Ensuring Physical Stability of Pharmaceuticals: Can/should we improve our ability to identify and prevent physical chang

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)