固体车间清洁验证预案

66/66上海金冀商务咨询有限公司,ShanghaiJinjiBusinessConsultingCo.,Ltd文件编号：固体车间清洁验证方案CleaningvalidationMasterPlanforSolidDosageWorkshop立项部门：质量保证部InitiationDepartment:QualityAssuranceDepartment工艺验证小组负责人：Leaderofvalidationteem:方案制订日期：年月日Date:YearMonthDay目录ListofContent一.验证概述Overviewofvalidation二.验证组织机构及人员安排Validationorganizagionandmembers三.应用范围AreasofApplication四.风险评估RiskEvaluation五验证方案表格ValidationMatrix六清洁溶剂CleansingAgents七.可同意标准的确定AcceptanceCriteria八.清洁验证取样CleaningValiationandSampling九清洁验证的实施Implementationofcleaningvalidation十.偏差、变更DeviationsandChanges十一.再验证Re-validation

验证概述OverviewofValidation1.验证目的依照GMP的要求，在口服固体制剂生产结束后，要对生产设备及操作间进行完全清洁，以幸免造成不同批号或不同品种产品之间的污染和交叉污染。依照各生产设备的《操作、清洁及维护保养》标准操作规程，进行风险分析，选出最坏情况产品。为了验证清洁方法的稳定性与可靠性，对所选的最坏产品进行三次清洁验证。每批产品生产结束后，对所有在生产中使用的生产设备及容器具进行清洁，清洁后取样检测化学残留及微生物残留，要求残留量低于设定的残留限度要求。AccordingtorequirementsofGMP,themanufacturingequipmentsandroomsmustbecompletelycleanedtoavoidcontaminationofdifferentbatchesofsameproductsorcross-contaminationofdifferentproductsaftermanufacturingoforalsoliddosage.TherearetwotypesofcleaningmethodbasedonSOPsofOperation/Cleaningandmaintenanceforindividualequipments:implementtheriskanalysisassessmenttochoosetheworstcaseproducts.Threeconsecutivecleaningvalidationwillbeconductedtovalidatethestabilityandreliabilityofcleaningmethod.Allequipmentsandutensilsusedinmanufacturingmustbecompletelycleanedonceeverybatchoftheworstcaseproductsarefinished,thensampletotestchemicalresidualandmicrobialresidual,therequirementisthelevelofresidualislessthanthelimitofresidual..二.验证组织机构及人员安排ValidationOrganizationandTeamMembers2.1制造部/ProductionDept.组织清洁验证方案及报告的起草；Preparethecleaningvalidationprotocol/report确定设备表面积、清洁方法、取样部位；Determinethesurfaceareaofequipments,cleaningmethodandsamplinglocations制定清洁操作规程；Establishcleaningprocedure按清洁操作规程清洁设备和容器具；Cleanequipmentsandutensilsaccordingtocleaningprocedure确保清洁记录填写完整；Makesurethecompletenessofcleaningrecords将完成的清洁验证文件提交给QA审查；SubmitthefinalizedcleaningdocumentationtoQAreview2.2质量保证部/QADept.QC审核清洁验证方案/报告；Reviewthecleaningvalidationprotocol/report制定清洁验证取样方法和检测方法；Establishsamplingmethodandanalyticalmethodofcleaningvalidation对清洁后设备、容器具进行取样和检测，报告检验结果；Sampleandtestcleanedequipmentsandutensils,thenreportthetestingresults.使用在校验有效期内的仪器设备进行检测。UsethoseinstrumentswithincalibrationexpireddateQA制定清洁验证打算及验证编号；EstablishcleaningvalidationplanandNo.负责组织审核清洁验证的方案/报告；Organizethereviewthecleaningvalidationprotocol/report组织清洁验证相关部门进行清洁验证方案的培训并记录；Organizethetrainingandrecordforcleaningvalidationprotocol负责验证实施过程的协调，保证验证项目实施进度；Coordinatetheactivitiesofcleaningvalidationtoensuretheperformance.验证实施中的监控检查；Supervisethevalidationactivities.保证经验证的参数符合预期的标准；Makesurevalidatedparametersmeetpre-determinedcriteria负责组织验证方案中改变操纵、偏差处理的调查；Organizetheinvestigationforthechangecontrolanddeviationhandling.负责将完成的清洁验证文件归档。Archivethecompletedcleaningvalidationdocumentation质量保证部经理：QAManager批准清洁验证方案、验证报告。Approvethecleaningvalidationprotocolandreport2.3设备动力部/EngineeringDept.保证清洁验证过程中，所用到的仪器仪表在校验有效期内；Ensuretheinstrumentsandmetersinvolvedinthecleaningvalidationhavebeencalibratedandwithincalibrationduedate.保证验证过程中空调、纯化水、压缩空气、热水等的供应，确保清洁验证的实施。EnsurethenormalworkingorderandoperationofHVAC,purifiedwatersystem,compressedair,hotwaterforthecleaningvalidation.2.4清洁验证小组人员名单/TeamMemberList组长TeamLeader部门Dept.岗位Position姓名Name制造部ProductionDept.业务经理Supervisor小组成员TeamMember部门Dept.岗位Position姓名Name设备动力部EngineeringDept.业务经理Supervisor制造部ProductionDept.工艺质量员Technician制造部ProductionDept.生产协调员ProductionCoordinator制造部ProductionDept.工艺质量员ProductionCoordinator制造部ProductionDept.工段长Teamleader制造部ProductionDept.技术员Technician制造部ProductionDept.工段长Teamleader制造部ProductionDept.技术员Technician制造部ProductionDept.工段长Teamleader制造部ProductionDept.技术员Technician制造部ProductionDept.工段长Teamleader制造部ProductionDept.技术员TechnicianQCQC主管QCSupervisorQC理化1组组长Leaderofphysicochemicalteam1QC微生物组组长LeaderofMicrobialteamQC微生物检验员AnalyzerQAQA检查员QAinspectorQAQA检查员QAinspectorQAQA检查员QAinspectorQA验证治理员Validationadministrator

