Scale-up vs. scale-out in bioprocessing

Understanding bioreactor scale-up and scale-out in cell culture expansion

Scaling processes and their application fields: Scale up vs scale out

Scalability is a fundamental challenge in bioprocessing, particularly in cell culture-based manufacturing. As the demand for advanced therapeutics, including cell and gene therapies, continues to grow, manufacturers must choose between two primary strategies for increasing production capacity: scale-up and scale-out.

Scale-up involves increasing batch size by transitioning to larger bioreactors, a common approach in industrial-scale biologics production. Scale-out, on the other hand, maintains smaller volumes but increases production by running multiple parallel flasks or vessels. This approach is particularly relevant for personalized medicine, where small-batch, patient-specific therapies require highly controlled manufacturing conditions.

This article explores the differences between scale-up and scale-out, the challenges associated with each, and their implications for bioreactor scale-up, scale-out bioprocessing, and cell culture expansion.

What is scale-up in bioprocessing?

Scale-up refers to the process of increasing production volume by using larger bioreactors. This method is widely used in the manufacturing of monoclonal antibodies, vaccines, and other large-scale biologics, where production needs to be centralized and efficient. The transition from small lab-scale bioreactors to large industrial bioreactors requires extensive process optimization to ensure that key parameters-such as oxygen transfer, nutrient distribution, and pH control-remain consistent at higher volumes.

One of the greatest challenges in scale-up is maintaining homogeneous conditions across an expanded culture volume. As bioreactor size increases, shear forces, mixing efficiency, and gas exchange become more difficult to control, potentially affecting cell viability and productivity. To address these challenges, manufacturers use advanced bioprocess modeling and computational fluid dynamics (CFD).

What is scale-out in bioprocessing?

Scale-out, in contrast, involves maintaining the same bioreactor volume of flask size but increasing the number of units operating in parallel. This strategy is particularly important in cell therapy and personalized medicine, where often each batch corresponds to an individual patient. Because these therapies require strictly controlled conditions and individualized manufacturing, scale-up is not always feasible.

Scale-out is commonly used in modular manufacturing environments where multiple small-scale bioreactors, often Single-Use Systems (SUS), operate simultaneously. This approach enables greater flexibility and ensures that process conditions remain consistent across all batches. However, managing multiple independent production runs introduces logistical challenges, including higher labor demands, increased facility footprint, and the need for precise batch tracking and process control systems.

Scale-out vs. scale-up: Key differences & when to use each

The decision between scale-up and scale-out depends on several factors, including product type, regulatory requirements, and operational constraints. Scale-up is often preferred for traditional biologics manufacturing, where economies of scale and centralized production drive efficiency. However, scale-out is the preferred approach for cell therapies, where individual batch integrity is crucial, and patient-specific treatments must be produced under tightly controlled conditions.

Scale-up is advantageous when:

• A single, high-volume batch is required to meet market demand.

• The production process can be engineered to maintain consistency across large volumes.

• Regulatory agencies approve large-scale process validation.

  
  

Scale-out is beneficial when:

• The therapy requires small, individualized batches, such as in autologous cell therapy, where each batch is produced for a specific patient.

• Maintaining identical culture conditions across different batches is necessary to ensure product consistency and therapeutic efficacy.

• Flexibility in production scheduling is more important than volume efficiency, particularly for therapies with short shelf lives that cannot be stored or frozen, requiring rapid and continuous production to meet clinical demand. Additionally, decentralized manufacturing plays a crucial role in scale-out strategies, allowing production facilities to be located closer to the point of care. This reduces logistical challenges, shortens delivery times, and ensures that therapies can be administered within their viability window.

Challenges in bioprocess scale-up and scale-out

Both scale-up and scale-out present distinct challenges that must be addressed to ensure efficient and compliant manufacturing.

Challenges in scale-up

Scaling up bioprocesses introduces significant engineering and biological challenges. Large bioreactors often struggle with oxygen transfer limitations, as gas exchange becomes less efficient with increased volume. Shear forces generated by mixing impellers can also damage shear-sensitive cells, particularly adherent and suspension cultures used in cell therapy manufacturing. Ensuring uniform nutrient distribution across an expanded culture is another difficulty, requiring advanced mixing strategies to avoid gradients in pH, dissolved oxygen, and metabolite accumulation.

Regulatory validation is also more complex in scale-up, as process changes at larger volumes must be demonstrated to be equivalent to small-scale conditions. This often necessitates extensive process development, computational modelling, and iterative testing before full-scale manufacturing can proceed.

Challenges in scale-out

While scale-out eliminates many of the engineering constraints of large-scale bioreactors, it introduces significant logistical and operational challenges. Running multiple small bioreactors in parallel increases labor intensity, as each unit requires monitoring, maintenance, and batch tracking. Automation and digital process control systems are often necessary to maintain consistency across batches, ensuring that all units operate under identical conditions.

Another major challenge in scale-out is facility space and resource allocation. Operating numerous independent production lines demands a greater facility footprint, additional cleanroom space, and higher consumable costs. The cost of maintaining quality control across multiple small batches can also be higher compared to a single large-scale production run.

The choice between scale-up and scale-out depends on process requirements, regulatory considerations, and production goals. While scale-up remains the dominant strategy for high-volume biologics manufacturing, scale-out is critical for patient-specific therapies and modular production models. As personalized medicine and advanced therapies continue to grow, scale-out solutions must evolve to address the logistical complexities of multi-batch manufacturing.

Both approaches require careful process optimization, validation, and regulatory compliance to ensure that bioreactor scale-up and scale-out bioprocessing strategies meet the demands of cell culture expansion and therapeutic production. By understanding the unique challenges of each method, manufacturers can design scalable and efficient bioprocesses that align with both industry needs and patient demands.