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Cultivating germs

The path to the new plant

Commitment to research

Science

Candidates from the cauldron

The recently refurbished research building Banting 1 is named after the Canadian scientist Frederick Banting who discovered insulin. It features a state-of-the-art fermentation plant, which produces enzymes and active chemical substances that could one day be used for the development of new drugs.

Text by Michael Mildner, photos by Laurids Jensen

The fermentation vessels can be used for enzyme and natural product propagation. They are connected by a new, highly efficient control software.

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Valuable link

Cultivating germs

The path to the new plant

Commitment to research

Published on 24/04/2023

Eric Weber, who heads up the pilot plant in Banting 1 on the Basel Campus, always keeps a cool head. Whether managing the complex fermentation processes or growing grain on his farm in Alsace, everything is carried out with aplomb. The fact that Weber enjoys growing things helps him excel at both farming and fermenting.

It was the work experience on his parents’ farm during his youth that helped him land a job in the agrochemical division at Sandoz in the 1990s, marking the first step on a long career path which ultimately led him to Banting 1. “I started 30 years ago with an internship in the agrochemical division, where I tested fermentation products.”

But even back then, Weber wanted to join the Natural Products group, which focuses on isolating biomolecules from organisms such as fungi or microbes and testing their suitability for use in medicine. “However, given my curriculum, the recruiters sent me to the agrochemicals team instead. It took four attempts before I was able to start my current job at the pilot plant in the Natural Products group,” Weber recalls.

As part of his career, Weber first completed a degree in bioengineering in Alsace. After an internship specializing in fermentation at chemicals company Lonza, he finally took up a position at Novartis in the cell cultures department in 1997. A year later, as a postgraduate, he eventually landed a permanent job at the pilot plant in the Natural Products group, where he remains to this day.

The nutrient solution is separated in the filtration system for enzymes.

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Weber’s lasting fascination with the pilot plant is nourished by its relevance in drug research. “We are the link between the discovery research laboratories in Banting 1 – where potential new molecular entities from soil samples are initially analyzed and selected – and the disease area labs, where the compounds are studied further. Without us, the substances cannot be produced in sufficient quantities to support subsequent research,” he says with great pride.

These days, starting materials such as soil and plant samples, which are processed in the pilot plant, are delivered to Novartis via certified institutes. Since the Nagoya Protocol entered into force in 2014, pharmaceutical companies are no longer allowed to collect their own soil samples as was the case in the past. For example, in the 1960s a Sandoz employee brought a tiny soil sample back from his holiday in Norway, which ultimately led to the development of a compound used in transplant medicine.

“This is actually a positive development,” says Weber. “It allows countries of origin such as Thailand to benefit from their resources and build up their own research know-how. The institutes now take soil or plant samples themselves and isolate fungi in them, for example, before characterizing them. We then get milliliter-sized ampoules from these countries containing pure cultures of the samples, which we test in our laboratories at Banting 1 to see what these substances produce and what potential they have for further development. If successful, we receive an order from our researchers and are then tasked with producing these prospective substances in larger quantities.”

The filtration of the enzymes is monitored and controlled.

Cultivating germs

As soon as Weber and his team receive a new order, the production process begins on the first floor of Banting 1 in the 14 reaction tanks – also known as fermenters – which look like huge cauldrons.

Fermentation generally refers to the transformation of organic material by microorganisms such as bacteria, fungi or single-cell organisms or their enzymes. Originally, fermentation referred exclusively to biological reaction without air. Nowadays, fermentation in biotechnology encompasses any microbial transformation of organic substances into bioreactors – in other words, even those supplied with air.

In a first step, Weber and his team ensure that the fungi and bacteria, which are used to produce the active ingredients, have an ideal environment in which to multiply. Like plants and animals on a farm, the microorganisms thrive best when the nutrient mix is tailored to their individual needs and all other growth conditions, including temperature, are ideal.

“To cultivate the germs, we use various flours, such as soy flour or oat flour, as well as sugar solutions. This is a very demanding task, because there are about 400 different ways of treating soy flour so that the germs produce the desired effect.” But the demands don’t stop here, Weber continues: “There are also differences when it comes to fungi. For example, a mushroom growing in the forest thrives on complex, long-chain sugars, while fungi on wheat needs starch to grow.”

