Advances in bioreactor control for production of biotherapeutic products.

Advanced control strategies are well established in chemical, pharmaceutical, and food processing industries. Over the past decade, the application of these strategies is being explored for control of bioreactors for manufacturing of biotherapeutics. Most of the industrial bioreactor control strategies apply classical control techniques, with the control system designed for the facility at hand. However, with the recent progress in sensors, machinery, and industrial internet of things, and advancements in deeper understanding of the biological processes, coupled with the requirement of flexible production, the need to develop a robust and advanced process control system that can ease process intensification has emerged. This has further fuelled the development of advanced monitoring approaches, modeling techniques, process analytical technologies, and soft sensors. It is seen that proper application of these concepts can significantly improve bioreactor process performance, productivity, and reproducibility. This review is on the recent advancements in bioreactor control and its related aspects along with the associated challenges. This study also offers an insight into the future prospects for development of control strategies that can be designed for industrial-scale production of biotherapeutic products.

Comparison of multi-column chromatography configurations through model-based optimization.

Integrated continuous bioprocessing has been identified as the next important phase of evolution in biopharmaceutical manufacturing. Multiple platform technologies to enable continuous processing are being developed. Multi-column counter-current chromatography is a step in this direction to provide increased productivity and capacity utilization to capture biomolecules like monoclonal antibodies (mAbs) present in the reactor harvest and remove impurities. Model-based optimization of two prevalent multi-column designs, 3-column and 4-column periodic counter-current chromatography (PCC) was carried out for different concentrations of mAbs in the feed, durations of cleaning-in-place and equilibration protocols. The multi-objective optimization problem comprising three performance measures, namely, product yield, productivity, and capacity utilization was solved using the Radial basis function optimization technique. The superficial velocities during load, wash, and elute operations, along with durations of distinct stages present in the multi-column operations were considered as decision variables. Optimization results without the constraint on number of wash volumes showed that 3-Column PCC performs better than 4-Column PCC. For example, at a feed concentration of 1.2 mg/mL, productivity, yield and capacity utilization, respectively, were 0.024 mg/mL.s, 0.94, and 0.94 for 3-Column PCC and 0.017 mg/mL.s, 0.87, and 0.83 for 4-column PCC. Similar trends were observed at higher feed concentrations also. However, when the constraint on number of wash volumes is included, 4-Column PCC was found to result in consistent productivity and product yield under different operating conditions but at the expense of reduced capacity utilization.

A novel spiral infinity reactor for continuous hydrothermal synthesis of nanoparticles.

Hydrothermal synthesis is an attractive route to make nanoparticles utilizing inexpensive precursors under moderate process conditions. Though it provides flexibility and robustness in controlling particle characteristics, process scale-up for continuous production is a major challenge. A novel 'infinity-' shaped spiral continuous flow reactor is proposed here, to exploit the large density difference between the precursor solution and supercritical water to provide rapid mixing, leading to uniform conditions for reaction kinetics and particle growth. Hydrothermal synthesis is simulated by coupling computational fluid dynamics with population balance modeling and appropriate reaction kinetics. Simulations indicate three distinct regimes of declining, recovering, and stable flow fields. These regimes are strongly dependent on the flow ratio between the precursor solution and supercritical water. The infinity reactor provides two distinct reaction environments: initial turns of the spiral which serve as a mixed flow reactor facilitating rapid mixing and uniform reaction, followed by a plug flow reactor stabilizing the particle growth. It produces particles with a relatively small mean diameter and a narrow size distribution in comparison to the conventional batch stirred tank reactor and the T-mixer.

Modeling drug release through stimuli responsive polymer hydrogels.

There is a rising interest in stimuli-responsive hydrogels to achieve controlled and self-regulated drug delivery. Stimuli responsive polymer hydrogels with their ability to swell/de-swell under varying pH conditions present themselves as a potential candidate for controlled drug delivery. It is important to develop a mechanistic understanding of the underlying phenomena that will help suggest ways to control the drug release from a polymer hydrogel. We present a mathematical model that couples Nernst-Planck, Poisson and force balance equations to incorporate diffusion of ionic species and drug along with deformation of hydrogel under osmotic pressure. The model can be used to simulate swelling behaviour of the hydrogel along with the kinetics of drug release. It has been validated with published experimental data for swelling of polyhydroxyl methacrylate-co-methacrylic acid (pHEMA-co-MA) gels and release kinetics of Phenylpropanolamine from these gels. Effect of formulation parameters such as polymer concentration and cross-linker concentration has also been evaluated. The model can be used to reduce the number of exploratory experiments required during design of a drug delivery system.

Mathematical modeling of polymer-induced flocculation by charge neutralization.

A detailed mathematical model for flocculation of colloidal suspensions in presence of salts and polymers is described and validated. In former case, the classical DLVO theory, which accounts for relevant variables such as pH and salt concentration, is incorporated into a geometrically sectioned discrete population balance model. For processes involving polymers, flocculation via simple charge neutralization is modeled using a modified DLVO theory in which the effect of adsorbed polymer layers on van der Waals attraction is included. The fractal dimension of aggregates is obtained by dynamic scaling of experimental data for time evolution of mean aggregate size. The particle surface potential is assumed to be approximately equal to the zeta potential. The model predictions are in close agreement with experimental results for flocculation of colloidal hematite suspensions in the presence of KCl and polyacrylic acid at different concentrations. In particular, given values of model parameters, e.g., Hamaker constant, fractal dimension, surface potential, and thickness of adsorbed polymer layer, the model can realistically describe the kinetics of flocculation by a simple charge neutralization mechanism and track the evolution of floc size distribution. Representative examples of sensitivity of the flocculation model to perturbations in surface potential and fractal dimension and to modification in the DLVO theory for polymer-coated particles are included.