What if we could reduce the cost of a two-million-dollar cell and gene therapy to just $200,000? This may still seem expensive, but it would bring groundbreaking treatments within reach for many more patients.
Let's envision the future of biotech: a child receives personalized cell therapy in under ten days. A chef cooks cultivated wagyu beef that never came from an animal. An oncologist monitors the production of custom antibodies in real-time.
Today, biotech leaders are pioneering ways to manufacture therapies more efficiently and affordably. These efforts are transforming how we approach medicine and food production. The potential impact is enormous, from treating rare diseases to making cultivated food more accessible and sustainable. This article is adapted from my recent Amphacademy keynote presentation.
Rethinking Bioprocess Design
One of the biggest levers of innovation I’ve worked on is the design of the bioprocess itself. When I was at Merck, I explored ways to increase antibody production more efficiently. Instead of using multiple seed train batch reactors, we transitioned the final seed reactor (N-1) to a perfusion mode. That change alone extended culture duration and boosted cell densities in production.
This inspired Ichnos Sciences to develop a high-density process for a difficult-to-express multispecific antibody. They optimized the cell line and employed a standard fed-batch approach, achieving approximately 20 million viable cells per milliliter and a titer of 6 g/L. By transitioning to a high-density process, they achieved 70 million viable cells per milliliter and titers of 10 to 11 g/L.
These gains demonstrate how intensifying the process can significantly improve output for complex proteins. This example illustrates how even difficult proteins can benefit from rethinking the upstream process strategy.
Innovations in Cell and Gene Therapy Platforms
In cell and gene therapy, Ori Biotech integrates biology, engineering, and digital technologies. Their fully closed and automated bioreactor system allows for small, flexible batch sizes. They focused on automating the most labor-intensive steps, including activation, transduction, expansion, and harvest. The result was a process that was not only more efficient but also more consistent and robust.
Because the process is less dependent on manual operations, variability is reduced, and repeatability is improved. Ori Biotech achieved a 2.5 times higher cell growth simply by switching to its advanced system. This transformation underscores how digital integration can improve yield and quality. It also reflects how solutions from biologics manufacturing are being adapted for cell and gene therapy.
Meeting Downstream Processing Challenges
With the shift toward new protein formats, downstream purification must also evolve. Many new molecules lack the Fc region that traditional Protein A resins target. Cytiva has developed a new affinity chromatography resin that works with Fc-lacking molecules to address this issue. The technique involves adding a custom amino acid sequence to the protein of interest, along with an expressed tag.
- The ligand in the column binds both the tag and protein during loading
- Upon elution, the tag remains on the ligand, while only the target protein is released
- This approach eliminates the need for tag removal steps
- It simplifies regulatory approval by reducing residual tag concerns
This strategy avoids regulatory complications associated with tag removal. It provides a clean, efficient purification route for non-traditional proteins. Such innovations are crucial as the diversity of biologics continues to increase.
Quality by Design in Stem Cell Production
Quality control is significant in cell and gene therapies. At Cyto-Facto in Kobe, Japan, teams use a closed, automated system to enhance stem cell production. These cells are susceptible to minor variations in stress, temperature, pH, and media components. Conventional process validation is not possible when treating a population of one.
Cyto-Facto's solution integrates process analytical technology (PAT) to monitor critical parameters in real-time. Its system handles seeding, culturing, passaging, and harvesting within one platform. It tracks media composition, growth rates, morphology, and clinical outcomes. By maintaining control at every step, it ensures consistent quality without relying on traditional validation methods.
Advanced Real-Time Monitoring and Predictive Models
Collaborations between Oxford Medica, UCL, ETH, and WattBE Innovation led to the development of a new PAT system for lentivirus production. Using HEK293T cells, this system monitored metabolic activity in real-time. Their model encompassed over 350 reactions and 335 metabolites, allowing for routine monitoring during production. This level of insight enables high-precision control, even for complex gene therapy processes.
