Cleaning-Process-Development-and-Validation.ppt

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1、Part IRegulatory/Compliance OverviewnApplicable regulations and requirementsn21 CFR 211.65 a)nEquipment . surfaces which contact components, in-process materials, or drug products shall not be reactive, additive or absorptive.n21 CFR 211.67 nEquipment and utensil . cleaned, maintained, and sanitized

2、 at appropriate intervals to prevent or contamination that would alter the safety, identity, strength, quality, or purity Regulatory/Compliance Overviewn21 CFR 211.182nWritten cleaning ProcedurenCleaning and use lognCholestyramine Resin USP recall due to the low level contamination with intermediate

3、s and degradants after reuse of recovered solvents from pesticide production increased FDA awareness. Regulatory/Compliance OverviewnGuidancenGuide to Inspection for Validation of Cleaning Processes. FDA, 1993nICH Q7A, GMP for Pharmaceutical Active IngredientsRegulatory/Compliance OverviewnFDA 21 Ce

4、ntury Risk-Based Quality System Initiative nDefine critical product attributes and control of critical processes (Process Capacity) to ensure:nSAFETY, PURITY, EFFICACY, QUALITYnDesign “Quality” into processes nScience-based risk managementnReal time QA Cleaning Validation OverviewnObjectivesnAssuran

5、ce of product purity, safety, efficacy and qualitynPrevention of product cross contamination by byproduct, residual product, microbial residue and residual detergentnWhen cleaning validation is required nIntroduction of new equipment/product nManufacturing/cleaning process changesnRaw material/clean

6、ing agent changesCleaning Validation OverviewnGood system designnComprehensive Master Validation ProgramnEffective cleaning process developmentnAdequate analytical techniquenJustifiable acceptance criteria product specific (How Clean is Clean?)nContinuous data monitoring and evaluationnAcceptance cr

7、iteria adjustment as necessaryCleaning Validation OverviewnRoutine review of deviations, excursions and change control related to cleaning process parameters, equipment, and materialsnRe-validation as requirednDefine what and how to revalidatenDefine when to revalidatenApplication of validation life

8、cycle managementCleaning Validation OverviewnCleaning Validation Lifecycle ManagementValidation Master PlanCleaning Cycle Development(Re)Validation (IQ/OQ/PQ)New product/EquipmentRoutine Testing Regular Data Review Evaluation of Cleaning ParametersCleaning Cycle DevelopmentnElements to considernDesi

9、gn/Construction complexity of equipmentnCharacteristics of residuals/product to cleannCleaning agentsnType of cleaning process (Automated vs. Manual)nManufacturing processnAnalytical methods and their sensitivityEquipment Design/Construction for Effective CleaningnAdequate design/structural complexi

10、ty and configurationnMaterial and SurfacenNon-Reactive and cleanabilitynCompatibility with detergentsnStage of Manufacturing Process nUpstreamnDown stream Increased RisknDrug productEquipment Design/Construction for Effective Cleaning nStructural/design complexitynSize and process piping configurati

11、on for CIPnPotential dead leg/space nAdequate turbulence nAdequate slopenNozzle design and locationsnBranch piping orientationEquipment Design/Construction for Effective CleaningInstrument Tee for CIP : L/D 1.5DLAdequate turbulence (Flow rate) for CIP ft/sec5 ft/sec5 ft/secEquipment Design/Construct

12、ion for Effective CleaningCIP ReturnCIP ReturnGoodBadEquipment Design/Construction for Effective CleaningBranch piping orientationBad DesignGood DesignUpDownParallelCharacteristics of ProductsnUnderstand (Bio)chemical characteristics of Product(s) nProduct matrixnType of active molecule (e.g., prote

13、in, DNA, peptide, small molecule)nExcipients/Process related components nProduct matrix is a critical element for: nCleaning process design nFor the determination of a detergent and process parametersCharacteristics of ProductsnPhysicochemical characteristics nSolubility with medium (e.g., water, or

14、ganic solvent)nReactivity is a critical element for the determination of process parameters nDegree of a reaction with a detergent or medium at different conditions.nDegradantsnChemical statenLiquidnSemi-solidnSolidCharacteristics of ProductsnMicrobe static propertynCritical for detergent selection

15、nToxicity/Pharmacological potencynCritical for acceptance criteria nPotential product and/or component degradants after reaction with a detergentnCritical for acceptance criteria Cleaning Agent SelectionnSelection of a Cleaning AgentnDepending on the particular type of chemicals (soils) to remove co

16、nsidering:nChemical/Physical nature of the molecule (soil) to removenReactivitynPhysicochemical characteristics of the moleculenChemical state of soilsCleaning Agent Selection nType of Detergent AcidicAcidic AlkalineAlkalinen Inorganic soils are more soluble in acidic detergentn Works well as blends

