关键性制程确效作业资料

關鍵性製程確效作業資料

林邦德

第1页製程確效（藥品優良製造確效作業基準88.04.13

4）製程確效:確認產品之製造程序及其管制條件，具有良好旳有效性與再現性。

確效計畫書:說明將如何進行確效之書面計畫書，內容涉及予以測試之指標，產品特質，生產設備，以及測試合格之鉴定標準。先期性確效：為一種產品於上市前所進行之確效措施，適用於下列兩類品：(一)新產品：新申請查驗登記之產品。(二)既有產品於更改配方(涉及成分及組成)、製造場所、製造設備、製程等製造條件而也许會重大影響產品之品質特性者。第2页ProcessDevelopment製程研發CommercialProductionProcess量產3batchesvalidation三批確效(ProcessChangeanother3batchesvalidation)製程更改則需另作三批ProcessScaleUp試製第3页內容

一、計畫書之核准二、產品詳細處方一覽表三、批量四、製造流程圖五、各製程操作條件六、關鍵製程步驟七、機器設備3Q一覽表第4页關鍵性製程確效作業查檢表

(CourtesyofformerBFDA-CDST)品名:_________主成分:_________劑型:_________指標分析成分:________一、確效計畫書與執行執行確效办法:

□先期性□併行性□回溯性

計畫書之核准 □制訂人□核定人□制訂日期□核定日期第5页確效計畫書（藥品優良製造確效作業基準7）確效或驗證之項目。確效或驗證之目旳及整體目標。預定實施頻率。該項確效或驗證之計畫書制訂及各次改訂日期，以及改訂事項。確效或驗證办法。合格標準範圍。數據或資料處理办法。確效或驗證書面資料之改訂程序及保管相關事項。執行確效或驗證之責任單位及負責人員。第6页產品詳細處方一覽表主成分(Activesubstance)賦形劑(Excipients)增量(Overages)Ref:ICHQ8PharmaceuticalDevelopment第7页批量PilotBatch:Batchsizeshouldcorrespondtoatleast10%ofthefutureindustrial-scalebatch.Fororalsoliddosageformsthissizeshouldbeatleast10%or100,000unitswhicheverisgreaterunlessotherwisejustified.ProductionBatch:Drugproductmanufacturedatproductionscalebyusingproductionequipmentinaproductionfacilityasspecifiedintheapplication.第8页Ashortdescriptionofthemanufacturingprocessinaschematicdrawingorflowchart製造流程圖第9页Ref:關鍵性製程及其指標（88.10.21公示）含量均一性固形製劑混合工程造粒工程打錠工程充填工程液劑溶解工程混合、溶解工程充填工程膏劑栓劑貼片劑練合工程充填工程塗布工程各製程操作條件第10页AcceptanceCriteria合格範圍ProductSpecifications產品既定規格PharmacopoeiaSpecifications產品藥典規格ProductIn-processSpecifications產品製程規格第11页設定合格範圍SettingLimits藥品查驗登記旳規格安定性規格成品檢驗放行規格確效規格成品放行規格產品查驗登記旳規格

依據安定性規格製程規格(Limits)第12页固型製劑之分類散、粉劑顆粒、錠劑、丸劑加衣錠膠囊、軟膠囊第13页散劑、粉劑之製造程序稱量顆粒粉碎過篩混合第14页固型製劑之製造程序（I）混合與造粒Mixing&GranulationGranulation造粒WetGranulation濕製粒RollCompaction/Slugging乾製粒DirectMixing直混第15页固型製劑之製造程序（II）Granulation製粒WetGranulationSlugging/RollCompactionDirectMixingWeighing稱量Sieving過篩

Mixing混合Kneading煉合Extrusion擠出Drying乾燥Milling/Sizing整粒FinalBlending最終混合Lubrication潤滑Weighing稱量Sieving過篩

