(157aa) Process Analytical Technologies for Recombinant Adeno-Associated Virus-Based Gene Therapy

Recent advancements in viral vector development for recombinant adeno-associated virus (rAAV)—the most commonly used viral vector for in vivo gene therapies—have facilitated a surge in product development, with up to 20 approved cell and gene therapies per year expected by 2025 [1].

Supporting this surge requires tackling two current challenges in viral vector manufacturing: the increased complexity of viral vectors compared to protein therapeutics, and the required production capacity. To overcome these challenges, it is critical to establish short process development timelines, and improve the process throughput by rigorous process modeling and control. Both depend strongly on the availability of fast, accurate, and reproducible analytical technologies for process characterization. While off-line technologies are useful for collecting data that can be used to construct data-driven models and perform lot-release assays, on- and at-line technologies are required for real-time feedback control systems. However, a comprehensive evaluation of analytical technologies for viral vectors and their suitability for use in process modeling and control has not been reported yet.

Here we review the current state of process analytical technologies for rAAV, for which control strategy design is in its infancy. Given the current developments, we discuss established and upcoming new technologies targeting rAAV-specific quality attributes [2,3]. We conclude with a discussion of control strategies that would be enabled by advances in analytical technologies, and suggestions guiding future investigations into these technologies.

References

[1] Gottlieb, S. (January 15, 2019). Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies. U. S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/statement-fda-commis...

[2] Wright, J. F. (2008). Manufacturing and characterizing AAV-based vectors for use in clinical studies. Gene Therapy, 15(11), 840–848. https://doi.org/10.1038/gt.2008.65

[3] Forsberg, N., Glover, C., Hughes, J.V., Jaluria, P., King, D., Madsen, J., Moore, A., Nilsson, J., Pettit, S., Pincus, S., Sargent, B., Schwartz, C. & TreDenick, T. L. (2018). Key Considerations in Gene Therapy Manufacturing for Commercialization. The Cell Culture Dish, Inc., Fort Collins, Colorado, https://cellculturedish.com/genetherapybook/