在线总有机碳（TOC）用户使用手册.pdf

8PHARMACEUTICAL ENGINEERING JANUARY/FEBRUARY 2009Cleaning ValidationContinued on page 10.This articleoffers analternativemethod tocleaningvalidation usingonline totalorganic carbonanalyzers todeterminecleaningvalidation in-situ.Methodsare comparedwith traditionallaboratoryanalysis.Online Total Organic Carbon(TOC)as aProcess Analytical Technology forCleaning Validation Risk Managementby Keith Bader,John Hyde,Peter Watler,andAmber LaneOnline Total Organic Carbon(TOC)analysis has progressed significantlyin the past few years,yet it remains anunder-utilized technology.The USFDA has stated that TOC is an acceptablemethod for both cleaning validation and rou-tine monitoring,provided the suitability of themethod has been established and documented.1Advances in TOC analyzer oxidation and analy-sis methodologies make their integration intoClean-in-Place(CIP)systems instrumentationrelatively easy as a means to provide near realtime cleaning process performance informa-tion.While it is currently possible and practi-cal to utilize online TOC analysis for the real-time assessment of CIP cycle performance,thebiopharmaceutical manufacturing industry hasbeen slow to adopt it without favorable andaccepted regulatory precedents.However,theseprecedents do exist in FDA guidance docu-ments on Process Analytical Technology(PAT),the Risk-Based Manufacture of Pharmaceuti-cal Products(both in 2004),and the Interna-tional Conference on Harmonization(ICH)Quality Risk Management guideline in 2005,which signal a regulatory environment recep-tive to active monitoring and control of criticalprocess parameters.The case study presented in this article wasconducted to test the relative cleanability ofthree different bottom mounted agitators.Thedata by which the cleaning process was evalu-ated was acquired using an online TOC ana-lyzer integrated into the return line of a CIPsystem as well as by conventional manualindirect and direct sampling and offline analy-sis.Implementing TOC as an online processanalytical technology requires first determin-ing if the analytical technology and method areappropriate for the application.Primarily,theinstallation of process analyzers on equipmentused in GMP manufacturing facilities shouldbe done only after risk analyses are performedto ensure that the installation does not ad-versely affect the process or product quality.The location,physical integration,and auto-mation of the online analyzer into the cleaningsystem return piping are important consider-ations as these factors may impact the accuracyand robustness of the measurements.Onceinstalled,the reliability of the technology mustbe demonstrated through a comparison of onlineresults with existing conventional test meth-ods,including any developmental studies sup-porting the efficacy and appropriateness of theparticular analytical method.In this case,theanalytical method TOC,is used to detect pro-cess and product residues in final rinse waterfollowing cleaning.Selection of a TOC AnalyzerBased on InstrumentalCharacteristics and CIP ProcessConsiderationsThe selection of an appropriate TOC analyzerrequires knowledge of its basic operating prin-ciples to ensure that CIP process conditions donot interfere with analytical results.Since thereis little opportunity to customize the availablefeatures of an online TOC analyzer,selection ofan analyzer with the appropriate oxidation andsensor equipment can accommodate both ana-lyzer specifications and CIP operational re-quirements.Though the basic operational prin-ciples for all TOC analyzers are much the same,the oxidation and sensor technologies vary be-tween manufacturers.Matching the character-Reprinted fromPHARMACEUTICALENGINEERINGThe Official Magazine of ISPEJanuary/February 2009,Vol.29 No.1Copyright ISPE 2009www.ISPE.org10PHARMACEUTICAL ENGINEERING JANUARY/FEBRUARY 2009Cleaning Validationistics of CIP processes with an array of specific sensor andoxidation technologies compatible with those characteristicswill yield a robust application of the online analyzer,enablingminimized operational and validation efforts with respect tocleaning processes.For CIP applications,accurate results from an onlineanalyzer must not be confounded by interference from ionicspecies,variations in sample pressure,or changes in sampletemperature.Since conductivity is used in some cases toquantify evolved CO2,the ionic species in many cleaningagent formulations must be considered as a potential sourceof interference.These conductive species may be addressedthrough the use of a membrane conductometric sensor as inFigure 1 or through the use of photometric detection schemesthat are insensitive to the presence of conductive ions.Mem-brane conductometric detectors allow selective permeabilityof CO2 across a membrane without permitting other conduc-tive ions into the measurement zone.Therefore,measuredconductivity results entirely from Inorganic Carbon(IC)orTotal Carbon(TC)oxidized to CO2,effectively eliminatingthis