Mixing混合RollCompaction滾壓Milling整粒Lubrication潤滑Weighing稱量Sieving過篩

Mixing混合Lubrication潤滑第16页固型製劑之製造程序（III）壓錠與膠充Compressing&EncapsulationCompression打錠單層錠雙層錠子母錠Encapsulation充填硬膠囊軟膠囊第17页固型製劑之製造程序（IV）加衣CoatingFilmCoating膜衣SugarCoating糖衣EntericCoating腸溶錠shellaccoatingsubcoatingcolorcoatingpolishingentericcoatingsubcoatingcolorcoatingpolishing第18页製程參數Mixing混合Kneading鍊合FluidBedGranulation流動床造粒Time/RPMTime/RPMLiquidadditionrate添加率Inletairtemp.進氣溫度Fluidizingairvol.空氣量Processairhumidity濕度AtomizationairPressure空壓第19页製程參數Extrusion擠出RollCompaction滾壓Drying乾燥Milling/Sizing整粒FinalBlending最終混合Lubrication潤滑Time/PressureTime/PressureTime/Temp.Mesh/BladeRPM網徑/切刀轉速Time/RPMTime/RPM第20页固型製劑之規格（I）PhysicalAnalysis Appearance外觀 AQ-UPDiameters大小 strengthHardness硬度 stabilityFriability脆度 stabilityWeightVariation重量偏差 strengthMoistureContent水份含量 stabilityDisintegration崩散時間 efficiency第21页固型製劑之規格（II）ChemicalAnalysisIdentity鑑定 safetyDissolution溶離度 efficiencyContentUniformity含量均一度 strengthContent含量 strengthImpurityContent不純物含量 purityStabilityAnalysis安定性分析 stabilityDecompositionProducts分解產物 purity第22页固型製劑之製程管制混合工程造粒工程乾燥工程整粒工程壓錠工程加衣工程膠囊充填工程含量均一度殘餘量水分含量粒徑分布、安息角、粗密度與輕擊密度外觀、厚度、硬度、脆度、重量均一度、崩散度或溶離度外觀、包覆百分率、釋離行為重量均一度第23页顆粒特性對錠劑之影響BulkdensityFlowabilityParticlesizedistribution粒度分佈MoistureContent水份含量WeightandcontentuniformityHardnessDisintegration/DissolutionWeightandcontentuniformityHardnessCapping/LaminationFriction/AdhesionHardnessDisintegration/DissolutionPoorPhysical/ChemicalStability第24页半固型製劑之處方組成ActiveIngredientsBasesOtherexcipientsAntimicrobialPreservativesAntioxidantsStabilizersEmulsifiersThickenersPenetrationEnhancers第25页半固型製劑之規格potencycontentuniformitydrugreleaseParticlesizeviscositypHPathogenMicrobialPreservativeefficacyAppearancePackagecompatibilityCrystalform第26页半固型製劑之製程管制真空乳化工程充填工程pH值、含量均一度、比重、黏度含量均一度、重量偏差第27页液劑之分類（中華藥典）Example:溶液劑-係含是一種或多種藥品溶解或分散於一適當溶劑，或互相混合溶劑之混合物。酏劑-為一種供內服用之澄明、甜味、含乙醇水溶液。醑劑-為一種含是揮發性物質之乙醇溶液，或含水乙醇溶液。酊劑-為生藥或化學藥品，經滲漉法、浸漬法或溶液法製成之一種乙醇溶液，或含水乙醇溶液。乳劑-為一種二相系統之液體製劑，其中一種液體呈小球狀分散於另一種液體中。第28页液劑旳製造程序第29页液劑之規格AppearancepHSpecificgravityViscosityAlcohol,v/v(%)Assayofactiveingredients第30页液劑劑之製程管制溶解工程充填工程pH值、含量均一度、比重、黏度含量均一度、重量偏差第31页Sampling取樣

