(528a) Process Design of a Fully Integrated Continuous Biopharmaceutical Process Using Economic and Ecological Impact Assessment

The majority of commercial-scale production of biological products is currently carried out in batch operation, that leads to some significant inefficiencies such as low productivity, low yield, batch-to-batch variation in product quality, and high capital and operating cost. With the rapid expansion of market demand, competition from biosimilars, and market pressure for lower drug prices, pharmaceutical industry is investigating different production alternatives such as continuous manufacturing ^1-3. Continuous biomanufacturing is a more cost-effective and flexible platform with higher productivity and yield, more consistent and better product quality, and smaller footprints ^{4, 5}. Although there is no fully integrated continuous platform, there have been some major advances recently ^{6, 7}. For the upstream process, intensified seed expansion and continuously operated perfusion bioreactors with different cell retention devices have been introduced ^{8, 9}. In terms of the downstream operations, multi-column periodic counter-current chromatography (PCC) for primary capture and polishing steps, different types of reactors (like coiled flow inversion reactor and plug flow reactor) for the continuous virus inactivation, and single-pass tangential flow filtration (SPTFF) for the final formulation have been developed ^10-12. There are also several successful lab-scale integrations of continuous perfusion cell culture with continuous downstream operations ^{13, 14}.

To facilitate the commercialization of continuous manufacturing, demonstration of economic and environmental viability is important. Many research groups have shown that there are tremendous economic benefits when the operation is transitioned from batch to continuous ^15-18. Continuous platforms with different unit procedures, including perfusion techniques, capture scenarios, and membrane chromatography, have been systematically assessed ^{19, 20}. The ecological and operational robustness benefits of continuous biomanufacturing have been illustrated ²¹. However, to the best of our knowledge, few papers have considered the media and buffer preparation when constructing continuous platforms, although studies have shown that buffer preparation can be significant in the overall operational and scheduling activities ^{22, 23}. The study of the bottleneck shifting with respect to the increase of upstream production is also limited. Furthermore, most papers only examine the effects of process variables on the economics when conducting scenario analysis ^{24, 25}, but few investigates the impacts on the environmental footprints ^{20, 26}.

This work aims to establish an in-silico fully integrated continuous platform for the production of monoclonal antibody (mAb). This developed platform incorporates media and buffer preparation steps and combine innovative technologies such as intensified seed expansion and continuous high cell density perfusion bioreactors, single-pass tangential flow filtration, and single-use technologies. After process design and development, scheduling is performed to achieve the continuous operation and real-time media and buffer addition, followed by economic and environmental analysis based on environmental indicators (E-factors). Scenario analysis is carried out to assess the effect of upstream titer and bioreactor scale on process economics and environment. The shift of process bottlenecks with the increase of the upstream production capacity is explored and analyzed. As an emerging technology, membrane chromatography can help eliminate pore diffusion, enhance the bio-separation efficiency, and lower buffer consumption ²⁷, so membrane chromatography is incorporated into the process design and its impact on the overall process performance is investigated in terms of economic and ecological benefits. The results will provide insights into the feasibility of transitioning from batch to continuous biomanufacturing from cost and environmental aspects.

