水系统培训教学课件

华润医药集团有限公司To examine the basic technology and requirements for:检查以下方面的基本技术和要求：检查以下方面的基本技术和要求：1)Water treatment systems 水处理系统水处理系统 2)Storage requirements 贮存要求贮存要求 3)Sampling and testing 取样和检测取样和检测 4)Different types of water used in pharmaceuticals 制药用水的不同类型制药用水的不同类型 5)Microbial limits,disinfection 微生物限度、消毒微生物限度、消毒Objectives目的华润医药集团有限公司C&Q-V-Model VV华润医药集团有限公司URS用户需求URS FDS DQSAT IQ OQ华润医药集团有限公司Water system design 水系统的设计水系统的设计 1)Pipes sloped so water does not pool and can drain easily 管道要有斜度，以防止管道要有斜度，以防止积水，水，易于排空易于排空 2)Sanitary fittings&connections 洁净配件和接口配件和接口 3)Constructed of suitable materials such as stainless steel 建造材料适合，如不建造材料适合，如不锈钢 4)Circulate the water 水要循水要循环华润医药集团有限公司Further water treatment purification stages downstream of the pre-treatment system预处理系统后水的进一步纯化预处理系统后水的进一步纯化 1)Filtration 过滤过滤 2)Disinfection 消毒消毒 3)Reverse osmosis or de-ionization 反渗透或去离子反渗透或去离子 4)Distillation or ultra-filtration 蒸馏或超滤蒸馏或超滤华润医药集团有限公司There should be no dead legs不应有死角Water scours deadlegIf D=25mm&distance X isgreater than 75mm,we havea dead leg that is too long.如果如果D=25mm，X大于大于75mm，则有较长的死角则有较长的死角Deadleg section死角部分死角部分3DFlow direction arrows on pipes are important管道中的流向很重要管道中的流向很重要Sanitary Valve洁净阀洁净阀DXWater system design(1)水系统设计（一）华润医药集团有限公司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）华润医药集团有限公司1)Sanitary pumps 洁净泵洁净泵2)Clamps and O rings versus threaded fittings 卡箍和卡箍和O环，不用螺纹配件环，不用螺纹配件3)Heat exchangers 换热器换热器4)Side arm level measuring devices are unacceptable 不可使用边侧不可使用边侧 臂状水位测量装置臂状水位测量装置Water system design(3)水系统设计（三）华润医药集团有限公司raw water原水High pressure高压高压Feed water Under pressure加压进水加压进水RejectWater不合格水不合格水Semi-permeableMembrane半渗透膜半渗透膜PermeateWater渗透水渗透水drain or recycle排放或循环排放或循环Low pressure低压低压Purified water纯化水纯化水Reverse osmosis(RO)theory反渗透（反渗透（RO）原理）原理华润医药集团有限公司Cationic columnAnionic columnHygienic pump卫生泵卫生泵Outlets or storage.Ozone generatorUV lightHClNaOHEluates toneutralizationplantAir break to sewer空气断开空气断开 Drain linefrom water softener软水机软水机Water must be kept circulatingTypical de-ionizer schematic典型的去离子示意图典型的去离子示意图123456123456Return to de-ioniserCartridgefilter 5 mCartridgefilter 1 m华润医药集团有限公司BranchBranchCartridgefilter 1 mSecond stage RO cartridge First stage filtrate feeds second stage RO with excess back to 1st stage buffer tank.1st stage reject concentrateAir breakto sewer Second stage reject water goes back to first stage buffer tank Second stage RO watermeets Pharmacopoeiastandards1st stage buffer tank Water from softener or de-ioniser Typical 2-stage RO schematic典型二级反渗透示意图典型二级反渗透示意图 Hygienic pumpFirst stage RO cartridgeHigh pressure pump华润医药集团有限公司Advantages 优点优点Disadvantages 缺点缺点Many uses 应用领域应用领域purified water 纯化水纯化水feeding of distillation units or ultra-filtration units 蒸馏器或超滤器的进水蒸馏器或超滤器的进水Water for Final Rinse 最终冲洗用水最终冲洗用水Water for Injections(if permissible)注射用水（如许可）注射用水（如许可）Use of reverse osmosis反渗透的应用反渗透的应用 华润医药集团有限公司Can be used for WFI or for Water For Final Rinsing 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）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，如内毒素去除有机污染物，如内毒素Operation at 65-80C,and sterilization at 121C 在在65-80C下运行，在下运行，在121C进行灭菌进行灭菌Ultra-filtration超滤超滤 华润医药集团有限公司Single-effect distillation 单效蒸馏单效蒸馏simple distillation,single effect 简单蒸馏，单效简单蒸馏，单效 vapour compression,thermo compression 蒸汽压缩，热压缩蒸汽压缩，热压缩Multi effect distillation 多效蒸馏多效蒸馏 multiple effect stills 多效蒸馏机多效蒸馏机Distillation 蒸馏蒸馏华润医药集团有限公司Typical water storage and distribution schematic典型的水贮存和分配示意图典型的水贮存和分配示意图Water must be kept circulatingSpray ballCartridgefilter 1 mAir breakto drainOutletsHygienic pumpOptionalin-line filter0,2 mUV lightFeed Water fromDI or ROHeat ExchangerOzone GeneratorHydrophobic air filter&burst disc 疏水性呼吸过滤器疏水性呼吸过滤器&安全隔膜安全隔膜华润医药集团有限公司StillStorage tankPumpBall valves0.22um filterPlate heat exchangerKEY华润医药集团有限公司StillStorage tankPumpsT CTOCDiaphragm valvesT-Temp probeC-ConductivityTOC-Total Organic CarbonDouble tube sheet heat exchangerKEYSpray ballBack