ThenewPDAdefinitionconsidersvalidationasa“ongoingprocess”(maintainingthevalidatedstatus)ValidationProcessProductEquipmentRulesandstanda
16、rdsCharacteristicsHandlingWrappingTerminallysterilizedSterilization?Terminalsterilization?Sterilizationmethod?ValidationStages of the qualification of a piece of equipment should include DQ, IQ, OQ and PQ.User Requirements SpecificationsFunctionalSpecificationsDesignSpecificationsProject execution I
17、nstallationQualificationOperationalQualificationPerformanceQualificationRelated toRelated toRelated toDesignQualificationVALIDATIONLIFECYCLEDESIGNQUALIFICATIONThedocumentsoftheprojectsatdisposalspecifyinanexaustivewaytheequipment,thesystems,andtheinstallationsthatcomposethatprojectThedocumentsrelate
18、dtotheuserrequirementsspecifications,tothebasicdesign(orfunctional)andtothedetaildesign(orexecutive)areclearlyidentifiedDESIGNQUALIFICATIONTheprojectdocumentsarecorrectlyapprovedbythecompetentfunctionsuponwhatestablishedinthequalityplanoftheprojectThefunctionalspecs(basicdesign)andtheengineeringdocu
19、ments(detaildesign)ofthesystemunderexamarebasedontheneedsoftheuser(userrequirements)ThedesignhasbeencarriedoutconsideringacompliancetothecGMPsandeventualapplicableguidelines“Installation Qualification is an essential step preceding the Process Validation exercise. It is normally executed by the Engi
20、neering group. The installation of equipment, piping, services and instrumentation is undertaken and checked to engineering drawings Piping & Instrument Drawings, (P&I.Ds) and Plant Functional Specifications developed during the project planning stage. During the project planning stage, Installation
21、 Qualification should involve the identification of all system elements, service conduits and gauges and the preparation of a documented record that all installed equipment satisfies the planned requirements.”Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-
22、Sterile Process Validation, Cleaning Validation PI 006-2, 1 July 2004INSTALLATIONQUALIFICATIONThe Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Qualification and Validation July 2001“IQ should include, but not limited to, the followi
23、ng:(a)installation of equipment, piping, services and instrumentation checked to current engineering drawing and specifications;(b)collection and collation of supplier operating and working instruction, and maintenance requirements;(c)calibration requirements;(d)verification of materials of construc
24、tion.”INSTALLATIONQUALIFICATIONOutlinePre-requirementsReference specs & purch. orderProcedure verificationCritical instruments calibration verif.“as-built” drawingsMain components verificationUtilities connection verificationLubricants verificationAttachmentsINSTALLATIONQUALIFICATIONINSTALLATIONQUAL
25、IFICATIONINSTALLATIONQUALIFICATION“OQ is an exercise oriented to the engineering function, generally referred to as commissioning. Studies on the critical variables (parameters) of the operation of the equipment or systems will define the critical characteristics for operation of the system or sub-s
26、ystem. All testing equipment should be identified and calibrated before use. Test methods should be authorized, implemented and resulting data collected and evaluated.It is important at this stage to assure all operational test data conform with pre-determined acceptance criteria for the studies und
27、ertaken.”Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation PI 006-2, 1 July 2004OPERATIONALQUALIFICATION“It is expected that during the Operational Qualification stage the manufacturer should develop draft stand
28、ard operating procedures (SOPs) for the equipment and services operation, cleaning activities, maintenance requirements and calibration schedules.”“The completion of a successful Operational Qualification should allow the finalisation of operating procedures and operator instructions documentation f
