apic 201405原料药厂清洁验证指南：5.0 清洁级别

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1、APIC201405原料药厂清洁验证指南：5.0清洁级别5.0LevelsofCleaning清洁级别5.1Introduction介绍ThemanufacturingprocessofanActivePharmaceuticalIngredient(API)typicallyconsistsofvariouschemicalreactionandpurificationstepsfollowedbyphysicalchanges.Ingeneral,earlystepsundergofurtherprocessingandpu

2、rificationandsopotentialcarryoverofthepreviousproductwouldberemoved.原料药的生产工艺一般由不同化学品经过反应和纯化步骤，再经过一些物理变化组成。一般来说，较早的步骤会经进进一步处理和纯化，因此上一产品潜在的残留会被清除掉。ThelevelofcleaningrequiredinordertoensurethattheAPIisfreefromunacceptablelevelsofcontaminationbyprevioussubstancesvariesde

3、pendingonthestepbeingcleanedandthenextsubstancebeingmanufacturedinthesamepieceofequipment(train).为保证下一原料药被上一产品污染水平可接受，所需进行的清洁程度取决于清洁所针对的工艺步骤，以及在同一设备（链）中生产的下一产品。API`sandrelatedintermediatesareoftenproducedinmulti-purposeequipmentwithfrequentproductchangeswhichresultsi

4、nahighamountofcleaning.TominimizethecleaningefforttheconceptofusingdifferentlevelsofcleaningasafunctionofthelevelofriskrelatedwiththepossiblecarryovermaybeappliedwithoutaffectingthesafetyoftheAPI.原料药和相关的中间体一般会在多用途设备中生产，频繁的更换产品会导致大量的清洁操作。为了将清洁工作量降至最小，在不影响原料药的安全性的前提下，可

5、以考虑使用不同的清洁级别来应对与可能的残留相关的不同风险水平。5.2Cleaninglevels清洁级别Itisrecommendedthatatleastthreelevelsofcleaningintheproductionofacommercialproductmaybeimplemented.Thisapproachisoutlinedinthetablebelow,howeveritshouldbementionedthatadditionallevelsmightbenecessarydependingonthena

6、tureoftheprocessandrequirementsofindividualcompaniesbutshouldalwaysbebasedonriskassessmentwherethecharacteristicsofthepreviousandsubsequentproductssuchassolubility,recoverystudies,natureofresidues,processstep,etc.shouldbeconsidered.在商业化产品生产中，推荐使用至少3个清洁水平。以下表格中列出了该方法，

7、但值得一提的是，根据各公司的工艺特性和要求，可能需要增加更多水平。不管怎样，要始终基于风险评估，考虑上一次品和下一产品的特性，如溶解度、回收率研究、残留特性、工艺步骤等来做决定。LevelThoroughnessofcleaningCleaningverificationCleaningvalidationVisualinspectionAnalyticalverification2Carryoverofthepreviousproductiscritical.Cleaningrequireduntilpredetermined

8、stringentcarryoverlimitsaremet.Highrisk.YesYesMandatory1Carryoverofthepreviousproductislesscritical.Cleaningshouldreducethepotentia