Quantification and Stability Impact Assessment of Drop Stresses in Biologic Drug Products.

Abstract

Product can experience a combination of cavitation and agitation stresses as a result of dropping post-manufacture. We optimized terephthalic acid (TA) dosimetry, hydroxyphenyl fluorescein fluorimetry, and p-nitrophenol calorimetry as tools to detect and quantify the levels of hydroxyl radicals generated in solution. Using TA dosimetry, we determined the level of hydroxyl radicals generated from a vial drop and found that it is a function of drop height and fill volume and that protein and excipients may serve to mitigate but not completely quench the radicals. Additionally, we optimized sonication and friability as scale-down models to simulate dropping stresses and applied them to assess the impact on the stability of biologics. Our results suggest that chemical degradation dominates when a protein is subjected to cavitation stress alone, and that physical degradation induced by air-liquid and solid-liquid interfaces is the dominant degradation mode when there is a combination of cavitation and agitation stress. Taken together, this work provides a quick and simplistic approach that can be applied during drug product process development to evaluate the impact of drop stresses on the stability of biologic drug product.