Visualizing and understanding batch heterogeneity during freeze-drying using shelf-scale infrared thermography

Abstract

Freeze-drying is widely used for manufacturing biopharmaceuticals in vials. One significant challenge in process design and optimization is heterogeneity among vials across a batch, which has been difficult to investigate due to the lack of adequate monitoring techniques. Here we leverage infrared thermography to quantify the freezing and drying behavior of all vials, hence enabling comprehensive studies of batch heterogeneity. Surprisingly, the stochasticity of nucleation, commonly considered the main driver of batch heterogeneity, only causes little heterogeneity. Instead, heterogeneity originates from heat transfer between vials: when ice is formed in one vial, the release of latent heat governs the freezing behavior of its neighboring vials. Guided by a mechanistic model and confirmed by experiments, the cooling rate and geometrical arrangement of the vials are identified as main drivers of batch heterogeneity. In conclusion, this contribution reports transformational insights into freeze-drying and supports practitioners in process design and optimization.