Freezing of pharmaceuticals

Freezing and freeze-drying are essential processes in the pharmaceutical industry to improve the stability and thus shelf life of biopharmaceuticals, such as protein-based formulations or vaccine suspensions. In freeze-drying, freezing is followed by drying at low pressure, so that the ice crystals formed during freezing are removed via sublimation and desorption. While freezing already leads to a stabilization of the product compared to the liquid state, the subsequent drying step often is beneficial in increasing potential storage temperatures and it further extends the shelf life. As the lack of stability is a major burden for most biopharmaceuticals, there is a need for a better understanding and control of the freezing and freeze-drying processes.

Numerous critical quality attributes of the frozen and freeze-dried products depend on the morphology, i.e. the size and shape, of the ice crystals that form during freezing. This morphology is highly sensitive to the thermal history of the vial; for example, the faster a material is frozen, the more the mean ice crystal size decreases. A smaller mean ice crystal size corresponds naturally to a larger specific interface area of the ice-product interface, which may lead to more denaturation of the active material. Additionally, smaller crystals result in a slower drying step in freeze-drying, thus reducing the manufacturing throughput and increasing the costs.

While the importance of the ice crystal morphology is widely acknowledged, predicting even the mean ice crystal size remains challenging and requires partially or completely empirical models. Even though we may consider freezing as a simple, every-day process, the formation of ice crystals during freezing of an aqueous solution is a complex, multistep process governed by the interplay between heat transfer, mass transfer and crystal growth kinetics. Ice nucleation is the first step of the freezing process, which is a stochastic phenomenon that occurs only in the supercooled state, i.e. below the melting temperature of the solution. Vials with identical products that experience similar heat transfer may nucleate at drastically different times and temperatures, which leads to a vial-to-vial variability in the properties of the frozen products. Such variability renders predictions on the ice crystal morphology even more challenging and is a major hurdle in freezing and freeze-drying process design and optimization. Indeed, we recently developed the first mechanistic framework that is able to predict and quantify such variability, and provided open source access to it in the form of a python package.