制藥用水系統(tǒng)介紹課件

1、Pharmaceutical Water Systems制藥用水系統(tǒng) Alfa LavalSlide 2Water storage and distribution system水的貯存和分配系統(tǒng)The most common and well known system in the pharmaceutical industry. 是最常規(guī)的Still, many confusions on how to select the most suitable, hygienic and cost effective solution然而，在怎么選擇最合適、衛(wèi)生和成本、效能方面最困惑The key

2、 is to understand the basic principle關(guān)鍵是要懂得基本的原理 Alfa LavalSlide 3Feed waterReverseosmosisElectro-deionisationTankDistillation systemTankWater purification & distribution loop純化和分配Purification processDistribution loop Alfa LavalSlide 4Definitions定義ISPE differentiate between three types of water: ISP

3、E區(qū)分三種水：USP Purified Water (PW) 美國藥典的純化水（PW）USP Water for Injection (WFI)注射水Non- compendial water (RO, DI, etc.)飲用水 Alfa LavalSlide 5Sterile bulk API or BPCWFI & PW, in practice WFI和PW的使用Injectable dosage formWFINon-injectable dosage formPWBulk API or BPCSuitable non-compendialAPI = Active Pharmaceut

4、ical Ingredient活性藥用成分（原料藥）BPC = Bulk Pharmaceutical Chemical（醫(yī)藥中間體）Minimum water typeEquipment cleaning and rinsingISPE recommendation ISPE推薦 Alfa LavalSlide 6USP Specifications定義: PW vs. WFI*In-line measurement, from equivalent values from USP table CFU=Colony Forming UnitsAll Pharmaceutical water

5、must 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 CF

6、U/ml)Endotoxin contentNot Specified 0.25 EU/mlProduction MethodsObtained by suitable processObtained by suitable process and purified by distillation. Alfa LavalSlide 7Bacteria basics for water systems水系統(tǒng)中的微生物基本知識Aerobic Bacteria 好氧菌Gram Negative 葛蘭氏陰性菌Gram Positive 葛蘭氏陽性菌Endotoxin 內(nèi)毒素Biofilm 生物膜 Al

7、fa LavalSlide 8Bacteria basics for water systems水系統(tǒng)中的微生物基本知識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 periodic sanitiz

8、ation and test procedures are recommended.通常在水系統(tǒng)中的微生物多為葛蘭氏陰性菌，在高于60C情況下不生長，然而，對于耐熱菌，建議要定期清潔處理Bacteria in pharmaceutical water systems generally range from 0,3 m 5 m. 水系統(tǒng)中的微生物大小通常在0,3 m 5 m Alfa LavalSlide 9Bacteria basics for water systems水系統(tǒng)中的微生物基本知識Killed Gram negative bacteria releases endotoxins

9、, 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 are a major conc

10、ern for every dosage form in contact with the blood stream.殺死葛蘭氏陰性菌會釋放內(nèi)毒素，內(nèi)毒素是一種多糖分子，當內(nèi)毒素被注射入血液時，就會導(dǎo)致熱病。（這些物質(zhì)的學(xué)術(shù)術(shù)語為“熱源”，即產(chǎn)生熱量，發(fā)熱的意思）Endotoxins are heat stable (boiling for 30 minutes does not destabilize endotoxin沸騰30分鐘不能降解內(nèi)毒素), but certain powerful oxidizing agents such as superoxide, peroxide and

11、hypochlorite, degrade them. 內(nèi)毒素是熱穩(wěn)定性物質(zhì)，但過氧化物、次氯酸鹽能夠降解Endotoxins are commonly removed by RO, UF, (UV*) and flushing 通常RO、UF(UV)和沖洗能夠去除內(nèi)毒素* Argued by some UV manufacturer Alfa LavalSlide 10Bacteria structure 細菌結(jié)構(gòu)Profiles of the cell envelope the Gram-positive and Gram-negative bacteria. The Gram-posit

12、ive 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 outer mem

13、brane. The space between the inner (plasma) and outer membranes (wherein the peptidoglycan resides) is called the periplasm. Gram-positive cell wall 葛蘭氏陽性菌細胞壁Gram-negative cell wall 葛蘭氏陰性菌 Alfa LavalSlide 11Bacteria basics for water systems 水系統(tǒng)中的微生物In order to grow in nature or in the laboratory, a

14、bacterium must have:微生物為了生長，必須具備：an energy source能量來源a source of carbon碳源other required nutrients其他要求的營養(yǎng)源a permissive range of physical conditions such as理化條件O2 concentration氧濃度Temperature溫度pH Alfa LavalSlide 12Bacteria and pH 微生物和pHGrowth rate vs. pH for three environmental classes of procaryotes.

