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1、Cleaning Process Development and Validation,June 16,2006Brian KimVP of QualityTanox,Inc.,Part I,Regulatory/Compliance Overview,Applicable regulations and requirements21 CFR 211.65 a)Equipment.surfaces which contact components,in-process materials,or drug products shall not be reactive,additive or ab
2、sorptive.21 CFR 211.67 Equipment and utensil.cleaned,maintained,and sanitized at appropriate intervals to prevent or contamination that would alter the safety,identity,strength,quality,or purity,Regulatory/Compliance Overview,21 CFR 211.182Written cleaning ProcedureCleaning and use logCholestyramine
3、 Resin USP recall due to the low level contamination with intermediates and degradants after reuse of recovered solvents from pesticide production increased FDA awareness.,Regulatory/Compliance Overview,GuidanceGuide to Inspection for Validation of Cleaning Processes.FDA,1993ICH Q7A,GMP for Pharmace
4、utical Active Ingredients,Regulatory/Compliance Overview,FDA 21 Century Risk-Based Quality System Initiative Define critical product attributes and control of critical processes(Process Capacity)to ensure:SAFETY,PURITY,EFFICACY,QUALITYDesign“Quality”into processes Science-based risk managementReal t
5、ime QA,Cleaning Validation Overview,ObjectivesAssurance of product purity,safety,efficacy and qualityPrevention of product cross contamination by byproduct,residual product,microbial residue and residual detergentWhen cleaning validation is required Introduction of new equipment/product Manufacturin
6、g/cleaning process changesRaw material/cleaning agent changes,Cleaning Validation Overview,Good system designComprehensive Master Validation ProgramEffective cleaning process developmentAdequate analytical techniqueJustifiable acceptance criteria product specific(How Clean is Clean?)Continuous data
7、monitoring and evaluationAcceptance criteria adjustment as necessary,Cleaning Validation Overview,Routine review of deviations,excursions and change control related to cleaning process parameters,equipment,and materialsRe-validation as requiredDefine what and how to revalidateDefine when to revalida
8、teApplication of validation lifecycle management,Cleaning Validation Overview,Cleaning Validation Lifecycle Management,Validation Master Plan,Cleaning Cycle Development,(Re)Validation(IQ/OQ/PQ),New product/Equipment,Routine Testing,Regular Data Review,Evaluation of Cleaning Parameters,Cleaning Cycle
9、 Development,Elements to considerDesign/Construction complexity of equipmentCharacteristics of residuals/product to cleanCleaning agentsType of cleaning process(Automated vs.Manual)Manufacturing processAnalytical methods and their sensitivity,Equipment Design/Construction for Effective Cleaning,Adeq
10、uate design/structural complexity and configurationMaterial and SurfaceNon-Reactive and cleanabilityCompatibility with detergentsStage of Manufacturing Process UpstreamDown stream Increased RiskDrug product,Equipment Design/Construction for Effective Cleaning,Structural/design complexitySize and pro
11、cess piping configuration for CIPPotential dead leg/space Adequate turbulence Adequate slopeNozzle design and locationsBranch piping orientation,Equipment Design/Construction for Effective Cleaning,Instrument Tee for CIP:L/D 1.5,D,L,Adequate turbulence(Flow rate)for CIP,ft/sec,5 ft/sec,5 ft/sec,Equi
12、pment Design/Construction for Effective Cleaning,CIP Return,CIP Return,Good,Bad,Equipment Design/Construction for Effective Cleaning,Branch piping orientation,Bad Design,Good Design,Up,Down,Parallel,Characteristics of Products,Understand(Bio)chemical characteristics of Product(s)Product matrixType o
13、f active molecule(e.g.,protein,DNA,peptide,small molecule)Excipients/Process related components Product matrix is a critical element for:Cleaning process design For the determination of a detergent and process parameters,Characteristics of Products,Physicochemical characteristics Solubility with med
14、ium(e.g.,water,organic solvent)Reactivity is a critical element for the determination of process parameters Degree of a reaction with a detergent or medium at different conditions.DegradantsChemical stateLiquidSemi-solidSolid,Characteristics of Products,Microbe static propertyCritical for detergent
15、selection Toxicity/Pharmacological potencyCritical for acceptance criteria Potential product and/or component degradants after reaction with a detergentCritical for acceptance criteria,Cleaning Agent Selection,Selection of a Cleaning AgentDepending on the particular type of chemicals(soils)to remove
16、 considering:Chemical/Physical nature of the molecule(soil)to removeReactivityPhysicochemical characteristics of the moleculeChemical state of soils,Cleaning Agent Selection,Type of Detergent,Cleaning Agent Selection,Biological soils alkaline Blending of other cleaning components with alkaline deter
17、gent enhances cleaning effects.Builders the group of complexing agents that enhance the cleaning effect and the effect of surfactantEDTA,polyphosphate,NTA,citrates,Cleaning Agent Selection,Surfactants several types based on the ion characteristics of the active groupAnionic,cationic,non-ionic and am
