1、Pharmaceutical Water Systems制药用水系统 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 industry.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
2、惑 The key is to understand the basic principle关键是要懂得基本的原理 Alfa LavalSlide 3Feed waterReverseosmosisElectro-deionisationTankDistillation systemTankWater purification&distribution loop纯化和分配Purification processDistribution loop Alfa LavalSlide 4Definitions定义定义ISPE differentiate between three types of w
3、ater:ISPE区分三种水：USP Purified Water(PW)美国药典的纯化水（PW）USP Water for Injection(WFI)注射水Non-compendial water(RO,DI,etc.)饮用水 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-compendialAPI=Active Pharmaceut
4、ical 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 Alfa LavalSlide 6USP Specifications定义定义:PW vs.WFI*In-line measurement,from equivalent values from USP table CFU=Colony Forming UnitsAll Pharmaceutical water mus
5、t also meet the EPA standard for microbiological quality of potable waterPW(Purified Water)WFI(Water for Injection)Water conductivity and pH 1,3 S/cm at 25C*pH 5-7 1,3 S/cm at 25C*pH 5-7Total Organic Carbon(TOC)0.5 ppm 0.5 ppmAerobic Microbial Contamination 100 CFU/ml 10 CFU/100 ml (0.1 CFU/ml)Endot
6、oxin contentNot Specified 0.25 EU/mlProduction MethodsObtained by suitable processObtained by suitable process and purified by distillation.Alfa LavalSlide 7Bacteria basics for water systems水系统中的微生物基水系统中的微生物基本知识本知识 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
7、生物膜 Alfa LavalSlide 8Bacteria basics for water systems水系统中的微生物基水系统中的微生物基本知识本知识Most common bacteria in pharmaceutical water systems are Gram negative bacteria.Gram negative bacteria do not grow above 60C,however,cautions for Gram positive bacteria,which are more heat resistant,should be taken and per
8、iodic 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 generally 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 Alfa LavalSlide 9Bacteria basics for water systems水系统中的微生物基水系统中的微生物基本知识本知识Killed Gram negative bact
9、eria releases endotoxins,which is a lipopolysaccharide molecule that cause fever when injected 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 a
10、re 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，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,p
11、eroxide 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 removed 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 Alfa LavalSlide 10Bacteria structure 细菌结构细菌结构Profiles of the cell envelope the Gram-positive and Gram-negative bacteria.The G
12、ram-positive wall is a uniformly thick layer 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 oute
13、r membrane.The space between the inner(plasma)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 Alfa LavalSlide 11Bacteria basics for water systems 水系统中的微生物水系统中的微生物In order to grow in nature or
14、 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 pH Alfa LavalSlide 12Bacteria and pH 微生物和微生物和pHGrowth rate vs.pH for three environm
15、ental classes of procaryotes.原核生物在不同pH条件下的生长速率 Alfa LavalSlide 13Bacteria and Temperature 微生物和温度微生物和温度Growth rate vs temperature for five environmental classes of procaryotes.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 Alfa LavalSlide 14Bac
16、teria and Temperature微生物和温度微生物和温度Pharmaceutical water systems are very low in organic materials,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 f
17、ound 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 Alfa LavalSlide 15Bacteria and Temperature微生物和温度微生物和温度O
18、ptimun and upper temperature 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
19、25-30/39(荧光假单胞菌)Vibrio cholerae 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）Alfa LavalSlide 16Microbial Growth-Mesophilic bacteria 微生物生长嗜温菌微生物生长嗜温菌 Microbial
20、 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 temperature/growth
21、curve for mesophilic bacteria(Listeria&Pseudomonas sp.)*Alfa LavalSlide 17Biofilm 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,which acts as a shield,protecting the biofilm from physical and chemical attack
22、.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.Alfa LavalSlide 18Biofilms 生物膜生物膜A biofilm is an assemblage of microbial cells that is irreversibly associated
23、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Noncellular 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
24、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 Alfa LavalSlide 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
25、面积增大Micro organism attach more rapidly to hydrophobic,nonpolar surfaces(such as 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 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 nut
26、rient concentration will increase the biofilm高营养浓度促进生物膜形成 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 nutrients 生物膜是微生物生长的营养源The complex biofilm matrix also w
27、orks 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 Alfa LavalSlide 22Biofilms 生物膜生物膜Pre-cautions in water systems 预先保证预先保证Minimization 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)
