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Validation boot camp 3


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Validation boot camp 3

  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.”Q to operator: “Why don’t you follow the cleaning procedure?”A: “The cleaning procedure really doesn’t work.” ABOVE NOT ACCEPTABLE – TRAINING NEEDED 2
  3. 3. MANUAL CLEANING -- Do you really know what is happening?Q to operator: “Why is there powder on the clean equipment?”A: “It’s clean enough.”Q to QA (equipment inspection person): “Did you approve that the equipment is 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 the procedure? 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 NEEDED 3
  4. 4. MANUAL CLEANING -- Do you really know what is happening?Q to management: “Did you finish cleaning the equipment? We are here to swab for cleaning validation.”A (very proudly): “We cleaned the equipment three times so that we won’t have any problems.”Q to validation person: “Did you know that the manufacturing people always 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 NEEDED 4
  5. 5. OUTLINELifecycle Approach Applied to Cleaning ValidationStage 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 5
  6. 6. OBJECTIVES1.  Application of lifecycle approach to cleaning validation2.  Cleaning lifecycle stage details •  Process development and understanding •  Process qualification •  Maintaining the validated state3.  Cleaning validation problems •  Global experiences 6
  7. 7. Lifecycle Approach to Cleaning Validation – Value? Does this make sense?•  Cleaning is a process•  Validation lifecycle concepts being applied to equipment, facilities, utilities, computers, etc., by validation and technical experts•  Who can argue with understanding, performing, and maintaining the validated state?•  Consistent with QbD and ICH approaches•  Lifecycle approach (i.e., understanding, performing, maintaining) vs. traditional approach – Which would you rather present to an auditor? 7
  8. 8. WHAT IS THE CLEANING PROCESS? Cleaning Process Performance Qualification (PPQ) Automated CIP SystemProcess steps Qualification1. Residue on equipment Equipment2. Water procedure Purified Water3. Cleaning agent procedure Computer / software4. Water procedure Compressed air5. Purified Water procedure Conductivity analysis6. Dry TOC analysis Equipment is clean -- Process is validated Process parameters à Quality attributes 8
  9. 9. WHAT IS THE CLEANING PROCESS? Cleaning Process Performance Qualification (PPQ) Manual CleaningProcess steps Qualification1. Residue on equipment Personnel2.  Water rinse Purified Water3. Scrub with cleaning agent Compressed air4. Water rinse5. Scrub6.  Water rinse7.  Purified Water rinse8. Dry Equipment is clean -- Process is validated Process parameters à Quality attributes 9
  10. 10. CLEANING VALIDATION OVERVIEW 1990s àpresent1.  Defined cleaning procedure (SOP) – basis?2.  Product A batch does not contaminate subsequent Product B batch3.  Acceptance limit calculated4.  Assume uniform contamination of all equipment5.  Three conformance lots = Validated cleaning procedure6.  Validated analytical method (original API)7.  Worst-case matrix approach One-time event 10
  11. 11. FDA PROCESS VALIDATION GUIDANCE LIFECYCLE APPROACH TRANSITION APPPLICATION TO CLEANING VALIDATIONPre LifecycleCleaning development (?) à PQ à change control ________________________Lifecycle Approach Development à PQ à Maintenance EXPANDED SCOPE OF VALIDATION INCREASED SPECIFIC STAGE REQUIREMENTS 11
  12. 12. LIFECYCLE APPROACH TO CLEANING VALIDATIONScientific and technical approachDesign and development –  Residue + cleaning agent + cleaning procedure à Clean equipmentPerformance demonstrationMonitoring and maintenanceRationale, responsibility, and accountabilityFuture process improvements Not the following: –  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 process•  Identify sources of variability•  Establish methods to control variability –  Process Analytical TechnologyRational analytical method and supporting workCharacterization of equipment to be cleaned and supporting workTrained sampling personnel DOCUMENT ALL OF THE ABOVE 13
  14. 14. DEVELOPMENT (STAGE 1) CLEANING PROCESS DEVELOPMENT•  Physical and chemical properties of the residue is basis for cleaning process•  Considerations for determination of most difficult-to-clean residue•  Residue solubility and stability in determining worst-case soils•  Residue chemistry critical for analytical method•  Cleaning agent chemistry consistent with residue chemistry•  Cleaning process chemistry and engineering and consistent with residue and cleaning agent. RESIDUE CHEMISTRY –  BASIS FOR CLEANING PROGRAM –  BASIS FOR ANALYICAL METHOD 14
