Implement Process Validation

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Implement Process Validation

  1. 1. Institute of Validation TechnologyValidation Week- PhiladelphiaSession 4: Best Practice to Implement ProcessValidation in Device Manufacturing Enterprise-wideTanya Fletcher-ScottValidation Manager- Greenville SC Solutions FacilityTanya.Fletcher-Scott@Bausch.com October 24, 2012 CONFIDENTIAL [1]
  2. 2. Agenda£  Getting Started-Overview£  Process Validation£  Enterprise wide Roll Out of Process Validation£  Interactive Exercise Look out for the Best Practice [2]
  3. 3. Getting Started-Overviewo  The Rules- Review of Standards and Guidances for Process Validation of Deviceso  Tools- Risk Assessments and Statisticso  The Team- Don’t go it alone!o  The Docs- Documenting the process validation activities [3]
  4. 4. Getting Started-OverviewThe Rules- Review of Standards and Guidances for ProcessValidation of Devices: •  21 CFR 820 Quality System Regulators •  ISO, EN ISO 13485 Medical devices- Quality management systems- Requirements for regulatory purposes •  ISO, EN ISO 14971 Medical devices-Application of risk management to medical devices Best Practice:• ISO, EN ISO 9001 Quality management systems —Requirements your Know regs and guidances [4]
  5. 5. Getting Started-OverviewThe Rules- Review of Standards and Guidances for ProcessValidation of Devices: •  GHTF, Global Harmonization Task Force- Quality management Systems-Process Validation Guidance* •  SOR/98-282 Canadian Medical Regulators Best Practice: Know your •  93/42/EEC Medical Device Directive regs and guidances*Copy provided as bonus material [5]
  6. 6. Getting Started-OverviewThe Rules- Review of standards and guidances for ProcessValidation of Devices:21 CFR 820 Quality System RegulatorsSec. 820.70 Production and process controls.b-Production and process changes. Each manufacturer shallestablish and maintain procedures for changes to a specification,method, process, or procedure. Such changes shall be verified orwhere appropriate validated according to 820.75 (ProcessValidation), before implementation and these activities shall bedocumented. Changes shall be approved in accordance with 820.40(Document controls). [6]
  7. 7. Getting Started-OverviewThe Rules- Review of standards and guidances for ProcessValidation of Devices:Sec. 820.75 Process Validation.a- Where the results of a process cannot be fully verified bysubsequent inspection and test, the process shall be validated witha high degree of assurance and approved according to establishedprocedures. The validation activities and results, including the dateand signature of the individual(s) approving the validation andwhere appropriate the major equipment validated, shall bedocumented.b- Each manufacturer shall establish and maintain procedures for monitoring and control of process parameters for validated process to ensure that the specified requirements continues to be met. [7]
  8. 8. Getting Started-OverviewThe Rules- Review of standards and guidances for ProcessValidation of Devices:ISO, EN ISO 13485 Medical devices- Quality management systems-Requirements for regulatory purposes7 Product realization, 7.1 Planning of product realizationThe organization shall plan and develop the processes needed for productrealization. Planning of product realization shall be consistent with therequirements of the other processes of the quality management system. Inplanning product realization, the organization shall determine the following, asappropriate:a) quality objectives and requirements for the product;b) the need to establish processes, documents, and provide resources specific tothe product;c) required verification, validation, monitoring, inspection and test activitiesspecific to the product and the criteria for product acceptance;d) records needed to provide evidence that the realization processes andresulting product meet requirements [8]
  9. 9. Getting Started-OverviewThe Rules- Review of standards and guidances for ProcessValidation of Devices:ISO, EN ISO 13485 Medical devices- Quality management systems-Requirements for regulatory purposes7.5.2 Validation of processes for production and service provisionThe organization shall validate any processes for production and serviceprovision where the resulting output cannot be verified by subsequent monitoringor measurement. This includes any processes where deficiencies becomeapparent only after the product is in use or the service has been delivered.Validation shall demonstrate the ability of these processes to achieve plannedresults. The organization shall establish arrangements for these processesincluding, as applicablea) defined criteria for review and approval of the processes,b) approval of equipment and qualification of personnel,c) use of specific methods and procedures,d) requirements for records ande) revalidation. [9]