Samplingtiming取樣時機Samplingpoints取樣點Samplesize取樣數Samplingtiming取樣時機duringtheprocessatthetimeofblenderdischargeordirectlyfromdrums第32页Samplingpoints取樣點不同Blender也许發生Segregation(PonyPanType)PoormixingDead–spot(RibbonBlender)Lumps(TumblerBlender)Re-crystallization(HighShearMixer)第33页Samplingpoints取樣點第34页第35页Samplingpoints取樣點第36页Samplingmethod取樣办法Simplesampling簡易取樣法Samplestakenfromthedischargedblend出料中取樣Thiefsampling取樣器法Samplestakenfromtheblender使用取樣器取樣第37页*滅菌工程□是□否（無菌製劑）□無菌充填/□最終滅菌□冷凍乾燥另附相關之查檢表無菌充填過程確效環氧乙烯滅菌確效放射線滅菌確效

___________________________________※製程確效三批結果彙整報告□是□否 批號及批量：____________________關鍵性製程確效作業查檢表(cont.)第38页關鍵性製程及其指標（88.10.21公示）指標製程階段劑型無菌性含量均一性無菌製劑最終滅菌製劑滅菌工程溶解工程混合、溶解工程充填工程無菌操作製劑無菌操作工程過濾滅菌工程無菌充填工程凍晶乾燥工程溶解工程混合、溶解工程充填工程第39页IntroductionSterilizationThermalMoistheatSterilizationDryheatSterilizationNonthermalGammairradiationChemicals:EthyleneOxide第40页MoistHeatSaturatedsteamCommoncycles:121°Cfor15minutes134°Cfor3minutesOthercyclesoflowertemperatureandlongertimemaybeused(e.g.115°Cfor30minutes)Usedforsterilizationof:terminalsterilizationofaqueousinjections,ophthalmicpreparations,irrigation&haemodialysissolutions,equipmentusedinasepticprocessing第41页PNSU-ProbabilityofaNon-SterileUnitTheprobabilityofaunit(productcontainer)beingnon-sterileaftertheapplicationofalethalagent.PNSUof1in106--theprobabilitythataunitisnon-sterileisoneinamillionFO-SterilizationProcessEquivalentTime

Theequivalentnumberofminutesat121.1°Cdeliveredtoaunitbyasterilizationprocess.FO=8minutes--thecycledeliveredamicrobiallethalityequivalentto8minutesat121.1°C第42页Validation-CycleDevelopmentConceptofFoLethalityfactorequivalenttotimeat121°C

1minuteat121°CisequivalenttoFoof1.LethalitycanaccumulateduringheatupandcooldownphasesTypicaltemperatureprofileofaheatsterilizationprocessWhatwouldbetheFoofacycleat121°Cfor15minutes?第43页OtherSterilizationProcessesSterilizationusingotherprocessesshouldfollowasimilarapproachasthatdescribedformoistheatValidationprotocolEquipmentcalibrationDeterminingtheprocessthatwilldeliverthedesiredSAL(10-6)IQ,OQ,PQRequirementsforroutinemonitoringandcontrol第44页無菌充填testfillingprocessperformfillingprocesswithnutrientmediarunatfullscaleforatleastonefillsizeworstcase;largevolumeandnumberofvialsfilledvialsincubated,observedandtestforcontaminationbyvalidatedsterilitytestmustbesterilefor3consecutiverunsmediafillperformedtwiceayearsizeofrunmustbelargeenoughtodetectlowlevelsofcontaminatione.g.contaminationrateof1/1000,3000unitsareneededtoprovide95%confidence第45页無菌作業DrugProductSterilizationProcessContainerClosureExcipientSterilizationProcessSterilizationProcessSterilizationProcessSterileClosureSterileExcipientAsepticProcessingSterileDrugProductSterileContainerCanusemultiplesterilizationprocesseseachoptimizedfortheindividualcomponentSterileFinalProduct第46页凍晶乾燥DoorSterileroomwallVacuumgaugeU