15、原核生物在不同pH條件下的生長速率 Alfa LavalSlide 13Bacteria and Temperature 微生物和溫度Growth rate vs temperature for five environmental classes of procaryotes. Most procaryotes will grow over a temperature range of about 30 degrees.原核生物在不同溫度下的生長速率比較，適宜溫度大多數(shù)在30度左右 Alfa LavalSlide 14Bacteria and Temperature微生物和溫度Pharmac

16、eutical 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. 制藥用水中有機物、礦物質(zhì)和鹽含量非常低，不適宜嗜熱菌的生長Also the Psychrophilic bacteria, which are mainly found in ice and melt water, are sel

17、dom found in pharmaceutical water systems.很少在制藥用水系統(tǒng)中發(fā)現(xiàn)主要生長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.這樣在制藥用水系統(tǒng)中主要考慮的就是嗜溫菌 Alfa LavalSlide 15Bacteria and Temperature微生物和溫度Optimun and upper temperature limits for

18、growth of some typical pure water organims and pathogens:不同微生物的生長適宜溫度：Bacterium Optimum (C)/Upper (C)Escherichia coli 37/45(埃希氏菌)Staphylococcus aureus 30-37/45(葡萄狀球菌)Pseudomonas maltophilia 35/41(嗜麥芽假單胞菌 )Pseudomonas aeruginosa 37/42(綠濃桿菌 )Pseudomonas fluorescens 25-30/39(熒光假單胞菌)Vibrio cholerae 18-3

19、7/43(霍亂孤菌）Listeria monocytogenes 30-37/45（單核增生性李斯特菌 ）Campylobacter jejuni 37-42/45（空腸彎曲菌）Bacillus cereus 28-42/55（蠟狀芽孢桿菌 ）Clostridium perfringens 37/50（產(chǎn)氣英膜梭菌 ）Shigella spp. 35-37/47（志賀菌 ） Alfa LavalSlide 16Microbial Growth - Mesophilic bacteria 微生物生長嗜溫菌Microbial growth mainly occur between 10-55C.通

20、常在1055度間適宜生長Conditions above 65-75C are considered self-sanitized在6575度間抑制生長Conditions below 10C are considered to limit bacterial growth在低于10度下限制生長*ANNE M. BRONIKOWSKI, ALBERT F. BENNETT, AND RICHARD E. LENSKI, Evolution, 55(1), 2001, pp. 3340Typical temperature/growth curve for mesophilic bacteria

21、 (Listeria & Pseudomonas sp.)* Alfa LavalSlide 17Biofilm 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.微生物相互粘結(jié)并附著在表面形成黏性的物質(zhì)稱之為生物

22、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A biofilm is an assemblage of microbial cells that is irreversibly associated with a surface (not remov

23、ed 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）包括起先的多糖矩陣Noncellular materials such as mineral crystals, corrosion particles, clay or silt particles, or blood components, may also be found in the biofilm matrix 在生物膜中能發(fā)現(xiàn)非細胞物質(zhì)，象礦物質(zhì)、腐蝕粒子、泥土或灰塵粒

24、子或血液成分Biofilm on a mild steel surface in a water system Alfa LavalSlide 19Biofilms 生物膜Substratum effects深層影響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，剪切力減小和表面積增大Micro organism attach

25、 more rapidly to hydrophobic, nonpolar surfaces (such as PTFE and other plastics) than to hydrophilic materials such as glass or metals. 相比親水性材料，微生物更易、更快附著在疏水性表面 Alfa LavalSlide 20Biofilms 生物膜Hydrodynamics:流體動力學(xué)High shear forces will detach biofilms 高剪切力可以分離生物膜A high nutrient concentration will incr

26、ease the biofilm高營養(yǎng)濃度促進生物膜形成 Alfa LavalSlide 21Biofilms 生物膜WarningsMore than 99% of all microbial activity occurs in biofilms. 99的微生物生長發(fā)生在生物膜上The biofilm is a favourable habitat for bacteria as it allows access to nutrients 生物膜是微生物生長的營養(yǎng)源The complex biofilm matrix also works as a defence against stre

27、ss, e.g. temperature, shear forces, chemicals, etc. 生物膜的復(fù)雜結(jié)構(gòu)能夠抵抗外界壓力，如溫度、剪切力、化學(xué)試劑等 Alfa LavalSlide 22Biofilms 生物膜Pre-cautions in water systems 預(yù)先保證Minimization of nutrients 最小營養(yǎng)濃度High shear forces高剪切力Hygienic design (right surface finish, no pocket, dead-legs or crevices) 衛(wèi)生設(shè)計（合適的表明處理、無凹槽、無死角、無縫隙Avo

