Validation Boot Camp


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This full day presentation gives an overview of the process validation lifecycle approach, the FDA PV Guidance, the lifecycle approach to cleaning validation, equipment qualification, and validation quality systems.

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Validation Boot Camp

  1. 1. VALIDATION BOOT CAMP LIFECYCLE APPROACH TO PHARMACEUTICAL VALIDATION –PRINCIPLES, IMPLEMENTATION, AND PRACTICE Paul L. Pluta, PhD Journal of Validation Technology Journal of GXP Compliance University of Illinois at Chicago (UIC) College of Pharmacy Chicago, IL, USA 1
  2. 2. OUTLINE•  Process Validation Lifecycle Approach Overview•  FDA PV Guidance•  Documentation•  Lifecycle Approach to Cleaning Process Validation•  Lifecycle Approach to Equipment Qualification•  Lifecycle Approach to Validation Quality System•  Implementation Strategy•  Interactive Discussion. Attendees discuss lifecycle approach to process, other applications, positives/ negatives, and impediments to implementation throughout day. PLEASE PARTICIPATE 2
  3. 3. OBJECTIVES•  Validation lifecycle approach basic understanding –  Terminology –  Validation and qualification –  History and basis –  Stages and activities•  Documentation for lifecycle approach –  Comprehensive –  New specific expectations•  Applications according to lifecycle approach –  Processes, Cleaning, EFU –  Validation quality system –  Other quality systems•  Implementation strategy QUESTIONS: DOES THIS MAKE SENSE? HOW DO YOU APPROACH VALIDATION? 3
  4. 4. SCHEDULE8:15 Registration, welcome and opening remarks8:30 Part I. Introduction, basis, lifecycle stages10:00 Break – Specific requests / clarifications10:30 Part II. Documentation11:50 Morning assessment12:00 Lunch – Specific requests / clarifications1:00 Part III. Applications -- Cleaning, EFU, Quality Systems2:30 Break – Specific requests / clarifications3:00 Part IV -- Implementation3:20 Loose ends, Final Q&A, etc.3:45 Summary4:00 End COMMENTS AND QUESTIONS ANY TIME 4
  5. 5. FILES#1. Overview and history#2. Documentation#3. Cleaning#4. Equipment#5. Validation Quality System#6. Implementation 5
  6. 6. INTRODUCTION, BASIS, LIFECYCLE STAGES•  History and Development•  Fundamental Concepts•  Consistency with Medical Devices IS THE LIFECYCLE APPROACH REALLY NEW? 6
  7. 7. PROCESS VALIDATION LIFECYCLE APPROACH OVERVIEW2004 – Health Canada guidance2005 – FDA initial presentations2007 – ICH Q102008 – FDA draft guidance2009 – ICH Q8(R2)2009 – Health Canada revision2011 – FDA guidance issued2012 – EMA draft guidance 7
  8. 8. HISTORY AND DEVELOPMENT – LIFECYCLE APPROACH PROCESS VALIDATION LIFECYCLE APPROACH IS IT REALLY NEW?Health Canada introduces lifecycle phases in 2004.FDA lifecycle approach (stages) to process validation incorporated concepts of ICH Q8, Q9, Q10, QbD, and PAT – presentations starting 2005.Many concepts previously mentioned in documents issued before 2000. See slides 8-42. 8
  9. 9. HEALTH CANADA -- VALIDATION GUIDELINES FOR PHARMACEUTICAL DOSAGE FORMS (GUI-0029)5.0 Phases of Validation Phase 1: Pre-Validation Phase Phase 2: Process Validation Phase (Process Qualification Phase Phase 3: Validation Maintenance Phase6.0 Interpretation Validation protocol Validation Master Plan Installation and Operational Qualification IQ OQ Re-Qualification Process validation Prospective validation Matrix or family approaches to prospective process validation Concurrent validation Retrospective validation Process Re-Validation Change control 9
  10. 10. ICH Q8 (R2) PHARMACEUTICAL DEVELOPMENTObjectives Harmonized regulatory submissions (CTD) Principles of Quality by Design (QbD) Consistent with Q9 Risk Management Problems addressed Inconsistency between all regions Inconsistent content Inclusion of development information 10
  11. 11. ICH Q8 PHARMACEUTICAL DEVELOPMENTDrug product development considerations Components: API and excipients Formulation development Overages Physicochemical and biological properties Manufacturing process development Container-closure systems Microbiological attributes Compatibility 11
  12. 12. ICH Q8 PHARMACEUTICAL DEVELOPMENTKey points“Information and knowledge gained from development studies and manufacturing experience provides scientific understanding to support the establishment of the design space, specifications, and manufacturing controls.”“Pharmaceutical development section should describe the knowledge…”“At a minimum, those aspects of drug substances, excipients, … that are critical to product quality should be determined and control strategies justified.”“…demonstrate a higher degree of understanding of material attributes, manufacturing processes …” 12
  13. 13. ICH Q8 PHARMACEUTICAL DEVELOPMENTKey points Examination Understanding Evaluation Identification Rationale and justification Others Discussion in submission 13
  14. 14. ICH Q8 PHARMACEUTICAL DEVELOPMENTImplications for Process Validation Process understanding Process development studies are basis for process validation Continuous process verification is alternate to process validation 14
  15. 15. ICH Q9 QUALITY RISK MANAGEMENTObjectives:•  Effective application of risk management•  Consistent science-based decisions Incorporate risk management into practiceProblems addressed:•  Inconsistent risk-management application•  Common understanding 15
  16. 16. ICH Q9 QUALITY RISK MANAGEMENTPrinciples of quality risk management•  General process: Initiation, assessment, control, communication, review•  Methodology•  Integration into industry and regulatory operations•  Methods and tools•  Potential specific applications 16
  17. 17. ICH Q9 QUALITY RISK MANAGEMENT•  Initiate risk management process•  Risk assessment•  Risk identification•  Risk analysis•  Risk evaluation•  Risk control•  Risk reduction•  Risk acceptance•  Output•  Risk review 17
  18. 18. ICH Q9 QUALITY RISK MANAGEMENTRisk Management Methods and Tools•  Basic methods: Flow charts, process maps, cause and effect (fishbone) diagrams•  FMEA / FMECA•  FTA•  HAACP•  HAZOP•  PHA•  Risk ranking and filtering 18
  19. 19. ICH Q9 QUALITY RISK MANAGEMENTApplications•  Integrated quality management: Documentation, training, defects, auditing, periodic review, change control, improvements•  Regulatory operations•  Development: Process knowledge, PAT development•  Facilities, equipment, utilities: Design, qualification, cleaning, calibration, PM•  Materials management: Material variation•  Production: Validation, in-process testing•  Laboratory control and stability•  Packaging and labeling 19
  20. 20. ICH Q9 QUALITY RISK MANAGEMENTKey points•  Methods of evaluation•  Potential applications – every function, every activity, entire product lifecycle 20
  21. 21. ICH Q9 QUALITY RISK MANAGEMENTImplications for Process Validation•  Development: Process knowledge•  Materials: Variation, change control•  Equipment: Qualification, cleaning, calibration, PM, change control•  Production: Validation, sampling, testing, change control•  Maintenance / monitoring: Testing 21