三应用范围Areasofapplication本清洁验证主打算应用于固体车间所有产品。见产品列表Thevalidationmasterplanisappliedtoalltheproductsinthesolidworkshop.产品名称Productname主成分API规格SpecificationABCDEFGHI四.风险评估RiskEvaluation1.FMEA风险项目Item阻碍/导致结果Influence/Reslult风险级不RiskLevel预防措施PrecautionaryMeasures是否能够将风险最小化Iftheriskcanbeminimized风险同意

(是/否)RiskAcceptance(Yes/No)操作人员对清洁方法不熟悉，清洁操作不规范Operatorsarenotfamiliarwithcleaningmethod;cleaningoperationsdon'tmeetstandard硝苯地平残留超标ResidueofNifedipineisoverspecifications高High培训相关清洁SOP培训；清洁后由生产主管和QA检查确认OperatorsshouldbetrainedforrelatedcleaningSOPs;productionsupervisorandQAshouldcheckaftercleaning是Yes是Yes取样方法及取样工具Samplingmethodsandtools取样方法和工具使用不正确将会阻碍最终结果Misuseofsamplingmethodsandtoolswillinfluencefinalresult.高High对取样人员进行相关培训，明确取样方法以及取样时刻。Samplersshouldbetrainedforsamplingmethodsandtime.是Yes是Yes活性成份残留物检验方法不满足残留限度检测TestingmethodofAPI'sresiduecan'tmeettestofresiduelimit.不能得到准确的检测结果Inaccuratetestingresult高High在本验证实施前进行残留物限度检测方法验证。Performingvalidationoftestingmethodofresiduelimitbeforeperformingthiscleaningvalidation.是Yes是YesQA人员取样错误WrongsamplesaretakenbyQA.不能得到准确的检测结果Inaccuratetestingresult高High在清洁验证方案中对取样点进行编号并用图片的方式进行标识。Samplinglocationsshouldbenumberedandindicatedwithpicturesinthecleaningvalidationprotocol是Yes是Yes检测人员对残留物检测方法不熟悉Testersarenotfamiliarwithtestingmethodsofresidue.不能得到准确的检测结果，清洁评估失败Inaccuratetestingresult;cleaningevaluationfails中medium对参加样品检测的分析人员进行《清洁验证分析方法验证方案》和《微生物验证方案》培训考核。Analyzersinvolvedintestingsamplesshouldbetrainedandassessedfor"ValidationProtocolofAnalyticalMethodinCleaningValidation"and"MicrobialValidationProtocol".是Yes是Yes人员卫生不符合要求Personnelhygienedoesn'tmeetrequirements.微生物污染Microbialcontamination低low培训卫生治理相关SOPPersonnelshouldbetrainedforrelatedSOPforhygienemanagement.是Yes是Yes

2最坏情况产品选择WorstcaseproductSelection将产品按活性成分溶解性，治疗剂量，处方（颜色，气味，难溶成分）进行分组，首先选择出无风险的产品。Groupalltheproductsaccordingtosolubility,therapeuticdose,formulation(colour,flavour,componentsthataredifficulttoremove),pickupthenoriskproductsfirst.2.1产品风险确定表格Assignmentofproductstoriskgroups产品Product溶解性组SolubilityriskgroupActivepharmaceuticalingredientispracticallyinsolubleAPI成分不溶于水药理学组PharmacologyriskgroupTherapeuticdoseis<100mg治疗剂量<100mg处方风险组FormulationriskgroupProductcontainsdye,flavoursorothercomponentsthataredifficulttoremove产品含有颜色，气味或其他难溶的成分无风险组NoriskA√---B-√--C√-√-D---√E√√--F-√--G--√-H√---I---√备注：实际操作中，选择低于所有产品治疗剂量范围的第三小的那个。Note:Inpractice,avalueisrecommendedthatiswithinthelowerthirdoftheavailabledosingrange-withrespecttotheentireproductrange.结论：由以上分组可知，产品D和产品I在溶解性，治疗剂量和颜色气味等方面均无风险，归为无风险组。Conclusion:Accordingtothegroup(seeabovetable),productDandIhasnoriskintheaspectofsolubility,therapeuticdose,colorandflavour,theyaredefinedasthenoriskproductinthecleaningvalidation