17、 of several acidsn Make organic soils water soluble via the change of chemical/physical nature of organic soilsn Easy to choosen Equipment corrosionn Difficult to choosen Less compatible with other cleaning componentsn Precipitation of water hardnessn No cleaning effect on mineral residuesn Limited

18、to organicsnVery concentration dependentCleaning Agent Selection nBiological soils alkaline nBlending of other cleaning components with alkaline detergent enhances cleaning effects.nBuilders the group of complexing agents that enhance the cleaning effect and the effect of surfactantnEDTA, polyphosph

19、ate, NTA, citratesCleaning Agent Selection nSurfactants several types based on the ion characteristics of the active groupnAnionic, cationic, non-ionic and amphotericnAnionic and Non-ionic: used as components for detergentnCationic and amphoteric: used in the formulations of disinfectants for their

20、microcidal effectnSurface tension capillary action Cleaning Agent Selection nComplexing agents complexing with minerals and inorganic componentsnSequestering agent prevention of scale formation (crystallization of water hardness)nMay reduce the need for acid cleaning following the base cleaningnDefo

21、rmersnOxidizing agents H2O2nCorrosion inhibitors - Silicates Cleaning Agent Selection0 2 4 6 8 10 12 14 Cleaning Time (mins)80706050403020100% Removed SoilCleaning agent + Builder + SurfactantSingle cleaning agentSurfactant BuilderCleaning Agent SelectionnApplication parameters for cleaning agents n

22、Type of cleaning agent nDepending on the type of soils to removenConcentrationnEffectivenessnEH&S consideration nTemperaturenContact timeCleaning Process Development nSelection of Cleaning ProcessnAutomated vs. ManualnAutomated CIP and/or COP nConsistency and reproducibility nReadily validatablenBet

23、ter process controlnManualnInconsistency nHard to validatenInadequate for most of the state-of-the-art facilitiesCleaning Process DevelopmentnConsider:nHistorical cleaning data (trending)nPrevious validation data if availablenComplexity and delicacy of manufacturing equipmentnLevel of facility autom

24、ationnCleaning cycle developmentnCIP or COP design and capacitynNature of soils Cleaning Process DevelopmentnComplexity and delicacy of equipment nNature of product contacting surfacenSequencenCritical parametersnLegging time between the end of equipment use and cleaningnTemperaturenPressure nVolume

25、 nProcess time Cleaning Process DevelopmentnTypes of CIP (Clean-in-place)nPortable CIPnSimple control and non re-circulationnMultiple-Tank Re-use CIPnSeparate tanks for detergents (Acid, Base) and washing solution (e.g., water)nRe-circulation and re-use of detergents and washing solutionnMay not be

26、adequate for biopharmaceutical in terms of prevent cross contamination (e.g., viral contamination) Cleaning Process DevelopmentnSingle and multiple-tank single usesingle use CIPnAppropriate for Biopharmaceuticals: re-circulationnRelatively easy for validation but depending on number of pumps, valves

27、, and the complexity of cycle nHigh degree of cycle flexibilitynNo re-use of cleaning agent for biopharmaceuticalsnValidation is depending on the complexity of the cleaning sequence.Cleaning Process DevelopmentnCOP (Clean-out of place)nUsed for miscellaneous fittings and parts out of the main equipm

28、ent (disassembly)nA single open tank for rinsing and washing nRe-circulation of detergent using a detergent feed pumpnAppropriate cycle development Cleaning Process DevelopmentnAutomated CIP system components and functionsnTemperature sensorsn Two for re-circulation system cleaning solution supply a

29、nd return monitoringnTemperature is a primary indicator of cleaning cycle performancenConductivity sensorsnDetergent conc. monitoringnConductivity a primary indicator of cleaning cycle performanceCleaning Process DevelopmentnpH sensorsnMonitoring of rinsing efficacynCIP supply flow sensorsnFlow rate

30、 and totalization are directly related to contact timenMagnetic flow sensors not recommended because of inability to sense non-conductive fluidnCIP supply pressure sensorsnIndicator of spray device performance and solution contact timeCleaning Process DevelopmentnCIP vessel level sensorsnIndirect in

31、dicator of performance of the systemnReturn flow switchnConductance based probenPrevention of inadvertent events such as mis-connection of supply and return circuits product contaminationnSpray devicenFixed and rotatingPart II SafetyPurityEfficacyCleaning Process DevelopmentnSequence developmentnPre

32、-rinse: piping and equipment to be cleaned by pressure washingnEnd pointnTotal volume or timenOn-line turbidity, conductivity or return flownMust be drained or to kill-tankCleaning Process DevelopmentnDetergent washingnAcid or alkali depending on the type of soilnContinuous feednEndpointnVolume or t

33、imenMust be drainednSoaking with detergent as necessarynChromatography systemCleaning Process DevelopmentnPost rinse and drainsnTo remove residue after pre-rinse and detergent washingnContinuous flow and drainnUsually not heated nNeutralization wash and drainnEndpoint total volume and/or elapse time

