Water Systems水系统知识专题讲座(ppt 55页).ppt

1、2020年8月14日,Water Systems 水系统 知识讲座 九新药业国际认证部经理 高级工程师 徐影,To examine the basic technology and requirements for: 检查以下方面的基本技术和要求： 1) Water treatment systems 水处理系统 2) Storage requirements 贮存要求 3) Sampling and testing 取样和检测 4) Different types of water used in pharmaceuticals 制药用水的不同类型 5) Microbial limits,

2、disinfection 微生物限度、消毒,Objectives目的,C&Q -V-Model VV,URS 用户需求,URS FDS DQSAT IQ OQ,Water system design 水系统的设计 1) Pipes sloped so water does not pool and can drain easily 管道要有斜度，以防止积水，易于排空 2) Sanitary fittings & connections 洁净配件和接口 3) Constructed of suitable materials such as stainless steel 建造材料适合，如不锈钢

3、 4) Circulate the water 水要循环,Further water treatment purification stages downstream of the pre-treatment system 预处理系统后水的进一步纯化 1) Filtration 过滤 2) Disinfection 消毒 3) Reverse osmosis or de-ionization 反渗透或去离子 4) Distillation or ultra-filtration 蒸馏或超滤,There should be no dead legs 不应有死角,Water system desi

4、gn (1)水系统设计（一）,3. The water is contaminated as it passes through the valve 当水通过阀门时，被污染,2. Bacteria can grow when the valve is closed 当阀门关闭时，会生长细菌,1. Ball valves are unacceptable 不可使用球阀,Stagnant water inside valve 阀门中的死水,Water system design (2)水系统设计（二）,1) Sanitary pumps 洁净泵 2) Clamps and O rings vers

5、us threaded fittings 卡箍和O环，不用螺纹配件 3) Heat exchangers 换热器 4) Side arm level measuring devices are unacceptable 不可使用边侧 臂状水位测量装置,Water system design (3)水系统设计（三）,Reverse osmosis (RO) theory 反渗透（RO）原理,Branch,Branch,Cartridge filter 1 m,Second stage RO cartridge,First stage filtrate feeds second stage RO

6、with excess back to 1st stage buffer tank,.,1st stage reject concentrate,Air break to sewer,Second stage reject water goes back to first stage buffer tank,Second stage RO water meets Pharmacopoeia standards,Water from softener or de-ioniser,Typical 2-stage RO schematic 典型二级反渗透示意图,Hygienic pump,High

7、pressure pump,Advantages 优点 Disadvantages 缺点 Many uses 应用领域 purified water 纯化水 feeding of distillation units or ultra-filtration units 蒸馏器或超滤器的进水 Water for Final Rinse 最终冲洗用水 Water for Injections (if permissible) 注射用水（如许可）,Use of reverse osmosis 反渗透的应用,Can be used for WFI or for Water For Final Rins

8、ing for parenteral manufacturing (if permitted) 可用作注射用水或生产注射剂的最终冲洗用水（如许可） Removes organic contaminants, such as endotoxins 去除有机污染物，如内毒素 Operation at 65 - 80C, and sterilization at 121C 在65 - 80C下运行，在121C进行灭菌,Ultra-filtration 超滤,Single-effect distillation 单效蒸馏 simple distillation, single effect 简单蒸馏，

9、单效 vapour compression, thermo compression 蒸汽压缩，热压缩 Multi effect distillation 多效蒸馏 multiple effect stills 多效蒸馏机,Distillation 蒸馏,Still,Storage tank,Pump,Ball valves,0.22um filter,Plate heat exchanger,KEY,Still,Storage tank,Pumps,T,C,TOC,Diaphragm valves,T - Temp probe C- Conductivity TOC - Total Organ

10、ic Carbon,Double tube sheet heat exchanger,KEY,Spray ball,Back Pressure Regulator,Water systems design水系统设计,Check检查,Why?,How,Feed Water Quality 进水质量,Subsequent treatment stages cannot cope with unrestricted microbial and endotoxin load 其后的处理阶段无法处置未受限制的微生物和内毒素负荷,Connections 连接,Sampling 取样,Minimal cre

