Process Validation Guidances: FDA and Global

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Process Validation Guidances: FDA and Global

  1. 1. PROCESS VALIDATION GUIDANCES FDA AND GLOBAL Paul L. Pluta, PhD Journal of Validation Technology Journal of GXP ComplianceUniversity of Illinois at Chicago (UIC) College of Pharmacy Chicago, IL, USA 1
  2. 2. OUTLINEProcess Validation Lifecycle Approach Overview•  History and development•  Is the lifecycle approach really new?•  FDA commentaryLifecycle Approach Stages•  #1 -- Process Understanding (Process Design)•  #2 -- Process Demonstration (Process Qualification)•  #3 -- Maintaining Validation (Continued Process Verification)Fundamental Concepts•  The “process of process validation”•  Enhanced execution•  Comparison to traditional approachRegulatory Guidances•  Health Canada•  FDA•  EMAApplications of PV Guidance•  Processes: Manufacturing, cleaning, packaging, analytical, others•  Equipment, facilities, utilities, others•  Quality SystemsImplementation•  Implementation is difficult 2
  3. 3. OBJECTIVES•  What is the lifecycle approach?•  Is the lifecycle approach new?•  How is it different?•  What are fundamental principles?•  US only or global?•  Is industry accepting this approach?•  Audit questions: What is your approach to validation? What is your approach to quality systems? 3
  4. 4. VALIDATION MANAGER COMMENTARYOrganizations implementing lifecycle approach -- Reasons•  US FDA guidance•  Health Canada guidance•  EMA draft guidance•  Global communication•  ICH Q8, Q11•  Logical approach – development, performance, and maintenance•  Application to other processes, equipment, facilities, etc.Organizations not implementing lifecycle approach -- Reasons•  “Its only a guidance.”•  “Let’s see what happens.”•  “It’s only for USA.”•  “We will consider it if we get observations.”•  Too costly, no headcount 4
  5. 5. PROCESS VALIDATION LIFECYCLE APPROACH OVERVIEW•  History and Development•  Fundamental Concepts•  Consistency with Medical Devices•  Is the lifecycle approach really new? 5
  6. 6. HISTORY AND DEVELOPMENT – LIFECYCLE APPROACH2004 – Health Canada guidance2005 – FDA initial presentations2007 – ICH Q102008 – FDA draft guidance2009 – ICH Q8(R2)2009 – Health Canada revision2011 – FDA guidance issued2012 – EMA draft guidance 6
  7. 7. PROCESS VALIDATION LIFECYCLE APPROACH A NEW PARADIGM FOR PHARMA – 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 8-41. 7
  8. 8. HEALTH CANADA -- VALIDATION GUIDELINES FOR PHARMACEUTICAL DOSAGE FORMS (GUI-0029)5.0 Phases of ValidationPhase 1: Pre-Validation PhasePhase 2: Process Validation Phase (Process Qualification PhasePhase 3: Validation Maintenance Phase6.0 InterpretationValidation protocolValidation Master PlanInstallation 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 8
  9. 9. ICH Q8 (R2) PHARMACEUTICAL DEVELOPMENTObjectives•  Harmonized regulatory submissions (CTD)•  Principles of Quality by Design (QbD)•  Consistent with Q9 Risk ManagementProblems addressed•  Inconsistency between all regions•  Inconsistent content•  Inclusion of development information 9
  10. 10. 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 10
  11. 11. 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 …” 11
  12. 12. ICH Q8 PHARMACEUTICAL DEVELOPMENTKey points•  Examination•  Understanding•  Evaluation•  Identification•  Rationale and justification•  OthersDiscussion in submission 12
  13. 13. 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 13
  14. 14. 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 14
  15. 15. ICH Q9 QUALITY RISK MANAGEMENT•  Principles of quality risk management•  General process: Initiation, assessment, control, communication, review•  Methodology•  Integration into industry and regulatory operations•  Methods and tools•  Potential specific applications 15
  16. 16. ICH Q9 QUALITY RISK MANAGEMENTInitiate risk management processRisk assessment•  Risk identification•  Risk analysis•  Risk evaluationRisk control•  Risk reduction•  Risk acceptanceOutputRisk review 16
