Fouling‐Free Inertial Microfluidic Cell Clarification for Lentivirus Manufacturing

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Abstract
Lentiviral vectors (LVVs) are widely used as gene‐delivery vehicles in cell and gene therapy, enabling stable integration of transgenes into target cells. However, efficient clarification of LVV harvest remains a major bottleneck in large‐scale manufacturing, as conventional depth filtration often results in significant product loss. Here, we introduce a fouling‐free microfluidic cell clarification (MCC) system that enables high‐efficiency LVV recovery. By precisely controlling the harvest flow rate and adjusting the recirculated cell density by adding buffer, we established a quantitative relationship between clarification efficiency and throughput. Under optimized conditions, the MCC achieved > 95% product recovery while maintaining > 95% cell removal efficiency. The MCC process closely followed the theoretical recovery model assuming negligible product loss within the device. Across three independent batch operations, apparent average LVV recovery remained substantially higher than that of a benchmark process employing a cellulose depth filter‐based process. Scalability tests demonstrated consistent performance at flow rates up to 1.5 L/h without loss of clarification efficiency, demonstrating its potential for large‐scale biomanufacturing. Beyond LVVs, the MCC platform is broadly applicable to cell‐based modalities that secrete therapeutic products, offering a continuous, low‐shear, and fouling‐free alternative to conventional filtration processes.

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