保证无菌药品的生产Sterility Processing AssuranceSpeaker: Henry Tjong, P. Eng, Senior GMP ConsultantMarch 05, 2010
关于我 张诚汝(Henry Tjong, P. Eng)任职于拜耳技术工程（上海）有限公司，他是医药保健工艺部门的高级GMP顾问和工程项目经理。 加拿大安大略省注册专业工程师，在工程、验证、项目管理等方面拥有29年的经验，在生物技术和医药工程领域拥有超过20年的经验，其中有17年在加拿大赛诺菲-巴斯德（人用疫苗制造厂和研究所）Sanofi Pasteur (项目经理, 采购经理, 验证项目经理); 和4年在中国医药领域的经验(GMP审计,培训和工程项目经理) •具有能力领导一个项目从可行性研究、概念设计、初步设计、详细设计、施工安装到最后验证、完成。•具有FDA cGMP, EU GMＰ和SFDAＧＭＰ知识。 擅长GMP审计•具有用中英文培训的经验，培训内容包括FDA cGMP、验证和项目管理。March 2010 Page 2
时间关于我们 拜耳技术工程－医药保健工程部门是一支富有经验的团队，为制药和生物制药工业提供良好服务。我们拥有优良的工程背景，对工艺技术的深入掌握和GMP的经验，以及广泛的服务范围。我们的目标是保证您的项目在预期、预计和预算下圆满完成。成本工程项目的 Magic Triangle March 2010 Page 3质量
我们是综合技术服务公司的一部分拜耳技术工程是在工程、过程管理和工艺技术等领域的资深的综合技术服务机构，这使得我们能够为医药和生物工业的客户提供广泛的总体服务。来自BTS-工艺技术的支持来自BTS-过程管理的支持 过程设计 物流管理 流程技术 过程控制系统 材料工程 制造执行系统(MES)医药保健工程项目团队来自其他BTS-工程部门的支持 土建(Civil/Structural/Architectural) 暖通(Heating/Ventilating/Air Conditioning） 厂房布置和管道连接 项目管理March 2010 Page 4
我们的专长h技术特点:-医药和生物领域，活性药和成品药的生产-符合GMP洁净要求的建筑设计和施工-无菌生产-纯水和注射水系统-在位清洗(CIP) 和在位灭菌(SIP) 系统-试车及确认-符合GMP及相关法规(包括美国FDA和欧盟标准)-物流和供应链管理-综合性工程服务: 土建、暖通、工艺、过程设备、过程控制等March 2010 Page 5
医药保健工程项目: 注射剂的工艺过程和灌装 为Chinoin公司建设的生产设施，位于一栋空置的现有支建持筑区中域。的该所项有目设包备括和生附产属设设备施、工人衣物室和技术: 无菌生产设备符合GMP对液体和半流体在100洁净 度下的要求（洁净等级B＋层流），非无菌生产为 等级D。 无菌灌装在100洁净度要求下进行（洁净等级B＋层 流），在等级F要求下包装。 周期: 总投资: 2000万美元 位置:墨西哥Aguas Calientes 基础及详细工程设计 采购 施工管理 试车及确认March 2010 Page 6
医药保健工程项目：制剂工厂的扩建 对制剂工厂的大规模的扩建，包括生产区，包装区，库房，生产设备的转置，现有设施的改造。工程建设与正常生产同步进行。项目时间:2006 to 2008 总投资: 20 Mio US $ 地点:中国北京 基础及详细设计, 设备选型及采购，施工管理, 试车及确认March 2010 Page 7
总论 BTS-医药保健工程部门是隶属于拜耳技术服务的一个综合性团队，我们能够为工艺过程开发、工程设计、工艺技术和项目管理等领域为客户提供广泛而专业的服务 拥有活性药、药剂及生物工艺方面的资深技术 工程师在医药保健领域拥有国际性项目的经验 我们立足于良好的项目管理和过程管理系统 我们将向你提供医药保健工程的良好方案:从可行性研究至最终投产March 2010 Page 8
联系我们 拜耳技术工程（上海）有限公司 中国上海化学工业区 目华路F3地块邮编：201507商务部医药保健工程部张杰赵春华电话: (86-21) 61465006电话: (86-21) 61465210传真: (86-21) 6712 0385传真: (86-21) 6712 0722邮件信箱: @邮件信箱: @ 2010 Page 9
保证无菌药品的生产Sterility Processing Assurance Elements 无菌保证 的基本要素 Operator Qualification -Operator s Behavior 洁净室操作人员资格-操作人员行为March 2010 Page 10
保证无菌药品的生产Aseptic Processing AssuranceSFDA, FDA and EU GMPMarch 2010 Page 11
GMP征求意见稿（附录1）修订说明第九条 无菌药品生产所需的洁净区可分为以下4个级别： A级 高风险操作区，如：灌装区、放置胶塞桶、敞口安瓿瓶、敞口西林瓶的区域及无菌装配或连接操作的区域。通常用层流操作台（罩）来维持该区的环境状态。层流系统在其工作区域必须均匀送风，风速为 在密闭的隔离操作器或手套箱内，可使用单向流或较低的风速。 B级 指无菌配制和灌装等高风险操作A级区所处的背景区域。 C级和D级 指生产无菌药品过程中重要程度较低的洁净操作区。March 2010 Page 12
GMP征求意见稿（附录1）修订说明洁净度级别悬浮粒子最大允许数/立方米(a)静态(b)动态(b)≥μm(d)≥5μm≥μm(d)≥5μmA级352020352020(e) B级(c) 3520293520002900C级(c) 3520002900352000029000D级(c) 352000029000不作规定不作规定March 2010 Page 13
GMP征求意见稿（附录1）修订说明 注：1.为了确定A级区的级别，每个采样点的采样量不得少于1m3。A级区空气尘埃粒子的级别为ISO ，以≥μm的尘粒为限度标准。B级区（静态）的空气尘埃粒子的级别为ISO 5，同时包括表中两种粒径的尘粒。对于C级区（静态和动态）而言，空气尘埃粒子的级别分别为ISO 7和ISO 8。对于D级区（静态）空气尘埃粒子的级别为ISO 8。测试方法可参照ISO14644-1。2.在确认级别时，应使用采样管较短的便携式尘埃粒子计数器，以避免在远程采样系统长的采样管中≥μm尘粒的沉降。在单向流系统中，应采用等动力学的取样头。3.可在常规操作、培养基模拟灌装过程中进行测试，证明达到了 动态 的级别，但培养基模拟试验要求在 最差状况 下进行动态测试。March 2010 Page 14
附录1：无菌药品洁净区微生物监测的动态标准(a)如下：级别浮游菌沉降菌表面微生物（φ90mm）cfu/m3 cfu /4小时(2) 接触碟5指手套（φ55mm）cfu /手套cfu /碟A级<1 <1 <1 <1 B级10 5 5 5 C级100 50 25 －D级200 100 50 －March 2010 Page 15
附录1：无菌药品 注： 表中各数值均为平均值。 单个沉降碟的暴露时间可以少于4小时，同一位置可使用多个沉降碟连续进行监测并累积计数。March 2010 Page 16
