On-lineblenduniformityofpharmaceuticalformulationsbyNear-IRNathanPixleyContributingauthors:JeffGivand,RobertL.Green,JohnP.Higgins,ErnestinaLuna,ArthurMateos,MarkSullivan,RobertA.Reed,GertThurauMerckResearchLaboratories,MerckandCo.,Inc.,P.O.Box4,WP78-110,WestPoint,PA19486利用近紅外測定藥劑的在線混料均勻度OutlineBackground–blendingunitoperation&characterizationofblendsNIRimplementation,acquisitionofspectratriggeredvs.continuoussamplingconsiderationsDataanalysis–movingblock,wavelengthcorrelationReproducibility,endpointdeterminationApplytoprocessingdevelopment&scale-upFillvolume,scale-up,activevs.blankformulationOutline背景–混料儀器操作和混料特征NIR應用，光譜獲取觸發vs.連續采樣注意事項數據分析–移動塊,波長相關性重現性,終端判定應用于處理開發和混料機尺寸增大情況填料體積，混料機尺寸增大,活性vs.無效配方BlendingofpharmaceuticalpowdersProcessoverview:SequentialadditionofmaterialsSpinblenderEquipment:Bohletoteblenders(binblenders)Scale:Pilot(300L)&Full-scale(1800L)Drypowderblending(API&excipients)&lubrication(ofpowderblends,orgranules)Processconditions–fillvolume,RPM’s,&formulationattributes藥品粉末混合過程概述:連續添加原料旋轉混料機設備：Bohletote混料機(桶式混料機)尺寸:試驗尺寸(300L)&全尺寸(1800L)干粉末混合(API&輔料)&潤滑(粉末混合，或顆粒)過程條件–填料體積、轉數和藥劑屬性CharacterizationofblendingprocessesSamplethieving:spatialsamplingatdiscretetimepoints->analyticalassayProvidesvariabilityofmaterialvs.timeCanidentifylocation-specificblendperformanceDrawbacks:TimeresolutionRepresentativesamplingResourcesrequiredAnopportunityforPAT…Near-IRSpectraateachrevolutionSampleprovidedbyprocessReal-timeinformation;automation混料過程特征取樣:在離散時間點內進行空間取樣->分析含量提供有差異的原料vs時間可以區分特定地點的混料性能缺陷:時間分辨率代表性取樣需要資源是PAT的機會…近紅外每次旋轉的光譜過程中進行采樣實時信息，自動化操作ImplementationapproachBrimroseLuminarNear-IRspectrometerBattery-powered,wirelesscommunicationInterfacedtolid–measurementthroughsapphirewindowAcquisition:1100-2300nm,6nmincrementPilotscale Full-scale實施方法BrimroseLuminar近紅外光譜儀電池供電，無線通訊直接檢測–通過藍寶石視窗檢測獲取:1100-2300nm,6nm增量試驗尺寸

全尺寸AcquisitionofspectraContinuousacquisition1spectrum~20%Rev.SeparationofspectraSinglewavelengthabsorbancevalueMinimalimpact…Thresholdvalue#spectra/revolutionincludedDirectindicationofwindowfouling(lackof)ApplytowardoptimizingtriggeredacquisitionTriggeredacquisitionS/NiftriggeroptimizedMoreamenabletoautomation,routineuseToteuprightandstationarySpectraofformulationSpectraofairChangesinblenderdirectionBlendingstopped.ToteuprightandstationarySpectraofair+formulation光譜獲取連續獲取1光譜~20%轉.光譜分離

單波長吸光度值最小影響…閾值#包含光譜/轉數窗口直接顯示(無)應用于最佳觸發獲取觸發獲取觸發優化后，S/N更適合自動化，常規應用ToteuprightandstationarySpectraofformulationSpectraofairChangesinblenderdirectionBlendingstopped.ToteuprightandstationarySpectraofair+formulationNear-IRsamplingofbatch~10mgformulationinterrogatedformulation&instrumentdependentStationaryvs.dynamicmeasurementCer-revolutionsComparisonwithsamplethief(example)NIR:10mgx100revolutions=1gAseriesof“micro-assessments”withhightimeresolutionThief:100mgsamplex10locations=1gMacro-assessmentatonerevolutionStopblenderbasedonasinglemeasurement(revolution)?近紅外批次取樣~10mg需測定的配方藥取決于配方和儀器靜態vs.動態檢測考慮外部-vs.內部-轉數與取樣對比(實例)NIR:10mgx100轉=1g一系列“微觀評估”，高時間分辨率

