Processes 2018, 6,82
Author Contributions: Under supervision of M.I., P.F. was responsible for development of research methodology
and modeling framework, model computation and analysis of the results.
Funding: This research received no external funding.
Acknowledgments: Financial support from the School of Engineering at Rutgers University is
gratefully acknowledged.
Conflicts of Interest: The authors declare no conflicts of interest.
References
1.
Moorkens, E.; Meuwissen, N.; Huys, I.; Declerck, P.; Vulto, A.G.; Simoens, S. The Market of Biopharmaceutical
Medicines: A Snapshot of a Diverse Industrial Landscape. Front. Pharmacol. 2017, 8, 314. [CrossRef][PubMed]
2.
Davidson, A.; Farid, S.S. Innovation in Biopharmaceutical Manufacture. BioProcess Int. 2014, 12, 12–19.
3.
Rader, R.A.; Langer, E.S. 30 years of upstream productivity improvements. BioProcess Int. 2015, 13, 10–15.
4.
Farid, S.S. Process economics of industrial monoclonal antibody manufacture. J. Chromatogr. B-Anal. Technol.
Biomed. Life Sci. 2007, 848, 8–18. [CrossRef][PubMed]
5.
Terry, C.; Lesser, N. Balancing the R&D Equation; Deloitte Center for Health Solutions: London, UK, 2017.
6.
Gyurjyan, G.; Thaker, S.; Westhues, K.; Zwaanstra, C. Rethinking Pharma Productivity; McKinsey & Company:
New York, NY, USA, 2017.
7.
Varma, V.A.; Reklaitis, G.V.; Blau, G.E.; Pekny, J.F. Enterprise-wide modeling & optimization—An overview
of emerging research challenges and opportunities. Comput. Chem. Eng. 2007, 31, 692–711.
8.
Grossmann, I.E. Advances in mathematical programming models for enterprise-wide optimization.
Comput. Chem. Eng. 2012, 47, 2–18. [CrossRef]
9.
Lara, A.R.; Galindo, E.; Ramírez, O.T.; Palomares, L.A. Living with heterogeneities in bioreactors.
Mol. Biotechnol. 2006, 34, 355–381. [CrossRef]
10. Xie, L.; Zhou, W.; Robinson, D. Protein production by large-scale mammalian cell culture. New Compr.
Biochem. 2003, 38, 605–623.
11. Spier, R.E. Encyclopedia of Cell Technology. In Wiley Biotechnology Encyclopedias; Wiley-Interscience:
Hoboken, NJ, USA, 2000.
12. Panda, T. Bioreactors: Analysis and Design; Tata McGraw-Hill Education Private Limited: New York, NY,
USA, 2011.
13. Ho, C.S.; Wang, D.I.C. Animal Cell Bioreactors; Biotechnology Series; Davies, J.E., Ed.; Butterworth-Heinemann:
Oxford, UK, 1991.
14. Mandenius, C.-F.; Titchener-Hooker, N.J. Measurement, Monitoring, Modelling and Control of Bioprocesses.
In Advances in Biochemical Engineering/Biotechnology; Springer: Berlin, Germany, 2013.
15. Meyer, H.-P.; Schmidhalter, D. Industrial Scale Suspension Culture of Living Cells; Wiley: Hoboken, NJ, USA,
2014.
16. Shuler, M.L.; Kargi, F. Bioprocess Engineering, 2nd ed.; Prentice Hall: Upper Saddle River, NJ, USA, 2002.
17. Prokop, A. Implications of Cell Biology in Animal Cell Biotechnology. In Animal Cell Bioreactors; Ho, C.S.,
Wang, D.I.C., Eds.; Butterworth-Heinemann: Oxford, UK, 1991.
18. Pigou, M.; Morchain, J. Investigating the interactions between physical and biological heterogeneities in
bioreactors using compartment, population balance and metabolic models. Chem. Eng. Sci. 2015, 126,
267–282. [CrossRef]
19. Meshram, M.; Naderi, S.; McConkey, B.; Ingalls, B.; Scharer, J.; Budman, H. Modeling the coupled
extracellular and intracellular environments in mammalian cell culture. Metab. Eng. 2013, 19, 57–68.
[CrossRef][PubMed]
20. Sidoli, F.R.; Asprey, S.P.; Mantalaris, A. A Coupled Single Cell-Population-Balance Model for Mammalian
Cell Cultures. Ind. Eng. Chem. Res. 2006, 45, 5801–5811. [CrossRef]
21. Mantzaris, N.V.; Daoutidis, P. Cell population balance modeling and control in continuous bioreactors.
J. Process Control 2004, 14, 775–784. [CrossRef]
22. Mantzaris, N.V. Stochastic and deterministic simulations of heterogeneous cell population dynamics. J. Theor.
Biol. 2006, 241, 690–706. [CrossRef][PubMed]
23. Dorka, P.; Fischer, C.; Budman, H.; Scharer, J.M. Metabolic flux-based modeling of mAb production during
batch and fed-batch operations. Bioprocess Biosyst. Eng. 2009, 32, 183–196. [CrossRef][PubMed]
127
Author Contributions: Under supervision of M.I., P.F. was responsible for development of research methodology
and modeling framework, model computation and analysis of the results.