FDA对洁净级别的定义Sterile Guide Grade (in FDA, CDER Sept. 2004 Guideline on Sterile Drug Products by operation)Aseptic Processing无菌生产指南洁净级别关于FDA，CDER 无菌工艺生产无菌药物指南（动态）In Operation动态Acceptable Maximum number of Microbiological Settling particulate quality per colony forming unitsPlates Action Levels m^3(dia. 90mm; cfu/4 hours)允许最大尘埃粒子数最大CFU/m^3沉降皿(直径90 mm; /m^3 cfu/4 小时) >=μm CFU/m^3 Class 1003,520 1 1 级别100 Class 10,000352,000 10 5 级别10,000 Class 100,0003,520,000 100 50 级别100,000March 2010 Page 17
EMEA对洁净级别的定义European Commission Annex 1, 2008 -Manufacture of Sterile Medicinal Products欧盟委员GMP 指南附录I，2008 -无菌药品制造DescriptiveAt RestIn Operation描述静态动态Maximum permitted number of Maximum permitted number of Maximum number of particles per m^3particles per m^3colony forming units允许最大尘埃粒子数/m^3 允许最大尘埃粒子数/m^3 最大CFU/m^3 μm 5 μm μm 5 μm CFU/m^3 (Air sample)Grade A3,520 203,52020Less than 1 级别A Grade B3,52029352,0002,90010 级别B Grade C352,0002,9003,520,00029,000100 级别C Grade D3,520,00029,000Not definedNot defined200 级别D March 2010 Page 18
保证无菌药品的生产Sterility Processing AssuranceSterility Assurance 无菌保证 March 2010 Page 19
Elements of the Daily Sterility Assurance Aseptic ProcessingFProcessacility & RoomFlowLayoutHVAC Media USterility tilitiesFillsAssuranceDDeviation & isinfection Environmental PracticesTrendsQA/QCPersonnelMarch 2010 Page 20
日常 无菌保证 的基本要素人流和物流;平面布局无菌工艺HVAC / 设施车间和功能间无菌培养基无菌保证消毒措施偏差和环境趋势QA/QC人员March 2010 Page 21
Layout平面布局March 2010 Page 22
保证无菌药品的生产Sterility Processing Assurance Filling room and filling machineMarch 2010 Page 23
保证无菌药品的生产Sterility Processing Assurance Vail integrated Wash, Depyrogenation, Filling lineMarch 2010 Page 24
保证无菌药品的生产Sterility Processing Assurance IsolatorMarch 2010 Page 25
保证无菌药品的生产Sterility Processing Assurance IsolatorMarch 2010 Page 26
Air Handling UnitMarch 2010 Page 27
HEPA Filters % Efficient 有效率 Controlled Testing 有控制的测试 Produces Air Class 产生的空气级别 10 100 1,000 10,000March 2010 Page 28
Purified Water GeneratorMarch 2010 Page 29
Water for InjectionMarch 2010 Page 30
Pure Steam GeneratorMarch 2010 Page 31
保证无菌药品的生产Sterility Processing AssurancePersonnel人员March 2010 Page 32
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为Topics 议题 Why 为什么 Management Polices 管理方针 Training 培训 Qualification 确认 Monitoring 监测 Ongoing Control (Trending, auditing) 运行中的控制（趋势，审计）March 2010 Page 33
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为Why need to control microorganisms in the cleanrooms?洁净室为什么要控制微生物Drug Products must be sterile 药品必须是无菌的 injected into the body, 注射药品 used on open wounds 用于开放的伤口 used in the eye. 眼科用药 Sterile free of microorganisms 无菌-没有微生物 Organisms can be harmful if injected into a patient 生物有机体注射到人体内可能是有害的March 2010 Page 34
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为 Two problems recognized 100 years ago still persist一百年前认识到的两个问题仍然存在 of microorganisms in the air 微生物在空气中的存在 of microorganisms by human being人类对微生物的传播March 2010 Page 35
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为What is known! 什么是已知的 There is a direct link between the number of operators and the extent of their activities to the number of microorganisms (microbial contamination) inside the cleanroom.洁净室里的微生物数量和洁净室里人员数量及活动程度有直接的关联 Proven by studies研究证明March 2010 Page 36