29、or the equipment. This information should be used as the basis for training of operators in the requirements for satisfactory operation of the equipment.”Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation PI 006-
30、2, 1 July 2004OPERATIONALQUALIFICATION“OQ should include, but not limited to, the following:(a)tests that have been developed from knowledge of process, systems and equipment;(b)tests to include condition or set of conditions encompassing upper and lower operating limits, sometimes referred to as “w
31、orst case” conditions.”The Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Qualification and Validation July 2001OPERATIONALQUALIFICATIONOutlineProcedure verificationCritical instruments calibration verif.Functional verificationOPERATI
32、ONALQUALIFICATIONOPERATIONALQUALIFICATIONQualificationofsteamautoclavesOperationalQualificationINDICE9.Verificationofsupportingdocumentation9.1VerificationofSOPs9.2Verificationoftheequipmentcalibrationinstalledonthesystem10.Operationalverificationofthesystem10.1Verificationoftheinput/outputsignalsof
33、thecontrolsystem10.2Verificationofthealarmsoperation10.3Verificationoftheoperationalsequences10.4Verificationofthebehaviorincaseofpowerfailure10.5Verificationoftheprotectionsystemwithpassword10.6Verificationoftheoperatorinterface10.7Verificationofthemonitoringandcontroldevicesfunctionality10.8Verifi
34、cationofthevacuumpumpfunctionality(ifapplicable)10.9Verificationofthevacuumtightness(ifapplicable)10.10Verificationofthebackpressure10.11Verificationoftheheatdistributioninemptyroom10.12Verificationofthedoorinterlocksystemfunctionality11.AttachmentsDocumented verification that the system is able to
35、fulfill, in a constant and repetitive way, all the tasks indicated in the URS.Usuallytheywillbedesigned,tothisaim,somechallengesfortheverification of the process parameters and of the operativeconditions,intheestablishedintervalsofvariability,incompliancewiththedatareportedintheofficialrecords.Theco
36、nditionslimittothechallenge,afterthedueconsiderations,canbedifferentfromtheonesthatrepresentthelimitoftheprocess.PERFORMANCEQUALIFICATION“PQ should include, but not limited to, the following:(a)tests, using production material, qualified substitutes or simulated product, that have been developed fro
37、m knowledge of the process and the facilities, systems or equipment;(b)tests to include a condition or set of conditions encompassing upper and lower operating limits.”The Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Qualification a
38、nd Validation July 2001PERFORMANCEQUALIFICATIONDefiningthesterilizationprocessDemonstratedPNSUDemonstratedPNSUExpectedShelfLifeExpectedShelfLifeInformationNeededInformationNeededForValidationForValidationHeatInputtoMaterialsHeatInputtoMaterialsBioburdenBioburdenMethodMethodBioburden/BIBioburden/BIMe
39、thodMethodOverkillOverkillMethodMethodValidation approachesOverkill(fromPDA,TM#1revised, Draft 13, Glossary):A cycle which provides a minimum 12-log reduction of a resistant biological indicator with a known D-value of not less than 1 minute at121.1C. This approach assures substantially greater than
40、 a 12-log reduction of the bioburden and therefore only minimal information on the bioburden is requiredBioburden(fromPDA,TM#1revised, Draft 13, Glossary):A process which provides a probability of survival of less than 1 in 106 for the most resistant bioburden expected in the load. It requires infor
41、mation on the number and heat resistance of bioburden and requires ongoing monitoring or control over the bioburdenValidation approachesBB/BIor“combination”(fromPDA,TM#1revised, Draft 13, Glossary):A process which provides a probability of survival of less than 1 in 106 for the bioburden as demonstr