Product产品溶解性组Solubility

riskgroupActivepharmaceuticalingredientispracticallyinsoluble活性成分不溶于水药理学Pharmacology

riskgroupTherapeuticdoseis<100mg治疗剂量<100mg（此处也能够MTDD计算）活性成分含量Contentofactive

pharmaceutical

ingredient处方风险组FormulationriskgroupProductcontainsdye,flavoursorothercomponentsthataredifficulttoremove产品含有颜色，气味或其他难容的成分A几乎不溶于水500mg50%-B溶于水5025%-C不溶于水20020%处方中有2%的染料2%dyeintheformulationE几乎不溶于水105%-F溶于水7550%-G溶于水15050%包衣层中有1%的颜料1%pigmentinfilmcoatingH几乎不溶于水15030%-

分组选择最坏情况Worstcaseproductchoosen按活性成分溶解性，治疗剂量和处方（颜色，气味，难溶成分）分组，在每个分组中再按溶解性最差，治疗剂量最低和活性成分含量最高的原则选出最坏情况产品Groupalltheproductsaccordingtosolubility,therapeuticdose,formulation(colour,flavour,componentsthataredifficulttoremove),ineachgroup,choosetheproductswithworstsolubility,lowesttherap.DoseandhighestcontentofAPI,definedtheseproductsastheworstcaseproducts产品Product活性成分含量Contentofactivepharmaceuticalingredient溶解性Solubility治疗剂量（MTDD）Therap.dose最坏情况Worstcase溶解性组SolubilityriskgroupA50%几乎不溶于水practicallyinsoluble500mg活性成分含量最高Contentofactivepharmaceuticalingredient,

isthehighestinthisgroupC20%不溶于水insoluble200mg-E5%几乎不溶于水practicallyinsoluble10mg治疗剂量最低therap.doseH30%几乎不溶于水practicallyinsoluble150mg-此组选择产品A和EChooseproductAandEinthisgroup药理组PharmacologyriskgroupB25

%溶于水soluble50mg-E5

%几乎不溶于水practicallyinsoluble10mg溶解性最差Solubility,therap.doseF50%溶于水Soluble75mg活性成分含量最高Contentofactivepharmaceuticalingredient此组选择产品E和FChooseproductEandFinthisgroup处方风险组FormulationriskgroupC处方中有2%的染料2%dyeintheformulation溶解性染料Solubledyen.a.染料DyeG包衣层中有1%的颜料1%pigmentinfilmcoating不溶解颜料Insolublepigmentn.a.颜料Pigment关于C产品，其处方中有2%的可溶性染料，尽管不是活性成分，但也会对后续产品产生交叉污染。在此我们采取目视方法，用白色湿抹布在设备关键部位擦拭，肉眼分辨其是否有颜色。关于G产品，其包衣层中有不溶解的颜料，因此只针对包衣机做目检，方法是用干抹布擦拭设备表面看，肉眼分辨否有颜色残留。ForproductC,thereis2%dyeintheit’sformulation,thedyeisnottheAPI,butstillwillaffectthesubsequentproduct,increasetheriskofcros-contamination.Thevisuallycheckisusedforit.Weusethecleanwetwhitetowerscrubinthecriticalpartoftheequipment,seeifthecolorisonthetower.ForproductG,theinsolublepigmentisinthecoatingformulation,thevisualcheckmethodistakenonlyforthecoatingmachine.Weusethecleanwhitedrytowertoscrubthescrubinthecriticalpartoftheequipmentseeifthecolorisonthetower.结论：通过上表的分析，所选取的最坏情况产品为A，E和F。Conclusion：Throughtheanalysisoftheabovetable,theworstcaseproductareProductA,EandF.五验证方案表格Validationmatrix序号SerialNo.设备名称Equipmentname产品AProductA产品EProductE产品FProductF验证方案Validationprotocol摇摆oscillating联机Link-up按设备验证（此设备上所要验证的产品数）(equipment-specific):Numberofproductstobevalidated1GHJ-50高效混和机HighEfficientMixer-√√-12PMA400湿法制粒机（不含筛网）WetTypeGranulator(excludingscreen)-√-√23PMA400湿法制粒机（含筛网）WetTypeGranulator(includingscreen)√-√-24DFX400流化床干燥器DFX400fluidbeddryer√√√√35GEA联机管道GEAlink-uppipes√-√-26SL600干式整粒机（不含筛网）SL600drytypestraighteninggranulator(excludingscreen)-√-√27SL600干式整粒机（1150μm筛网）SL600drytypestraighteninggranulator(1150μmscreen)√18SL600干式整粒机（1350μm筛网）SL600drytypestraighteninggranulator(1350μmscreen)--√-19HZD800自动提升料斗混合机800L)HZD800AutomaticLiftingHopperMixer800L-√-√210HZD800自动提升料斗混合机(400L)HZD800AutomaticLiftingHopperMixer400L√-√-211HZD800自动提升料斗混合机(200L)HZD800AutomaticLiftingHopperMixer200L√112S250/40EU-B压片机（5.5mm）S250/40EU-BTabletPress（5.5mm）-√√-113S250/40EU-B压片机（8mm）S250/40EU-BTabletPress（8mm）√114UPS1030MTI铝塑包装机thermoformingmachine√√√√315剥药机√√√√316YK160A摇摆颗粒机oscillatinggranulator-√-√217CT-C-Ⅱ热风循环烘箱circulatinghotairoven18ZS-650型漩涡振荡筛Eddytypeoscillatingscreen19LSH-220型湿法造粒机Wettypegranulator20HLSG-10湿法混合制粒机Wettypemixinggranulator21FL-5沸腾制粒机Fluidbeddryer22GFK2000胶囊充填机GelatineCapsuleFillingandClosingMachine√123DXDP350双铝遮光包装机Doublealuminumpackagingmachine244S1000四封小袋包装机AutomaticPackagingMachineForSingle-doseSachet25BGB-10C包衣机Coatingmachine26GSHP150F包衣机Coatingmachine√127FL-350风冷式粉碎机Coolingaircrusher√128称量设备Weighingfacility29周转桶AContainertypeA30周转桶BContainertypeB验证方案Validationprotocol按产品：所涉及的设备(product-specific):Numberofproductionequipmentitems10999由上表数据，对三个最坏产品做连续三批的清洁验证。Fromthedatainthetableabove,thethreeworstcaseproductsisforthecontinuouslythreebatchescleaningvalidation.