References

1. Zydney, A. L., Perspectives on integrated continuous bioprocessing—opportunities and challenges. Curr. Opin. Chem. Eng. 2015, 10, 8-13.
2. Erickson, J.; Baker, J.; Barrett, S.; Brady, C.; Brower, M.; Carbonell, R.; Charlebois, T.; Coffman, J.; Connell-Crowley, L.; Coolbaugh, M.; Fallon, E.; Garr, E.; Gillespie, C.; Hart, R.; Haug, A.; Nyberg, G.; Phillips, M.; Pollard, D.; Qadan, M.; Ramos, I.; Rogers, K.; Schaefer, G.; Walther, J.; Lee, K., End-to-end collaboration to transform biopharmaceutical development and manufacturing. Biotechnol Bioeng 2021.
3. Ding, C.; Ierapetritou, M., A novel framework of surrogate-based feasibility analysis for establishing design space of twin-column continuous chromatography. International Journal of Pharmaceutics 2021, 609, 121161.
4. Yang, O.; Qadan, M.; Ierapetritou, M., Economic Analysis of Batch and Continuous Biopharmaceutical Antibody Production: A Review. J. Pharm. Innov. 2019, 14, 1-19.
5. Croughan, M. S.; Konstantinov, K. B.; Cooney, C., The future of industrial bioprocessing: batch or continuous? Biotechnol. Bioeng. 2015, 112 (4), 648-51.
6. Chen, Y.; Yang, O.; Sampat, C.; Bhalode, P.; Ramachandran, R.; Ierapetritou, M., Digital Twins in Pharmaceutical and Biopharmaceutical Manufacturing: A Literature Review. Processes 2020, 8 (9).
7. Khanal, O.; Lenhoff, A. M., Developments and opportunities in continuous biopharmaceutical manufacturing. MAbs 2021, 13 (1), 1903664.
8. Bielser, J. M.; Wolf, M.; Souquet, J.; Broly, H.; Morbidelli, M., Perfusion mammalian cell culture for recombinant protein manufacturing - A critical review. Biotechnol. Adv. 2018, 36 (4), 1328-1340.
9. Walther, J.; Lu, J.; Hollenbach, M.; Yu, M.; Hwang, C.; McLarty, J.; Brower, K., Perfusion cell culture decreases process and product heterogeneity in a head‐to‐head comparison with fed‐batch. Biotechnology journal 2019, 14 (2), 1700733.
10. Gomis-Fons, J.; Andersson, N.; Nilsson, B., Optimization study on periodic counter-current chromatography integrated in a monoclonal antibody downstream process. J. Chromatogr. A 2020, 1621, 461055.
11. Gillespie, C.; Holstein, M.; Mullin, L.; Cotoni, K.; Tuccelli, R.; Caulmare, J.; Greenhalgh, P., Continuous In-Line Virus Inactivation for Next Generation Bioprocessing. Biotechnol J 2019, 14 (2), e1700718.
12. Jabra, M. G.; Yehl, C. J.; Zydney, A. L., Multistage continuous countercurrent diafiltration for formulation of monoclonal antibodies. Biotechnol Prog 2019, 35 (4), e2810.
13. Karst, D. J., Steinebach, F., Soos, M., Morbidelli, M. , Process performance and product quality in an integrated continuous antibody production process. Biotechnol. Bioeng. 2017, 114 (2), 298-307.
14. Coffman, J.; Bibbo, K.; Brower, M.; Forbes, R.; Guros, N.; Horowski, B.; Lu, R.; Mahajan, R.; Patil, U.; Rose, S.; Shultz, J., The Design Basis for the Integrated and Continuous Biomanufacturing Framework. Biotechnol Bioeng 2021.
15. Xenopoulos, A., A new, integrated, continuous purification process template for monoclonal antibodies: Process modeling and cost of goods studies. J Biotechnol 2015, 213, 42-53.
16. Arnold, L.; Lee, K.; Rucker-Pezzini, J.; Lee, J. H., Implementation of Fully Integrated Continuous Antibody Processing: Effects on Productivity and COGm. Biotechnol. J. 2019, 14 (2), e1800061.
17. Grilo, A. L.; Mateus, M.; Aires-Barros, M. R.; Azevedo, A. M., Monoclonal Antibodies Production Platforms: An Opportunity Study of a Non-Protein-A Chromatographic Platform Based on Process Economics. Biotechnol J 2017, 12 (12).
18. Nandi, S.; Kwong, A. T.; Holtz, B. R.; Erwin, R. L.; Marcel, S.; McDonald, K. A., Techno-economic analysis of a transient plant-based platform for monoclonal antibody production. MAbs 2016, 8 (8), 1456-1466.
19. Pollock, J.; Ho, S. V.; Farid, S. S., Fed-batch and perfusion culture processes: economic, environmental, and operational feasibility under uncertainty. Biotechnol. Bioeng. 2013, 110 (1), 206-19.
20. Cataldo, A. L.; Burgstaller, D.; Hribar, G.; Jungbauer, A.; Satzer, P., Economics and ecology: Modelling of continuous primary recovery and capture scenarios for recombinant antibody production. J Biotechnol 2020, 308, 87-95.
21. Pollock, J.; Coffman, J.; Ho, S. V.; Farid, S. S., Integrated continuous bioprocessing: Economic, operational, and environmental feasibility for clinical and commercial antibody manufacture. Biotechnol Prog 2017, 33 (4), 854-866.
22. Petrides, D.; Carmichael, D.; Siletti, C.; Koulouris, A., Biopharmaceutical Process Optimization with Simulation and Scheduling Tools. Bioengineering (Basel) 2014, 1 (4), 154-187.
23. Hummel, J.; Pagkaliwangan, M.; Gjoka, X.; Davidovits, T.; Stock, R.; Ransohoff, T.; Gantier, R.; Schofield, M., Modeling the downstream processing of monoclonal antibodies reveals cost advantages for continuous methods for a broad range of manufacturing scales. Biotechnology journal 2019, 14 (2), 1700665.
24. Yang, O.; Prabhu, S.; Ierapetritou, M., Comparison between Batch and Continuous Monoclonal Antibody Production and Economic Analysis. Ind. Eng. Chem. Res. 2019, 58 (15), 5851-5863.
25. Gupta, P.; Kateja, N.; Mishra, S.; Kaur, H.; Rathore, A. S., Economic assessment of continuous processing for manufacturing of biotherapeutics. Biotechnol Prog 2021, 37 (2), e3108.
26. Madabhushi, S. R.; Gavin, J.; Xu, S.; Cutler, C.; Chmielowski, R.; Rayfield, W.; Tugcu, N.; Chen, H., Quantitative assessment of environmental impact of biologics manufacturing using process mass intensity analysis. Biotechnol Prog 2018, 34 (6), 1566-1573.
27. Orr, V.; Zhong, L.; Moo-Young, M.; Chou, C. P., Recent advances in bioprocessing application of membrane chromatography. Biotechnol Adv 2013, 31 (4), 450-65.