42、ated using a resistant biological indicator with a known D-value. The biological indicator may not be fully inactivated during the sterilization cycle. It requires information on the number and heat resistance of bioburden and requires ongoing monitoring or control over the bioburdenValidation appro
43、achesDandzvaluesIftheBiologicalIndicatorsareusedtoreleasetheproductionbatchestheresistanceoftheinoculatedsporehastobe.VerifiedDeterminedBIsfromtheshelfHomemadeBIsValidation approachesMicrobiologicalqualificationMicroorganismresistanceD:decimalreductiontimeThetimerequired,ataspecifictemperatureT,tore
44、ducethemicrobialpopulationbeingconsideredbyonelogarithmicvalue,i.e.from100%to10%z:temperaturecoefficientofmicrobialdestructionThenumberofdegreesoftemperaturewhichcausesa10-foldvariationofD(or,moregenerally,ofthesterilizationrate)MicroorganismresistanceBIERBiologicalIndicatorEvaluatorResistometerTove
45、rifytheresistance(D,z)ofthecommercialBis(Overkillapproach)Todetermineandverifytheresistanceoftheself-madeBiologicalIndicator(Bioburdenapproach)MicrobiologicalqualificationValidation approachesDandzvaluesdeterminationB.I.E.R.BiologicalIndicatorEvaluatorResistomertimetemperatureRealTheoreticalSquaredc
46、urveforaBIERvesselBiological Indicator Evaluator ResistometerValidation issuesCalibrationLeaktestValidationactivities(physical)ThermocouplescalibrationHeatdistributionHeatpenetrationSterilizatioCycleVerificationofcalibrationProceduradiconvalida(Microbiologica)ReviewofresultsMaintainingthevalidationV
47、alidation Calibrationa)TemperatureTemperatureb)PressurePressurec)TimeTimeValidation issuesCalibrationLeaktestValidationactivities(physical)ThermocouplescalibrationHeatdistributionHeatpenetrationSterilizatioCycleVerificationofcalibrationProceduradiconvalida(Microbiologica)ReviewofresultsMaintainingth
48、evalidationValidation leak testValidation issuesCalibrationLeaktestValidationactivities(physical)ThermocouplescalibrationHeatdistributionHeatpenetrationSterilizatioCycleVerificationofcalibrationProceduradiconvalida(Microbiologica)ReviewofresultsMaintainingthevalidationHeat distribution and penetrati
49、onTheUniformityhastobereferredtotheemptychamberortothefreespaceoftheloadedchamberTemperaturesensorsTheHeatPenetrationisreferredtotheinnerpartoftheproducts:TemperaturesensorsBiologicalIndicatorsTemperature mappingLethality mapsApplicationConsiderationsPlaceinthemostdifficulttosterilizelocationUseforv
50、alidationUseforroutinemonitoringMapsUseFOCalculatedFromEachMapsUseFOCalculatedFromEachThermocoupleLocationThermocoupleLocationLethality mapsMapsUseFOCalculatedFromEachMapsUseFOCalculatedFromEachThermocoupleLocationThermocoupleLocationLethality mapsFront of ChamberLethality Map, Lower ShelfLethality
51、mapsApplicationsCertainidentificationofthecoldpointsPlacementofBIinleastlethal(worstcase)location(s)CorrectreplicationoftheexpositionenvironmentoftheBIsLethality mapsRandomBIDistributionBIBIBIBIBILethality mapsClusterBIDistributionBIsLethality mapsWaterforsterilizationmaybeInitiallypresentinthebulko
52、fsealedcontainersofaqueoussolutions(steamistheheatingmedium)Transferredfromthesteam(heatingandsterilizingmedium)tothesurfaceoftheproductand/orintoPossible failure causesWatertransferandheatingAreobtainedbycondensationofthefeedsteamDemanduniformthermodynamicpropertiesinsidetheautoclave(temperature,pr
53、essureandchemicalcomposition)Possible failure causesUniformconditionsintheautoclavemaybeaffectedbyIneffectiveairremovalPoorqualityoffeedsteama)Excessofsuperheatb)PresenceofnoncondensablegasesIneffectiveair/steamhomogenizationInadequatesuperheatedwaterdistributionPossible failure causesTheone-to-onec
54、orrespondencebetweenPandTnolongerexistsifOnlyonesinglephaseispresent,eitherliquidorsteamOtherchemicalcomponentsarepresentsimultaneouslywithwater(eitherliquidorsteam)Possible failure causesNoncondensablegasesAlltheeffortstoeliminateairbecomeuselessifnoncondensablegasesre-enterwithsteamTheaboveislessc