source of interference.For online TOC analyzers in which samples are directlyintroduced to the analyzer from the CIP return manifold,sample temperature and pressure are relevant parameters toconsider.Sufficient pressure is required in the sample line toensure that the analyzed sample concentration doesnt sig-nificantly lag in the CIP return piping.Additionally,care alsoshould be taken to protect the analyzer from pressuresexceeding manufacturers recommendations.In most cases,CIP pressures will not exceed the pressure specifications foran instrument;however,close attention must still be given tothe configuration,size,and placement of automated sam-pling valves and associated sample lines drawing from CIPsystem return lines.Stabilization of analyzer inlet pressureand flowrate will allow for consistency in the residence timeof fluid in the sample lines.Temperature fluctuations are a relevant concern depend-ing on the selected analyzer,especially if the analysis methodis conductometric.Conductivity is a temperature dependantmeasurement that each instrument manufacturer accommo-dates in a different manner.Temperature variations in thesample stream may be addressed through temperature com-pensated conductivity sensors,or measurement of raw con-ductivity data with sampling apparatus that allow for tem-perature equilibration through ambient dissipation or activeheat exchange.Alternatively,a detection method that is nottemperature dependant(such as NDIR)may be used.TOC concentration is indirectly obtained by calculatingthe difference between two directly measured parameters;TC and IC.Equation 1 illustrates this relationship.TOC=TC-IC(Eq1)Total Carbon is determined by oxidizing organic carboncontaining compounds to CO2 and quantifying both the inor-ganic carbon already present in the sample along with theevolved CO2.In the case of a membrane conductometricanalyzer(Figure 1),Inorganic Carbon(IC)in analyzed samplesresults from dissolved CO2 species(HCO3-,CO3-2),and may bemeasured directly without oxidation of the sample.As depicted in Figure 1,solution from the sample vial isinjected into the analyzer where acid is introduced to theFigure 1.Diagram of a membrane conductometric UV/persulfate TOC analyzer-optional inorganic carbon removal units may be employedif samples have higher levels of dissolved atmospheric CO2.Continued on page 12.Process EngineeringGEA Liquid ProcessingGEA Process Engineering Inc.9165 Rumsey Road Columbia MD 21045 Tel:[phone] Fax:[phone] E-mail: Website:The PANDA NS1001 2K is a bench top unit capable of handling a broad range of applications including cell rupture,particle size reduction and emulsions.The PANDA 2K with its?ideal for processing small batches of product with results that are directly scalable through to pilot and production machines operating at up to 5500 l/h.?Performance:Operating pressure 0 1500 bar Flow rate up to 12 l/h 1500 bar Minimum sample volume 200ml Maximum product viscosity 2000 cPs(20,000 with optional pressure feed)Maximum inlet particle size=0.5mm Optional 2nd stage homogenizing valve Suitable for CIP and SIP ”Tri Clamp inlet/outlet connections Dimensions L800mm x W460mm x H420mm Weight 85 kg 1.8 kW 3ph/60Hz/208,230 or 460V motor(only utility requirement)Optional inverter available to allow 1ph/60Hz/200-240V power supplyEngineering Excellence.GEA Niro Soavi Laboratory Homogenizer type PANDA 2K 1001LBeforeAfter12PHARMACEUTICAL ENGINEERING JANUARY/FEBRUARY 2009Cleaning Validationsample stream.The added acid shifts the equilibrium suchthat inorganic carbon species convert to CO2.After the acidaddition,a persulfate oxidant is added and the sample streammixed to ensure homogeneity.The sample stream is thensplit with one stream passing through a reactor and exposedto UV light,initiating a photolysis reaction.As the sample inthe reactor is oxidized,CO2 evolves and is transferred acrossa gas permeable membrane into a deionized water streamwhere its conductivity is measured.The formation of theconductive species occurs via the carbonate buffer pathwayshown in Equation 2.CO2+H2O H2CO3H2CO3+H2O H3O+HCO-(Eq2)HCO-+H2O H3O+CO-2333The other sample stream flows through a hydro-dynamicallyidentical path(identified in Figure 1 as the delay coil)wheredissolved CO2 is transferred across the membrane and con-ductivity is measured to provide an inorganic carbon refer-ence measurement required for the calculation of TOC.Analytical and Sampling MethodDevelopmentFor this study,two analyzers were employed;both equippedwith membrane conductometric sensors.The offline analyzerused a methodology based upon UV and persulfate oxidation,whereas the online analyzer used only UV oxidation.Toensure the reliability and comparability of the measure-ments from the online and offline analyzers,USP systemsuitability tests were preformed to confirm response effi-ciency using 1,4 benzoquinone and sucrose standards.Theinstrumental limit of detection of 50 ppb TOC required perthe USP2 was met for both analyzers.Once