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
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