Bioreactor control systems in the biopharmaceutical industry: a critical perspective

Abstract

Industrial-scale bioprocessing underpins much of the production of pharmaceuticals, nutraceuticals, food, and beverage processing industries of the modern world. The profitability of these processes increasingly leverages the economies of scale and scope that are critically dependent on the product yields, titers, and productivity. Most of the processes are controlled using classical control approaches and represent over 90% of the industrial controls used in bioprocessing industries. However, with the advances in the production processes, especially in the biopharmaceutical and nutraceutical industries, monitoring and control of bioprocesses such as fermentations with GMO organisms, and downstream processing has become increasingly complex and the inadequacies of the classical and some of the modern control systems techniques is becoming apparent. Therefore, with increasing research complexity, nonlinearity, and digitization in process, there has been a critical need for advanced process control that is more effective, and easier process intensification and product yield (both by quality and quantity) can be achieved. In this review, industrial aspects of a process and automation along with various commercial control strategies have been extensively discussed to give an insight into the future prospects of industrial development and possible new strategies for process control and automation with a special focus on the biopharmaceutical industry.

Keywords

Bioreactor control systems / Digitization / Advanced process control / Industrial automation / Single-use technology / Biopharmaceuticals

References

[1] KoutinasM, KiparissidesA, PistikopoulosEN, MantalarisA. Bioprocess systems engineering: transferring traditional process engineering principles to industrial biotechnology. Comput Struct Biotechnol J, 2012, 3. e201210022

[2] SabraW, DietzD, TjahjasariD, ZengAP. Biosystems analysis and engineering of microbial consortia for industrial biotechnology. Eng Life Sci, 2010, 10: 407-421.

[3] WangY, ChuJ, ZhuangY, WangY, XiaJ, ZhangS. Industrial bioprocess control and optimization in the context of systems biotechnology. Biotechnol Adv, 2009, 27: 989-995.

[4] Pallavi S. Lesson introduction to industrial automation and control. 2013; 1–18

[5] Zulkeflee SA, Aziz N, Campus E, Ampangan S, Tebal N. Control implementation in bioprocess system : a review. Int Conf Control Instrum Mechatron Eng. 2007; 798–804

[6] MandeniusCF. Recent developments in the monitoring, modeling and control of biological production systems. Bioprocess Biosyst Eng, 2004, 26: 347-351.

[7] MarwickJD, WrightPC, BurgessJG. Bioprocess intensification for production of novel marine bacterial antibiotics through bioreactor operation and design. Mar Biotechnol, 1999, 1: 495-507.

[8] MurthyGS, JohnstonDB, RauschKD, TumblesonME, SinghV. Design and evaluation of an optimal controller for simultaneous saccharification and fermentation process. Appl Biochem Biotechnol, 2012, 166: 87-111.

[9] BettsJI, BaganzF. Miniature bioreactors: current practices and future opportunities. Microb Cell Fact, 2006, 5: 1-14.

[10] Bioreactors—an overview. ScienceDirect Topics. 2021. https://www.sciencedirect.com/topics/neuroscience/bioreactors. Accessed 28 May 2021

[11] Murthy GS. Development of a controller for fermentation in the dry grind corn process. 2006

[12] Selker M, Paldus B. Single-use solutions for scale-up and technology transfer. Innov Pharm Technol. 2009; 57–59

[13] MednisM, MeitalovsJ, VilumsS, VanagsJ, GalvanauskasV. Bioprocess monitoring and control using mobile devices. Inf Technol Control, 2010, 39: 195-201.

[14] Rathore AS, Kateja N, Agarwal H. Part five continuous downstream bioprocessing. Contin Biomanufacturing Innov Technol Methods Innov Technol Methods. 2017; 261–279

[15] GomesJ, ChopdaV, RathoreAS. Monitoring and control of bioreactor: basic concepts and recent advances, bioprocess. Technol Prod Biopharm Bioprod, 2018.

[16] KnospeC. PID control. IEEE Control Syst, 2006, 26: 30-31.

