GMPWaterSystem(cGMP培訓(xùn)系列1)ppt課件

1、GMP Water System GMP水系統(tǒng)GMP Training Module 121DisclaimerThe following slides are copied from WHO presentation on water system in Shanghai on Feb 28 March 4, 2005. 聲明根據(jù)世界衛(wèi)生組織的有關(guān)培訓(xùn)資料改寫而成2Part IWater Pre-treatment3水的預(yù)處置Water Introduction and treatment水的引入和處置4Objectives目的Introduction to Water for Pharma

2、ceutical UseReview WHO GMP guidance Sources and types of water for pharmaceutical useStorage of bulk, untreated raw waterPre-treatment of water5Principles (1) Like any starting material, water must conform to Good Manufacturing Practice normsIt must be “potable and comply with WHO Guidelines for dri

3、nking-water quality原那么 1必需符合GMP對原料的根本要求必需至少是飲用水規(guī)范6Principles (2)Potential for microbial growthSystems must be properly validatedWater for parenteral use could be contaminated with pyrogens or endotoxinsSpecifications and periodic testing is required原那么2微生物生長能夠系統(tǒng)必需被論證注射用水能夠被污染定期測試7Types of water used

4、 in pharmaceutical processes Purified water Water for Injections PFW & WFI Softened Water Water for Final Rinse Pure, or clean Steam Water for cooling Autoclaves原那么2微生物生長能夠系統(tǒng)必需被論證注射用水能夠被污染定期測試8Why purify raw water?水為什么要凈化？Although reasonably pure, it is always variableSeasonal variations may occur i

5、n waterSome regions have very poor quality waterMust remove impurities to prevent product contamination.Control microbes to avoid contaminating products9Contaminants of water (1)水的能夠污染源There is no pure water in nature, as it can contain up to 90 possible unacceptable contaminantsContaminant groups:I

6、norganic compoundsOrganic compoundsSolids GasesMicro-organisms無機，有機，固體，液體，微生物10Contaminants of water (2)水的污染源2Treatment depends on waters chemistry and contaminants, influenced by: Rainfall Erosion Pollution Dissolution Evaporation Sedimentation Decomposition雨水，腐蝕，污染，水溶物，蒸發(fā)物，沉淀物及分解物11Contaminants of

7、 water (3)Problem minerals 水的污染物 3 礦物質(zhì)Calcium and magnesium Iron and manganeseSilicatesCarbon dioxideHydrogen sulfidePhosphates12Contaminants of water (4)Further problem minerals 水的污染物4重金屬CopperAluminiumHeavy metalsArsenic, lead, cadmiumNitrates13Contaminants of water (5)Micro-organisms Biofilm水的污染物

8、5 生物膜水草，原生動物，細菌AlgaeProtozoaCryptosporidiumGiardiaBacteriaPseudomonasGram negative, non-fermenting bacteriaEscherichia coli and coliforms14Water hardness classificationmg/L or ppm as CaCO3Soft0-60Moderate61-120Hard121-180Very Hard 180Water hardness水的硬度15Source of raw water -水源Rain waterSurface or gr

9、ound water Well or boreholeMunicipal or civil “tap waterPurchased in bulk16 Water treatment guidance水處置指點 The following should be monitored Sources of water Treatment procedures Water treatment equipment Treated water tests Monitoring records required17水源處置程序處置設(shè)備水測試記錄監(jiān)視Pre-treatment stepsPrimary fil

10、tration and multi-media filterCoagulation or flocculation DesalinationSoftening預(yù)處置程序預(yù)過濾，多媒質(zhì)過濾凝結(jié)去鹽軟化18 raw water inS trap to sewerWater is kept circulatingTo water softener & DI plant Pretreatment schematic drawingcartridgefilter5 micrometersactivatedcarbonfilterspray ballbreak tankair break to drain

11、centrifugal pumpair filterfloatoperatedvalvesand filterexcess water recycledfrom deioniser19圖表brine and salt tankbrinehard waterinzeolite water softenerexchangesCa and Mg for Nadrainsoft water to deioniserby pass valve Water Softener schematic drawing軟化劑圖表20Part IIWater Purification水凈化 21ObjectivesT