  17. 17. 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 17
  18. 18. 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 18
  19. 19. ICH Q9 QUALITY RISK MANAGEMENTKey points•  Methods of evaluation•  Potential applications – every function, every activity, entire product lifecycle 19
  20. 20. 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 20
  21. 21. 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 terminology 21
  22. 22. ICH Q10 PHARMACEUTICAL QUALITY SYSTEMS•  Overview and definitions•  Management responsibility: Commitment, policy, planning, resources, communication, review, outsourcing•  Continual improvement of performance and quality: Lifecycle stages and elements•  Continual improvement of quality system: Management, monitoring, outcomes 22
  23. 23. 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 23
  24. 24. ICH Q10 PHARMACEUTICAL QUALITY SYSTEMSKey pointsContinual 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. 24
  25. 25. ICH Q10 PHARMACEUTICAL QUALITY SYSTEMSImplications for Process Validation•  Product performance and monitoring•  CAPA system enhances process understanding•  Change management system•  Process improvements 25
  26. 26. ICH Q11 DEVELOMENT AND MANUFACTURE OF DRUG SUBSTANCES•  Consistent with ICH Q8, Q9, and Q10•  Lifecycle approach•  CQA, CPP•  Design space•  Control of variables•  Process validation•  Risk management 26
  27. 27. 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 27
  28. 28. SUPPORTING DOCUMENTS PROCESS VALIDATION – 1987 GUIDANCEAssurance of product quality:•  Quality parts and materials•  Adequate product and process design•  Control 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 processEquipment: Installation QualificationProcess: Performance QualificationProduct (devices only): Performance QualificationRevalidation. Change controlDocumentation. Proper maintenance of documentationReference: FDA Guideline on General Principles of Process Validation. May, 1987 28
  29. 29. SUPPORTING DOCUMENTS VALIDATION – PHARMACEUTICAL DOSAGE FORMS FDA INSPECTION GUIDELINESThree phases of the validation process:•  Product development•  Design of the validation protocol•  Demonstration runs (validation) – full scaleProcess validation:•  Documented 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 proceduresVariables 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) 29
  30. 30. SUPPORTING DOCUMENTS VALIDATION – MEDICAL DEVICESPlanning the Process Validation StudyInstallation and Operational QualificationProcess Performance Qualification•  Eliminate controllable causes of variationProduct Performance Qualification•  Evaluate 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 30
  31. 31. SUPPORTING DOCUMENTS PROCESS VALIDATION – APICritical parameters / attributes identified during developmentQualification 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 Guide for Active Pharmaceutical Ingredients. November, 2000. 31
  32. 32. SUPPORTING DOCUMENTS PROCESS VALIDATION – PRODUCTS / APIA validated manufacturing process has a high level of scientific assurance that it will reliably product acceptable product.Proof of validation is obtained through rational experimental design and the ongoing evaluation of data, preferably beginning from the process development phase continuing through the commercial production phase.Reference: FDA Section 490.199. CPG 7132c.08. Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval. 2004 revision. 32
  33. 33. SUPPORTING DOCUMENTS PROCESS VALIDATION – PRODUCTS / APIBefore commercial distribution:•  Product and process development•  Scale-up studies•  Equipment and system qualification•  Conformance batchesIdentify and control all critical sources of variabilityAdvance manufacturing control technology may eliminate validation lots.Reference: FDA Section 490.199. CPG 7132c.08. Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval. 2004 revision. 33
