Gene Therapy Manufacturing Scales Up: New Solutions for Large-Scale Production

Gene therapy manufacturers are racing to scale up production to meet growing demand, with bioreactor sizes pushing beyond the standard 200-liter capacity to 1,000 liters and more. This shift presents significant challenges in maintaining efficiency and product quality, but recent innovations are paving the way for successful large-scale manufacturing.

The Scale-Up Challenge: Transfection Complex Stability

As therapeutic developers target larger patient populations for conditions like Parkinson's disease, the need for increased production capacity has become critical. However, scaling up from 200-liter to 1,000-liter bioreactors introduces a major bottleneck: the stability of transfection complexes.

These complexes, composed of plasmid DNA and transfection reagents, have traditionally had an extremely short window of stability—typically 15-30 minutes. Beyond this timeframe, the complexes tend to aggregate, becoming too large to effectively cross cell membranes and reducing transfection efficiency.

For a 200-liter bioreactor, manufacturers need to add about 10 liters of transfection complex within 5-10 minutes to achieve optimal efficiency. Scaling up to a 1,000-liter bioreactor increases this volume to 50 liters, with the same tight time constraint. Fletcher Malcom, Head of Strategy, Product and Business Development at Mirus Bio LLC, explains, "At that volume, the transfection complex solution is difficult to deliver quickly to a production bioreactor."

Innovative Solutions: Extending Stability and Reducing Volume

To address these challenges, companies like Mirus Bio have developed new technologies to enhance transfection complex stability and reduce the required volume. Mirus Bio's VirusGEN Stabilizer additive extends the stability of transfection complexes from 30 minutes to three hours—a six-fold increase.

This extended stability window allows manufacturers more time to add the complex to the bioreactor, reducing stress on employees and minimizing the risk of errors that could impact yield and titer. "That means less scrambling to add the solution to your bioreactor, and more opportunities to scale up production into the thousands of liters," Malcom notes.

Additionally, Mirus Bio's transfection reagent and enhancer technologies enable manufacturers to achieve higher titers and percentages of full capsids while reducing the transfection complex volume. Malcom highlights, "When you're manufacturing in the thousands of liters, being able to reduce the transfection complex to 2% of culture volume instead of 5% goes a long way in streamlining your workflow and making life easier for your staff."

Implications for the Gene Therapy Industry

These advancements in transfection technology have significant implications for the gene therapy industry. Manufacturers can now increase capacity while maintaining high productivity levels, manage costs more effectively, and reduce the risk of wasted batches due to transfection complex instability.

The ability to scale up production efficiently is crucial as gene therapies increasingly target polygenic indications with larger patient populations. By overcoming the limitations of traditional manufacturing methods, these innovations are helping to ensure that the promise of gene therapies can be delivered to patients on a larger scale, potentially impacting millions of lives.