(288b) Particulate Impurities Control the Rate of Ice Nucleation in Pharmaceutical Formulations Under Conditions of Industrial Relevance

Keywords: Freezing, Freeze-Drying, Lyophilization, Nucleation, Modeling, Pharmaceutical Manufacturing, Stochastic processes

Main body

Most commercially available biopharmaceuticals are frozen or freeze-dried in vials. The temperature at which ice nucleates and its distribution among vials in a batch is pivotal to the design of both freezing and freeze-drying processes. This work reports experimental data on the ice nucleation behavior of milliliter-scale solutions containing different concentrations of sucrose that have been prepared with different levels of particulate impurities [1]. Independent of sucrose concentration, the spiking of solutions with silver iodide (AgI) resulted in significantly higher and less variable nucleation temperatures compared to the reference solutions without AgI. Samples prepared under particulate-free conditions, in contrast, nucleated at significantly lower temperatures and with more variability.

We further measured nucleation temperatures for the Janssen COVID-19 vaccine at different cooling rates and observed values similar to the particulate-free sucrose solutions between −15°C and −27°C, with no relevant effect of cooling rate. This confirms our earlier findings that temperatures below −20°C are required to ensure successful ice formation in all vials in the vaccine’s commercial freezing process [2]. In conclusion, these findings emphasize that the effect of particulate impurities on ice nucleation must be considered when designing pharmaceutical freezing processes. This can be done using the mechanistic freezing models that we have made available to the public in the form of a Python package called SNOW – Stochastic Nucleation Of Water [3].

References

[1] L.-T. Deck, N. Gusev, V. Deligianni, M. Mazzotti: From the dirty lab to the clean manufacturing of pharmaceuticals: how particulate impurities affect ice nucleation, manuscript in preparation.

[2] L.-T. Deck, D.R. Ochsenbein, M. Mazzotti: Stochastic ice nucleation governs the freezing process of biopharmaceuticals in vials, Int. J. Pharm. (2022), 625, 122051

[3] L.-T. Deck, A. Košir, D.R. Ochsenbein, M. Mazzotti: SNOW – Stochastic Nucleation of Water, GitHub Repository, https://github.com/SPLIfA/snow/, (2021–2024).