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(yīng)用，光譜獲取觸發(fā)vs.連續(xù)采樣注意事項數(shù)據(jù)分析–移動塊,波長相關(guān)性重現(xiàn)性,終端判定應(yīng)用于處理開發(fā)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(xù)添加原料旋轉(zhuǎn)混料機設(shè)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(zhuǎn)數(shù)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(nèi)進行空間取樣->分析含量提供有差異的原料vs時間可以區(qū)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(zhuǎn)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(xù)獲取1光譜~20%轉(zhuǎn).光譜分離

單波長吸光度值最小影響…閾值#包含光譜/轉(zhuǎn)數(shù)窗口直接顯示(無)應(yīng)用于最佳觸發(fā)獲取觸發(fā)獲取觸發(fā)優(yōu)化后，S/N更適合自動化，常規(guī)應(yīng)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(tài)vs.動態(tài)檢測考慮外部-vs.內(nèi)部-轉(zhuǎn)數(shù)與取樣對比(實例)NIR:10mgx100轉(zhuǎn)=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(zhuǎn)處的微觀評估

基于單次檢測（轉(zhuǎn)數(shù)），停止混料機?DataanalysisapproachesMeanspectralstandarddeviationNocalibrationSpectralvariability->formulationvariabilityPre-processing:SNVWavelengthcorrelationCorrelationvalueofindividualspectratolibrary(dotproduct)Librarybasedonend-pointspectrafrompreviousbatchesPre-processing:2ndderivative123456RevolutionNumberSpectra數(shù)據(jù)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(yù)處理:SNV波長相關(guān)系數(shù)單光譜與光譜庫（點積）的相關(guān)值光譜庫基于先前批處理的終點光譜預(yù)處理:二次微分123456轉(zhuǎn)數(shù)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(dāng)終點

基于Y軸值（1點）或圖示斜率小移動塊適當(dāng)終點

基于連續(xù)的Y軸值（多點）byminimalprofilevariabilityProfilereproducibility:Movingblock9batchesSameprocessingconditionsAPIblendingBlocksize=3Blocksize=20Profile重現(xiàn)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(xiàn)性:波長相關(guān)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(guān)性波長相關(guān)性9批內(nèi)閾值，基于終點可變性17-26轉(zhuǎn)代表10連續(xù)“傳遞”值與移動塊對應(yīng)CorrespondencetothiefdataSamplethiefandNIRappliedtosamebatchEarlytimepointsamplethievingThiefdatabasedon10locations/timepoint對應(yīng)取樣數(shù)據(jù)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(shù)據(jù)Applicationtoprocessdevelopmentandscale-upFillvolumeAPIvs.blankformulationAPI/excipientblendingLubricationPilotvs.full-scaleAPI/excipientblendingLubricationBlenddynamics(largefillvolume)應(yīng)用于處理開發(fā)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(guān)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(jié)與結(jié)論在處理開發(fā)，體積增加和監(jiān)控過程中應(yīng)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(shù)據(jù)分析方法:移動塊

免校準每個點對應(yīng)多轉(zhuǎn)數(shù)