Characterization of key manufacturing uncertainties in next generation therapeutics and vaccines across scales

Abstract

AbstractViral vectors are advanced therapy products used as genetic information carriers in vaccine and cell therapy development and manufacturing. Despite the first product receiving market authorization in 2012, viral vector manufacturing has still not reached the level of maturity of biologics and is still highly susceptible to process uncertainties, such as viral titers and chromatography yields. This was exacerbated by the COVID‐19 pandemic when viral vector manufacturers were challenged to respond to the global demand in a timely manner. A key reason for this was the lack of a systematic framework and approach to support capacity planning under uncertainty. To address this, we present a methodology for: (i) identification of process cost and volume bottlenecks, (ii) quantification of process uncertainties and their impact on target key performance indicators, and (iii) quantitative analysis of scale‐dependent uncertainties. We use global sensitivity analysis as the backbone to evaluate three industrially relevant vector platforms: adeno‐associated, lentiviral, and adenoviral vectors. For the first time, we quantify how operating parameters can affect process performance and, critically, the trade‐offs among them. Results indicate a strong, direct proportional correlation between volumetric scales and propagation of uncertainties, while we identify viral titer as the most critical scale‐up bottleneck across the three platforms. The framework can de‐risk investment decisions, primarily related to scale‐up and provides a basis for proactive decision‐making in manufacturing and distribution of advanced therapeutics.