60. Paul K, Böttinger K, Mitic BM, Scherfler G, Posch C, Behrens D, Huber CG, Herwig C (2020)
Development, characterization, and application of a 2-compartment system to investigate the
impact of pH inhomogeneities in large-scale CHO-based processes. Eng Life Sci 20:368–378
61. Paul K, Hartmann T, Posch C, Behrens D, Herwig C (2020) Investigation of cell line specific
responses to pH inhomogeneity and consequences for process design. Eng Life Sci
20:412–421
62. Buchholz J, Graf M, Freund A, Busche T, Kalinowski J, Blombach B, Takors R (2014) CO
2/HCO 3À perturbations of simulated large scale gradients in a scale-down device cause fast
transcriptional responses in Corynebacterium glutamicum. Appl Microbiol Biotechnol
98:8563–8572
63. Spadiut O, Rittmann S, Dietzsch C, Herwig C (2013) Dynamic process conditions in
bioprocess development. Eng Life Sci 13:88–101
64. Limberg MH, Joachim M, Klein B, Wiechert W, Oldiges M (2017) pH fluctuations imperil the
robustness of C. glutamicum to short term oxygen limitation. J Biotechnol 259:248–260
65. Xu S, Jiang R, Mueller R, Hoesli N, Kretz T, Bowers J, Chen H (2018) Probing lactate
metabolism variations in large-scale bioreactors. Biotechnol Prog 34:756–766
66. Brunner M, Doppler P, Klein T, Herwig C, Fricke J (2018) Elevated pCO2 affects the lactate
metabolic shift in CHO cell culture processes. Eng Life Sci 18:204–214
67. Delvigne F, Noorman H (2017) Scale-up/scale-down of microbial bioprocesses: a modern
light on an old issue. Microb Biotechnol 10:685–687
68. Cortés JT, Flores N, Bolívar F, Lara AR, Ramírez OT (2016) Physiological effects of pH
gradients on Escherichia coli during plasmid DNA production. Biotechnol Bioeng
113:598–611
69. Junne S, Klingner A, Kabisch J, Schweder T, Neubauer P (2011) A two-compartment
bioreactor system made of commercial parts for bioprocess scale-down studies: impact of
oscillations on Bacillus subtilis fed-batch cultivations. Biotechnol J 6:1009–1017
70. Käß F, Hariskos I, Michel A, Brandt HJ, Spann R, Junne S, Wiechert W, Neubauer P, Oldiges
M (2014) Assessment of robustness against dissolved oxygen/substrate oscillations for
C. glutamicum DM1933 in two-compartment bioreactor. Bioprocess Biosyst Eng
37:1151–1162
71. Schilling BM, Pfefferle W, Bachmann B, Leuchtenberger W, Deckwer W-DD (1999) A
special reactor design for investigations of mixing time effects in a scaled-down industrial
L-lysine fed-batch fermentation process. Biotechnol Bioeng 64:599–606
72. Delvigne F, Boxus M, Ingels S, Thonart P (2009) Bioreactor mixing efficiency modulates the
activity of a prpoS::GFP reporter gene in E. coli. Microb Cell Fact 8:15
73. Junne S, Neubauer P (2018) How scalable and suitable are single-use bioreactors? Curr Opin
Biotechnol 53:240–247
74. Löffler M, Simen JD, Jäger G, Schäferhoff K, Freund A, Takors R (2016) Engineering E. coli
for large-scale production – strategies considering ATP expenses and transcriptional
responses. Metab Eng 38:73–85
75. Delvigne F, Baert J, Sassi H, Fickers P, Grünberger A, Dusny C (2017) Taking control over
microbial populations: current approaches for exploiting biological noise in bioprocesses.
Biotechnol J 12:1600549
76. Lemoine A, Delvigne F, Bockisch A, Neubauer P, Junne S (2017) Tools for the determination
of population heterogeneity caused by inhomogeneous cultivation conditions. J Biotechnol
251:84–93
77. Avery SV (2006) Microbial cell individuality and the underlying sources of heterogeneity. Nat
Rev Microbiol 4:577–587
78. Binder D, Drepper T, Jaeger KE, Delvigne F, Wiechert W, Kohlheyer D, Grünberger A (2017)
Homogenizing bacterial cell factories: analysis and engineering of phenotypic heterogeneity.