18、photericAnionic and Non-ionic:used as components for detergentCationic and amphoteric:used in the formulations of disinfectants for their microcidal effectSurface tension capillary action,Cleaning Agent Selection,Complexing agents complexing with minerals and inorganic componentsSequestering agent p
19、revention of scale formation(crystallization of water hardness)May reduce the need for acid cleaning following the base cleaningDeformersOxidizing agents H2O2Corrosion inhibitors-Silicates,Cleaning Agent Selection,0 2 4 6 8 10 12 14 Cleaning Time(mins),80706050403020100,%Removed Soil,Cleaning agent+
20、Builder+Surfactant,Single cleaning agent,Surfactant,Builder,Cleaning Agent Selection,Application parameters for cleaning agents Type of cleaning agent Depending on the type of soils to removeConcentrationEffectivenessEH&S consideration TemperatureContact time,Cleaning Process Development,Selection o
21、f Cleaning ProcessAutomated vs.ManualAutomated CIP and/or COP Consistency and reproducibility Readily validatableBetter process controlManualInconsistency Hard to validateInadequate for most of the state-of-the-art facilities,Cleaning Process Development,Consider:Historical cleaning data(trending)Pr
22、evious validation data if availableComplexity and delicacy of manufacturing equipmentLevel of facility automationCleaning cycle developmentCIP or COP design and capacityNature of soils,Cleaning Process Development,Complexity and delicacy of equipment Nature of product contacting surfaceSequenceCriti
23、cal parametersLegging time between the end of equipment use and cleaningTemperaturePressure Volume Process time,Cleaning Process Development,Types of CIP(Clean-in-place)Portable CIPSimple control and non re-circulationMultiple-Tank Re-use CIPSeparate tanks for detergents(Acid,Base)and washing soluti
24、on(e.g.,water)Re-circulation and re-use of detergents and washing solutionMay not be adequate for biopharmaceutical in terms of prevent cross contamination(e.g.,viral contamination),Cleaning Process Development,Single and multiple-tank single use CIPAppropriate for Biopharmaceuticals:re-circulationR
25、elatively easy for validation but depending on number of pumps,valves,and the complexity of cycle High degree of cycle flexibilityNo re-use of cleaning agent for biopharmaceuticalsValidation is depending on the complexity of the cleaning sequence.,Cleaning Process Development,COP(Clean-out of place)
26、Used for miscellaneous fittings and parts out of the main equipment(disassembly)A single open tank for rinsing and washing Re-circulation of detergent using a detergent feed pumpAppropriate cycle development,Cleaning Process Development,Automated CIP system components and functionsTemperature sensor
27、s Two for re-circulation system cleaning solution supply and return monitoringTemperature is a primary indicator of cleaning cycle performanceConductivity sensorsDetergent conc.monitoringConductivity a primary indicator of cleaning cycle performance,Cleaning Process Development,pH sensorsMonitoring
28、of rinsing efficacyCIP supply flow sensorsFlow rate and totalization are directly related to contact timeMagnetic flow sensors not recommended because of inability to sense non-conductive fluidCIP supply pressure sensorsIndicator of spray device performance and solution contact time,Cleaning Process
29、 Development,CIP vessel level sensorsIndirect indicator of performance of the systemReturn flow switchConductance based probePrevention of inadvertent events such as mis-connection of supply and return circuits product contaminationSpray deviceFixed and rotating,Part II,Safety,Purity,Efficacy,Cleani
30、ng Process Development,Sequence developmentPre-rinse:piping and equipment to be cleaned by pressure washingEnd pointTotal volume or timeOn-line turbidity,conductivity or return flowMust be drained or to kill-tank,Cleaning Process Development,Detergent washingAcid or alkali depending on the type of s
31、oilContinuous feedEndpointVolume or timeMust be drainedSoaking with detergent as necessaryChromatography system,Cleaning Process Development,Post rinse and drainsTo remove residue after pre-rinse and detergent washingContinuous flow and drainUsually not heated Neutralization wash and drainEndpoint t
32、otal volume and/or elapse timeFinal rinse and drainEndpoint total volume and/or elapse time,pH,conductivity,Cleaning Process Development,Parameter and range determinationFactoring experimental design(example),Cleaning Process Development,Study approachCoupon studySame materials as manufacturing equi
33、pmentEquivalent surface treatmentExperimental runWorst case approachResidues to be cleanedEquipment surfaceAppropriate sampling and analytical methods,Cleaning Process Development,Sampling Direct surface samplingSelection of:Appropriate sample dissolving mediumSample containerSampling material(s)Swa
