在线总有机碳(TOC)用户使用手册.pdf
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1、8PHARMACEUTICAL ENGINEERING JANUARY/FEBRUARY 2009Cleaning ValidationContinued on page 10.This articleoffers analternativemethod tocleaningvalidation usingonline totalorganic carbonanalyzers todeterminecleaningvalidation in-situ.Methodsare comparedwith traditionallaboratoryanalysis.Online Total Organ
2、ic 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
3、 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
4、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 anda
5、ccepted 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
6、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 acquir
7、ed 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 areapprop
8、riate 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,an
9、d 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
10、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
11、 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 availablefeat
12、ures 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 technolo
13、gies 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 sp
14、ecific 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 confound
15、ed 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
16、 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 c
17、onduc-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
18、 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 pressu
19、resexceeding 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 retu
20、rn 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 temperat
21、ure 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-peratur
22、e 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 illustrate
23、s 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 ana
24、lyzed 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 a
25、nalyzer-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:410 997 8700 Fax:410 997 5021 E-mail: Website:The
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