  22. 22. ICH Q10 PHARMACEUTICAL QUALITY SYSTEMSObjectives•  Global harmonization of quality systems•  Consistency with ICH Q8 and Q9•  Application throughout product lifecycleProblems addressed•  Inconsistent application•  Inconsistent definitions of common terms 22
  23. 23. ICH Q10 PHARMACEUTICAL QUALITY SYSTEMSOverview and definitions Management responsibility: Commitment, policy, planning, resources, communication, review, outsourcingContinual improvement of performance and quality: Lifecycle stages and elementsContinual improvement of quality system: Management, monitoring, outcomes 23
  24. 24. ICH Q10 PHARMACEUTICAL QUALITY SYSTEMSKey points:•  Quality system application throughout product lifecycle•  Pharmaceutical development•  Technology transfer•  Manufacturing•  Product discontinuation•  Product realization, maintain control, improvements•  Enable by knowledge and risk management•  Management responsibility: Commitment, policy, planning, resources, communication, review, outsourcing oversight 24
  25. 25. ICH Q10 PHARMACEUTICAL QUALITY SYSTEMSKey points:•  Continual improvement•  Product performance / quality monitoring system•  Control strategy, identify variation, problem feedback, enhance process understanding•  CAPA system•  Enhance process understanding•  Change management system•  Risk management, evaluation, technical justification•  Management review•  Audits, inspections, changes, CAPA, etc. 25
  26. 26. ICH Q10 PHARMACEUTICAL QUALITY SYSTEMSImplications for Process Validation•  Product performance and monitoring•  CAPA system enhances process understanding•  Change management system•  Process improvements 26
  27. 27. ICH Q11 DEVELOMENT AND MANUFACTURE OF DRUG SUBSTANCESConsistent with ICH Q8, Q9, and Q10Lifecycle approachCQA, CPPDesign spaceControl of variablesProcess validationRisk management 27
  28. 28. QUALITY BY DESIGN (QbD)Quality target product profile (QTTP)Critical quality attributes (CQA), critical material attributes (CMA)Critical process parameters (CPP)Design spaceScale-up and technology transferIdentify input variablesInput variable control strategyContinuous improvementOther considerations: PAT, risk analysis 28
  29. 29. SUPPORTING DOCUMENTS PROCESS VALIDATION – 1987 GUIDANCEAssurance of product quality:Quality parts and materialsAdequate product and process designControl of the process In-Process and end-product testing.Basic principles:Quality, safety, and effectiveness designed and built into the product Quality cannot be inspected or tested in the product Each process step must be controlled to maximize meeting quality and design specifications.R&D phase: Product definition and characteristicsEquipment and process Equipment: Installation Qualification Process: Performance Qualification Product (devices only): Performance QualificationRevalidation. Change controlDocumentation. Proper maintenance of documentationReference: FDA Guideline on General Principles of Process Validation. May, 1987 29
  30. 30. VALIDATION – PHARMACEUTICAL DOSAGE FORMS FDA INSPECTION GUIDELINESThree phases of the validation process:•  Product development•  Design of the validation protocol•  Demonstration runs (validation) – full scaleProcess validationDocumented evidence•  Consistency•  Predetermined specificationsDocumented evidence includes experiments, data, and resultsProduct Development ReportsControl of the physical characteristics of the excipientsParticle size testing of multi-source excipientsCritical process parametersDevelopment data serves as the foundation for the manufacturing procedureVariables are identified in the development phaseRaw materials may vary lot-to-lotReferences: FDA Guides to Inspections. Oral Solid Dosage Forms (January 1994), Topical Drug Products (July 1994), Oral Solutions and Suspensions (August 1994) 30
  31. 31. SUPPORTING DOCUMENTS VALIDATION – MEDICAL DEVICESPlanning the Process Validation StudyInstallation and Operational QualificationProcess Performance QualificationEliminate controllable causes of variationProduct Performance QualificationEvaluate routine production process monitoring data for trendsProcess operating in a state of control is determined by analyzing day-to-day process control data and finished device test data for conformance with specifications and for variability.Reference: FDA Medical Device Quality Systems Manual. January 07, 1997 31
  32. 32. SUPPORTING DOCUMENTS PROCESS VALIDATION – APICritical parameters / attributes identified duringdevelopmentQualification of equipment and systems: DQ, IQ, OQ, PQ.Process Validation ProgramCritical process parameters controlled and monitoredNon-critical parameters not included in validationPeriodic review of validated systemsReference: ICH Q7. Good Manufacturing Practice Guidefor Active Pharmaceutical Ingredients. November, 2000. 32
  33. 33. SUPPORTING DOCUMENTS PROCESS VALIDATION – PRODUCTS / APIA validated manufacturing process has a high level ofscientific assurance that it will reliably product acceptableproduct.Proof of validation is obtained through rational experimentaldesign and the ongoing evaluation of data, preferablybeginning from the process development phase continuingthrough the commercial production phase.Reference: FDA Section 490.199. CPG 7132c.08.Process Validation Requirements for Drug Products andActive Pharmaceutical Ingredients Subject to Pre-MarketApproval. 2004 revision. 33
  34. 34. SUPPORTING DOCUMENTS PROCESS VALIDATION – PRODUCTS / APIBefore commercial distribution:Product and process developmentScale-up studiesEquipment and system qualificationConformance batchesIdentify and control all critical sources of variabilityAdvance manufacturing control technology mayeliminate validation lots.Reference: FDA Section 490.199. CPG 7132c.08.Process Validation Requirements for Drug Products andActive Pharmaceutical Ingredients Subject to Pre-MarketApproval. 2004 revision. 34
  35. 35. SUPPORTING DOCUMENTS VALIDATION -- PHARMACEUTICAL CGMPSCross-Agency workgroup CDER, CBER, ORA, and CVM.“The CPG clearly signals that a focus on three full-scaleproduction batches would fail to recognize the completestory on validation.”Reference: FDA. Pharmaceutical CGMPs for the 21stCentury – A Risk-Based Approach. Final Report,September 2004. 35
  36. 36. SUPPORTING DOCUMENTS PROCESS VALIDATION – MEDICAL DEVICESProcess evaluation – Validation or verificationProtocol developmentProcesses well thought outWhat could go wrongInstallation QualificationOperational Qualification“Worst case” testingDOE and screening studiesPerformance QualificationProcess repeatabilityAttributes for continuous post-validation monitoring and maintenanceEliminate controllable causes of variation.Maintaining a state of validation – Monitor and controlChange controlStatistical MethodsRisk Analysis MethodsReference: Global Harmonization Task Force (GHTF) Study Group 3. QualityManagement Systems – Process Validation Guidance. January 2004. 36
