Lifecycle Approach to Cleaning Validation

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In this presentation from IVT's 4th Annual Validation Week EU, Paul Pluta, discussed the differences between the traditional approach to cleaning validation and the lifecycle approach, applicable regulatory guidance, current industry trends, the necessary phases of the lifecycle approach (design and definition, cycle development, validation, and implementation), how to continously monitor the process, change control, and common obstacles to compliance.

Lifecycle Approach to Cleaning Validation

  1. 1. LIFECYCLE APPROACHC C O CTO CLEANING VALIDATIONPaul L. Pluta, PhDValidation Week EU, 20131
  2. 2. MANUAL CLEANING -- Do you really know what is happening?Q to operator: “Why is there so much foam in the tub?”A: “I put in extra soap because the equipment was really dirty.”Q to operator: “Why is there powder on the (clean) equipment?”A: “No problem -- We’ll get the residue when we set up ”A: No problem -- We ll get the residue when we set up.Q to operator: “Why don’t you follow the cleaning procedure?”Q to operator: Why don t you follow the cleaning procedure?A: “The cleaning procedure really doesn’t work.”ABOVE NOT ACCEPTABLE – TRAINING NEEDED2
  3. 3. MANUAL CLEANING -- Do you really know what is happening?Q to operator: “Why is there powder on the clean equipment?”p y p q pA: “It’s clean enough.”Q to QA (equipment inspection person): “Did you approve that the equipmentis clean?”A: “It’s clean enough.”Q to management: “Do you know that your equipment is not clean?”A: “It’s clean enough.”Q to operator: “You cleaned the gasket with pure soap – this is not theprocedure? Also it is dangerous – these are corrosive chemicals.”A: “That is the only way to get it clean.”Q: “So why don’t you tell someone to change the procedure?”A: “We don’t have time.”ABOVE NOT ACCEPTABLE – TRAINING NEEDED3
  4. 4. MANUAL CLEANING -- Do you really know what is happening?Q to management: “Did you finish cleaning the equipment? We arehere to swab for cleaning validation.”A ( dl ) “W l d th i t th ti th tA (very proudly): “We cleaned the equipment three times so that wewon’t have any problems.”Q to validation person: “Did you know that the manufacturing peoplealways clean the equipment multiple times before it is swabbed?”A: “Sure, we knew.Q: “Why didn’t you stop this?”A: “These people are our friends. We have to work with these people.”ABOVE NOT ACCEPTABLE – TRAINING NEEDED4
  5. 5. OUTLINEOUTLINELifecycle Approach Applied to Cleaning ValidationStage 1 ActivitiesStage 1 Activities• Cleaning Method Development• Analytical Method Development• Site equipmentStage 2 Activities• Cleaning documentation• Validation conformance lotsStage 3 Activities• Maintaining Validation• Change Control• Management review• Management review5
  6. 6. OBJECTIVESOBJECTIVES1. Application of lifecycle approach to cleaningvalidation2. Cleaning lifecycle stage details• Process development and understanding• Process qualification• Maintaining the validated stateg3. Cleaning validation problems• Global experiences6
  7. 7. Lifecycle Approach to Cleaning Validation –Value? Does this make sense?Value? Does this make sense?• Cleaning is a process• Validation lifecycle concepts being applied to equipment,facilities, utilities, computers, etc., by validation andtechnical expertsp• Who can argue with understanding, performing, andmaintaining the validated state?g• Consistent with QbD and ICH approaches• Lifecycle approach (i.e., understanding, performing,maintaining) vs. traditional approach – Which wouldyou rather present to an auditor?you rather present to an auditor?7