  34. 34. SUPPORTING DOCUMENTS VALIDATION -- PHARMACEUTICAL CGMPSCross-Agency workgroup CDER, CBER, ORA, and CVM.“The CPG clearly signals that a focus on three full-scale production batches would fail to recognize the complete story on validation.”Reference: FDA. Pharmaceutical CGMPs for the 21st Century – A Risk-Based Approach. Final Report, September 2004. 34
  35. 35. SUPPORTING DOCUMENTS PROCESS VALIDATION – MEDICAL DEVICESProcess evaluation – Validation or verificationProtocol development –  Processes well thought out –  What could go wrongInstallation QualificationOperational Qualification –  “Worst case” testing –  DOE and screening studiesPerformance Qualification –  Process 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. Quality Management Systems – Process Validation Guidance. January 2004. 35
  36. 36. SUPPORTING DOCUMENTS VALIDATION – INTERNATIONAL PIC/S PHARMACEUTICAL INSPECTION CONVENTIONA series of experiments should be devised to determine the criticality of process parameters / factorsTest processes with starting materials on the extremes of specificationMonitoring and in-process controlsReference: PIC/S Recommendations on Validation. July 2004. 36
  37. 37. SUPPORTING DOCUMENTS FDA -- QUALITY BY DESIGN (QbD)•  Product is designed to meet patient requirements•  Process is designed to consistently meet product critical quality attributes•  Impact of starting materials and process parameters on product quality is understood•  Critical sources of process variability are identified and controlled•  Process is continually monitored and updated to assure consistent quality over timeReference: FDA. Chi-wan Chen, ISPE, Japan, June, 2006 37
  38. 38. SUPPORTING DOCUMENTS PROCESS ROBUSTNESS (PQRI)Robust Process: Able to tolerate expected variability of raw materials, operating conditions, process equipment, environmental conditions, and human factors •  Development •  MaintenanceProcess understanding is key to developing a robust process.Reference: Product Quality Research Institute (PQRI). Pharmaceutical Engineering, November-December, 2006 38
  39. 39. SUPPORTING DOCUMENTS ASTM WK 9935 Standard Guide Continuous Quality Verification (CQV) A Science and Risk-Based Alternative Approach to Traditional Process Validation of Biopharmaceutical and Pharmaceutical Manufacturing ProcessesCONTINUOUS QUALITY VERIFICATIONProcess design / Risk assessment / Process understanding •  Development phase •  Scale-up phase •  Commercialization phaseProcess capability evaluationContinuous process improvement 39
  40. 40. SUPPORTING DOCUMENTS PROCESS ANALYTICAL TECHNOLOGY (PAT)Processes verified by PAT are not validatedAll associated PAT equipment and analytical methods are validatedReference: FDA. PAT -- A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. September 2004 40
  41. 41. SUPPORTING DOCUMENTS PROCESS ANALYTICAL TECHNOLOGY (PAT)Process Understanding•  All critical sources of variability are identified and explained.•  Variability is managed by the process•  Product quality attributes can be accurately and reliably predicted over the design space •  Materials used •  Process parameters •  Manufacturing •  Environmental •  Other conditionsReference: FDA. PAT -- A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. September 2004 41
  42. 42. LIFECYCLE APPROACH OVERVIEW•  The “process of process validation”•  Process understanding, demonstration, and maintaining the validated state throughout entire commercial life of product.•  Comparison to previous approach 42
  43. 43. PROCESS VALIDATION HISTORY1978FDA CGMP includes Validation1987Development -- VALIDATION -- Control2004-2011Lifecycle approachContinuum of understanding – validation – maintenanceUNDERSTANDING -- VALIDATION -- MAINTENANCE 43
