Design of a novel continuous flow reactor for low pH viral inactivation

Abstract

Insufficient mixing in laminar flow reactors due to diffusion-dominated flow limits their use in applications where narrow residence time distribution (RTD) is required. The aim of this study was to design and characterize a laminar flow (Re 187.7-375.5) tubular reactor for low pH viral inactivation with enhanced radial mixing via the incorporation of curvature and flow inversions. Toward this aim, the reactor described here, Jig in a Box (JIB), was designed with a flow path consisting of alternating 270° turns. The design was optimized by considering the strength of secondary flows characterized by the Dean No., the corresponding secondary flow development length, and the reactor turn lengths. Comprehensive CFD analysis of the reactor centerline velocity profile, cross-sectional velocity, and secondary flow streamlines confirmed enhanced radial mixing due to secondary flows and changes in flow direction. For initial CFD and experimental studies the reactor was limited to a 16.43 m length. Pulse tracer studies for the reactor were computationally simulated and experimentally generated to determine the RTD, RTD variance, and minimum residence time for the tracer fluid elements leaving the reactor, as well as to validate the computational model. The reactor was scaled length wise to increase incubation time and it was observed that as the reactor length increases the RTD variance increases linearly and the dimensionless RTD profile becomes more symmetrical and tighter about the mean residence time.

Truly continuous low pH viral inactivation for biopharmaceutical process integration

“…Increasing the linear velocity to up to 300 cm/hr (or 10.1 ml) has a limited impact on initial peak steepness (see Figure 2a), which highlights the flexibility and simplicity of operation of the packed bed CVIR. Such flexibility—the possibility to operate at either 1 or 60 min incubation time with narrow RTD—has not been demonstrated for reactors based on Dean vortices, possibly because narrow RTD is achieved for a limited range of Reynolds number, Dean number, and coil‐to tube diameter (Klutz et al, 2015; Parker et al, 2018; Rossi, Gargiulo, Valitov, Gavriilidis, & Mazzei, 2017). The HETP increased with increasing linear—this is expected as hydrodynamic dispersion dominates in this range of linear velocities (Carta & Jungbauer, 2010; the linear velocity range assessed—4.90–300 cm/hr—is equivalent to a reduced velocity range of 3.58–219 in the van Deemter plot).…”

“…The coiled flow inverter (CFI) reactor (Klutz, Kurt, Lobedann, & Kockmann, 2015; Maiser, Schwan, Holtman, & Lobedann, 2016) and the jig‐in‐a‐box (JIB) reactor (Orozco et al, 2017; Coffman, Goby, Godfrey, Orozco, & Vogel, 2015) rely on Dean vortices to narrow the RTD in coiled open tube. Dean vortices—a secondary flow pattern that provides axial mixing—are generated by a fine balance of centripetal forces and centrifugal forces over a narrow Reynolds number range (Parker et al, 2018). An alternative approach based on the packed bed was suggested (Hammerschmidt et al, 2019).…”

Continuous Solvent/Detergent Virus Inactivation Using a Packed‐Bed Reactor

“…The developed secondary flow pattern (Dean vortices) enables radial mixing and thereby a narrower RTD compared with a straight tube. More recently, Orozco suggested a similar approach, Jig in a Box (JIB), for continuous VI . The JIB can be regarded as an adaptation and optimization of a CFI arranged in a 3D fashion.…”

Leveraging flow mechanics to determine critical process and scaling parameters in a continuous viral inactivation reactor

“…The JIB was designed from previous development projects (Parker et al, ; Orozco et al, ), and was 3D printed utilizing SLA Technology by 3D Systems (Rock Hill, SC). The riboflavin and dextrose used in creating the mobile phases and pulse tracer were purchased through Thermo Fisher Scientific (Suwanee, GA).…”