机械5

目录 1.前言............................................................................................................................................. 1 1.1背景...................................................................................................................................1 1.1.1指南说明.................................................................................................................1 1.1.2法规背景.................................................................................................................1 1.1.3技术背景.................................................................................................................1 1.2范围...................................................................................................................................2 2.质量管理...................................................................................................................................... 4 3.人员........................................................................................................................................... 34 3.1无菌药品生产对人员的基本要求和原则.......................................................................34 3.1.1人员的培训...........................................................................................................34 3.1.2人员卫生...............................................................................................................35 3.1.3人员监测计划.......................................................................................................36 3.1.4实验室人员...........................................................................................................37 3.2关键区域人员的良好行为规范......................................................................................37 3.3无菌区着装和更衣确认..................................................................................................39 4.厂房设施.................................................................................................................................... 44 4.1设计和布局......................................................................................................................44 4.2功能区设计.......................................................................................................................52 4.2.1无菌操作区............................................................................................................52 4.2.2气锁........................................................................................................................53 4.2.3无菌准备区和辅助区............................................................................................59 4.3.4传递区域................................................................................................................60 4.2.5仓贮区....................................................................................................................60 4.3建筑设计与房间装饰.......................................................................................................60 4.3.1建筑设计................................................................................................................60 4.3.2房间装饰................................................................................................................62 5.公用系统.................................................................................................................................... 63 5.1概论.................................................................................................................................63 5.1空调净化系统（HVAC）.................................................................................................63 5.2水系统..............................................................................................................................69 5.3气体系统..........................................................................................................................71 5.3.1压缩空气...............................................................................................................71 5.3.2氮气.......................................................................................................................73 5.4无菌产品生产的电力系统..............................................................................................74 6仪器设备..................................................................................................................................... 75 6.1设备的选型与设计...........................................................................................................78 6.1.1净化、清洗和灭菌的要求....................................................................................78 6.1.2材质、外观和安全设计要求................................................................................78 6.1.3结构设计要求........................................................................................................79 6.1.4在线监测、控制和验证的要求............................................................................79 6.1.5对公用工程的要求................................................................................................79 6.2仪器、仪表......................................................................................................................80 6.2.1仪器、仪表和计量................................................................................................80 6.2.2仪器、仪表的设计、性能、定位........................................................................80 6.2.3仪器仪表的周期校准............................................................................................82 6.2.4仪器仪表校准的内容............................................................................................83 6.3设备维修...........................................................................................................................83 目录无菌制剂GMP实施指南 ii 6.4电脑系统...........................................................................................................................83 6.4.1概述........................................................................................................................83 6.4.2计算机验证...........................................................................................................84 7物料............................................................................................................................................ 86 7.1无菌药品生产对物料的基本要求和原则......................................................................92 7.2无菌药品物料的风险控制..............................................................................................95 8生产管理..................................................................................................................................... 98 8.1工艺流程...........................................................................................................................99 8.2过程控制.........................................................................................................................100 8.2.1计划管理..............................................................................................................101 8.2.2时限管理..............................................................................................................101 8.2.3内毒素控制..........................................................................................................102 8.2.4批次划分..............................................................................................................106 8.2.5.清场管理..............................................................................................................107 8.2.6取样......................................................................................................................108 8.2.7物料平衡..............................................................................................................110 8.3生产管理控制要点的实例分析.....................................................................................110 8.3.1药液称量配制......................................................................................................111 8.3.2制袋管理..............................................................................................................111 8.3.3灭菌管理..............................................................................................................111 8.3.4灭菌后样品的传输..............................................................................................112 8.3.5粉体分装..............................................................................................................112 8.3.6阻隔膜包装..........................................................................................................112 8.3.7产品检漏..............................................................................................................112 9清洗和准备............................................................................................................................... 