28、id hydrophobic nonpolar surfaces such as plastics避免疏水性表面，如塑料。Others, only if the above is not enough如果以上不足以的話Disinfectants in high concentration 高濃度的消毒劑Drying the system completely 徹底干燥系統(tǒng) Alfa LavalSlide 23USP Specifications in Practice 實踐中的藥典規(guī)范Purified water used for non-injectable drugs can accept

29、 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 commonly specified. In WFI endotoxin are a

30、 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 no possibility to grow.Goals for Wate

31、r Systems 水系統(tǒng)旨要Maintain the water quality within acceptable limits維護水質(zhì)在可接受的標準內(nèi)Deliver the water to the points-of-use at required flow & temperature 在既定要求的流量和溫度下輸送到用水點Minimize capital & operating expense 最少的投資和運行成本An Optimum System 最適宜的系統(tǒng)Minimizes the time water is held at conditions which favor grow

32、th 微生物最適宜的生長條件停留時間最小化Minimizes amount of water which changes temperature變化溫度的水量最少化Minimize the exposure of the water to the environment (closed system)暴露于環(huán)境的水最少化Contact all surfaces during sanitization 接觸經(jīng)衛(wèi)生處理的表面Hygienically designed system where pockets, crevices and dead-legs are minimised 衛(wèi)生設(shè)計的系統(tǒng)

33、，凹槽、縫隙和死角最少化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組成 Alfa LavalSlide 26Sanitization 清潔Typically with hot water at 75-85C. 典型的7585度Temperatures above 85C will increase the risk for rouging, cavitations or boiling in c

34、irculation pump 溫度高于85度會增加紅銹現(xiàn)象、氣蝕、泵腔內(nèi)沸騰的風(fēng)險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*) 用合格的水沖洗整個系統(tǒng)，包括取樣點和用水點Other types of sanitization can be Steam, Ozo

35、ne, (chemical) 其他清潔形式：蒸汽、臭氧等* Depending on system Alfa LavalSlide 27CFU/mlEU/mlTimeAcceptance limit EU/mlBacteria and Endotoxin growth in ambient water system 水系統(tǒng)中微生物和內(nèi)毒素Acceptance limit CFU/mlHeat SanitizationSanitization 清潔BacteriaEndotoxinHeat Sanitization Alfa LavalSlide 28Storage and distributi

36、on examples 貯存和分配舉例ISPE* present 8 common distribution configurationsISPE列舉8種常用分配方式* ISPE Baseline Guides Volume 4: Water and Steam Systems January 2001These can be divided in 3 different temperature types:分為3個不同溫度形式Hot water systems (self sanitised)熱水系統(tǒng)Ambient water systems (needs sanitization)常溫水系

37、統(tǒng)Cold water systems (needs sanitization)冷水系統(tǒng) Alfa LavalSlide 29Questions to be raised 問題體現(xiàn)Quality of water from purification process?純化水質(zhì)Capacity of purification process?純化能力Water usage and frequency?水的使用頻率Temperature of water?水溫Quality of water?水質(zhì)Possibility for sanitization cycles清潔周期的可能性TSteamCon

38、d.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 熱貯存、熱分配 Alfa LavalSlide 31Point of Use, Steamed 用水點，蒸汽滅菌Sanitization in this e

39、xample is accomplished using low pyrogen steam or flushing before use. 每次使用前要蒸汽滅菌和沖洗 Alfa LavalSlide 32Point of Use Installed in Subloop 小循環(huán)的用水點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 b

40、y 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 which leads to the use of a larger circulation pump小循環(huán)會因壓力降增大而導(dǎo)致更大的循環(huán)泵 Alfa LavalSlide 33Point of Use Heat Exchanger

41、 with Multiple, Branched Users 用換熱器的多支路用水點Sanitization in this example is accomplished by flushing hot water from the main loop once through to drain. SteamHotStorageTankCooling HeatExchangerCoolantCoolantTCond.Reheat ExchangerTCond.SteamControl Valve(optional)Most Advantageous When:Water is generat

42、ed 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 熱貯存、冷卻并再加熱SteamHotStorageTankCooling HeatExchangerCoolantCoolantTCond.Reheat ExchangerTCond.SteamC

43、ontrol Valves(optional)Most Advantageous When:Multiple temperatures are requiredA single loop becomes cost prohibitiveHydraulic limitingLeast Advantageous When:Loop balancing is criticalParallel Loops, Single Tank 單罐平行回路NOTE: Identical configuration for Cold Storage, Cold Distribution SystemControl

44、ValveCoolantCoolantAmbientStorageTankSanitizing /CoolingHeat ExchangerTCond.Steam(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

45、 into operating scheduleAmbient Storage, Ambient Distribution常溫貯存、常溫分配SteamHotStorageTankCooling 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 Ad

