97. Morchain J, Gabelle J-C, Cockx A (2013) Coupling of biokinetic and population balance
models to account for biological heterogeneity in bioreactors. AICHE J 59:369–379
98. Pigou M, Morchain J (2015) Investigating the interactions between physical and biological
heterogeneities in bioreactors using compartment, population balance and metabolic models.
Chem Eng Sci 126:267–282
99. Lapin A, Müller D, Reuss M (2004) Dynamic behavior of microbial populations in stirred
bioreactors simulated with EulerÀLagrange methods: traveling along the lifelines of single
cells. Ind Eng Chem Res 43:4647–4656
100. Lapin A, Klann M, Reuss M (2010) Multi-scale spatio-temporal modeling: lifelines of
microorganisms in bioreactors and tracking molecules in cells. Adv Biochem Eng Biotechnol
121:23–43
101. Anane E, López DC, Neubauer P, Cruz Bournazou MN (2017) Modelling overflow metabolism in Escherichia coli by acetate cycling. Biochem Eng J 125:23–30
102. Lara AR, Taymaz-Nikerel H, Mashego MR, Van Gulik WM, Heijnen JJ, Ramirez OT, van
Winden WA, Van Gulik WM, Heijnen JJ, Van Winden WA, Ramírez OT, van Winden WA
(2009) Fast dynamic response of the fermentative metabolism of Escherichia coli to aerobic
and anaerobic glucose pulses. Biotechnol Bioeng 104:1153–1161
103. Soini J, Ukkonen K, Neubauer P (2011) Accumulation of amino acids deriving from pyruvate
in Escherichia coli W3110 during fed-batch cultivation in a two-compartment scale-down
bioreactor. Adv Biosci Biotechnol 02:336–339
104. Barz T, Sommer A, Wilms T, Neubauer P, Cruz Bournazou MN (2018) Adaptive optimal
operation of a parallel robotic liquid handling station. IFAC-PapersOnLine 51:765–770
105. Lemoine A, Martnez-Iturralde NM, Spann R, Neubauer P, Junne S (2015) Response of
Corynebacterium glutamicum exposed to oscillating cultivation conditions in a two- and a
novel three-compartment scale-down bioreactor. Biotechnol Bioeng 112:1220–1231
106. Korneli C, Bolten CJ, Godard T, Franco-Lara E, Wittmann C, Universita T (2012)
Debottlenecking recombinant protein production in Bacillus megaterium under large-scale
conditions—targeted precursor feeding designed from metabolomics. Biotechnol Bioeng
109:1538–1550
107. Janakiraman V, Kwiatkowski C, Kshirsagar R, Ryll T, Huang YM (2015) Application of highthroughput mini-bioreactor system for systematic scale-down modeling, process characterization, and control strategy development. Biotechnol Prog 31:1623–1632
108. Gábor A, Banga JR (2015) Robust and efficient parameter estimation in dynamic models of
biological systems. BMC Syst Biol 9:74
109. Rollié S, Mangold M, Sundmacher K (2012) Designing biological systems: systems engineering meets synthetic biology. Chem Eng Sci 69:1–29
110. Bareither R, Pollard D (2011) A review of advanced small-scale parallel bioreactor technology
for accelerated process development: current state and future need. Biotechnol Prog 27:2–14
111. Rameez S, Mostafa SS, Miller C, Shukla AA (2014) High-throughput miniaturized bioreactors
for cell culture process development: reproducibility, scalability, and control. Biotechnol Prog
30:718–727
112. Herwig C, Garcia-Aponte OF, Golabgir A, Rathore AS (2015) Knowledge management in the
QbD paradigm: manufacturing of biotech therapeutics. Trends Biotechnol 33:381–387
113. Rathore AS (2009) Roadmap for implementation of quality by design (QbD) for biotechnology products. Trends Biotechnol 27:546–553
114. Velez-Suberbie ML, Betts JPJ, Walker KL, Robinson C, Zoro B, Keshavarz-Moore E (2017)
High-throughput automated microbial bioreactor system used for clone selection and rapid
scale-down process optimization. Biotechnol Prog 15:1–11
115. de Lorenzo V, Schmidt M (2018) Biological standards for the knowledge-based BioEconomy:
what is at stake. New Biotechnol 40:170–180
116. Schallmey M, Frunzke J, Eggeling L, Marienhagen J (2014) Looking for the pick of the bunch:
high-throughput screening of producing microorganisms with biosensors. Curr Opin
Biotechnol 26:148–154
28
P. Neubauer et al.
models to account for biological heterogeneity in bioreactors. AICHE J 59:369–379
98. Pigou M, Morchain J (2015) Investigating the interactions between physical and biological
heterogeneities in bioreactors using compartment, population balance and metabolic models.