  37. 37. SUPPORTING DOCUMENTS VALIDATION – INTERNATIONALPIC/S PHARMACEUTICAL INSPECTION CONVENTIONA series of experiments should be devised to determine thecriticality of process parameters / factorsTest processes with starting materials on the extremes ofspecificationMonitoring and in-process controlsReference: PIC/S Recommendations on Validation. July2004. 37
  38. 38. SUPPORTING DOCUMENTS FDA -- QUALITY BY DESIGN (QbD)Product is designed to meet patient requirementsProcess is designed to consistently meet product criticalquality attributesImpact of starting materials and process parameters onproduct quality is understoodCritical sources of process variability are identified andcontrolledProcess is continually monitored and updated to assureconsistent quality over timeReference: FDA. Chi-wan Chen, ISPE, Japan, June,2006 38
  39. 39. SUPPORTING DOCUMENTS PROCESS ROBUSTNESS (PQRI)Robust Process: Able to tolerate expected variability ofraw materials, operating conditions, process equipment,environmental conditions, and human factorsDevelopmentMaintenanceProcess understanding is key to developing a robustprocess.Reference: Product Quality Research Institute (PQRI).Pharmaceutical Engineering, November-December, 2006 39
  40. 40. SUPPORTING DOCUMENTS ASTM WK 9935 Standard GuideContinuous Quality Verification (CQV)A Science and Risk-Based Alternative Approach toTraditional Process Validation of Biopharmaceuticaland Pharmaceutical Manufacturing ProcessesCONTINUOUS QUALITY VERIFICATIONProcess design / Risk assessment / ProcessunderstandingDevelopment phaseScale-up phaseCommercialization phaseProcess capability evaluationContinuous process improvement 40
  41. 41. SUPPORTING DOCUMENTS PROCESS ANALYTICAL TECHNOLOGY (PAT)Processes verified by PAT are not validatedAll associated PAT equipment and analytical methods arevalidatedReference: FDA. PAT -- A Framework for InnovativePharmaceutical Development, Manufacturing, and QualityAssurance. September 2004 41
  42. 42. SUPPORTING DOCUMENTS PROCESS ANALYTICAL TECHNOLOGY (PAT)Process UnderstandingAll critical sources of variability are identified and explained.Variability is managed by the processProduct quality attributes can be accurately and reliably predictedover the design spaceMaterials usedProcess parametersManufacturingEnvironmentalOther conditionsReference: FDA. PAT -- A Framework for Innovative PharmaceuticalDevelopment, Manufacturing, and Quality Assurance. September2004 42
  43. 43. TERMINOLOGY: PROCESS VALIDATION Process Validation – Process Qualification Process Performance Qualification (PPQ)Qualification Qualification Equipment #1 HVAC UO #1 Utilities Equipment #2 Facilities UO #2 Computers Equipment #3 UO #3Analytical methods validationCleaning process validationPackaging process validation Process is validated 43
  44. 44. FDA PROCESS VALIDATION GUIDANCE (2011)Definition: Collection and evaluation of data, from the process design stage throughout commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. Process validation involves a series of activities over the lifecycle of the product and process.Three stages of activities:•  Stage 1 – Process Design – Development and scale-up activities•  Stage 2 – Process Qualification – Reproducible manufacturing•  Stage 3 – Continued Process Verification – Routine manufacturing STAGE 1 AND STAGE 3 EMPHASIS – NEW PARADIGM 44
  45. 45. FDA PROCESS VALIDATION GUIDANCE“Before …commercial distribution to consumers, a manufacturer should have gained a high degree of assurance in the performance of the manufacturing process…consistently produce …”Manufacturers should:•  Understand the sources of variation•  Detect the presence and degree of variation•  Understand the impact of variation on the process and product attributes•  Control the variation in a manner commensurate with risk to process and product.”“…to justify commercial distribution of the product.”“… use ongoing programs to collect and analyze product and process data … state if control of the process.” 45
  46. 46. FDA PROCESS VALIDATION GUIDANCEGood project management and good archiving to capture scientific knowledge.Enhance accessibility of information later in lifecycle.Integrated team approach: Process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance.Scientific studies throughout the product lifecycle planned, documented, and approved.Greater control over higher-risk attributes.Reevaluate risks throughout product/process lifecycle.Homogeneity with batch and consistency between batches are goals of process validation. 46
  47. 47. STAGE 1, PROCESS DESIGN (PROCESS UNDERSTANDING)1. Building and capturing process knowledge and understanding.2. Establishing a strategy for process control.Define commercial-scale processDefine unit operations and process parametersIdentify and understand sources of variabilityIdentify critical process parametersStudies to understand effects of scaleEstablish mechanisms to control variability•  Process Analytical TechnologyDesigned experimentsLab scale and pilot scale experiments 47
  48. 48. PROCESS DESIGN (PROCESS UNDERSTANDING)ObjectiveAPI and excipient pharmaceuticsQuality attributesRisk analysisProcess parametersDesign of experimentsDesign spaceNormal operating rangeIn-process controlsProduct development – key inputs to design stageVariability by different component lots, production operators, environmental conditions, and measurement systemsUse risk analysis tools to screen variablesEstablish a strategy for process control 48
  49. 49. QUALITY BY DESIGN (QbD)1. Quality target product profile (QTTP)2.  Critical quality attributes (CQA), critical material attributes (CMA)3.  Critical process parameters (CPP)4.  Design space5.  Scale-up and technology transfer6.  Identify input variables7.  Input variable control strategy8.  Continuous improvementOther considerations: PAT, Risk analysis 49
  50. 50. STAGE 2, PROCESS QUALIFICATION (VALIDATION PERFORMANCE)1.  Design of a facility and qualification of utilities and equipment2.  Process performance qualification3.  PPQ protocol4.  PPQ protocol execution and reportConfirmation at commercial scale of process design informationQualification of equipment, utilities, facilitiesPerformance qualificationConclusion that process consistently produces quality product.Conformance batches•  All support systems, documents, training, personnel, etc. in place•  Target / nominal operating parameters within design space•  Additional testing•  Decision to “release process” for routine commercial manufacturing 50
  51. 51. STAGE 2, PROCESS QUALIFICATION Conformance LotsProceduresValidation plansProtocolsSamplingTestingResultsPlan to maintain validationALL EQUIPMENT, ANALYTICAL, AND SUPPORTING SYSTEMS MUST BE QUALIFIED. 51
  52. 52. PERFORMANCE QUALIFICATION APPROACHHigher level of sampling, testing, and scrutiny of process performance.Protocol should address:•  Operating parameters, processing limits, and raw material inputs•  Data to be collected and how evaluated•  Test to be performed and acceptance criteria•  Sampling plan – sampling points, number of samples, frequency•  Statistical methods used•  Statistical confidence levels•  Provisions to address deviations and non-conformances•  Facility, utility, and equipment qualification•  Personnel training•  Status of analytical method validation•  Review and approval by appropriate departments and quality unit DETAILS FROM PV GUIDANCE 52