operation of both analyzers was demonstrated to beacceptable,methods were developed using the offline ana-lyzer to characterize the Bovine Serum Albumin(BSA)to beused as a representative process soil and to evaluate andquantify the systemic and experimental error associatedwith TOC surface swab sampling.Stainless steel couponsalso were spiked at multiple weight loadings to develop arecovery response curve.From a 10%by weight solution of BSA,a series of dilutionswere prepared with target concentrations of 500,1000,5000,7500,and 10,000 ppb TOC.The solutions were then analyzedto ensure that the TOC response curve for BSA was linear andto empirically characterize the samples carbon content toestablish a correlation between the concentrations of TOCand BSA.Analysis of the samples produced the response curveshown in Figure 2.Also reported are the linear regressiontrend line through the data points,which provides an indica-tion of the linearity of the relationship,Limits of Detection(LOD)and Limits of Quantitation(LOQ).The regression linecorrelation coefficient(R2)of 0.9998 demonstrates that theregression line fits the data and is a reasonable model for theplotted data.To ascertain the surface swab recovery characteristicsfor BSA,a study was conducted using stainless steel cou-pons spiked with known concentrations of BSA.The targetorganic carbon loading(ppb)is indicated by the Sample IDnumbers in Table A.To account for the inter-individualvariability,the study was conducted with three techniciansindependently executing the swab sampling method.Swabsampling recovery was evaluated by comparing the TOCrecovered from the coupons to the TOC content of positivecontrol samples in which equivalent amounts of BSA solu-tion to that spiked on the surface of the correspondingcoupons was spiked into a vial containing 40mL of diluent.The results are summarized in Table A,and shown graphi-cally in Figure 3 and Figure 4.The correlation coefficient(R2)value greater than 0.99 foreach of the technicians provides assurance that the recoveryfits a linear model when inter-individual variability is takeninto account.Evaluation of the LOD and LOQ for the sam-pling method for each technician is shown in Table A andranges from 122 to 195 ppb TOC,and 371 to 589 ppb TOC,respectively.The slope of each recovery curve also is arepresentation of the overall surface swab recovery over theTable A.Surface swab recovery results.SamplingPositive ControlBlank CorrectedTechnicianSample IDTOC(ppb)Sample TOC(ppb)Percent RecoverySampler LODSampler LOQ125023118178.550063359493.812537710001137101689.3225023119484.150063356188.51223711000113793682.3325028019368.850080864980.219558910001105101792.0Figure 2.TOC response curve for Bovine Serum Albumin.Continued on page 14.Intelligen Suite The Market-Leading Engineering Suite for Modeling,Evaluation,Scheduling,and Debottlenecking of Single&Multi-Product FacilitiesUse SuperPro Designer to model,evaluate,and debottleneck batch and continuous processesSwitch to SchedulePro to schedule,model,and debottleneck multi-product facilitiesSuperProScheduleProTracking of equipment occupancyin multi-product facilitiesTracking demand for resources(e.g.,labor,materials,utilities,etc.)Inventory tracking for raw materials,intermediates,products,and wastesSuperPro Designer is a comprehensive process simulator that facilitates modeling,cost analysis,debottlenecking,cycle timereduction,and environmental impact assessment of biochemical,specialty chemical,pharmaceutical(bulk&fine),food,consumerproduct,mineral processing,water purification,wastewater treatment,and related processes.Its development was initiated at theMassachusetts Institute of Technology(MIT).SuperPro is already in use at more than 400 companies and 500 universities aroundthe world(including 18 of the top 20 pharmaceutical companies and 9 of the top 10 biopharmaceutical companies).SchedulePro is a versatile finite capacity scheduling tool that generates feasible production schedules for multi-product facilitiesthat do not violate constraints related to the limited availability of facilities,equipment,resources and work areas.It can be usedin conjunction with SuperPro(by importing its recipes)or independently(by creating recipes directly in SchedulePro).Any industrythat manufactures multiple products by sharing production lines and resources can benefit from the use of SchedulePro.Engineering companies use it as a modeling tool to size utilities for batch plants,identify equipment requirements,reduce cycletimes,and debottleneck facilities.Visit our website to download detailed product literature and functional evaluation versions of our toolsINTELLIGEN,INC.2326 Morse Avenue Scotch Plains,NJ 07076 USATel:[phone] Fax:[phone]Email: Website:Intelligen also has offices in Europe and representatives in countries around the worldRecipeDB14PHARMACEUTICAL ENGINEERING JANUARY/FEBRUARY 2009Cleaning ValidationFigure 4.Characterization of TOC surface swab sampling method(BSA