12、o examine the basic technology and requirements for:Water treatment systemsStorage requirementsSampling and testingDifferent types of water used in pharmaceuticalsMicrobial limits, disinfection22目的水處置系統(tǒng)存儲要求取樣，測試水的種類微生物，消毒W(wǎng)ater system design Pipes sloped so water does not pool and can drain easilySan

13、itary fittings & connectionsConstructed of suitable materials such as stainless steelCirculate the waterIncorporate non-return valves (NRV)23水系統(tǒng)測試管子呈一定坡度，以防止回流和方便排放衛(wèi)生要求不銹鋼資料堅持循環(huán)不回復(fù)閥門Further water treatment purification stages downstream of the pre-treatment system Filtration Disinfection Reverse osm

14、osis or de-ionization Distillation or ultra-filtration24預(yù)處置后的凈化步驟過濾消毒反浸透/去離子蒸餾或超凈化Water system design (1)There should be no dead legsWater scours deadlegIf D=25mm & distance X isgreater than 50mm, we havea dead leg that is too long.Deadleg section2DFlow direction arrows on pipes are importantSanitar

15、y ValveDX25絕對要防止盲管的發(fā)生!3. The water is contaminated as it passes through the valve2. Bacteria can grow when the valve is closedWater system design (2)1. Ball valves are unacceptable Stagnant water inside valve26球閥不可用Sanitary pumps Clamps and O rings versus threaded fittingsHeat exchangersSide arm lev

16、el measuring devices are unacceptableWater system design (3) 27Cationic columnAnionic columnHygienic pumpOutlets or storage.Ozone generatorUV lightHClNaOHEluates toneutralizationplantAir break to sewer Drain linefrom water softenerWater must be kept circulatingTypical de-ionizer schematic12345612345

17、6Return to de-ioniserCartridgefilter 5 mCartridgefilter 1 m28水必需堅持循環(huán)raw waterHigh pressureFeedwaterunderpressureRejectwaterSemi-permeablemembranePermeatewaterdrain or recycleLow pressurePurified waterReverse osmosis (RO) theory29反浸透BranchBranch2nd stage buffer tankCartridgefilter 1 mSecond stage RO

18、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 PharmacopoeiastandardsOutlets or storage1st stage buffer tank Water f

19、rom softener or de-ioniser Water returns to 1st stage buffer tankTypical 2-stage RO schematicHygienic pumpFirst stage RO cartridgeHigh pressure pump30Use of reverse osmosis AdvantagesNo harmful by-productsEnergy efficientDisadvantagesSlow speedPossible contamination Waste waterMany uses purified wat

20、er feeding of distillation units or ultra-filtration unitsWater for Final RinseWater for Injections (if permissible)31RO優(yōu)點和缺陷Ultra-filtration超越濾 Can be used for WFI or for Water For Final Rinsing for parenteral manufacturing (if permitted)Removes organic contaminants, such as endotoxinsOperation at

21、80C, and sterilization at 121 C32Single-effect distillationsimple distillation, single effect vapour compression, thermo compressionMulti effect distillation multiple effect stillsClean steam generatorsused where steam can come into contact with product contact surfaces, e.g. sterilization-in-place

22、(SIP)33Typical water storage and distribution schematicWater must be kept circulatingSpray ballCartridgefilter 1 mAir breakto drainOutletsHygienic pumpOptionalin-line filter0,2 mUV lightFeed Water fromDI or ROHeat ExchangerOzone GeneratorHydrophobic air filter& burst disc34典型水儲存和流向圖Disinfection (1)殺

23、菌Heat One of the most reliable methods of disinfection of water systemsOzone Produced easilyLeaves no residue 35Disinfection (2)UV UV does not “sterilizeFlow rate criticalPost-irradiation recontamination may be an issueLamps have finite lifeOther chemicals XO2HalogenFormaldehyde36Sampling (1)取樣There

24、 must be a sampling procedureSample integrity must be assuredSampler trainingSample point Sample size37Sampling (2)Sample container Sample labelSample storage and transportArrival at the laboratory Start of test38Testing - setting specifications for purified water or WFI - (1) Ph. Eur. JP USPInt. Ph