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为Cleanroom Personnel 洁净室人员Expectation预期 Highly trained and qualified operators are required for the cleanroom 洁净室的操作人员需要培训有素并且经过确认 Basic knowledge of Microbiology is must 有微生物的基础知识 Task oriented 任务 Healthy individual with good hygienic habits 身体健康,有良好的卫生习惯March 2010 Page 37
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为Cleanroom Personnel 洁净室人员 Even the state of the art and highly sophisticated cleanroom cannot ensure product sterility, if the cleanroom operators do not follow the protocols for aseptic techniques. 假如洁净室的操作工不按照无菌工艺的方案操作，那么即使是最先进的和完善的洁净室也不能保证产品的无菌。 A breach in an aseptic technique can be resulted in a sterility failure and cost thousands of $$$$ due to the product rejection. 违反无菌操作工艺可能会造成无菌操作的失败，并且由于产品报废而破费成千上万元。March 2010 Page 38
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为Company Polices for Cleanroom Operators公司为洁净室操作人员制定的方针 Management Polices 管理方针 Training 培训 Qualification 确认 Monitoring 监测 Ongoing Control (Trending, auditing) 运行中的控制（趋势，审计)March 2010 Page 39
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为Cleanroom Personnel Management Polices洁净室人员的管理方针March 2010 Page 40
Cleanroom Personnel Management Polices洁净室人员的管理方针Cleanroom Personnel Health 洁净室人员健康Management Polices 管理方针 Health Policy 健康政策 Hiring Policy 雇佣政策 Formal Health Screening at the time of hiring 雇佣时进行正规身体检查 Free from any Communicable diseases Free from any chronic Respiratory Infections 无传染病 无慢性呼吸道感染March 2010 Page 41
Cleanroom Personnel Management Polices洁净室人员的管理方针Cleanroom Personnel Health 洁净室人员健康Management Polices管理方针 Initial Testing 初始检查 Annual Re-testing 每年复检March 2010 Page 42
Cleanroom Personnel Management Polices洁净室人员的管理方针 Cleanroom Personnel 洁净室人员 Daily screening prior to gowning 在穿戴洁净服前的每日检查 Report any sickness to Manager 向经理报告任何不健康的状况 Open wound 暴露的伤口 Fever 发热 Respiratory infection 呼吸道感染 List all above in Gowning SOP 在洁净服穿戴SOP中需要列出以上各项March 2010 Page 43
Cleanroom Personnel Management Polices洁净室人员的管理方针Cleanroom Personnel洁净室人员Action Plan; 行动计划 Company Health Policy 公司健康政策 SOP for annual screening 每年复检SOP Procedure for screening 检查程序 How to handle a positive case怎样处理一个案例March 2010 Page 44
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划March 2010 Page 45
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划Formal Training for GowningQualification 穿洁净衣确认的正式培训 Qualification Procedure 确认程序 Training 培训 Initial Gowning Qualification Studies 初始穿戴技术确认 Routine Monitoring 常规监测 Retraining 再培训 Requalification 再确认March 2010 Page 46
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划Formal Training for Gowning Qualification穿洁净衣确认的正式培训 SOP 标准操作规程 Qualification Procedure 确认程序 Identify and list all the relevant SOP 列出所有相关的SOP Demo 演示 Demonstrate the gowning procedure by senior/experienced operatoror Microbiologist 由资深和有经验的操作工或微生物学家展示怎样穿洁净服 Provide rational for each step 为每个步骤提供合理依据 Other 其他 Basic Microbiology 基本微生物学 DOs and DON Ts of gowning techniques 穿戴技术的注意事项 Good Aseptic Techniques 良好的无菌工艺March 2010 Page 47
