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1、Pharmaceutical Microbiology PM221These lecturesTypes of water used in pharmaceutical manufacturingStandardsComponents of water purification systemWater treatment:Deionisation,reverse osmosis and distillationWater storage and distributionWater system designWater testing第1页/共28页Pharmaceutical Microbio
2、logy PM222Pharmaceutical WaterThere are various types of water used in pharma industry.May be used in:formulation,processing operations(e.g.cooling,cleaning,sterilisation)Final rinsing of product contact surface.Different grades required depending on use and type of productWater classified based on
3、its source,quality(chemical and microbiological purity),treatment and use.Note that water also required for microbial growth.第2页/共28页Pharmaceutical Microbiology PM223Water types3 main types used in pharma industry:Potable water:Ordinary drinking water from mains(tap water)Fit to drink but not usuall
4、y suitable for pharma applications,especially manufacture of sterile products.Contains wide range of dissolved solids and gases harmless if swallowed,but potentially harmful if injected,could also interact with product.Has variable degree of hardness and added Cl for microbial control.第3页/共28页Pharma
5、ceutical Microbiology PM224Water Types(contd)Purified water:Specifications for purified water contained in British Pharmacopoeia(BP),EP and USP that describe chemical purity limits.Not necessarily sterile,therefore not suitable for manufacture of parenterals.Used for non-parenteral product formulati
6、onCan also be used as initial cleaning agent for some processes.Usually prepared from potable water by deionisation,which removes dissolved substances.May also be produced by distillation or reverse osmosis第4页/共28页Pharmaceutical Microbiology PM225Water types(contd):Water for Injections(WFI):Standard
7、s contained in BP,EP and USPPrepared from potable or purified water by distillation.Water normally deionsied before distillation(stops still“furring up”like kettle).Higher the quality of water fed to still,the greater the quality assurance that water produced by the still will be of high quality.Hig
8、h chemical purity and free from pyrogens.Bulk WFI has low bioburden(sterilised afterwards)Commercially supplied WFI is sterile.第5页/共28页Pharmaceutical Microbiology PM226Standards:US Pharmacopoeia defines water for pharmaceutical use as follows:Water for Injection:Water purified by distillation(or oth
9、er process)to remove chemicals and microorganismsPrepared from water complying with suitable standardContains no added substance Purified water:Water obtainable by a suitable process,prepared from water complying with suitable standard,contains no added substance.第6页/共28页Pharmaceutical Microbiology
10、PM227USP 23 standardsPurified WaterWFIOrganics0.5ppm TOC0.5ppm TOCConductivity1.3mS/cm at 25oC in-line measurement1.3mS/cm at 25oC in-line measurementEndotoxin by LALNo specification0.25 EU/mlBacteria100 cfu/ml80oCMulti-cartridge filtersRO unit Deionisation unit0.5m mm pre-filter-reduce particle and
11、 microbial content and extends life of final filter UV sanitizer-(254nm)reduces microbial flora,ozone and chlorine content(but can generate endotoxins)0.2 m mm final filterStorage tank,distribution loop(“dead legs”and low flow should be avoided)and pumps.Distillation still(for WFI production)第8页/共28
12、页Pharmaceutical Microbiology PM229DeionisationUsually consists of 1 to 4 cylindrical cartridgesGood at removing dissolved solids and gasesPoor at removing other impurities.Stagnant water in cartridges may increase bioburden of water!Needs to be combined with other purification systems for high grade
13、 water.第9页/共28页Pharmaceutical Microbiology PM2210Deionisation(contd)Deionisation works by:Water passed through deionisation resins(tiny spherical plastic beads)cationic contaminants in water exchanged with hydrogen ions in resinanionic contaminants in water exchanged for hydroxyl ions in resin.Impur
14、ities eventually replace hydrogen and hydroxy ions in resin and resin has to be replaced.第10页/共28页Pharmaceutical Microbiology PM2211第11页/共28页Pharmaceutical Microbiology PM2212Reverse OsmosisOsmosis=movement of water across a semipermeable membrane from an area of high concentration to an area of low
15、 concentration.In Reverse osmosis the process is reversed,due to presence of a high pressure pump.Pump applies pressure to the concentrated side(i.e.impure water),forcing molecules over to the pure side,leaving impurities behind to be removed as waste.Often combined with deionisers第12页/共28页Pharmaceu