六清洁溶剂Cleansingagents产品A,E和F所用设备的清洁溶剂如下：ThecleansingagentfortheproductequipmentsusedinproductA,EandFarelisted:设备名称Equipmentname文件编号DocumentCode设备清洁操作SOPEquipmentcleaningSOP所用清洁溶剂CleansingagentsusedGHJ-50高效混和机HighEfficientMixerGHJ-50高效混和机清洁规程SOPforCleaningHighEfficientMixer纯化水PW75%乙醇75%EthanolPMA400湿法制粒机PMA400湿法制粒机清洁规程SOPforCleaningPMA400WetTypeGranulator纯化水PW75%乙醇75%EthanolDFX400流化床干燥器DFX400流化床干燥器清洁规程SOPforCleaningDFX400FluidBedDryer纯化水PW75%乙醇75%EthanolSL600干式整粒机SL600干式整粒机清洁规程SOPforCleaningSL600DryTypeStraighteningGranulator纯化水PW75%乙醇75%EthanolHZD800自动提升料斗混合机HZD800自动提升料斗混合机清洁规程SOPforCleaningHZD800AutomaticLiftingHopperMixer纯化水PW75%乙醇75%EthanolS250/40EU-B压片机S250/40EU-B压片机清洁规程SOPforCleaningS250/40EU-BTabletPress纯化水PW75%乙醇75%EthanolGSHP包衣机GSHP包衣机清洁规程SOPforCleaningGSHPCoatingMachine纯化水PW75%乙醇75%EthanolGFK2000胶囊充填机GFK2000胶囊充填机清洁规程GelatineCapsuleFillingandClosingMachine纯化水PW75%乙醇75%EthanolUPS1030MTI铝塑包装机UPS1030MTI铝塑包装机清洁规程SOPforCleaningUPS1030MTIThermoformingMachine纯化水PW75%乙醇75%EthanolFL-350风冷式粉碎机CoolingaircrusherFL-350风冷式粉碎机SOPforCleaningCoolingaircrusher纯化水PW75%乙醇75%Ethanol……….………..以上设备均用纯化水和乙醇清洁，无其他溶剂。Alltheequipmentsarecleanedwithpurifiedwaterandethanol,noothercleansingagentsorsolventareused.

