Design, construction, and optimization of a novel, modular, and scalable incubation chamber for continuous viral inactivation

Abstract

We designed, built or 3D printed, and screened tubular reactors that minimize axial dispersion to serve as incubation chambers for continuous virus inactivation of biological products. Empirical residence time distribution data were used to derive each tubular design's volume equivalent to a theoretical plate (VETP) values at a various process flow rates. One design, the Jig in a Box (JIB), yielded the lowest VETP, indicating optimal radial mixing and minimal axial dispersion. A minimum residence time (MRT) approach was employed, where the MRT is the minimum time the product spends in the tubular reactor. This incubation time is typically 60 minutes in a batch process. We provide recommendations for combinations of flow rates and device dimensions for operation of the JIB connected in series that will meet a 60-min MRT. The results show that under a wide range of flow rates and corresponding volumes, it takes 75 ± 3 min for 99% of the product to exit the reactor while meeting the 60-min MRT criterion and fulfilling the constraint of keeping a differential pressure drop under 5 psi. Under these conditions, the VETP increases slightly from 3 to 5 mL though the number of theoretical plates stays constant at about 1326 ± 88. We also demonstrated that the final design volume was only 6% ± 1% larger than the ideal plug flow volume. Using such a device would enable continuous viral inactivation in a truly continuous process or in the effluent of a batch chromatography column. Viral inactivation studies would be required to validate such a design. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:954-965, 2017.

Implementation of Fully Integrated Continuous Antibody Processing: Effects on Productivity and COGm

“…In short, pH adjustment occurred before and after a flow through “hold” design, similar to other theorized methods . While other flow through viral inactivation approaches were tested, use of a column to achieve required residence time was a compact, inexpensive, scalable, and easily designed solution compared to other technologies or periodic processes found in literature . The column dimensions and flow rate were sized such that the residence time matched the target low pH hold time for viral inactivation.…”

Truly continuous low pH viral inactivation for biopharmaceutical process integration

“…To achieve such a goal, three reactors have been patented and published. 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).…”

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.…”

“…The RTD for any given reactor can be assessed by a pulse of non‐interacting tracer and calculation of the F ‐curve, the cumulative RTD function . The ratio between the time at 50% cumulative RTD curve ( F 0.5 ) and the time at 0.5% cumulative RTD curve ( F 0.005 ), t [ F 0.5 ]/ t [ F 0.005 ], has been used to measure and compare the RTD narrowness, where t [ F 0.5 ]/ t [ F 0.005 ] = 1 for an ideal plug flow. The CFI and the JIB have reported t [ F 0.5 ]/ t [ F 0.005 ] values ranging from 1.037 to 2.043.…”

“…Furthermore, scaling up (or down) such a continuous VI process would require building a new custom‐designed reactor for that specific scale. Additionally, the pressure drop might become a limiting factor at larger scales due to the long thin flow path …”