Mixing of Monoclonal Antibody Formulated Drug Substance Solutions in Square Disposable Vessels

Fill & finish manufacturing processes of biologics drug product involve multiple unit operations. In particular they often include a mixing step to reduce non-uniformities in fluids by eliminating gradients of concentration and pH may occur during freezing. This step should be conducted carefully to avoid any degradation of the protein under mechanical stress. This study was aimed at characterizing disposable vessels of square cross-section such as Levmixer® from Sartorius Stedim in terms of fluid dynamics and mixing in turbulent regime. The investigation included two tree large vessels (50, 200 & 650-l) and one 4-l vessel designed in house. For that purpose, the impact of stirrer speed, filling volume and duration of mixing on product quality attributes were studied, using a surrogate. Moreover, a scale-up rule, based on first principle, was established and allows prediction of the mixing time as a function of stirring speed and filling volume. A lab-scale test, using drug product, was performed at the same stress intensity but for a much longer duration than the commercial operation and did not reveal any trend to aggregation. Finally, based on the correlation, lab scale stress test and a single verification test at large scale, a design space within which the product can be processed without altering product quality was proposed.