1. 1 Dissolution Measurement System: Current State and Opportunities for Improvement Dr. Lucinda Buhse Director, Division of Pharmaceutical Analysis

2. 2 Measurement System for Dissolution Rate Apparatus Current State of Calibration and Validation Sources of Variability Opportunities for Improvement

3. 3 USP Dissolution Apparatus Apparatus 1 - Basket (37º) Apparatus 2 - Paddle (37º) Apparatus 3 - Reciprocating Cylinder (37º) Apparatus 4 – Flow-Through Cell (37º) Apparatus 5 – Paddle over Disk (32º), Transdermal Delivery System, use paddle and vessel from Apparatus 2 with a stainless steel disk assembly to hold the transdermal on the bottom of vessel. Apparatus 6, Cylinder (32º), Transdermal Delivery System, use Apparatus 1 except replace the basket shaft with a stainless steel cylinder element. Apparatus 7, Reciprocating Holder, for transdermal delivery systems and also a variety of dosage forms

4. 4 Apparatus 1 Basket Apparatus 2 Paddle

5. 5 Apparatus 3 (shown) Glass reciprocating cylinder Apparatus 7 Holders a) Reciprocating disk sample holder b) Transdermal system holder - angled disk (32º) c) Transdermal system holder - cylinder (32º) d) Oral extended-release tablet holder—rod, pointed for gluing e) Oral extended-release tablet holder—spring holder

6. 6 Apparatus 4: Flow Through Cells

7. 7 Current State for Dissolution Test Methods Most use: Apparatus 1 (Basket) or Apparatus 2 (Paddle) USP Equipment Set-Up and Calibration Criteria One point acceptance criteria for Immediate Release

8. 8 Current State for Dissolution Test Methods Instrument Suitability –Choice of instrument –Mechanical Calibration (affecting hydrodynamics) –Calibrator Tablets (USP, not EP, BP or JP) Method Development / Validation

9. 9 Current State: Instrument Suitability USP Mechanical Calibration Parameters include: Basket/Shaft Wobble (No significant wobble) Vessel/Shaft Centering (2 mm from centerline) Height check/Basket or Paddle Depth as measured at basket bottom or Paddle bottom (25 + 2 mm) No significant vibration Rotational speed (+ 4%) Vessel Temperature (37.0  + 0.5  C) Basket Wobble (bottom rim) (+ 1mm)

10. 10 Calibrator Tablets 1970’s : USP Calibrator Tablets Introduced –Disintegrating – 50 mg Prednisone (Upjohn) –Non Disintegrating – 300 mg Salicylic Acid (Hoffman LaRoche) 1997 : 50 mg Prednisone replaced with 10 mg Prednisone manufactured at University of Maryland 2004 : USP begins search for replacement for 10 mg Prednisone tablet USP: Both Calibrators on a given apparatus (i.e. 4 calibration tests if instrument is used for paddle and basket methods) JP, BP and EP: No calibrator tablets

11. 11 Current State: Instrument Suitability Calibrators Every 6 months 10 mg Prednisone Tablet (Lot O0C056) Basket: 53 – 77% (now 51-81%) (DPA 72.6 +/- 5.4, n=36) Paddle: 27 – 48% (now 26-47%) (DPA 31.7 +/- 2.0, n=24) Salicylic Acid Tablet (Lot O) Basket: 23 – 29% Paddle: 17 – 26% Action with Out of Specification value Gets in the way of continuous improvement

12. 12 Current State: Method Development / Validation Development –Discriminatory? Repeatable? Instrument – which one to use? Media Degassing Sinkers Validation: Determinative Step – Main Focus –Linearity and Recovery –Filtering –Stability of solutions –Interferences Even if we don’t understand development, we need to understand variability of our system (product, measurement, random)

13. 13 Managing Variability Total variability σ 2 Total Assuming independent variable (if not independent for example interaction between measurement and product a covariance term needs to be included) σ 2 Total = σ 2 Product + σ 2 Measurement σ 2 Measurement = σ 2 Repeatability + σ 2 Reprodicibility Common Cause Vs. Special Cause variability Process capability: Customer Needs Process Ability

