(493c) Model-Based Control for Column-Based Continuous Viral Inactivation of Biopharmaceuticals

The continuous manufacturing of biologics has been of interest to academia and industry due to reduced costs, increased flexibility, ease of standardization and scale up, and improvements in product quality [1,2]. The complexity of these processes brings with them control challenges and opportunities [3,4]. Biologics derived from mammalian sources are expected to undergo two orthogonal virus removal processes in order to remove adventitious viruses or retroviruses that may be present in the master cell bank [5–7]. One common processing step is a batch low-pH hold [8] to inactivate enveloped viruses [9].

Strategies proposed to convert batch low-pH hold to continuous processing are cyclic batch operation [10], continuous-flow tubular reactors [11–15], and continuous-flow column-based reactors [16,17]. Past studies of these continuous flow reactors have not directly addressed the control aspects of this unit operation. The operating pH and the residence time distribution are critical process parameters in determining viral clearance and impacts to product quality from over-incubation or excessive pH adjustment.

This presentation describes a low-cost column-based continuous-flow viral inactivation system constructed with off-the-shelf components. A fast and accurate model-based pH feedback control scheme allows for rapid startup and effective suppression of the effects of disturbances on the outflow. The residence time distribution (RTD) is estimated periodically during operation through inverse tracer experiments and used to estimate the minimum residence time (MRT), which in turn is used to adjust the feed flow rates. Controller validation experiments demonstrate the performance in pH and MRT setpoint tracking and feed buffer and column residence time disturbance rejection. Viral inactivation testing demonstrates tight control of logarithmic reduction values (LRV) over extended operation.

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