Making Solutions a Perfect Fit

Bioprocess Technology

Sometimes you need special expertise to integrate a new platform into an existing process. Finding the ideal solution is precisely what Bayer Technology Services offered when introducing membrane adsorption technology to isolate an active pharmaceutical ingredient.

Cells are becoming increasingly important as manufacturers of active ingredients, not only for the rFVIII product. A cleanroom at Bayer HealthCare.

"Can you imagine moving to Berkeley for a few years?” When Dirk Fischer was first asked this question at the beginning of 2007, he had to pause to take a deep breath. The process engineer employed by Bayer Technology Services had an interesting job at the Wuppertal site and in his private life, he and his wife were just thinking about having a second child. How can you transfer to California at such a critical point in your life?

At the time the then 34-year-old had already been to Berkeley several times and had spent a few weeks there helping with an important development project. However, it increasingly became clear that this might not be enough. “As the site was preparing for growth, we needed more permanent support from Germany,” says Dr. Scott Probst, who then was with Bayer Technology Services in Berkeley. So, Probst asked Fischer the crucial question.

The project focused on an improvement to the existing rFVIII product manufacturing process. Bayer HealthCare has been synthesizing Factor VIII in bioreactors in Berkeley for the past 20 years. The recombinant factor VIII treatment, synthesized from modified hamster cells, helps people with hemophilia A around the world to lead a nearly normal life. Bayer HealthCare works continually on process improvements, and Bayer Technology Services has been an important partner in many of these projects (see technology solutions 1/2011).

In this case, the project involved a new additive that was meant to protect the hamster cells from mechanical stress. Bayer HealthCare wanted to substitute this new substance for the protein used up until then – for which the company was dependent on a very specific supplier. The new additive is more readily available and cost effective – two important factors to strengthen the competitiveness.

However, it was a long path from the idea to the technical implementation on an industrial production scale. It was precisely here that colleagues from Bayer Technology Services could help. “The entire manufacturing process had to be adjusted, as some of the classical process steps no longer functioned as before,” explains Probst, who was the leading process engineer. 

“Once again, we have jointly realized an important process improvement.”

Jörg Heidrich

Senior Vice President Product Supply Biotech, Bayer HealthCare

In the solution that is continually harvested from the bioreactors the factor VIII is present in a highly diluted form. “Traditionally, the concentration is achieved through ultrafiltration,” says Probst. The ultrafiltration process separates water, salts and low molecular weight species from the clarified harvest, thus concentrating the factor VIII in the solution. “With the new additive this filtration is only possible to a limited extent,” explains Probst. “The substance precipitates out of the solution and would therefore end up blocking the pores of the filter.”

Bayer HealthCare already developed the idea for an alternative technology to ultrafiltration some years ago: membrane adsorption. With this process step, the bioreactor harvest flows through a filter membrane that has chromatography ligands on the surface. Under the load conditions, the factor VIII attaches to the ligands, and under the elution conditions, the factor VIII desorbs from the ligands. Through this step, the factor VIII is concentrated and impurities are removed.

Such was the theory; however, the technical implementation was anything but simple. Although you can freely purchase modules for membrane adsorption, it is not possible for them to be integrated immediately into your particular process technology with all its special features. 

It is here that Dirk Fischer’s expertise was going to come into play. Thankfully, the German consented to the move. He and his wife agreed quickly, and by April, the family had settled into their new home on the west coast of the United States. At the time the process engineer had already amassed eight years of experience in various biotech projects, all of which involved the production of active ingredients. As a result, Fischer was well acquainted with the strict regulations of the pharmaceutical industry’s Good Manufacturing Practices, which also proved to be very useful in the work on membrane adsorption technology.

First of all, Fischer carried out detailed research to determine what is essential for the integration of the membrane adsorption process. As it turned out, membrane adsorption systems were meant to be connected to the feeds of six bioreactors in total. It was also necessary to connect the system to all of the chromatography and cleaning solutions required for the process. Due to space limitations, some of these solutions could only be stored as concentrates. “That means we had to be able to dilute them in the system itself,” says Fischer. Another requirement was that the entire system had to be able to tolerate hot steam sanitization procedures. The system also had to carefully control fluid temperatures and flow rates. In the end 105 automated valves were installed to regulate all of the required flow paths and system functions. The membrane adsorption recipe sequences are completely automated because they must be executed very precisely. Automation also saves labor, which reduces costs and, once again, increases competitiveness.

Product concentration by means of membrane adsorption is not only a practical alternative to the conventional ultrafiltration process, but it also offers a number of other advantages. “This technology platform is also much faster,” lead process engineer Probst is pleased to say. But that is not all. At the same time, it also fulfills two tasks as part of the purification process that, using the conventional technology, have to be carried out separately This shortens the overall processing, which is beneficial. “Factor VIII molecules are relatively unstable and can disintegrate over time,” explains Probst. “Therefore, with every minute saved and the faster the product can be frozen, we also increase the production yield.”

The project team is proud of something else too: the new manufacturing process was built right next to rooms where GMP manufacturing operations for a high-value product were ongoing. “Over and over again we had to carry out safety analyses to ensure we would not jeopardize normal production,” recalls Probst. For example, special considerations had to be taken into account when modifying utility lines that were directly adjacent to those utility lines supporting ongoing operations. “We had to be very careful to make sure that we were cutting the correct pipes because the alternative was potential disaster,” says Probst. Even though the new process is now ready for start-up, it still has not received authorization for use. Due to the modified process technology, the rFVIII therapies produced in this way must first be tested in clinical trials.

In the meantime Dirk Fischer is back in Wuppertal, where Bayer HealthCare is building another production facility for rFVIII therapies. Fischer will be able to make use of his experience from Berkeley. And so can Scott Probst. Much like in Fischer’s case, one day he was asked, “Can you imagine a move to Germany?” His family agreed quickly as well, and Probst accepted the offer.

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