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1、经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用Pharmaceutical Water Systems制药用水系统经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用 Alfa LavalSlide 2Water storage and distribution system水的贮存和分配系统水的贮存和分配系统The most common and well known system in the pharmaceutical ind
2、ustry.是最常规的Still,many confusions on how to select the most suitable,hygienic and cost effective solution然而，在怎么选择最合适、卫生和成本、效能方面最困惑The key is to understand the basic principle关键是要懂得基本的原理经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用 Alfa LavalSlide 3Feed waterReverseosmosisElectro-d
3、eionisationTankDistillation systemTankWater purification&distribution loop纯化和分配Purification processDistribution loop经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用 Alfa LavalSlide 4Definitions定义定义ISPE differentiate between three types of water:ISPE区分三种水：USP Purified Water(PW)美国药典的纯
4、化水（PW）USP Water for Injection(WFI)注射水Non-compendial water(RO,DI,etc.)饮用水经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用 Alfa LavalSlide 5Sterile bulk API or BPCWFI&PW,in practice WFI和和PW的使用的使用Injectable dosage formWFINon-injectable dosage formPWBulk API or BPCSuitable non-compendia
5、lAPI=Active Pharmaceutical Ingredient活性药用成分（原料药）BPC=Bulk Pharmaceutical Chemical（医药中间体）Minimum water typeEquipment cleaning and rinsingISPE recommendation ISPE推荐经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用 Alfa LavalSlide 6USP Specifications定义定义:PW vs.WFI*In-line measurement,fro
6、m equivalent values from USP table CFU=Colony Forming UnitsAll Pharmaceutical water must also meet the EPA standard for microbiological quality of potable water经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用 Alfa LavalSlide 7Bacteria basics for water systems水系统中的微生物基本知识水系统中的微生物基本知识
7、Aerobic Bacteria 好氧菌Gram Negative 葛兰氏阴性菌Gram Positive 葛兰氏阳性菌Endotoxin 内毒素Biofilm 生物膜经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用 Alfa LavalSlide 8Bacteria basics for water systems水系统中的微生物基本知识水系统中的微生物基本知识Most common bacteria in pharmaceutical water systems are Gram negative bacte
8、ria.Gram negative bacteria do not grow above 60C,however,cautions for Gram positive bacteria,which are more heat resistant,should be taken and periodic sanitization and test procedures are recommended.通常在水系统中的微生物多为葛兰氏阴性菌，在高于60C情况下不生长，然而，对于耐热菌，建议要定期清洁处理Bacteria in pharmaceutical water systems general
9、ly range from 0,3 m 5 m.水系统中的微生物大小通常在0,3 m 5 m经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用 Alfa LavalSlide 9Bacteria basics for water systems水系统中的微生物基本知识水系统中的微生物基本知识Killed Gram negative bacteria releases endotoxins,which is a lipopolysaccharide molecule that cause fever when inj
10、ected into the bloodstream.(These substances are termed”pyrogens”meaning generating heat,fever).Pyrogens have also been linked to more serious reactions when injected into the blood(e.g.lethal septic shock)and are a major concern for every dosage form in contact with the blood stream.杀死葛兰氏阴性菌会释放内毒素，
11、内毒素是一种多糖分子，当内毒素被注射入血液时，就会导致热病。（这些物质的学术术语为“热源”，即产生热量，发热的意思）Endotoxins are heat stable(boiling for 30 minutes does not destabilize endotoxin沸腾30分钟不能降解内毒素),but certain powerful oxidizing agents such as superoxide,peroxide and hypochlorite,degrade them.内毒素是热稳定性物质，但过氧化物、次氯酸盐能够降解Endotoxins are commonly re
12、moved by RO,UF,(UV*)and flushing 通常RO、UF(UV)和冲洗能够去除内毒素*Argued by some UV manufacturer经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用Bacteria structure 细菌结构细菌结构Profiles of the cell envelope the Gram-positive and Gram-negative bacteria.The Gram-positive wall is a uniformly thick laye
13、r external to the plasma membrane.It is composed mainly of peptidoglycan(murein).The Gram-negative wall appears thin and multilayered.It consists of a relatively thin peptidoglycan sheet between the plasma membrane and a phospholipid-lipopolysaccharide outer membrane.The space between the inner(plas
