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1、CHINA ANNUAL CONFERENCE 16th 17th April 2012,Beijing,无菌工艺设计及风险控制ASEPTIC ENGINEERING AND RISK CONTROL,杨 军中国石化集团上海工程有限公司SINOPEC SHANGHAI ENGINEERING CO.,LTD.,2012 ISPE CHINA ANNUAL CONFERENCE,无菌 没有活体微生物存在。Aseptic No Viable Microbe Exists无菌药品-法定药品标准中列有无菌检查项目的制剂和 原料药，包括无菌制剂和无菌原料药。-摘自中国GMP（2010年修订）Asepti
2、c Drug Product The drug product which needs to be tested for their sterility by the legal standards,including aseptic formulation and APIs.-From Chinese GMP(2010),无菌药品的生产工艺Type of Manufacturing Process,按去除微生物方法的不同：Removing of microbe from product:最终灭菌工艺 Process with final sterilization非最终灭菌工艺 Proces
3、s without final sterilization,非最终灭菌工艺Process without final sterilizing,适用于产品不耐高温，不能采用通常的热力学方法最后进行灭菌以去除产品中的微生物。For those product which are thermal-sensitive and the microbe in it can not be removed by thermal sterilization.常用于冻干粉针、粉针、无菌原料药的生产。Normally used in manufacturing of freeze drying powders,as
4、eptic powdersand APIs 非最终灭菌工艺又称为无菌生产工艺。This process is also called Aseptic Processing,2012 ISPE CHINA ANNUAL CONFERENCE,无菌生产工艺的特点Characteristics of Aseptic Process,在无菌生产工艺中，产品、容器、密封件等分别经过灭菌后再进行灌装、封口，而液体产品则通过无菌过滤以去除微生物。由于产品装入最终容器后不再作进一步的灭菌处理，因此整个生产过程必须保证不被微生物所污染。All the product/container/closures are
5、 pre-sterilized All the product-liquid must be sterile filtered No further sterilization required after filling and closing Microbe contamination must be avoided during the whole processing,2012 ISPE CHINA ANNUAL CONFERENCE,无菌生产工艺设计的关键,无菌生产核心区的确定 Critical Area/Core Area,2012 ISPE CHINA ANNUAL CONFER
6、ENCE,什么是无菌生产核心区?What is Critical/Core Area,核心区就是无菌产品、容器、包装物及其产品接触的表面直接暴露在环境条件下的区域，该区域的设计必须保证产品的无菌度要求。(FDA/ISPE)A CRITICAL AREA is one in which the sterilized drugproduct,containers/closures or product contact surfacesare exposed to environmental conditions that must bedesigned to maintain product st
7、erility.(FDA/ISPE),如何确定无菌生产核心区？How to define the Critical/Core Area?,产品流向 Product Flows 容器/包装物流向 Container/Closure Flow 操作人员 Operators 工艺设备 Process Equipment（摘自ISPE 无菌生产指南）From ISPE Guideline of Sterile Manufacturing Facilities,2012 ISPE CHINA ANNUAL CONFERENCE,称量Weighing,配料Liq.Prep.,无菌过滤Sterile Fil
8、tration,灌装、半加塞Filling,Semi-Stopper,灭菌Sterilization,洗瓶、洗塞Washing,冻干、压塞Lyophilizing,轧盖Capping,贴签、包装Labeling&Packaging,成品Finished Goods,瓶、胶塞Vials,Stoppers,原辅料R.M.,例：无菌冻干粉针生产工艺 Typical LYO Process,2012 ISPE CHINA ANNUAL CONFERENCE,无菌冻干粉针工艺布置图 Typical Layout,瓶塞,原辅料,人员,人员,铝盖,成品,包装物流向,人员流向,物料流向,产品流向,包物流向,人
