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A correct stirrer is a must

Aerated stirred tank reactors have virtually become a standard piece of equipment in bioprocess engineering. No other bioprocess engineering bioreactor is as versatile, meaning that significant time- and cost savings are made. Sophisticated methods of numerical flow simulation such as those used at the Institute for Biochemical Engineering (IBVT) at the University of Stuttgart make these reactors even more effective.

Whether in food preparation, in a washtub or in the hods of Middle Age alchemists – there have always been things to ‘stir’. Bioprocess engineering is no exception: stirred tank reactors involving rotating mixing tools have been key to common production processes for many decades. The first industrial method for the production of penicillin during WWII used this specific assembly. “Back then, stirrer tanks were the only biorectors that were able to mix the highly viscous reaction medium of the penicillin fungus with a consistency similar to apple sauce and provide it with oxygen,” said Professor Matthias Reuss, Head of the IBVT.

The industry likes versatility

Head of the Institute: Professor Dr.-Ing. Dr. h.c. Matthias Reuss (Photo: IBTV)
Since then, the stirred tank reactor has become standard in the pharmaceutical industry: less because of its single advantages, but more because it can be used for a broad range of different applications. “It is possible to end a biotechnological process and start another one relatively quickly without needing to design a new reactor. Companies save a lot of time and money as well,” said Reuss.

However, global competition and increasing cost pressure now require the development of even larger and more efficient stirring systems that have higher yields. Up to a certain limit, higher yields can also be achieved by increasing the production capacity of microorganisms through genetic modifications. However, an optimal result can only be achieved when the whole system works effectively. “I don't think the best way is to think of each individual cell as an isolated production system,” said Reuss adding that “the interactions of the bacteria or yeasts used with their extracellular environment in the bioreactor are equally as important.”

The fine difference – ideal versus actual mixing

In many cases, even small modifications of the stirring elements or the appliances used to apply oxygen and nutrients can have a drastic effect on the production result. Insufficient mixing might lead to high concentration differences in the bioreactor to which the microorganisms often have a very sensitive reaction. “Some cells might suddenly be exposed to very high glucose concentrations and others to very low glucose concentrations. This of course has a drastic effect on their function,” said Reuss explaining the practical consequences such modifications could have. But also critical shear stress affecting the cells during stirring cannot be explained without looking at what really happens specifically in such situations. Metrological methods quickly reach their limits and are also very expensive.
These problems can be solved by a numerical method known as computational fluid dynamics (CFD). This method, which was originally developed for the aerospace/space industry, enables the precise modelling and simulation of numerical processes to analyse fluid flows inside bioreactors. “Instead of just assuming that the fluid inside the bioreactor is completely mixed, the new method provides us with specific information about the three-dimensional transport phenomena that are happening in a reaction tank. In addition, it also gives us details about the individual environments of every single cell,” said Reuss.

Looking for optimal stirring tools

These simulations are increasingly complementing the classical experimental examinations and interpretations relating to the optimal adaptation of the stirred reactors to the actual operation situation. CFD enables the realistic modelling of the different reactor constituents independently of scale. CFD is particularly suited for assessing the effect of different mixing elements on the mixing in the reactor. Apart from the design and size, it is also possible to simulate different angles of inclinations and assemblies. This led to the discovery that certain stirrer types are insufficient for axial mixing, but on the other hand enable the excellent supply of oxygen to the reaction medium – and with other stirrer types it is exactly the opposite.

That is why nowadays the practice is to combine several different stirrer types. “The simulations provide us with details about which stirrers to use, where to position them and how heavily the broth has to be stirred,” said Reuss summarising the advantages of the new method that is already used in industry.

But the method also has its limits. Two- and multiphase systems such as for example gas-fluid dispersion cannot be effectively simulated with CFD. “In addition, many phenomena are not yet physically understood and can therefore not be described mathematically – for example the occurrence of turbulence,” said Reuss.

This will not hamper the success of numerical flow simulations in the field of bioprocess engineering because the method already enables new and fascinating insights into the inner life of stirred tank reactors, something that would otherwise not be possible. 

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/a-correct-stirrer-is-a-must