CERSI Collaborators: Sarah L. J. Michel, PhD (PI), University of Maryland, Baltimore, MD

FDA Collaborators: Ashutosh Rao, PhD, CDER

Project Start Date: October 30, 2019

Regulatory Science Challenge

Trace, or small amounts of metals, such as iron, copper, and zinc, can be found nearly everywhere to varying degrees. In pharmaceutical products, they are found as leachables from the container closure system, the buffer system used, and reactions in their presence can occur due to exposure to light, heat, agitation or freeze/thaw cycles. Leachable metals in drug products represent a real and contemporary challenge to the stability, purity and potency of the drugs regulated by CDER/FDA. These metals may damage protein drug products via fragmentation and aggregation and should therefore be analyzed as accurately as possible to ensure product quality. Aggregated proteins can trigger the immune system and cause serious adverse events, including death in patients. The levels and types of metals that preferentially cause protein aggregation are not known. Also not known are standardized methods for measuring free versus bound metals in complex biological samples.

Project Description and Goals

This study aims to bridge the gap in knowledge on which metals interact with therapeutic proteins, how they bind to certain proteins, what levels of metal binding are pharmaceutically relevant, and how drug developers could mitigate metal-catalyzed adverse events. We will analyze these metals in products and biological samples and determine their propensity for damage. These data will allow reviewers to better ensure product quality, safety, and efficacy, and contribute to science-based decision-making.