  10. 10. Getting Started-OverviewTools- Risk Assessments and Statistics Best Practice: Use your statisticians Statistics Sec. 820.250 Statistical techniques. (a)  Where appropriate, each manufacturer shall establish and maintain procedures for identifying valid statistical techniques required for establishing, controlling, and verifying the acceptability of process capability and product characteristics. (b) Sampling plans, when used, shall be written and based on a valid statistical rationale. Each manufacturer shall establish and maintain procedures to ensure that sampling methods are adequate for their intended use and to ensure that when changes occur the sampling plans are reviewed. These activities shall be documented. [ 10 ]
  11. 11. Getting Started-OverviewTools- Risk Assessments and Statistics ISO 13485 8 Measurement, analysis and improvement, 8.1 General The organization shall plan and implement the monitoring, measurement, analysis and improvement processes needed a)  to demonstrate conformity of the product, b) to ensure conformity of the quality management system, and c)to maintain the effectiveness of the quality management system. This shall include determination of applicable methods, including statistical techniques, and the extent of their use. [ 11 ]
  12. 12. Getting Started-Overview Risk AnalysisTools- Risk Assessments and Statistics Risk Assessments ISO 14971 Medical devices — Application of risk management Risk Evaluation to medical devices Risk Control The ISO Standard defines risk as combination of the probability of occurrence of harm and the severity of that harm Evaluation of overall residual risk acceptability Risk Management Report Production and post- production information [ 12 ]
  13. 13. Getting Started-OverviewTools- Risk Assessments and Statistics Risk Management Tools •  Preliminary Hazard Analysis (PHA) is a technique that can be used early in the development process to identify the hazards, hazardous situations, and events that can cause harm when few of the details of the medial device design are known. •  Fault Tree Analysis (FTA) is especially useful in safety engineering, early in the development stages, for the identification and prioritization of hazards and hazardous situations as well as for analyzing adverse events. [ 13 ]
  14. 14. Getting Started-OverviewTools- Risk Assessments and Statistics Risk Management Tools •  Failure Mode and Effects Analysis (FMEA) and Failure Mode, Effects and Criticality Analysis (FMECA) are techniques by which an effect or consequences of individual components are systematically identified and is more appropriate as the design matures. •  Hazard and Operability Study (HAZOP) and Hazard Analysis and Critical Control Point (HACCP) are typically used in the latter stages of the development phase to verify and then optimize design concepts or changes. [ 14 ]
  15. 15. Getting Started-OverviewThe Team- Don’t go it alone!The types of products manufactured in theGreenville facility are lens care solutions.When we are conducting a process validationto support a product transfer or significantformulation change, we need the support of across functional group inclusive of corporateand site wide subject matter experts. [ 15 ]
  16. 16. Getting Started-OverviewThe Team- Don’t go it alone!The Global Harmonization Task Force- Quality Management Systems –Process Validation Guidance suggests the following subject matter teammembers:•  Quality Assurance* Best•  Engineering* Practice:•  Manufacturing* Project Managers are key to any•  Laboratory (Chemistry and Microbiology)* success tech•  Technical Services transfer•  Research & Development*•  Regulatory Affairs*•  Clinical Engineering•  Purchasing/Planning•  Process Excellence / Statistician*•  Project Manager**B+L’s typical team core members for major process validation projects [ 16 ]
  17. 17. Getting Started-OverviewThe Docs- Documenting the process validation activitiesSec. 820.75 Process Validation.a- Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures. The validation activities and results, including the date and signature of the individual(s) approving the validation and where appropriate the major equipment validated, shall be documented. [ 17 ]
