Bioreactor Operational Excellence: Best Practices from Scale-up to Control

In biomanufacturing, knowledge of scale-up, processing and control should be shared and documented in order to achieve and sustain operational excellence.

By Brian J. Stamper and Cillian McCabe, BioProcess Research and Development, Eli Lilly and Company

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The modern cell culture bioprocess has been successfully scaled up to volumes greater than 25,000L through sound engineering fundamentals and thorough process understanding. This hasn’t happened by accident, but rather by bioprocessing professionals taking a systematic approach to characterizing the bioreactor’s capabilities and tendencies, developing robust and reliable scale-up procedures, and establishing and maintaining proper control criteria. Those manufacturers that identify and document operational best practices for a cGMP cell culture plant also tend to be those that sustain operational success and deliver high-quality biopharmaceuticals to patients in a timely and reliable manner.

Identifying and documenting bioreactor operation best practices allows for more robust processing by helping to properly educate the operations, engineering and technical staff who oversee the bioreactor processes. Shared learning helps to reduce the amount of “tribal knowledge” that exists within a group and to maintain high levels of operational excellence even in times of employee turnover, with the end result being a sustainable and reliable supply of biopharmaceuticals.

With these ideas in mind, we have set out to document best practices that we have learned for bioprocessing, most notably in the areas of equipment design and overall process control.

Bioreactor Design

Starting off with the proper bioreactor design can resolve many process issues before they arise. One key bioreactor design issue that should not be underestimated is the importance of geometric similarity between bioreactors: maintaining aspect ratios, impeller sizing ratios, impeller spacing ratios and baffle size and location will greatly increase the probability of success at scale. A properly designed bioreactor can lead to reduced qualification and process validation timeframes, as well as increased apparent process robustness and operational success. 

Another key aspect to bioprocess scale-up success is the design of the sparger. Often, two spargers are installed in the production bioreactors while only one sparger is used for the seed bioreactors. While various types of spargers have been utilized within the industry, we have successfully implemented the use of drilled pipes and sparge stones. The drilled pipe yields large bubbles and a lower kLa (which will be discussed below), while the sparge stone yields small bubbles and a very high kLa such that a greater amount of oxygen can be delivered into the cell broth for the same gas flow rate. Figures 1 and 2 illustrate the sparger location and two sparger types.

Figure 1.  Illustration of the sparger location within a bioreactor (not drawn to scale).
(Click to enlarge image) Figure 1.  Illustration of the sparger location within a bioreactor (not drawn to scale).
Figure 2. Comparison of bubble sizes erupting from sparge stone and drilled pipe.
(Click to enlarge image) Figure 2. Comparison of bubble sizes erupting from sparge stone and drilled pipe (reproduced from

The ability of the bioreactor to deliver oxygen to the cells is defined by the mass transfer relationship shown in Equation 1. The change in oxygen concentration is controlled by kLa, the average saturation oxygen concentration of the bubbles,, dissolved oxygen concentration ([O2]dissolved) and the oxygen uptake by any cells present (OUR).

Equation 1

The kLa can be mapped as a power law function of the power/volume and superficial gas velocity. Understanding of the kLa allows for estimation of the OUR capacity of the bioreactor, prediction of required oxygen flow rates and prediction of the time-course profile of the dissolved carbon dioxide levels.

Based on process needs and sparger capabilities, the process engineer must determine the preferred configuration for the bioreactors. If process OUR needs are sufficiently low, the default configuration can be the use of one drilled pipe in the seed bioreactors, and two drilled pipes in the production bioreactors. The combination of a drilled pipe and sparge stone may also be used, but the oxygen transfer ability afforded by the sparge stone is typically not necessary. Use of the sparge stone should be avoided if possible due to the increased operational complexity associated with bioreactor set-up, manual changes in gas flows during a process to maintain dissolved carbon dioxide levels, increased foaming and potential cleaning concerns. 

Mixing Characterization

When scaling up a free suspension cell culture bioreactor, a thorough understanding of the mixing characteristics is essential. If the mixing inside the bioreactor is appropriately controlled, then the cells will experience an environment very similar to that of the bench-scale bioreactor and will therefore be much more likely to behave as they did in the scale-down bioreactors. 

The literature shows that many methods of scale-up have been considered, including matching power/volume, impeller blade tip speeds, bulk mixing Reynolds numbers and bulk mixing times. Due to the nature of these various parameters, it is not possible to maintain them all during scale-up under one set of conditions.     

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