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. Chance to characterize variability on clinical or bio-batch
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. DPA Gauge R&R Study Operator 1 2 Apparatus A B A B
Vessel
6 repetitions

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

8. Comparison of Variance Components
Operator
Tablet
Vessel
Variance Components
Apparatus A
Apparatus B
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. 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.
Mechanical Calibration Status
% Dissolution at 30 min.
Avg. SD
Vessels Centered (Avg. of 30)
29.2
1.0
Vessels Offset 1 mm (Avg. of 12)
30.6
1.8
Vessels Offset 2 mm (Avg. of 12)*
35.6
3.9
Vessels Tilted 1.2º (Avg. of 12)
31.4
1.2
Vessels Tilted 2.3º (Avg. of 12)
36.3
2.6
* Current USP Mechanical Calibration Tolerance

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

12. Comparison of Variance Components after “2 Points Centering Check” for Apparatus A
Operator
Vessel
Tablet
1pt centering
2pts centering
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. Per USP illustrations and dimensions
Apparatus Set Up
USP
FDA
Vessel Dimensions
Per USP illustrations and dimensions
Basket Dimensions (including use of Basket Clips)
Paddle Dimensions
Belts and Ball Bearings
None
Belts are tight, clean, free of cracks, properly aligned, shafts turn freely

15. Mechanical Calibration Tolerances
USP
FDA
Shaft Wobble
No significant wobble
≤ 0.5 mm total run out
Vessel/Shaft Centering and Vessel Verticality
2 mm from centerline
1 mm from centerline at 2 points
Height check/Basket or Paddle Depth as measured at Basket or Paddle bottom mm
Shaft Verticality
None
Centered in bubble level at 2 pts 90 apart
Rotational speed
+ 4%
+ 2 rpm
Basket Wobble (Bottom Rim)
+ 1mm
+ 0.5mm
(≤ 1.0mm total)
FDA Tolerances consistent with specs or performance of Varian, Distek, Erweka and Hanson instruments. PhRMA Dissolution Expert Team participated in setting tolerances.

16. Operation Basket and Paddle Examination Vessel Temperature Vibration
USP
FDA
Basket and Paddle Examination
None
No gross defects as determined by visual inspection
Vessel Temperature
37  0.5 °C
Vibration
No significant vibration
No significant vibration (pending further studies)
Sinkers
A few turns of wire helix may be attached to dosage unit that would otherwise float. Other validated sinker devices may be used.
Recommend USP sinker or ensure commercial sinker does not affect results

17. Vibration 1999 Collaborative Study: Displacement
1998 Japanese Study: Acceleration
Apparatus 1, 50 rpm, Enteric Coated product
Average of 5 – 8 apparatus
Low Vibration Acceleration < 0.01 m/s2
32  1
High Vibration: Acceleration > 0.09 m/s2
39  4
Study by Bryan Crist and Dan Spisak, Varian Inc. : Frequency
Apparatus 2, 50 rpm 10 mg Prednisone USP Lot #O0C056
Average 6
Benchmark
34  4
Vibration Displacement < 0.20 mils Frequency at 20 Hz
34  2
Vibration Displacement < 0.02 mils Frequency at 130 Hz
42  9

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 Training of FDA Labs
Hydrodynamics
Vibration
New approaches to assess drug release (PAT, spectroscopy, first principles and modeling)
Training of FDA Labs
Compliance Policy Guide
Future Guidance