  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 years•  Unknown peaks on original cleaning validation attempts•  API insolubleSecond method: Alkaline soap wash, water, PurW, dry•  Unknown peaks again•  API insolubleFinal method: Acid wash, alkaline soap wash, water, PurW, dry•  No residues•  Unknown peaks determined to be degradants and flavors.•  API dissolves (acid-base neutralization) Consider active drug and other residue chemistry in development of cleaning process 15
  16. 16. DETERMINATION OF MOST DIFFICULT TO CLEAN RESIDUE BASIS 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 liquid•  Understand solubility in cleaning agent liquid 16
  17. 17. pH SOLUBILITY PROFILE, pH 1-12Solubilitymg/ml Drug A Drug BpH 1 7 12 17
  18. 18. RESIDUE SOLUBILITY AND STABILITY FOR DETERMINING WORST-CASE SOILSSolubility considerations•  Hydrophilic and hydrophobic molecules•  Ionization – Effect of pH•  Effect of temperature•  Surface active molecules•  Liquid and semisolid product vehicle polarityStability considerations•  Hydrolysis, oxidation, photolysis, physical changes What residue is really present? Consider chemistry of residues 18
  19. 19. CLEANING MATRIX Determine Worst-Case Soil SOLUBILITY (mg / ml) pH 1 Water pH 12 Alkaline Cleaning AgentDrug A 25 25 25 25Drug B 15 15 15 15Drug C 5 5 150 250Drug D 150 10 10 50Drug E 125 10 100 250Consider acid cleaning agent for drugs D and E 19
  20. 20. WORST CASE CLEANINGDetermination of worst-case cleaning based on API toxicity, worst-case dose, etc. –  Standard calculationCleaning procedure may be based on excipients having greatest effect on cleaning –  Hydrophilic polymers –  Dyes –  Hydrophobic vehicles 20
  21. 21. BIOTECH CLEANING CHEMISTRY -- APIProtein molecules degrade in alkaline conditionsDegradation rate is milder in acidic conditionsDegradation rate increases with temperatureAPI residues typically consist of protein fragments and aggregatesAnalytical method: Non-specific analysisReference: Kendrick, Canhuto, and Kreuze. Analysis of Degradation Products of Biopharmaceutical API Caused by Cleaning Agents and Temperature. Journal of Validation Technology, V15, #3, Summer 2009. 21
  22. 22. BIOTECH CLEANING CHEMISTRY – GROWTH MEDIUMMedium Composition•  Acids or bases•  Monovalent salts•  Polyvalent salts•  Amino acids•  Proteins (polypeptides)•  Carbohydrates•  Aqueous soluble organics•  Non-aqueous soluble organicsConsider medium composition at end of cycle.Reference: Azadan and Canhoto. A Scientific Approach to the Selection of Cleaning Validation Worst-Case Soils for Biopharmaceutical manufacturing. Cleaning and Cleaning Validation, Volume 1. 2011. 22
  23. 23. CLEANING CHEMISTRY MECHANISMS•  Wetting•  Emulsification•  Dispersion•  Solubility•  Chelation•  Oxidation•  Hydrolysis 23
  24. 24. CLEANING AGENT OPTIONS•  Water•  Commodity alkalis and acids•  Organic solvents•  Surfactants –  Anionic –  Cationic –  Amphoteric –  Nonionic•  Formulated detergents 24
  25. 25. COMPONENTS OF FORMULATED DETERGENTS•  Surfactants•  Alkalis•  Acids•  Sequestrants / chelants•  Dispersants / anti-redeposition agents•  Corrosion inhibitors•  Oxidizing agents•  Enzymes•  Buffers / builders•  Preservatives MUST HAVE CONTROL OF CLEANING AGENT HAVE CONFIDENTIALITY AGREEMENT WITH SUPPLIER 25
  26. 26. CLEANING ENGINEERINGFactors affecting cleaning•  Soil 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 design 26
  27. 27. CLEANING PROCESS SOURCES 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 in campaign – residue level build-up•  Campaign length – residue level build-up•  Time to initiate cleaning (dirty hold time)•  Residue chemical and physical changes 27
  28. 28. EQUIPMENT TO BE CLEANEDCleaning-related qualification•  Product-contact materials•  Compatibility with cleaning agents•  Surface areas – need for residue calculations•  Equipment equivalence•  Most-difficult-to-clean locations on equipment -- Highest risk locations for sampling•  Non-uniform contamination equipment•  Non-uniform contamination sampling locations•  Sampling methods (swab / rinse) Part of IQ/OQ/PQ for manufacturing equipment 28