34、nFinal rinse and drainnEndpoint total volume and/or elapse time, pH, conductivityCleaning Process DevelopmentnParameter and range determinationnFactoring experimental design (example)pHpH5.56.06.53010TempTemp4020Conc Conc (%)(%)(C)(C)5030102030TimeTime(min)(min)Cleaning Process DevelopmentnStudy app

35、roachnCoupon studynSame materials as manufacturing equipmentnEquivalent surface treatmentnExperimental runnWorst case approachnResidues to be cleanednEquipment surfacenAppropriate sampling and analytical methodsCleaning Process DevelopmentnSampling nDirect surface samplingnSelection of:nAppropriate

36、sample dissolving mediumnSample containernSampling material(s)nSwab Interference by adhesive, Variability Swabbing unidirectionally with a new wet swab for each direction Wet swab and finish with a dry swabCleaning Process DevelopmentnRinse water samplenDilution effectnUnreliable, inconsistent recov

37、ery nVisual inspectionCleaning Process DevelopmentnAnalytical MethodsnDepending on the types of analytesnProteinsnOrganic compoundsnInorganic compoundsnOther biological contaminantsnAdversary agents nMycoplasma, virusnResidual host bacteriaCleaning Process DevelopmentnType of analytical methodsnSpec

38、ific nMulti-product equipmentnPotent productnToxic or potent degradants or contaminantsnNon-specificnBroad applicationnHolistic evaluationnSelection of methods based on the nature of analytesCleaning Process DevelopmentnDevelopment of specific method(s) requires longer timenMatrix of the material fo

39、r method development should be the representative of the cleaning sample.nInhibitory or enhance effects of the sample matrix must be evaluated and appropriate sample preparation and method should be developed.nSensitive and specific Cleaning Process DevelopmentnSelection of appropriate method(s) is

40、a key for successful cleaning validationnRoutine and validationnMethods must be validated for nSensitivity (LOD/LOQ)nSpecificitynPrecisionnAccuracyCleaning Process DevelopmentnExamples of methods widely used in biopharmaceutical cleaning processSpecific MethodsSpecific MethodsNon-specific MethodsNon

41、-specific Methodsn Bioassayn ELISAn HPLCn Q-PCRn SDS-PAGEn LALn TOC n pHn Conductivityn UVn Bioburdenn OsmolarityCleaning Process DevelopmentnUse methods in combination nValidation and routine cleaning sample analysisnTest intended routine cleaning samples during the validation study and establish c

42、o-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 nValidation ApproachnDevelopment of Validation Master Plan to desc

43、ribe:nObjective, scope, references, responsibilitiesnNature of products (dosage form and therapeutic areas) all productsnManufacturing processnInclude equipment list nCleaning system and process for each type of equipmentCleaning ValidationnValidation StrategynMulti-use vs. dedicated equipmentnIndiv

44、idual vs. group vs. matrixnScope of use vs. configuration nEach product basis vs. worst case approach nDefine the worst case or group nProvide a scientifically sound justification if chosen (e,g., degree of difficulty in cleaning, toxicity) nList of Equipment and qualification statusnEquipment P&IDs

45、nCleaning system (e.g., CIP) qualification (I/OQ) statusCleaning ValidationnAnalytical method selection and validation requirementsnRecovery study requirements recovery factornDetermination of sampling methodsnLot requirements for validation nDocumentation requirementsnProtocolnReportsnRaw datanRe-v

46、alidation requirements and frequencynValidation project planning (Generic)Cleaning ValidationnCleaning Validation PrerequisitesnEnsure that all cleaning process equipment are adequately qualified.nDraft a cleaning SOP based on the development study.nPrepare P&ID for each piece of equipment and defin

47、e sampling locations and/or methods.nEnsure that analytical methods are validated.Cleaning ValidationnConduct a recovery study per type of equipment construction material.nProtocol drivennReport recovery factor for each type of equipment construction materialnDefine acceptance criteria.nJustificatio

48、n must be established.nDevelop a detailed plan and responsibilities.Cleaning Validation nRecovery studynRecovery rate is directly related to the condition of equipment surface and sampling technique.nDefine appropriate sampling methods and techniques.nRecovery factor must be reflected on the residue

49、 calculation during the cleaning validation.Cleaning ValidationnConsiderations for recovery study nCoupons and other materials nRepresentative of all types of equipment (316L SS, Glass, plastic)nSame surface treatment (e.g., electropolishing)nSampling materialsnSample containernSampling methodsnSpik

50、ing solution preparationnSimulated cleaning samplenConcentration should be at a level of acceptance acceptance criteriaCleaning ValidationnSpiking and spiked coupon handling procedures nClean coupons before spikingnSimulate actual cleaning condition nAllow the spiked solution to be on the coupon the