1. Establishing Drug release/Dissolution Specifications – QBD Approach Moheb M. Nasr, Ph.D. Office of New Drug Quality Assessment (ONDQA), OPS, CDER Advisory Committee of Pharmaceutical Science (ACPS) October 25, 2005

2. Outline FDA Presentations  IntroductionMoheb Nasr  In-Vivo RelevanceAjaz Hussain  Measurement System Lucinda Buhse,  CMC System Based ApproachVibhakar Shah  ICH Q8 ConsiderationsAjaz Hussain  Summary and next steps Moheb Nasr

3. Establishing Drug release/Dissolution Specifications – QbD Approach  Scope of today’s discussion  Utility of dissolution testing  Current system Deficiencies Challenges Root Cause Analysis

4. Scope of today’s discussion  Today’s discussion is limited to immediate release oral dosage forms (tablets, capsules and suspensions)  QbD concepts discussed here could be extended to other dosage forms Modified release oral dosage forms Non-oral dosage forms

5. Utilities of dissolution testing  To guide drug development to select formulations for further in vivo studies  To evaluate comparability between products before and after changes in formulation and/or manufacturing  To serve as surrogate for in vivo bioequivalence (IVIVC) and/or as justified per Biopharmaceutics Classification System (BCS)  To be used as a quality control tool to ensure batch-to-batch consistency of product performance (Today’s Focus)

6. Current System - Deficiencies  Empirical approach to setting specification to fit the available data  Clinical linkage (safety and efficacy) not always assured  Negotiation to set specification because of limited data, and lack of systematic scientific approach to product development  Specifications may not be reflective of the “true” product quality  Out of specification (OOS) results leading to: Non-compliance and subsequent investigations Product quarantine/delays or recall from the market depending upon the situation Drug shortage in the market in certain cases  Regulatory hurdle for continuous improvement

7. Current System - Challenges  Is empirical approach to setting dissolution specification appropriate? Non-statistical sample size Limited data Absolute Q values (based on mean but without SD) Lack of adequate product/process understanding  Is dissolution a suitable indicator (sensitive and discriminating test) of product performance for all drug products? Highly soluble and highly permeable drug products Potent and/or narrow therapeutic index drug products with low solubility Addressing post-approval manufacturing changes to demonstrate equivalence to the approved drug product

8. Current System - Challenges  Can disintegration or some other quality attribute substitute dissolution? Under what circumstances?  Are there any circumstances/cases for which dissolution and/or disintegration testing may no longer be needed/provide any additional values to product quality assurance at release? How to assure product quality/performance for such DPs throughout their intended shelf-life?

9. Current System - Root Cause Analysis  In most cases root cause is unknown  Poor understanding of observed variability Product related variability  Formulation components  Manufacturing process  Operator  Other Measurement system variability  Analytical methods (e.g., USP calibrator tablet)  Dissolution apparatus  Operator  Other

10. Current System - Root Cause Analysis  Drug development efforts with poor or lack of understanding: Raw material properties Effect of formulation components’ properties on manufacturing processes (unit operations) Effect of manufacturing process on the critical quality attributes of the drug product Causal link between critical material attributes of formulation components (API, excipients) and critical quality attributes of the drug product Associated risk(s) to product quality