  8. 8. WHAT IS THE CLEANING PROCESS?Cleaning Process Performance Qualification (PPQ)A t t d CIP S tAutomated CIP SystemProcess steps QualificationProcess steps Qualification1. Residue on equipment Equipment2. Water procedure Purified Water3 Cleaning agent procedure Computer / software3. Cleaning agent procedure Computer / software4. Water procedure Compressed air5. Purified Water procedure Conductivity analysis6. Dry TOC analysisy yEquipment is clean -- Process is validatedProcess parameters Quality attributes8
  9. 9. WHAT IS THE CLEANING PROCESS?Cleaning Process Performance Qualification (PPQ)M l Cl iManual CleaningProcess steps QualificationProcess steps Qualification1. Residue on equipment Personnel2. Water rinse Purified Water3 S b ith l i t C d i3. Scrub with cleaning agent Compressed air4. Water rinse5. Scrub6. Water rinse7. Purified Water rinse8 Dry8. DryEquipment is clean -- Process is validatedProcess parameters Quality attributes9
  10. 10. CLEANING VALIDATION OVERVIEW1990 t1990s present1. Defined cleaning procedure (SOP) – basis?g p ( )2. Product A batch does not contaminate subsequentProduct B batch3. Acceptance limit calculated4. Assume uniform contamination of all equipment5 Three conformance lots = Validated cleaning procedure5. Three conformance lots = Validated cleaning procedure6. Validated analytical method (original API)7 Worst-case matrix approach7. Worst case matrix approachOne-time event10
  11. 11. FDA PROCESS VALIDATION GUIDANCELIFECYCLE APPROACH TRANSITIONLIFECYCLE APPROACH TRANSITIONAPPPLICATION TO CLEANING VALIDATIONPre LifecyclePre LifecycleCleaning development (?) PQ change control________________________Lif l A hLifecycle ApproachDevelopment PQ MaintenanceEXPANDED SCOPE OF VALIDATIONINCREASED SPECIFIC STAGE REQUIREMENTSINCREASED SPECIFIC STAGE REQUIREMENTS11
  12. 12. LIFECYCLE APPROACH TO CLEANING VALIDATIONScientific and technical approachDesign and development– Residue + cleaning agent + cleaning procedure Clean equipmentPerformance demonstrationMonitoring and maintenanceRationale, responsibility, and accountabilityRationale, responsibility, and accountabilityFuture process improvementsNot the following:St d d it th d ( b i ti l )– Standard site method (no basis or rationale)– Personnel driven (no control)– “Do whatever it takes” (high variation)– SOP (no accountability)– Validation (?) – One-time event.12
  13. 13. STAGE 1, PROCESS DESIGN (PROCESS UNDERSTANDING)APPLICATION TO CLEANINGFDA Guidance Topics1. Building and capturing process knowledge and understanding.2. Establishing a strategy for process control.Application to CleaningUnderstand residue chemistry (solubility, stability)Determine cleaning agent based on residue chemistryDetermine cleaning agent based on residue chemistryDetermine cleaning process• Identify sources of variability• Establish methods to control variabilityEstablish methods to control variability– Process Analytical TechnologyRational analytical method and supporting worky pp gCharacterization of equipment to be cleaned and supporting workTrained sampling personnelDOCUMENT ALL OF THE ABOVE13
  14. 14. DEVELOPMENT (STAGE 1)CLEANING PROCESS DEVELOPMENTCLEANING PROCESS DEVELOPMENT• Physical and chemical properties of the residue is basis for cleaningprocessprocess• Considerations for determination of most difficult-to-clean residue• Residue solubility and stability in determining worst-case soilsResidue chemistry critical for analytical method• Residue chemistry critical for analytical method• Cleaning agent chemistry consistent with residue chemistry• Cleaning process chemistry and engineering and consistent withresidue and cleaning agent.RESIDUE CHEMISTRY– BASIS FOR CLEANING PROGRAM– BASIS FOR ANALYICAL METHOD14
