關鍵性制程確效作業資料

制程確效（藥品優良制造確效作業基準88.04.13

4）

制程確效:確認產品之制造程序及其管制條件，具有良好的有效性與再現性。

確效計劃書:說明將如何進行確效之書面計劃書，內容包括予以測試之指標，產品特質，生產設備，以及測試合格之判定標準。

先期性確效：為一種產品于上市前所進行之確效措施，適用于下列兩類品：(一)新產品：新申請查驗登記之產品。(二)既有產品于更改配方(包括成分及組成)、制造場所、製造設備、製程等製造條件而可能會重大影響產品之質量特性者。ProcessDevelopment制程研發CommercialProductionProcess量產3batchesvalidation三批確效(ProcessChangeanother3batchesvalidation)制程更改則需另作三批ProcessScaleUp試制內容

一、計劃書之核準二、產品詳細處方一覽表三、批量四、制造流程圖五、各制程操作條件六、關鍵制程步驟七、機器設備3Q一覽表關鍵性制程確效作業查檢表

(CourtesyofformerBFDA-CDST)品名:_________主成分:_________劑型:_________指標分析成分:________一、確效計劃書與執行執行確效方法:

□先期性□并行性□回溯性計劃書之核準

□制訂人□核定人

□制訂日期□核定日期確效計劃書（藥品優良制造確效作業基準7）確效或驗證之項目。確效或驗證之目的及整體目標。預定實施頻率。該項確效或驗證之計劃書制訂及各次改訂日期，以及改訂事項。確效或驗證方法。合格標準范圍。數據或資料處理方法。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。

產品詳細處方一覽表主成分(Activesubstance)賦形劑(Excipients)增量

(Overages)Ref:ICHQ8PharmaceuticalDevelopment

批量PilotBatch:Batchsizeshouldcorrespondtoatleast10%ofthefutureindustrial-scalebatch.Fororalsoliddosageformsthissizeshouldbeatleast10%or100,000unitswhicheverisgreaterunlessotherwisejustified.ProductionBatch:Drugproductmanufacturedatproductionscalebyusingproductionequipmentinaproductionfacilityasspecifiedintheapplication.Ashortdescriptionofthemanufacturingprocessinaschematicdrawingorflowchart

制造流程圖Ref:關鍵性制程及其指標（88.10.21公告）含量均一性固形制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涂布工程

各制程操作條件AcceptanceCriteria合格范圍ProductSpecifications

產品既定規格PharmacopoeiaSpecifications

產品藥典規格ProductIn-processSpecifications

產品制程規格設定合格范圍SettingLimits藥品查驗登記的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的規格

依據安定性規格制程規格(Limits)固型制劑之分類散、粉劑顆粒、錠劑、丸劑加衣錠膠囊、軟膠囊散劑、粉劑之制造程序稱量顆粒粉碎過篩混合固型制劑之制造程序（I）混合與造粒Mixing&GranulationGranulation造粒WetGranulation濕制粒RollCompaction/Slugging干制粒DirectMixing直混固型制劑之制造程序（II）Granulation制粒WetGranulationSlugging/RollCompactionDirectMixingWeighing稱量Sieving過篩

Mixing混合Kneading煉合Extrusion擠出Drying干燥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潤滑固型制劑之制造程序（III）壓錠與膠充Compressing&EncapsulationCompression打錠單層錠雙層錠子母錠Encapsulation充填硬膠囊軟膠囊固型制劑之制造程序（IV）加衣CoatingFilmCoating膜衣SugarCoating糖衣EntericCoating腸溶錠shellaccoatingsubcoatingcolorcoatingpolishingentericcoatingsubcoatingcolorcoatingpolishing制程參數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空壓制程參數Extrusion擠出RollCompaction滾壓Drying干燥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固型制劑之規格（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固型制劑之規格（II）ChemicalAnalysisIdentity鑒定 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固型制劑之制程管制混合工程造粒工程干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余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顆粒特性對錠劑之影響BulkdensityFlowabilityParticlesizedistribution

粒度分布MoistureContent

水份含量WeightandcontentuniformityHardnessDisintegration/DissolutionWeightandcontentuniformityHardnessCapping/LaminationFriction/AdhesionHardnessDisintegration/DissolutionPoorPhysical/ChemicalStability半固型制劑之處方組成ActiveIngredientsBasesOtherexcipientsAntimicrobialPreservativesAntioxidantsStabilizersEmulsifiersThickenersPenetrationEnhancers半固型制劑之規格potencycontentuniformitydrugreleaseParticlesizeviscositypHPathogenMicrobialPreservativeefficacyAppearancePackagecompatibilityCrystalform半固型制劑之制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