14. 14 Current State: Variability Instrument Suitability –Apparatus Variability –Operator Set-up –Calibrator Assignment Variability Manufacturing of Calibrator Tablet Stability Instrument Set-up Degassing Product Specific –Media including degassing –Manufacturing –Dissolution equipment parameters (clips, sensitivity to set-up) –Sinkers –Determinative Step

15. 15 Variability: Instrument Suitability Set-up Parameters: Shaft WobbleNo significant wobble ≤ 0.5 mm total run out Vessel/Shaft Centering2 mm from centerline 1 mm from centerline Height check/Basket or Paddle Depth as measured at Basket or Paddle bottom 25 + 2 mm25 + 1 mm Vibration as measured at center of vessel support plate while operating at 100 rpm/head above plate, 900 ml medium in vessels No significant vibration ≤ 0.1 mil displacement Rotational speed+ 4%+ 1 rpm Basket Wobble (Bottom Rim)+ 1mm≤ 0.1mm total USPDPA

16. 16 Used for determining water quality in agriculture, fisheries and industry A B Total Dissolved Gas and Oxygen Meter Variability: Media and Degassing

17. 17 Total Gas Pressure and Oxygen Gas Pressure in Water Degassing by Various Methods Variability: Media and Degassing

18. 18 Variability: Media and Degassing Product 1: paddle, 50 rpm, DI WaterProduct 2: basket, 100 rpm, pH 1.2 Product 3: paddle, 50 rpm, pH 7.4 buffer

19. 19 pH 7.2pH 6.8 Variability: Media or Manufacturing?

20. 20 What are the sources of variability at pH 6.8? Product handling during testing? Tablet to tablet differences? Instrumentation variation? –Vessel defects? –Inconsistent Centering? –RPM variations –Etc. Variability: Media or Manufacturing?

21. 21 Microscope Images of the Coating Variability: Media or Manufacturing?

22. 22 Variability Sinkers Product 1: paddle, 50rpm, DI water, off-center 10mm Sinkers are sometimes needed to hold product at the bottom of the dissolution vessel.

23. 23 Variability Sinkers 60% - 72% Dissolved at 30 min. 66% ± 4% 89% – 99% Dissolved at 30 min. 95% ± 4% Commercial Sinker3 Wire Turns

24. 24 Opportunities for Improvement Alternative regulatory approach to dissolution calibration and validation –Understand and control measurement system variability –Understand the product specific sources of variability –Understand relationship between physicochemical properties and dissolution results Understand the benefits and limitations of different dissolution apparatus – develop scientific criteria Investigate new approaches to assess product quality and availability Communication and training of FDA personnel

25. 25 Alternative approach to dissolution calibration and validation Stringent Mechanical Calibration to replace the need for a calibrator tablet ID and Control all sources of variability –Apparatus Type including sinkers –Set-up Parameters –Media including degassing Understanding of interaction between instrument and product during pharmaceutical development If necessary, establish an internal calibrator (biobatch or clinical batch) for system suitability and stability Confirm suitability using Gauge R&R using pivotal clinical trial product or pivotal “bio-batch”

26. 26 Gauge R&R Design Chance to characterize variability on an internal reference –Make it representative –Controlled manufacturing process For design include variables such as –Instrument –Personnel –Media

27. 27 Understand the benefits and limitations of different dissolution apparatus Use design and development information to help choose an apparatus Model dissolution environments and understand hydrodynamics from first principles Look beyond apparatus 1 and 2 to alternative systems that may be easier to model and test (i.e., flow through?)

28. 28 Investigate new approaches to assess product quality and availability New tools to assess product and media variability –Spectroscopy? NIR, RAMAN, Terahertz PAT including feedback loops First principles and modeling

29. 29 Acknowledgements Terry Moore Zongming Gao Lawrence Yu Ajaz Hussain

30. 30 % Dissolved Paddle Limits: 27 - 48% DPA: 31.7 +/- 2.0 n=24 Basket Limits: 53 - 77% DPA: 72.6 +/- 5.4 n=36 10-mg Prednisone Tablet DPA Distribution USP Limits