9、员流向,无菌冻干粉针生产人物流向分析 Operator and Material Flow for LYO Production,冻干生产核心区示意 Typical Core Area of LYO Production,无菌生产区 BAseptic Area,核心区 ACritical area,核心区 ACritical area,D,C,B,A,2012 ISPE CHINA ANNUAL CONFERENCE,无菌生产区的风险控制Risk Control of Aseptic Manufacturing Area,2012 ISPE CHINA ANNUAL CONFERENCE,无菌
10、生产风险类型The type of risks in Aseptic Manufacturing Area,尘埃粒子污染 Particles Contamination微生物污染 Microbe Contamination物料的交叉污染 Cross Contamination,2012 ISPE CHINA ANNUAL CONFERENCE,风险的来源 The Sources of Risk,空气 Air物料 Materials设备、器具 Equipment/Tools人员 Operators,2012 ISPE CHINA ANNUAL CONFERENCE,空气的处理 Air Treat
11、ment,室外空气中含有大量的微粒和微生物 Large amount of particles and microbe in atmosphere 空气必须经高效过滤 Air must be filtered with HEPA filter 无菌生产区的空气洁净等级必须满足GMP的要求 Clean air class in compliance with GMP principle,无菌药品生产环境的洁净度标准,The cleanliness standards of production area,无菌药品生产环境的微生物检测标准,The microbe standards of prod
12、uction area,2012 ISPE CHINA ANNUAL CONFERENCE,无菌生产区的气流组织、送风口和回（排）风口位置、相对邻近区域的压差等均需经过合理设计 Air flow pattern,Location of air outlets,Air pressure differences必须关注无菌生产区A级单向流的回风对B级环境气流的 影响 Minimizing the influence of return air flow of class A to air supply pattern of class B area尘埃粒子和微生物进行动态监控 Monitoring
13、 of particles and microbe in aseptic area,A级单向流罩回风位置的影响-顶回风,LF,气流短路,HEPA,Filling Room,传统单向流罩顶回风，有气流上升和短路现象,LF 顶回风,上升气流,A,B,LF,Return Air,HEPA,Return Air,Filling Room,侧下回风，B级气流全部顶送下回，无短路和上升气流现象,A级单向流罩回风位置的影响-下侧回风,粒子在线监控点Particle Monitoring,粒子监控点Monitoring Point,粒子监控点Monitoring Point,2012 ISPE CHINA A
14、NNUAL CONFERENCE,物料的控制 Material Control,无菌区的物料 Materials in Sterile Area原料、辅料 Raw and aux.materials内包装材料（小瓶、胶塞）Packaging materials direct contact with sterile product(vials,stoppers)工艺用水及气体 Process water and gas成品 Finished goods生产废品 Wastes during production,2012 ISPE CHINA ANNUAL CONFERENCE,物料所致的污染M
15、aterial Contamination 物料本身未经过彻底灭菌/除菌处理 Materials not thoroughly sterilized/filtered 物料进出无菌生产区的传递过程 Pass way through aseptic area(in/out)物料间的相互交叉污染 Cross contamination,2012 ISPE CHINA ANNUAL CONFERENCE,液体物料必须经过除菌过滤 Liquid materials must be filtered 无菌物料暴露操作必须在A级保护下进行 Class A protection for the expose
16、d operation of product 无菌区必须采用注射用水 Only the WFI allowed into aseptic area 环境消毒液必须采用注射用水配制，并经除菌过滤 Disinfectant must be prepared by WFI and be filtered before use,物料的控制 Material Controls,2012 ISPE CHINA ANNUAL CONFERENCE,进入无菌区的物料外包装必须彻底消毒 A proper sterilization of the product packaging is needed 无菌区所用
