title: Concentrated fed-batch cell culture increases manufacturing capacity without additional volumetric capacity.
abstract: Biomanufacturing factories of the future are transitioning from large, single-product facilities toward smaller, multi-product, flexible facilities. Flexible capacity allows companies to adapt to ever-changing pipeline and market demands. Concentrated fed-batch (CFB) cell culture enables flexible manufacturing capacity with limited volumetric capacity; it intensifies cell culture titers such that the output of a smaller facility can rival that of a larger facility. We tested this hypothesis at bench scale by developing a feeding strategy for CFB and applying it to two cell lines. CFB improved cell line A output by 105% and cell line B output by 70% compared to traditional fed-batch (TFB) processes. CFB did not greatly change cell line A product quality, but it improved cell line B charge heterogeneity, suggesting that CFB has both process and product quality benefits. We projected CFB output gains in the context of a 2000-L small-scale facility, but the output was lower than that of a 15,000-L large-scale TFB facility. CFB's high cell mass also complicated operations, eroded volumetric productivity, and showed our current processes require significant improvements in specific productivity in order to realize their full potential and savings in manufacturing. Thus, improving specific productivity can resolve CFB's cost, scale-up, and operability challenges.
authors.affiliation: Biogen, Inc., Cell Culture Development, 5000 Davis Drive, Research Triangle Park, NC 27709, United States. Electronic address: william.yang@biogen.com.
authors.forename: William C
authors.initials: WC
authors.lastname: Yang
authors.affiliation: Biogen, Inc., Cell Culture Development, 5000 Davis Drive, Research Triangle Park, NC 27709, United States.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Minkler
authors.affiliation: Biogen, Inc., Cell Culture Development, 14 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kshirsagar
authors.affiliation: Biogen, Inc., Cell Culture Development, 14 Cambridge Center, Cambridge, MA 02142, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ryll
authors.affiliation: Biogen, Inc., Cell Culture Development, 5000 Davis Drive, Research Triangle Park, NC 27709, United States.
authors.forename: Yao-Ming
authors.initials: YM
authors.lastname: Huang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000302:isolation & purification; D061249:Batch Cell Culture Techniques / Q000379:methods*; D018533:Biomass; D019149:Bioreactors; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D011786:Quality Control; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins
keywords: CHO cell culture; Concentrated fed-batch; Perfusion; Product quality; Productivity; Volumetric capacity