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划Formal Training for GowningQualification穿洁净衣确认的正式培训 Qualification Procedure 确认程序 Initial Gowning Qualification初始穿戴技术资格 Three consecutive testing ( with good results)连续三次的测试（有好的结果） Testing procedure (follow up detail)测试程序（细节） Testing sites (gloves, chest, fore arms)测试部位（手套，胸部，前臂） Limits限度 Recording of data数据记录March 2010 Page 48
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划Media Fill Participation 培养基 Initial Qualification 初始确认 By filling 500 sterile MF units 500个无菌培养基OR Full media Fill 全培养基 Requalification 再确认 Annual (testing same as initial qualification)每年（和初始检查一样） Participate in at least one successful MF 至少参加一个成功的培养基灌装March 2010 Page 49
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划Training materials 培训教材Training in Basic Microbiology 基本微生物学培训Personal Hygiene 个人卫生Aseptic techniques 无菌工艺DO s and DON Ts 注意事项March 2010 Page 50
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划Basic Microbiology 基础微生物学The contamination associated to human body or activity 与人体或行为相关的污染Source Number of microorganisms found来源微生物数量Human Skin 人体皮肤1000 per cm2Human Saliva 人体唾液10,000 per mlEar Wax耳垢100,000 / gmModerate Activity 中度活动Shed 1,000,000 particles /hourMarch 2010 Page 51
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划 Sources of Microorganisms微生物源Operators carrying particles and microbial contaminants on theirclothing, cosmetics, hair, from home / life style 操作人员的衣服，化妆品，头发（从家里和生活习惯）带来的颗粒和微生物污染Common type: Gram positive cocci常见类型：革兰氏阳性球菌 Staphylococcus species 金黄色葡萄球菌物种 Micrococcus微球菌 Corynebacterium棒状杆菌 Propionicbacterium丙酸菌素March 2010 Page 52
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划 Sources of Microorganisms微生物源 Gram positive Cocci are most common flora of human skin, act as a carrier革兰氏阳性球菌是人体皮肤最常见的微生物系 Staphylococcus epidermidis表皮葡萄球菌 Staphylococcus epidermidis and Micrococcus species are commonly found in cleanrooms洁净室通常能发现表皮葡萄球菌和微球菌March 2010 Page 53
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划Dirt污垢Dirt carries the gram positive rods and their spores污垢带有革兰氏阳性棒菌及其孢子Dirt particles are carried by operators and airinside the cleanroom 操作工和空气把污垢粒子带进洁净室March 2010 Page 54
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划 Pictures of common Mold found in the environment, food (blue green colonies)图示环境中常见的菌群（蓝绿菌落）Penicillium species 青霉属March 2010 Page 55
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划 Pictures of common Mold found in the environment图示环境中常见的霉菌Mold Aspergillus曲霉菌Black spores with white cottony filamentsMarch 2010 Page 56
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划Prove the presence of microorganisms on human skin人类皮肤上的微生物Inc的lu一de部 a分 demo test, as a part of annual training 包括一个证明检测,作为年度培训 select any two operators 选择任何两个操作人员 One operator washed hand with cleanroom soap 一个操作工用洁净室肥皂洗手 Other operator with no hand washing 操作人员未洗手 Microbiologist take finger samples on a petri plate containing TSA medium from both operators separately从两名操作人员取下TSA培养基的指样 I些nc板ub块ate these plates for 24 to 48 hours at 30-35oC 在30-35oC的情况下培养这24-28小时 Observe plates for microbial growth after incubation 培养后观察微生物的生长 Count the number of colonies on the plate统计板上菌群的数量 Prepare a gram stain slide 制作一张幻灯片 Show to trainees (cleanroom operators) 对洁净室员工进行培训March 2010 Page 57