  15. 15. RESIDUE PROPERTIES -- BASIS FOR CLEANING PROCESSCase study: Antibiotic suspension containing insoluble API (base)Original cleaning method: Water, PurW, dry• No documented cleaning validation for many yearsNo documented cleaning validation for many years• Unknown peaks on original cleaning validation attempts• API insolubleSecond method: Alkaline soap wash water PurW drySecond method: Alkaline soap wash, water, PurW, dry• Unknown peaks again• API insolubleFi l th d A id h lk li h t P W dFinal method: Acid wash, alkaline soap wash, water, PurW, dry• No residues• Unknown peaks determined to be degradants and flavors.API di l ( id b t li ti )• API dissolves (acid-base neutralization)Consider active drug and other residue chemistry in developmentof cleaning processof cleaning process15
  16. 16. DETERMINATION OFMOST DIFFICULT TO CLEAN RESIDUEMOST DIFFICULT TO CLEAN RESIDUEBASIS FOR CLEANING PROGRAMWater solubility – USP Tables• Is this adequate? NO!pH effect – API with ionizable groups?Solubility in cleaning agent?• Determine solubility at range pH 1-12• Understand solubility at pH of cleaning liquidUnderstand solubility at pH of cleaning liquid• Understand solubility in cleaning agent liquid16
  17. 17. pH SOLUBILITY PROFILE, pH 1-12p SO U O , pSolubilitymg/mlDrug ADrug BpH 1 7 1217
  18. 18. RESIDUE SOLUBILITY AND STABILITY FORDETERMINING WORST CASE SOILSDETERMINING WORST-CASE SOILSSolubility considerations• Hydrophilic and hydrophobic molecules• Ionization – Effect of pHEff t f t t• Effect of temperature• Surface active molecules• Liquid and semisolid product vehicle polarityLiquid and semisolid product vehicle polarityStability considerationsHydrolysis oxidation photolysis physical changes• Hydrolysis, oxidation, photolysis, physical changesWhat residue is really present?Consider chemistry of residues18
  19. 19. CLEANING MATRIXDetermine Worst-Case SoilSOLUBILITY (mg / ml)H 1 W t H 12 Alk lipH 1 Water pH 12 AlkalineCleaning AgentDrug A 25 25 25 25Drug B 15 15 15 15Drug C 5 5 150 250Drug C 5 5 150 250Drug D 150 10 10 50Drug E 125 10 100 250Consider acid cleaning agent for drugs D and E19
  20. 20. WORST CASE CLEANINGDetermination of worst-case cleaning basedon API toxicity, worst-case dose, etc.on API toxicity, worst case dose, etc.– Standard calculationCleaning procedure may be based onCleaning procedure may be based onexcipients having greatest effect oncleaningcleaning– Hydrophilic polymersD– Dyes– Hydrophobic vehicles20
  21. 21. BIOTECH CLEANING CHEMISTRY -- APIProtein molecules degrade in alkaline conditionsDegradation rate is milder in acidic conditionsgDegradation rate increases with temperatureAPI residues typically consist of protein fragments andaggregatesAnalytical method: Non-specific analysisReference: Kendrick, Canhuto, and Kreuze. Analysis ofDegradation Products of Biopharmaceutical API Causedg pby Cleaning Agents and Temperature. Journal ofValidation Technology, V15, #3, Summer 2009.21
  22. 22. BIOTECH CLEANING CHEMISTRY – GROWTH MEDIUMMedium Composition• Acids or bases• Monovalent salts• Monovalent salts• Polyvalent salts• Amino acids• Proteins (polypeptides)• Carbohydrates• Aqueous soluble organicsq g• Non-aqueous soluble organicsConsider medium composition at end of cycle.Reference: Azadan and Canhoto. A Scientific Approach to the Selection ofCleaning Validation Worst-Case Soils for Biopharmaceutical manufacturing.Cleaning and Cleaning Validation, Volume 1. 2011.Cleaning and Cleaning Validation, Volume 1. 2011.22
  23. 23. CLEANING CHEMISTRY MECHANISMS• Wetting• Emulsification• Dispersion• Solubilityy• Chelation• OxidationOxidation• Hydrolysis23
  24. 24. CLEANING AGENT OPTIONS• Water• Commodity alkalis and acidsy• Organic solvents• Surfactants– Anionic– Cationic– Amphoteric– Nonionic• Formulated detergents24