  53. 53. PERFORMANCE QUALIFICATION APPROACH“The PPQ lots should be manufacturer under normal conditions by personnel expected to routinely perform each step of each unit operation in the process. Normal operating conditions should cover the utility systems (air handling and water purification), material, personnel environment, and manufacturing procedures.”PQ report:•  Discuss all aspects of protocol•  Summarize and analyze data as specified in protocol•  Evaluate unexpected observations and additional data•  Summarize and discuss non-conformances•  Describe corrective actions or changes•  Clear conclusions•  Approval by appropriate departments and quality unit DETAILS FROM PV GUIDANCE 53
  54. 54. STAGE 3, CONTINUED PROCESS VERIFICATION (VALIDATION MONITORING AND MAINTENANCE)Activities to assure process remains in validated stateAnnual Product ReviewTrend and assess dataStudy OOS and OOT (Out of Trend) dataTimely monitoring of critical operating and performance parameters.Monitor product characteristics, materials, facilities, equipment, and SOP changesEstablish process history based on ongoing process performanceImprove processImprove control to detect and reduce variabilityChange control; evaluate impact of change and test as necessary 54
  55. 55. CONTINUED PROCESS VERIFICATIONMonitoringStatistical process controlTrend analysisChange controlContinuous improvementRevalidationManagement review STATISTICIAN RECOMMENDED BY FDA 55
  56. 56. CONTINUED PROCESS VERIFICATIONITEMS TO BE REVIEWED•  Product and process data•  Relevant process trends•  Quality of incoming materials or components•  In-process material•  Finished products•  Defect complaints•  OOS findings•  Deviations•  Yield variations•  Batch records•  Incoming raw material records•  Adverse event reports•  Production operator and quality staff feedbackAbove should help identify possible product / process improvements DETAILS FROM PV GUIDANCE 56
  57. 57. SUMMARY OF GUIDANCE RECOMMENDATIONSStage 1: Product Design•  QTPP, Development information, Identification of CQA, CMA, and CPP•  Identification of sources of variation and control plan•  Experimental studies•  Technology transfer / scale upStage 2: Process Qualification•  PPQ protocol requirements•  Statistical sampling and acceptance criteria•  Equipment qualification and analytical method validationStage 3: Continued Process Verification•  Post PQ plan•  APR, batch data, yields, deviations, OOS, non-conformances, etc.•  Incoming material data•  Change control•  Statistical analysis of data / control charting•  Product complaints 57
  58. 58. PROCESS VALIDATION HISTORY1978CGMP includes Validation1987Development -- VALIDATION -- Control2008-2011Lifecycle approachContinuum of understanding – validation – maintenanceUNDERSTANDING -- VALIDATION -- MAINTENANCE 58
  59. 59. VALIDATION PHILOSOPHY•  Validation is confirmation.•  Acceptable (passing) results are expected.•  Validation is not –  R&D –  Final stage of development process –  Optimization –  Fine-tuning –  Debugging 59
  60. 60. SUMMARYLifecycle Approach to Process Validation•  New document•  Compilation of concepts pre-2000 to current•  Three stages identified –  Understand –  Demonstrate –  Maintain•  Comprehensive•  Detailed improvements QUESTIONS: DOES THIS MAKE SENSE? HOW DO YOU APPROACH VALIDATION? 60
  61. 61. SUMMARY WHERE WE ARE -- CURRENT PRACTICER&D Validation Commercialization 61
  62. 62. SUMMARY -- VALIDATION – CURRENT PRACTICEEmphasis on repeatability (3x)One-time effortDocumentation importantLast step in development“Hope we can pass validation”Required for product release to marketKey regulations: •  1987 Process Validation Guidance •  1990’s Pharma Inspection Guidelines •  1997 Medical Device Quality Systems Manual 62
  63. 63. SUMMARY -- WHERE WE ARE GOING – LIFECYCLE APPROACH TO PROCESS VALIDATIONLifecycle approach:•  Validation is never completed•  Validation is always ongoingObjectives:•  Scientific and technical process•  Demonstrate process works as intended•  Process must remain in control throughout lifecycle EFFECTIVE DOCUMENTS CONSISTENT WITH THE ABOVE 63
  64. 64. LIFECYCLE APPROACH TO PROCESS VALIDATIONProcess Design•  Studies to establish process•  Identify critical process parameters•  Identify sources of variation•  Consider range of variation possible in processes•  Process understandingProcess Qualification•  Equipment, facilities, and utilities•  Confirm commercial process design•  Validation performanceContinued process verification•  Monitor, collect information, assess•  Maintenance, continuous verification, process improvement•  Change control•  Validation maintenance “The process of process validation.” 64
  65. 65. SUMMARY PROCESS VALIDATION HISTORY1978CGMP includes Validation1987Development -- VALIDATION -- Control2008-2011Lifecycle approachContinuum of understanding – validation – maintenanceUNDERSTANDING -- VALIDATION -- MAINTENANCE 65
  66. 66. SUMMARY VALIDATION -- FUTUREDevelopment Performance Maintenance Stage 1 à Stage 2 à Stage 3 66
  67. 67. 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: 67
  69. 69. OUTLINE•  Validation Documents Overview•  Validation Policy Documents•  Stage 1 Process Design Documents•  Stage 2 Process Qualification Documents –  Validation Requests and Plans –  Validation Protocols –  Validation Results and Reports•  Stage 3 Continued Process Verification Documents•  Associated Documents•  Document Outlines / Templates•  Document Problems 2
  70. 70. IMPORTANCE OF VALIDATION DOCUMENTS•  Validation documents always requested in regulatory audits•  Documentation is retained forever•  Documents reviewed long after people are gone –  Documents must “stand alone”•  Early documents (Request, Plan, Protocol) reviewed when project is in-progress or not completed•  FDA auditors often focus on documentation – validation documents often requested ahead of audit Above sometimes difficult for technical people 3
  71. 71. SCOPE OF VALIDATION DOCUMENTSFDA Process Validation Guidance has greatly expanded the scope of validation•  Lifecycle approach – documents from development through commercialization•  Traditional validation documents (protocol and results) less importantValidation organizations should lead sites in transition to lifecycle approach•  Multiple groups at site must now contribute to process validation lifecycle approach documentsLifecycle approach being applied to all validation and qualification (equipment, facilities, cleaning, etc.) 4
  72. 72. VALIDATION DOCUMENTS -- BASICS•  Written for the reader – US vs. Europe•  Objective: Understanding•  Clarity much more important than brevity•  Stand-alone document•  Potential for review in 10+ years•  Author / Management not available for explanation•  Spelling and grammar correct –  Need good writers –  Simple sentences –  Simple words 5