  29. 29. PROCEDURE TO DETERMINE SAMPLING LOCATIONSSpecific documented procedure recommended•  Equipment technical evaluation•  Observation of equipment after processing•  Equipment disassembly review•  Cleaning procedure review•  Equipment evaluation review•  Operator interviewsSOP describing aboveDocumentation of above for equipment sampling 29
  30. 30. TIME TO INITIATE CLEANING “DIRTY HOLD TIME”1. Make Product A2. Clean3.  Make Product BHow long between end of #1 and start #2?Is residue same? Does residue change?What can happen to the residue?•  Wet and dry processes•  Chemical changes (hydrolysis, oxidation, etc.)•  Physical changes 30
  31. 31. CAMPAIGN LENGTHHow many lots in manufacturing campaign before cleaning must be done?What about “cleaning” between batches?•  Equipment should be visually clean•  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 be monitored and maintained with increased scrutiny compared to non-manual procedures•  More frequent training of cleaning personnel•  Increased supervision•  Periodic (annual?) revalidation batches Manual cleaning is high risk 32
  33. 33. ANALYTICAL METHOD DEVELOPMENTEarly stage 1 (development) analysis – validation not required but must be soundValidated method when used for Stage 2 cleaning validation and post-validation testing (change control) All methods and data (including stage 1) subject to regulatory audit 33
  34. 34. ANALYTICAL METHOD DEVELOPMENTAnalytical method must measure actual residue – what residue is actually present on equipment surfaces?•  Small molecules –  API –  API degraded – specific or non-specific method•  Biotech molecules –  API degraded – non-specific method UNDERSTAND RESIDUE CHEMISTRY 34
  35. 35. ANALYTICAL METHOD DEVELOPMENTCleaning agent residue•  Analytical method to determine residual cleaning agent.•  Information from cleaning agent vendor 35
  36. 36. ANALYTICAL METHOD DEVELOPMENTRecovery studiesCan sampling procedure adequately recover residue from equipment surfaces?•  Product contact materials•  High % of total surface area•  Obtain representative coupons from equipment fabricators•  High (e.g., >80%) acceptance criteria•  Factor may be used in calculation –  Multiple approaches –  Factor every calculation? All sampled surfaces must have recovery data 36
  37. 37. SAMPLINGSampling methods•  Sampling (swab) critical activity•  Training program•  Trained sampling personnel –  Demonstrated acceptable performance•  Documented training and retraining•  Worst case compounds / procedures in training –  Volatile solvents (importance of rapid technique)•  Worst case sampling equipment –  Extension poles•  Retraining considerations –  Who does sampling? Personnel skills 37
  38. 38. SAMPLING TRAININGSampling is extremely critical to cleaning validation programInadequate sampling = false negative –  Insufficient pressure on surface –  Swab solvent evaporation –  Insufficient area sampledAuditors routinely ask for sampling program training methods and training records 38
  39. 39. STAGE 2, PROCESS QUALIFICATION – (VALIDATION PERFORMANCE) APPLICATION TO CLEANING1.  Design of a facility and qualification of utilities and equipment2.  Process performance qualification3.  PPQ protocol4.  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 use•  Post validation monitoring plan – Based on risk –  Drug residue properties –  Manual or CIP 39
  40. 40. CLEANING EQUIPMENTCIP system must be qualified (IQ/OQ/PQ or ASTM E2500)Riboflavin (or other) coverage testingTemperature controlsFlow rates, etc.PAT inline systems –  Drug disappearance – spectrophotometry, other methods –  Cleaning agent rinse -- conductivity 40
  41. 41. CLEANING PROCEDURE DOCUMENTATION (Cleaning Batch Record)SOP•  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 air 41
  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 1,2,3,4,5•  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 airKEY POINTSExact 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 process improvements•  Strategy and approach•  Scientific and technical basis•  Specify required protocols and other work to accomplish validation•  Risk-based•  References: Stage 1 Design / development reports 43
  44. 44. VALIDATION PROTOCOLCleaning validation protocols and other work as specified in Validation Plan –  Risk basedInclude sampling pages indicating worst case sampling locations.Specify acceptance criteria 44
