Why the scale-up of cell culture is essential for manufacturing Cell and Gene therapies

Bioreactor scale-up as a critical factor in early process development

From lab-scale to large-scale: Manufacturing of CGT requires scalable cultivation of cells (Illustration generated with the assistance of OpenAI DALL·E via ChatGPT).

The successful commercialization of cell and gene therapies (CGTs) depends on the ability to scale production efficiently while maintaining product consistency, safety, and regulatory compliance. A well-designed bioreactor scale-up strategy is critical in ensuring that processes developed in early-stage research can transition seamlessly into commercial-scale biomanufacturing. Without scalable processes, therapies face production bottlenecks, increased costs, and delayed market entry. 

How Manufacturing Processes Evolve from Early Development to Commercial Scale

In the initial stages of cell therapy and gene therapy development, small-scale systems are used for process optimization and proof-of-concept studies. These systems include:

• Multi-layered cell stacks – Used for adherent cell culture but require labor-intensive media exchanges and face heterogeneity issues.

• T-flasks and roller bottles – These are common in research labs but impractical for large-scale production.

• Small stirred-tank bioreactors – Used for suspension culture but often need adjustments for scale-up and are not suitable for adherent cell cultures such as stem cell therapies

  
  

As therapies progress toward clinical trials and commercial production, the need for scalable, automated systems becomes apparent. The transition typically involves moving from static culture systems to stirred-tank or perfusion bioreactors, which enable higher cell densities and more efficient production (1). However, this transition presents several challenges that can impact process efficiency and regulatory approval.

Challenges in Scaling Up Cell Culture for CGT Manufacturing

1. System Switch Alters the Culture Environment

Moving from early-stage small-scale culture systems to large-scale bioreactors introduces significant environmental differences (2), including:

• Changes in shear forces – Stirred-tank bioreactors create higher shear stress, impacting sensitive cells

• Oxygen and nutrient gradients – Large bioreactors require precise mixing to maintain uniform conditions

• Process re-optimization – Parameters such as media composition, agitation speed, and gas exchange must be adjusted

  
  

These changes often require a new evaluation of the product, including cell viability, potency, and genetic stability, which can lead to additional regulatory hurdles and production delays.

2. Scale-Out Strategies Increase Manual Work & Handling Risks

To avoid system changes, many CGT manufacturers opt for a scale-out approach, meaning they use multiple identical small-scale systems rather than transitioning to larger bioreactors. While this maintains process consistency, it introduces new challenges:

• Increased labor costs – More systems require more manual handling and monitoring (1), as well as manufacturing space, a currently limited capacity (3)

• Greater contamination risks – Multiple open culture systems elevate the risk of contamination.

• Complex logistics – Managing dozens or hundreds of units creates workflow inefficiencies, and repetitive work, leading to higher failure rates.

  
  

Although scale-out is a feasible short-term solution, it limits long-term cost-effectiveness and throughput.

3. Early Consideration of Scaling Leads to Faster Time-to-Market

Integrating scalability considerations early in development can significantly reduce time-to-market. A lack of scalable processes is one of the most common reasons for delays in CGT commercialization, with “manufacturing remaining the Achilles heel of the CGT sector” (4).

By designing processes that are scalable from the start, CGT manufacturers can:

• Reduce process re-validation efforts when transitioning to larger-scale production.

• Avoid costly late-stage process failures.

• Ensure a faster path to regulatory approval and commercialization.

Optimizing bioreactor scale-up for CGT manufacturing

To ensure efficient scale-up of bioprocesses, manufacturers must implement strategies that minimize risks and improve productivity. Using scalable cultivation platforms, that allow for seamless transitions from small-scale to commercial production and implement automated and closed systems effectively reduces associated hurdles upfront. Without a well-planned bioreactor scale-up strategy, manufacturers face process inefficiencies, higher costs, and regulatory setbacks. Early investment in scalable, automated bioprocess solutions ensures a faster, more efficient path to market, ultimately making life-saving CGTs more accessible to patients worldwide.

References

(1) Bellani CF, Ajeian J, Duffy L, Miotto M, Groenewegen L, Connon CJ. Scale-Up Technologies for the Manufacture of Adherent Cells. Frontiers in Nutrition [Internet]. 2020 Nov 4;7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672005/

(2) M.R. Spier, L.P. de Souza Vandenberghe, A.B. Pedroni 56 Medeiros et al. Applications of different types of bioreactors in bioprocesses, Bioreactors: Design, Properties and Applications (2011), ISBN: 978-1-62100-164-5

(3) BioPlan Associates. 17th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production [Internet]. United States: BioPlan Associates; 2020. Available from: https://www.bioplanassociates.com/17th/

(4) Greg Slabodkin, Cell and gene therapy manufacturing challenges to persist in 2025, (2024), Pharma manufacturing available from https://www.pharmamanufacturing.com/all-articles/article/55251398/cell-and-gene-therapy-manufacturing-challenges-to-persist-in-2025