  73. 73. PROCESS VALIDATION DOCUMENTS•  Validation policy – Reference PV Guidance approach –  Corporate templates•  Validation Master Plan (VMP) – Reference PV Guidance approach•  Stage 1 documents – Process Design•  Stage 2 documents – Process Qualification –  Validation Request / Plan -- Reference PV Guidance –  Validation Protocol(s) – Reference PV Guidance –  Engineering Studies –  Others –  Validation Results / Report – Reference PV Guidance•  Stage 3 documents – Continued Process Verification –  PQ requirements –  Routine monitoring – Reference PV Guidance•  Associated validation and qualification -- Reference PV Guidance•  Other associated documents 6
  74. 74. VALIDATION POLICY•  Corporate or company policies•  High level overview documents•  Apply to all global manufacturing sites•  State agreement with local regulatory requirements•  State agreement with customer regulatory documents•  Specific corporate requirements•  Describe general validation approach 7
  75. 75. VALIDATION POLICYDescribe general validation approach•  Design and development . Science and technical basis•  Validation performance•  Maintain validated state through monitoring, change control, and management review•  Risk analysis – emphasis on highest risk –  Sampling, testing, acceptance criteria•  Variation identification and control•  Continuing improvements GENERAL POLICY WITH KEY POINTS 8
  76. 76. VALIDATION MASTER PLAN (VMP)PROGRAM DESCRIPTION AT SITE•  Comprehensive lifecycle approach based on risk•  Consistent with general policyMULTI-CHAPTER DOCUMENT•  Chapter for each major area (may have individual VMP per area) –  Process –  Equipment –  Facilities –  Analytical –  Computer –  OthersUPDATED AS NEEDED (Annual, quarterly, monthly)•  VMP must be current for auditsIMPROVEMENT PROJECTS COMMITMENTS AND TIMELINES 9
  77. 77. VALIDATION MASTER PLAN (VMP)SITE PROGRAM DESCRIPTION•  Design and development . Science and technical basis•  Validation performance•  Maintain validated state through monitoring, change control, and management review•  Risk analysis – emphasis on high risk activities•  Variation identification and control•  Continuing improvements 10
  78. 78. VALIDATION MASTER PLAN (VMP)CHAPTER CONTENTContent for processes, cleaning, analytical, etc.•  Strategy and approach•  Procedures•  Supporting information (reference) –  Ex: Product validation families, Cleaning matrix•  Validation references –  Ex: Products, equipment, utilities, etc. document ID•  Validation commitments and timelines•  Improvement projects and timelines 11
  79. 79. VMP CHAPTER EXAMPLE – CLEANING VALIDATIONStrategy and approach•  Comprehensive lifecycle approach, Science and technical basis, Risk analysis, Variation identification and control (consistent with site and corporate docs)Procedures•  List of approved proceduresSupporting information with reference documentation•  Product cleaning matrix•  Equivalent equipment•  Equipment surface area calculations•  Residue calculations•  Technical reports•  TemplatesValidation references•  List of all completed cleaning validationValidation commitments and timelines•  Planned validationsImprovement projects and timelines•  Planned projects 12
  80. 80. STAGE 1 DOCUMENTS -- PROCESS DESIGNTechnical areas must be aware that their documents are critical to validation throughout the product lifecycle.•  Direct support of Stage 2 PQ – their work is basis of validation•  R&D technical reports consistent with raw data•  Rapidly retrieved (within 30 minutes)•  Accessed throughout product lifecycle•  Personal support of regulatory audits•  Stand-alone documents•  Applies to processes, cleaning, analytical, equipment, facilities, utilities, control systems, others. R&D / TECHNICAL AREAS NOT ACCUSTOMED TO THESE REQUIREMENTS AND EXPECTATIONS 13
  81. 81. STAGE 1 DOCUMENTS – POTENTIAL PROBLEMS•  Reports not available•  Reports not retrievable•  Reports incomplete•  Reports poorly written•  Reports not approved•  Personnel not available•  Original data not available•  Substandard documentation practices – original data•  No signature / date•  Data transpositions•  Data transfer problems•  Data transfer not verified•  Inconsistent data•  Multiple sources of same data inconsistent 14
  82. 82. VALIDATION STAGE 2 DOCUMENTSOPTIONS•  Outlines•  Templates•  Model documentsRECOMMENDATION1.  Develop outlines for authors – get agreements from functional organizations and approval committee2.  Write or collect good documents3.  Documents available to writers4.  Replace (upgrade) as appropriate 15
  83. 83. STAGE 2 DOCUMENTS – PROCESS QUALIFICATION VALIDATION REQUEST AND VALIDATION PLAN INITIATION OF VALIDATIONRequest: Statement of recommended validation•  What?•  Why needed?•  Why acceptable?•  Impact of validation – risk analysis•  Approach to accomplish – Validation Plan•  ApprovalsPlan: Details of work to accomplish validation•  Description of strategy and approach•  References from Stage 1 work supporting validation•  Approvals MAY BE SINGLE DOCUMENT OR TWO SEPARATE DOCUMENTS 16
  84. 84. VALIDATION REQUEST OUTLINE•  Objective of validation•  Why needed?•  Impact of validation –  Risk analysis•  Why acceptable? –  Compliance to internal requirements, policies, engineering standards, etc. –  Regulatory impact (Prior approval, CBE, CBE30, etc.) –  Other systems or product impacted –  Procedure changes or other document changes –  Notifications to affected groups (internal, external, labs)•  Validation plan -- Approach to accomplish validation Above applicable to equipment and other qualification HAVE MODEL DOCUMENTS AVAILABLE 17
  85. 85. VALIDATION REQUEST -- PROBLEMS•  Poorly written –  Inadequate information•  Prematurely written –  Written to meet business goals –  Written to demonstrate future intent•  Amendments necessary -- changes usually requiredValidation requests should be submitted for approval only after objective and scope of validation is determined and work details (risk/testing/sampling) determined.Amendments are a planning failure regardless of justification. HAVE MODEL DOCUMENTS AVAILABLE 18
  86. 86. VALIDATION REQUEST TERMINOLOGY EXAMPLESValidation request:Process validation of Product ASystem: New product validationChange impact: High impact. New product validationReason: New product to be manufactured at siteAcceptability:•  Compliant with policies•  Regulatory approval•  Other systems impacted (e.g., cleaning)•  Procedures approved•  Notifications (Labs)Justification: See Validation PlanApprovals SIMPLE AND CLEAR 19
  87. 87. VALIDATION REQUEST TERMINOLOGY EXAMPLESValidation request:Qualification of 150 cu. ft. blenderSystem: New equipment qualificationChange impact: High impact. New equipment and new size at siteReason: New equipment to increase manufacturing efficiency and throughputAcceptability:•  Compliant with policy•  Regulatory approval•  Other systems impacted (e.g., cleaning)•  Procedures approved•  Notifications (Labs)Justification: See Validation PlanApprovals SIMPLE AND CLEAR 20