液劑之分類（中華藥典）Example:溶液劑-系含是一種或多種藥品溶解或分散于一適當溶劑，或相互混合溶劑之混合物。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、浸漬法或溶液法制成之一種乙醇溶液，或含水乙醇溶液。乳劑-為一種二相系統之液體制劑，其中一種液體呈小球狀分散于另一種液體中。液劑的制造程序液劑之規格AppearancepHSpecificgravityViscosityAlcohol,v/v(%)Assayofactiveingredients液劑劑之制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

Sampling取樣

Samplingtiming取樣時機Samplingpoints取樣點Samplesize取樣數Samplingtiming取樣時機duringtheprocessatthetimeofblenderdischargeordirectlyfromdrumsSamplingpoints取樣點不同Blender可能發生Segregation(PonyPanType)PoormixingDead–spot(RibbonBlender)Lumps(TumblerBlender)Re-crystallization(HighShearMixer)Samplingpoints取樣點Samplingpoints取樣點Samplingmethod取樣方法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*滅菌工程□是□否（無菌制劑）□無菌充填/□最終滅菌□冷凍干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

___________________________________※制程確效三批結果匯整報告□是□否 批號及批量：____________________關鍵性制程確效作業查檢表(cont.)關鍵性制程及其指標（88.10.21公告）指標制程階段劑型無菌性含量均一性無菌制劑最終滅菌制劑滅菌工程溶解工程混合、溶解工程充填工程無菌操作制劑無菌操作工程過濾滅菌工程無菌充填工程凍晶干燥工程溶解工程混合、溶解工程充填工程IntroductionSterilizationThermalMoistheatSterilizationDryheatSterilizationNonthermalGammairradiationChemicals:EthyleneOxideMoistHeatSaturatedsteamCommoncycles:121°Cfor15minutes134°Cfor3minutesOthercyclesoflowertemperatureandlongertimemaybeused(e.g.115°Cfor30minutes)Usedforsterilizationof:terminalsterilizationofaqueousinjections,ophthalmicpreparations,irrigation&haemodialysissolutions,equipmentusedinasepticprocessingPNSU-ProbabilityofaNon-SterileUnitTheprobabilityofaunit(productcontainer)beingnon-sterileaftertheapplicationofalethalagent.PNSUof1in106--theprobabilitythataunitisnon-sterileisoneinamillionFO-SterilizationProcessEquivalentTime

Theequivalentnumberofminutesat121.1°Cdeliveredtoaunitbyasterilizationprocess.FO=8minutes--thecycledeliveredamicrobiallethalityequivalentto8minutesat121.1°CValidation-CycleDevelopmentConceptofFoLethalityfactorequivalenttotimeat121°C

1minuteat121°CisequivalenttoFoof1.Lethalitycanaccumulateduringheatupandcooldown

phasesTypicaltemperatureprofileofaheatsterilizationprocessWhatwouldbetheFoofacycleat121°Cfor15minutes?OtherSterilizationProcessesSterilizationusingotherprocessesshouldfollowasimilarapproachasthatdescribedformoistheatValidationprotocolEquipmentcalibrationDeterminingtheprocessthatwilldeliverthedesiredSAL(10-6)IQ,OQ,PQRequirementsforroutinemonitoringandcontrol無菌充填testfillingprocessperformfillingprocesswithnutrientmediarunatfullscaleforatleastonefillsizeworstcase;largevolumeandnumberofvialsfilledvialsincubated,observedandtestforcontaminationbyvalidatedsterilitytestmustbesterilefor3consecutiverunsmediafillperformedtwiceayearsizeofrunmustbelargeenoughtodetectlowlevelsofcontaminatione.g.contaminationrateof1/1000,3000unitsareneededtoprovide95%confidence無菌作業DrugProductSterilizationProcessContainerClosureExcipientSterilizationProcessSterilizationProcessSterilizationProcessSterileClosureSterileExcipientAsepticProcessingSterileDrugProductSterileContainerCanusemultiplesterilizationprocesseseachoptimizedfortheindividualcomponentSterileFinalProduct凍晶干燥DoorSterileroomwallVacuumgaugeUpp