1. Rocky Mountain RAPS Process Validation Presentation 6/7/06 By Clay Anselmo

2. Learning Objectives Understand the purpose of process validation. Understand the key components of a good process validation (IQ, OQ, PQ). Understand how these elements and their definitions have changed over the years. Be able to categorize processes and determine the extent of validation required. Understand documentation requirements for validation and the process for storage and retrieval of these documents. CONFIDENTIAL

3. Concepts and Definitions Let’s be perfectly clear! ◦Process Validation (QSR): Establishing by objective evidence (documented) that a process consistently produces a result or product meeting its pre-determined specifications. ◦Design (Product) Validation: Establishing by objective evidence (documented) that device specifications conform with user needs and intended use(s). CONFIDENTIAL

4. Concepts and Definitions Verification: Confirmation by examination and provision of objective evidence that specified requirements have been fulfilled. Prospective Validation: A validation that establishes documented evidence that a product or process conforms to its specifications prior to final release of the product or process. Retrospective Validation: A validation that establishes evidence that a product or process performs to its specifications based on a review and analysis of historical performance data. CONFIDENTIAL

5. Concepts and Definitions Installation Qualification (IQ): ◦Installation and Installation Conditions (electrical, air, water, etc.) ◦Calibration and Preventive Maintenance ◦Safety Features ◦Complete Documentation including equipment and software ◦Environmental Conditions ◦Training ◦Does NOT typically require statistically based sampling or data analysis CONFIDENTIAL

6. Concepts and Definitions Operational Qualification (OQ): ◦Show equipment functionality over the range of specifications ◦Show equipment stability and capability in worst case conditions (considering all process inputs)  Equipment settings  Raw material  Supply variations (air, water, etc.) ◦Establishment of action and alert limits as appropriate ◦Confirmation of failure modes ◦Uses valid statistical methods for analysis of data and variation CONFIDENTIAL

7. Concepts and Definitions Performance Qualification (PQ): ◦Demonstrate longer-term stability and capability of the process under nominal conditions ◦Evaluates acceptability of product against specification ◦Utilizes valid sampling and statistical techniques  Multiple Lots  Multiple Operators CONFIDENTIAL

8. Concepts and Definitions WHEN IS IT NECESSARY TO PERFORM VALIDATION? ◦21 CFR 820.75 – 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… ◦ISO 13485:2003 – The organization shall validate any processes for production and service provision where the resulting output cannot be verified by subsequent monitoring and measurement. This includes any processes where deficiencies become apparent only after the product is in use or the service has been delivered. CONFIDENTIAL

9. GHTF Flow Chart CONFIDENTIAL

10. Concepts and Definitions What/When Processes Should be Validated? ◦End product tests that verify device conformance to specifications and requirements ◦When destructive testing is required to show product conformance to specification ◦When even state-of-the-art testing methods cannot demonstrate conformance to specification ◦Process capability is unknown or it is suspected that the process is barely capable of meeting device specifications CONFIDENTIAL

11. Validation Overview Define product requirements and specifications Define process inputs/outputs and specifications Plan the validation process Develop Protocols ◦Test Method Verification / Validation  Measuring equipment suitability (i.e. – gage R&R) ◦IQ – Installation Qualification ◦OQ – Operational Qualification ◦PQ – Performance Qualification Execute Protocols Compile and Analyze Data Corrective Action and Re- execution as Necessary Create / Approve Final Report CONFIDENTIAL

12. Validation Planning Elements Why Create a Validation Plan ◦Allows quick overview of validation activities ◦Reduced approval cycle iteration Pre-Requisites ◦Clear Requirements/Specifications ◦Basic Test Methods (verified or validated) Test Definition/Description ◦Plan should include a clear description of each set of tests to be performed Purpose ◦Plan should contain the purpose of each set of tests CONFIDENTIAL

13. Validation Planning Elements Requirements ◦Plan should briefly describe the requirements for each set of tests and be traceable to product or process specifications Acceptance Criteria ◦Plan should contain the general acceptance criteria for each set of tests or cross reference the location. Analytical Techniques ◦Define the method for analyzing data using commonly accepted statistical techniques. CONFIDENTIAL

14. Protocol Development All Validations should be executed per a formal, pre-approved protocol ◦Pre-approval is not a regulatory requirement, just a good practice that prevents delays and re-executions. Protocol format is OPTIONAL but must include the following key sections: ◦Purpose / Background ◦Configuration of product or process ◦Material and Equipment (including Calibration data) ◦Sampling, Data Analysis Methods ◦Test Procedure ◦Clear Acceptance Criteria CONFIDENTIAL

15. Protocol Development Key Protocol Sections (cont.) ◦Data Sheets ◦Conclusions ◦Deviations ◦Revision History Key Points ◦Provide background and justification for approach ◦Ensure test method is appropriate (verified or validated) Protocol Review Protocol Pre-Execution Approval CONFIDENTIAL

16. Validation Completion Execution ◦Follow the protocol! ◦Note any deviations ◦Use good documentation practices ◦Sign the data sheets ◦Collect equipment calibration information ◦Make sure training is documented CONFIDENTIAL

17. Validation Completion Final Report ◦May be an addition to protocol or a separate document ◦Summarize the results specifically related to each test or challenge ◦Document and justify your deviations  Deviations are not for changes to acceptance criteria ◦Document your data analysis ◦Reach formal conclusions regarding the overall outcome of the validation ◦Needs approval CONFIDENTIAL

18. Special Considerations Deviations ◦Document all deviations from pre-approved procedure in the Deviations section of the protocol. ◦Changes to acceptance criteria should be documented in the protocol and re-approved prior to re-executing the testing. CONFIDENTIAL

19. Special Considerations Test Method Verification ◦Suitability of Test Instrumentation  Gage Accuracy and Sensitivity  Operator Variation  Characterization of Alpha and Beta Errors ◦Training and Confirmation of Effectiveness ◦Yes, it applies to visual inspection, dimensional verification, and automated test methods CONFIDENTIAL

20. Software Validation Equipment With Embedded Software ◦Software must be validated ◦Can be done stand-alone (if possible), or as a part of verifying equipment function (IQ or OQ) ◦Requires an understanding of the software logic and the functions to be utilized ◦Should include nominal/margin testing and error handling CONFIDENTIAL

21. Special Considerations IQ / OQ / PQ ◦Question: Does it really matter what goes where? ◦Answer: Sometimes, if one validation activity depends on others. (i.e. – training) ◦Question: I often hear the terms PQ, PPQ, Product Performance Qualification, Process Performance Qualification. What’s the difference?? ◦Answer: These are often defined differently across organizations. However, typically PQ is the overarching term that refers to both process and product performance qualifications. CONFIDENTIAL

22. Common Mistakes Poor Organization ◦Lack of program structure ◦Lack of templates and rules for ensuring program consistency Poor Planning ◦No documentation to tie stand-alone validations together (i.e. – Master Validation Plan) ◦No method to ensure re-validations occur when required (i.e. – sterilization) Poor Documentation ◦Little background information ◦Story not told ◦No links to CO/ECO process to ensure changes do not invalidate prior validation activities CONFIDENTIAL