Measuring and Managing Method Variability

1. Measuring and Managing Method Variability Lucinda (Cindy) Buhse, PhD Director, Division of Pharmaceutical Analysis Advisory Committee for Pharmaceutical Science (ACPS) October 25, 2005

2. FDA Proposal to Advisory Committee in May Alternative approach to dissolution calibration and validation: • Perform stringent mechanical calibration to replace the need for a calibrator tablet • ID and control all sources of variability • Apparatus type including sinkers • Set-up,calibration and operational parameters • Media including degassing • Understand interaction between instrument and product during pharmaceutical development • If necessary, establish an internal calibrator (bio-batch or clinical batch) for system suitability and stability • Confirm suitability using Gauge R&R using pivotal clinical trial product or pivotal “bio-batch”

3. Advisory Committee Response May 3, 2005 DR. COONEY: So, the request is to embrace the content of slides…? We have 11 yes, zero no and zero abstentions for the vote. Wonderful!

4. Gauge R&R Design • Chance to characterize variability on clinical or bio-batch • Sample from throughout manufacturing process to demonstrate control • Benchmark variability prior to establishing specifications • Establish internal reference • For design include variables such as • Location (beginning, middle and end of lot) • Instrument • Operator

5. DPA gauge R&R study • Product: NCDA#2 10mg Prednisone Tablet • Stable • History at DPA – known to be sensitive to degassing and mechanical calibration tolerances • Design of Study: • 2 operators • 2 mechanically calibrated USP Apparatus (Paddle) • Nested study design, N= 2x2x6 • 6 replications for each operator on each apparatus

6. Operator 1 2 Apparatus A B A B Vessel 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 6 repetitions DPA Gauge R&R Study

7. Comparison of % Dissolved at 30 Minutes for Two Apparatuses %Diss0@30 A B Based on ANOVA results, no significant differences were observed between two USP apparatus 2 in testing NCDA#2 tablets.

8. Variance Components Apparatus A Apparatus B Vessel Tablet Operator Comparison of Variance Components • Results • Tablet is the main contribution to the variance. • Variability component from vessels for Apparatus A is larger than for Apparatus B. • Operator contributes minimally to variability for DPA.

9. %Diss0@30 Vessel 30 Minute Dissolution for Individual Vessels for Apparatus A • Some vessels are above average and some below. • Vessels were moved to different positions and trends above and below average were found to follow the vessel and not the shaft position. • Although apparatus was level and shafts were vertical, vessels were found to be not vertical because of unevenness around their rims.

10. Vessel Centering and Vessel Verticality affect Hydrodynamics • 10 mg Prednisone Tablets, Lot PRED96-21, paddle, 50 RPM, degassed water • Data Range: 26.3 – 44.5%: so these effects would not be detected by a calibrator tablet with assigned values similar to the current lot. * Current USP Mechanical Calibration Tolerance

11. Solution: Two-Point Method for Vessel Centering and Vessel Verticality

12. Variance Components 1pt centering 2pts centering Tablet Vessel Operator Comparison of Variance Components after “2 Points Centering Check” for Apparatus A 2 point centering to ensure verticality of the vessels eliminated the vessel component of the variability.

13. Dissolution Testing Good Practices • Apparatus Set Up • Vessel Dimensions • Basket Dimensions (Basket Clips) • Paddle Dimensions • Belts and Ball Bearings • Mechanical Calibration • Shaft Wobble • Vessel Centering / Vessel Verticality • Basket and Paddle Depth • Paddle and Basket Shaft Verticality • Rotational Speed • Basket Wobble • Operation • Basket Examination • Paddle Examination • Vessel Temperature • Vibration • Sinkers

14. Apparatus Set Up USP FDA

15. Mechanical Calibration Tolerances USP FDA FDA Tolerances consistent with specs or performance of Varian, Distek, Erweka and Hanson instruments. PhRMA Dissolution Expert Team participated in setting tolerances.

16. Operation USP FDA

17. Vibration • 1999 Collaborative Study: Displacement • 1998 Japanese Study: Acceleration 3. 2005 Study by Bryan Crist and Dan Spisak, Varian Inc. : Frequency

18. Hydrodynamics Challenges • Paddle method is operated at flow conditions between laminar and turbulent which makes modeling difficult and shear stress distribution is non-uniform at base of vessel. • Degree of mixing with basket method is limited leading to solute stratification in the vessels, and the dosage form remaining in the basket is subjected to different shear stress than the fragments that settle at bottom of vessel. • Hydrodynamic variables that are important to a calibrator tablet may not be important to tested drug product. Statements based on information from Dr. Armenante, Dr. Muzzio and Dr.Kakhi

19. Benefits of Mechanical Calibration and Gauge R&R • The sources of variability in the dissolution measurement system can be identified and minimized. • If done during clinical or bio-batch lot, knowledge of variability can assure development of meaningful specifications. • An internal calibrator can be developed from clinical or bio-batch which is more applicable to specific product than the USP calibrator tablets. • This approach provides a higher assurance of quality than the current system where failure results can be caused by product failure OR measurement system variability.

20. Next Steps • Additional Collaborative Research • Hydrodynamics • Vibration • New approaches to assess drug release (PAT, spectroscopy, first principles and modeling) • Training of FDA Labs • Compliance Policy Guide • Future Guidance