14、ma)and outer membranes(wherein the peptidoglycan resides)is called the periplasm.Gram-positive cell wall 葛兰氏阳性菌细胞壁葛兰氏阳性菌细胞壁Gram-negative cell wall 葛兰氏阴性菌葛兰氏阴性菌10 Alfa Laval经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用Bacteria basics for water systems 水系统中的微生物水系统中的微生物In order to g
15、row in nature or in the laboratory,a bacterium must have:微生物为了生长，必须具备：an energy source能量来源a source of carbon碳源other required nutrients其他要求的营养源a permissive range of physical conditions such as理化条件O2 concentration氧浓度Temperature温度pH11 Alfa Laval经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或
16、接受服务的费用Bacteria and pH 微生物和微生物和pHGrowth rate vs.pH for three environmental classes of procaryotes.原核生物在不同pH条件下的生长速率12 Alfa Laval经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用Bacteria and Temperature 微生物和温度微生物和温度Growth rate vs temperature for five environmental classes of procaryot
17、es.Most procaryotes will grow over a temperature range of about 30 degrees.原核生物在不同温度下的生长速率比较，适宜温度大多数在30度左右13 Alfa Laval经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用 Alfa LavalSlide 14Bacteria and Temperature微生物和温度微生物和温度Pharmaceutical water systems are very low in organic material
18、s,minerals and salts.These conditions are not suitable for Thermophilic bacteria,which require very unique physical conditions.制药用水中有机物、矿物质和盐含量非常低，不适宜嗜热菌的生长Also the Psychrophilic bacteria,which are mainly found in ice and melt water,are seldom found in pharmaceutical water systems.很少在制药用水系统中发现主要生长在冰
19、水中的喜寒性菌This only leaves the Mesophilic bacteria as the main candidate for bacteria that are found in pharmaceutical water systems.这样在制药用水系统中主要考虑的就是嗜温菌经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用 Alfa LavalSlide 15Bacteria and Temperature微生物和温度微生物和温度Optimun and upper temperature
20、limits for growth of some typical pure water organims and pathogens:不同微生物的生长适宜温度：Bacterium Optimum(C)/Upper(C)Escherichia coli 37/45(埃希氏菌)Staphylococcus aureus 30-37/45(葡萄状球菌)Pseudomonas maltophilia 35/41(嗜麦芽假单胞菌)Pseudomonas aeruginosa 37/42(绿浓杆菌)Pseudomonas fluorescens 25-30/39(荧光假单胞菌)Vibrio choler
21、ae 18-37/43(霍乱孤菌）Listeria monocytogenes 30-37/45（单核增生性李斯特菌）Campylobacter jejuni 37-42/45（空肠弯曲菌）Bacillus cereus 28-42/55（蜡状芽孢杆菌）Clostridium perfringens 37/50（产气英膜梭菌）Shigella spp.35-37/47（志贺菌）经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用Microbial Growth-Mesophilic bacteria 微生物生长嗜温菌
22、微生物生长嗜温菌Microbial growth mainly occur between 10-55C.通常在1055度间适宜生长Conditions above 65-75C are considered self-sanitized在6575度间抑制生长Conditions below 10C are considered to limit bacterial growth在低于10度下限制生长*ANNE M.BRONIKOWSKI,ALBERT F.BENNETT,AND RICHARD E.LENSKI,Evolution,55(1),2001,pp.3340Typical temp
23、erature/growth curve for mesophilic bacteria(Listeria&Pseudomonas sp.)*16 Alfa Laval经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用Biofilm 生物膜生物膜A biofilm is defined as bacterial cells adherent to each other and/or to surfaces or interfaces and are covered by a slimy substance,whic
24、h acts as a shield,protecting the biofilm from physical and chemical attack.微生物相互粘结并附着在表面形成黏性的物质称之为生物膜Ref:Biofilms Survival and growth of bacteria in compendial high purity water systems by Frank Riedewald and Aidan W.Sexton:Pharmaceutical engineering Vol.27 No 1.17 Alfa Laval经营者提供商品或者服务有欺诈行为的，应当按照消
25、费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用 Alfa LavalSlide 18Biofilms 生物膜生物膜A biofilm is an assemblage of microbial cells that is irreversibly associated with a surface(not removed by gentle rinsing)and enclosed in a matrix of primarily polysaccharide material.生物膜是微生物聚集在表面（普通淋洗不能去除）包括起先的多糖矩阵Noncellu
