Identifying and mitigating risks during biologic drug product manufacturing: A case study using computational fluid...

This case study highlights the use of computational fluid dynamics (CFD) modeling to identify and mitigate the risk of increased high molecular weight species (HMWS) formation during biologic drug product (DP) manufacturing of a multi-dose product. Following process validation, elevated HMWS levels were observed in certain batches, prompting a root cause investigation. Sampling across seven manufacturing steps revealed the largest HMWS increase occurred during manual addition of the preservative, m-cresol, into the formulation vessel. CFD simulations confirmed that rapid addition and above-surface addition of m-cresol led to air entrainment and localized concentration gradient hot spots that promoted protein aggregation. Modeling the vessel mixing dynamics identified two mitigation measures to minimize air entrainment and improve homogeneity: an optimal addition rate and optimal J-tube location. Implementing a controlled, slow addition protocol restored HMWS levels to historical ranges, mitigating risk without requiring process revalidation. This work highlights the value of CFD in enhancing mechanistic process understanding when liquid-air interfaces are present and for mitigating risk within validated pharmaceutical manufacturing.