Nearly half of the therapeutic proteins undergo freeze drying process to improve their long-term storage stability but the inability to directly control the product temperature during freeze-drying process can lead to non-uniform distribution of critical quality attributes (CQAs) in product vials, even for biosimilars having similar formulation. Therefore, a better understanding of product temperature variations is needed to assess the influence of distribution in CQAs, like protein degradation and aggregation, on the probability of releasing out of specification drug product. To understand the impact of product temperature variation on distribution of CQAs, following investigations are currently in progress:
1. Analysis of 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. Quantification of position-dependent differences in product temperature history caused by differences in ice nucleation temperature and assess whether or not these differences are likely to cause differences in stability, particularly aggregation (which can potentially generate adverse immune response).
Preliminary results indicate that significant intra-batch variations in ice nucleation temperature result in modest variations in specific surface area and higher order protein structure with possible stability consequences, which should be thoroughly investigated, on a case by case basis. Although, the current research focuses on proteins, the general scale-up technology will also apply to generics and vaccine products and an understanding of these variations in CQAs will be key to reduce the probability of releasing out-of-specification product.
Audience take away:
• The audience will understand the underlying science responsible for degradation of therapeutic protein formulations and therefore, will be able to improve the design of their biologic formulations and optimize their drug delivery systems.
• Currently 35% of biologic drugs are freeze dried to improve their long-term stability. Therefore, stability and degradation of therapeutic protein formulations is a priority area of interest for regulatory agencies like US-FDA. A deep understanding of degradation processes like chemical degradation and adverse immune response associated with such degradation is critical for improving the formulation and drug delivery of this emerging class of therapeutic molecules.
• As an area of priority research for drug regulatory agencies, the data presented in this US-FDA funded research will bring faculty and researchers up to the speed with current trends and benchmark in US regulatory landscape. Additionally, the research data will help pharmaceutics and drug delivery researchers to optimize their formulation and drug delivery systems from an early stage and avoid the common pitfalls observed in the late stage drug development process.