Funding: This research received no external funding.
Acknowledgments: Financial support from the School of Engineering at Rutgers University is
gratefully acknowledged.
Conflicts of Interest: The authors declare no conflicts of interest.
References
1.
Moorkens, E.; Meuwissen, N.; Huys, I.; Declerck, P.; Vulto, A.G.; Simoens, S. The Market of Biopharmaceutical
Medicines: A Snapshot of a Diverse Industrial Landscape. Front. Pharmacol. 2017, 8, 314. [CrossRef][PubMed]
2.
Davidson, A.; Farid, S.S. Innovation in Biopharmaceutical Manufacture. BioProcess Int. 2014, 12, 12–19.
3.
Rader, R.A.; Langer, E.S. 30 years of upstream productivity improvements. BioProcess Int. 2015, 13, 10–15.
4.
Farid, S.S. Process economics of industrial monoclonal antibody manufacture. J. Chromatogr. B-Anal. Technol.
Biomed. Life Sci. 2007, 848, 8–18. [CrossRef][PubMed]
5.
Terry, C.; Lesser, N. Balancing the R&D Equation; Deloitte Center for Health Solutions: London, UK, 2017.
6.
Gyurjyan, G.; Thaker, S.; Westhues, K.; Zwaanstra, C. Rethinking Pharma Productivity; McKinsey & Company:
New York, NY, USA, 2017.
7.
Varma, V.A.; Reklaitis, G.V.; Blau, G.E.; Pekny, J.F. Enterprise-wide modeling & optimization—An overview
of emerging research challenges and opportunities. Comput. Chem. Eng. 2007, 31, 692–711.
8.
Grossmann, I.E. Advances in mathematical programming models for enterprise-wide optimization.
Comput. Chem. Eng. 2012, 47, 2–18. [CrossRef]
9.
Lara, A.R.; Galindo, E.; Ramírez, O.T.; Palomares, L.A. Living with heterogeneities in bioreactors.
Mol. Biotechnol. 2006, 34, 355–381. [CrossRef]
10. Xie, L.; Zhou, W.; Robinson, D. Protein production by large-scale mammalian cell culture. New Compr.
Biochem. 2003, 38, 605–623.
11. Spier, R.E. Encyclopedia of Cell Technology. In Wiley Biotechnology Encyclopedias; Wiley-Interscience:
Hoboken, NJ, USA, 2000.
12. Panda, T. Bioreactors: Analysis and Design; Tata McGraw-Hill Education Private Limited: New York, NY,
USA, 2011.
13. Ho, C.S.; Wang, D.I.C. Animal Cell Bioreactors; Biotechnology Series; Davies, J.E., Ed.; Butterworth-Heinemann:
Oxford, UK, 1991.
14. Mandenius, C.-F.; Titchener-Hooker, N.J. Measurement, Monitoring, Modelling and Control of Bioprocesses.
In Advances in Biochemical Engineering/Biotechnology; Springer: Berlin, Germany, 2013.
15. Meyer, H.-P.; Schmidhalter, D. Industrial Scale Suspension Culture of Living Cells; Wiley: Hoboken, NJ, USA,
2014.
16. Shuler, M.L.; Kargi, F. Bioprocess Engineering, 2nd ed.; Prentice Hall: Upper Saddle River, NJ, USA, 2002.
17. Prokop, A. Implications of Cell Biology in Animal Cell Biotechnology. In Animal Cell Bioreactors; Ho, C.S.,
Wang, D.I.C., Eds.; Butterworth-Heinemann: Oxford, UK, 1991.
18. Pigou, M.; Morchain, J. Investigating the interactions between physical and biological heterogeneities in
bioreactors using compartment, population balance and metabolic models. Chem. Eng. Sci. 2015, 126,
267–282. [CrossRef]
19. Meshram, M.; Naderi, S.; McConkey, B.; Ingalls, B.; Scharer, J.; Budman, H. Modeling the coupled
extracellular and intracellular environments in mammalian cell culture. Metab. Eng. 2013, 19, 57–68.
[CrossRef][PubMed]
20. Sidoli, F.R.; Asprey, S.P.; Mantalaris, A. A Coupled Single Cell-Population-Balance Model for Mammalian
Cell Cultures. Ind. Eng. Chem. Res. 2006, 45, 5801–5811. [CrossRef]
21. Mantzaris, N.V.; Daoutidis, P. Cell population balance modeling and control in continuous bioreactors.
J. Process Control 2004, 14, 775–784. [CrossRef]
22. Mantzaris, N.V. Stochastic and deterministic simulations of heterogeneous cell population dynamics. J. Theor.
Biol. 2006, 241, 690–706. [CrossRef][PubMed]
23. Dorka, P.; Fischer, C.; Budman, H.; Scharer, J.M. Metabolic flux-based modeling of mAb production during
batch and fed-batch operations. Bioprocess Biosyst. Eng. 2009, 32, 183–196. [CrossRef][PubMed]
127