A Steady Eye on the Future

Biological Process Engineering

Biologics are increasingly gaining importance in the field of medicine. However, optimized manufacturing processes are crucial if these giant molecules are to remain a success. These processes need to be fast, flexible and economical. The MoBiDiK concept is paving the way.

Together with partners from academia and industry, Dr. Andrea Vester is developing economical and flexible solutions for the manufacture of biologics. This method allows production for small groups of patients.

The wine-crate-sized container looks surprisingly like a beating heart. Surrounded by surveillance monitors, hoses and pumps, it swings back and forth every second, keeping its liquid contents in constant motion. In fact, the object that swings so steadily in the E 41 building at the Leverkusen Chempark is a heart – the heart of an innovative concept for the production of biologics.

Biologics? Dr. Andrea Vester positively glows at the mention of the word. Sitting just a few feet away in her office, she gladly explains the term: “Biologics are large, very complex molecules that can only be manufactured biotechnologically.” The best example is antibodies for cancer therapy. As active pharmaceutical ingredients, biologics are becoming increasingly important, which is why their efficient manufacture is equally gaining in significance. Together with her team at Bayer Technology Services, Vester is currently working on optimizing the industrial production of biologics – with the aim of more diversity and lower manufacturing costs. This is the great advantage of these innovative active substances: in future, many drugs will be manufactured in small quantities for specialized therapies, and thus will be beneficial for the patients as they will receive the optimum treatment available. 

However, as opposed to small active substance molecules, biologics cannot be created using conventional chemical syntheses. “The molecules have very complex structures, for example, certain patterns in groups of atoms that cannot be produced chemically,” says Vester. Fortunately, certain bacteria and cell cultures are able to take on the production process. This is because most biologics are proteins whose genetic blueprint can be transferred by way of DNA snippets into the genetic material of organic producers.

“This new procedure could bring significant advantagesfor the production of antibody preparations.”

Dr. Maria-Luisa Binda

Head of Innovation Management Product Supply, Bayer HealthCare

Together with a nutrient solution, cells prepared in this way are placed in a type of incubator, called a fermenter. Once the conditions are right, the cells will start producing the desired biomolecules. Finally, once this process is completed, the product is separated from the nutrient solution and purified.

It may sound simple, but in practice, it is an extremely sensitive and inflexible procedure. Starting new production inside the equipment, or even changing to another active substance is extremely time-consuming. “All the parts that have been in contact with the previous product have to be meticulously cleaned,” Vester explains. “This is carried out according to an officially approved cleaning protocol and subject to thorough examination. New processes cannot go into operation without these validation procedures. This ensures that the process and the equipment used can be reproduced to result in the desired product every single time.” The authorization process alone can take as long as twelve months.

Minimizing this timeconsuming step is exactly what Andrea Vester and her team are working on. The concept the group is investigating, together with its laboratory version swinging every second, is called Mo- BiDiK. The abbreviation is derived from “modular bioproduction – disposable and continuous.” While MoBiDiK may have nothing to do with a white whale, it could still make large waves and revolutionize the industrial manufacturing of biologics. “The individual process stages, such as synthesis, filtration, and purification, are carried out in separate modules, which we’ve designed as sterile one-off systems made of plastic,” says Vester. Exactly as previously stated: modular and disposable. The advantage of this system is that at the end of the production process, all those components that came into contact with the product can be simply exchanged for new components. This omits the need for time-consuming cleaning and validation. “This type of production saves resources, time, and costs,” she explains. 

The 37-year-old is obviously in her element. Biologics production seems second nature to Vester. But then she did gain her PhD in biological process engineering in Munich after completing a mechanical engineering degree in Aachen. She particularly enjoys the fact that she and her current team can work across disciplines, developing solutions with other engineers, as well as with chemists and microbiologists. And there is something else that she likes: the strong links to academia five years after graduation. MoBiDiK is a collaboration with INVITE, the joint research company run by Bayer Technology Services and the Technical University Dortmund, and with other university institutes. The 30-member team not only includes colleagues from Bayer, but also from the universities in Dortmund and Aachen.

Biologics are currently manufactured in a batch process. Production takes place in fermenters, which can occupy several stories and contain up to 30,000 liters. Once sufficient product molecules are formed within a single batch, they are isolated, filtered and purified. Meanwhile production comes to a standstill. Only when this process has been completed does production start again with the next batch. Vester and her team aim to be producing continuously soon, no longer in batches. Instead, the liquid will be constantly removed from the fermenter during the production process and the active ingredient separated. The production cells are retained and, together with a fresh nutrient solution, returned to the reactor.

With the next generation of active ingredient molecules the task of conventional fermenters will be replaced by much smaller disposable bioreactors, some of which, holding 200 liters, are barely larger than a bathtub. These small fermenters run continuously and can supply the same amounts of active ingredients as their larger counterparts. 

This new concept is currently undergoing rigorous testing in Leverkusen. Bayer HealthCare is also following developments closely, since the number of biologics among the company’s pharmaceutical range of products is constantly growing. “This new procedure could bring significant advantages for the production of antibody preparations,” stresses Dr. Maria Luisa-Binda, Head of Innovation Management at Bayer HealthCare Product Supply in Leverkusen.

While the new concept is still being scrutinized, Vester already has a further development in mind – small, automated production lines that manufacture high-quality products at a low cost, independent of volume and location. Does this mean MoBiDiK is paving the way for personalized medicine? “This is certainly an important goal,” says Andrea Vester. Moreover, being able to provide patients around the world with affordable, tailor-made drugs would lend her profession a real sense of purpose. 

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