55、riticalifcondensateiscontinuouslysuckedoutofthechamberandnotsimplydrainedviaasteamtrapPossible failure causesCONTENTRegulatoryaspectsMoistHeatSterilizationChoosing the right processValidatingasterilizationprocessCalibration of instrumentsChamber leak test“Utilities”Validation Physical issuesValidati
56、on Microbiological issuesValidatingalyophilizationprocessProcessControllerRiskAnalysisOPERATIONAL QUALIFICATION 8Verification of documentation8.1Standard Operative Procedures8.2Calibration certificate of critical instruments9Verification of system functionalities9.1Input/Output9.2Alarms9.3Production
57、 receipes9.4Security and Access9.5Back-up & Restore10Operational verification10.1Maximum and minimum temperature of shelfs10.2Control loop (for temperature of the shelf)10.3Temperature distribution10.4Temperature of condenser10.5Vacuum system10.6Vacuum deep10.7Leak Rate of system and lyophilizater c
58、hamber10.9Cleaning In Place10.9Sterilization cycle10.10Load lyophilization10.11Defrost of condenserLyophilizationVerifythattheUltimateCoolingTemperatureandtheUltimateHeatingTemperaturecomplytotechnicalspecifications.Maximum and minimum temperature of shelfsLyophilization:OQCondenser temperatureVerif
59、ythattheCondenserCoolingRateandtheUltimateCondenserCoolingTemperaturecomplytotechnicalspecifications.Verification of shelf temperatureShelf Temperature:Verificatin of control loop for the temperature. Usual acceptance criteria: +/- 1.5 C respect to the set-point.Temperature distributionVerification
60、of temperature distribution in the shelfsExample:5 TCs by shelf.Test temperature: -40, +20, +40 CMax temperature diff: 2 C (between TCs on different shelfs).Lyophilization:OQVerifythat,inthesystemfreeofhumidity,theEvacuationRateandtheUltimateVacuum)complytothetechnicalspecifications.Verification of
61、Vacuum SystemVerifytheperformanceofcontrolloopforvacuumsystem.Theacceptancecriteriashouldbe+/-5microbaroftheset-point.Verification of Control Loop for VacuumLyophilization:OQVerification of Leak RateAny leak in to the lyophilizer could introduce a risk of microbiological or chemical contamination.Th
62、e leak rate test carried out during qualification represents baseline for future maintenance. For a new equipment it is strongly suggested to carry out a test the presence of nay leak with Helium to confirm the integrity of the chamber and the condenser.Test procedure: Start cooling and vacuum syste
63、m. Open isolating valve of vacuum system and valve between chamber and condensed.Wait for reaching 100 microbar and let the system be dried and degassed.Close the valve and stop vacuum systemRecord internal pressure of the chamber at zero time and after one hour.Calculate the leak rate and compare i
64、t with the specification.Repeat the procedure, closing the valve between chamber and condenser.Acceptance Criterria: 0.01 mbar*l/s. Lyophilization:OQQUALIFICATION AND VALIDATION9Verification of documentation9.1Verification of SOPs9.2Verification of calibration certificatre of critical instrumentatio
65、n10Verification of the performance10.1Verification if product complies to specifications10.2Verification of residual humidity in the product10.3Verification of stopperingPERFORMANCEQUALIFICATIONLyophilizationThe consistence of the product in terms of quality attribute inside the same batch and in di
66、fferent batches is essential for process reproducibility.Theuniformityoflyophilizationdependson:PositionofthestopperinthevialTemperatureinsidethechamberVialshapeVialpositionDifferenceinheattransferduetoiceontheshelfLyophilization:PQvResidual Humidity in lyophilized productTest is carried out samplin