16、tical Microbiology PM2213Reverse OsmosisReverse osmosis is a very efficient process.Removes:100%suspended solids99.5%bacteria,viruses,pyrogens.97-99.5%organics94-99%inorganics.第13页/共28页Pharmaceutical Microbiology PM2214Reverse Osmosis第14页/共28页Pharmaceutical Microbiology PM2215DistillationWater heate
17、d to boiling point and resultant water vapour,or steam,is condensed.Condensate(or distillate)is then collected.Not an“on-demand”method.Water has to be distilled and then stored in advance.Wasteful process as much as 95%of feedwater may be wasted,leaving only about 5%as pure product.Also requires hig
18、h energy input.Still design important to avoid carry-over(“entrainment”)of water droplets that contain impurities第15页/共28页Pharmaceutical Microbiology PM2216Distillation第16页/共28页Pharmaceutical Microbiology PM2217Water Storage and DistributionOnce water has been distilled,it must be held in appropriat
19、e holding and distribution system in order to prevent microbial contamination and growth.This can be achieved as follows:Use water immediately on collection from stillOnly applicable to small-scale useCollect water in clean vessel,seal and sterilseOnly applicable to small-scale use.Collect water,pip
20、e directly from still to insulated holding tank and hold at 80oC.Pump from tank when required.Connect insulated holding tank to ring-piping system,continuously circulate water back to tank at 80oC.Method most commonly used in large-scale sterile manufacturing.第17页/共28页Pharmaceutical Microbiology PM2
21、218SteamWhere steam comes in contact with product or with product-contact surfaces,“clean steam”required.E.g.steam supplied to autoclave chamberSIP systems.Clean steam produced in specially designed“Clean steam generators”or“Pure steam generators”from purified or distilled water第18页/共28页Pharmaceutic
22、al Microbiology PM2219Water System DesignQualityWhat type of water will be used and where?QuantityHow much water will be used,flow rate?TimeUsage profile:e.g.8 hrs per day,24/7?SpaceWhere is water system/loop being placed?MoneyOverall budget.第19页/共28页Pharmaceutical Microbiology PM2220Water System De
23、signPhysical layoutCreate a usage layoutStart with a drawing of the building and mark use pointsColour code the use points to indicate usage needsFlow,daily usage,quality,ergonimics.第20页/共28页Pharmaceutical Microbiology PM2221第21页/共28页Pharmaceutical Microbiology PM2222Water treatment 第22页/共28页Pharmac
24、eutical Microbiology PM2223Ozone(O3)Loop SanitisationUser points interlockedOzone generator activated,UV unit deactivatedOzone concentration monitoredSanitisation timer started when ozone concentration in return rises to 200 ppb When time out period expires,Ozone generator deactivated,UV unit activa
25、tedUser points unlocked when concentration at UV outlet falls to 10 ppb第23页/共28页Pharmaceutical Microbiology PM2224Microbiological Water testingGuidelines e.g.USP Standard Methods for the examination of water and wastewater.Pour plate method or membrane filtration method used for enumeration of micro
26、bes in sample,MPN/serial dilutions and selective agar for detection of coliforms.Endotoxins(WFI)tested by LAL or other method(rabbit test)第24页/共28页Pharmaceutical Microbiology PM2225Chemical testingTOC can be determined using a spectrophotometer Sample placed in cuvette,absorbance read第25页/共28页Pharma
27、ceutical Microbiology PM2226Routine monitoringSampling sites and frequencies to be establishedEstablish alert and action limitsWorksheets to record test resultsTrend results over timeCarry out investigation/corrective action if action limits exceeded or alert limits exceeded a number of times.第26页/共
28、28页Pharmaceutical Microbiology PM2227SummaryThe 3 main types of water used in pharmaceutical manufacturing are potable water,purified water and WFI.Standards for water are defined in the pharmacopoeias.A typical water purification system includes pre-filters,filters,softeners,a RO unit,a deionisatio
29、n unit,a sanitiser and possibly a still.Deionisation removes dissolved solids and gases by exchange of impurities with ions contained in resins.RO removes impurities by applying pressure to impure water and forcing impurities out through a semi-permeable membrane.Distillation involves heating water to produce steam and then cooling it again to collect the condensate.Water systems are designed around the water usage needs of the companyWater must be routinely tested microbiologically and chemically.第27页/共28页Pharmaceutical Microbiology PM2228谢谢您的观看！第28页/共28页