To comply with the highest production standards, Weber and his team rely on the so-called animal-free principle. This requires them to replace animal-based nutritional solutions, which were often used in the past, with plant-based solutions wherever possible.

If all conditions in the fermenters are met, the team can produce up to 500 liters within 14 days – all from an ampoule containing one milliliter of fungal germs.

In a nutshell, the process works as follows: As the liquid grows in volume, it is pumped into the next-largest tank, where various parameters such as pH, temperature, oxygen intake, nitrogen intake, glucose content or agitator settings can be regulated using state-of-the-art software. Ideally, after the process of extracting and preparing the substances on the ground floor of Banting 1 is complete, a pure active ingredient is produced in quantities ranging from 10 milligrams to one kilogram.

Besides natural products, enzyme production from the Novartis substance library is another focal point of Weber’s team. These enzyme-producing strains are supplied in ampoules and propagated in an aqueous solution at a temperature of 37 degrees Celsius. This slightly simpler fermentation process can be completed within three days, after which the producing cells are separated using a centrifuge and then released and filtered for final enzyme purification. This process is generally referred to as harvesting, and for Weber the parallels are clear: “Of course, this reminds me of my work on the farm at home. However, we can perfectly control the conditions for growth here in the plant, which is not the case outdoors in the fields.”

The natural products are extracted after fermentation with organic solvents in the basement.

The path to the new plant

In 2019, Weber was entrusted with planning, setting up and managing the completely new plant in Banting 1. “This task was both a great challenge and immensely satisfying. On the one hand, the 3000-square-meter pilot plant that was previously spread over two buildings now had to be rebuilt and brought up to date in a single 800-square-meter space. On the other hand, this investment was also a positive signal from the company that our jobs on the Campus would be retained. Of course, this also gave me extra motivation,” explains Weber.

The decision to establish the new plant was a timely one, as the existing buildings in which Weber and his team were working all stemmed from the 1960s and were already destined for demolition.

Since the available space in Banting 1 was four times smaller than in the old facility, Weber teamed up with an external consulting firm to develop innovative solutions to meet productivity goals. “Instead of the largest fermentation tank with a volume of 3000 liters, we now had only 500 liters to play with. But thanks to the new control software, which connects all the tanks, we can control the process more precisely and efficiently than in the past. Also, the biochemical reaction processes have been optimized, which means that we are able to reach our goal,” says Weber with visible satisfaction.

There were also other improvements. “In the past, we had to run the samples from one building to another, and some fermentation tanks were already 40 to 50 years old. Today, everything is concentrated in a single building and the technical facilities are state-of-the-art. This not only saves us time, but has also enabled us to further improve safety and meet high environmental standards.”

In the new plant, for example, organic solvents are completely separated, purified and reused during extraction. After about five production cycles, the solvents are reused as an energy source for combustion so that no solvents are released into the environment.

However, the road to commissioning the new plant was not always smooth, as Weber recalls: “We were in despair one evening at the mandatory factory acceptance test. For half an hour, we tried in vain to pump out the liquid until we finally realized that a locksmith had welded the drainpipe shut.”

By evaporation, the solvents can be purified and reused.

Commitment to research

Weber and his team still have a lot of work ahead of them. Around 400 individual production campaigns are planned each year, with the tanks almost never coming to a standstill. Work is carried out from January 5 to December 15, including on-call and weekend service.

“At best, what we manufacture here today will not be on the market until many years later,” explains Weber. “That’s why we focus on providing our internal customers – in other words, the research areas – with sufficient quantities and perfect quality for further development.”

With a modest smile, he recalls one quick-fire success in particular: “We once produced a substance that was later found to be ideally suited to the environmentally friendly removal of rust on rail tracks. Unfortunately, the price for this application was too high.”

Whether the substance can be applied in farming is unknown. What is certain, however, is that Weber and his team are at little risk of rusting since nature continues to offer countless unexplored active ingredients waiting to be processed in the tanks of the pilot plant in Banting 1.

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