17、的气体必须无菌过滤 All process gas must be filtered 无菌区内成品和废品必须采用可靠方法运出 A proper way out of finished goods/waste from aseptic area 生产完毕，所有与物料直接接触的设备、器具必须经过 彻底清洗、灭菌，防止物料残留引起交叉污染 A proper cleaning and sterilizing of equipment/closure contacting with the materials is required after production,2012 ISPE CHINA AN
18、NUAL CONFERENCE,无菌区物料的运出 Goods out,A级保护Class A,成品的运出-1：传送带+单向流保护 Chain+Class A,无菌区,B,传送带分段,正压气流,A级保护,灭菌前室,P,成品的运出-2：缓冲+传递柜Buffer Area+Pass Box,无菌区,灭菌前室,正压气流,传递柜,HEPA,P,B,缓冲,成品的运出-3：单向流传递柜Pass Box with Class A,正压气流,带层流传递柜,无菌区,B,灭菌前室,P,成品的运出-4 不建议采用气锁方式Buffer is not suggested,HEPA,正压气流,无菌区,B,有交叉污染风险,气
19、锁,灭菌前室,2012 ISPE CHINA ANNUAL CONFERENCE,操作人员的风险控制Risk Control of Operators,操作人员的风险The Risk of Operators,操作人员身上会散发大量的微粒 Large particles from operator操作人员散发的微粒含有大量的微生物 The particles are viable with microbe,操作人员是无菌生产区内的最大污染源，也是最难控制的污染源 The Operators are the largest sources of pollutions in aseptic are
20、aand very difficult to control,2012 ISPE CHINA ANNUAL CONFERENCE,操作人员的控制 Operators Control,人员在无菌区的操作站位和行为Position and action of operators in aseptic area人员的正确更衣程序Gowning procedures,2012 ISPE CHINA ANNUAL CONFERENCE,人员位置和动作 Positions and Actions,人员位于核心区下风向 Position and action of operators in aseptic
21、area 使用灭菌工具，避免直接干预 No direct intervene to process,use tools 行为缓慢，避免剧烈动作造成微粒和微生物增加 Slowly moving，no strong action to increase particles and microbe,2012 ISPE CHINA ANNUAL CONFERENCE,操作人员的控制 Operators Control,操作人员的正确更衣程序Gowning procedures,GMP 对净化更衣的条款 GMP Requirement for Gowning,中国GMP（2010年修订）对操作人员进出洁
22、净区域的更衣控制，制定了许多具体的要求（新版GMP附录1：无菌药品，第19条第27条、第30条）Chinese GMP(2010)Requirement for Gowning(Annex 1,items 19-27,30),第三十条 应当按照气锁方式设计更衣室，使更衣的不同阶段分开，尽可能避免工作服被微生物和微粒污染。更衣室应当有足够的换气次数。更衣室后段的静态级别应当与其相应洁净区的级别相同。必要时，可将进入和离开洁净区的更衣间分开设置。一般情况下，洗手设施只能安装在更衣的第一阶段。,Changing rooms should be designed as air lock,in orde
23、r to separate its differentstages.A suitable air change rate is required.The grade of final stage in rest shouldbe same as the area into which it leads.A separate area changing area for enteringand leaving are required in some cases.In general hand washing facilities should beonly provided at its fi
24、rst stage of changing room.,GMP关于洁净更衣的要点：Key Points of Gowning by GMP,更衣分段 Different Gowning Area气锁设计 Air Lock Design更衣分级 Classification退出通道 Leaving Way,更衣分段 Different Gowning Area,以进入无菌区为例，更衣程序一般分为：换鞋-脱外衣-洗手-穿无菌内衣-手消毒-穿无菌外衣-手消毒 Gowning Procedure:Shoes Changing-Overcoat removing-hands washing-steril
25、e underwear-hands disinfection-sterile overcoat-hands disinfection,前段“换鞋-脱外衣-洗手-穿无菌内衣”属于相对“污”First steps:Shoes Changing-Overcoat removing-hands washing-sterile underwear“Dirty”后段“穿无菌外衣-手消毒”，属于相对“洁”Second Steps:sterile overcoat-hands disinfection“Clean”洁净更衣的核心是“污”和“净”分离，以避免干净的 工作服在更衣过程中被微生物和微粒污染。Two