28、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如果以上不足以的如果以上不足以的话话Disinfectants in high concentration 高浓度的消毒剂Drying the system completely 彻底干燥系统 Alfa LavalSlide 23USP Specifications in Practice 实践中的药典规范实践中的药典规范Purified wat
29、er used for non-injectable drugs can accept a small amount of microbial contamination and has no specifications on endotoxin.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
30、commonly specified.In WFI endotoxin are a concern and if bacteria are introduced to the system and killed,these bacteria 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
31、 no possibility to grow.Goals for Water Systems 水系统水系统旨要旨要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An Optimum System 最适宜的系统最适宜的系统 Minimizes the tim
32、e 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 pock
33、ets,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 Alfa LavalSlide 26Sanitization 清洁清洁 Typically with hot water at 75-85C.典型的7585度 Temperatures above 85C will incre
34、ase 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 achieved(typically 2 to 3 hours*)用合格的水冲洗整个系统，包括取样点
35、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 system Alfa LavalSlide 27CFU/mlEU/mlTimeAcceptance limit EU/mlBacteria and Endotoxin growth in ambient water system 水系统中微生物和内毒素Acceptance limit CFU/mlHeat SanitizationSanitization 清洁BacteriaEndotoxinHeat Sanitiz
36、ation Alfa LavalSlide 28Storage 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*ISPE 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)
37、热水系统 Ambient water systems(needs sanitization)常温水系统 Cold water systems(needs sanitization)冷水系统 Alfa LavalSlide 29Questions 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 w
38、ater?水质 Possibility for sanitization cycles清洁周期的可能性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、热分热贮存、热分配配 Alfa
39、 LavalSlide 31CoolantPoint of UseTHot LoopHot LoopPoint of Use,Steamed 用水点，蒸汽灭用水点，蒸汽灭菌菌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 Alfa LavalSlide 32Point of Use Installed in Subloop 小循环的用水点小循环的用水点Sanitization is accomplished by circulati
40、ng 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.This subloop leads to added pressure drop in the main loop whic
41、h 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CoolantPoint of UseTHot LoopHot LoopRestriction Orifice Alfa LavalSlide 33Point of Use Heat Exchanger with Multiple,Branched Users 用换热器的多支用换热器的多支路用水点路用水点CoolantPoint of UseHot LoopHot LoopSanitization in this example is accomplished b
42、y flushing hot water from the main loop once through to drain.SteamHotStorageTankCooling HeatExchangerCoolantCoolantTCond.Reheat ExchangerTCond.SteamControl Valve(optional)Most Advantageous When:Water is generated hotTight microbial control is requiredThere is little time for sanitizationWater consu
43、mption is critical(no flushing)Least Advantageous When:Energy consumption is criticalHot Storage,Cool&Reheat 热贮存、冷却并热贮存、冷却并再加热再加热SteamHotStorageTankCooling HeatExchangerCoolantCoolantTCond.Reheat ExchangerTCond.SteamControl Valves(optional)Most Advantageous When:Multiple temperatures are requiredA s
44、ingle loop becomes cost prohibitiveHydraulic limitingLeast Advantageous When:Loop balancing is criticalParallel Loops,Single Tank 单罐平行单罐平行回路回路NOTE:Identical configuration for Cold Storage,Cold Distribution SystemControl ValveCoolantCoolantAmbientStorageTankSanitizing/CoolingHeat ExchangerTCond.Steam
45、(optional)CoolantCoolantMost Advantageous When:High peak demands for ambient or cold waterWater is generated at ambient temperatureThere is adequate time for sanitizationLeast Advantageous When:Sanitization will not fit into operating scheduleAmbient Storage,Ambient Distribution常温贮存、常温分配常温贮存、常温分配Ste
46、amHotStorageTankCooling HeatExchangerCoolantCoolantTCond.Control Valve(3-way)(80%of flow)(20%offlow)Most Advantageous When:Water is generated hotThere are many low temperature water usersEnergy consumption is criticalLeast Advantageous When:Per unit energy cost is a concernTank turnover is a concern
47、Hot Storage,Self-Contained Distribution热贮存、自带分配热贮存、自带分配Batched Tank Recirculating System 多个罐再循环系统多个罐再循环系统Control Valve(optional)Most Advantageous when:Non-reliable generation methodQA release required before water useLeast Advantageous when:Capital and operating cost are a concernCoolantCoolantStora
48、geTankControl Valve(optional)UV Light(Ozone Destruct)OzoneGeneratorv v v v v v vSparge BarAITOzoneMost Advantageous When:Production allows periodic automatic sanitizationEnergy costs are highAll users are ambientLeast Advantageous When:Capital cost is tightProduct is ozone sensitiveOzonated Storage&
49、Distribution加臭氧灭菌的贮存和分配系统加臭氧灭菌的贮存和分配系统Branched/One Way 分支分支/单路系单路系统统TPoints Of UseRestriction Orifice(mount in vertical)SteamTCond.Most Advantageous When:Capital is tightMicrobial control is not critical or not requiredWater use is continuousFrequent flushing or sanitizationLeast Advantageous When:W
50、ater use is sporadic,because line stays stagnantOperating cost is a concernThe Key Points 关键点关键点 Select the design based on“return on investment,where“return”is defined as the reduction in contamination risk 选择什么样的设计基于收回投资，在哪里收回要定义到减少污染风险 Utilize design features that provide the greatest reduction i