11、vices 最小裂缝,Inspection 检查,Water systems design水系统设计,Check检查,Why?,How,Finishes 抛光,Reduce bacterial adhesion 减少细菌粘着,Pipe slopes 管道倾斜度,Certification证书,Drain ability especially of condensate after steam sanitising 排水性,尤其是蒸汽消毒后的冷凝水,Inspection检查 spirit level水平仪 Isometrics等容法,Water systems design水系统设计,Check

12、检查,Why?,How,To produce unfavourable conditions for microbial growth and attachment 制造不利于微生物生长和附着的条件,Sanitisation 消毒,Flow meter 流速计,Records记录,Velocity in loop 回路中流速,For control of microbial proliferation and in response to problems 控制微生物繁殖,解决问题,Water systems design水系统设计,Check,Why?,How,Not “reactive,

13、additive or absorptive” 不产生反应,添加或吸附,Instruments 仪器,Certificates 证书,Certificates证书 Inspection检查,Materials of construction材质,Calibrated已校正 Sanitary清洁,Water systems design水系统设计,Check,Why?,How,Minimal crevices 最小裂缝,Passivation 钝化,Documentation (Welders Qualification, weld logs) Sample welds,Weld inspect

14、ion 文件 (焊接工资质确认,焊接日志) 焊接取样, 焊接检查,Documentation (Procedures, Passivation log) 文件 (规程,钝化日志),Welding 焊接,Maximum corrosion resistance 最大耐受腐蚀 性,Water Systems design,Check,Why?,How,Demonstration of consistent ability to produce water of right quality 证实有持续产生高品质水的能力,Master Plan, 验证主计划 Protocols, 验证方案 summa

15、ry reports 总结报告,Validation 验证,Heat 热 -One of the most reliable methods of disinfection of water systems 最可靠的消毒水系统的方法之一 Ozone 臭氧 -Produced easily 容易制备 -Leaves no residue 没有残留,Disinfection (1) 消毒（一）,UV 紫外 -UV does not “sterilize” 紫外不可灭菌 -Flow rate critical 流速很关键 -Post-irradiation recontamination may b

16、e an issue 后放射再污染可能是个问题 -Lamps have finite life 灯的寿命有限 Other chemicals 其他化学法 -XO2 -Halogen 卤素 -Formaldehyde 甲醛,Disinfection (2) 消毒（二）,There must be a sampling procedure 必须有取样规程 Sample integrity must be assured 必须保证样品的完整性 Sampler training 取样人培训 Sample point 取样点 Sample size 取样多少,Sampling (1) 取样（一）,Sam

17、ple container 取样容器 Sample label 样品标签 Sample storage and transport 样品储存和转移 Arrival at the laboratory 到达实验室 Start of test 开始测试,Sampling (2) 取样（二）,Testing - setting specifications for purified water or WFI测试 规定纯化水或注射用水标准,Purified Water纯化水 Ph. Eur. 中国药典（2005） USP Nitrates硝酸盐 0.2ppm 0.06ppm - Conductivit

18、y电导率 5.1S/cm25oC - 1.3S/cm25oC TOC 0.5mg/l - 0.5mg/l Heavy metals重金属 0.1ppm 0.5ppm - Microbia微生物 100cfu/ml 100cfu/ml 100cfu/ml,Testing - setting specifications for purified water or WFI测试 规定纯化水或注射用水标准,WFI注射用水 Ph. Eur. 中国药典（2005） USP Nitrates硝酸盐 0.2ppm 0.06ppm - Conductivity电导率 1.3S/cm25oC - 1.3S/cm2

