When Science Bears Fruit

Biotechnology

Biotechnological production processes are gaining in significance. They are, however, very delicate and also more complex than pure chemical syntheses. At Bayer Technology Services, a whole team is dedicated to designing optimal fermentation processes.

In his early years as a process engineer, Dr. Helmut Brod could hardly have imagined doing anything more complicated than what he was already doing: spinning elastic thread of consistently high quality from a polymer solution. Now, more than ten years later and having seen his career at Bayer take him from purely chemical reactors to biotechnological fermenters, Brod knows that it can get a lot more complicated than that. Suddenly he was introduced to hamster cells that synthesize a gigantic protein. “The number of chemical reactions that take place in a living cell is many times greater than those in a purely chemical system,” Brod observes today That made a lasting impression on the engineer, who only began to take an interest in biology at a comparatively late stage in his career. 

Over the years, he has gathered an ever-increasing amount of knowledge and experience in the field of biotechnology, such that he is currently in charge of the Fermentation & Cell Culturing group at Bayer Technology Services. In addition, he is chair of a company-wide committee in which Bayer bundles its expertise relating to biotechnological production. 

And its expertise is diverse. Bayer HealthCare produces in its fermenters active substances for treating hemophilia and diabetes, for example, as well as the intermediate stages of hormonal contraceptives. Fermenters are also becoming more important for Bayer CropScience. It has only been two years since the company first began developing its biological pesticides division by way of acquisitions, and already the plan is to expand the capacity of the reactors. Now, when the question is asked – “What does the ideal large fermenter look like?” – Helmut Brod’s team is able to provide an answer. “Usually a chemical reactor can simply be replaced by a taller one,” says Brod, “but in a biotechnological process, you have to look at a couple of parameters first before you can undertake an upscaling like that.” This primarily has to do with the fact that biotechnology involves dealing with living cells, and they are very particular about their environmental conditions. These include the concentration levels of dissolved carbon dioxide – and this is where the height of the fermenter has a direct effect. “Most cells release CO2 as part of their metabolic process, and this gas escapes since it is only dissolved to a limited extent within the reactor liquid medium,” explains Brod. In a taller fermenter, the lower layers are subjected to greater pressure – and more CO2 is dissolved and does not escape. “The question then is whether this has an impact on the activity of the cells,” remarks Brod. 

Winegrowers in the USA already rely on the benefits of biotechnological pesticides to protect their vineyards.
Winegrowers in the USA already rely on the benefits of
biotechnological pesticides to protect their vineyards.

In  a past project for Bayer HealthCare, for example, when new and larger fermenters were needed to replace the old, smaller ones, the issue of increased pressure led to them being made wider instead of taller. Jörg Kauling, a member of Dr. Brod’s team, remembers the experiments at that time, “Tests had shown the productivity of the bacteria involved was seriously diminished above a certain concentration of CO2.” The conclusion drawn from this was that fermenters should not exceed a certain height and so were constructed wider. The fact that this is not the general rule is due to the difficulties involved in transporting wider reactors.

In the meantime, Bayer Technology Services has also examined the CO2 issue relative to the bacteria in the Bayer Crop- Science fermenters. All that was needed here were lab tests using a one-liter fermenter. “We simply specified varying concentrations of CO2 and then measured the resulting product yield,” explains Brod. The result was an all-clear: higher amounts of carbon dioxide in the fermenter’s liquid medium would in no way impede the production of the particular crop protection agent concerned. This meant that a new fermenter could be built taller than its predecessor, thus providing the assurances needed for future planning.

“It was very impressive to see how quickly Bayer Technology Services was able to simulate the effects of CO2,” extols Dr. Hong Zhu, who researches biological crop protection agents at Bayer CropScience. He adds, “We are very fortunate to have access to such high caliber expertise within our own company.” Dr. Lothar Döllinger, who is responsible for global technology activities at Bayer Crop- Science, is of much the same opinion. “Thanks to recent acquisitions, we now have quite a few biotech production plants. Being able to access the relevant know-how in other areas of the company is very useful when it comes to upgrading these sites.” 

“We are very fortunate to have access to suchhigh caliber expertise within our own company.”

Dr. Hong Zhu

Biologics Process Development, Bayer CropScience

However, the fermentation experts at Bayer Technology Services help not only in the designing of new bioreactors, but also in optimizing existing biotechnology processes. When Dr. Brod talks about these tasks, he repeatedly uses the term, “debottlenecking.” What he means is identifying the bottleneck in the process as it has been managed up until now and eliminating it. An example of such a bottleneck might be when a depletion of a specific nutrient occurs somewhere in the reactor during a fermentation process. The cells in such a zone are then left on the back burner.

The capacity of production fermenters is anywhere from several hundred liters up to hundreds of cubic meters, depending on the product. “Of course, we cannot do our optimization tests on that scale,” notes Brod, since, as he points out, the cost of the nutrients alone would make it too expensive. “At the moment, we are working on defining the operation of small fermenters with ten or sixteen liters in such a way that we can draw reliable conclusions, which we can then apply on a large scale.” Defining a representative downscaling like this, however, is anything but a trivial matter. The precise downscaling of simply the stirring, which is meant to provide an even distribution throughout the fermenter, is a demanding task in itself. Another issue being investigated is the formation of foam, typical of many microbiological processes. In addition, to making their experimental work as effective as possible, the team is also attempting to simulate the complex reactor events in computer models to derive useful predictions.

And there is yet another trend in biotechnology that Brod and his team are currently supporting with their expertise: the transition from classic batch production to continually operating systems that produce a constant product yield (see "A Steady Eye on the Future").

In this respect, Dr. Brod is positively overjoyed at the diversity of expertise related to biotechnological production at Bayer. “We all compare notes regularly, meet at the relevant production sites, and learn from each other.” Although he still fondly recalls his time in polymer process engineering, he has long since become a passionate biotech process engineer.

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