  25. 25. COMPONENTS OF FORMULATED DETERGENTS• Surfactants• Alkalis• Acids• Sequestrants / chelants• Dispersants / anti-redeposition agents• Corrosion inhibitors• Corrosion inhibitors• Oxidizing agents• Enzymes• Buffers / builders• PreservativesMUST HAVE CONTROL OF CLEANING AGENTHAVE CONFIDENTIALITY AGREEMENT WITH SUPPLIER25
  26. 26. CLEANING ENGINEERINGFactors affecting cleaning• Soil residueSoil residue– Soil levels, soil condition, hold times, soil mixing,water quality and residue,• Cleaner and parameters (TACT)– Time, Action, Concentration, Temperature– Others• Surface and equipment design26
  27. 27. CLEANING PROCESSSOURCES OF VARIATIONSOURCES OF VARIATION• Cleaning agent preparation – must be exact• Automated cleaning vs. manual cleaning• Manual cleaning process variation• Human physical strength variation• “Cleaning” between same-product batches ing pcampaign – residue level build-up• Campaign length – residue level build-up• Time to initiate cleaning (dirty hold time)• Residue chemical and physical changesp y g27
  28. 28. EQUIPMENT TO BE CLEANEDCleaning-related qualification• Product-contact materials• Compatibility with cleaning agents• Surface areas – need for residue calculationsE i t i l• Equipment equivalence• Most-difficult-to-clean locations on equipment -- Highestrisk locations for samplingrisk locations for sampling• Non-uniform contamination equipment• Non-uniform contamination sampling locationsg• Sampling methods (swab / rinse)Part of IQ/OQ/PQ for manufacturing equipment28
  29. 29. PROCEDURE TO DETERMINE SAMPLINGLOCATIONSLOCATIONSSpecific documented procedure recommendedSpecific documented procedure recommended• Equipment technical evaluation• Observation of equipment after processingObservation of equipment after processing• Equipment disassembly review• Cleaning procedure review• Cleaning procedure review• Equipment evaluation review• Operator interviews• Operator interviewsSOP describing aboveDocumentation of above for equipment sampling29
  30. 30. TIME TO INITIATE CLEANING“DIRTY HOLD TIME”DIRTY HOLD TIME1. Make Product A2 Cl2. Clean3. Make Product BHow long between end of #1 and start #2?Is residue same? Does residue change?Wh h h id ?What can happen to the residue?• Wet and dry processes• Chemical changes (hydrolysis oxidation etc )• Chemical changes (hydrolysis, oxidation, etc.)• Physical changes30
  31. 31. CAMPAIGN LENGTHHow many lots in manufacturing campaign beforecleaning must be done?cleaning must be done?What about “cleaning” between batches?What about cleaning between batches?• Equipment should be visually cleanTerminology: “Between lot procedure”• Terminology: Between lot procedure• How much residue “build-up?”DO NOT IDENTIFY AS “BETWEEN LOT CLEANING”31
  32. 32. MANUAL CLEANING• Manual cleaning procedures should bemonitored and maintained with increasedscrutiny compared to non-manual procedures• More frequent training of cleaning personnel• Increased supervision• Periodic (annual?) revalidation batchesManual cleaning is high riskManual cleaning is high risk32
  33. 33. ANALYTICAL METHOD DEVELOPMENTEarly stage 1 (development) analysis –validation not required but must be soundvalidation not required but must be soundValidated method when used for Stage 2cleaning validation and post validationcleaning validation and post-validationtesting (change control)All methods and data (including stage 1) subject toregulatory auditregulatory audit33
  34. 34. ANALYTICAL METHOD DEVELOPMENTAnalytical method must measure actual residue –what residue is actually present on equipmentsurfaces?• Small molecules– API– API degraded – specific or non-specific methodBi t h l l• Biotech molecules– API degraded – non-specific methodUNDERSTAND RESIDUE CHEMISTRY34
  35. 35. ANALYTICAL METHOD DEVELOPMENTCleaning agent residue• Analytical method to determine residual cleaningagent.• Information from cleaning agent vendor35