34、b Interference by adhesive,Variability,Swabbing unidirectionally with a new wet swab for each direction,Wet swab and finish with a dry swab,Cleaning Process Development,Rinse water sampleDilution effectUnreliable,inconsistent recovery Visual inspection,Cleaning Process Development,Analytical Methods
35、Depending on the types of analytesProteinsOrganic compoundsInorganic compoundsOther biological contaminantsAdversary agents Mycoplasma,virusResidual host bacteria,Cleaning Process Development,Type of analytical methodsSpecific Multi-product equipmentPotent productToxic or potent degradants or contam
36、inantsNon-specificBroad applicationHolistic evaluationSelection of methods based on the nature of analytes,Cleaning Process Development,Development of specific method(s)requires longer timeMatrix of the material for method development should be the representative of the cleaning sample.Inhibitory or
37、 enhance effects of the sample matrix must be evaluated and appropriate sample preparation and method should be developed.Sensitive and specific,Cleaning Process Development,Selection of appropriate method(s)is a key for successful cleaning validationRoutine and validationMethods must be validated f
38、or Sensitivity(LOD/LOQ)SpecificityPrecisionAccuracy,Cleaning Process Development,Examples of methods widely used in biopharmaceutical cleaning process,Cleaning Process Development,Use methods in combination Validation and routine cleaning sample analysisTest intended routine cleaning samples during
39、the validation study and establish co-relationship between specific and non-specific sample test results.Use the ratio as a correction factor during the routine cleaning sample analysis if the results show relative difference in a consistent manner.,Cleaning Validation,Validation ApproachDevelopment
40、 of Validation Master Plan to describe:Objective,scope,references,responsibilitiesNature of products(dosage form and therapeutic areas)all productsManufacturing processInclude equipment list Cleaning system and process for each type of equipment,Cleaning Validation,Validation StrategyMulti-use vs.de
41、dicated equipmentIndividual vs.group vs.matrixScope of use vs.configuration Each product basis vs.worst case approach Define the worst case or group Provide a scientifically sound justification if chosen(e,g.,degree of difficulty in cleaning,toxicity)List of Equipment and qualification statusEquipme
42、nt P&IDsCleaning system(e.g.,CIP)qualification(I/OQ)status,Cleaning Validation,Analytical method selection and validation requirementsRecovery study requirements recovery factorDetermination of sampling methodsLot requirements for validation Documentation requirementsProtocolReportsRaw dataRe-valida
43、tion requirements and frequencyValidation project planning(Generic),Cleaning Validation,Cleaning Validation PrerequisitesEnsure that all cleaning process equipment are adequately qualified.Draft a cleaning SOP based on the development study.Prepare P&ID for each piece of equipment and define samplin
44、g locations and/or methods.Ensure that analytical methods are validated.,Cleaning Validation,Conduct a recovery study per type of equipment construction material.Protocol drivenReport recovery factor for each type of equipment construction materialDefine acceptance criteria.Justification must be est
45、ablished.Develop a detailed plan and responsibilities.,Cleaning Validation,Recovery studyRecovery rate is directly related to the condition of equipment surface and sampling technique.Define appropriate sampling methods and techniques.Recovery factor must be reflected on the residue calculation duri
46、ng the cleaning validation.,Cleaning Validation,Considerations for recovery study Coupons and other materials Representative of all types of equipment(316L SS,Glass,plastic)Same surface treatment(e.g.,electropolishing)Sampling materialsSample containerSampling methodsSpiking solution preparationSimu
47、lated cleaning sampleConcentration should be at a level of acceptance acceptance criteria,Cleaning Validation,Spiking and spiked coupon handling procedures Clean coupons before spikingSimulate actual cleaning condition Allow the spiked solution to be on the coupon the maximum time as cleaning time l
48、imit is defined the SOP.Evenly spike the solution on the defined area of the coupon.The coupon spiking area should be an equal to the actual sampling area on the actual equipment.,Cleaning Validation,Coupon arrangement Coupon to be arranged to have areas or separate coupons for:Background blank Cont
49、rol spiking sample prep solution Sample spiking area Sampling Protocol and reportDefine expected acceptance criteriaExample:60 120%RECOVERYThe recovery factor=Spiked value/recovered value,Cleaning Validation,Acceptance Criteria ApproachVisually cleanliness Prerequisite of cleaning acceptance.Cannot
50、be an acceptance criterion alone.Cleaning capabilityStatistical analysis of historical cleaning dataProduct specific dataNon-specific data(e.g,rinse water TOC)to be evaluated based on the worst case(toxicity)residual.Data should be analyzed from the toxicity and dosage level perspective,Cleaning Val
