Side-by-side comparability of batch and continuous downstream for the production of monoclonal antibodies.

Continuous processing is the future production method for monoclonal antibodies (mAbs). A fully continuous, fully automated downstream process based on disposable equipment was developed and implemented inside the MoBiDiK pilot plant. However, a study evaluating the comparability between batch and continuous processing based on product quality attributes was not conducted before. The work presented fills this gap comparing both process modes experimentally by purifying the same harvest material (side-by-side comparability). Samples were drawn at different time points and positions in the process for batch and continuous mode. Product quality attributes, product-related impurities, as well as process-related impurities were determined. The resulting polished material was processed to drug substance and further evaluated regarding storage stability and degradation behavior. The in-process control data from the continuous process showed the high degree of accuracy in providing relevant process parameters such as pH, conductivity, and protein concentration during the entire process duration. Minor differences between batch and continuous samples are expected as different processing conditions are unavoidable due to the different nature of batch and continuous processing. All tests revealed no significant differences in the intermediates and comparability in the drug substance between the samples of both process modes. The stability study of the final product also showed no differences in the stability profile during storage and forced degradation. Finally, online data analysis is presented as a powerful tool for online-monitoring of chromatography columns during continuous processing.

Developing the biofacility of the future based on continuous processing and single-use technology.

To maintain or strengthen their market position, biopharmaceutical producers have to adapt their production facilities to a drastically changed market environment. Contrary to currently used large scale batch-wise operated production facilities, where stainless steel equipment is widely applied, small scale and flexible production processes are desired. Consequently, the concept of the "biofacility of the future" has been developed, which combines the attributes fast, flexible, small, inexpensive and sustainable. Four design principles build the facility's basis and are presented within this work: continuous processing, 100% single-use equipment, closed processing and adopting the ballroom concept. However, no publication presents a completely continuously operated platform process for the production of monoclonal antibodies up to now. Therefore, this work establishes the proof of concept regarding continuous antibody manufacturing. A pilot plant for the production of monoclonal antibodies has been built 100% in single-use equipment. It was operated fully continuous and automated in the upstream and the downstream part. The concepts that allow continuously operating the pilot plant are presented within this work, i.e., continuously operated filtration, continuously operated viral inactivation, continuously operated chromatography and a continuously operated formulation. Analytics showed that the produced product was within specification limits of industrial bulk drug substances.