Manufacturing Challenges and Rational Formulation Development for AAV Viral Vectors

Adeno-associated virus (AAV) has emerged as a leading platform for gene delivery for treating various diseases due to its excellent safety profile and efficient transduction to various target tissues. However, the large-scale production and long-term storage of viral vectors is not efficient resulting in lower yields, moderate purity, and shorter shelf-life compared to recombinant protein therapeutics.

The mechanisms of various physical and chemical instabilities that the viral vector may encounter during its production and shelf-life because of various stressed conditions such as thermal, shear, freeze-thaw, and light exposure are highlighted. The role of buffer, pH, excipients, and impurities on the stability of viral vectors is also discussed. As such, the aim of this review is to outline the tools and a potential roadmap for improving the quality of AAV-based drug products by stressing the need for a mechanistic understanding of the involved processes.

This review provides a comprehensive analysis of upstream, downstream and formulation unit operation challenges encountered during AAV vector manufacturing and discusses how desired product quality attributes can be maintained throughout product shelf-life by understanding the degradation mechanisms and formulation strategies.

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Author

Arvind Srivastava, Ph.D.

Technical Fellow, Research - Bioprocessing

Dr. Arvind Srivastava is a Vice President at Avantor, leading contract development and manufacturing organization (CDMO). Before joining Avantor, Dr. Srivastava was Research Advisor at Eli Lilly and Company, where he managed drug product development from early development stage through commercial registration. Dr. Srivastava did his postdoctoral training from the University of North Carolina at Chapel Hill, NC, USA. He got his Ph.D. degree in biochemistry from the prestigious Tata Institute of Fundamental Research (TIFR) and M.S. in chemistry from the Banaras Hindu University (BHU). Dr. Srivastava has published numerous papers in international journals and has been frequently invited to present his research at the national and international conferences.

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