(371v) Uncertainty-Conscious Model-Based Design of Human Mesenchymal Stem Cell Manufacturing Processes

Human mesenchymal stem cells (MSCs) are considered as a promising cell source for therapeutic applications because of the self‐renewability, multipotency, immunosuppression without ethical concerns. The demand of MSCs is expected to grow in the future, and the industrial-scale manufacturing processes are needed to be designed to produce clinical-grade cells. To this end, models are needed for the unit operations that constitutes the processes of MSC manufacturing, considering exogenic and endogenic uncertainties characteristic to the bioprocessing.

We developed unit operation models for two-dimensional seeding, cultivation, and harvesting of MSCs, and passaging as the interconnected process of the units. The seeding unit was modeled by computational fluid dynamics (CFD) that can simulate the resulting cell distributions depending on the seeding conditions [1]. The cultivation unit was described as a hybrid model that incorporates the seeding heterogeneity by parameterizing the cell culture image data into the ordinary differential equation (ODE)-based kinetic model [2]. The harvesting unit was modeled by considering experimental data. Finally, these three units were integrated to describe the entire passaging process, which is the state-of-the-art design tool proposed by this work.

The model was used to analyze the systems behavior of the passaging process, e.g., simulating the overall harvested cell numbers as a function of initial seeding and cultivation conditions. One industrially relevant application was the determination of “design space” indicating the feasible ranges of critical process parameters (CPPs; e.g., seeding density) that can assure the critical quality attributes (CQAs; e.g., the final cell numbers). The model could successfully propagate the uncertainty of the CPPs through the system to quantify the impact on the CQAs, and could produce recommendations for the design of MSC passaging processes.

[1] Benedikt X. Scholz, Yusuke Hayashi, Isuru A. Udugama, Masahiro Kino-oka, Hirokazu Sugiyama “A CFD model-based design of seeding processes for two-dimensional mesenchymal stem cell cultivation” Computers & Chemical Engineering, 171, 108157 (2023)

[2] K. Hirono, Y. Hayashi, I.A. Udugama, Y. Takemoto, R. Kato, M. Kino-oka, H. Sugiyama “Image-based hybrid model incorporating initial spatial distribution for mesenchymal stem cell cultivation process design” AIChE Journal, in press