  44. 44. FDA 2011 PV GUIDANCE – PROCESS VALIDATION REVISITED Paula Katz (FDA) and Cliff Campbell JGXP Compliance, Vol .16, #4, Fall, 2012Among other motivating factors, the Agency sought to emphasize process design and maintenance of process control during commercialization. By aligning process validation activities with a lifecycle approach, the 2011 Guidance communicates that process validation is an ongoing program rather than a discrete and isolated activity. Under the 2011 Guidance, process validation is presented as a series of activities that manufacturers carry out over the lifecycle of the product and process. This view of process validation underscores the importance of detecting, understanding, and controlling sources of variability over time in order to consistently produce safe, effective drugs that meet all quality attributes. In turn, the emphasis on understanding and controlling process variability leads to a clarification that the Agency expects manufacturers to employ objective measures and appropriate statistical tools and analysis. 44
  45. 45. PROCESS VALIDATION GUIDANCES•  Health Canada•  FDA•  EMA 45
  46. 46. HEALTH CANADA -- VALIDATION GUIDELINES FOR PHARMACEUTICAL DOSAGE FORMS, 2009Phase 1. Pre-validation phase or qualification phase. Product R&D, pilor studies, scale-up, stability studies, equipment qualification, IQ, OQ, master production documents, others.Phase 2. Process validation phase or process qualification phase. Verify that all limits of critical process parameters are valid and satisfactory product produced under worst-case conditions.Phase 3. Validation maintenance phase. Frequent reviews of process-related documents to assure no changes, deviations, or failures, and that SOPs have been followed, including change control No changes that should have results in revalidation. 46
  47. 47. 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 – Demonstrate reproducible manufacturing through conformance lots•  Stage 3 – Continued Process Verification – Routine manufacturing and monitoring of performance. STAGE 1 AND STAGE 3 EMPHASIS – NEW PARADIGM 47
  48. 48. 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.” 48
  49. 49. 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. 49
  50. 50. 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 50
  51. 51. 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 51
  52. 52. 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 52
  53. 53. 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 53
  54. 54. STAGE 2, PROCESS QUALIFICATION Conformance LotsProceduresValidation plansProtocolsSamplingTestingResultsPlan to maintain validationALL EQUIPMENT, ANALYTICAL, AND SUPPORTING SYSTEMS MUST BE QUALIFIED. 54
  55. 55. 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 FDA PV GUIDANCE 55
  56. 56. 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 FDA PV GUIDANCE 56
  57. 57. HEALTH CANADA -- VALIDATION PROTOCOLMinimum information•  Objective, scope of coverage of the validation study•  Validation team membership, qualifications, and responsibilities•  Type of validation – prospective, concurrent, retrospective, re-validation•  Number and selection of batches•  List of all equipment used. Normal and worst-case operating parameters•  Outcome of IQ and OQ for critical equipment•  Requirements for calibration of all measuring devices•  Critical process parameters and tolerances•  Description of processing steps. Copy of master documents•  Sampling points, stages of sampling, methods of sampling, sampling plans•  Statistical tools for data analysis•  Training requirements for processing operators•  Validated test methods•  Specification for raw and packaging materials and test methods•  Forms and charts for documenting results•  Format for presentation of results, documenting conclusions, and approval of study results 57
  58. 58. 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 58
  59. 59. CONTINUED PROCESS VERIFICATIONMonitoringStatistical process control (SPC)Trend analysisChange controlContinuous improvementRevalidationManagement review STATISTICIAN RECOMMENDED BY FDA 59
  60. 60. 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 FDA PV GUIDANCE 60
  61. 61. SUMMARY OF FDA 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•  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 61
