Assessment of AMBR<sup>TM</sup> as a model for high-throughput cell culture process development strategy

Abstract

The development and delivery of high quality therapeutic products necessitates the need for highthroughput (HTP) process development tools. Traditionally, these works requires a combination of shake flask and small-scale stirred tank bioreactor (STR) which are labor and resource intensive and time-consuming. Here we demonstrate a strategy for rapid and robust cell culture process development by evaluating and implementing the use of a new HTP disposable micro bioreactor (MBR) called AMBR TM system (Advanced Microscale Bioreactor) that has the capabilities for automated sampling, feed addition, pH, dissolved oxygen (DO), gassing and agitation controls. In these studies the performance of two monoclonal antibody (MAb) producing cell lines (MAb1 and MAb2) was evaluated both in the AMBR system and 3-L STR. We demonstrated that cell culture performance (growth and viability, production titer and product quality) were similar in both vessel systems. Furthermore, process control and feed optimization were demonstrated in an additional cell line (MAb3) in the disposable MBR and its performance confirmed at STR scale. The results indicate that the AMBR system can be used to streamline the process development effort and facilitate a rapid and robust cell culture process development effort for MAb programs in a HTP manner.

Cell line development for biomanufacturing processes: recent advances and an outlook

“…To simulate the manufacturing processes in stirred tanks, commercial miniscale multi-tube/flask systems or miniaturized cell culture systems with various mechanisms of mixing are available to increase the capacity of process performance evaluation (Girard et al 2001;De Jesus et al 2004). Some systems allow for control of pH and periodic nutrient feeding (Frison et al 2002;Chen et al 2009;Legmann et al 2009;Hsu et al 2012;Moses et al 2012). To alleviate the need of a sensor and a pH control mechanism, a hydrogel based platform of slow release of neutralizing agent in situ for pH maintenance has been used (Pradhan et al 2012).…”

Pushing the limits of high-throughput chromatography process development: current state and future directions

“…The recent development of single use disposable bioreactors from TAP Biosystems that can operate either 24 bioreactors in parallel at 250 ml volumes or 48 bioreactors at 15 ml has greatly increased the throughput and accuracy with which scale-down bioreactors can be run [21][22][23][24]. Resin slurry plates or micropipette tips that can be run in a 96-well format could prove to be crucial techniques for providing rapid quality assessments of material generated in these disposable bioreactors.…”

Are automated disposable small-scale reactors set to dominate the future of pharmaceutical bioprocess development?

“…This eliminates the need for the laborious and mundane shake flask passaging. Final clone selection and media screening can now be completed in a high throughput manner using arrays of 24 disposable reactors (15 ml) with liquid handling capability [6]. These successful efficiency gains for cell line development have focused attention to improving the speed of upstream process development by the integration of disposable reactors with automation.…”