Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Aug;121(8):2435-2448.
doi: 10.1002/bit.28402. Epub 2023 Apr 22.

Process economics evaluation and optimization of adeno-associated virus downstream processing

Annabel Lyle  1 , Christos Stamatis  1 , Thomas Linke  2 , Martyn Hulley  3 , Albert Schmelzer  2 , Richard Turner  3 , Suzanne S Farid  1
Affiliations

Process economics evaluation and optimization of adeno-associated virus downstream processing

Annabel Lyle et al. Biotechnol Bioeng. 2024 Aug.

Abstract

Adeno-associated virus (AAV) manufacturing has traditionally focused upon lab-scale techniques to culture and purify vector products, leading to limitations in production capacity. The tool presented in this paper assesses the feasibility of using non-scalable technologies at high AAV demands and identifies optimal flowsheets at large-scale that meet both cost and purity targets. The decisional tool comprises (a) a detailed process economics model with the relevant mass balance, sizing, and costing equations for AAV upstream and downstream technologies, (b) a built-in Monte Carlo simulation to assess uncertainties, and (c) a brute-force optimization algorithm for rapid investigation into the optimal purification combinations. The results overall highlighted that switching to more scalable upstream and downstream processing alternatives is economically advantageous. The base case analysis showed the cost and robustness advantages of utilizing suspension cell culture over adherent, as well as a fully chromatographic purification platform over batch ultracentrifugation. Expanding the set of purification options available gave insights into the optimal combination to satisfy both cost and purity targets. As the purity target increased, the optimal polishing solution moved from the non-capsid purifying multimodal chromatography to anion-exchange chromatography or continuous ultracentrifugation.

Keywords: Monte Carlo simulation; adeno‐associated vectors; chromatography; cost of goods modeling; optimization; ultracentrifugation.

PubMed Disclaimer

References

REFERENCES

    1. Bracewell, D. G., Francis, R., & Smales, C. M. (2015). The future of host cell protein (HCP) identification during process development and manufacturing linked to a risk‐based management for their control. Biotechnology and Bioengineering, 112(9), 1727–1737. https://doi.org/10.1002/BIT.25628
    1. Bulcha, J. T., Wang, Y., Ma, H., Tai, P., & Gao, G. (2021). Viral vector platforms within the gene therapy landscape. Signal Transduction and Targeted Therapy, 6(1), 53. https://doi.org/10.1038/s41392-021-00487-6
    1. Cameau, E., Pedregal, A., & Glover, C. (2020). Vector channel: Adherent cost modelling comparison of adherent multi‐trays with suspension and fixed‐bed bioreactors for the manufacturing of gene therapy products. Cell & Gene Therapy Insights, 5(11), 1663–1675. https://doi.org/10.18609/cgti.2019.175
    1. Chen, H., Marino, S., & Ho, C. Y. (2016). 97. Large scale purification of AAV with continuous flow ultracentrifugation. Molecular Therapy, 24, S42. https://doi.org/10.1016/s1525-0016(16)32906-9
    1. Comisel, R. M., Kara, B., Fiesser, F. H., & Farid, S. S. (2021a). Gene therapy process change evaluation framework: Transient transfection and stable producer cell line comparison. Biochemical Engineering Journal, 176(May), 108202. https://doi.org/10.1016/j.bej.2021.108202

MeSH terms

LinkOut - more resources