67、g closed vials, following an approved sampling plan and procedure.The sampling vials should be representative of the overall batch. Usually vials are sampled in groups of three.Usually humidity is more for vials in the middle of the shelf, because of irradiation of chamber walls and door.Lyophilizat
68、ion:PQPDA TR 22 identifies three possible approaches:Lyophilization with diluite brothSimulate lyophilizationSimulation of load-unload with a reduced hold time Lyophilization:MediaFillVials are filled with a diluite broth (65%)Lyophilization goes on until real concentration for not diluited broth.Ly
69、ophilization:MediaFill1/3:LyophilizationwithdiluitebrothVials are filled with a sterile liquidStoppers are leant on the vialsProcess is carried out with a partial vacuum at room temperature. Duration is the same of the real process.Lyophilization:MediaFill2/3:SimulationofLyophilizationVials are fill
70、ed with a sterile liquidStoppers are leant on the vialsProcess is carried out with a partial vacuum at room temperature. Duration is the same of the real process.Lyophilization:MediaFill2/3:SimulationofLyophilizationLyophilization:MediaFill3/3:Simulationofload-unloadwithareducedholdtimeVials are fil
71、led with a sterile liquidStoppers are leant on the vialsProcess is carried out with a partial vacuum at room temperature. Duration is the same of the real process.Performance QualificationOutlineExample of testsPERFORMANCEQUALIFICATIONPERFORMANCEQUALIFICATIONPERFORMANCEQUALIFICATIONPERFORMANCEQUALIF
72、ICATIONPERFORMANCEQUALIFICATION“Documentation”A report that cross-references the qualification and/or validation protocol should be prepared, summarising the results obtained, commenting on any deviations observed, and drawing the necessary conclusions including recommending changes necessary to cor
73、rect deficiencies. Any changes to the plan as defined in the protocol should be documented with appropriate justification.”The Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Qualification and Validation July 2001Validation & Qualifica
74、tion Report Validation & Qualification Report (Summary)(Summary)The Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Qualification and Validation July 2001“Documentation”After completion of a satisfactory qualification, a formal release
75、 for the next step in qualification and validation should be made as a written authorisation”Validation & Qualification ReportValidation & Qualification Report“The following items should be included in the validation report:(a)A description of the process Batch/Packaging Document, including details
76、of critical steps,(b)A detailed summary of results obtained from in-process and final testing, including data from failed tests. When raw data are not included reference should be made to the sources used and where it can be found,Recommendations on Validation Master Plan, Installation and Operation
77、al Qualification, Non-Sterile Process Validation, Cleaning Validation PI 006-2, 1 July 2004Validation & Qualification ReportValidation & Qualification ReportCONTENTRegulatoryaspectsMoistHeatSterilizationChoosing the right processValidatingasterilizationprocessCalibration of instrumentsChamber leak t
78、est“Utilities”Validation Physical issuesValidation Microbiological issuesValidatingalyophilizationprocessProcessControllerRiskAnalysisProcess Control SystemWhatshoulditdo?ControlandmonitorthemanufacturingprocessGuaranteeasafeuseoftheequipmentComplywithapplicablestandardsandrulesGenerateacompleteanda
79、ccurateprocessdocumentationIntegratewithexternalsystemsforcollectingorprocessingdataExchangeinformationwithexternalsystemsingeneralRegulatory requirementsThecriticalityofthesesystemshastobereferredtotheirroleinpharmaceuticalproductionIn2003ISPEissuedaGoodPracticeGuideonthevalidationofPCScontrollingt
