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

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.

Development and Testing of a 4-Columns Periodic Counter-Current Chromatography System Based on Membrane Adsorbers

“…In addition, the up-and down-scale of membrane adsorbers is simple because the capacity depends only on the membrane surface [23]. A continuous chromatography system, in which MA can be operated as an alternative to classical columns, could further increase productivity of a purification process [24,25]. This applies particularly to the purification of special pharmaceuticals or highly valuable proteins from complex mixtures such as antibodies, proteins from human serum, growth factors, etc.…”

Accelerating Biologics Manufacturing by Modeling: Process Integration of Precipitation in mAb Downstream Processing

“…Further, yield and purity must be included as a function of ionic strength, pH value, PEG content, and dissolution ratio. Thus, a development and validation concept was presented, which has already been successfully implemented for model building of valid physico-chemical models for other unit operations [49,55,56,66,72]. Due to the fact that the model is based on physical principals and laws, less experimental effort for parameter determination is necessary to transfer the model to novel material systems.…”

“…Due to the fact that the use of models is still sparse because of validation, Sixt et al established a workflow that ensures the development of valid physico-chemical models [49]. This has already been described in various papers and the execution was shown using the example of liquid-liquid [55] and solid-liquid extraction [49], chromatography [56], and cultivation [57].…”

Distinct and Quantitative Validation Method for Predictive Process Modelling in Preparative Chromatography of Synthetic and Bio-Based Feed Mixtures Following a Quality-by-Design (QbD) Approach

“…For more details on this exact approach, please see also [31,85]. For a similar approach for membrane chromatography see [86].…”

“…Since speed is more important than level of detail in this case, the lumped pore diffusion model is used. Again, this was used for previous work, no further actions are needed in this step [30,31,86].…”