  62. 62. HEALTH CANADA -- VALIDATION MASTER PLAN•  Company philosophy, intentions and approaches to establish performance adequacy•  Management agreement•  Meticulous preparation and planning of steps in process•  Structured according to SOP•  List of items to be validated and schedule•  Documentation 62
  63. 63. HEALTH CANADA VALIDATION GUIDELINESAdditional sections•  Installation and Operational Qualification•  Requalification•  Process Validation –  Prospective –  Concurrent –  Retrospective•  Process Re-Validation – “Periodic review and trend analysis …at scheduled intervals”•  Change control 63
  64. 64. EMA GUIDELINE ON PROCESS VALDIATION Draft March, 2012•  “…applying enhanced process understanding coupled with risk management tools under an efficient quality system as described by ICH Q8, Q9, and Q10.”•  Definition•  Continuous process verification (PAT)•  Validation “…not a one-off event.”•  “A lifecycle approach should be applied linking product and process development, validation of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production.” 64
  65. 65. EMA GUIDELINE ON PROCESS VALDIATION Draft March, 2012•  Traditional process validation –  Annex I details•  Continuous process verification•  Hybrid approach 65
  66. 66. EMA GUIDELINE ON PROCESS VALDIATION Draft March, 2012Definitions•  Control Strategy•  Continued Process Verification•  Continuous Process Verification•  Critical Process Parameter (CPP)•  Critical Quality Attribute (CQA)•  Design Space•  High Impact Models•  Lifecycle•  Pharmaceutical Quality System (PQS)•  Process Validation 66
  67. 67. FUNDAMENTAL CONCEPTS•  Scientific and technical basis in development (Stage 1)•  Validation (Stage 2 ) confirms tage 1 development•  Acceptable (passing) results are expected.•  Validation is not –  R&D, Final stage of development process –  Optimization, Fine-tuning, or Debugging•  Monitor and maintain validated state throughout product lifetime (Stage 3). 67
  68. 68. FUNDAMENTAL CONCEPTS•  Critical quality attributes (CQA)•  Critical process parameters (CPP) related to CQA•  Identify and control variation•  Statistical applications –  DOE –  Statistical Process Control (SPC)•  Rationale and justification – sampling, testing, etc.•  Detailed expectations in guidance –  Protocol and results –  Monitoring•  Monitoring and maintenance à Continuous improvements•  Risk – All decisions based on risk analysis 68
  69. 69. APPLICATIONS OF PV GUIDANCE•  Processes: Manufacturing, cleaning, packaging, analytical, others•  Equipment, facilities, utilities, others•  Other new applications•  Quality Systems and compliance 69
  70. 70. PROCESSESManufacturingPackagingCleaningAnalyticalOtherALL PROCESSES MUST BE APPROPRIATELY DESIGNED AND DEVELOPED, DEMONSTRATE PERFORMANCE, AND BE MONITORED AND MAINTAINED.PROCESSES MUST BE CONTINUALLY IMPROVED. 70
  71. 71. QUALIFICATIONEquipmentFacilitiesUtilitiesControl systemsComputer systemsOthersALL QUALIFIED EQUIPMENT MUST BE APPROPRIATELY DESIGNED AND DEVELOPED, DEMONSTRATE PERFORMANCE, AND BE MONITORED AND MAINTAINED.QUALIFIED EQUIPMENT MUST BE CONTINUALLY IMPROVED. 71
  72. 72. EQUIPMENT à PROCESSESHVAC Systems – Process variable incoming airWater Systems – Process variable incoming waterALL QUALIFIED EQUIPMENT THAT FUNCTIONS AS PROCESSES MUST BE APPROPRIATELY DESIGNED AND DEVELOPED, DEMONSTRATE PERFORMANCE, AND BE MONITORED AND MAINTAINED.QUALIFIED EQUIPMENT MUST BE CONTINUALLY IMPROVED.Reference: “The HVAC Process.” Delli Paoli, Alexander. J Validation Technology, Volume 17, #4, Autumn 2011. 72
  73. 73. QUALITY SYSTEMSFDA QUALITY SYSTEMS•  Quality system•  Material system•  Production and equipment system•  Laboratory systemALL QUALITY SYSTEMS MUST BE APPROPRIATELY DESIGNED AND DEVELOPED, DEMONSTRATE PERFORMANCE, AND BE MONITORED AND MAINTAINED.QUALITY SYSTEMS MUST BE CONTINUALLY IMPROVED. 73
