Cell Culture Scale-Up in Stirred-Tank Single-Use Bioreactors

Bioprocess development usually is carried out in systems with small working volumes. This helps save time and resources because, at small scale, several experiments can be conducted in parallel. Costs for media are kept low, and relatively little laboratory space is required to operate small-scale bioreactors. But over the course of development, biopharmaceutical companies need more material for characterization, trial runs, and finally for commercialization. They transition to bench scale and then up to pilot or production scale with the intent to maintain constant yield and constant product characteristics. Often that brings some challenges.

To deal with those, development groups must consider shear-stress levels, concentration gradients, and oxygen supply capabilities of production bioreactor systems during scale-up. One important factor is the culture mixing time. As cultures increase in scale, developers want to ensure consistency in mixing because that can influence cells physiology. Therefore, both product quality and yield can be influenced by gradients in glucose concentration, oxygen, and pH. As companies scale up to pilot/production bioreactor(s), they need to maintain culture homogeneity to ensure an ideal growth environment at all scales.

Key process engineering parameters related to scale-up include power input/volume ratio (P/V), impeller tip speed, constant mixing time, constant volumetric mass transfer, and constant oxygen transfer rate (OTR). The latter is an important factor for aerobic cultures. The volumetric mass transfer coefficient (k_La) describes the efficiency with which oxygen can be delivered to a bioreactor culture for a given set of parameter conditions. For proper cell culture scale-up, it is important to select equipment of different sizes with similar k_La capabilities so that small-scale success can be replicated at larger scales. Mixing time is another important factor. As you scale up, you want to prevent concentration gradients and achieve homogeneity throughout each vessel.

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