  18. 18. Getting Started-OverviewThe Docs- Documenting the process validation activitiesThe Global Harmonization Task Force- Quality Management Systems –Process Validation Guidance suggests the following elements in yourprocess validation protocols: Elements Validation IQ OQ PQ PV Strategy Identification of the process to be validated X X X X X Identification of device(s) to be manufactured X X X X X using this process Objective and measurable criteria for a X X X X X successful validation Identification of operators and required operator X X Best qualification Practice: Validation Strategies are a great tool for ‘big scope’ projects [ 18 ]
  19. 19. Getting Started-OverviewThe Docs- Documenting the process validation activitiesThe Global Harmonization Task Force- Quality Management Systems –Process Validation Guidance suggests the following elements in yourprocess validation protocols: Elements Validation IQ OQ PQ PV Strategy X Length and duration of the validation X X Shifts, operators, equipment to be used in the process X X X X Any subjective criteria used to evaluate the product X X Identification of utilities for the process equipment and quality of the utilities X X X X X Complete description of the process [ 19 ]
  20. 20. Getting Started-OverviewThe Docs- Documenting the process validation activitiesThe Global Harmonization Task Force- Quality Management Systems –Process Validation Guidance suggests the following elements in yourprocess validation protocols: Elements Validation IQ OQ PQ PV Strategy X X X X Relevant specifications that relate to the product, components, manufacturing materials, etc X X Process parameters to be monitored, and methods for controlling and monitoring* X X Product characteristics to be monitored and method for monitoring* X X Any subjective criteria used to evaluate the product *Use of a Control Plan is a great tool and best practice. Example included in bonus material [ 20 ]
  21. 21. Getting Started-OverviewThe Docs- Documenting the process validation activitiesThe Global Harmonization Task Force- Quality Management Systems –Process Validation Guidance suggests the following elements in yourprocess validation protocols: Elements Validation IQ OQ PQ PV Strategy X X X X X Definition of what constitutes non- conformance for both measurable and subjective criteria X X X X Statistical methods for data collection and analysis X Consideration of maintenance and repairs of manufacturing equipment X Criteria for revalidation When it’s all done, generate the final report summarizing all requirements, results, issues and conclusions [ 21 ]
  22. 22. Agenda£  Getting Started-Overview£  Process Validation£  Enterprise wide Roll Out of Process Validation£  Interactive Exercise [ 22 ]
  23. 23. Process Validationo  Creating a strategy/validation plano  Strategies for new and existing productso  Runs and sampleso  When are you done? [ 23 ]
  24. 24. Process ValidationCreating a strategy/validation planA Validation plan which defines what needs to be validated (i.e.equipment, systems and processes) and how validation needs will bemet for a given project.The strategy also provides a roadmap to follow ensuring therequirements are defined and agreed upon up-front and that allrequirements are met prior to implementation or launch Best Practice: Wait until you have created or updated your risk assessment before generating a strategy. [ 24 ]
  25. 25. Process ValidationCreating a strategy/validation planB+L’s validation systems does not require validation strategies for smaller, lesscomplex validation projects whose strategy can be fully detailed within a protocol.The strategy is useful to communicate completion of validation strategy activitiesand results of the testing performed to support product Launch or Design ChangeImplementation <Let’s review the sample validation strategy in your bonus material> [ 25 ]
  26. 26. Process ValidationStrategies for new and existing productsNew ProductsPer ISO 9001, all new products must under Design and developmentwhich includes:•  Planning•  Design and development inputs•  Design and development outputs•  Design and development review•  Design and development verification•  Design and development validation*•  Control of design and development changes**At the completion of the design and development validation andbefore the control of design changes, product transfer and processvalidation occurs. [ 26 ]
  27. 27. Process ValidationStrategies for new and existing productsNew ProductsDuring the product transfer process, the product is being evaluatedat the manufacturing site for scale up.It is at this stage that the use of statistician can help evaluateprocess capability and readiness for process validation. Alsohelpful with defining acceptance criteria, number of Bestsamples, etc. Practice: During the product transfer stage thereRisk analysis can be a great tool in defining worse needs to be highcase conditions a process can potential see in routine engagement with site validationmanufacturing. These failure modes can be testedin product evaluation and/or validation trials.(reference validation strategy risk mitigation table) [ 27 ]