80、hemanufacturingprocessesandhavingadirectimpactontheproductprocessing,transferringorstoringprocessinformationinelectronicformatProcess Control SystemVersione 5 - Drivers GAMPguidelineVers 5 - OverviewGAMPComputerized System LifecycleElectronic process dataelectronic records (ER)electronic signatures
81、(ES)DEFINITIONSELECTRONIC RECORD(as specified in the Guidance of August 2003)“Records that are required to be maintained under predicate rule requirements and that are maintained in electronic format in place of paper format”.Records that are required to be maintained under predicate rules, that are
82、 maintained in electronic format in addition to paper format, and that are relied on to perform regulated activities. CONTROLS FOR CLOSED SYSTEM11.10 SUBPART B, ERs require:vValidationvAccurate and complete copiesvProtection of recordsvLimiting system accessvAudit trailvOperational system checksvAut
83、hority checksvValidity of sourcevTraining and experiencevPolicies and procedures defining responsibilitiesvControl over system documentationvHow can we improve our awareness vin approaching validation?CONTENTRegulatoryaspectsMoistHeatSterilizationChoosing the right processValidatingasterilizationpro
84、cessCalibration of instrumentsChamber leak test“Utilities”Validation Physical issuesValidation Microbiological issuesValidatingalyophilizationprocessProcessControllerRiskAnalysisGuidelineICHQ9/Annex20“QualityRiskManagement”1.Introduction2.Scope3.PrinciplesofQualityRiskManagement(QRM)4.GeneralQuality
85、RiskManagementProcess5.RiskManagementMethodology6.IntegrationofQRMintoindustry®ulatoryoperations7.Definitions8.ReferencesICHGuidanceforIndustryQ9QualityRiskManagement(June2006)ThisAnnexprovidesaframeworkthatmay bemay be appliedtoall aspectsall aspectsofpharmaceuticalquality,includingdevelopment,m
86、anufacturing,distribution,inspectionandsubmission/reviewprocessesthroughoutthelifecycleofdrugsubstancesanddrugproducts,biologicalandbiotechnologicalproducts,andtheuseofrawmaterials,solvents,excipients,packagingandlabelingmaterials.SCOPESCOPEAnnex20TwoTwoprimaryprinciples:1.Theevaluationevaluationoft
87、hequalityriskshouldultimatelylinkbacklinkbacktothepotentialharmtothepatient.2.Thelevellevelofeffort,formalityanddocumentationofthequalityriskmanagementprocessshouldbecommensuratecommensuratewiththelevelofrisk.PrincipleofQualityRiskManagementPrincipleofQualityRiskManagementAnnex20DEFINITIONSDEFINITIO
88、NSAnnex20QUALITYRISKMANAGEMENTPROCESS“Initiateaqualityriskmanagementprocess”Definetheproblemand/orriskquestion,includingpertinentassumptions,forpotentialriskidentificationAssemblebackgroundinformationand/ordataonthepotentialhazard,harmorhumanhealthimpactrelevanttotheriskassessmentIdentifyaleaderandc
89、riticalresourcesSpecifyatimeline,deliverables,andappropriatelevelofdecisionmakingfortheriskmanagementprocess“Riskassessment”“Consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards”1) RISK INDENTIFICATIONWhatmightgowrong?2) RISK AN
90、ALYSISWhat is the likelihood (probability) it will go wrong?What are the consequences (severity)?Is the hazard detectable (detectability)?RISKIDENTIFICATION+RISKANALYSIS+RISKEVALUATION“Riskassessment”RISKIDENTIFICATION+RISKANALYSIS+RISKEVALUATION3)RISKEVALUATIONComparetheidentifiedandanalyzedriskaga
91、instriskcriteria.Aqualitativeandquantitativeprocessmightbeusedtoassigntheprobabilityandseverityofarisk.R R I I S S K KHighMediumLowQUALITATIVERISKEVALUATIONRiskcontrol:riskreduction+riskacceptanceIncludesdecisionmakingtoreduceand/oracceptrisks.Thepurposeofriskcontrolistoreducetherisktoanacceptablele
92、vel.Theamountofeffortusedforriskcontrolshouldbeproportionaltothesignificanceoftherisk.Decisionmakersmightusedifferentprocessesforunderstandingtheoptimallevelofriskcontrolincludingbenefit-costanalysis.1.Istheriskaboveanacceptablelevel?2.Whatcanbedonetoreduce,controloreliminaterisks?3.Whatistheappropr
