434841 Application of Scale-Down Modeling for Improving Robustness of a Manufacturing Process By Supplementation of Limiting Nutrients

Thursday, November 12, 2015: 1:36 PM
151D/E (Salt Palace Convention Center)
Benjamin Orbon, Vijay Janakiraman, Rashmi Kshirsagar and Thomas Ryll, Cell Culture Development, Biogen, Morrisville, NC

Representative scale-down models of manufacturing processes allow for troubleshooting and improvement of the cell culture process at scale. In this work, we applied scaling parameters such as volumetric flow rate for oxygen transfer and CO2 stripping, mass transfer coefficient (kLa) for oxygen delivery, and feed strategy alignment between scales to create a representative 5L scale-down model of a manufacturing process at the 15,000L scale. Multivariate analysis (MVA) was implemented to compare the process performance between bench scale and manufacturing scale, and univariate analysis was used for product quality comparison. The confirmed scale-down model was statistically similar to two Biogen manufacturing facilities in process performance and product quality. Further, the scale-down model was applied to understand two growth phenotypes observed in manufacturing. Two critical nutrients were identified to be depleting in the higher cell density growth phenotype, leading to a faster drop in cell viability. A simple feed supplementation did not improve process performance. Subsequently, methods of delivering higher levels of the limiting nutrients in the form of a stock solution addition during the process or upfront supplementation in the feed formulation proved to increase the process performance. The current work shows the successful application of a scale-down model developed systematically, to improve the robustness of an existing process in manufacturing.

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