关键性制程确效作业资料

关键性制程确效作业资料

制程确效（药品优良制造确效作业基准88.04.13

4）

制程确效:确认产品之制造程序及其管制条件，具有良好的有效性与再现性。

确效计划书:说明将如何进行确效之书面计划书，内容包括予以测试之指标，产品特质，生产设备，以及测试合格之判定标准。

先期性确效：为一种产品于上市前所进行之确效措施，适用于下列两类品：(一)新产品：新申请查验登记之產品。(二)既有产品于更改配方(包括成分及組成)、制造场所、製造設備、製程等製造条件而可能会重大影响产品之质量特性者。ProcessDevelopment制程研发CommercialProductionProcess量产3batchesvalidation三批确效(ProcessChangeanother3batchesvalidation)制程更改则需另作三批ProcessScaleUp试制内容

一、计划书之核准二、产品详细处方一览表三、批量四、制造流程图五、各制程操作条件六、关键制程步骤七、机器设备3Q一览表关键性制程确效作业查检表

(CourtesyofformerBFDA-CDST)品名:_________主成分:_________剂型:_________指标分析成分:________一、确效计划书与执行执行确效方法:

□先期性□并行性□回溯性计划书之核准

□制订人□核定人

□制订日期□核定日期确效计划书（药品优良制造确效作业基准7）确效或验证之项目。确效或验证之目的及整体目标。预定实施频率。该项确效或验证之计划书制订及各次改订日期，以及改订事项。确效或验证方法。合格标准范围。数据或资料处理方法。确效或验证书面资料之改订程序及保管相关事项。执行确效或验证之责任单位及负责人员。

产品详细处方一览表主成分(Activesubstance)赋形剂(Excipients)增量

(Overages)Ref:ICHQ8PharmaceuticalDevelopment

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

制造流程图Ref:关键性制程及其指标（88.10.21公告）含量均一性固形制剂混合工程造粒工程打锭工程充填工程液剂溶解工程混合、溶解工程充填工程膏剂栓剂贴片剂练合工程充填工程涂布工程

各制程操作条件AcceptanceCriteria合格范围ProductSpecifications

产品既定规格PharmacopoeiaSpecifications

产品药典规格ProductIn-processSpecifications

产品制程规格设定合格范围SettingLimits药品查验登记的规格安定性规格成品检验放行规格确效规格成品放行规格产品查验登记的规格

依据安定性规格制程规格(Limits)固型制剂之分类散、粉剂颗粒、锭剂、丸剂加衣锭胶囊、软胶囊散剂、粉剂之制造程序称量颗粒粉碎过筛混合固型制剂之制造程序（I）混合与造粒Mixing&GranulationGranulation造粒WetGranulation湿制粒RollCompaction/Slugging干制粒DirectMixing直混固型制剂之制造程序（II）Granulation制粒WetGranulationSlugging/RollCompactionDirectMixingWeighing称量Sieving过筛

Mixing混合Kneading炼合Extrusion挤出Drying干燥Milling/Sizing整粒FinalBlending最终混合Lubrication润滑Weighing称量Sieving过筛

Mixing混合RollCompaction滚压Milling整粒Lubrication润滑Weighing称量Sieving过筛

Mixing混合Lubrication润滑固型制剂之制造程序（III）压锭与胶充Compressing&EncapsulationCompression打锭单层锭双层锭子母锭Encapsulation充填硬胶囊软胶囊固型制剂之制造程序（IV）加衣CoatingFilmCoating膜衣SugarCoating糖衣EntericCoating肠溶锭shellaccoatingsubcoatingcolorcoatingpolishingentericcoatingsubcoatingcolorcoatingpolishing制程参数Mixing混合Kneading鍊合FluidBedGranulation

