Application of high‐throughput mini‐bioreactor system for systematic scale‐down modeling, process characterization, and control strategy development

Abstract

High-throughput systems and processes have typically been targeted for process development and optimization in the bioprocessing industry. For process characterization, bench scale bioreactors have been the system of choice. Due to the need for performing different process conditions for multiple process parameters, the process characterization studies typically span several months and are considered time and resource intensive. In this study, we have shown the application of a high-throughput mini-bioreactor system viz. the Advanced Microscale Bioreactor (ambr15(TM) ), to perform process characterization in less than a month and develop an input control strategy. As a pre-requisite to process characterization, a scale-down model was first developed in the ambr system (15 mL) using statistical multivariate analysis techniques that showed comparability with both manufacturing scale (15,000 L) and bench scale (5 L). Volumetric sparge rates were matched between ambr and manufacturing scale, and the ambr process matched the pCO2 profiles as well as several other process and product quality parameters. The scale-down model was used to perform the process characterization DoE study and product quality results were generated. Upon comparison with DoE data from the bench scale bioreactors, similar effects of process parameters on process yield and product quality were identified between the two systems. We used the ambr data for setting action limits for the critical controlled parameters (CCPs), which were comparable to those from bench scale bioreactor data. In other words, the current work shows that the ambr15(TM) system is capable of replacing the bench scale bioreactor system for routine process development and process characterization.

A model‐based framework for parallel scale‐down fed‐batch cultivations in mini‐bioreactors for accelerated phenotyping

“…A few studies that consider the operating conditions of larger‐scale bioreactors in high‐throughput screening systems are reported in the literature. For instance, Janakiraman, Kwiatkowski, Kshirsagar, Ryll, and Huang () matched the volumetric aeration rates (vvm) between parallel ambr15 TM cultivations of CHO cells and a 15,000‐L production‐scale bioreactor, whereas Velez‐Suberbie et al () used the power per unit volume (P/V) as a scale‐down criterion to compare ambr15f cultivations of E. coli with 20‐L bioreactor cultivations. Other works involving high‐throughput cultivations in complex integrated facilities have also been reported (see recent review in Hemmerich, Noack, Wiechert, & Oldiges, ).…”

Cell Culture Processes for Biopharmaceutical Manufacturing

“…Concern over the lack of control of process parameters during screening led to significant interest in the use of microbioreactors to enable assessment of clones under controlled pH and DO conditions for better screening outcomes 60,61 . Simcell was among the first microbioreactor to be commercially available with culture volumes of less than a millilitre 62 .…”

A novel scale‐down mimic of perfusion cell culture using sedimentation in an automated microbioreactor (SAM)

“…The ambr15 system allows reasonable throughput (24–48 parallel vessels) and low liquid handling volumes, high automatization, and little need for manual user interventions. It has been used to perform DoE (Design of Experiments) studies in fed‐batch mode, to compare a fed‐batch CHO process performed in an ambr system to bench‐top bioreactor and shake flasks and to successfully predict the performance of 3, 15, and 200 L as well as 15,000 L manufacturing scale cultures. These studies show that a good alignment between the ambr system and larger scale bioreactors can be achieved in a fed batch mode with respect to cell growth, productivity, and product quality even though some physical characteristics of the ambr system differ from production‐scale equipment .…”