Challenges in AAV manufacturing: the interplay of process variations, in-process characterization, and drug product quality

A large focus for cell and gene therapy in recent years has been Chemistry Manufacturing and Controls (CMC) regulations related to production processes and analytical testing. Regulatory agencies have issued multiple guidelines for these novel biological products focusing on improving production, reproducibility, and testing expectations. With the increase in the number of clinical trials, there has also come a suite of clinical holds related to product quality or process reproducibility concerns. In remarks released from the FDA in 2018, they discussed how in contrast to traditional drug development, nearly 80% of the review process in cell and gene therapy applications is focused on the manufacturing process and product characterization methods. The focus of this article is discussing the current modalities for manufacturing, the available methods for evaluating in-process and final product characteristics, and the impact both the complex matrices and final formulation have on understanding changes to product quality and performance.