Using AI, sensors can be linked to a virtual bioreactor, allowing for predictive monitoring and real-time adjustments during production. Sanofi's digital factory adopted this approach, combining equipment, operations, and analytics into an 80 times more productive system. Their system connects operations teams with real-time data and smart quality control, redefining what's possible in modern manufacturing.
Unexpected Discoveries in Metabolite Engineering
Innovation sometimes comes from unexpected places. While reviewing a paper on the effects of pistachios on athletes, I discovered a link to metabolite shifts. One sugar molecule, raffinose, has been shown to impact inflammation and stress markers. This prompted an experiment to see if raffinose could also influence CHO cells.
- Raffinose was supplemented in the culture media
- Glycosylation profiles of antibodies were significantly modified
- High-mannose glycans were selectively reduced
- Receptor binding affinity and ADCC potency were increased
By supplementing cell culture media with raffinose, my team could modify glycosylation patterns. Glycosylation affects the efficacy and stability of antibodies. They improved the glycan profile and enhanced antibody performance without changing the cell line. Using this approach, a more complex fusion antibody with three glycan sites also showed increased receptor affinity and ADCC potency.
Disruptive Technologies Reshaping the Field
The final area of exploration involves disruptive innovation. At Merck, teams tested Berkeley Light's Beacon platform, which cultivates cells in nanopens on a chip. These tiny chambers allow real-time visualization and growth monitoring. High-throughput workflows facilitate the identification of top-performing clones early in the development process.
Triple Bar Bio from Silicon Valley asked a bold question: What is the smallest possible bioreactor? Their answer was a single cell in a droplet. Using microfluidics and AI, they developed a platform to screen millions of cells at the picoliter scale. These systems can analyze omics data in real-time, rapidly selecting optimal producers for biologics and food applications.
Hybrid Models and Predictive AI
DataHow has pioneered hybrid models that use AI to predict process outcomes and product qualities. In collaboration with Bristol Myers Squibb, they improved the accuracy of critical quality attribute predictions. These models can transfer learning between different systems and cell lines, even when unrelated. This has the potential to revolutionize how we optimize production processes across modalities.
This approach can reduce experimental requirements by 50 to 80 percent, saving time and resources. By starting with the right conditions, teams can optimize processes faster and discover better molecules. Hybrid modeling bridges gaps in data and provides a more reliable foundation for process development. As modeling and AI improve, the pace of development can only accelerate.
Rethinking the Bioreactor: Nature-Inspired Innovation
To make biomanufacturing truly accessible, we must challenge conventional thinking. What if tomorrow's bioreactor doesn't look like a vessel at all? One provocative idea involves using transgenic goats. A startup in Belgium, BioSourcing, utilizes gene therapy and in vitro fertilization (IVF) to create goats that produce therapeutic proteins in their milk.
Though still in early development, the concept has shown promising calculations. If proven robust, this approach could reduce production costs by several orders of magnitude, significantly improving access to critical treatments. It may be unconventional, but it directly addresses the accessibility problem.
The Future is Now
Bioprocess innovation is enabling these once-impossible scenarios. The decisions you make in the lab have ripple effects far beyond the facility. Every improvement in yield and quality expands access to patients. Every digital upgrade shortens timelines and lowers costs. Every innovation pushes us closer to a more sustainable and equitable future.
The future of bioprocessing is not confined to reactors. It is unfolding in hospitals, kitchens, and other places worldwide. You are part of this transformation. The question is not whether we will get there. The question is, how fast can we make it happen?
David Brühlmann is a strategic advisor who helps C-level biotech leaders reduce development and manufacturing costs to make life-saving therapies accessible to more patients worldwide.
He is also a biotech technology innovation coach, technology transfer leader, and host of the Smart Biotech Scientist podcast—the go-to podcast for biotech scientists who want to master biopharma CMC development and biomanufacturing.
Hear It From The Horse’s Mouth
Want to listen to the full interview? Go to Smart Biotech Scientist Podcast.
Want to hear more? Do visit the podcast page and check out other episodes.
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