  28. 28. Process ValidationStrategies for new and existing productsNew ProductsProcess Validation Readiness should include the following:• Design review confirms process is capable• All prerequisite validations are complete (e.g. equipment,facility, software, etc.)• Process control plan has been created or updated*• Risk analysis has been updated*<Let’s review the sample control plan in your bonus material> [ 28 ]
  29. 29. Process Validation [ 29 ]
  30. 30. Process ValidationStrategies for new and existing productsNew ProductsProcess Validation Readiness should include the following:• All procedures, batch records, inspection plans,specifications, drawings are updated and approved.• All impacted personnel are trained on procedure, batchrecords, inspection plans, etc.• All raw materials are procured and in approved status• All new suppliers are in approved status <Let’s review the sample readiness form in your bonus material> [ 30 ]
  31. 31. Process Validation [ 31 ]
  32. 32. Process ValidationStrategies for new and existing productsExisting ProductsExisting products are defined as validated products that havebeen transferred to the manufacturing site for routinemanufacture. For validations involving any existing product,B+L follows a global change management process.Sec. 820.70 Production and process controls.b-Production and process changes. Each manufacturer shall establishand maintain procedures for changes to a specification, method,process, or procedure. Such changes shall be verified or whereappropriate validated according to 820.75 (Process Validation), beforeimplementation and these activities shall be documented. Changes shallbe approved in accordance with 820.40 (Document controls). [ 32 ]
  33. 33. Process ValidationStrategies for new and existing productsExisting ProductsB+L’s global change management software tracks all changes forexisting products.Depending on the scope of the change; a limited, extensive or fullrevalidation may need to be conducted. A key element of change controlis the impact analysis. The impact analysis considers the impact of thechange to the risk management file. Best Practice: A Validation representative needs to evaluate changes impacting validated state. [ 33 ]
  34. 34. Process ValidationStrategies for new and existing productsExisting ProductsA useful tip is to work with your Research and Development groupor Technical Services group to evaluate the capability of theproduct device after proposed change.Pros:• Better process understanding• Greater confidence in the process to pass when you go into livevalidation.Cons:• May require additional equipment, line time, resources, lab support togenerate data• Cost of material/product that may need to be scrapped It’s a Risk decision [ 34 ]
  35. 35. Process ValidationRuns and Samples How many runs do we need??? [ 35 ]
  36. 36. Process ValidationRuns and Samples How many runs do we need??? How many samples do we need to take??? [ 36 ]
  37. 37. Process ValidationRuns and Samples How many runs do we need??? How many samples do we need to take??? Can we runs this concurrent with production??? [ 37 ]
  38. 38. Process ValidationRuns and Samples How many runs do we need??? How many samples do we need to take??? Can we runs this concurrent with production???It depends on the scope, level of risk and confidence we have in the process. It’s a question of risk! [ 38 ]
  39. 39. Process ValidationRuns and SamplesFor the number of runs, we use 3 as a starting point. We let our riskassessment drive the number of runs needed. Example: There is a process change that will impact the manufacturing of a formulation in 2 different tanks. Our engineering data indicates that although the 2 tanks are the same size they are both designed differently and have different heating and agitation profiles. A risk analysis indicates that heating and agitation may have significant impact on product acceptance. For this process validation a minimum of 6 runs (3 runs/tank) may be recommended in addition to engineering trials to confirm capability of the formulation. [ 39 ]
  40. 40. Process ValidationRuns and SamplesIn sampling, we target confidence level of at least 90%. We also let ourrisk analysis drive the number and type of samples needed. Thereneeds to be an understanding of what’s important to your process.Let’s illustrate this point with the validation of Product XYZ [ 40 ]