  45. 45. VALIDATION RESULTS / REPORTTest results as required in validation protocol.•  Discussion. Consistency with Stage 1 development work.•  Clear statement the cleaning process is (or is not) validated.•  Recommendations for Stage 3 monitoring and maintenance. –  Additional limited testing based on data and risk –  Routine monitoring based on risk 45
  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) as necessaryTrend and assess data –  PAT rinse times –  Conductivity dataStudy OOS and OOT (Out of Trend) dataImprove processImprove 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 management•  Documented review 46
  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 maintenance –  Risk based3. Change control program CHANGE CONTROL MOST IMPORTANT AND DIFFICULT TO ADMINISTER PERSONNEL MUST RECOGNIZE “CHANGE” 47
  48. 48. POST-VALIDATION MONITORING AND MAINTENANCEResidue toxicity risk•  Residue that can be visually seen –  Room lighting must be adequate –  Provide additional lighting if necessary•  Residue that cannot be visually seen –  Swab after each batch? CONSIDER PATIENT RISK AND COMPANY RISK 48
  49. 49. CHANGE CONTROL•  All associated personnel must be aware of change control•  Change control system developed•  Process improvements expected based on ongoing experience•  Process improvements should be evaluated by technical people (i.e., Stage 1)•  Stage 2 PPQ conducted when appropriate based on Stage 1 technical evaluation. 49
  50. 50. POST-VALIDATION MONITORINGPeriodic review of cleaning performance•  Deviations•  Non-conformances (dirty equipment)•  Re-cleaning•  Change control•  Other monitoring (CIP data)•  Product APR data•  Statistical Process Control data treatment•  Management review -- documented 50
  51. 51. CLEANING DOCUMENTATION•  High level documents•  Specific cleaning validation documents –  Design/Development, performance, monitoring/maintenance•  Specific cleaning validation support documents (equipment qualifications)•  Cleaning validation approach documents (Worst case matrix, calculations, sampling locations, etc.)•  Production documents (Cleaning Procedure Records) –  Production cleaning policies•  Management review documents•  Associated documents –  Personnel training in direct and associated areas –  HR records 51
  52. 52. CLEANING DOCUMENTATIONHigh level documents•  Corporate policy•  VMP (Cleaning VMP)Stage 1 documents•  Cleaning process development report•  Analytical method development report•  Supporting equipment documents (materials, surface areas, equivalent equipment, sampling, etc.)Stage 2 documents•  Validation PPQ request, protocol, results•  Cleaning equipment qualification•  Cleaning procedure recordStage 3 documents•  Change control documents•  Process monitoring•  Management review CONSISTENT LIFECYCLE STRATEGY AND APPROACH 52
  53. 53. SUMMARY STAGE 1 -- DESIGN AND DEVELOPMENT INCLUDING COMMON PROBLEMSUnderstanding cleaning process•  Residue properties –  Residue degradation•  Rational cleaning process based on residue•  Scientific and technical cleaning matrixUnderstand and control sources of variation•  Dirty hold time•  CampaignsRational analytical method based on residue propertiesEquipment to be cleaned characterized•  Worst case sampling 53
  54. 54. SUMMARY – EQUIPMENT TO BE CLEANED INCLUDING COMMON PROBLEMS•  Equipment characterization•  Residue calculations•  Materials of product contact•  Surface areas•  Worst-case areas for sampling based on risk –  Non-uniform contamination•  Equivalent equipment 54
  55. 55. SUMMARY – ANALYTICAL INCLUDING COMMON PROBLEMSUnderstand residue•  Solubility and stability•  Validated analytical method for actual residue –  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 sites•  Use of auxiliary sampling equipment (extension pole)Swab / rinse training of sampling personnel 55
  56. 56. SUMMARY STAGE 2 – PERFORMANCE INCLUDING COMMON PROBLEMSCleaning Process Conformance LotsCleaning equipment qualifiedCleaning procedure specified (Not SOP)Cleaning documentation –  Request –  Protocol –  Results / ReportManual cleaning – high risk 56
  57. 57. SUMMARY STAGE 3 -- MAINTAINING VALIDATIONChange control -- evaluate impact of change and validate (test) as necessaryImprove processImprove control to detect and reduce variabilityCleaning non-conformances and deviationsPeriodic Management Review 57
  58. 58. PAUL L. PLUTA, PhDEditor-in-Chief Journal of Validation Technology Journal of GXP Compliance Advanstar CommunicationsAdjunct Associate Professor University of Illinois at Chicago (UIC) College of Pharmacy Chicago, IL, USAPharmaceutical industry experienceContact: 58