Dissolution Measurement System: Current State and Opportunities for Improvement

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

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

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. Apparatus 1 Basket Apparatus 2 Paddle

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. Apparatus 4: Flow Through Cells

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. 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. 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. 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. 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. 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. Managing Variability • Total variability σ2Total • Assuming independent variable (if not independent for example interaction between measurement and product a covariance term needs to be included) • σ2Total = σ2Product + σ2Measurement • σ2Measurement = σ2Repeatability + σ2Reprodicibility • Common Cause Vs. Special Cause variability • Process capability: Customer Needs Process Ability

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. Variability: Instrument Suitability Set-up Parameters: USP DPA

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

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

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

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

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

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

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. Variability Sinkers Commercial Sinker 3 Wire Turns 60% - 72% Dissolved at 30 min. 66% ± 4% 89% – 99% Dissolved at 30 min. 95% ± 4%

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

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