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划What is Good Personal Hygiene?什么是良好的个人卫生习惯 Bathe daily 每天洗澡 Shampoo hair daily 每日用洗发水洗头发 Wash hands after rest room use 上厕所后洗手 Wash hands before and after meals 饭前饭后洗手 Wear clean clothing 穿干净的衣服 Keep fingernails short and clean保持指甲短和干净 No nail polish or false nails 没有假指甲和指甲油 Good skin care 良好的皮肤护理March 2010 Page 58
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划Good Aseptic Techniques良好无菌工艺 No touching of the gown 不要接触洁净服 Reduced number of entry and exit 限制进出的人口 Minimal talking, motion, and traffic flow减少说话，动作和交通流量 Frequent glove sanitization or change 经常消毒和更换手套 Use only sterile forceps NO GLOVED HAND!使用无菌工具 要带手套 Use only sterile tools for contacting sterile equipment 使用无菌工具接触无菌设备 Change of gloves prior to any critical operation 在任何关键操作前更换手套March 2010 Page 59
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划Good Aseptic Techniques良好无菌工艺 Slow and deliberate movements 缓慢的运动 No reaching over open vials or stoppers 不接触暴露的瓶子和胶塞 Proper wrap removal适当包装拆除 Minimal touching of objects减少接触物体 Avoidance of blockage between HEPA filters and critical articles 避免高效过滤器和关键部位的堵塞 No kneeling directly on the floor 不要直接跪在地板上 Change garments if torn immediately 如果洁净服破损立即更换March 2010 Page 60
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划Restricted Materials 限制的物料 Food, drink 食物，饮料 Tobacco 烟草 Cosmetics 化妆品 Jewelry 首饰Break Room休息室 Regular paper and paper products 常规纸张和纸制品 Cardboard 纸板March 2010 Page 61
Formal Training Program for Cleanroom Operators洁净室操作人员正式培训计划Prohibited Actions禁止行为 Horseplay 嬉戏 Fast movements 快速活动 Movements near critical surfaces 在关键表面活动 Interruption of airflow 阻断气流 Sitting on equipment 坐在设备上 Writing on equipment 在设备上写字 Removal of items from underneath cleanroom garments在洁净服下移动物体March 2010 Page 62
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为Personnel Monitoring人员监控 Frequency 频率 At every exit 在每个出口 Locations 位置 Gloves (both right and left hands, all five fingers)手套（双手，5个手指） Chest 胸膛 Hood and mask 口罩和面具 Sleeves 袖子March 2010 Page 63
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为Personnel MonitoringMicrobial Limits人员监控的微生物限度 Microbial Limits (critical operation)微生物限度（关键操作） Based on historical data 基于历史数据 Based on regulatory requirements基于监管要求 Based on criticality of operation基于操作的重要性 Based on classification of working zone基于工作区的洁净级别 Establish Action limits 建立行动限 Establish Alert limits建立警戒限March 2010 Page 64
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为Personnel MonitoringMicrobial Limits人员监控的微生物限度 Microbial Limits (critical operation)微生物限度（关键操作） Glove <1 cfu / hand 手套<1 cfu/手 Gown <2 cfu / plate 洁净服<2 cfu/板 Microbial Limits (for less critical operation)微生物限度（非关键操作） Glove <2 cfu / hand 手套<2 cfu/手 Gown <5 cfu / plate 洁净服<5cfu/板March 2010 Page 65
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为Personnel Monitoring人员监测 Investigation of failures失败调查 Microbial identification微生物鉴别 Operator Interview (the task performed at the time of testing)操作工调查 Consequence of misconduct错误行为的后果 Evaluation of impact on Product sterility对无菌产品影响的评估 Corrective actions正确的行为 Preventive actions预防措施 Evaluation of Data数据评估March 2010 Page 66
