1. Analytical considerations in the dissolution testing of oral modified release products Graham Clarke Bristol-Myers Squibb Moreton, UK The British Pharmaceutical Conference, 26 th 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, 26 th 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 Level Number Tested Acceptance Criteria L16No individual value lies outside each of the stated ranges and no individual value is less than the stated amount at the final test time. L26The average value of the 12 units (L1 + L2) lies within each of the stated ranges and is not less than the stated amount at the final test time; none is more than 10% of labeled content outside each of the stated ranges; and none is more than 10% of labeled content below the stated amount at the final test time. L312The average value of the 24 units (L1 + L2 + L3) lies within each of the stated ranges, and is not less than the stated amount at the final test time; not more than 2 of the 24 units are more than 10% of labeled content outside each of the stated ranges; not more than 2 of the 24 units are more than 10% of labeled content below the stated amount at the final test time; and none of the units is more than 20% of labeled content outside each of the stated ranges or more than 20% of labeled content below the stated amount at the final test time.

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.  Avoiding evaporation Evident as higher than theoretical values obtained  Accuracy demonstrated Solution  Tightly fitting lids  Parafilm seal

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

22.  The Future Alternate technologies ? More physiological media?