七可同意标准的确定AcceptanceCriteria1.目检VisualCheck各设备按照相应SOP清洁后，目检无残留。如设备用乙醇清洗，则需过半小时后进行目检，确保设备内表面无残留。ThereshouldbenoresidualaftervisualcheckafterequipmentcleaningaccordingtotherelatedSOP.Iftheethanolisusedforcleaning,visualcheckafterhalfhourtoensurethere’snoresidualonthesurfaceoftheequipment.2化学残留可同意标准的确定CalculationofMaximumAcceptanceResidue（MAR）（1）1/1000原则：下一产品的最大日剂量中含有的上一产品残留物不得多于上一产品最低有效量的千分之一。Nomorethan0.1%criterion:nomorethan0.1%oftheminimaleffectivedoseofanyproductwillappearinthemaximumdailydoseofthefollowingproduct.Nomorethan1/1000criterion:硝苯地平同意在设备内表面上的最大残留量总和R：allowabletotalmaximumresidueofNifedipineleftoninnersurfaceofequipmentR:（2）10ppm原则：上一产品的主药在下一产品中的含量不得超过10ppm。Nomorethan10ppmcriterion:nomorethan10ppmofmaindrugofanyproductwillappearinthecontentofthefollowingproduct.最大同意残留总量=10x10-6x10x10-6x产品性质（表格内容请厂家以自己情况填写自行填写）产品名称Productname最低日服用剂量(mg)（MTDD）Minimumdailydose批量(Kg)Batchsize单位制剂质量Massofdoseform（mg）日最多使用制剂数MaximumdailyintakeABCDEFGHI分不计算先前产品为A，E和F的最大同意残留总量（在模版中此处省略计算内容，实际请厂家自行计算并列表。）1）1/1000原则1/1000criterion后续生产品种Subsequentproduct先生产品种previousproductABCDEFGHIA/E/F/2）10ppm原则后续生产品种Subsequentproduct先生产品种previousproductABCDEFGHIA/E/F/结论Conclusion：（模板中仅为示例数据）产品Product千分之一原则1/1000criteria[mg]10ppm原则ppmcriteria[mg][mg]A10,0001,0001,000E2001,000200F1,5001,0001,000

与所选产品接触面积表Tableforthecontactarea序号SerialNo.设备名称Equipmentname表面积/cm2Surfacearea产品A产品E产品F摇摆oscillating联机Link-up1GHJ-50高效混和机HighEfficientMixer8063√√2PMA400湿法制粒机（不含筛网）WetTypeGranulator(excludingscreen)46810√√3PMA400湿法制粒机（含筛网）WetTypeGranulator(includingscreen)48214√√4DFX400流化床干燥器DFX400fluidbeddryer47491√√√√5GEA联机管道GEAlink-uppipes6572√√6SL600干式整粒机（不含筛网）SL600drytypestraighteninggranulator(excludingscreen)20302√√7SL600干式整粒机（1150μm筛网）SL600drytypestraighteninggranulator(1150μmscreen)21706√8SL600干式整粒机（1350μm筛网）SL600drytypestraighteninggranulator(1350μmscreen)21706√9HZD800自动提升料斗混合机800L)HZD800AutomaticLiftingHopperMixer800L45748√√10HZD800自动提升料斗混合机(400L)HZD800AutomaticLiftingHopperMixer400L29153√√11HZD800自动提升料斗混合机(200L)HZD800AutomaticLiftingHopperMixer200L19040√12S250/40EU-B压片机（5.5mm）S250/40EU-BTabletPress（5.5mm）30325√√13S250/40EU-B压片机（8mm）S250/40EU-BTabletPress（8mm）30541√14UPS1030MTI铝塑包装机thermoformingmachine10125√√√√15剥药机1191√√√√16YK160A摇摆颗粒机oscillatinggranulator12268√√17CT-C-Ⅱ热风循环烘箱circulatinghotairoven32894418ZS-650型漩涡振荡筛Eddytypeoscillatingscreen4185519LSH-220型湿法造粒机Wettypegranulator1183020HLSG-10湿法混合制粒机Wettypemixinggranulator528221FL-5沸腾制粒机Fluidbeddryer1562222GFK2000胶囊充填机GelatineCapsuleFillingandClosingMachine42938√23DXDP350双铝遮光包装机Doublealuminumpackagingmachine6954244S1000四封小袋包装机AutomaticPackagingMachineForSingle-doseSachet651025BGB-10C包衣机Coatingmachine819026GSHP150F包衣机Coatingmachine√27FL-350风冷式粉碎机Coolingaircrusher19904√28称量设备Weighingfacility29周转桶AContainertypeA30周转桶BContainertypeB各产品总接触面积Totalcontactareaforeachproduct269,760222,323202,840246,777“√”表示产品每批生产只与对应的设备直接接触一次；无“√”表示产品与对应的设备无直接接触；Remark:“√”meansproducthasdirectcontactwithequipmentinvolvedforonetime;no“√”meansproducthasnodirectcontactwithequipmentinvolved