  74. 74. IMPLEMENTATION•  MPLEMENTATION VERY DIFFICULT –  Time –  Cost –  Change•  Integration of Validation Approval Committee, R&D/technical groups, and QA functions•  Lifecycle involvement – new to traditional validation•  Technical groups not accustomed to validation•  Post PQ monitoring –  Prescribed testing based on risk –  Special testing•  Enhanced PQ and post PQ execution as prescribed in guidance (statistics, etc.)•  Note direction of global guidances, conferences, meetings•  Great challenges for validation personnel 74
  75. 75. SUMMARY PROCESS VALIDATION GUIDANCESProcess Validation Guidances have greatly expanded the scope of validation•  Lifecycle approach – documents from development through commercialization –  Understanding –  Demonstration –  Monitoring and maintenance•  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 75
  76. 76. SUMMARY WHERE WE ARE -- CURRENT PRACTICER&D Validation Commercialization 76
  77. 77. 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 77
  78. 78. 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 IMPLEMENTATION AND EFFECTIVE DOCUMENTS CONSISTENT WITH THE ABOVE 78
  79. 79. LIFECYCLE APPROACH TO PROCESS VALIDATIONProcess Design and Development – Pre-validation work•  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 qualified•  Analytical methods validated•  Confirm commercial process design•  Validation performanceMaintaining the Validated State•  Monitor, collect information, assess•  Maintenance, continuous verification, process improvement•  Change control•  Validation maintenance “The process of process validation.” All activities 79 based on risk.
  80. 80. SUMMARY PROCESS VALIDATION HISTORY1978CGMP includes Validation1987Development -- VALIDATION -- Control2004-2011Lifecycle approachContinuum of understanding – validation – maintenanceUNDERSTANDING -- VALIDATION -- MAINTENANCE 80
  81. 81. SUMMARY VALIDATION -- FUTUREDevelopment Performance Maintenance Stage 1 à Stage 2 à Stage 3 81
  82. 82. SUMMARY – FUNDAMENTAL CONCEPTS•  Lifecycle approach•  Scientific and technical basis in development•  Validation is confirmation•  Monitor and maintain•  Management review•  Continuous improvements•  Risk analysis 82
  83. 83. SUMMARY – FUNDAMENTAL CONCEPTS•  CQA and CPP•  Variation – identify and control•  Statistical applications –  DOE –  Statistical Process Control (SPC)•  Rationale and justification•  Risk analysis – work appropriate for level of risk•  Enhanced detailed requirements in guidance –  Protocol and results –  Monitoring 83
  84. 84. SUMMARY -- APPLICATIONSManufacturing process validationOther processes – cleaning, packaging, analytical, etc.Equipment, facilities, utilities, computer systems, etc.Equipment processes – HVAC, water THERE IS NO ARGUMENT AGAINST DESIGN, DEMONSTRATE, AND MAINTAINLIFECYCLE APPROACH INCREASING APPLICATIONS 84
  85. 85. SUMMARY FINALLifecycle Approach Status -- 2012:•  Lifecycle approach globally accepted –  Health Canada 2004 –  FDA 2011 –  EMA draft issued March, 2012•  Design à Demonstrate à Maintain: No argument•  Approach specifics (QbD, CQA, etc.) accepted and consistent with ICH and other guidances•  Usage increasing – Application to equipment, facilities, utilities, computers, quality systems, etc. Stage approach and associated concepts increasing application. UNDERSTANDING à PERFORMANCE à MAINTENANCE 85
  86. 86. SUMMARY FINAL -- DID WE MEET OBJECTIVES?•  What is the lifecycle approach?•  Is the lifecycle approach new?•  How is it different?•  What are fundamental principles?•  US only or global?•  Is industry accepting this approach?•  Audit questions: What is your approach to validation? What is your approach to quality systems? UNDERSTAND – DEMONSTRATE -- MAINTAIN 86
  87. 87. PAUL L. PLUTA, PhDEditor-in-Chief Journal of Validation Technology Journal of GXP Compliance Advanstar Communications, USAVisiting Clinical Associate Professor University of Illinois at Chicago (UIC) College of Pharmacy Chicago, IL, USAExtensive pharmaceutical industry experienceContact: paul.pluta@comcast.net 87

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