25、.pH 5.0-7.05.0-7.0 5.0-7.0 pass testCl 0.5 pass test - pass testSO4 pass test pass test - pass testNH4 0.2 0.05 - pass testCa/Mg pass test - - pass testNitrates 0,2 pass test - pass testNitrites - pass test - -39水的目的 Ph. Eur. JP USPInt. PhConductivity (S/cm) - 1.3 -Oxidizable subs.pass test pass tes

26、t -pass testSolids (ppm) 10 10 - nmt(*) 10TOC (ppm) - 0.5 0.5 -Heavy metals - -pass testCO2 - -pass testTesting - setting specifications for purified water or WFI (2)40Testing測試Method verification方法驗證Chemical testing化學(xué)測試Microbiological testing微生物測試test methodtypes of media usedincubation time and te

27、mperatureobjectionable and indicator organismsmanufacturer must set specifications41Suggested bacterial limits 細菌含量(CFU /mL)Sampling locationTargetAlertActionRaw water200300500Post multimedia filter100300500Post softener100300500Post activated carbon filter50300500Feed to RO20200500RO permeate105010

28、0Points of Use11010042Part III Water System Inspection 水系統(tǒng)的檢驗43Raw water storage水的儲存May be required prior to pre-treatment Check material of construction Concrete, steel are acceptable but check corrosionPlastics or plastic linings may leachCheck cover To keep out insects, birds and animalsCheck dis

29、infection practicesWater for Pharmaceutical Use44Water treatment system inspection (1)Checks may include: dead legs filters pipes and fittingsIonic bedsstorage tanksby-pass linesWater for Pharmaceutical Use45盲管過濾器管道離子床儲存罐支管Water treatment system inspection (2)Checks may include: pumpsUV lightssample

30、 pointsreverse osmosisvalvesheat exchangersInstruments, controls, gauges, etc.Water for Pharmaceutical Use46泵紫外燈取樣點反向浸透閥熱交換器設(shè)備，儀表等Other checks (1)Stainless steel PVC and most plastics not recommended Weld qualityWater for Pharmaceutical Use47資料焊接點Other checks (2)Pipes and pumpshygienic couplingsweld

31、ed pipeshygienic pumpshygienic sampling pointsacceptable floorno leaksWater for Pharmaceutical Use48Staining on water storage tanksCorrosion on plates of heat exchangers indicates possible contaminationOther checks (3) Check condition of equipmentWater for Pharmaceutical Use49Other checks (4) Mainte

32、nance records, maintenance of pump seals and O rings Water for Pharmaceutical Use50維修記錄Air filters Integrity testing, sterilization and replacement frequency Check burst discsOther checks (5)Water for Pharmaceutical Use51Other checks (7)Activated carbon bed sanitizationTemperature-compensated conduc

33、tivity metersInfluence of plastic pipe adhesive on TOCNon-condensable gases in pure steamWater for Pharmaceutical Use52Other checks (8)Polypropylene welding inspection checking pin holesRetrospective validation of WFI systemRouging of WFI storage systemsSpray ball efficacyWater for Pharmaceutical Us

34、e53Other checks (9)UV light monitoring performance and lamp life and intensityValidating ozone dosageSpecifications for acids, alkalis for DI and sodium chloride for water softener“Normally open and “normally closed valvesWater for Pharmaceutical Use54Then review additional documentationQualificatio

35、n protocols and reportsChange control request (where applicable)Requalification (where applicable)QC and microbiology laboratory:SOP for samplingProcedures and records55Sampling (1)取樣There must be a sampling procedureSample integrity must be assuredSampler trainingSample point Sample size56Sampling

36、(2)取樣Sample container Sample labelSample transport and storageArrival at the laboratory Test methodWhen is the test started?57Testing測試Review method verificationChemical testingMicrobiological testingtest methodtypes of media usedincubation time and temperatureobjectionable and indicator organismsma

37、nufacturer must set specifications58Suggested bacterial limits (CFU /mL)Sampling locationTargetAlertActionRaw water200300500Post multimedia filter100300500Post softener100300500Post activated carbon filter50300500Feed to RO20200500RO permeate1050100Points of Use11010059Does Yinjing have two separate

38、d parts in the water system purification and distribution?Where is the “dead lake at the beginning? Before which stage of purification system?For the RO column/system, how often do they get changed?Does Yinjing have stainless steel for the distribution system to prevent biofilm buildup?Valves can only used a