Analytical considerations in the dissolution testing of oral modified release products

1. Analytical considerations in the dissolution testing of oral modified release products Graham Clarke Bristol-Myers Squibb Moreton, UK The British Pharmaceutical Conference, 26th September 2005

2. Fit for purpose dissolution methods for testing oral modified release products Graham Clarke Bristol-Myers Squibb Moreton, UK The British Pharmaceutical Conference, 26th September 2005

3. Analytical considerations in the dissolution testing of oral modified release products • Presentation Outline • Purpose • Practicalities • Specifications • Method Validation • Unusual case studies • Future

4. Analytical considerations in the dissolution testing of oral modified release products • Purpose of dissolution test • IV/IVC (next Speaker) • Safety/Quality requirements • Release profile • Integrity of action e.g. enteric coat

5. Analytical considerations in the dissolution testing of oral modified release products • Selection of test methodology • Choice of apparatus • Baskets (1970, USP 18) • Paddles • Reciprocating Cylinder • Flow through cell • Other • Choice of medium, deaeration • Media switching • Adequate sampling • Analytical finish • UV, Fast LC, other?

6. Analytical considerations in the dissolution testing of oral modified release products • Making it practical (avoiding late nights in the lab) • On-line (UV or on-line LC). • Autosampling (off-line)

7. Analytical considerations in the dissolution testing of oral modified release products • In-situ • Fibre-optic (different probes)

8. Analytical considerations in the dissolution testing of oral modified release products • Developing Specifications • Regulatory/Pharmacopoeial guidance • Control dose dumping or non-release • 3-phase specification • Early – avoid dose dumping • Middle – appropriate control • Late – demonstrate full release (80% or plateau) • FDA Guidance for Industry • ER oral Dosage Forms: Development, Evaluation and Application of In Vitro/In Vivo Correlations (Sept 1997) • SUPAC- MR: Modified Release Solid Oral Dosage Forms (Sept 1997)

9. Analytical considerations in the dissolution testing of oral modified release products • USP Extended Release Dosage Forms

10. Analytical considerations in the dissolution testing of oral modified release products • Validation of methods (fit for purpose) • UV/HPLC • ICH Guidance Q2A and Q2B

11. Analytical considerations in the dissolution testing of oral modified release products • Validation • Specificity • UV – Interference from excipients • LC – Demonstrate separation • Carryover or binding • Tubing, syringes? Not necessary as concentration increasing.

12. Analytical considerations in the dissolution testing of oral modified release products • Validation • Linearity (range) • “evaluate the linear range of the analytical procedure” • “for dissolution testing: +/- 20% over the specified range” • General – six points between 20 and 120% • Correlation coefficient • Residual sum of squares • Standard alone and also in presence of excipients.

13. Analytical considerations in the dissolution testing of oral modified release products • Validation • Accuracy • “application of the analytical procedure to synthetic mixtures of the drug product components” • aka “spiking” • Over the Range or Worst case scenario • Use a minimum of 9 determinations over a minimum of 3 concentration levels covering the specified range. • Report % recovered and confidence intervals

14. Analytical considerations in the dissolution testing of oral modified release products • Validation • Precision • Repeatability • 9 determinations over the range (3 reps at 3 concs) or • 6 reps at 100% of the test concentration • Intermediate precision • “Establish the effect of random events” • Different days, analysts, equipment etc.

15. Analytical considerations in the dissolution testing of oral modified release products • Robustness • Effect of filtration • Stability of solutions • Are samples collected/stored before analysis? • Automated procedure • Demonstrate equivalence to manual • FDA Guidance for Industry • Analytical Procedures and Methods Validation (Aug 2000)

16. Analytical considerations in the dissolution testing of oral modified release products • Floating or Sticking to surfaces e.g. hydrophilic polymer matrix • Problem results in reduced agitation in inadequate exposure to medium • Solution • Observe and invalidate test • Deaerate • Baskets vs paddles

17. Analytical considerations in the dissolution testing of oral modified release products • Degrading active • e.g. ER enteric coated beadlets, meadia switch • Acid catalysed hydrolysis product • Low dose drug – degradant has different UV response factor. • Required LC for sensitivity • Response factor and calculate

18. Analytical considerations in the dissolution testing of oral modified release products • Avoiding evaporation • Evident as higher than theoretical values obtained • Accuracy demonstrated

19. Analytical considerations in the dissolution testing of oral modified release products

20. Analytical considerations in the dissolution testing of oral modified release products • Avoiding evaporation • Evident as higher than theoretical values obtained • Accuracy demonstrated • Solution • Tightly fitting lids • Parafilm seal

21. Analytical considerations in the dissolution testing of oral modified release products • Equipment issues • Problem – Extended release product using cross linked alginates give inconsistent dissolution profiles. • Solution – Copper ions increase the degree of cross linking in alginates. De-aerator had brass fitting.

22. Analytical considerations in the dissolution testing of oral modified release products • The Future • Alternate technologies ? • More physiological media?