  36. 36. ANALYTICAL METHOD DEVELOPMENTR t diRecovery studiesCan sampling procedure adequately recover residuefrom equipment surfaces?from equipment surfaces?• Product contact materials• High % of total surface area• Obtain representative coupons from equipmentfabricatorsHi h ( 80%) t it i• High (e.g., >80%) acceptance criteria• Factor may be used in calculation– Multiple approachesMultiple approaches– Factor every calculation?All sampled surfaces must have recovery dataAll sampled surfaces must have recovery data36
  37. 37. SAMPLINGSampling methodsSampling methods• Sampling (swab) critical activity• Training programTraining program• Trained sampling personnel– Demonstrated acceptable performance• Documented training and retraining• Worst case compounds / procedures in training– Volatile solvents (importance of rapid technique)– Volatile solvents (importance of rapid technique)• Worst case sampling equipment– Extension poles• Retraining considerations– Who does sampling? Personnel skills37
  38. 38. SAMPLING TRAININGSampling is extremely critical to cleaningvalidation programvalidation programInadequate sampling = false negativeInsufficient pressure on surface– Insufficient pressure on surface– Swab solvent evaporationI ffi i t l d– Insufficient area sampledAuditors routinely ask for sampling program trainingmethods and training records38
  39. 39. STAGE 2, PROCESS QUALIFICATION –(VALIDATION PERFORMANCE)APPLICATION TO CLEANINGAPPLICATION TO CLEANING1. Design of a facility and qualification of utilities and equipment2. Process performance qualification3. PPQ protocol4 PPQ t l ti d t4. PPQ protocol execution and reportQualification of equipment, utilities, facilities• Cleaning equipment (CIP)Process Performance Qualification (PPQ) – commercial scaleConclusion that process consistently produces clean equipmentConformance batches• All support systems, documents, training, personnel, etc. in place• Target / nominal operating parameters within design space• Additional testing (swab / rinse)• Decision to “release cleaning process” for routine commercial useDecision to release cleaning process for routine commercial use• Post validation monitoring plan – Based on risk– Drug residue properties– Manual or CIP39
  40. 40. CLEANING EQUIPMENTCLEANING EQUIPMENTCIP system must be qualified (IQ/OQ/PQ or ASTMCIP system must be qualified (IQ/OQ/PQ or ASTME2500)Riboflavin (or other) coverage testing( ) g gTemperature controlsFlow rates etcFlow rates, etc.PAT inline systems– Drug disappearance – spectrophotometry, other methodsg pp p p y– Cleaning agent rinse -- conductivity40
  41. 41. CLEANING PROCEDURE DOCUMENTATION(Cl i B t h R d)(Cleaning Batch Record)SOPFill t k h lf f ll• Fill tank half full• Add half scoop of soap• Scrub as needed• Rinse until clean• Re-scrub and re-rinse if neededCLEANING PROCEDURE RECORD• Fill tank with 500 L water. Sign/date __________• Add 20.0 kg cleaning agent. Sign/date __________• Disassemble Part A. Steps 1,2,3,4,5• Scrub for 20 minutes. Sign/date __________• Disassemble Part B. Steps 1,2,3,4,5• Soak Part B in cleaning liquid for 10 minutes. Sign/date __________• Rinse Part A and Part B with 50 L water. Sign/date __________• Rinse with 50 L Purified Water. Sign/date __________• Dry with compressed airy p41
  42. 42. CLEANING PROCEDURE RECORD• Fill tank with 500 L water. Sign/date __________• Add 20.0 kg cleaning agent. Sign/date __________• Disassemble Part A. Steps 1,2,3,4,5p• Scrub for 20 minutes. Sign/date __________• Disassemble Part B. Steps 1,2,3,4,5• Soak Part B in cleaning liquid for 10 minutes. Sign/date __________g q g __________• Rinse Part A and Part B with 50 L water. Sign/date __________• Rinse with 50 L Purified Water. Sign/date __________• Dry with compressed airy pKEY POINTSExact concentration of cleaning agent liquidExact concentration of cleaning agent liquidSignature on quantitative stepsGrouping non-quantitative steps (e.g., disassembly)42
