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. 2018 Mar 2;7(1):13.
doi: 10.3390/antib7010013.

Evaluation of Continuous Membrane Chromatography Concepts With an Enhanced Process Simulation Approach

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Free PMC article

Evaluation of Continuous Membrane Chromatography Concepts With an Enhanced Process Simulation Approach

Steffen Zobel-Roos et al. Antibodies (Basel). .
Free PMC article

Abstract

Modern biopharmaceutical products strive for small-scale, low-cost production. Continuous chromatography has shown to be a promising technology because it assures high-capacity utilization, purity and yield increases, and lower facility footprint. Membrane chromatography is a fully disposable low-cost alternative to bead-based chromatography with minor drawbacks in terms of capacity. Hence, continuous membrane chromatography should have a high potential. The evaluation of continuous processes goes often along with process modeling. Only few experiments with small feed demand need to be conducted to estimate the model parameters. Afterwards, a variety of different process setups and working points can be analyzed in a very short time, making the approach very efficient. Since the available modeling approaches for membrane chromatography modules did not fit the used design, a new modeling approach is shown. This combines the general rate model with an advanced fluid dynamic distribution. Model parameter determination and model validation were done with industrial cell cultures containing Immunoglobulin G (IgG). The validated model was used to evaluate the feasibility of the integrated Counter Current Chromatography (iCCC) concept and the sequential chromatography concept for membrane adsorber modules, starting with a laboratory-type module used for sample preparation. A case study representing a fed-batch reactor with a capacity from 20 to 2000 L was performed. Compared to batch runs, a 71% higher capacity, 48.5% higher productivity, and 38% lower eluent consumption could be achieved.

Keywords: continuous bio-manufacturing; continuous chromatography; membrane chromatography; process modeling.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic overview of the scheduling differences in upstream and downstream processing for batch and continuous production. In the upstream Fed Batch and Perfusion, in the Downstream Bachth; SMB, Simulated Moving Bed; Sequential; iCCC, integrated Counter Current Chromatography.
Figure 2
Figure 2
Scheduling of loading and separation phases for a three-column sequential chromatography after batch upstream.
Figure 3
Figure 3
Schematic overview of column capacity utilization for different numbers of columns in the loading zone.
Figure 4
Figure 4
Sequence of an integrated Counter Current Chromatography (iCCC) cycle. IEX, Ion-Exchange Chromatography; HIC, Hydrophobic Interaction Chromatography; NB, Non-Binding; W, Weak-Binding; P, Product; S, Strong-Binding; SB, Stronger-Binding; F, Feed.
Figure 5
Figure 5
Overview of different fluid dynamic models. (A) Distributed plug flow model; (B) Roper–Lightfoot model [64]; (C) zonal rate model [59,60]. PFR, Plug Flow Reactor.
Figure 6
Figure 6
Fluid dynamic distribution in a membrane chromatography module.
Figure 7
Figure 7
Comparison between simulations (red line) and tracer experiments (blue dots) for a volumetric flow of 0.5 mL/min.
Figure 8
Figure 8
Langmuir isotherms for immunoglobulins (IgG) on ion-exchange membrane (IEX) (a) and hydrophobic interaction membrane (HIC) (b).
Figure 9
Figure 9
Experimental (blue dots) and simulation (red line) results for the hydrophobic interaction module with a 5 Column Volume (CV) gradient, as an example for simulation results with a low coefficient of determination (R² = 0.647).
Figure 10
Figure 10
iCCC simulation runs: (a) ion-exchange module (b) hydrophobic interaction module.
Figure 11
Figure 11
Increase in total loading of the first adsorber module depending on the number of modules used in the sequential loading step. The blue columns indicate the protein loading of the first column, the red columns represent the loading increase compared to only one module.
Figure 12
Figure 12
Experimental determination of the pressure drop of one module depending on the volumetric flow.
Figure 13
Figure 13
Simulation and experimental results for a membrane stack in a glass column.

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