  41. 41. Process ValidationRuns and SamplesOverview of product and manufacturing process for Product XYZ£  Raw Materials: Best Practice: •  Sterile Water A key to the •  NaCL sampling rationale is found in the •  Raw Material A CQA’s. They define what’s •  Raw Material B (new) important •  Excipients£  Critical Quality Attributes (CQAs). •  Solution is safe and effective for intended purpose (attribute or go/no-go) •  Batch is homogeneous (variable data) •  Raw Materials A and B must meet label claim (attribute or go/no-go) [ 41 ]
  42. 42. Process ValidationRuns and Samples Product XYZ Bulk Sterile Packaging Compounding Filling Step 1 • Purified Water Step 3 • Add Excipents • Mix and Sterile filter Raw • Heat sterilize mixture Materials A and B CPPs=batch temp, agitation speed 19,000 L CPP=batch temp, mix time Tank Step 4 Step 2 • Mix dissolve and Sterile filter NaCL and excipients • Mix, dissolve and Sterile filter excipents CPP=batch temp, mix time CPP=batch temp, mix time CPP=Critical Process Parameter [ 42 ]
  43. 43. Process ValidationRuns and Samples Product XYZ Bulk Sterile Packaging Compounding Filling CPP= Line length, product conditioning 19,000 L volume, filling speed, etc. Tank [ 43 ]
  44. 44. Case Study- Process Validation for Product XYZRuns and Samples Bulk Sterile Packaging Compounding Filling• Our product and process risk assessment identified both the bulk compoundingand sterile filling process steps as having the highest potential risk. Critical QualityAttributes (CQAs). •  Solution is safe and effective for intended purpose (most likely impacted in bulk compounding and sterile filling process) •  Batch is homogeneous (most likely impacted in bulk compounding) •  Raw Materials A and B must meet label claim (most likely impacted in bulk compounding)• We focused more effort (sampling and runs) on these high risk process stepsduring scale up and process validation [ 44 ]
  45. 45. Process ValidationRuns and Samples Bulk Sterile Packaging Compounding Filling• Based on historical data and information from our risk assessments, the heaviestuse of statistics (sampling) was focused on the bulk compounding and sterile fillingprocesses as we needed to demonstrate a high level of assurance at these stages.• We used process capability data from similar products and development work toestablish standard deviations for Raw Materials A and B.• Our sample size was based on the use of standard deviations from engineeringtrials, 90% Confidence• For batch and bottle homogeneity we demonstrated with 90%Confidence thatbatch and bottle sample sets were homogeneous.* [ 45 ]
  46. 46. Process ValidationWhen are you done? Now that the execution is complete with your Process Validation and Final Report has been written and approved, Are You Done? [ 46 ]
  47. 47. Process ValidationWhen are you done?According to GHTF - Quality Management Systems ProcessValidation Guidance, you should maintain a state ofvalidation:•  Monitor and control•  Changes in processes and/or product•  Continued state of control [ 47 ]
  48. 48. Process ValidationWhen are you done?Most companies including B+L are using the product quality reviewprocess to confirm medical device products are maintained in a state ofcontrol. Key attributes include:•  In process and final product manufacturing trend data•  Complaints•  Non-conformances•  Corrective Preventive Actions•  Stability•  Changes and subsequent validations [ 48 ]
  49. 49. Agenda£  Getting Started-Overview£  Process Validation£  Enterprise wide Roll Out of Process Validation£  Interactive Exercise [ 49 ]
  50. 50. Enterprise wide Roll Out of Process Validationo  Enterprise-wide policies and procedureso  Quality System standardization, design management, change management and validationo  Train personnel [ 50 ]
  51. 51. Enterprise wide Roll Out of Process ValidationEnterprise-wide policies and proceduresThe CFR requires established procedures to conduct process validation andsupport monitoring and control of process parameters. Sec. 820.75 Process Validation. a- Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures. The validation activities and results, including the date and signature of the individual(s) approving the validation and where appropriate the major equipment validated, shall be documented. b- Each manufacturer shall establish and maintain procedures for monitoring and control of process parameters for validated process to ensure that the specified requirements continues to be met. [ 51 ]