  43. 43. VALIDATION REQUEST / PLANInitiates cleaning validation• New cleaning validation or change control processi timprovements• Strategy and approach• Scientific and technical basis• Scientific and technical basis• Specify required protocols and other work to accomplishvalidation• Risk-based• References: Stage 1 Design / development reports43
  44. 44. VALIDATION PROTOCOLCleaning validation protocols and other workas specified in Validation Planas specified in Validation Plan– Risk basedInclude sampling pages indicating worstInclude sampling pages indicating worstcase sampling locations.S if t it iSpecify acceptance criteria44
  45. 45. VALIDATION RESULTS / REPORTTest results as required in validation protocol.• Discussion Consistency with Stage 1• Discussion. Consistency with Stage 1development work.• Clear statement the cleaning process is (or isClear statement the cleaning process is (or isnot) validated.• Recommendations for Stage 3 monitoring andRecommendations for Stage 3 monitoring andmaintenance.– Additional limited testing based on data and risk– Routine monitoring based on risk45
  46. 46. STAGE 3, CONTINUED PROCESS VERIFICATION(VALIDATION MONITORING AND MAINTENANCE)APPLICATION TO CLEANINGActivities to assure process remains in validated stateChange control -- evaluate impact of change and validate (test) asg p g ( )necessaryTrend and assess data– PAT rinse timesConductivity data– Conductivity dataStudy OOS and OOT (Out of Trend) dataImprove processImprove control to detect and reduce variabilityImprove control to detect and reduce variabilityCleaning non-conformances and deviationsRe-validation – definition: Actual batch or “paper”• Is re-testing necessary?• When should re-testing be considered?Periodic Management Review• Documentation reviewed by managementD d i46• Documented review
  47. 47. POST-VALIDATION MONITORING AND MAINTENANCE1. Stage 2 specific requirements– Additional testing based on actual data– Ex: One location has high (acceptable result)2. Routine monitoring and maintenance2. Routine monitoring and maintenance– Risk based3 Change control program3. Change control programCHANGE CONTROL MOST IMPORTANT ANDCHANGE CONTROL MOST IMPORTANT ANDDIFFICULT TO ADMINISTERPERSONNEL MUST RECOGNIZE “CHANGE”PERSONNEL MUST RECOGNIZE CHANGE47
  48. 48. POST-VALIDATION MONITORING AND MAINTENANCEResidue toxicity risk• Residue that can be visually seenResidue that can be visually seen– Room lighting must be adequateProvide additional lighting if necessary– Provide additional lighting if necessary• Residue that cannot be visually seeny– Swab after each batch?CONSIDER PATIENT RISK AND COMPANY RISK48
  49. 49. CHANGE CONTROLCHANGE CONTROL• All associated personnel must be aware ofh t lchange control• Change control system developed• Process improvements expected based onongoing experienceP i t h ld b l t d b• Process improvements should be evaluated bytechnical people (i.e., Stage 1)St 2 PPQ d t d h i t• Stage 2 PPQ conducted when appropriatebased on Stage 1 technical evaluation.49
  50. 50. POST-VALIDATION MONITORINGPeriodic review of cleaning performance• Deviations• Deviations• Non-conformances (dirty equipment)R l i• Re-cleaning• Change controlO h i i (CIP d )• Other monitoring (CIP data)• Product APR data• Statistical Process Control data treatment• Management review -- documented50
  51. 51. CLEANING DOCUMENTATION• High level documents• Specific cleaning validation documents– Design/Development, performance, monitoring/maintenance• Specific cleaning validation support documents (equipmentqualifications)• Cleaning validation approach documents (Worst case matrix,g pp ( ,calculations, sampling locations, etc.)• Production documents (Cleaning Procedure Records)– Production cleaning policiesg p• Management review documents• Associated documents– Personnel training in direct and associated areasPersonnel training in direct and associated areas– HR records51