Pressure Regulator华润医药集团有限公司Water systems design水系统设计Check检查Why?HowFeed 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 crevices最小裂缝Inspection检查华润医药集团有限公司Water systems design水系统设计Check检查Why?HowFinishes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等容法华润医药集团有限公司Water systems design水系统设计Check检查Why?HowTo 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,解决问题华润医药集团有限公司Water systems design水系统设计CheckWhy?HowNot“reactive,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清洁华润医药集团有限公司Water systems design水系统设计CheckWhy?HowMinimal crevices最小裂缝Passivation钝化Documentation(Welders Qualification,weld logs)Sample welds,Weld inspection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最大耐受腐蚀性华润医药集团有限公司Water Systems designCheckWhy?HowDemonstration 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 summary reports总结报告Validation验证华润医药集团有限公司Heat 热热 -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最可靠的消毒水系统的方法之一Ozone 臭氧臭氧-Produced easily 容易制备容易制备-Leaves no residue 没有残留没有残留Disinfection(1)消毒（一）消毒（一）华润医药集团有限公司UV 紫外紫外-UV does not“sterilize”紫外不可灭菌紫外不可灭菌-Flow rate critical 流速很关键流速很关键-Post-irradiation recontamination may be an issue后放射再污染可能是个问题后放射再污染可能是个问题-Lamps have finite life灯的寿命有限灯的寿命有限Other chemicals 其他化学法其他化学法-XO2-Halogen卤素卤素-Formaldehyde甲醛甲醛Disinfection(2)消毒（二）消毒（二）华润医药集团有限公司There must be a sampling procedure必必须有取有取样规程程Sample integrity must be assured必必须保保证样品的完整性品的完整性Sampler training取取样人培人培训Sample point 取取样点点Sample size取取样多少多少Sampling(1)取样（一）取样（一）华润医药集团有限公司Sample container 取取样容器容器Sample label样品品标签Sample storage and transport样品品储存和存和转移移Arrival at the laboratory 到达到达实验室室Start of test开始开始测试Sampling(2)取样（二）取样（二）华润医药集团有限公司Testing-setting specifications for purified water or WFI测试 规定纯化水或注射用水标准Purified Water纯化水纯化水 Ph.Eur.中国药典中国药典（2019）USPNitrates硝酸盐 0.2ppm 0.06ppm -Conductivity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华润医药集团有限公司Testing-setting specifications for purified water or WFI测试测试 规定纯化水或注射用水标准规定纯化水或注射用水标准WFI注射用水注射用水 Ph.Eur.中国药典中国药典（2019）USPNitrates硝酸盐 0.2ppm 0.06ppm-Conductivity电导率 1.3S/cm25oC -1.3S/cm25oC TOC 0.5mg/l -0.5mg/lMicrobial微生物 10cfu/100ml 10cfu/100ml 10cfu/100mlEndotoxin内毒素 0.25IU/ml 0.25EU/ml 0.25EU/ml华润医药集团有限公司Suggested bacterial limits for Purified Water(CFU/mL)建议的微生物限度建议的微生物限度 纯化水纯化水（CFU/ml）Sampling location取样位置取样位置Alert报警限报警限Action行动限行动限Raw water 原水原水300500Post multimedia filter多介质过滤器后多介质过滤器后300500Post softener 软化剂后软化剂后300500Post activated carbon filter活性炭后活性炭后300500Feed to RO 回水至回水至RO200500RO permeate RO渗透渗透50100Points of Use 使用点使用点10100华润医药集团有限公司The action limit is the EU guidance limit(where provided)If no guidance is given,when you have historical 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 行动限和警戒限华润医药集团有限公司Example(Purified Water User Points)56 53 44 55 65 45 33 50 56 57 46 55 59 43 56 44 54 59 58 61 Mean=52.45Standard deviation is 7.732SD=15.463SD=23.19Alert limit(mean plus 2SD)=68Action limit(mean plus 3SD)=76Action limit(regulatory guidance)=100Microbiological Monitoring微生物监测华润医药集团有限公司02 七月七月 202433Methodologies that can be recommended as generally satisfactory for microbiological monitoring pharmaceutical water system are as follows水系统微生物监测的推荐方法水系统微生物监测的推荐方法:Purified Water纯化水纯化水 Pour Plate Method平皿法平皿法 Minimum sample 1.0 ml.最小取样量最小取样量1.0毫升毫升 Plate count agar 48 to 72 hours incubation 培养基培养基 培养培养48-72小时小时 Water for Injection注射用水注射用水 Membrane Filtration Method薄膜过滤法薄膜过滤法 Minimum sample 100 ml.