Automated disposable small scale reactor for high throughput bioprocess development: a proof of concept study.

The acceleration of bioprocess development for biologics and vaccines can be enabled by automated high throughput technologies. This will alleviate the significant resource burden from the multi-factorial statistical experimentation required for controlling product quality attributes of complex biologics. Recent technology advances have improved clone evaluation and screening, but have struggled to combine the scale down criteria required for both high cell density cell culture and microbial processes, with sufficient automation and disposable technologies to accelerate process development. This article describes the proof of concept evaluations of an automated disposable small scale reactor for high throughput upstream process development. Characterization studies established the small scale stirred tank disposable 250 mL reactor as similar to those of lab and pilot scale. The reactor generated equivalent process performance for industrial biologics processes for therapeutic protein and monoclonal antibody production using CHO cell culture, Pichia pastoris and E. coli. This included similar growth, cell viability, product titer, and product quality. The technology was shown to be robust across multiple runs and met the requirements for the ability to run high cell density processes (>400 g/L wet cell weight) with exponential feeds and sophisticated event triggered processes. Combining this reactor into an automated array of reactors will ultimately be part of a high throughput process development strategy. This will combine upstream, small scale purification with rapid analytics that will dramatically shorten timelines and costs of developing biological processes.

A review of advanced small-scale parallel bioreactor technology for accelerated process development: current state and future need.

The pharmaceutical and biotech industries face continued pressure to reduce development costs and accelerate process development. This challenge occurs alongside the need for increased upstream experimentation to support quality by design initiatives and the pursuit of predictive models from systems biology. A small scale system enabling multiple reactions in parallel (n ≥ 20), with automated sampling and integrated to purification, would provide significant improvement (four to fivefold) to development timelines. State of the art attempts to pursue high throughput process development include shake flasks, microfluidic reactors, microtiter plates and small-scale stirred reactors. The limitations of these systems are compared to desired criteria to mimic large scale commercial processes. The comparison shows that significant technological improvement is still required to provide automated solutions that can speed upstream process development.

Single limb performance following contralateral bimanual limb training.

Recent studies on intermanual transfer of reaching movements suggest that this transfer is conducted over an "extrinsic" coordinate system. We hypothesize that training reaching movements in a force field with both hands at the same time, in the same position (bimanual grip) will be more beneficial in promoting transfer of the learned skill to the dominant hand than training the unimpaired limb on the same movements in the same force field since the representation of the movement should be invariant of the limb. However, unlike intermanual transfer, bimanual transfer has the potential to involve infinite number of actuator combinations, or joint configurations, interfering with consistent transfer. The efficacy of this method of transfer has implications for people with hemiparesis since the less-affected arm could potentially "instruct" the more-affected arm how to move. Here, we report on an experiment that evaluates and compares the skill transfer between limbs in a reaching task: 1) intermanual transfer (from the nondominant to the dominant hand) and 2) bimanual transfer (from a bimanual grip to the dominant hand) with healthy subjects. We used two methods from which to judge the transfer: performance in the presence of the force field or by errors made during "catch trials" when the forces were unexpectedly removed as subjects changed hands (known as after effects of adaptation). We found only a small amount of transfer (20% of that seen in the practiced limb) with both types of training, and surprisingly there was no significant difference in the movement accuracy between these two training methods. Moreover, the direction of the after effects supports the assertion that the nervous system generalizes these movements in an extrinsic coordinate system. Accordingly, the limb must experience the dynamics singularly in order to develop an internal model.