Reactor engineering in large scale animal cell culture

Area of Science:

• Biotechnology
• Biochemical Engineering
• Cell Culture Technology

Background:

• Industrial bioprocessing increasingly relies on large-scale free suspension culture in agitated bioreactors exceeding 10,000 L.
• Limited large-scale studies necessitate extrapolation from small-scale data, posing challenges for quantitative analysis.

Purpose of the Study:

• To review and synthesize findings on engineering challenges in large-scale free suspension culture.
• To address issues that escalate with increasing bioreactor size, focusing on industrial applications.

Main Methods:

• Review and extrapolation of data from small-scale studies to large-scale bioreactor operations.
• Analysis of factors including agitation, bubble bursting, homogeneity, feeding strategies, and cell retention systems.

Main Results:

• Shear sensitivity from agitation and bubble bursting is less critical at large scales.
• Maintaining homogeneity of pH and nutrients is crucial for large-scale cultures; sub-surface feeding is advised.
• Cell retention/recycle systems face challenges with fouling, capacity, and shear sensitivity.
• Fed-batch operations increase oxygen demand and CO2 evolution, impacting pH control, pCO2, and osmolality.

Conclusions:

• Optimizing oxygen transfer through higher sparge and agitation intensities can mitigate CO2-related issues.
• The perception of shear sensitivity continues to influence commercial-scale animal cell culture development.
• Recommendations for bioreactor configuration and operating strategies are provided for improved large-scale culture performance.