Consistent development of bioprocesses from microliter cultures to the industrial scale

Bioprocess development today is slow and expensive compared to chemical process development. A drastic paradigm shift is necessary and possible by the consistent application of engineering strategies that are typically used in the process development phase already in the early product development. Aside from providing a consistent pathway, strategies such as statistical‐based design of experiments, fed‐batch, minibioreactors, new on‐line sensors, process modeling, and control tools in combination with automation of manual steps offer a higher success rate and the opportunity to find the optimum parameters and operation point. This also directly benefits the early phases of biomolecular screening and initial production of small amounts of the target molecule. The paper reviews the bioprocess developmental phases from a business perspective and the available systems and technologies.     

Exploring the linkage between cell culture process parameters and downstream processing utilizing a plackett‐burman design for a model monoclonal antibody

Linkage of upstream cell culture with downstream processing and purification is an aspect of Quality by Design crucial for efficient and consistent production of high quality biopharmaceutical proteins. In a previous Plackett‐Burman screening study of parallel bioreactor cultures we evaluated main effects of 11 process variables, such as agitation, sparge rate, feeding regimens, dissolved oxygen set point, inoculation density, supplement addition, temperature, and pH shifts. In this follow‐up study, we observed linkages between cell culture process parameters and downstream capture chromatography performance and subsequent antibody attributes. In depth analysis of the capture chromatography purification of harvested cell culture fluid yielded significant effects of upstream process parameters on host cell protein abundance and behavior. A variety of methods were used to characterize the antibody both after purification and buffer formulation. This analysis provided insight in to the significant impacts of upstream process parameters on aggregate formation, impurities, and protein structure. This report highlights the utility of linkage studies in identifying how changes in upstream parameters can impact downstream critical quality attributes. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:163–170, 2017     

Design of Viral Dynamic Studies for Efficiently Assessing Potency of Anti‐HIV Therapies in AIDS Clinical Trials

The study of HIV dynamics is one of the most important developments in recent AIDS research. It greatly improves our understanding of the pathogenesis of HIV infection. Recently it has been proposed to use HIV dynamics to evaluate the efficacy of antiviral treatments. Currently a large number of AIDS clinical trials on HIV dynamics are in development worldwide. However, many design issues that arise from HIV dynamic studies have not been addressed. In this paper, we study these problems using intensive Monte Carlo simulations and analytic methods. We evaluate a finite number of feasible candidate designs, which are currently used and proposed in AIDS clinical trials from different perspectives. We compare the viral dynamic marker and classical viral load change markers in terms of power for identifying treatment difference, asymptotic relative efficiency, and sensitivity. Finally we propose some useful suggestions for practitioners based on our results.