26、lar materials such as mineral crystals,corrosion particles,clay or silt particles,or blood components,may also be found in the biofilm matrix 在生物膜中能发现非细胞物质，象矿物质、腐蚀粒子、泥土或灰尘粒子或血液成分Biofilm on a mild steel surface in a water system 经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用 Alfa L
27、avalSlide 19Biofilms 生物膜生物膜Substratum effects深层影响深层影响The extent of microbial colonisation appears to increase as the surface roughness increase shear forces are diminished and surface area is larger.微生物菌落增加表面的粗糙度，剪切力减小和表面积增大Micro organism attach more rapidly to hydrophobic,nonpolar surfaces(such as
28、PTFE and other plastics)than to hydrophilic materials such as glass or metals.相比亲水性材料，微生物更易、更快附着在疏水性表面经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用 Alfa LavalSlide 20Biofilms 生物膜生物膜Hydrodynamics:流体动力学流体动力学High shear forces will detach biofilms 高剪切力可以分离生物膜A high nutrient concentra
29、tion will increase the biofilm高营养浓度促进生物膜形成经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用 Alfa LavalSlide 21Biofilms 生物膜生物膜WarningsMore than 99%of all microbial activity occurs in biofilms.99的微生物生长发生在生物膜上The biofilm is a favourable habitat for bacteria as it allows access to nutrie
30、nts 生物膜是微生物生长的营养源The complex biofilm matrix also works as a defence against stress,e.g.temperature,shear forces,chemicals,etc.生物膜的复杂结构能够抵抗外界压力，如温度、剪切力、化学试剂等经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用 Alfa LavalSlide 22Biofilms 生物膜生物膜Pre-cautions in water systems 预先保证预先保证Minimiz
31、ation of nutrients 最小营养浓度High shear forces高剪切力Hygienic design(right surface finish,no pocket,dead-legs or crevices)卫生设计（合适的表明处理、无凹槽、无死角、无缝隙Avoid hydrophobic nonpolar surfaces such as plastics避免疏水性表面，如塑料。Others,only if the above is not enough如果以上不足以的话如果以上不足以的话Disinfectants in high concentration 高浓度的消
32、毒剂Drying the system completely 彻底干燥系统经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用 Alfa LavalSlide 23USP Specifications in Practice 实践中的药典规范实践中的药典规范Purified water used for non-injectable drugs can accept a small amount of microbial contamination and has no specifications on endot
33、oxin.WFI used for injectable drugs are expected to be free from microorganisms but since some microorganisms may be encountered during sampling,an action limit of 10 CFU/100 ml is commonly specified.In WFI endotoxin are a concern and if bacteria are introduced to the system and killed,these bacteria
34、 will release endotoxin.Therefore,strict measurement has to be taken not to introduce any bacteria into the system and to secure that the small amount of bacteria in the system has no possibility to grow.经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用Goals for Water Systems 水系统旨要水系
35、统旨要Maintain the water quality within acceptable limits维护水质在可接受的标准内Deliver the water to the points-of-use at required flow&temperature 在既定要求的流量和温度下输送到用水点Minimize capital&operating expense 最少的投资和运行成本经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用An Optimum System 最适宜的系统最适宜的系统Minimize
36、s the time water is held at conditions which favor growth 微生物最适宜的生长条件停留时间最小化Minimizes amount of water which changes temperature变化温度的水量最少化Minimize the exposure of the water to the environment(closed system)暴露于环境的水最少化Contact all surfaces during sanitization 接触经卫生处理的表面Hygienically designed system where
37、 pockets,crevices and dead-legs are minimised 卫生设计的系统，凹槽、缝隙和死角最少化Secure high shear forces at the surfaces 表面可靠的高剪切力Are made of safe materials and avoids plastic materials所有表面避免塑性材料并由安全的材料组成经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用Sanitization 清洁清洁Typically with hot water at 7
38、5-85C.典型的7585度Temperatures above 85C will increase the risk for rouging,cavitations or boiling in circulation pump 温度高于85度会增加红锈现象、气蚀、泵腔内沸腾的风险Flushing of the whole system,including sampling points and point of use,with a water at least as good as the water to be used until required water quality achi