[17] BelhajW, BoubakerO. On MIMO PID control of the quadruple-tank process via ILMIs approaches: minimum and non-minimum case studies. IFAC Proc, 2013, 46: 481-486.

[18] Tatjewski P. Advanced control of industrial processes: structures and algorithms. 2007. http://www.springer.com/engineering/control/book/978-0-85729-634-4%0A. https://books.google.com/books?hl=en&lr=&id=e_QEnZB0PLoC&pgis=1.

[19] Tang YJ, Heider R. Bridging the gap between academia and industry—Washington university’s process control laboratories. In: Department of Energy, Environmental and Chemical Engineering at Washington University, St. Louis, MO 63130, United States, 2009; pp. 2730–2734. Doi: https://doi.org/10.1109/ACC.2009.5160506.

[20] Huusom JK. Control of bioprocesses. In: Fundam. Bioeng., Wiley Blackwell, Technical University of Denmark, Department of Chemical and Biochemical Engineering, Anker Engelunds Vej 1 Bygning 101A, Kgs Lyngby, 2800, Denmark. 2015; pp. 439–462. Doi: https://doi.org/10.1002/9783527697441.ch15.

[21] BarkerM, RawtaniJ, MackayS. Batch control technologies. Pract Batch Process Manag, 2005.

[22] LakerveldR, BenyahiaB, BraatzRD, BartonPI. Model-based design of a plant-wide control strategy for a continuous pharmaceutical plant. AIChE J, 2013, 59: 3671-3685.

[23] HopkinsD, St AmandM, PriorJ. Bioreactor automation. Man Ind Microbiol Biotechnol, 2014.

[24] Faedo NE, Lucero M, Mazzone V, Suarez M, Rojas NL. Low cost SCADA for a laboratory-scale bioreactor, 2015 16th Work. Inf Process Control RPIC 2015. 2016. Doi: https://doi.org/10.1109/RPIC.2015.7497090.

[25] Prado-RubioOA, JørgensenSB, JonssonGControl system development for integrated bioreactor and membrane separation process, 2010AmsterdamElsevier.

[26] Liljequist V. Development of a bioreactor simulator for supporting automation software test and verification. 2017. http://www.diva-portal.org/smash/get/diva2:1117825/FULLTEXT01.pdf.

[27] WangB, WangZ, ChenT, ZhaoX. Development of novel bioreactor control systems based on smart sensors and actuators. Front Bioeng Biotechnol, 2020, 8: 7.

[28] FigueroaJL, DesagesAC, PalazogluA, RomagnoliJA, RomagnoliJA. Trade-offs in robust controller design. Int J Control, 1993, 58: 1265-1278.

[29] Harris I. Animal cell culture. 1993. Doi: https://doi.org/10.1016/0307-4412(93)90121-f

[30] Moysis L, Kafetzis I, Iliadou M, Tsiaousis M, Charalampidis N. An introduction to control theory applications with matlab. 2015. Doi: https://doi.org/10.13140/RG.2.1.3926.8243

[31] ShimizuK. An overview on the control system design of bioreactors. Meas Control, 1993, 50: 65-84.

[32] HititZY, OzyurtB, ErtuncS. The application of system identification and advanced process control to improve fermentation process of baker’s yeast. Yeast Ind Appl, 2017.

[33] KondeKS, ModakJM. Optimization of bioreactor using metabolic control analysis approach. Biotechnol Prog, 2007, 23: 370-380.

[34] FematRControl in bioprocessing : modelling, estimation and the use of soft sensors, 2019HobokenWiley2-4

[35] MesquitaTJB, SargoCR, FuzerJR, ParedesSAH, GiordanoRDC, HortaACL, ZangirolamiTC. Metabolic fluxes-oriented control of bioreactors: a novel approach to tune micro-aeration and substrate feeding in fermentations. Microb Cell Fact, 2019.

[36] KorneckiM, StrubeJ. Process analytical technology for advanced process control in biologics manufacturing with the aid of macroscopic kinetic modeling. Bioengineering, 2018.

[37] ClarkeDJ, Blake-ColemanBC, CalderMR, CarrRJG, MoodySC. Sensors for bioreactor monitoring and control—a perspective. J Biotechnol, 1984, 1: 135-158.