  52. 52. CLEANING DOCUMENTATIONHigh level documents• Corporate policy• VMP (Cleaning VMP)Stage 1 documentsCl i d l t t• Cleaning process development report• Analytical method development report• Supporting equipment documents (materials, surface areas, equivalent equipment,sampling, etc.)p g, )Stage 2 documents• Validation PPQ request, protocol, results• Cleaning equipment qualification• Cleaning procedure recordStage 3 documents• Change control documents• Process monitoring• Process monitoring• Management reviewCONSISTENT LIFECYCLE STRATEGY AND APPROACHCONSISTENT LIFECYCLE STRATEGY AND APPROACH52
  53. 53. SUMMARYSTAGE 1 DESIGN AND DEVELOPMENTSTAGE 1 -- DESIGN AND DEVELOPMENTINCLUDING COMMON PROBLEMSUnderstanding cleaning process• Residue properties– Residue degradationResidue degradation• Rational cleaning process based on residue• Scientific and technical cleaning matrixU d t d d t l f i tiUnderstand and control sources of variation• Dirty hold time• CampaignsRational analytical method based on residue propertiesEquipment to be cleaned characterized• Worst case samplingWorst case sampling53
  54. 54. SUMMARY – EQUIPMENT TO BE CLEANEDINCLUDING COMMON PROBLEMSINCLUDING COMMON PROBLEMS• Equipment characterization• Equipment characterization• Residue calculations• Materials of product contact• Materials of product contact• Surface areasW t f li b d i k• Worst-case areas for sampling based on risk– Non-uniform contaminationEquivalent equipment• Equivalent equipment54
  55. 55. SUMMARY – ANALYTICALINCLUDING COMMON PROBLEMSINCLUDING COMMON PROBLEMSUnderstand residue• Solubility and stability• Validated analytical method for actual residue– Specific or non-specific analytical methods– Specific or non-specific analytical methods• API and cleaning agent residueRecovery studies from product contact materials• API and cleaning agentSwab / rinse testing on equipment• Most difficult to clean sampling sitesMost difficult to clean sampling sites• Use of auxiliary sampling equipment (extension pole)Swab / rinse training of sampling personnel55
  56. 56. SUMMARYSTAGE 2 – PERFORMANCESTAGE 2 – PERFORMANCEINCLUDING COMMON PROBLEMSCleaning Process Conformance LotsCleaning equipment qualifiedCleaning equipment qualifiedCleaning procedure specified (Not SOP)Cleaning documentationCleaning documentation– Request– Protocol– Results / ReportManual cleaning – high risk56
  57. 57. SUMMARYSTAGE 3 MAINTAINING VALIDATIONSTAGE 3 -- MAINTAINING VALIDATIONChange control evaluate impact of changeChange control -- evaluate impact of changeand validate (test) as necessaryImprove processImprove processImprove control to detect and reducevariabilityyCleaning non-conformances and deviationsPeriodic Management Reviewg57
  58. 58. CLEANING AND CLEANING VALIDATIONCLEANING AND CLEANING VALIDATIONFor the Pharmaceutical and Medical DeviceI d t iIndustriesV1 Basics Expectations and PrinciplesV1. Basics, Expectations, and PrinciplesV2. Applications of Basics and PrinciplesV3 Lifecycle Approach to Cleaning ValidationV3. Lifecycle Approach to Cleaning Validation(Expected end 2013)Paul L. Pluta, PhD, editor58
  59. 59. PAUL L PLUTA PhDPAUL L. PLUTA, PhDEditor-in-ChiefJo rnal of Validation TechnologJournal of Validation TechnologyJournal of GXP ComplianceAdvanstar CommunicationsAdjunct Associate ProfessorUniversity of Illinois at Chicago (UIC) College of PharmacyChicago, IL, USAPharmaceutical industry experiencey pContact: paul.pluta@comcast.net59

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