The clinical pipeline for cell and gene therapies is expanding rapidly, but a significant gap remains between preclinical success and regulatory approval. Very few of these advanced therapies reach patients due to manufacturing inefficiencies and high production costs. To address these bottlenecks, Goncalo Regalo, senior product manager for Cell and Gene Therapy at FUJIFILM Biosciences, highlights the importance of designing scalable therapies from the start. Drawing on over 10 years of expertise in process development and compliance, Regalo argues that selecting the right raw materials and automation strategies early is crucial for commercial success.
Key Takeaways
- The Pipeline Funnel: A massive gap exists between preclinical work and approved cell therapies due to high manufacturing costs and lack of scalability.
- Early Raw Material Selection: Moving early to chemically defined, serum-free, and animal-free media formulations minimizes lot-to-lot variability and prevents costly comparability studies.
- Aseptic Closed Systems: Cellular therapies cannot undergo terminal sterilization; therefore, implementing closed, automated systems drops cleanroom requirements from Grade A or Grade B to Grade D.
- Modular Automation Benefits: Modular setups are more efficient for commercial scale-up than single-box systems, which leave expensive components idle during cell expansion.
- Perfusion Bioreactor Advantages: Hollow-fiber bioreactors provide semi-physiological conditions that facilitate high-density T-cell expansion with consistent quality.
Upstream Derisking: Moving to Chemically Defined Media
Cell culture media represents a major biological and regulatory risk in cell therapy workflows. Historically, developers have relied heavily on animal-derived components like fetal bovine serum to support early-stage cell growth. However, animal serum introduces viral contamination risks and profound batch-to-batch variability that undermine process consistency. Even human-derived serum, while biologically advantageous, introduces strict traceability requirements and donor-sourcing compliance risks, particularly under rigorous European regulatory frameworks. Other common laboratory additives, such as phenol red and antibiotics, can trigger allergic reactions in patients, presenting clinical safety concerns.
The solution is clear: Cell therapy developers must derisk their starting raw materials as early as possible. Shifting to animal-free, serum-free, or ideally chemically defined media formulations reduces lot-to-lot variability, improves scalability, and streamlines the regulatory path. The danger of delayed transition is significant. Locking in the critical quality attributes of cell therapy drug products using research-grade media or serum forces developers to conduct highly expensive and complex comparability studies midway through clinical trials to satisfy regulators.
Closed-System Automation: Modular Workflow Design
Unlike traditional small molecules or monoclonal antibodies, living cellular therapies cannot undergo terminal sterilization, such as filtration or irradiation. Therefore, sterility must be designed directly into the process. Manual, open-system processing, such as pipetting in and out of culture flasks, requires Grade A laminar flow hoods within a Grade B cleanroom. This operational model demands elaborate gowning protocols, intensive manual labor, and astronomical operating costs. By contrast, transitioning to closed systems using automated platforms and single-use, disposable fluid circuits allows developers to drop cleanroom requirements to less stringent Grade D environments. This transition significantly lowers manufacturing costs and reduces the potential for human error.
Gonçalo Regalo, senior product manager for Cell and Gene Therapy at FUJIFILM Biosciences, discusses ways to mitigate challenges in manufacturing advanced therapies at scale.
Courtesy of Gonçalo Regalo, FUJIFILM Biosciences
When evaluating automation, manufacturers must choose between integrated single-box instruments and modular workflow designs. While single-box systems provide an easy entry point for early-stage automation, they introduce significant inefficiencies at commercial scales. A single-box system typically houses enrichment, expansion, and harvesting modules in a single unit. Because cell selection is only performed on day one and harvesting on the final day, these expensive modules sit idle during the multi-day expansion phase. A more rational approach involves designing a modular workflow. By using dedicated, closed automated systems for distinct steps—such as magnetic bead enrichment for selection, hollow-fiber bioreactors for expansion, and automated fill-and-finish platforms—manufacturers can choose the best-performing equipment for each stage, maximizing both yield and equipment utility.
Optimizing the Seed Train and Bioreactor Selection
Scaling cells from a small starting population to a clinical dose required careful optimization of the seed train. Many researchers initially expanded cells in culture plates or flasks, which relied on top-down gas distribution. Regalo explained that this top-down aeration was biologically limiting, especially when using serum-free, chemically defined media.
Transitioning to larger-scale bioreactors required a rational evaluation of how different physical forces impacted cell biology. Stirred tank bioreactors introduced mechanical shear stress, and rocking motion bioreactors altered aeration patterns. Regalo highlighted hollow fiber bioreactors as an effective platform for T-cell expansion. Hollow fiber bioreactors provide a semi-physiological environment that can promote high cell densities and support the desired T-cell phenotype through highly controlled growth kinetics.
Regalo concluded that designing for scale early, utilizing closed automated platforms, and collaborating closely with technology providers allowed developers to successfully translate complex cell biology into clinically ready therapeutics.
Use of AI Declaration: This article was produced under The Scientist’s AI Editorial Policy.