93、iatebalanceamongbenefits,risksandresources?4.Arenewrisksintroducedasaresultoftheidentifiedrisksbeingcontrolled?Theoutputofthequalityriskmanagementprocessshouldbedocumentedwhenaformalprocesshasbeenutilized.Risk communication isthesharingofinformationaboutriskandriskmanagementbetweenthedecisionmakersa
94、ndothers.RiskCommunicationRiskreviewTheoutput/resultsoftheriskmanagementprocessshouldbereviewedtotakeintoaccountnewknowledgeandexperience.Riskmanagementshouldbeanongoingqualitymanagementprocessandamechanismtoperformperiodicreviewofeventsshouldbeimplemented.Thefrequencyofthereviewshouldbebaseduponthe
95、levelofrisk.Riskreviewmightincludereconsiderationofriskacceptancedecisions.5.RISKMANAGEMENTMETHODOLOGY5.RISKMANAGEMENTMETHODOLOGYAnnex20FailureModeEffectsAnalysis(FMEA)Faulttreeanalysis(FTA)HazardAnalysisofCriticalControlPoints(HACCP)HazardOperabilityAnalysis(HAZOP)FMEAFMEA (Failure Modes and Effect
96、s Analysis) can be applied to equipment,facilities,mightbeusedtoanalyzeamanufacturingoperationanditseffectontheproductorprocess.CaseStudy:IdentificationTestforAutoclaveQualificationSpecificationdocumentationGuidelinesePoliciesP&IDTeamRISK PRIORITY INDEXRISK PRIORITY INDEXRPI = SEVERITY (S) x OCCURAN
97、CE (O) RPI = SEVERITY (S) x OCCURANCE (O) x DETECTABILITY(R)x DETECTABILITY(R)FMEAResultsevaluation1RPI(TOTALRiSK)27CaseStudy:sterilizationofsolids:processFMEA1)ListProcesssteps2)DefineFailuremodes3)Identifycausesandeffect4)Evaluatetherisk5)ControltheriskCaseStudy:sterilizationofsolids:processFMEA1)
98、ListProcesssteps1)Pre-sterilization2)Sterilization3)Post-sterilization2)DefineFailuremodes3)Identifycausesandeffect4)Evaluatetherisk5)ControltheriskCaseStudy:sterilizationofsolids:processFMEA1)ListProcesssteps1)Pre-sterilizationI.Iniatial vacuumII.Pulsed vacuum1)Heating2)Sterilization1)Temperature h
99、olding3)Post-sterilizationI.VacuumII.Hot air pulses III.Hot air holding1)Atmospheric balanceCaseStudy:sterilizationofsolids:processFMEA1)ListProcesssteps2)DefineFailuremodes3)Identifycausesandeffect4)Evaluatetherisk5)ControltheriskCaseStudy:sterilizationofsolids:processFMEA1)ListProcesssteps2)Define
100、Failuremodes3)Identifycausesandeffect4)Evaluatetherisk5)ControltheriskStepstepFailure ModeCauseEffectSterilizationTemperature holdingSterilization temperature not reachedutilities product not sterilizedPIDsensor calibrationSterilization band not respectedPIDprocess out of specification. Stability co
101、uld be affectedsensor calibrationsteam qualityHeat distribution out of specAutoclave working cycle not correctly executedProduct not sterilizedAutoclave: lack of performance Temperature probes out of operation or not calibratedTime not controlledprocess controlled not validatedproduct not sterilized
102、F0 function not calculatedprocess controlled not validatedproduct not sterilizedCaseStudy:sterilizationofsolids:processFMEA1)ListProcesssteps2)DefineFailuremodes3)Identifycausesandeffect4)Evaluatetherisk5)ControltheriskCaseStudy:IdentificationTestforAutoclaveQualificationSpecificationrequirementsThe
103、temperaturedistributioninsidethechambershouldbeintherange(set-point+/-1.0C)FTAFTA(Fault tree Analysis)canbeusedtoestablishthepathwaytotherootcauseofthefailure.Itcanbeusedtoinvestigatecomplaintsordeviations.TOP EVENT definitionTOP EVENT definitionTop EventTop EventCAUSES identificationCAUSES identifi
104、cationManaginganonconformity/outofspecsGOAL:GOAL:DeterminetherootcauseofthedeviationHazard=?Hazard=?(OOS)(OOS)Managinganonconformity:outofspecsforsterilizationofwrappedelastomericclosuresLetsseemoredetailsCreditsJim Agalloco Agalloco & AssociatesJAJohn G. Gillis, Ph.D. SGM Biotech, I CTP Tecnologie di PFedegari AFURTHER INFORMATION?“Innovation in Biological Indicator Evaluator Resistometer Vessel Technology”Phttp:/ resourceshttp:/http:/www.fda.govhttp:/pharmacos.eudra.org/F2/home.htmlThank you for your kind