Metab Eng 42:145–156
26
P. Neubauer et al.
Development, characterization, and application of a 2-compartment system to investigate the
impact of pH inhomogeneities in large-scale CHO-based processes. Eng Life Sci 20:368–378
61. Paul K, Hartmann T, Posch C, Behrens D, Herwig C (2020) Investigation of cell line specific
responses to pH inhomogeneity and consequences for process design. Eng Life Sci
20:412–421
62. Buchholz J, Graf M, Freund A, Busche T, Kalinowski J, Blombach B, Takors R (2014) CO
2/HCO 3À perturbations of simulated large scale gradients in a scale-down device cause fast
transcriptional responses in Corynebacterium glutamicum. Appl Microbiol Biotechnol
98:8563–8572
63. Spadiut O, Rittmann S, Dietzsch C, Herwig C (2013) Dynamic process conditions in
bioprocess development. Eng Life Sci 13:88–101
64. Limberg MH, Joachim M, Klein B, Wiechert W, Oldiges M (2017) pH fluctuations imperil the
robustness of C. glutamicum to short term oxygen limitation. J Biotechnol 259:248–260
65. Xu S, Jiang R, Mueller R, Hoesli N, Kretz T, Bowers J, Chen H (2018) Probing lactate
metabolism variations in large-scale bioreactors. Biotechnol Prog 34:756–766
66. Brunner M, Doppler P, Klein T, Herwig C, Fricke J (2018) Elevated pCO2 affects the lactate
metabolic shift in CHO cell culture processes. Eng Life Sci 18:204–214
67. Delvigne F, Noorman H (2017) Scale-up/scale-down of microbial bioprocesses: a modern
light on an old issue. Microb Biotechnol 10:685–687
68. Cortés JT, Flores N, Bolívar F, Lara AR, Ramírez OT (2016) Physiological effects of pH
gradients on Escherichia coli during plasmid DNA production. Biotechnol Bioeng
113:598–611
69. Junne S, Klingner A, Kabisch J, Schweder T, Neubauer P (2011) A two-compartment
bioreactor system made of commercial parts for bioprocess scale-down studies: impact of
oscillations on Bacillus subtilis fed-batch cultivations. Biotechnol J 6:1009–1017
70. Käß F, Hariskos I, Michel A, Brandt HJ, Spann R, Junne S, Wiechert W, Neubauer P, Oldiges
M (2014) Assessment of robustness against dissolved oxygen/substrate oscillations for
C. glutamicum DM1933 in two-compartment bioreactor. Bioprocess Biosyst Eng
37:1151–1162
71. Schilling BM, Pfefferle W, Bachmann B, Leuchtenberger W, Deckwer W-DD (1999) A
special reactor design for investigations of mixing time effects in a scaled-down industrial
L-lysine fed-batch fermentation process. Biotechnol Bioeng 64:599–606
72. Delvigne F, Boxus M, Ingels S, Thonart P (2009) Bioreactor mixing efficiency modulates the
activity of a prpoS::GFP reporter gene in E. coli. Microb Cell Fact 8:15
73. Junne S, Neubauer P (2018) How scalable and suitable are single-use bioreactors? Curr Opin
Biotechnol 53:240–247
74. Löffler M, Simen JD, Jäger G, Schäferhoff K, Freund A, Takors R (2016) Engineering E. coli
for large-scale production – strategies considering ATP expenses and transcriptional
responses. Metab Eng 38:73–85
75. Delvigne F, Baert J, Sassi H, Fickers P, Grünberger A, Dusny C (2017) Taking control over
microbial populations: current approaches for exploiting biological noise in bioprocesses.
Biotechnol J 12:1600549
76. Lemoine A, Delvigne F, Bockisch A, Neubauer P, Junne S (2017) Tools for the determination
of population heterogeneity caused by inhomogeneous cultivation conditions. J Biotechnol
251:84–93
77. Avery SV (2006) Microbial cell individuality and the underlying sources of heterogeneity. Nat
Rev Microbiol 4:577–587
78. Binder D, Drepper T, Jaeger KE, Delvigne F, Wiechert W, Kohlheyer D, Grünberger A (2017)
Homogenizing bacterial cell factories: analysis and engineering of phenotypic heterogeneity.
Metab Eng 42:145–156
26
P. Neubauer et al.