[38] Hanafi R, Mayasari RD, Masmui A, Raharjo J, Nuryadi R. Electrochemical sensor for environmental monitoring system: a review. AIP Conf Proc. 2019; p. 2169. Doi: https://doi.org/10.1063/1.5132657

[39] BusseC, BiecheleP, de VriesI, ReardonKF, SolleD, ScheperT. Sensors for disposable bioreactors. Eng Life Sci, 2017, 17: 940-952.

[40] MaroseS, LindemannC, UlberR, ScheperT. Optical sensor systems for bioprocess monitoring. Trends Biotechnol, 1999, 17: 30-34.

[41] LourençoND, LopesJA, AlmeidaCF, SarraguçaMC, PinheiroHM. Bioreactor monitoring with spectroscopy and chemometrics: a review. Anal Bioanal Chem, 2012, 404: 1211-1237.

[42] ShioyaS, ShimizuK, YoshidaT. Knowledge-based design and operation of bioprocess systems. J Biosci Bioeng, 1999, 87: 261-266.

[43] DuysensLNM, AmeszJ. Fluorescence spectrophotometry of reduced phosphopyridine nucleotide in intact cells in the near-ultraviolet and visible region. BBA Biochim Biophys Acta, 1957, 24: 19-26.

[44] KongD, GentzR, ZhangJ. Development of a versatile computer integrated control system for bioprocess controls. Cytotechnology, 1998, 26: 227-236.

[45] KustererA, KrauseC, KaufmannK, ArnoldM, Weuster-BotzD. Fully automated single-use stirred-tank bioreactors for parallel microbial cultivations. Bioprocess Biosyst Eng, 2008, 31: 207-215.

[46] GogatePR, BeenackersAACM, PanditAB. Multiple-impeller systems with a special emphasis on bioreactors: a critical review. Biochem Eng J, 2000, 6: 109-144.

[47] ChenX, HuR, HuL, HuangY, ShiW, WeiQ, LiZ. Portable analytical techniques for monitoring volatile organic chemicals in biomanufacturing processes: recent advances and limitations. Front Chem, 2020.

[48] BrooksSL, TurnerAPF. Biosensors for measurement and control. Meas Control, 1987, 20: 37-43.

[49] O’MaraP, FarrellA, BonesJ, TwomeyK. Staying alive! Sensors used for monitoring cell health in bioreactors. Talanta, 2018, 176: 130-139.

[50] LuttmannR, BracewellDG, CornelissenG, GernaeyKV, GlasseyJ, HassVC, KaiserC, PreusseC, StriednerG, MandeniusCF. Soft sensors in bioprocessing: a status report and recommendations. Biotechnol J, 2012, 7: 1040-1048.

[51] Satya EswariJ, VenkateswarluC. Dynamic modeling and metabolic flux analysis for optimized production of rhamnolipids. Chem Eng Commun, 2016, 203: 326-338.

[52] PertevC, TürkerM, BerberR. Dynamic modeling, sensitivity analysis and parameter estimation of industrial yeast fermenters. Comput Chem Eng, 1997.

[53] RosaLFM, HungerS, ZschernitzT, StrehlitzB, HarnischF. Integrating electrochemistry into bioreactors: effect of the upgrade kit on mass transfer, mixing time and sterilizability. Front Energy Res, 2019.

[54] GalvanauskasV, SimutisR, LevišauskasD, UrniežiusR. Practical solutions for specific growth rate control systems in industrial bioreactors. Processes, 2019.

[55] SarkarD, ModakJM. Optimisation of fed-batch bioreactors using genetic algorithms. Chem Eng Sci, 2003, 58: 2283-2296.

[56] RaniKY, RaoVSR. Control of fermenters—a review. Bioprocess Eng, 1999, 21: 77-88.

[57] ZhongJJ. Recent advances in bioreactor engineering. Korean J Chem Eng, 2010, 27: 1035-1041.

[58] AshokA, DoriyaK, RaoDRM, KumarDS. Design of solid state bioreactor for industrial applications: an overview to conventional bioreactors. Biocatal Agric Biotechnol, 2017, 9: 11-18.

