World Drug Delivery and Formulation Summit

Biography:

Abstract:

Statement of the Problem:

Currently nearly half of the therapeutic proteins are freeze dried but the freeze-drying does not guarantee stability partly because the product temperature during a freeze drying cycle cannot be directly controlled. Variations in product temperature can significantly impact the product critical quality attributes (CQAs), even for biosimilars having the similar formulations. Therefore, a better understanding of product temperature variations and their impact on meaningful critical quality attributes (CQAs) will enable development of sampling strategies to better assess the influence of distribution in CQAs like protein chemical degradation and aggregation on the probability of releasing out of specification product.  

Methodology & Theoretical Orientation:

Currently, we are evaluating the variations in CQAs related to protein degradation by:

1. Assessing the variations in key physical properties like phase composition (i.e. phase separation and crystallinity), specific surface area, and glass transition temperature (Tg) in the product vials, as well as levels of product degradation. Attempts are being made to identify the physical properties that are predictive of chemical degradation and aggregation.

2. Quantify the position-dependent differences in product temperature history caused by differences in vial heat transfer coefficient (Kv) and assess whether or not these differences are likely to cause differences in stability, particularly aggregation (which can potentially generate adverse immune response).

Conclusion:

Preliminary results indicate that temperature history differences due to variations in Kv are not likely to result in significant differences in stability. Significant intra-batch variations in ice nucleation temperature result in modest variations in specific surface area with possible stability consequences, but current results indicate a large difference in ice nucleation temperature between laboratory and manufacturing with likely adverse stability consequences.

Significance:

Although, the current research focuses on proteins, the general scale-up technology will also apply to generics and vaccine products. An understanding of these variations in CQAs will reduce the probability of releasing out-of-specification product.