Issue link: https://www.e-digitaleditions.com/i/1468049
32 Pharmaceutical Technology TRENDS IN MANUFACTURING 2022 eBOOK P h a r mTe c h . c o m Continuous Manufacturing Chotteau (AdBIOPRO): My group at KTH is a leader in high cell-density perfusion for the production of glycoproteins. We develop methods and ap- proaches for the development of these processes, push the limits, and identify the boundaries. Pro- fessor Bernt Nilsson's research group at Lund University is leading in modeling of continuous purification processes aiming at optimization and automation of these systems. Professor Sophia Hober is a well-recognized expert in protein en- gineering; her group has developed a new ligand for a new type of protein A, ZCa, that eliminates the need for very low pH for the detachment of the antibody from the protein A. So, we are responsible for the perfusion culture; Bernt's group for the design, realisation and au- tomation of the continuous purification; and So- phia's group for the new type of protein A used in the capture step. We have developed our respective parts and then put everything together thanks to four PhD students from the respective groups. The next steps are to continue to apply this ac- quired knowledge for other glycoproteins, which could potentially be more challenging; to apply more process analytical technology (PAT); and to increase the level of automation. We plan to apply this successful concept of gathering multi- disciplinary expertise in close collaboration for other types of modalities, such as viral vectors for gene therapy. Challenges for connecting upstream and downstream PharmTech: What are the technical challenges in creating a fully continuous process? Chotteau (AdBIOPRO): Building both purification and production in one workf low was complicated. The system is a continuous cell culture, operated in perfusion mode, that is directly and automati- cally connected to a continuous purification pro- cess consisting of three chromatography steps and a virus reduction step, where the continuous purification process is also completely automated. The whole process runs completely unattended from late afternoon to morning. The whole sys- tem had to be optimized and automated, while ensuring robustness. The culture was pushed to a very high cell den- sity of 100 x 10 6 cells/mL. [In this situation], small deficiencies in the feeding and aeration strategy, among other things, can rapidly lead to failure. Classical purification processes are operated in batch mode, with each step performed batch-wise; material is stored and buffer may be changed be- tween the different steps. In a continuous pro- cess, however, these steps are now connected automatically; the f low between the steps has to be well designed, and buffer changes have to be avoided. To achieve this, a mathematical model of the process is used for optimization, and it can also be used for process control. Furthermore, the "Classical purification processes are operated in batch mode, with each step performed batch-wise; material is stored and buffer may be changed between the different steps." — Veronique Chotteau, AdBIOPRO