  88. 88. VALIDATION REQUEST TERMINOLOGY EXAMPLESValidation request:Change air supply and return ductwork to coincide with Line 1 floor space changesSystem: HVAC system #3Change impact: Medium impact. Change to direct product contact support utilityReason: Room configuration change to increase manufacturing efficiencyAcceptability:•  Compliant with policy•  Regulatory approval not needed•  Other systems impacted•  Procedures approved, drawings modified, etc.•  NotificationsJustification: See Validation PlanApprovals SIMPLE AND CLEAR 21
  89. 89. VALIDATION PLAN OUTLINE•  Introduction•  Technical information•  Validation strategy and testing•  Validation documentation –  List of required protocols, reports, procedures, etc. –  Administrative benefit•  References –  List of reports and scientific references (including Stage 1 reports) HAVE MODEL DOCUMENTS AVAILABLE 22
  90. 90. VALIDATION PLANINTRODUCTION•  Overview describing validation / product / process / equipment / etc. (consistent with request)•  Requirements to complete validation –  Conformance to regulations and internal policy –  Impact of change to maintain the validated state –  Impact on regulatory submission –  Impact of change on procedures, drawings, other documents –  Notifications to other areas internal and external (e.g., environmental agency, internal test labs) impacted by validation 23
  91. 91. VALIDATION PLANTECHNICAL INFORMATION•  Basic product / process / equipment description –  Formula –  Process –  Specifications –  Include non-technical description information•  Technical aspects of validation / qualification•  Reference to technical reports from Design Stage•  Total validation approach –  Experimental studies –  Past data (retrospective data) –  Validation protocols –  Other work –  New procedures•  Number of lots – related to impact of change and risk WRITTEN FOR THE READER 24
  92. 92. VALIDATION PLANVALIDATION STRATEGY AND TESTING•  Prospective validation only•  Types of testing -- general –  Regulatory specifications –  Internal controls –  Process tests•  Tests and rationale – general –  Address changes – based on risk analysis•  Sampling and rationale – general –  Exceed routine QA testing – based on impact and risk analysis•  Data treatment – general –  Statistical data treatment and confidence limits•  Acceptance criteria – general DETAILS OF ABOVE PROVIDED IN PROTOCOLS 25
  93. 93. VALIDATION PLAN VALIDATION DOCUMENTATIONDoc # Title Date closed01 Validation request02 XXX Dryer Engineering Study03 XXX Dryer Qualification04 XXX Process Scale-up Engineering Study05 XXX Process Validation06 Update Validation Master Plan – Product and Equipment sections07 XXX Project Summary Report 26
  94. 94. VALIDATION PLANREFERENCES•  R&D Reports•  Development and analytical reports•  Published literatureScientific and technical support to validation planReport copies should be stored in validation area or readily accessible (within 30 minutes) 27
  95. 95. PRODUCT / PROCESS DESIGN INFORMATION•  Technical reports from R&D•  Pharmaceutics reports•  Formulation and process development reports (CQA, CMA, CPP)•  Technology transfer / Scale-up reports•  Identification of sources of variation•  Variation control plans•  Analytical methods•  Other technical reports REPORTS SHOULD BE REVIEWED FOR CONSISTENCY BETWEEN GROUPS REPORTS SHOULD BE REFERENCED IN VALIDATION PLAN 28
  96. 96. TECHNICAL REPORTS•  Readily available•  Consistent across large technical groups•  Approved by management•  Linked to original data –  Observe / store original data –  Original documentation practices?VALIDATION MUST REVIEW ORIGINAL DATA•  Rapidly retrievable•  Consistent with technical report•  Documentation practices 29
  97. 97. VALIDATION PROTOCOLS•  Execution of the Validation Plan•  Testing details•  Sampling details•  Data sheets•  Data treatment•  Acceptance criteria•  Minimal text repetition from Validation Plan PROTOCOL EASILY WRITTEN IF VALIDATION PLAN IS THOROUGH 30
  98. 98. VALIDATION PROTOCOL•  Objective of validation – specific protocol•  Validation description – specific•  Validation approach•  Testing and rationale -- specific•  Sampling and rationale -- specific•  Data sheets (summary)•  Data treatment -- specific•  Acceptance criteria – specific –  All testing must have acceptance criteria –  No FYI testing in validation VALIDATION IS CONFIRMATION 31
  99. 99. VALIDATION PROTOCOLTESTING AND SAMPLING•  Based on product specifications and testing•  Exceed routine QA testing based on impact and riskConsider the following:•  Product for seizures•  Product for hypertension•  New product•  Change in compressing machine•  Increase compressing machine speed•  Change in granulation method•  Change in batch size Risk analysis in above 32
  100. 100. VALIDATION PROTOCOLFDA Powder Blends and Finished Dosage Units – Stratified Sampling and AssessmentBlend sampling. n = 10, Individuals, RSDTablets. 20 samples, n = 3-7 per location, mean, range, RSD.Application is possible approach for high risk productsSupportive of USP Uniformity of Dosage Units on composite / stratified samplesProduct types: Potency and weight testing 33
  101. 101. VALIDATION SAMPLINGWhat is routine QA sampling?Impact of change•  High impact•  Medium impact•  Low impact•  No impactRisk analysis – Related to numerical RPN analysis•  High risk•  Medium risk•  Low risk RISK LEVEL MUST BE ACKNOWLEDGED 34
  102. 102. ENGINEERING STUDY•  Conducted in advance of validation•  No acceptance criteria•  Trial run•  Examples: Manufacturing process without bulk drug (low dose API)•  Process runs with placebo•  Categories of Engineering StudiesConduct Engineering Study concurrently with validation? -- Not recommended 35
  103. 103. SAMPLING PAGESDesigned sheet with space for expected dataData treatment specifiedSignature and data of person supplying dataHighly recommended for Operators or persons not familiar with samplingData pages consistent with sampling pages•  Prevents missing data in complex protocols•  Record sampling and / or testing 36
  104. 104. SAMPLING / DATA PAGE EXAMPLEUNIT OPERATION: Tablet compressing, lot # ________________TEST: Content Uniformity (SOP # XX-XXX)SAMPLE: 10 Tables each from beginning, middle, and end of batchSample #1 by _________ Date _________Sample #2 by _________ Date _________Sample #3 by _________ Date _________TEST RESULTS (Circle P -- Pass or F -- Fail)Sample #1 Sample #2 Sample #3_____ P/F _____ P/F _____ P/F_____ P/F _____ P/F _____ P/F_____ P/F _____ P/F _____ P/F_____ P/F _____ P/F _____ P/F_____ P/F _____ P/F _____ P/F_____ P/F _____ P/F _____ P/F_____ P/F _____ P/F _____ P/F_____ P/F _____ P/F _____ P/F_____ P/F _____ P/F _____ P/F_____ P/F _____ P/F _____ P/FRECORDED BY:__________ __________ __________VERIFIED BY:_____________ _____________ _____________ 37
  105. 105. PROCESS VALIDATION PROTOCOL (PPQ) FDA GUIDLINE RECOMMENDATIONSHigher level of sampling, testing, and scrutiny of process performance.Protocol should address:•  Operating parameters, processing limits, and raw material inputs•  Data to be collected and how evaluated•  Test to be performed and acceptance criteria•  Sampling plan – sampling points, number of samples, frequency•  Statistical methods used•  Statistical confidence levels•  Provisions to address deviations and non-conformances•  Facility, utility, and equipment qualification•  Status of analytical method validation•  Review and approval by appropriate departments and quality unit 38