113 9.1胶塞...............................................................................................................................115 9.1.1胶塞的清洗和准备.............................................................................................115 9.1.2胶塞清洗机.........................................................................................................119 9.2玻璃容器........................................................................................................................122 9.2.1玻璃容器的清洗和准备.....................................................................................122 9.2.2洗瓶机.................................................................................................................125 9.2.3隧道烘箱.............................................................................................................127 9.3塑料容器.........................................................................................................................129 9.4颗粒杂质........................................................................................................................130 9.5传递................................................................................................................................131 10药液的配制............................................................................................................................. 133 10.1起始物料.......................................................................................................................135 10.2溶液的配制...................................................................................................................138 10.3微生物污染水平控制...................................................................................................143 10.4除菌过滤......................................................................................................................146 10.5药液配制设备..............................................................................................................160 11灌装......................................................................................................................................... 167 11.1 C级下大容量灌装........................................................................................................169 11.2小容量灌装..................................................................................................................172 11.2.1 A/B级下小容量灌装.........................................................................................172 11.2.2 A/C级下小容量灌装.........................................................................................175 11.3粉针剂的分装..............................................................................................................176 11.4灌装设备......................................................................................................................180 12冻干......................................................................................................................................... 184 12.1冻干流程......................................................................................................................184 12.2冻干工艺的验证...........................................................................................................189 无菌制剂GMP实施指南目录 iii 12.3冻干机.........................................................................................................................197 12.3.1设备技术要求...................................................................................................197 12.3.2设备确认...........................................................................................................200 13轧盖......................................................................................................................................... 205 13.1轧盖工序......................................................................................................................206 13.2轧盖的环境要求..........................................................................................................207 13.3轧盖机.........................................................................................................................209 14灭菌方法................................................................................................................................. 212 14.1灭菌概述......................................................................................................................212 14.2湿热灭菌.......................................................................................................................213 14.2.1湿热灭菌概述...................................................................................................214 14.2.2湿热灭菌程序的开发........................................................................................221 14.2.3湿热灭菌确认与验证........................................................................................228 14.2.4灭菌系统的日常维护.......................................................................................230 14.3干热灭菌.......................................................................................................................231 14.3.1干热灭菌概述....................................................................................................232 14.3.2干热灭菌确认与验证.......................................................................................236 14.3.3干热灭菌设备日常管理要点...........................................................................243 14.4辐射灭菌......................................................................................................................243 14.4.1辐射灭菌概述...................................................................................................244 14.4.2辐射灭菌的确认和验证...................................................................................246 14.4.3辐射灭菌的日常管理要点...............................................................................249 14.5环氧乙烷灭菌..............................................................................................................257 14.5.1环氧乙烷灭菌概述...........................................................................................258 14.5.2环氧乙烷灭菌的确认和验证............................................................................261 14.6过滤除菌工艺...............................................................................................................268 14.6.1除菌级过滤器的验证/细菌截留......................................................................268 14.6.2完整性检测........................................................................................................ 276 14.6.3过滤器的选择和特性描述................................................................................287 15无菌药品的最终处理............................................................................................................. 295 15.1密封完整性测试...........................................................................................................295 15.2颗粒/可见异物和其它缺陷检查................................................................................302 15.3半成品的灯检、贴签和包装......................................................................................309 16无菌工艺模拟试验................................................................................................................. 311 16.1无菌工艺模拟试验方法...............................................................................................312 16.2无菌工艺模拟试验的实施...........................................................................................316 16.3无菌工艺模拟试验结果解读.......................................................................................321 17清洁和消毒............................................................................................................................. 326 17.1概述..............................................................................................................................326 17.2清洁消毒体系建立......................................................................................................329 17.3清洁消毒效果...............................................................................................................334 18环境监控................................................................................................................................. 342 18.1污染来源.......................................................................................................................342 18.2洁净区级别的划分......................................................................................................343 18.3监测方案......................................................................................................................345 18.3.1限度...................................................................................................................346 18.3.2监测方法和设备................................................................................................349 18.3.3取样计划............................................................................................................354 18.3.4取样点及取样量的设置....................................................................................355 18.4超标处理......................................................................................................................358 18.5数据分析......................................................................................................................360 目录无菌制剂GMP实施指南 iv 18.6环境微生物的鉴别......................................................................................................360 19无菌检查................................................................................................................................. 362 19.1参数放行法..................................................................................................................362 19.2无菌检查的环境条件..................................................................................................365 19.3方法描述......................................................................................................................371 19.4检验数量和检验量......................................................................................................372 