Estimating the shelf life of freeze-dried drugs in vial, and to optimize the storage conditions

Significance 

Freeze-drying is a commonly used drying technique to produce highly stabilized drying products with longer shelf life. It is widely used in the preservation of food and drug products. Freeze-drying involves freezing and drying, and the drying step involves two steps: primary and secondary drying.: primary and secondary drying. The former is characterized by the removal of the ice crystals to aid pore microstructure formation, while the latter involves the removal of the water associated with the freeze-concentrated phases. Most importantly, it produces porous cakes (also known as freeze-dried cakes) obtained from the microstructures and triggered by the freezing process and solid properties. These cakes play a fundamental role in endowing freeze-dried product is beneficial in stabilizing sensitive biological materials, and excellent rehydration properties allow for rapid reconstitution of those sensitive biomaterials. Nevertheless, freeze-drying induces a large surface area and high hygroscopicity that dramatically increases the moisture absorption capacity of the freeze-dried products during storage. Although most current industrial freeze-dryers are equipped with automatic systems for capping vials, moisture ingress over long-term storage is still a big problem. Undesired moisture sorption not only affects the storage stability but could also induce collapse during long time preservation, resulting in the loss of the pore microstructure of the porous cakes. This needs to be prevented to preserve the quality and stability of the products, especially for sensitive biological products.

The humidity-induced collapse is governed by the glass-rubber transition temperature of the freeze-dried matrix or the freeze-concentrated liquid phase mechanisms, which depend on the dehydration rate, temperature and dried layer strength. Since this transition temperature increases as the drying progress, the collapse occurrence is influenced by the balance between the flowability and the drying rate of the matrix. To this end, it has been speculated that the time taken for the absorbed moisture to reach the glass transition point corresponds to the time humidity-induced collapse occurs. Thus, a modeling strategy relating the glass transition point and the moisture sorption kinetics is fundamental in predicting the collapse occurrences, though such models are yet to be reported.

In their recent work, Professor Kyuya Nakagawa, Mr. Hiroki Kamisaki, Dr. Tetsuo Suzuki and Professor Noriaki Sano from Kyoto University developed a new mathematical model of moisture sorption kinetics applicable to glassy freeze-dried matrices. In addition to the glass transition properties, the model was also based on the sorption equilibrium data, including the sorption rate constant rate and the specific surface area of the freeze-dried cake. Their work is currently published in the journal, Chemical Engineering Science.

The research team showed that incorporating the experimentally obtained moisture sorption isotherms and glass transition lines in the development of the model enabled the prediction of the time preceding the occurrence of the collapse with improved accuracy. Results were summarized visually in stability maps as a function of the most critical storage conditions, including relative humidity and temperature. The cases in which humidity-induced collapse of freeze-dried cakes in vials, which this paper deals with, becomes an industrial problem occur over a long time span of months to a year. To validate the model developed in this study, conditions were set such that collapse occurs within 24 hours. The actual cases where we would like to apply this model would be in long time spans, which would be difficult to experiment with.

The stable zone associated with the storage relative humidity and temperatures that did not cause collapse were also visualized based on the induction time line of the collapse. The positions of the limit lines were observed to be dependent on the sorption rate constant, moisture sorption isotherm and the glass transition temperature of the selected material. As anticipated, the matrix with a relatively higher transition temperature exhibited a wider stable zone. The ability of the model to predict the time of collapse induction when freeze-dried cake was subjected to conditions outside that of the stable zone was also demonstrated.

In summary, a mathematical modeling approach relating the glass transition point and the moisture sorption kinetics was proposed for predicting the occurrence of humidity-induced collapse of freeze-dried cakes during freeze-drying. The impacts of different parameters on the initiation of the collapse were studied and discussed. In a statement to Advances bin Engineering, Professor Kyuya Nakagawa, first and corresponding explained that the presented model would be a robust tool for predicting appropriate formulations and storage conditions to produce stable and high-quality freeze-dried products.

Estimating the shelf life of freeze-dried drugs in vial, and to optimize the storage conditions - Advances in Engineering

About the author

Kyuya Nakagawa is an associate professor in the Department of Chemical Engineering at Kyoto University. He received his PhD in chemical engineering at Kyoto University in 2003. He was a postdoctoral fellow at Chulalongkorn University (Thailand) in 2003 and at Université Claude Bernard Lyon 1 (France) from 2004 to 2006. He became an assistant professor at the University of Hyogo in 2006 and promoted to an associate professor in 2011, and moved to Kyoto University as an associate professor in 2013. His research interests include processing technologies for freeze-drying of pharmaceuticals and foods, and basic research on freezing and drying related to glassy matters.

Reference

Nakagawa, K., Kamisaki, H., Suzuki, T., & Sano, N. (2022). Model-based prediction of the moisture sorption kinetics and humidity-induced collapse for freeze–dried cakesChemical Engineering Science, 248, 117129.

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