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为Microbiological Control of Cleanroom Personnel 洁净室人员微生物控制 Verification of Training 培训验证核查 Re-training 再培训 Action for any failure (scrutinize, an interview)任何失败后的行动（仔细检查，采访） Trending of individual data 独立数据的趋势 Historical trend (shedder, carrier of specific contamination) 历史趋势（脱落，载体的具体污染）March 2010 Page 67
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为Co通n过tro生ls产 in管tr理od控u制ce和d 执an行d implemented by Production Management Minimal number of people (qualified as per MF)最少的人数 Good Hygiene practices良好卫生习惯 Provide proper gowning design and materials提供适当的洁净服设计和材料 D（etailed Gowning procedure (SOP with pictures)穿戴洁净服的细节程序SOP中用图表示） Include in Internal audit包含内部审计 好Go无od菌 a操se作pt（ic 提pr供ac接tic触es关 (p键ro表vid面e的 st无eri菌le 工to具ols） for touching critical surfaces)良 Gown washing and sterilization Practices洁净服清洗和消毒 Repair and replacement of garments修理和更换服装 Continuous improvement program不断改进程序 M核anagement review of Annual trending of Personal monitoring data 管理审 年度人员监测数据趋势 March 2010 Page 68
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为Controls introduced and implemented by Production Management通过生产管理控制和执行 There should be an established maximum number of people allowed in the critical zone at any one time (specify in SOP)应规定在同一时间能被允许进入关键区域的最大人数（在SOP中规定） Total number of operators in the Change room during gowning穿戴洁净服时在更衣间的总人数 Inside the cleanroom during aseptic operation在无菌操作时洁净室里的人数March 2010 Page 69
Cleanroom Operator Qualification -Operator s Behavior洁净室操作人员资格-操作人员行为QA Audit for Aseptic Behavior and risk associated with various steps QA对以下环节的风险和无菌行为进行审计 Movement of personnel 人的运动 Handling of sterilized items 无菌项目的处理 Product component handling 产品组成部分的处理 Equipment set-up 设备安装 Equipment dismantling 设备卸载 Line clearance 生产线清洁 Storage of items 储存条目 Loading of vials on a tray 负载药品托盘 Loading of stoppers 负载胶塞 Cleaning and disinfecting techniques 清洁和消毒工艺 Items dropped on the floor (not be picked up)物品掉到地板上（未被拣起）March 2010 Page 70
483Compliance Issues 483 s483中存在的问题 Personnel in the aseptic filling room routinely touch non-sterile objects without re-sanitizing their hands. 无菌分装间人员触碰非无菌物体后未再消毒他们的手 Personnel observed reaching directly over open units awaiting filling.操作人员在封装时直接接触开口的产品 Level of personnel activity (number of people) 人员活动的水平（人员数量) Aseptic techniques not used 未使用无菌工艺 Sequence of Gowning 穿戴洁净服的顺序 Glove sanitization practices 手套消毒程序March 2010 Page 71
483Compliance Issues 483 s483中存在的问题 Failure to make aseptic connections under class 100 conditions.未在100级洁净级别条件下处理无菌连接 Failure to follow validated holding times for sterile tanks, equipment, components, gowns and sterile product.未根据验证过的时间来灭菌的灭菌罐，设备，部件，洁净服和无菌产品处理 Dust & dirt were observed on floors, pipes and equipment. Smudges were noted on walls and around door handles.地板，管道和设备上能观察到灰尘和污垢，墙上和门把上有污点 Dead insects were observed in overhead light fixtures in the filling room.在分装间的灯具上看到死的昆虫March 2010 Page 72
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