19、5oC TOC 0.5mg/l - 0.5mg/l Microbial微生物 10cfu/100ml 10cfu/100ml 10cfu/100ml Endotoxin内毒素 0.25IU/ml 0.25EU/ml 0.25EU/ml,Suggested bacterial limits for Purified Water (CFU /mL) 建议的微生物限度 纯化水（CFU/ml）,The action limit is the EU guidance limit (where provided) If no guidance is given, when you have histori

20、cal data you can set action limit at 3 Standard deviations from mean. The alert limit is set at 2 SD from mean. 如果没有给出指导值，可采用EU指南的限度(前面提到的）做为行动限。如果有历史数据，可以将行动限定为 3倍的平均值的标准偏差，警戒限定为2倍的平均值的标准偏差,Action and Alert Limits 行动限和警戒限,Example (Purified Water User Points) 56 53 44 55 65 45 33 50 56 57 46 55 59 4

21、3 56 44 54 59 58 61 Mean = 52.45 Standard deviation is 7.73 2SD = 15.46 3SD = 23.19 Alert limit (mean plus 2SD) = 68 Action limit (mean plus 3SD) = 76 Action limit (regulatory guidance) = 100,Microbiological Monitoring微生物监测,2020年8月14日星期五,34,Methodologies that can be recommended as generally satisfac

22、tory for microbiological monitoring pharmaceutical water system are as follows水系统微生物监测的推荐方法: Purified Water纯化水 Pour Plate Method平皿法 Minimum sample 1.0 ml. 最小取样量1.0毫升 Plate count agar 48 to 72 hours incubation 培养基 培养48-72小时 Water for Injection注射用水 Membrane Filtration Method薄膜过滤法 Minimum sample 100 ml

23、. 最小取样量100毫升 Plate count agar 48 to 72 hours incubation 培养基 培养48-72小时,Method verification 方法确认 Chemical testing 化学测试 Microbiological testing 微生物测试 test method 测试方法 types of media used 使用的培养基类型 incubation time and temperature 培养时间和温度 objectionable and indicator organisms 异议和指示有机体 dont understand manu

24、facturer must set specifications 生产商必须制定标准,Testing 检测,International pharmacopoeia requirements for WFI are those for purified water plus it must be free from pyrogens 国际药典对注射用水的要求除了那些对纯化水的要求外，还要求必须不含有热源 Usually prepared by distillation 通常由蒸馏器制得 Storage time should be less than 24 hours 储存时间应少于24小时 M

25、icrobial limits must be specified 必须制定微生物限度,Water for Injections 注射用水,Water for final rinse must be of the same quality as the water required for pharmaceutical preparation 最终冲洗用水的质量必须与药品制备所要求的水的质量相同,Water for Final Rinse 最终冲洗用水,Any compound injected into mammals which gives rise to fever is a “Pyro

26、gen” 任何注入哺乳动物体内可引起发烧的物质称为“热源” Endotoxins are pyrogenic, come from Gram negative bacterial cell wall fragments 内毒素具有热源性，来源于革兰阴性菌细胞壁 Detect endotoxins using a test for lipopolysaccharides (LPS) 检测内毒素使用脂多糖的测试 rabbit test detects pyrogens 兔子试验检测热源 LAL test detects endotoxins 鲎试剂检测内毒素 Ultrafiltration, di

27、stillation, & RO may remove pyrogens 超滤、蒸馏和反渗透可能会去除热源,Pyrogens and endotoxins 热源和内毒素,Trending趋势分析,Describe the microbiological problems of this WFI system.描述注射用水系统的微生物问题,Counts are total number of Colony Forming Units per 100ml,Action,Alert,SOPs,SOPs should address SOPs中应包括以下内容: Operation and routin

28、e monitoring操作和日常监控 Maintenance and calibration 维护和校正 Cleaning and sanitization 清洁和消毒 Validation 验证,2020年8月14日星期五,42,Operation and Routine Monitoring 运行和日常监控,Describe system (generating components, number of loops, materials, control system) 系统描述（制备系统组件，循环的数量，物料，控制系统） List users 列明使用点 List requireme

