Scale up of a viscous fungal fermentation: Application of scale‐up criteria with regime analysis and operating boundary conditions

Abstract

The scale up of the novel, pharmaceutically important pneumocandin (B(0)), from the filamentous fungus Glarea lozoyensis was successfully completed from pilot scale (0.07, 0.8, and 19 m(3)) to production scale (57 m(3)). This was accomplished, despite dissimilar reactor geometry, employing a combination of scale-up criteria, process sensitivity studies, and regime analysis using characteristic time constants for both oxygen mass transfer and bulk mixing. Dissolved oxygen tension, separated from the influence of agitation by gas blending at the 0.07 m(3)-scale, had a marked influence on the concentrations of pneumocandin analogs with different levels of hydroxylation, and these concentrations were used as an indicator of bulk mixing upon scale up. The profound impact of dissolved oxygen tension (DOT) (low and high levels) on analog formation dictated the use of constant DOT, at 80% air saturation, as a scale-up criterion. As a result k(L)a, Oxygen uptake rate (OUR) and hence the OTR were held constant, which were effectively conserved across the scales, while the use of other criterion such as P(g)/V(L), or mixing time were less effective. Production scale (57 m(3)) mixing times were found to be faster than those at 19 m(3) due to a difference in liquid height/tank diameter ratio (H(L)/D(T)). Regime analysis at 19 and 57 m(3) for bulk mixing (t(c)) and oxygen transfer (1/k(L)a) showed that oxygen transfer was the rate-limiting step for this highly shear thinning fermentation, providing additional support for the choice of scale-up criterion.

Production of the biocontrol agent Pantoea agglomerans PBC-1 in a stirred tank reactor by batch and fed-batch cultures

“…These parameters influence the volumetric mass transfer coefficient, K L a, an experimental factor extremely important in aerobic cultures with severe oxygen demands. With the intention of understanding the impact of mass transfer and mixing in the performance of stirred bioreactors, different reports have appeared in the literature (Puthli et al 2005;Cascaval et al 2006;Hadjiev et al 2006;Puthli et al 2006;Raposo and Lima-Costa 2006;Fujasová et al 2007;Kao et al 2007;Littlejohns and Daugulis 2007;Pollard et al 2007;Potumarthi et al 2007). …”

Scale‐up analysis for a CHO cell culture process in large‐scale bioreactors

“…This system was rarely reported in large-scale bioreactors in literature due to the limitation of cost and weight of marine impellers. Instead, multiple pitched blade impellers with good pumping characteristics were used in large-scale bioreactors when a good vertical mixing was required; for instance, a 19,000-L fermentor for viscous fungal fermentation (Pollard et al, 2007) and a 2,500-L bioreactor for animal cell culture (Yang et al, 2007). Marine impeller was occasionally used in microbial fermentation such as Kluyveromyces marxianus, of which much high agitation rate (450 rpm) was used (Yépez SilvaSantisteban and Maugeri Filho, 2005).…”

Bioeconomy Initiative at MBI International

“…Scaling with respect to agitator tip speed was employed as fungal fermentation performance has been shown to be impacted by changes in production tank shear forces (Chen et al, 2007;Pollard, et al, 2007).…”