46、vantageous When:Per unit energy cost is a concernTank turnover is a concernHot Storage, Self-Contained Distribution熱貯存、自帶分配Batched Tank Recirculating System 多個罐再循環(huán)系統(tǒng)Control Valve(optional)Most Advantageous when:Non-reliable generation methodQA release required before water useLeast Advantageous when

47、:Capital and operating cost are a concernCoolantCoolantStorageTankControl 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:Capi

48、tal cost is tightProduct is ozone sensitiveOzonated Storage & Distribution加臭氧滅菌的貯存和分配系統(tǒng)Branched/One Way 分支/單路系統(tǒng)TPoints Of UseRestriction Orifice (mount in vertical)SteamTCond.Most Advantageous When:Capital is tightMicrobial control is not critical or not requiredWater use is continuousFrequent flush

49、ing or sanitizationLeast Advantageous When:Water use is sporadic, because line stays stagnantOperating cost is a concernThe Key Points 關(guān)鍵點Select the design based on “return on investment, where “return” is defined as the reduction in contamination risk 選擇什么樣的設(shè)計基于收回投資，在哪里收回要定義到減少污染風(fēng)險Utilize design fe

50、atures that provide the greatest reduction in contamination risk at the most reasonable cost 利用設(shè)計的特點在合理的成本下最大限度降低污染風(fēng)險Add the more expensive features only if they are required to maintain quality within the acceptable limits維持水質(zhì)在可接受的限度內(nèi)才增加更昂貴的投資Total Cost總成本 (= Investment投資 + Operating運行)TimeInvestme

51、ntcostTypical Dilemma 兩難境地 Alfa LavalSlide 43Best Practice for cost efficient systems最有效的方法Invest in hygienic design minimise pockets, crevices and dead-legsAvoid unions and use automatic (orbital) welding where possible0.8 m Ra (20 inch) mechanically polished enough for hot systems with hygienic de

52、signMaximise surface shear forcesUse high grade SS and avoid plastic materialsMinimise disturbance of the systemUse plate heat exchanger with circulation where possibleHot systems kept at 65-75C or longer intervals between sanitisation in ambient systemsProlonged lifetime of equipmentDecreased energ

53、y consumption Alfa LavalSlide 44PHE with circulation as POU cooler 小循環(huán)板式換熱器用于用水點Control ValveCoolantCoolantAmbientStorageTankSanitizing /CoolingHeat ExchangerTCond.Steam(optional)CoolantCoolantPHE with circulation as in-line heater板式換熱器用于在線加熱Validation of water systems*水系統(tǒng)驗證Design/installation revie

54、w設(shè)計/安裝回顧SOP development and confirmation SOP的建立和確認Demonstration of effectiveness 效能實證Data compilation and sign-off 數(shù)據(jù)收集及簽發(fā)*FDA Guideline - HIGH PURITY WATER SYSTEMS Alfa LavalSlide 47Validation strategy 驗證策略Design/installation review:設(shè)計/安裝回顧 A complete and up-to-date description and design drawing o

55、f the system included in the final report (including all components and clearly identify all sample points and their designation) to ensure that the validation is not put at risk and is successfully completed 在總結(jié)報告中包括完整的系統(tǒng)設(shè)計圖紙和描述（包括明確所有組成部分和取樣點）確保驗證無風(fēng)險并順利完成 Alfa LavalSlide 48Validation strategy驗證策略S

56、OP development and confirmation SOP的建立和確認Develop the operational parameters and cleaning and sanitising protocols. Collect data over a period of two to four weeks, samples collected daily after each purification step and from all point of use. If successful, these procedures are established as the w

57、ater systems SOPs建立操作參數(shù)，清洗及消毒方案，收集24周的數(shù)據(jù)，日常純化步驟后從所有使用點的取樣數(shù)據(jù)，如果成功的話，可以建立這個規(guī)程作為水系統(tǒng)的SOP Alfa LavalSlide 49Validation strategy驗證策略Demonstration of effectiveness效能實證Demonstrate that the water system consistently produces water of the desired quality when operated within the parameters outlined in the SOP

58、s over a long period of time. WFI system samples are taken daily at a minimum from one point of use and weekly from all point of use. This identifies any inconsistence in the feed water quality due to seasonal variations. The water system can be considered validated after the manufacturer has a years worth of operational data.根據(jù)SOP在操作參數(shù)范圍內(nèi)長時間連續(xù)生產(chǎn)出符合既定質(zhì)量要求的水。WFI取樣每日至少取一點，每周所有用水點取樣一次。為了確認季節(jié)的變化對水質(zhì)量的影響，考慮連續(xù)一年的操作數(shù)據(jù)收集驗證 Alfa LavalSlide 50Validation strategy 驗證策略Data compilation and sign-off 數(shù)據(jù)收集和核簽發(fā)Assembly the data into a valid