rAAV production cost analysis: Indication-specific cost per dose and reduction strategies

Abstract

Recombinant adeno-associated virus (rAAV) vectors underpin many approved and late-stage gene therapies, yet manufacturing costs remain a major driver of therapy price. Here, we present the first comprehensive, platform-resolved cost analysis of rAAV production across three industrially relevant suspension platforms: transient transfection, baculovirus infection, and producer cell line (PCL). Using a bottom-up model, we decompose total cost-of-goods (COGs) into upstream, downstream, drug product, and quality control contributions at bioreactor scales from 50 L to 2000 L. We show that, on a per-batch basis, baculovirus infection is the most cost-efficient platform, followed by transient transfection and PCLs however, when costs are normalized to vector titer (cost per 1 × 10¹² vg), the ranking shifts, with transient transfection becoming the lowest-cost platform under the modeled assumptions, followed by baculovirus infection and PCL platforms, underscoring the dominant influence of productivity on unit cost. We identify platform-specific cost drivers—plasmids, transfection reagent, and media in transient transfection; media and perfusion consumables in PCL platforms; and affinity capture chromatography in baculovirus processes—with buffer preparation consistently representing the largest downstream material cost across platforms. We further quantify the impact of process development levers: transfection optimization and perfusion-based intensification reduce cost per dose by up to an order of magnitude, whereas affinity resin reuse and capsid enrichment strategies provide modest, incremental savings. Incorporating indication-specific annual viral genome demand reveals how process optimization and scale-up together reduce batch burden and lower dose cost by up to two orders of magnitude, suggesting the potential for improved supply feasibility, even for high-dose neuromuscular indications, under the modeled assumptions of productivity improvement and process optimization. Together, these results provide a quantitative framework linking platform choice, process scale, and unit operations to rAAV manufacturing COGs.