Bioprocess scale‐up: quest for the parameters to be used as criterion to move from microreactors to lab‐scale

Abstract

Advances in high-throughput process development and optimization involve the rational use of miniaturized stirred bioreactors, instrumented shaken flasks and microtiter plates. As expected, each one provides different levels of control and monitoring, requiring a compromise between data quantity and quality. Despite recent advances, traditional shaken flasks with nominal volumes below 250 mL and microtiter plates are still widely used to assemble wide arrays of biotransformation/bioconversion data, because of their simplicity and low cost. These tools are key assets for faster process development and optimization, provided data are representative. Nonetheless, the design, development and implementation of bioprocesses can present variations depending on intrinsic characteristics of the overall process. For each particular process, an adequate and comprehensive approach has to be established, which includes pinpointing key issues required to ensure proper scaleup. Recently, focus has been given to engineering characterization of systems in terms of mass transfer and hydrodynamics (through gaining insight into parameters such as k L a and P/V at shaken and microreactor scale), due to the widespread use of small-scale reactors in the early developmental stages of bioconversion/biotransfomation processes. Within this review, engineering parameters used as criteria for scaling-up fermentation/bioconversion processes are discussed. Particular focus is on the feasibility of the application of such parameters to small-scale devices and concomitant use for scale-up.

The physical characterisation of a microscale parallel bioreactor platform with an industrial CHO cell line expressing an IgG4

“…There has recently been a trend for the development of microscale bioreactor systems which are mechanically and functionally similar to large scale bioreactors [3,4,11]. Ideally these should maintain, the key characteristics of a larger bioreactor such as mechanical agitation, sparged gas entry into the impeller region and allow for the monitoring and control of dO 2 , pH and pCO 2 .…”

Evaluation of scale-up parameters of bioethanol production from Escherichia coli KO11

“…However if the fermentation broth is viscous, constant mixing time is used through scaling. Mixing time is defined as the time required for the reactor composition to achieve a specified level of homogeneity following addition of a tracer pulse at a single point in the vessel [6]. Mixing time contains some information on flow and mixing within the reactor and can be useful for the scale-up of growth-regulated products.…”

Anchoring high-throughput screening methods to scale-up bioproduction of siderophores

“…4). This criterion is regularly used for scaling-up bioprocess as shown in recent reviews and references therein [11,34,35] and was chosen since the bioprocess tested was based on aerobic growing bacterial cells in a simple aqueous system. The k L a was set at 0.044 s −1 which corresponds to a shaking frequency of 200 rpm in the MTP system and to 475 rpm in the STR.…”

“…Although all these platforms are clearly fit for high-throughput applications, limitations can be pointed out within them, such as: (i) limited culture volumes, (ii) medium evaporation and (iii) difficult process control. Furthermore, engineering characterization of these miniaturized devices is still far from being fully established [11].…”