  106. 106. VALIDATION PROTOCOL OUTLINEIntroductionUnit operationsTesting with justificationSampling with justificationSampling and data pagesData treatmentAcceptance criteria with justification HAVE MODEL DOCUMENTS AVAILABLE 39
  107. 107. VALIDATION PROTOCOL -- PROBLEMSNo planNo basic explanation of validationNo statement of strategy and approachNo test rationaleNo sampling rationaleMissing samples – missing dataHow to treat dataNo discussion of resultsNo acceptance criteria rationaleNo validation statementPoorly written WRITTEN FOR THE READER 40
  108. 108. VALIDATION PROTOCOL -- PROBLEMSHow many lots should be tested?Consider impact of change.Consider product.Consider process.Consider risk. ABOVE ADDRESSED IN VALIDATION PLAN 41
  109. 109. VALIDATION RESULTS•  Compilation of testing required in protocol•  Deviations or adverse events•  Discussion•  Conclusion WRITE GOOD PLAN PROTOCOL CONSISTENT WITH PLAN RESULTS CONSISTENT WITH PROTOCOL WRITE DISCUSSION FIRST – MOST IMPORTANT SECTION 42
  110. 110. VALIDATION RESULTS OUTLINEIntroductionData sheets compiledData treatmentResultsDeviations, Non-conformances, etc.Discussion•  “Results pass” is not sufficient.Validation statement: “Results indicate that ___ is validated.”Post-validation monitoring plan WRITE DISCUSSION SECTION FIRST – MOST IMPORTANT SECTION HAVE MODEL DOCUMENTS AVAILABLE 43
  111. 111. VALIDATION RESULTS PROBLEMS•  Missing data•  Documentation practices on raw data•  Raw data and results inconsistent•  Inadequate or no discussion of results•  Inadequate or no discussion of amendments or deviations•  No conclusion statement•  Poor grammar and composition 44
  112. 112. VALIDATION RESULTS / REPORT -- PROBLEMSProtocol requires BME samples for potency.Acceptance criteria: 95-105%B = 95%M = 100%E = 105%All results passConclusion? POST PQ MONITORING? 45
  113. 113. VALIDATION RESULTS / REPORTS -- PROBLEMSProtocol requires BME testingAcceptance Criteria: Not More Than 6.0%Results:B = 2.0%M = 2.1%E = 6.0%All data pass acceptance conclusions.Conclusions? POST PQ MONITORING? 46
  114. 114. VALIDATION REPORTRecommended for complex projectsRecommended for multiple protocol projects PRIMARY REPORT FOR AUDIT “Cut and Paste” exercise from multiple documents Best approach to avoid inconsistency 47
  115. 115. VALIDATION REPORT FORMAT•  Introduction•  Key information from Validation Plan•  Supporting information•  Protocol #1 results – “Cut and paste”•  Protocol #2 results – “Cut and paste”•  Protocol #3 results – “Cut and paste”•  Protocol #n results – “Cut and paste”•  Write transitional narrative•  Project conclusions (for Validation Plan)•  Validation statement –  “Results indicate that ______ is validated.” HAVE MODEL DOCUMENTS AVAILABLE 48
  116. 116. STAGE 3 DOCUMENTS – CONTINUED PROCESS VERIFICATION POST PQ DOCUMENTSTYPES OF DOCUMENTS•  Post PQ requirements – work required based on PQ results•  Ongoing monitoring – routine process monitoring 49
  117. 117. STAGE 3 DOCUMENT RESONSIBILITIES PQ REQUIREMENTSRequirements specified in PQ results•  Continued monitoring of critical test results –  High risk activities•  Continued monitoring of aberrant values•  Continued monitoring of statistical (CL) failures 50
  118. 118. STAGE 3 DOCUMENT RESPONSIBILITIES ONGOING MONITORINGRESPONSIBILITYMonitoring results (Annual Product Review) QAChange control validation results/reports and monitoring ValidationNon-conformances ProductionDeviations ProductionProcess monitoring (control charts) QAProcess changes ProductionImprovement projects instituted ValidationOther changes -----Record of management review QA ANNUAL REVIEW NOT GOOD ENOUGH, ESPECIALLY FOR HIGH RISK PROCESSES 51
  119. 119. STAGE 3 DOCUMENTSRegular management review of manufacturing dataData analysis by statistical process control (SPC) principlesReview of all associated events, investigations, changes, etc.Record of management reviewExpanded Annual Product Review, conducted at appropriate intervals based on risk. 52
  120. 120. ASSOCIATED VALIDATION AND QUALIFICATION DOCUMENTSEquipment qualification•  All manufacturing process equipment and associated control systems•  Example: Drug dispensing qualification (equipment, facilities, HVAC, personnel, etc.)•  All facilities, utilities, systems, etc.Analytical method validation•  Analytical equipment qualification ABOVE MENTIONED IN PV GUIDANCE 53
  121. 121. EQUIPMENT, FACILITIES, UTILTIES, ETC. QUALIFICATION•  IQ, OQ, PQ•  ASTM E2500•  Same approach as with processes•  Same philosophy•  Same requirements•  Same approval•  Critical tests only•  Non-critical tests in FAC, SAC, etc.•  Do as much as possible in commissioning•  Difference from PV: Do tests only once•  Validation statement – –  “Results indicate that _____is qualified.” 54
  122. 122. ANALYTICAL•  Analytical methods validated•  Analytical equipment qualified•  QbD for analytical methods evolving 55
  123. 123. OTHER ASSOCIATED DOCUMENTSTraining records•  Operators•  Approvers•  SupervisorsPersonnel qualifications•  FDA Warning Letter for inconsistent job requirements (HR) and personnel resumesEnvironmental monitoring historyOther 56
  124. 124. DOCUMENT OUTLINES / TEMPLATESDocument templates very difficult•  Labor intensive•  Do not fit every situationSuggested approach•  Document outline of major sections•  Document outline evolves•  Model approved documents available•  Model approved documents improved and are replaced 57
  125. 125. VALIDATION DOCUMENT APPROVAL VALIDATION APPROVAL COMMITTEE (VAC)VAC must review documents with perspective of an external regulatory auditor•  Assure acceptability of technical validation and product quality•  Assure compliance with regulations, policies, and industry expectations•  Assure acceptability of documentation. –  Spelling and grammar VAC IMPORTANT PARTNER WITH VALIDATION 58
  126. 126. VALIDATION DOCUMENT APPROVALTechnical validation•  Scientific and technical principles•  Consistent approach•  Supports objective of validation•  Supports routine manufacturing in type of testing and sampling•  Support routine manufacturing in duration of sampling and testing•  Results and discussion support data•  Correct technical conclusions•  Equipment testing support entire operating range used in manufacturing 59
  127. 127. VALIDATION APPROVAL COMMITTEE•  Training consistent with area of expertise•  Specialized training on validation function•  Emphasize role of internal auditor VALIDATION APPROVAL COMMITTEE IS NOT Training for new personnel Expeditor for engineering documents 60
  128. 128. PROCESS ANALYTICAL TECHNOLOGY (PAT)Processes verified by PAT are not validatedAll associated PAT equipment are validatedAll associated PAT control systems are validatedAll new analytical equipment is validatedAll new analytical methods are validated “WHEN PAT IS IN PLACE, WILL THERE BE ANY MORE VALIDATION?” 61
