The Challenge
The task was to transition the upstream bioprocess of cell culture from the Thermo Single-Use Bioreactor (SUB) to the Cytiva Xcellerex Disposable Reactor (XDR) for two products, a monoclonal antibody (mAb) and a bi-specific antibody. This strategic move was essential to meet increasing production demands while ensuring process integrity and quality were not compromised.
The complexity of the challenge was multilayered, involving both scale-dependent and scale-independent parameters. Scale-independent parameters, such as pH, temperature, dissolved oxygen, and seeding viable cell density (VCD), had to remain constant across different bioreactor scales to ensure process consistency. Conversely, scale-dependent parameters like volumetric mass transfer coefficient (kLa), tip speed, and power per unit volume are sensitive to changes in bioreactor type and scale, necessitating careful adjustment and monitoring. Additionally, transitioning to a new bioreactor brand introduced variables such as differences in film composition, bag properties, and process regulation capabilities that could potentially affect the outcome.
The AGC Biologics Solution
The AGC Biologics team employed a comprehensive, methodical approach to process transfer. Initial steps included small-scale pilot studies aimed at identifying the optimal process parameters within the Cytiva XDR system without risking large-scale production. These studies were crucial for understanding how the new system responded to traditional process settings and for pinpointing necessary adjustments.
Following the pilot studies, extensive validation tests were conducted to rigorously compare the performance of the Cytiva XDR against the Thermo SUB. This comparative analysis was critical for verifying that the new system could achieve the same or better results, particularly focusing on critical quality attributes such as product purity and viability.
A significant part of the solution was also the integration of advanced monitoring tools. A CO2 sensor was incorporated to provide real-time data on CO2 levels, a critical parameter in bioprocessing that affects cell growth and product quality. This tool was instrumental in addressing unforeseen mixing or gassing differences that emerged due to the new bioreactor’s design and operational dynamics.
Feasibility studies were performed for the mAb and bi-specific antibody, testing processes utilizing the 200 L Cytiva XDR, which is representative of the 100/500/2,000 L Cytiva XDR. Parallel runs were conducted using 2x 5 L bioreactors as control and satellite bioreactors. The data from the bioreactors were compared daily in terms of viable cell density, viability, titer, and metabolites, which were then benchmarked against the data from the 2,000 L Thermo SUB.
The Results
The transition to the Cytiva XDR bioreactor was highly successful. Detailed data comparison across the 200 L Cytiva XDR, the 5 L control bioreactor, and the 2000L GMP Thermo SUB demonstrated that the new system met all benchmarks for viable cell density, viability, integral viable cell count (IVC), and titer. For both processes (the mAb and bispecific antibody), VCD, viability, IVC, and titer from the 5 L and 200 L XDR bioreactors were comparable to the manufacturing scale GMP run (2,000 L Thermo SUB), indicating successful transfer of the process to XDR SUB.
The CO2 monitoring also proved effective, allowing the team to maintain optimal culture conditions by adjusting aeration rates in response to real-time CO2 levels, thus avoiding adverse effects on cell growth. The online and offline CO2 values showed comparability during the the upstream process. For instance, the data was comparable for the mAb, although during the bispecific antibody process, a drift between the online and offline value was observed after a shift in temperature within the upstream process.
The integration of the Cytiva XDR not only addressed the initial capacity enhancement goals but also introduced a higher level of process control and efficiency. The system’s advanced features facilitated more precise adjustments and reduced the risk of variability, leading to consistent, high-quality biopharmaceutical production. Furthermore, the successful implementation of the new bioreactor system has set a precedent for future transitions, promising the team’s ability to pursue upgrades and optimizations for the client’s product and profitability.
The strategic foresight in adopting the Cytiva XDR and the meticulous execution of the transition plan underscored a commitment to maintaining the highest standards of quality and efficiency. As a result, the process is now better positioned to meet both current and future production demands. AGC Biologics continues to innovate and pioneer process improvement with state-of-the-art technology and rigorous methodology.
