(476a) Novel Stirred High-Throughput Mini-Bioreactors for Bioprocess Development: Evaluation of Scale-Down From a Typical Bench-Scale Bioreactor

High-throughput
bioreactors could offer an economical alternative to bench-scale systems for
Bioprocess development. They could also bridge the gap between un-instrumented
culture devices such as shake-flasks, and instrumented bench-scale systems thus
lowering the development time at the bench-scale. Bench-scale bioreactors that
are the mainstay in cell culture process development are widely accepted as
scale-down models of large-scale impeller driven bioreactors. The novel
high-throughput mini-bioreactors (HTBRs) not only have the advantage of
non-invasive, disposable optical sensing and control for %DO and pH, but also
have overhead stirring that sets them apart from the existing high-throughput
systems that mainly rely on magnetic stirring or shaking. However, the new HTBR
system needs to be validated as a scale-down model of the existing bench-scale
bioreactors to be certain that HTBR data is transferable to other bioreactor
scales. Generally, physical parameters such as k_La, mixing time, P/V are used for scaling.  However, it is recognized that
engineering challenges exist to obtain complete comparability between the two
scales, as depicted by cell growth and product quality which are the true
measures of scalability. This scale-down study aims to study the effect of HTBR
and conventional reactor design as well as environmental parameters on cell
culture process scale-down, including a comparison at the gene level using DNA
microarrays. This study is also a first demonstration of mammalian cell culture
in new controlled mini-bioreactors. 
To achieve a 150-fold scale-down from bench-scale to the HTBR, oxygen
transfer rate (OTR) was matched. 
However, complete cell growth and product comparability was not achieved.
An initial growth lag as well as lower end product titer was observed. These
were surmised to be attributable to oxidative stress and free-radical damage
conditions in the HTBRs; and preliminary DNA microarray results corroborated
this. Further scale-down evaluation was done by comparing the mixing times
between the mini-bioreactor and bench-scale, using the paddle and pitched blade
impeller configurations. Based on our findings, if relevant modifications can be
made to the HTBRs, scalability can be achieved pending further scale-down
studies.