3.7.单位面积残留限度(擦拭法swabtest)产品Product[mg]cm2cm2A1,000269,7603.71E200摇摆oscillating联机Link-up摇摆oscillating联机Link-up222,323202,8400.900.99F1,000246,7774.053）微生物可同意限度为≤50CFU/25cm2×50%=25CFU/25cm2，其中50%为微生物取样回收率，因此微生物可同意限度为≤25CFU/25cAcceptablemicrobiallimitis≤50CFU/25cm2×50%=25CFU/25cm2,50%ofitismicrobialsamplingrecovery,thereforeacceptablemicrobiallimitis≤25CFU/25c八.清洁验证取样SamplingofCleaningValidation我们将在固体制剂车间生产的产品三批工艺验证批次生产结束后，对相关设备按相应SOP清洁、消毒。待设备干燥后由QA先对设备内表面进行目检，应无目视可见残留物。目检合格后按顺序在取样位置上先进行微生物取样，再进行化学残留取样，微生物取样及化学残留留取样位置不能重复，其中微生物取样面积为25cm2、化学残留取样面积为25cm2。WewillcleananddisinfecttheinvolvedequipmentaccordingtorelatedSOPafterproducing3batchesofproductsforprocessvalidationinsolidpreparationworkshop.Whentheequipmentisdry,innersurfaceoftheequipmentwillbeundervisualinspectionbyQAfirstly,thereshouldbenovisibleresidue.Iftheequipmentisqualifiedaftervisualinspection,takemicrobialsamplesinsamplinglocationsinsequence,thentakesamplesofproductchemicalresidue.Locationsfortakingmicrobialsamplesandfortakingchemicalresidueshouldbedifferentfromeachother.Microbialsamplingareais25cm2,andsamplingareaforNifedipineresidueis253.取样人员：生产现场QA，取样编号原则：年份＋月份＋流水号，如2010-12-01进行01点的取样，取样编号为20101201。Samplers:QAinproductionsite.Numberingprincipleforsamples:Year+Month+serialnumber.Forexample,ifsamplingpoint01istakenon01-12-2010,thenthecodeofthispointis20101201.4.取样工具和容器samplingtoolsandcontainers项目item取样工具samplingtools化学残留Chemicalresidue聚酯纤维棉，取样溶液，25ml容量瓶，100cm2清洁PVC取样模板Polyesterfibercotton,samplingsolution,25mlvolumetricflask,100cm2cleanPVCsamplingtemplate微生物限度Microbiallimit无菌棉签，生理盐水，25ml无菌容量瓶，25cm2清洁、灭菌PVC取样模板Sterileswab,normalsaline，25mlsterilevolumetricflask,25cm2cleanandasepticPVCsamplingtemplate5.取样方法samplingmethod取样时取样人员带上一次性洁净手套，先将PVC取样模板紧贴在取样位置处，将一根用取样溶液润湿并已挤去多余溶液的取样棉签按在取样位置上，用力使其稍弯曲，平稳而缓慢地擦拭取样表面，在向前移动的同时将其从一边移动另一边，当棉签移动至中央位置时翻转棉签，让棉签的另一面按同法擦拭剩余的位置。将已擦拭棉签放入10ml容量瓶中（其中微生物取样棉签放入灭菌的容量瓶中），紧闭容量瓶瓶塞。再取一根用取样溶液润湿并已挤去多余溶液的聚酯纤维棉签在与前次擦拭移动方向垂直的方向上按同法擦拭取样。（注意：棉签擦拭取样过程应覆盖整个PVC取样模板内所有表面）

