Design considerations impacting flow dynamics in packed beds for virus inactivation.

Residence times of multiple particles in non-newtonian holding tube flow: Effect of process parameters and development of dimensionless correlations

Continuous viral inactivation at low pH value in antibody manufacturing

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.

Batch low-pH hold is a common processing step to inactivate enveloped viruses for biologics derived from mammalian sources. Increased interest in the transition of biopharmaceutical manufacturing from batch to continuous operation resulted in numerous attempts to adapt batch low-pH hold to continuous processing. However, control challenges with operating this system have not been directly addressed. This article describes a low-cost, column-based continuous viral inactivation system constructed with off-the-shelf components. Model-based, reaction-invariant pH controller is implemented to account for the nonlinearities with Bayesian estimation addressing variations in the operation. The residence time distribution is modeled as a plug flow reactor with axial dispersion in series with a continuously stirred tank reactor, and is periodically estimated during operation through inverse tracer experiments. The estimated residence time distribution quantifies the minimum residence time, which is used to adjust feed flow rates. Controller validation experiments demonstrate that pH and minimum residence time setpoint tracking and disturbance rejection are achieved with fast and accurate response and no instability. Viral inactivation testing demonstrates tight control of logarithmic reduction values over extended operation. This study provides tools for the design and operation of continuous viral inactivation systems in service of increasing productivity, improving product quality, and enhancing patient safety.

Continuous virus inactivation (VI) remains one of the missing pieces while the biopharma industry moves toward continuous manufacturing. The challenges of adapting VI to the continuous operation are two-fold: 1) achieving fluid homogeneity and 2) a narrow residence time distribution (RTD) for fluid incubation. To address these challenges, a dynamic active in-line mixer and a packed-bed continuous virus inactivation reactor (CVIR) are implemented, which act as a narrow RTD incubation chamber. The developed concept is applied using solvent/detergent (S/D) treatment for inactivation of two commonly used model viruses. The in-line mixer is characterized and enables mixing of the viscous S/D chemicals to ±1.0% of the target concentration in a small dead volume. The reactor's RTD is characterized and additional control experiments confirm that the VI is due to the S/D action and not induced by system components. The CVIR setup achieves steady state rapidly before two reactor volumes and the logarithmic reduction values of the continuous inactivation process are identical to those obtained by the traditional batch operation. The packed-bed reactor for continuous VI unites fully continuous processing with very low-pressure drop and scalability.

Invasive plants as feedstock for biochar and bioenergy production

Anaerobic degradation performance of a laboratory-scale packed-bed reactor (PBR) was compared with two fluidized-bed biofilm reactors (FBRs) on molasses and whey feeds. The reactors were operated under constant pH (7) and temperature (35 degrees C) conditions and were well mixed with high recirculation rates. The measured variables were chemical oxygen demand (COD), individual organic acids, gas composition, and gas rates. As carrier, sand of 0.3-0.5 mm diameter was used in the FBR, and porous clay spheres of 6 mm diameter were used in the PBR. Startup of the PBR was achieved with 1-5 day residence times. Start-up of the FBR was only successful if liquid residence times were held low at 2-3 h. COD degradations of 86% with molasses (90% was biodegradable) were reached in both the FBR and PBR at 6 h residence time and loadings of 10 g COD/L day. At higher loadings the FBR gave the best performance; even at 40-45 g COD/L day, with 6 h residence times, 70% COD was degraded. The PBR could not be operated above 20 g COD/L day without clogging. A comparison of the reaction rates show that the PBR and FBR per formed similarly at low concentrations in the reactors up to 1 g COD/L, while above 3 g COD/L the rates were 17.4 g COD/L day for the PBR and 38.4 g COD/L day for the FBR. This difference is probably due to diffusion limitations and a less active biomass content of the PBR compared with the fluidized bed.The results of dynamic step change experiments, in which residence times and feed concentrations were changed hanged at constant loading, demonstrated the rapid response of the reactors. Thus, the response times for an increase in gas rate or an increase in organic acids due to an increase in feed concentration were less than 1 day and could be explained by substrate limitation. Other slower responses were observed in which the reactor culture adapted over periods of 5-10 days; these were apparently growth related. An increase in loading of over 100% always resulted in large increases inorganic acids, especially acetic and propionic, as well as large increases in the CO(2) gas content. In general, the CO(2) content of the gas was very low, due to the large amount of dissolved CO(2) that exited with the liquid phase at low residence times. The performance of the FBR with whey was comparable to its performance with molasses, and switching of molasses to whey feed resulted in immediate good performance without adaptation.

Effect of channel size on solute residence time distributions in rivers

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.

This paper contains the results of a design optimization study performed on the steady-casting operation of the Columbus Stainless single-strand stainless steel caster tundish. Residence Time Distribution (RTD) data such as minimum residence time (or plug flow volume fraction) and dead volume are used as objective functions in the mathematical optimization process. Water is used in the first two case studies as modeling fluid to allow for comparison with water model results. Liquid steel is used in the last case study to investigate the effect of temperature and buoyancy on the resulting flow patterns and the optimum design. Two separate tundish configurations are considered. The first has one dam and one weir, while the second comprises a baffle with angled holes and an impact pad. Significant improvements of up to 34% in minimum residence time are obtained for the second configuration.

A continuous viral inactivation (CVI) chamber has been designed to operate with acceptable residence time distribution (RTD) characteristics. However, altering the CVI's geometry and operation to accommodate the scale was not obvious. In this work, we elucidate the influence of Dean vortices and leverage the transition into the weak turbulent regime to establish relationships between input variables and process outputs. This study was targeted to understand and quantify the impact of viscosity, Dean number, internal diameter, and path length on the RTD. When the Dean number exceeds 70, radial mixing generated by the Dean vortices began to consistently alter the axial dispersive effects experienced by the pulse injection. Increasing to a Dean number of >100, the axial dispersive effects were dominated by the Dean vortices which allowed the calculation of the minimum and maximum residence time to be generated. This work provides a method to calculate operational solutions for a tubular incubation reactor in terms of path length, internal diameter, flow rate, and target minimum and maximum residence time specifications that assures both viral residence times while also establishing criteria to maximize product quality during continuous operation.

Sustaining low pressure drop and homogeneous flow by adopting a fluidized bed biofilter treating gaseous toluene

Odor control has gained importance for ensuring a comfortable living environment. In this paper, the authors report the experimental results of a study of the detailed characteristics of a barrier-type packed-bed nonthermal plasma reactor used for odor control. This plasma reactor has been widely used for volatile organic compound (VOC) decomposition and NOx reduction. The reactor is energized by a low-cost 60 Hz AC power supply. Removal efficiency and the concentrations of byproducts are studied under various experimental conditions. The complete decomposition of the main odor component, namely, NH3, is obtained with minimal reaction byproduct formation (maximum N2O concentration, 10 ppm) in a dry environment. The decomposition is deteriorated by the addition of moisture. The minimum residence time is determined for the complete removal of NH3 in the case of the packed-bed plasma reactor. The pellet diameter has little effect on the removal tendency, and the reactor performed better than a silent corona. Mixing another odor component such as CH3CHO into the gas stream has little effect on the NH3 removal efficiency.

Flow Profiles in the Plates of a Milk Pasteurizer

A computational fluid dynamics analysis of transient flow through a generic Chemical Biological Radiological and Nuclear respirator canister