19.4.1检验数量............................................................................................................372 19.4.2样品量（检验量）...........................................................................................373 19.5培养基出现浑浊时的处理程序...................................................................................375 19.6观察和评价..................................................................................................................375 19.7培养基.........................................................................................................................377 19.7.1培养基种类........................................................................................................377 19.7.2培养基控制（培养基的适用性检查）............................................................378 19.8方法验证.......................................................................................................................381 20吹-灌-封技术.......................................................................................................................... 383 20.1工艺流程.......................................................................................................................384 20.2设备设计和气体质量...................................................................................................386 20.2.1设备设计............................................................................................................386 20.2.2气体质量............................................................................................................387 20. 3验证和确认..................................................................................................................388 20.4批监测和控制...............................................................................................................389 21隔离技术................................................................................................................................. 391 21.1隔离技术的要求及应用...............................................................................................391 21.2隔离系统的验证...........................................................................................................405 21.3隔离系统的维护体系...................................................................................................412 22 EHS .......................................................................................................................................... 415 22.1环境——空气..............................................................................................................415 22.1.1废气排放...........................................................................................................415 22.1.2 VOC's（可挥发性有机化合物），异味.............................................................416 22.1.3消耗臭氧层物质...............................................................................................417 22.2环境——废水..............................................................................................................418 22.2.1污水处理...........................................................................................................418 22.2.2预防措施...........................................................................................................419 22.2.3应急措施...........................................................................................................419 22.2.4废水分质处理...................................................................................................420 22.2.5回收与废物最小化...........................................................................................420 22.3环境——噪音..............................................................................................................421 22.3.1外界噪音...........................................................................................................421 22.3.2噪音敏感区域...................................................................................................422 22.3.3噪声治理...........................................................................................................422 22.4环境——固体废物......................................................................................................423 22.4.1管理要求...........................................................................................................423 22.4.2垃圾填埋地.......................................................................................................424 22.4.3废物运输...........................................................................................................425 22.4.4焚烧处理...........................................................................................................425 22.4.5废物的回收利用...............................................................................................426 22.5健康和安全..................................................................................................................426 22.5.1危险物质和有毒产物.......................................................................................426 22.5.2工作环境中的噪音...........................................................................................427 22.5.3健康体检...........................................................................................................427 22.5.4物料控制...........................................................................................................428 无菌制剂GMP实施指南目录 v 22.5.5表面和安全通道...............................................................................................429 22.5.6防火..................................................................................................................429 22.5.7设施防护...........................................................................................................430 22.5.8电气安全和静电危害.......................................................................................431 22.5.9压力系统的安全性...........................................................................................431 22.5.10粉尘爆炸.........................................................................................................432 22.6厂址选择......................................................................................................................432 22.6.1环境空气洁净度...............................................................................................432 22.6.2供水..................................................................................................................433 22.6.3环境敏感区.......................................................................................................433 22.6.4选址的其它问题...............................................................................................434 22.7能源供应......................................................................................................................434 22.7.1热能..................................................................................................................434 22.7.2燃料储存...........................................................................................................434 22.7.3电力供给...........................................................................................................435 22.7.4能源节约...........................................................................................................435 22.8监测和管理措施..........................................................................................................436 22.8.1环境现状公示...................................................................................................436 22.8.2环境影响评价...................................................................................................436 22.8.3排污注册与申报...............................................................................................437 22.8.4应急预案...........................................................................................................438 22.8.5管理体系...........................................................................................................438 22.9信息安全......................................................................................................................439 22.9.1技术保密...........................................................................................................439 22.9.2文件存放...........................................................................................................439 22.9.3标签存放...........................................................................................................440 22.9.4资料与物品销毁...............................................................................................440 附录：无菌药品生产风险控制实例........................................................................................... 441 附1.1注射剂质量风险分析与质量风险控制...................................................................441 附1.2注射剂车间风险评估实例.......................................................................................448 参考资料....................................................................................................................................... 474 词汇表.......................................................................................................................................... 475 术语表.......................................................................................................................................... 479 关键词列表................................................................................................................................... 487