Chem Eng Sci 126:267–282
99. Lapin A, Müller D, Reuss M (2004) Dynamic behavior of microbial populations in stirred
bioreactors simulated with EulerÀLagrange methods: traveling along the lifelines of single
cells. Ind Eng Chem Res 43:4647–4656
100. Lapin A, Klann M, Reuss M (2010) Multi-scale spatio-temporal modeling: lifelines of
microorganisms in bioreactors and tracking molecules in cells. Adv Biochem Eng Biotechnol
121:23–43
101. Anane E, López DC, Neubauer P, Cruz Bournazou MN (2017) Modelling overflow metabolism in Escherichia coli by acetate cycling. Biochem Eng J 125:23–30
102. Lara AR, Taymaz-Nikerel H, Mashego MR, Van Gulik WM, Heijnen JJ, Ramirez OT, van
Winden WA, Van Gulik WM, Heijnen JJ, Van Winden WA, Ramírez OT, van Winden WA
(2009) Fast dynamic response of the fermentative metabolism of Escherichia coli to aerobic
and anaerobic glucose pulses. Biotechnol Bioeng 104:1153–1161
103. Soini J, Ukkonen K, Neubauer P (2011) Accumulation of amino acids deriving from pyruvate
in Escherichia coli W3110 during fed-batch cultivation in a two-compartment scale-down
bioreactor. Adv Biosci Biotechnol 02:336–339
104. Barz T, Sommer A, Wilms T, Neubauer P, Cruz Bournazou MN (2018) Adaptive optimal
operation of a parallel robotic liquid handling station. IFAC-PapersOnLine 51:765–770
105. Lemoine A, Martnez-Iturralde NM, Spann R, Neubauer P, Junne S (2015) Response of
Corynebacterium glutamicum exposed to oscillating cultivation conditions in a two- and a
novel three-compartment scale-down bioreactor. Biotechnol Bioeng 112:1220–1231
106. Korneli C, Bolten CJ, Godard T, Franco-Lara E, Wittmann C, Universita T (2012)
Debottlenecking recombinant protein production in Bacillus megaterium under large-scale
conditions—targeted precursor feeding designed from metabolomics. Biotechnol Bioeng
109:1538–1550
107. Janakiraman V, Kwiatkowski C, Kshirsagar R, Ryll T, Huang YM (2015) Application of highthroughput mini-bioreactor system for systematic scale-down modeling, process characterization, and control strategy development. Biotechnol Prog 31:1623–1632
108. Gábor A, Banga JR (2015) Robust and efficient parameter estimation in dynamic models of
biological systems. BMC Syst Biol 9:74
109. Rollié S, Mangold M, Sundmacher K (2012) Designing biological systems: systems engineering meets synthetic biology. Chem Eng Sci 69:1–29
110. Bareither R, Pollard D (2011) A review of advanced small-scale parallel bioreactor technology
for accelerated process development: current state and future need. Biotechnol Prog 27:2–14
111. Rameez S, Mostafa SS, Miller C, Shukla AA (2014) High-throughput miniaturized bioreactors
for cell culture process development: reproducibility, scalability, and control. Biotechnol Prog
30:718–727
112. Herwig C, Garcia-Aponte OF, Golabgir A, Rathore AS (2015) Knowledge management in the
QbD paradigm: manufacturing of biotech therapeutics. Trends Biotechnol 33:381–387
113. Rathore AS (2009) Roadmap for implementation of quality by design (QbD) for biotechnology products. Trends Biotechnol 27:546–553
114. Velez-Suberbie ML, Betts JPJ, Walker KL, Robinson C, Zoro B, Keshavarz-Moore E (2017)
High-throughput automated microbial bioreactor system used for clone selection and rapid
scale-down process optimization. Biotechnol Prog 15:1–11
115. de Lorenzo V, Schmidt M (2018) Biological standards for the knowledge-based BioEconomy:
what is at stake. New Biotechnol 40:170–180
116. Schallmey M, Frunzke J, Eggeling L, Marienhagen J (2014) Looking for the pick of the bunch:
high-throughput screening of producing microorganisms with biosensors. Curr Opin
Biotechnol 26:148–154
28
P. Neubauer et al.