取樣:100mg樣品x10個位置=1g一轉處的微觀評估

基于單次檢測（轉數），停止混料機?DataanalysisapproachesMeanspectralstandarddeviationNocalibrationSpectralvariability->formulationvariabilityPre-processing:SNVWavelengthcorrelationCorrelationvalueofindividualspectratolibrary(dotproduct)Librarybasedonend-pointspectrafrompreviousbatchesPre-processing:2ndderivative123456RevolutionNumberSpectra數據分析方法平均光譜標準偏差無校準光譜變異性->配方變異性預處理:SNV波長相關系數單光譜與光譜庫（點積）的相關值光譜庫基于先前批處理的終點光譜預處理:二次微分123456轉數光譜Blendprofiles:movingblockspectralstandarddeviationLargeblocksizeSuitableendpointbasedony-axisvalue(1point)orprofileslopeSmallblocksizeSuitableendpointbasedonconsecutivey-axisvalues(multiplepoints)byminimalprofilevariability混料圖:移動塊光譜標準偏差大移動塊適當終點

基于Y軸值（1點）或圖示斜率小移動塊適當終點

基于連續的Y軸值（多點）byminimalprofilevariabilityProfilereproducibility:Movingblock9batchesSameprocessingconditionsAPIblendingBlocksize=3Blocksize=20Profile重現性:移動塊9批相同處理條件API混合移動塊尺寸=3移動塊尺寸=20Profilereproducibility:wavelengthcorrelation9批相同處理條件API混合EachprofilevaluerepresentsasinglerevolutionEndpoint–multipleprofilepointsProfile重現性:波長相關性9批相同處理條件API混合EachprofilevaluerepresentsasinglerevolutionEndpoint–multipleprofilepointsMovingblockvs.wavelengthcorrelationWavelengthcorrelationThresholdbasedonendpointvariabilityacross9batches17-26Revrepresents10consecutive“passing”valuesCorrespondencetomovingblockprofilevalue移動塊vs.波長相關性波長相關性9批內閾值，基于終點可變性17-26轉代表10連續“傳遞”值與移動塊對應CorrespondencetothiefdataSamplethiefandNIRappliedtosamebatchEarlytimepointsamplethievingThiefdatabasedon10locations/timepoint對應取樣數據在相同批次中使用取樣和NIR方法早期時點取樣10個位置/時點的取樣數據Applicationtoprocessdevelopmentandscale-upFillvolumeAPIvs.blankformulationAPI/excipientblendingLubricationPilotvs.full-scaleAPI/excipientblendingLubricationBlenddynamics(largefillvolume)應用于處理開發和混料機體積增加填料體積

APIvs.無效配方API/輔藥混合潤滑試驗尺寸vs.全尺寸API/輔藥混合潤滑混合動力(大填料體積)FillvolumeeffectAPIblending,pilotscale5%differenceinfillvolumeMovingblockWavelengthcorrelation填料體積效果API混料,試驗尺寸填料體積，5%差異移動塊

波長相關性Activevs.blankformulationActivevs.blankformulationPilotscale活性vs.無效配方活性vs.無效配方試驗尺寸Activevs.blankformulation:lubricationLubricationofactivevs.blankformulationPilotscale活性vs.無效配方:潤滑活性vs.無效配方的潤滑試驗尺寸Processscale-upPilotvs.full-scaleSameformulation過程混料機尺寸增大試驗vs.全尺寸相同配方Processscale-up-lubricationPilotvs.fullscaleLubricationofblankformulation過程混料機尺寸增大-潤滑試驗vs.全尺寸無效配方潤滑Blenddynamics–largefillvolumeLubricationofgranuleformulation~95%fillvolumeLubricantaddedthroughbottomofblender混料動力–大的填料體積顆粒配方的潤滑~95%填料體積通過混料機底端添加潤滑劑Summary&ConclusionsArapid,non-invasive,&information-richapproachtoblenduniformityhasbeenappliedtowardprocessdevelopment,scale-up,&monitoringTwodataanalysisapproachesconsidered:MovingblockCalibration-freeEachpointcorrespondstomultiplerevolutionsWavelengthcorrelationRequirespre-definedlibraryEachpointcorrespondstoonerevolutionEndpointcriteria--basedonsamplingconsiderationsanddataanalysisapproachNear-IRandtraditionalcharacterization(samplethief)arecomplementarytoolsDifferentinformationValueduringdevelopment總結與結論在處理開發，體積增加和監控過程中應用了一個快速無損和信息豐富的方法測定混料均勻性使用了兩種數據分析方法:移動塊

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