26、gowning steps must be separate,气锁设计 Air Lock Design,更衣前后段要分开设置，不在同一个区域内，并且穿洁净衣房间按气锁设计，连锁门和压差控制。Air lock design for gowning room with door interlock and pressure control由于按气锁设计，且静态级别与生产区一致，因此更衣最后的缓冲间可以取消（某些情况下由于男女更衣室布置需要，可以保留，但不是必须)。Buffer room after 2nd gowning not required,更衣分级 Clean Class for Gown
27、ing,更衣后段的洁净级别，与其服务的洁净生产区的静态级别相一致（无动态要求）Clean class of 2nd gowning room is equal to production area at rest更衣前段不定级，但需送入经过 HEPA 过滤的洁净空气，有一定的换气次数（可视所服务的生产区级别的不同，分别参照C级或D级标准设计），但不定级。前段和后段之间要保持合理的气流流向和压差。Clean air is preferred for 1st gowning area,with reliable air pattern and pressure different controls
28、,退出通道 Leaving Way,GMP第30条要求：必要时，可将进入和离开洁净区的更衣间分开设置。Entering/Leaving changing rooms can be separately if necessary 什么是必要时？What is necessary?退出时衣服上所带微粒和微生物污染洁净更衣区 Change room may be contaminated by the particles and microbe with the clothes生产操作产生的有害物质通过更衣区外溢；To avoid polluted air blow out from process
29、 area,要考虑的因素 Considerations:产品特点（致敏、强效、毒性、活菌）Characteristics of product(susceptibility,high potent,toxic,viable)空气污染情况(粉尘散发严重)Air pollution(dust)无菌区操作人员数量 vs.更衣空间大小 The number of operator vs.space of changing area 人员进出洁净区频率 Frequency of enter/leaving clean area,无菌生产区（风险分析结果需要设置的）Aseptic area(if nece
30、ssary required)含活菌、活毒类生物制品生产区 Bio-pharmaceutical area with Viable and Toxic特殊药品生产区（高致敏、高活性、激素、毒性类）Special drug manufacturing area(susceptibility/high potent/hormone/toxic)粉尘散发严重的生产区 Dust release production为防止有害物质通过更衣区溢出，需设置正/负压气锁 Where positive/negative air lock is required,传统更衣设计 Traditional Gownin
31、g Layout,男脱外衣,换鞋,气锁/手消毒,女脱外衣,无菌内衣,洗手,无菌外衣,无菌外衣,洗手,无菌生产区 B,无菌内衣,换鞋-脱衣-洗手-穿无菌内衣-手消毒-穿无菌外衣-手消毒一个步骤一个房间，比较烦琐,I,I,门连锁 Interlock,洁净更衣设计举例（1）-普通区进入C级区Gowning room to C area,气流方向Air Flow,门连锁 Interlock,50,洁净更衣举例-（2）(带退出通道）Gowning room to B area w/return pass,门连锁 Interlock,退出通道R.Pass,洁净更衣举例（3）-普通区-C级-B级区Gowni
32、ng room:Normal Area-C-B,门连锁 Interlock,洁净更衣举例（4）-特殊药品生产区更衣设计 Gowning room for high patent production,正压气锁,负压气锁,换鞋/脱外衣,穿无菌内衣,穿无菌外衣,退出更衣,缓冲,衣服灭菌存放,洗衣 D级,穿洁净衣/洗手,灭菌柜,B级无菌生产区,整衣台,洁净洗衣房的设计 Clean Laundry Design,洗手,结论 Conclusion,无菌工艺设计的关键 Critical Points to Sterile Process Design正确认识无菌生产工艺的特殊性 The Specialists of Aseptic Processing寻找影响无菌产品质量的风险所在 Risks during production采取相应措施避免或降低风险的发生 Correct measurement avoiding risks,本次交流引用的参考资料：中国GMP(2010年修订)，附录1：无菌药品 欧盟GMP 第四卷，附录1：无菌药品的生产，FDA 工业指南-用无菌工艺生产的无菌药品，2004.10ISPE 基本指南3：无菌药品生产设施，1999ISPE 实施指南-HVAC,2008中国药品GMP指南，2011,欢迎提出意见和建议谢谢！Thank You,