流动床造粒Time/RPMTime/RPMLiquidadditionrate添加率Inletairtemp.进气温度Fluidizingairvol.空气量Processairhumidity湿度AtomizationairPressure空压制程参数Extrusion挤出RollCompaction滚压Drying干燥Milling/Sizing整粒FinalBlending最终混合Lubrication润滑Time/PressureTime/PressureTime/Temp.Mesh/BladeRPM网径/切刀转速Time/RPMTime/RPM固型制剂之规格（I）PhysicalAnalysis Appearance外观 AQ-UPDiameters大小 strengthHardness硬度 stabilityFriability脆度 stabilityWeightVariation重量偏差 strengthMoistureContent水份含量 stabilityDisintegration崩散时间 efficiency固型制剂之规格（II）ChemicalAnalysisIdentity鉴定 safetyDissolution溶离度 efficiencyContentUniformity含量均一度 strengthContent含量 strengthImpurityContent不纯物含量 purityStabilityAnalysis安定性分析 stabilityDecompositionProducts分解产物 purity固型制剂之制程管制混合工程造粒工程干燥工程整粒工程压锭工程加衣工程胶囊充填工程含量均一度残余量水分含量粒径分布、安息角、粗密度与轻击密度外观、厚度、硬度、脆度、重量均一度、崩散度或溶离度外观、包覆百分率、释离行为重量均一度颗粒特性对锭剂之影响BulkdensityFlowabilityParticlesizedistribution

粒度分布MoistureContent

水份含量WeightandcontentuniformityHardnessDisintegration/DissolutionWeightandcontentuniformityHardnessCapping/LaminationFriction/AdhesionHardnessDisintegration/DissolutionPoorPhysical/ChemicalStability半固型制剂之处方组成ActiveIngredientsBasesOtherexcipientsAntimicrobialPreservativesAntioxidantsStabilizersEmulsifiersThickenersPenetrationEnhancers半固型制剂之规格potencycontentuniformitydrugreleaseParticlesizeviscositypHPathogenMicrobialPreservativeefficacyAppearancePackagecompatibilityCrystalform半固型制剂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

液剂之分类（中华药典）Example:溶液剂-系含是一种或多种药品溶解或分散于一适当溶剂，或相互混合溶剂之混合物。酏剂-为一种供内服用之澄明、甜味、含乙醇水溶液。醑剂-为一种含是挥发性物质之乙醇溶液，或含水乙醇溶液。酊剂-为生药或化学药品，经渗漉法、浸渍法或溶液法制成之一种乙醇溶液，或含水乙醇溶液。乳剂-为一种二相系统之液体制剂，其中一种液体呈小球状分散于另一种液体中。液剂的制造程序液剂之规格AppearancepHSpecificgravityViscosityAlcohol,v/v(%)Assayofactiveingredients液剂剂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取样

Samplingtiming取样时机Samplingpoints取样点Samplesize取样数Samplingtiming取样时机duringtheprocessatthetimeofblenderdischargeordirectlyfromdrumsSamplingpoints取样点不同Blender可能发生Segregation(PonyPanType)PoormixingDead–spot(RibbonBlender)Lumps(TumblerBlender)Re-crystallization(HighShearMixer)Samplingpoints取样点Samplingpoints取样点Samplingmethod取样方法Simplesampling简易取样法Samplestakenfromthedischargedblend出料中取样Thiefsampling取样器法Samplestakenfromtheblender使用取样器取样*灭菌工程□是□否（无菌制剂）□无菌充填/□最终灭菌□冷冻干燥另附相关之查检表无菌充填过程确效环氧乙烯灭菌确效放射线灭菌确效

___________________________________※制程确效三批结果汇整报告□是□否 批号及批量：____________________关键性制程确效作业查检表(cont.)关键性制程及其指标（88.10.21公告）指标制程阶段剂型无菌性含量均一性无菌制剂最终灭菌制剂灭菌工程溶解工程混合、溶解工程充填工程无菌操作制剂无菌操作工程过滤灭菌工程无菌充填工程冻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无菌充填testfillingprocessperformfillingprocesswithnutrientmediarunatfullscaleforatleastonefillsizeworstcase;largevolumeandnumberofvialsfilledvialsincubated,observedandtestforcontaminationbyvalidatedsterilitytestmustbesterilefor3consecutiverunsmediafillperformedtwiceayearsizeofrunmustbelargeenoughtodetectlowlevelsofcontaminatione.g.contaminationrateof1/1000,3000unitsareneededtoprovide95%confidence无菌作业DrugProductSterilizationProcessContainerClosureExcipientSterilizationProcessSterilizationProcessSterilizationProcessSterileClosureSterileExcipientAsepticProcessingSterileDrugProductSterileContainerCanusemultiplesterilizationprocesseseachoptimizedfortheindividualcomponentSterileFinalProduct冻晶干燥DoorSterileroomwallVacuumgaugeUpp