29、nts for system e.g.:列明系统要求，例如： Generating capacity 制备能力 Storage capacity 储存容量 Diversity (how many points of use can be opened simultaneously) 差异性 （可以同时开启几个使用点） Flow rate 流速 Temperature 温度 Specifications for water quality at each stage 每个阶段的水质标准,2020年8月14日星期五,43,Operation and Routine Monitoring 运行和日常

30、监控,Describe system operation including:系统的运行描述包括 System start up 系统启动 System shut down 关机 Emergency shutdown 紧急停机 Normal operations 正常运行 Monitoring during routine operation 日常运行的监控 Describe sampling activities 描述取样活动 At each purification stage (type of tests, frequency acceptance criteria)在每一步纯化阶段（监

31、测类型，频次，接受标准） pH, Conductivity, TOC, Chlorine, Microbial, Endotoxin etc Response to OOS OOS应对,2020年8月14日星期五,45,Maintenance and Calibration维护和校正,Routine inspection and maintenance activities carried out:进行的日常检查及维护活动 Daily 每日 Weekly 每周 Monthly 每月 Annually 每年 Trigger events (e.g. after observation of a

32、specific condition) “触发”事件 （例如，观察到特殊状况） Include procedure, acceptance criteria, forms包括规程，接受限度，表格,2020年8月14日星期五,46,Maintenance and Calibration 维护和校正,Periodic Calibration activities carried out:应进行定期校正，包括 List instruments make, model 仪器清单-厂家，型号 Range 范围 Tolerance 限度 Criticality 重要性 Time interval betw

33、een calibration 频次 If carried out by contractor, refer to SOP for control of third parties 如果由合同商校正，应参照第三方管理SOP If carried out in house, ensure there are individual SOPs for calibration procedures如果内部校正，确保每个校正规程有单独的SOP,2020年8月14日星期五,47,Cleaning and sanitization清洁和消毒,Describe cleaning and sanitizatio

34、n activities for each component:描述每个组件的清洁和消毒活动 Methods 方法 Chemicals used 使用的化学物质 Frequency 频次 Duration 持续时间 Chemical concentration/temperature 化学浓度/温度,2020年8月14日星期五,48,Cleaning and sanitization 清洁和消毒,Describe cleaning and sanitization activities required after shutdown 描述系统停机后需要的清洁和消毒 Define maximum

35、 duration of shutdown permitted before sanitization is required 定义系统停机后最长多久需要消毒 Define other events that require sanitization prior to use of water (e.g. opening loop, contamination etc)定义使用前，哪些情况需要消毒 （例如，敞开的循环，污染等） Define duration of monitoring after shutdown or unusual events 定义关闭或非正常情况下需要监控的时间,20

36、20年8月14日星期五,49,Validation 验证,Describe company policy and practices for validating water systems 描述公司方针和水系统验证活动 Duration of monitoring 监控时间 Sampling locations 取样位置 Types of testing 监测类型 Requirements for revalidation 再验证要求 SOP will not describes specific system or activities, this will be in Project s

37、pecific VMP and Protocols. SOP provides guidance to those writing the project specific documents SOP中不会描述具体的系统或活动，而应是每个项目的验证主计划和方案中的内容。SOP为编写具体项目验证文件提供指导,2020年8月14日星期五,50,Validation验证,Initial phase 初始阶段 During this phase the operational parameters and the cleaning/ sanitization procedures and freque

38、ncies will be developed. Sampling should be daily after each step in the purification process and at each point of use for two to four weeks. The sampling procedure for point of use sampling should reflect how the water is to be. At the end of the two to four week time period the firm should have developed its SOPs for operation of the water system.在此阶段,会制订操作参数和清洁/消毒规程和频率。2-4周内，在纯化过程的每一步，以及在每一个使用点，应每日取样。取样点的取样规程应反映水的质量。2-4周结束时，公司应制订出水系统操作的SOP。,2020年8月14日星期五,51,Validation验证,第二阶段 -The second phase of the system validation is to demonstrate that t