1. USP and Dissolution Testing Advisory Committee for Pharmaceutical Sciences 2 May 2005 Will Brown Staff Liaison to the Biopharmaceutics Expert Committee Department of Standards Development

2. Biopharmaceutics Expert Committee 2005-2010  Thomas Foster, chair "Diane Burgess "Bryan Crist "Mario Gonzalez "Vivian Gray "Johannes Krämer "Lewis Leeson "Alan Parr "James Polli  Leon Shargel  Eli Shefter  William Simon  Clarence Ueda  David Young

3. The USP Performance Test  Dissolution or Disintegration  Tests within the specification for a dosage form  Procedure  Acceptance Criteria  Dissolution  General description of techniques  Modified case-by-case: monograph

4. The USP Performance Test  Study design and analysis: S1, S2, S3  Number of units tested fixed for each stage  Acceptance criteria determined by FDA working with Applicants (NDA’s and ANDA’s)  Details of the test communicated by sponsor (Applicant)  Testing by attribute: pass or fail  Some control over distribution: e.g., Q-25% at S3

5. Biopharmaceutics Expert Committee  Workplan includes revising General Chapters to have a performance test by dosage form by route of administration  Intention of working with FDA and pharmaceutical manufacturers as appropriate  Advisory panels formed in 2000-2005 cycle

6. Meetings can be productive  1993 FDA Advisory Committee  Follow-on IR and ER Guidance documents  Pharmaceutical Discussion Group  Harmonization for Dissolution and Disintegration General Chapters

7. Theoretical Approaches  W Hauck et al., Oral Dosage Form Performance Tests: New Dissolution Approaches Pharm Res 22(2):182-187, 2005  Explicit hypothesis testing  Parametric tolerance intervals  Improved way to set dissolution acceptance criteria  More flexible protocol design to assess conformity

8. Theoretical Approaches  Allow industry more control on study design  Tiers possible  Number of units within tiers  Can differ between manufacturers  Set P value (fraction of units in the reference batch that must conform)  Risk clearly assessed, managed and communicated  Corresponds to approaches for uniformity of metered dose inhalers (Wednesday session)

9. Calibrators  GMP-related concept  Done occasionally (six month maximum)  Rule out test assemblies that do not perform, extremes  Inter-Laboratory variability is a major contributor to width of ranges but must be captured  Criteria derived from analysis of data collected in collaborative studies  Acceptable values fall in ranges representing performance by the “best of the best”

10. Calibrators  Salicylic Acid Tablets  Unit packaging  Prednisone Tablets  Scale up from U of Md batches (reproduction of NCDA#2)  New batch in production  Theophylline Beads  Deleted from system suitability requirement for Apparatus 3 Reciprocating Cylinder

11. Thank you for your attention