最小取样量最小取样量100毫升毫升 Plate count agar 48 to 72 hours incubation 培养基培养基 培养培养48-72小时小时华润医药集团有限公司Method verification方法确认方法确认Chemical testing化学测试化学测试Microbiological testing微生物测试微生物测试test method测试方法测试方法types of media used使用的培养基类型使用的培养基类型incubation time and temperature培养时间和温度培养时间和温度objectionable and indicator organisms异议和指示有机体异议和指示有机体 dont understandmanufacturer must set specifications生产商必须制定标准生产商必须制定标准Testing 检测检测 华润医药集团有限公司International pharmacopoeia requirements for WFI are those for purified water plus it must be free from pyrogens国国际际药药典典对对注注射射用用水水的的要要求求除除了了那那些些对对纯纯化化水水的的要要求求外外，还要求必须不含有热源还要求必须不含有热源Usually prepared by distillation 通常由蒸馏器制得通常由蒸馏器制得Storage time should be less than 24 hours储存时间应少于储存时间应少于24小时小时Microbial limits must be specified必须制定微生物限度必须制定微生物限度Water for Injections 注射用水注射用水 华润医药集团有限公司Water for final rinse must be of the same quality as the water required for pharmaceutical preparation最最终终冲冲洗洗用用水水的的质质量量必必须须与与药药品品制制备备所所要要求求的的水的质量相同水的质量相同Water for Final Rinse最终冲洗用水最终冲洗用水 华润医药集团有限公司Any compound injected into mammals which gives rise to fever is a“Pyrogen”任何注入哺乳任何注入哺乳动物体内可引起物体内可引起发烧的物的物质称称为“热源源”Endotoxins are pyrogenic,come from Gram negative bacterial cell wall fragments 内毒素具有内毒素具有热源性，来源于革源性，来源于革兰阴性菌阴性菌细胞壁胞壁Detect endotoxins using a test for lipopolysaccharides(LPS)检测内毒素使用脂多糖的内毒素使用脂多糖的测试rabbit test detects pyrogens兔子兔子试验检测热源源LAL test detects endotoxins鲎试剂检测内毒素内毒素Ultrafiltration,distillation,&RO may remove pyrogens超超滤、蒸、蒸馏和反渗透可能会去除和反渗透可能会去除热源源Pyrogens and endotoxins热源和内毒素热源和内毒素 华润医药集团有限公司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华润医药集团有限公司Counts are total number of Colony Forming Units per 100ml华润医药集团有限公司ActionAlert华润医药集团有限公司SOPsSOPs should address SOPs中应包括以下内容:Operation and routine 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02 七月七月 202441华润医药集团有限公司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 requirements 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02 七月七月 202442华润医药集团有限公司华润医药集团有限公司Operation and Routine Monitoring 运行和日常监控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（监测类型，频次，接受标准）pH,Conductivity,TOC,Chlorine,Microbial,Endotoxin etcResponse to OOS OOS应对02 七月七月 202444华润医药集团有限公司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 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02 七月七月 202445华润医药集团有限公司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 between 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SOPIf 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SOP02 七月七月 202446华润医药集团有限公司Cleaning and sanitization清洁和消毒Describe cleaning and sanitization 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02 七月七月 202447华润医药集团有限公司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 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02 七月七月 202448华润医药集团有限公司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 specific 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02 七月七月 202449华润医药集团有限公司Validation验证Initial phase 初始阶段During this phase the operational parameters and the cleaning/sanitization procedures and frequencies 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。02 七月七月 202450华润医药集团有限公司Validation验证第二阶段第二阶段-The second phase of the system validation is to demonstrate that the system will consistently produce the desired water quality when operated in conformance with the SOPs.The sampling is performed as in the initial phase and for the same time period.At the end of this phase the data should demonstrate that the system will consistently produce the desired quality of water.系统验证的第二阶段应证明，在符合SOP下运行，能持续产生高品质水。取样的频次（每日）和时间（2-4周）应和初始阶段相同。在此阶段结束时，应有数据显示系统能持续产生高品质水。51华润医药集团有限公司Validation验证第三阶段第三阶段The third phase of validation is designed to demonstrate that when the water system is operated in accordance with the SOPs over a long period of time it will consistently produce water of the desired quality.Any variations in the quality of the feed water that could affect the operation and ultimately the water quality will be picked up during this phase of the validation.Sampling is performed according to routine procedures and frequencies.验证的第三阶段应证明当系统在符合SOP下运行较长时间，能持续产生高品质水。任何会影响系统运行并会影响最终水质的进水质量的变异，都会在此验证阶段进行考察。应按照日常的规程和频次进取样。52华润医药集团有限公司Validation验证For Water for Injection systems the samples should be taken daily from a minimum of one point of use,with all points of use tested weekly.The validation of the water system is completed when the firm has a full years worth of data.对于注射用水系统取样应每日至少一个使用点，所有点每周轮检。当公司收集一整年有效数据后，水系统验证完成。53华润医药集团有限公司54Thank You谢谢谢谢Questions?问题？问题？END