药品生产质量管理规范(GMP).ppt

WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO药品生产质量管理规范培训（GMP）厂房和无菌生产厂房和无菌生产 WORKSHOP ON GOOD MANUFACTURING PRACTICES WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION)INSPECTIONWORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO目的目的1.对总的要求的回顾 2.对无菌产品生产设施所必需的检查要素进行培训WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO原则原则厂房首先需选址、设计、建造、操作调试和维修保养：降低差错和交叉污染的危险性有利于有效清洁有利于有效保养维修降低灰尘和颗粒消灭任何对质量有影响的因素WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO原则厂房应位于降低交叉污染危险性的地方,如：厂房建筑不能与啤酒厂相邻，因为空气中有大量的酵母菌WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO厂房厂房的建造应的建造应:有利于卫生清洁.易于保养和清洁有服务保障避免昆虫和其他动物进入WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO辅助区辅助区休息和就餐的房间更衣、洗手和卫生间区域维修保养间动物房WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO设计设计原则原则生产流向物料流向人员流向WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO厂房物流和人流举例物流和人流举例 物品到达 参观者入口 员工入口 物品运输 Zone:Clean Zone:Packaging Zone:Controlled Material FlowPersonnel FlowWORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHOA级区域严格的无菌生产区域，无菌产品及暴露在环境中与产品接触的材料。在该区域进行高风险的操作（灌装、最后的除菌过滤、无菌连接、收获）。WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHOB级区域无菌生产区域，无菌产品接触的材料应避免环境的污染。B级生产区域用在无菌产品的传输，包裹除菌过滤用具，具有A级生产区域的背景环境。WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHOC级区域非严格区域，材料暴露在环境中，还未进行最后的灭菌。C级区域是生产活动的支持区域，灭菌前的成分制备、设备准备等。WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHOD级区域非严格生产活动的支持区域，未加工的成分或材料能够暴露在环境中。所有其他的产品或材料必须装在密闭的容器中。清洁区域用于无菌产品的非严格阶段。WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO无菌生产最终灭菌WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO典型生产步骤典型生产步骤无菌生产无菌生产最终消毒最终消毒背景背景暴露暴露背景背景暴露暴露原材料原材料分发分发C局部保护局部保护CC混合和混合和过滤过滤CBCC过滤过滤(除菌除菌)BACA准备准备/清洗清洗DDDD最后淋洗最后淋洗CCDC灭菌柜装货灭菌柜装货CCDC灭菌柜卸货灭菌柜卸货BA 或包裹或包裹好的好的CA或包裹好或包裹好的的WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO典型生产步骤典型生产步骤无菌生产无菌生产最终消毒最终消毒背景背景暴露暴露背景背景暴露暴露灌装和灌装和 压塞压塞BACA冻干操作冻干操作_密闭系统密闭系统_冻干转移冻干转移BA_压盖压盖D局部保护局部保护D局部保护局部保护外观检查外观检查DDDD贴签和贴签和包装包装DDDDWORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO环境级别控制颗粒物质生物载量温度室温 20-25湿度 45-55%压力换气次数送风速度WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO微生物污染限度级别空气样品（CFU/m3)沉降碟(直径 90 mm,CFU/4 小时）接触碟(直径 55 mm)CFU/Plate手套印压(手指%CFU/手套)A3335.0um 动态颗粒最大允许量/m3 0.5-5um 5.0umA3500035000B350003500002000C350,00020003,500,00020,000D3,500,00020,000Not defined Not definedWORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO洁净区不同空气颗粒分级系统的比较洁净区不同空气颗粒分级系统的比较WHO GMP)United States 209 EUnited States 惯用ISO/TC209EEC(GMP)A级M 3.5 100级1S0 5 A级 B级M 3.5100级ISO 5 B级 C级M 5.5.10,000级ISO 7 C级 D级M 6.5 100,000级ISO 8 D级WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO人员人体是最大的污染源。洁净区域环境60%的污染物是人带入的。WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO颗粒散落活动活动颗粒产生数颗粒产生数/分分坐或静立坐或静立100,000坐，手臂或头部的轻微运动坐，手臂或头部的轻微运动500,000坐，运动手臂，腿或头坐，运动手臂，腿或头1,000,000站立站立2,500,000慢走慢走5,000,000正常走正常走7,500,000快走（快走（2.5m/秒）秒）10,000,000进行工作进行工作15-30 x 1,000,000WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO接触平皿法计数皮肤细菌手和颈部位部位平皿法计数前额348太阳穴560鼻子TNTC上嘴唇TNTC脸颊584颈316WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO接触平皿法计数皮肤细菌上躯干和手臂部位部位平皿法计数上臂42肘8前臂41手腕TNTC手224WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO下躯干和手臂部位部位平皿法计数肩43胸部50腿之间TNTC臀部104大腿内侧TNTC接触平皿法计数皮肤细菌WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO设备传送带不能在A级区域和C级区域之间通过如果可能,设备必须蒸汽消毒用洁净工具进行设备保养灭菌注射用水仅用于最终制品WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO无菌产品生产企业的检查以下最关键的部分需作趋势分析:净化室空气质量的监控,静态和动态空气中颗粒数,微生物载量,接触皿,空气压力,换气次数,净化室湿度,压力和温度监控警告值和 采取行动值失误和调查纠正行动WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO人员资格和培训无菌灌装是最关键的生产步骤。在该区域工作的人员必须具有资质和进行适当的培训.建议学微生物专业的人从事本岗位工作。WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO验证空气净化系统（HVAC）的安装确认（IQ）,运行确认（OQ）和性能确认（PQ）文件 保养记录滤膜完整性实验无菌灌装验证培训记录WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO产品趋势无菌试验失败产品中的非特异性颗粒产品、瓶子、瓶塞、铝盖、标签和盒子的一致性QC 对产品和各种组分的签发WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO产品、设备和设施配制和签发产品签发、原液、终产品容器产品和设备的灭菌记录无菌灌装区域的清洁记录灌装体积和监控记录人员携带微生物监控记录和趋势WORKSHOP ON GOOD MANUFACTURING PRACTICES(WORKSHOP ON GOOD MANUFACTURING PRACTICES(GMPsGMPs)INSPECTION FOR VACCINES)INSPECTION FOR VACCINESWHO参考书1.Good manufacturing practices for pharmaceutical products.In:WHO ExpertCommittee on Specifications for Pharmaceutical Preparations.Thirty-secondreport.Geneva,World Health Organization,1992,Annex 1(WHO TechnicalReport Series,No.823).2.Airborne particulate cleanliness classes in cleanrooms and clean zones.Federal Standard 209E.Mount Prospect,IL,Institute of EnvironmentalSciences,1992.3.Cleanrooms and associated controlled environments.Part 1:classification ofairborne particulates.Geneva,International Organization for Standardization,1999.4.The rules governing medicinal products in the European Union.Vol.4.Goodmanufacturing practices:medicinal products for human and veterinary use.Brussels,European Commission,1998.