Abstract
Continuous virus inactivation (VI) has received little attention in the efforts to realize fully continuous biomanufacturing in the future. Implementation of continuous VI must assure a specific minimum incubation time, typically 60 min. To guarantee the minimum incubation time, we implemented a packed bed continuous viral inactivation reactor (CVIR) with narrow residence time distribution (RTD) for low pH incubation. We show that the RTD does not broaden significantly over a wide range of linear flow velocities—which highlights the flexibility and robustness of the design. Prolonged exposure to acidic pH has no impact on bed stability, assuring constant RTD throughout long term operation. The suitability of the packed bed CVIR for low pH inactivation is shown with two industry‐standard model viruses, that is xenotropic murine leukemia virus and pseudorabies virus. Controls at neutral pH showed no system‐induced VI. At low pH, significant VI is observed, even after only 15 min. Based on the low pH inactivation kinetics, the continuous process is equivalent to traditional batch operation. This study establishes a concept for continuous low pH inactivation and, together with previous reports, highlights the versatility of the packed bed reactor for continuous VI, regardless of the inactivation method.
Highlights
The same continuous viral inactivation reactor (CVIR) was characterized at linear velocities ranging from 4.90 to 300 cm/hr, corresponding to incubation times from 1 to 60 min
| 1415 to accommodate the elution from a periodic counter‐current chromatography (PCC) system before continuous virus inactivation (VI)
Constant protein concentration and consequentially viscosity are especially important for reactors, whose narrow residence time distribution (RTD) is enabled by Dean vortices, as such secondary flow patterns depend heavily on the solution's viscosity and its acceptable range must be studied (Brown et al, 2019)
Summary
Continuous processing are many‐fold; process intensification and cost savings (Baur, Angarita, Müller‐Späth, Steinebach, & Morbidelli, 2016; Continuous viral inactivation (VI) is a key building block to complete the Hummel et al, 2018; Pagkaliwangan, Hummel, Gjoka, Bisschops, &. Continuous low pH VI must assure that critical process parameters (CPPs) stay within prevalidated operation limits throughout the whole process These include, at least, pH‐value, temperature, and minimum incubation time (Brorson et al, 2003; Mattila et al, 2016). For the specific case of continuous VI, the chance of any fluid element leaving the reactor before the target incubation time should be minimized, which highlights the requirement for a narrow RTD (Jungbauer, 2018). To achieve such a goal, three reactors have been patented and published. Two industry‐relevant model viruses are used (a) to control for any equipment‐induced viral inactivation and (b) to assess the effectiveness of the CVIR for continuous low pH viral inactivation and show process performance equivalent to batch mode
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