title: 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.
authors.affiliation: Bioprocess R&D, Merck Research Laboratories, Merck & Co., Inc., 126 Lincoln Avenue, Rahway, New Jersey 07065, USA. david_pollard@merck.com
authors.forename: D J
authors.initials: DJ
authors.lastname: Pollard
authors.forename: T F
authors.initials: TF
authors.lastname: Kirschner
authors.forename: G R
authors.initials: GR
authors.lastname: Hunt
authors.forename: I-T
authors.initials: IT
authors.lastname: Tong
authors.forename: R
authors.initials: R
authors.lastname: Stieber
authors.forename: P M
authors.initials: PM
authors.lastname: Salmon
mesh_terms: D001203:Ascomycota / Q000378:metabolism*; D019149:Bioreactors; D054714:Echinocandins; D005285:Fermentation; D015394:Molecular Structure; D010100:Oxygen / Q000378:metabolism; D010456:Peptides, Cyclic / Q000096:biosynthesis*; D014783:Viscosity
chemical_list: D054714:Echinocandins; D010456:Peptides, Cyclic; C079465:pneumocandin B(0); D010100:Oxygen