[59] Mitchell DA, Krieger N, Berovič M. Solid-state fermentation bioreactors: fundamentals of design and operation, Springer Berlin Heidelberg, Federal University of Paraná, Department of Biochemistry and Molecular Biology, P.O. Box 19046, 81531–990 Curitiba-PR, Brazil. 2006. Doi: https://doi.org/10.1007/3-540-31286-2

[60] StoneKA, HilliardMV, HeQP, WangJ. A mini review on bioreactor configurations and gas transfer enhancements for biochemical methane conversion. Biochem Eng J, 2017, 128: 83-92.

[61] GianettoA, SpecchiaV. Trickle-bed reactors: state of art and perspectives. Chem Eng Sci, 1992, 47: 3197-3213.

[62] PradoRC, BorgesER. Microbioreactors as engineering tools for bioprocess development. Braz J Chem Eng, 2018, 35: 1163-1182.

[63] MaharbizMM, HoltzWJ, HoweRT, KeaslingJD. Microbioreactor arrays with parametric control for high-throughput experimentation. Biotechnol Bioeng, 2004, 85: 376-381.

[64] KostovY, HarmsP, Randers-EichhornL, RaoG. Low-cost microbioreactor for high-throughput bioprocessing. Biotechnol Bioeng, 2001, 72: 346-352.

[65] Hong MS, Braatz RD. Mechanistic modeling and parameter-adaptive nonlinear model predictive control of a microbioreactor. Food Pharm Bioeng Div 2018—Core Program. Area 2018 AIChE Annu Meet. 2018; 2: 918–920. Doi: https://doi.org/10.1016/j.compchemeng.2021.107255

[66] JunneS, NeubauerP. How scalable and suitable are single-use bioreactors?. Curr Opin Biotechnol, 2018, 53: 240-247.

[67] AlfordJS. Bioprocess control: advances and challenges. Comput Chem Eng, 2006, 30: 1464-1475.

[68] OuanoEAR. Oxygen mass transfer scale up in rotating biological filters. Water Res, 1978, 12: 1005-1008.

[69] AbrahamE, GuptaS, JungS, McAfeeEBioreactor for scale-up: process control, 2017AmsterdamElsevier Inc..

[70] XiaJ, WangG, LinJ, WangY, ChuJ, ZhuangY, ZhangS. Advances and practices of bioprocess scale-up. Adv Biochem Eng Biotechnol, 2016, 152: 137-151.

[71] Garcia-OchoaF, GomezE. Bioreactor scale-up and oxygen transfer rate in microbial processes: an overview. Biotechnol Adv, 2009, 27: 153-176.

[72] MouchaT, RejlFJ, KordačM, LabíkL. Mass transfer characteristics of multiple-impeller fermenters for their design and scale-up. Biochem Eng J, 2012, 69: 17-27.

[73] KuhnD, BlankLM, SchmidA, BühlerB. Systems biotechnology—rational whole-cell biocatalyst and bioprocess design. Eng Life Sci, 2010, 10: 384-397.

[74] RanjanAP, GomesJ. Simultaneous dissolved oxygen and glucose regulation in fed-batch methionine production using decoupled input-output linearizing control. J Process Control, 2009, 19: 664-677.

[75] PeukerT, BognerA. Equipment design and facility layout for flexible biomanufacturing processes. Eng Life Sci, 2011, 11: 443-451.

[76] SpannR, LantzAE, GernaeyKV, SinG, LyngbyKModeling for process risk assessment in industrial bioprocesses, 2018AmsterdamElsevier Inc..

[77] Okhio-SeamanL. Validation, quality, and regulatory considerations in continuous biomanufacturing. Contin Biomanufacturing Innov Technol Methods, 2017.

[78] VaurioJK. Importance measures in risk-informed decision making: ranking, optimisation and configuration control. Reliab Eng Syst Saf, 2011, 96: 1426-1436.

