(664f) Advancing Biopharmaceutical Process Development: The Role of Computational Fluid Dynamics and Digital Twins in Standardizing Scale-up and Scale-Down Strategies

The commercialization of biopharmaceutical processes is a complex and multifaceted endeavor that requires meticulous planning and execution. One of the critical aspects of this process is the development of a scalable and reproducible manufacturing process that has high productivity and a suitable product quality profile. This involves multiple rounds of development, starting from laboratory-scale experiments and progressing to pilot-scale and eventually manufacturing-scale operations. Each stage of this development process presents unique challenges, particularly due to the hydrodynamic differences that exist between different scales. These differences can be further exacerbated if the vessels used at each scale are geometrically dissimilar or have different configurations. To overcome these challenges, computational fluid dynamics (CFD) has emerged as a valuable tool in the biopharmaceutical industry. CFD allows for the detailed analysis of fluid flow and mixing characteristics within vessels, providing insights into critical parameters such as specific power input, mixing times, oxygen transfer rates (k_La), and shear forces. By leveraging CFD, researchers can gain a deeper understanding of the hydrodynamic environment within their processes, enabling them to make informed decisions about scale-up/scale-down and tech transfer strategies.

Recently, we have developed models that integrate kinetics of the bioprocess using mechanistic models with fluid dynamics simulations (1). This integration has been made possible by the advent of graphics processing units (GPUs), which allow for the rapid and efficient execution of complex simulations. By incorporating kinetic models, researchers can create a digital twin of the biopharmaceutical process, which is a virtual representation of the bioprocess that can be used to simulate and analyze various scenarios. This capability is particularly valuable for manufacturing investigations, risk assessments, and as a substitute for engineering runs, which can be time-consuming and costly.

Yet, despite the numerous benefits and advances of CFD and digital twin technology, there are still several challenges that need to be addressed. One of the primary issues is the lack of standardization in CFD studies in the pharmaceutical industry. Different software programs often use different computational frameworks, which can lead to variations in the results obtained from similar studies. This lack of standardization and availability of suitable benchmarking tools, makes it difficult to compare results across different studies and can hinder the adoption of CFD as a reliable tool for regulatory submissions. To address this issue, the authors propose a standardization approach for CFD studies in the biopharmaceutical industry derived from existing guidelines such as the ASME V&V standards. This approach involves the development of protocols and guidelines for conducting CFD simulations, including the selection of appropriate computational frameworks, validation of simulation results, and reporting of key parameters. By establishing these standards, the industry can ensure that CFD studies are conducted consistently and that the results are reliable and comparable across different studies.

In this talk, the authors will present a case study on the use of CFD for the characterization of single-use pilot-scale vessels. Single-use systems are increasingly being adopted in the biopharmaceutical industry due to their flexibility, reduced risk of cross-contamination, and lower capital investment compared to traditional stainless-steel systems. However, the hydrodynamic behavior of single-use vessels can significantly impact the bioprocess under consideration, necessitating detailed CFD studies to understand their mixing and oxygen transfer characteristics for aerobic processes.

The case study will focus on power characterization, mixing studies and k_La analyses for upstream bioreactor characterization. Mixing is a critical parameter in bioreactor operations, as it affects the homogeneity of the culture environment and the distribution of nutrients and oxygen to the cells. The authors will discuss the considerations that need to be made when conducting mixing studies using CFD, including the selection of appropriate grid resolution, and boundary conditions. They will also present the results of k_La analyses, which provide insights into the oxygen transfer capabilities of the bioreactor and discuss similar considerations for aerobic parameters that enable the evaluation of gas mass transfer capabilities. This standardization will enable the use of CFD studies in regulatory reports as viable replacements for engineering runs, ultimately reducing the time and cost associated with process development and commercialization.

The integration of CFD and kinetic models has the potential to revolutionize the development of biopharmaceutical processes. By creating digital twins of bioprocesses, researchers can gain valuable insights into the hydrodynamic environment within their systems, enabling them to make informed decisions about scale-up and scale-down strategies. However, to fully realize the benefits of CFD, it is essential to address the challenges associated with the lack of standardization in CFD studies. By developing standardized protocols and guidelines, the biopharmaceutical industry can ensure that CFD studies are conducted consistently and that the results are reliable and comparable across different studies. This will ultimately enable the use of CFD as a reliable tool for regulatory submissions and facilitate the commercialization of biopharmaceutical processes.

References:

(1) Dasgupta, A.; Anand, A.; McCahill, M.; Thomas, J.; Sood, A.; Kinross, J.; Rajendran, A. A Hydro-Kinetic Model of Single Use Scale-down Bioreactor Systems for Mammalian Cell Culture.