化学残留取样位置samplinglocationsforchemicalresidue1.1HZD800自动提升料斗混合机（200L）HZD800AutomaticLiftingHopperMixer(200L)编号：01SerialNo.01取样位置Samplinglocations选择缘故Reasons此处为料斗上内壁，清洁难度大Thispointisoninnersurfaceofhopperwhichishardtoclean.料斗上内壁取样点：samplingpointoninnersurfaceofhopper编号：02SerialNo.02取样位置Samplinglocations选择缘故Reasons由于此取样的位置在最下面，各种残留物容易在此积聚。Thissamplinglocationisatthebottom,whichiseasyforallkindsofresiduetoaccumulate.料斗出料阀取样点：samplingpointondischargevalveofhopper1.2.PMA400湿法制粒机wettypegranulator编号：03SerialNo.03取样位置Samplinglocations选择缘故ReasonsPMA400湿法制粒机采纳在线清洗模式进行清洗，清洁时靠搅拌桨的作用将纯化水溅射至锅盖内表面，效果不够好PMA400wettypegranulatoriscleanedbyWIP.Whilecleaning,thepurifiedwaterissplashedbyrotatingstirringpaddletoinnersurfaceofpotcover,whichisnotsoeffective.制粒锅盖取样点：samplingpointtopotcover编号：04SerialNo.04取样位置Samplinglocations选择缘故Reasons此处靠近制粒锅出水口，容易残留化学活性成分Thispointisnearwaterdischargeoutletwhichiseasyforchemicalactiveingredientstoaccumulate.靠近出料口锅底取样点：samplingpointatthebottomofthepotnearthedischargeoutlet编号：05SerialNo.05取样位置Samplinglocations选择缘故Reasons清洗时搅拌桨的转动时清洗水呈漩涡状，靠近搅拌桨轴心处的桨叶接触水的机会少Thewaterislikeeddywhenstirringpaddlerotateswhilecleaning.Thepartwhichisclosetotheaxisofstirringpaddlehaslittlecontactwithwater.搅拌桨取样点：samplingpointofstirringpaddle编号：06SerialNo.06取样位置Samplinglocations选择缘故Reasons切碎刀轴部靠搅拌桨转动而溅射起的水清洗，相比锅壁，此处受到的溅射力较弱Axisofshreddingknifeiswashedbythewatersplashedbyrotatingstirringpaddle.Comparedwithwallofthepot,thesplashingpowerofaxisisweak.切碎刀轴部取样点:samplingpointonaxisofshreddingknife编号：07SerialNo.07取样位置Samplinglocations选择缘故Reasons湿法整粒机利用制粒锅排水清洗，而此处高于制粒锅排水口且非排水口正对面，水的溅射强度低Wettypestraighteninggranulatoriswashedbydrainingwaterfromgranulationpot.Thispointishigherthanandnotrightacrossfromdrainingpot.Splashingpowerofwaterisweak.湿式整粒机上部内壁取样点：samplingpointonupperinnerwallofwettypestraighteninggranulator1.3.GEA联机管道GEAlink-uppipeline编号：08SerialNo.08取样位置Samplinglocations选择缘故Reasons此处通过制粒锅排水清洗，但排水会因流化床负压缘故瞬间被吸至流化床，此处接触水的机会相对少Thispointiswashedbydrainingwaterfromgranulationpot.Butthewaterwillbedrawntofluidbedinstantlybecauseofnegativepressureoffluidbeddryer.Asaresult,thispointhaslittlecontactwithwater.整粒机下料斗内壁取样点：samplingpointoninnerwalloffeedinghopperofstraighteninggranulator.编号：09SerialNo.09取样位置Samplinglocations选择缘故Reasons物料转移管道通过制粒锅向流化床的高速排水而冲刷清洗，清洗时刻相对短Materialtransferringpipesareflushedbyhighspeeddrainingwaterfromgranulationpottofluidbed.Cleaningdurationtimeofthispointisshort.转移管道内壁取样点：samplingpointoninnerwalloftransferringpipe.编号：10SerialNo.10取样位置Samplinglocations选择缘故Reasons此处管道直径远大于物料转移管道，水从物料转移管道流至此处时流速降低，且此处为上表面，水接触机会相对小Diameterofthispipeisfarlargerthanthatofmaterialtransferringpipes.Thewaterflowingfrommaterialtransferringpipetothispointrunsslower.Andthispointisonuppersurfaceandhaslittlecontactwithwater.流化床进料管道上壁取样点：samplingpointonrsurfaceoffeedingpipeoffluidbed1.4.DFX400流化床干燥器编号：11SerialNo.11取样位置Samplinglocations选择缘故Reasons物料转移和干燥过程中均与进料口充分接触，且进料口边缘不规则，易残留化学活性成分。Duringtheprocessoftransferringmaterialanddrying,thispointhasfullcontactwithfeedingport.Andtheedgeoffeedingportisirregular,soit'seasyforchemicalactiveingredientstostayon.上筒内壁进料口取样点：samplingpointoffeedingportoninnerwallofuppercylinder编号：12SerialNo.12取样位置Samplinglocations选择缘故Reasons物料在干燥过程中与物料锅壁充分接触，上筒壁观看窗边缘面不规则，边角处易残留化学活性成分。Materialhasfullcontactwithpotwallduringdrying.Edgeofinspectionwindowonsurfaceofuppercylinderisirregular,whichallowschemicalactiveingredientstostayeasilyintheedge.上筒内壁观看窗取样点：samplingpointoninspectionwindowoninnersurfaceofuppercylinder编号：13SerialNo.13取样位置Samplinglocations选择缘故Reasons物料在干燥过程中与物料锅壁充分接触，筛网与锅壁结合处存在边角，易残留化学活性成分。