[79] Biophorum. A risk-based blueprint for process control of continuous bioprocessing : phase 1 : generic risk assessment and process control parameters. 2021

[80] Biopharmaceutical quality optimization. 2016

[81] LarrocheC, SanrománMA, DuG, PandeyACurrent developments in biotechnology and bioengineering: bioprocesses bioreactors and controls, 2016AmsterdamElsevier

[82] JenzschM, SimutisR, LübbertA. Optimization and control of industrial microbial cultivation processes. Eng Life Sci, 2006, 6: 117-124.

[83] An Environmental Lifecycle Assessment of Single-Use and Conventional Process Technology: Comprehensive Environmental Impacts. 2021. https://www.biopharminternational.com/view/environmental-lifecycle-assessment-single-use-and-conventional-process-technology-comprehensive-envi. Accessed 29 May 2021

[84] FerreroG, Rodríguez-RodaI, ComasJ. Automatic control systems for submerged membrane bioreactors: a state-of-the-art review. Water Res, 2012, 46: 3421-3433.

[85] WanJ, MarjanovicO, LennoxB. Disturbance rejection for the control of batch end-product quality using latent variable models. J Process Control, 2012, 22: 643-652.

[86] AlbertosP, GarciaP, GaoZ, LiuT. Disturbance rejection in process control. Proc World Congr Intell Control Autom, 2015.

[87] HarrisonRG, ToddPW, RudgeSR, PetridesDPBioprocess design and economics, 2015OxfordOxford University Press.

[88] CardosoVM, CampaniG, SantosMP, SilvaGG, PiresMC, GonçalvesVM, de GiordanoRC, SargoCR, HortaACL, ZangirolamiTC. Cost analysis based on bioreactor cultivation conditions: Production of a soluble recombinant protein using Escherichia coli BL21(DE3). Biotechnol Rep, 2020.

[89] Minimizing the Environmental Footprint of Bioprocesses—BioProcess InternationalBioProcess International. 2021. https://bioprocessintl.com/manufacturing/facility-design-engineering/minimizing-the-environmental-footprint-of-bioprocesses-303905/. Accessed 29 May 2021

[90] NollP, HenkelM. History and evolution of modeling in biotechnology: modeling and simulation, application and hardware performance. Comput Struct Biotechnol J, 2020, 18: 3309-3323.

[91] Camacho EF, Alba CB. Model predictive control (google ebook). 2013; p, 427. http://books.google.com/books?hl=en&lr=&id=tXZDAAAAQBAJ&pgis=1.

[92] Major Players Operating in the Global Bioreactors Market 2019–2023. Technavio. Business Wire. 2021. https://www.businesswire.com/news/home/20190726005097/en/Major-Players-Operating-Global-Bioreactors-Market-2019-2023/?feedref=JjAwJuNHiystnCoBq_hl-f-Mqy7--9RYfS_LXgrtWW7rOkYSjTKorE14c7uwcjIHj_R0p0VFN6GsXdq8PYoIcFEYGffXvFUnUBNNmxNkJdnQqLx557vS7ZRxiEolcr-hHrZo_gzQzmbSVgCo2ySDfw%3D%3D. Accessed 29 May 2021

[93] Bioreactors Market Growth Analysis. Global Forecast Report 2027. 2021. https://www.gminsights.com/industry-analysis/bioreactor-market. Accessed 29 May 2021

[94] Coronavirus: Operation Warp Speed. 2021. https://www.defense.gov/Explore/Spotlight/Coronavirus/Operation-Warp-Speed/. Accessed 17 July 2021

[95] OlsonDL, SwensethSR. Trade-offs in supply chain system risk mitigation. Syst Res Behav Sci, 2014, 31: 565-579.

[96] Download PDF Brochure—Bioreactors Market. Growing at a CAGR of 6.8%. MarketsandMarkets. 2021. https://www.marketsandmarkets.com/pdfdownloadNew.asp?id=59253123. Accessed 29 May 2021

[97] Control Engineering. Biopharmaceutical company optimizes manufacturing processes with modern DCS. 2021. https://www.controleng.com/articles/biopharmaceutical-company-optimizes-manufacturing-processes-with-modern-dcs/. Accessed 2 July 2021

RIGHTS & PERMISSIONS

Jiangnan University