  129. 129. SUMMARY COMPREHENSIVE, CONSISTENT, AND EFFECTIVE VALIDATION DOCUMENTSValidation documents consistent with validation guidelines and expectations – based on riskPolicies and VMPStage 1 -- Emphasis on development work supporting Stage 2•  Technical basis for validationStage 2 -- Work should consider validation guidance recommendations•  Plans, protocols, resultsStage 3 – Emphasis on maintaining validated state through lifecycle•  Specific needs and routine monitoringAssociated documents 62
  130. 130. SUMMARY – VALIDATION POLICIES•  Corporate or company policies•  High level overview documents•  State agreement with local regulatory requirements and customer regulatory documents•  Describe general validation approach•  State key points from Process Validation Guidance•  Risk-based approach 63
  131. 131. SUMMARY – VALIDATION MASTER PLAN•  Program description at site•  Multi-chapter document•  Updated as needed (annual, quarterly, monthly)•  Improvement projects commitments and timelines•  Consistent with corporate policies•  State key points from Process Validation Guidance•  Risk-based approach 64
  132. 132. SUMMARY – STAGE 1 DOCUMENTS•  Technical understanding of processes -- basis of validation•  Reports readily available•  Accessed throughout product lifecycle•  Stand-alone documents•  Applies to processes, cleaning, analytical, equiment, facilities, utilities, control systems, others. R&D / TECHNICAL AREAS NOT ACCUSTOMED TO THESE REQUIREMENTS 65
  133. 133. SUMMARY – STAGE 2 DOCUMENTS VALIDATION REQUEST / PLAN•  Initiates validation•  Provides basis and details of future work•  Lists all specific requirements to complete validation•  Administrative importance•  Most important document – all subsequent documents based on validation plan•  Risk based 66
  134. 134. SUMMARY – STAGE 2 DOCUMENTS VALIDATION PROTOCOLS•  Specific guidance requirements•  Strategy and approach•  Impact of change•  Risk based•  Testing and sampling rationale•  Acceptance criteria•  Statistical data treatment•  Data sheets•  Post-validation monitoring plan 67
  135. 135. SUMMARY – STAGE 2 DOCUMENTS VALIDATION RESULTS / REPORTS•  Data sheets•  Discussion of results – Evaluate results –  Additional post-validation testing if necessary•  Validation statement – “___ is validated.”•  Summary report for multiple protocol validation or complex projects•  Stage 3 Plan included in results document•  Most important validation document•  Simple sentences, simple words•  Written for the reader 68
  136. 136. SUMMARY – STAGE 3 DOCUMENTS CONTINUED PROCESS VERIFICATION•  Specialized post-PQ requirements•  Routine monitoring –  Risk based 69
  137. 137. SUMMARY – ASSOCIATED DOCUMENTS•  Equipment, facilities, utilities, etc. qualification•  Analytical methods and equipment•  Training records•  Personnel qualification•  Environmental monitoring 70
  138. 138. SUMMARY – OTHER CONSIDERATIONS•  Follow FDA PV Guidance•  Use outlines•  Have model documents available•  Continually improve model documents –  Based on guidance requirements –  Example information to provide expectations for writers and approvers –  Write most important document sections first•  Consider problem examples•  FMEA risk analysis included with validation plan 71
  139. 139. 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: 72
  141. 141. 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
  142. 142. 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
  143. 143. 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
  144. 144. 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
  145. 145. 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
  146. 146. 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
  147. 147. 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
  148. 148. 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
  149. 149. 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
  150. 150. 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
  151. 151. 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
  152. 152. 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
  153. 153. 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
  154. 154. 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
  155. 155. 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
  156. 156. pH SOLUBILITY PROFILE, pH 1-12Solubilitymg/ml Drug A Drug BpH 1 7 12 17
  157. 157. 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
  158. 158. 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
  159. 159. 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
  160. 160. 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
  161. 161. 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
  162. 162. CLEANING CHEMISTRY MECHANISMS•  Wetting•  Emulsification•  Dispersion•  Solubility•  Chelation•  Oxidation•  Hydrolysis 23
  163. 163. CLEANING AGENT OPTIONS•  Water•  Commodity alkalis and acids•  Organic solvents•  Surfactants –  Anionic –  Cationic –  Amphoteric –  Nonionic•  Formulated detergents 24
  164. 164. 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
  165. 165. 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
  166. 166. 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
  167. 167. 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
  168. 168. 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
  169. 169. 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
  170. 170. 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
  171. 171. 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
  172. 172. 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
  173. 173. 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
  174. 174. ANALYTICAL METHOD DEVELOPMENTCleaning agent residue•  Analytical method to determine residual cleaning agent.•  Information from cleaning agent vendor 35
  175. 175. 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
  176. 176. 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
  177. 177. 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
  178. 178. 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
  179. 179. 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
  180. 180. 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
  181. 181. 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
  182. 182. 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
  183. 183. 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
  184. 184. 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
  185. 185. 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
  186. 186. 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
  187. 187. 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
  188. 188. 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
  189. 189. 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
  190. 190. 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
  191. 191. 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
  192. 192. 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
  193. 193. 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