Materialhasfullcontactwithpotwallduringdrying.Thereisanedgeonthelocationwherescreenconnectingtopotwall,whichallowschemicalactiveingredientstostay.筛网与锅壁衔接处取样点：samplingpointonthelocationwherescreenconnectingtopotwall编号：14SerialNo.14取样位置Samplinglocations选择缘故Reasons物料在干燥过程中与物料锅壁充分接触，料斗观看窗边缘面不规则，边角处易残留化学活性成分。Materialhasfullcontactwithpotwallduringdrying.Theedgeofinspectionwindowisirregular,whichallowschemicalactiveingredientstostay.观看窗边缘取样点：samplingpointontheedgeofinspectionwindow编号：15SerialNo.15取样位置Samplinglocations选择缘故Reasons处此处有缝隙，易残留化学活性成分。Thereisgaphere,whichallowschemicalactiveingredientstostay.取样口取样点：samplingpointonsamplingport1.5.SL600干式整粒机SL600drytypestraighteninggranulator编号：16SerialNo.16取样位置Samplinglocations选择缘故Reasons干式整粒机出料口，清洗水中的化学活性残留物容易残积Dischargeportofdrytypestraighteninggranulatorisalocationallowschemicalactiveingredientstostayeasily.干整机出料阀取样点：samplingpointondischargevalve编号：17SerialNo.17取样位置Samplinglocations选择缘故Reasons筛网遍布小孔，容易残积化学活性成分Therearemanymeshesonthescreen,whichallowschemicalactiveingredientstostayeasily.筛网取样点：samplingpointonscreen编号：18SerialNo.18取样位置Samplinglocations选择缘故ReasonsSL600干式整粒机通过手工清洗，此处手工清洗难度大，清洗效果相对差SL600drytypestraighteninggranulatoriswashedmanually,.Thispartishardtobecleanedbyhand.Cleaningeffectisnotverygood.整粒机上内壁取样点：samplingpointoninnersurface1.6.HZD800自动提升料斗混合机（400L）HZD800AutomaticLiftingHopperMixer（400L）编号：19SerialNo.19取样位置Samplinglocations选择缘故Reasons此处为料斗上内壁，清洁难度大Thispointisoninnersurfaceofhopper,whichishardtoclean.料斗上内壁取样点：samplingpointoninnersurfaceofhopper编号：20SerialNo.20取样位置Samplinglocations选择缘故Reasons由于此取样的位置在最下面，各种残留物容易在此积聚。Thissamplinglocationisatthebottom,whichiseasyforallkindsofresiduetoaccumulate.料斗出料阀取样点：samplingpointondischargevalve1.7.S250/40EU-B编号：21SerialNo.21取样位置Samplinglocations选择缘故Reasons清洗料斗时，清洗水需通过排水阀排水，容易残积活性成分Whilecleaninghopper,cleaningwaterisdrainedthroughdrainingvalve,whichallowsactiveingredientstostay.料斗出料阀取样点：Samplingpointondischargevalve编号：22SerialNo.22取样位置Samplinglocations选择缘故Reasons压片机供料靴底座不能拆卸清洗，只能通过人工擦拭方法进行清洗，清洗效果不如其他可拆卸部件Themountofsupplybootcan'tbedisassembledwhilecleaning.Itcanonlybecleanedbywiping,sothecleaningeffectisnotasgoodasthatofotherpartscanbedisassembled.供料靴取样点：samplingpointofsupplyboot编号：23SerialNo.23取样位置Samplinglocations选择缘故Reasons压片机冲台不能拆卸清洗，只能通过人工擦拭方法进行清洗，清洗效果不如其他可拆卸部件Platformoftabletpresscan'tbedisassembledwhilecleaning.Itcanonlybecleanedbywiping,sothecleaningeffectisnotasgoodasthatofotherpartscanbedisassembled.压片机冲台取样点：samplingpointonplatform编号：24SerialNo.24取样位置Samplinglocations选择缘故Reasons轨道形状不规则，有清洗难度，不易清洁，残留物容易在此积聚。Theshapeofrailisirregular,soit'snoteasytocleantherail.Residuecanaccumulatehereeasily.振荡筛轨道:railofoscillatingscreen1.8.GSHP150包衣机coatingmachine编号：25SerialNo.25取样位置Samplinglocations选择缘故Reasons包衣时出风桨叶插入片床，为包衣出风通道，接触活性成分机会大，且桨叶表面镂空，清洗难度大Thepaddleinsertsintothebedwhilecoating.Itisanair-outchannelforcoatingandhasmorecontactwithactiveingredients.Thepaddleishollowsoit'shardtoclean.编号：26SerialNo.26取样位置Samplinglocations选择缘故Reasons此处靠近包衣锅排水口，容易残积化学活性成分Thispointisclosetodrainingportofcoatingpot,whichallowschemicalingredientstostay.1.9.UPS1030MTI铝塑包装机thermoformingmachine编号：27SerialNo.27取样位置Samplinglocations选择缘故Reasons药品包装时，此处为药品通道，接触化学活性成分，为代表性取样点Whilepackagingproducts,thisistheproductchannelwhichcontactschemicalactiveingredients.Thispointisarepresentativesamplingpoint.铲形料斗取样点：samplingpointofshovel-shapedhopper.编号：28SerialNo.28取样位置Samplinglocations选择缘故Reasons药品包装时，此处为药品通道，接触化学活性成分，为代表性取样点Whilepackagingproducts,thisistheproductchannelwhichcontactschemicalactiveingredients.Thispointisarepresentativesamplingpoint.下料斗观看窗