1. PAT Validation Working Group Process and Analytical Validation Working Group Arthur H. Kibbe, Ph.D. Chair June 13, 2002

2. PAT Validation Working Group Process Analytical Technologies Systems for the analysis and control of manufacturing processes based on timely measurements during processing of critical quality parameters and performance attributes of raw and in- process materials and processes, to assure acceptable end-product quality at the completion of the process. Definition of validation Three lots and done? Follow the C in CGMP. The science continues to move forward. In many cases, existing validation processes are adequate for PAT Internal buy-in may be most difficult. Case studies (examples) will help educate inside the company

3. PAT Validation Working Group PAT Validation Background - Existing validated measurements invariably correlate poorly with process performance - Univariate measurements used to infer compliance of multivariate dynamic systems - Measure what we can measure, not what needs to be measured - Measurement has not been seen as process related - Measurement needs to respond to process need over the product life cycle - Need to understand the process - Recognize that the conventional approach to validation might be limiting

4. PAT Validation Working Group Understand the Process - Break down into unit operations - Assess risk potential for each unit individually and collectively using techniques, e.g. experimental design - Design systems to manage risk Univariate measurement Multivariate systems - Develop systems - Establish proof of concept - Challenge validation Objective - confirm processes and measurement validity in “real” time across life cycle

5. PAT Validation Working Group Validation Postulates 1. Validation Protocols will be different for new products associated with well-designed understood manufacturing processes and existing products where PAT is applied retrospectively 2. The validation plan will reflect the total system design concept since an RTQC/QA manufacturing process, statistically based, essentially revalidates itself on every manufacturing batch 3. The rationale for model validation incorporating pass/fail criteria must be clearly defined thereby establishing the authenticity of predictions in routine manufacturing and ensuring compliance

6. PAT Validation Working Group A Checklist for Sensor and Chemometrics Validation Sensor validation Software validation including multivariate algorithms Sensor calibration and calibration transfer validation Process monitoring protocol (batch vs.continuous) Process modeling (fundamental process) Process control protocol Data management and storage protocol

7. PAT Validation Working Group A Checklist of Targets for Validation Method Types Primary method (no other method required, e.g., endpoint detection) Secondary Method (requires primary method to validate) Analyte Types Direct measure (e.g., active ingredient) Indirect measure (e.g., dissolution) Virtual measure (e.g. customer satisfaction or quality index value) Dimensionality univariate multivariate

8. PAT Validation Working Group PAT Implementation Questions What information is needed and why? Where are the appropriate measurement points? When (how often) are the measurements needed? How is PAT provided information to be used? Who will interpret this information? (i.e., who receives and interprets?)

9. PAT Validation Working Group It is possible to define three distinct ways of analyzing unit operations and releasing products that are being developed and manufactured. Condition 1: This is generally the current operating scenario. Product is manufactured according to fixed process conditions set during development and confirmed during initial process and product validation. Release is conducted by physical and chemical testing subsequent to manufacture. Condition 2: Product is manufactured according to process conditions that have been shown during development and manufacturing to infer product performance and is confirmed during initial process and product validation. Relationships are developed and confirmed with physical and chemical testing subsequent to manufacturing runs. Release is conducted by review of process conditions during each batch manufacture.

10. PAT Validation Working Group Condition 3: Product is manufactured according to process conditions that are responding to direct measurement of in-process product quality or unit dosage forms as they are being manufactured. Relationships are developed between process and product performance that are optimized and bounded by data obtained in development and manufacturing runs. Release is conducted by data collected from in-process product or each dosage form during manufacture. Release specification form and validation criteria can be defined for each condition based on the nature of their release.

11. PAT Validation Working Group Questions to Move Forward on Improving PAT Validation Should there be a difference in expectations between developmental product released for PI, PII, PIII than for routine manufactured lots? Current validation practice requires each unit operation in a manufacturing process to be tested individually. Is it more appropriate to design ‘validation testing’ around a total systems approach that includes multiple unit operations? If so, what level of process and product understanding is required during design, development, scale- up and manufacture? Could and should there be official designations for products and processes that are inherently capable of being appropriately measured and controlled that would allow for predicting product release characteristics?

12. PAT Validation Working Group Content Recommendations for Guidance Document 1. Suitable for intended purpose 2. General validation criteria 3. References to existing guidance documents (ICH Q2: a and b Analytical Validation, Q6: a and b, Specifications, FDA Analytical Procedures and Methods Validation) 4. Research exemption 5. OOT/OOS 6. Encourage use of PAT. FDA should have a mechanism to institute these new technologies and methods

13. PAT Validation Working Group Ex. 1. How to handle validation of PAT method for a process monitoring or set-up parameter that will be used for learning or decision-making? As for other analytical methods: use scientific judgement to develop appropriate validation and long-term maintenance protocol. New parameters appear that need to be measured during a product life cycle, especially for research purposes like process optimization (the “safe harbor” issue) Example PAT Method Validation Issues

14. PAT Validation Working Group Ex. 2. A validated laboratory method exists for a regulatory parameter across an NDA range. How do we replace this with a PAT method? Validate PAT method, including long-term maintenance program to monitor performance (both instrument function and calibration model), and submit supplemental regulatory method change documentation to FDA. PAT method should correlate to validated lab method as appropriate for intended use, and should provide the same or increased assurance of identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application.

15. PAT Validation Working Group Ex. 3. PAT Method is used in pilot plant for process monitoring and development of a new drug. When and how to validate? Steps: 1. Calibrate PAT method for use in pilot plant 2. Calibrate and validate internally for factory process monitoring 3. Validate and file method with FDA if it ends up as a regulatory parameter.

16. PAT Validation Working Group Ex. 4. PAT method has been validated but probe has a mechanical problem or sampling problem (e.g., window fouling). An equivalent validated laboratory method exists. State up front in internal process control documentation the preferred method and circumstances in which the equivalent method could be used.

17. PAT Validation Working Group Ex. 5. A PAT method can only be calibrated during factory processing. Process is optimally run within an operating range narrower than the fully validated range, so it is not always possible to easily calibrate at the ends of the range. Validate PAT method and use hybrid approach. Specify the validated range for the PAT method. When operating outside of this range, must use laboratory method until PAT method is revalidated to include the new range.

18. PAT Validation Working Group Ex. 6. PAT method is validated for typical batches over a fixed range. Want to expand calibration range/incorporate process change or reworks. Include provision in PAT method validation for controlled updating of calibration model and revalidating as needed

19. PAT Validation Working Group Ex. 7. Accuracy of PAT method is different than previously validated laboratory method. Validate analytical method to the accuracy required BY THE PROCESS rather than to the limits of the method. A long-term maintenance program to monitor performance (both instrument function and calibration model) should be in place.