39、eved(typically 2 to 3 hours*)用合格的水冲洗整个系统，包括取样点和用水点Other types of sanitization can be Steam,Ozone,(chemical)其他清洁形式：蒸汽、臭氧等*Depending on system26 Alfa Laval经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用CFU/mlEU/mlTimeAcceptance limit EU/mlBacteria and Endotoxin growth in ambient wate
40、r system 水系统中微生物和内毒素Acceptance limit CFU/mlHeat SanitizationSanitization 清洁BacteriaEndotoxinHeat Sanitization27 Alfa Laval经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用Storage and distribution examples 贮存和分配举例贮存和分配举例ISPE*present 8 common distribution configurationsISPE列举8种常用分配方式*I
41、SPE Baseline Guides Volume 4:Water and Steam Systems January 2001These can be divided in 3 different temperature types:分为3个不同温度形式Hot water systems(self sanitised)热水系统Ambient water systems(needs sanitization)常温水系统Cold water systems(needs sanitization)冷水系统28 Alfa Laval经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其
42、受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用Questions to be raised 问题体现问题体现Quality of water from purification process?纯化水质Capacity of purification process?纯化能力Water usage and frequency?水的使用频率Temperature of water?水温Quality of water?水质Possibility for sanitization cycles清洁周期的可能性29 Alfa Laval经营者提供商品或者服务有欺诈行为的，应当按照消
43、费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用TSteamCond.HotStorageTankControl Valve(optional)Most Advantageous When:Hot water is requiredHot water is generatedMicrobial control is criticalLeast Advantageous When:Ambient temperature water requiredHot Storage,Hot Distribution 热贮存、热分配热贮存、热分配经营者提供商品或者服务有欺诈
44、行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用Point of Use,Steamed 用水点，蒸汽灭菌用水点，蒸汽灭菌Sanitization in this example is accomplished using low pyrogen steam or flushing before use.每次使用前要蒸汽灭菌和冲洗31 Alfa Laval经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用Point of Use Installed in Sub
45、loop 小循环的用水点小循环的用水点Sanitization is accomplished by circulating hot water from the loop,through the point of use exchanger to the main loop.The operation can be facilitated by installing a block valve at the return of the main loop.The initial draw of point of use water would be diverted to drain.Thi
46、s subloop leads to added pressure drop in the main loop which leads to the use of a larger circulation pump小循环会因压力降增大而导致更大的循环泵32 Alfa Laval经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用Point of Use Heat Exchanger with Multiple,Branched Users 用换热器的多支路用水用换热器的多支路用水点点Sanitization in t
47、his example is accomplished by flushing hot water from the main loop once through to drain.33 Alfa Laval经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用SteamHotStorageTankCooling HeatExchangerCoolantCoolantTCond.Reheat ExchangerTCond.SteamControl Valve(optional)Most Advantageous Whe
48、n:Water is generated hotTight microbial control is requiredThere is little time for sanitizationWater consumption is critical(no flushing)Least Advantageous When:Energy consumption is criticalHot Storage,Cool&Reheat 热贮存、冷却并再加热热贮存、冷却并再加热经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费
49、用SteamHotStorageTankCooling HeatExchangerCoolantCoolantTCond.Reheat ExchangerTCond.SteamControl Valves(optional)Most Advantageous When:Multiple temperatures are requiredA single loop becomes cost prohibitiveHydraulic limitingLeast Advantageous When:Loop balancing is criticalParallel Loops,Single Tan
50、k 单罐平行回路单罐平行回路经营者提供商品或者服务有欺诈行为的，应当按照消费者的要求增加赔偿其受到的损失，增加赔偿的金额为消费者购买商品的价款或接受服务的费用NOTE:Identical configuration for Cold Storage,Cold Distribution SystemControl ValveCoolantCoolantAmbientStorageTankSanitizing/CoolingHeat ExchangerTCond.Steam(optional)CoolantCoolantMost Advantageous When:High peak demand