  52. 52. Enterprise wide Roll Out of Process ValidationEnterprise-wide policies and proceduresBest practices for a multi-site / global company to deploy process validationprocedures is Enterprise-wide policies and procedures:Pros:• Provides clear instruction for ‘how things are done’.• Offers consistent approach to validation to train to and follow regardless of sitelocation, manufacturing platform, products manufactured• Presents to regulators the company’s position on process validation• Capitalize on best practices at each site. Best• Ensures alignment to guidances, standards and industry best Practice:practices In addition to policies and procedures, templates provide consistency [ 52 ]
  53. 53. Enterprise wide Roll Out of Process ValidationEnterprise-wide policies and proceduresCons:• Difficult to gain consensus with multiple sites who have always ‘done ittheir way’.• Procedures and templates may not be flexible to meet needs of differentproducts, manufacturing platforms• Learning curve and time to implementTips for Enterprise-Wide roll out are:• Getting engagement and feedback from stakeholders at themanufacturing site. Feedback should be from each type ofmanufacturing site.• Deploy procedures and templates on a trial basis to ‘validate’ its use.• Allow extended phase in period (60-90 days) for training [ 53 ]
  54. 54. Enterprise wide Roll Out of Process ValidationQuality System standardization, design management, changemanagement and validationThe success of any Validation Program is contingent on ahealthy Quality System.ISO 9001 identifies the some of the Quality Systems evaluated duringmanagement review:5.6.2 Review input- The input to management review shall include informationon:a) results of audits, (Internal and External Audits)b) customer feedback, (Complaints)c) process performance and product conformity, (NonConformance Management)d) status of preventive and corrective actions, (NonConformance Management)e) follow-up actions from previous management reviews,f) changes that could affect the quality management system, and (Change Mgmt)g) recommendations for improvement. (Continuous Improvement) [ 54 ]
  55. 55. Enterprise wide Roll Out of Process ValidationQuality System standardization, design management, changemanagement and validationISO 9001 state the following responsibilities of Management Review:5.6.3 Review output- The output from the management review shall include anydecisions and actions related to:a) improvement of the effectiveness of the quality management system and itsprocesses,b) improvement of product related to customer requirements, andc) resource needs. [ 55 ]
  56. 56. Enterprise wide Roll Out of Process ValidationQuality System standardization, design management, changemanagement and validationStandardization of key quality systems like design management, changemanagement and validation ensures:• Provides clear instruction for ‘how things are done’.• Offers consistent approach to train and follow regardless of site location,manufacturing platform, products manufactured• Presents to regulators the company’s position on key quality systems• Ensures alignment to guidances and standards <Reference a sample global final report template in bonus material> [ 56 ]
  57. 57. Agenda£  Getting Started-Overview£  Process Validation£  Enterprise wide Roll Out of Process Validation£  Interactive Exercise [ 57 ]
  58. 58. Interactive ExerciseFirm is rebranding a legacy medical device product in anew bottle.Product is a sterile liquid. Bottle is being sourced from anew supplier. Bottle requires a different sterilizationmethod. New equipment will be needed to run this bottle.Validation needs to be conducted to launch to ‘newproduct’. What will the validation strategy be? [ 58 ]
  59. 59. Interactive Exercise•  Product ABC is currently filled in an oval and opaque HDPE. New bottle is round, transparent (without colorant) HDPE•  Sterilization Method for current bottle is Ethylene Oxide. New bottle will require gamma irradiation•  Bottle will be filled in Fill Room C. Fill Room C only has change parts for oval bottles.•  Instead of using the checkweighing system, the firm would like to use fill volume sensors that were always integrated on Fill Room C but never used because firm uses opaque bottles.•  Original validation for Product ABC was conducted 15 ago. [ 59 ]
  60. 60. Interactive ExerciseEach team, take 5-10 minutes to develop a validation strategy.Demonstrate the use of the following:•  Success criteria•  Team Members•  Any necessary pre-work (engineering, develop studies, etc.)•  Training•  Proposed risk analysis•  Proposed statistics•  Process steps to focus validation effort [ 60 ]
  61. 61. Questions??? [ 61 ]

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