1. Ensuring Physical Stability of Pharmaceuticals: Can/should we improve our ability to identify and prevent physical changes? Ajaz S. Hussain, Ph.D. Deputy Director, Office of Pharmaceutical Science, CDER, FDA

2. Outline Introduction –Ajaz Hussain A scientific perspective –Prof. Rhodes Overview of current stability requirements –Chi-wan Chen ACPS Deliberations and Recommendations

3. Awareness Topic: Introduction Regulatory stability testing requirements are effective in minimizing stability problems. So why are we discussing this topic today? Lingering concern that certain gaps exist with respect to ensuring “physical stability” –Especially for complex product types such as CR parenterals

4. Awareness Topic: Introduction Do such concerns contribute to “excessive” stability testing? Is there an opportunity to further improve (regulatory) utility of pre-formulation and development data to understand mechanisms of physical and chemical changes?

5. Physical Stability: Concerns A critical quality and performance attribute –Example: Changes in dissolution rate (in absence of detectable chemical changes) a prominent cause for recalls (quality problems) –Accelerated stability test conditions are more reliable for identifying potential for chemical changes

6. Physical Stability: Concerns –Mechanisms governing physical changes are not well understood or characterized Dissolution rate changes may occur due to a change in morphic form of drug and/or excipient, a change in processing (e.g., milling, granulation,..), packaging,.. –Recall investigations often do not result in identification of a “root cause” –Increasing number of parenteral CR products Do these pose a higher risk of failure than oral products?

7. Physical Stability: Opportunity Significant advances in pre-formulation material characterization/optimization –Improved ability to identify and eliminate problems? –Can we use this information to reduce the need for stability testing and prior approval supplement process? Risk Based CMC Program (Dr. Yuan-Yuan Chiu)

8. Shelf-Life of Products DOD-FDA Shelf-Life Extension program –Results from 1122 lots (96 drug products) were evaluated. 84% of the lots were extended for an average of 57 months past the original expiration date. Of the 946 lots extended, 14% were eventually terminated due to failure. The rest are still active or discontinued by the military. 22 Drug Products showed no signs of stability failure (at least 5 lots of each tested). 10 Drug Products were unstable with most lots failing initial extension. –Stability Period is highly variable from lot to lot.

9. Extensions: Example 1

10. Extensions: Example 2

11. Questions Should this topic be developed for a more detailed discussion by ACPS? Should FDA labs develop a research project to elucidate mechanisms of (physical) stability failures? –To provide information on how to prevent stability problems Based on “recall” and SLEP database –Complex dosage forms (e.g., CR Parenterals)