No Chance for Viruses

Biotechnology

More than ten years ago, Bayer Technology Services developed a process to render viruses in liquids harmless. Long proven in the laboratory, UVivatec is now launching at an industrial level.

Hurricanes are the best proof: circular motion creates turbulence. The makers of UVivatec have taken advantage of precisely this principle (see box).

We can count ourselves lucky that, far above our heads, we have the ozone layer. After all, it is the ozone layer that ensures that no type C (UV-C) ultraviolet radiation from the sun penetrates the atmosphere and makes it down to the earth’s surface. If it did, UVC would represent a very real hazard for all life on earth. Its energy can alter certain components of DNA – and ultimately prevent reproduction as a result.

But what sounds dangerous can also become a beneficial weapon. Surfaces, for example, can be kept sterile by employing artificially generated UV-C light. Bayer Technology Services, in turn, has developed a system that, based on UV-C radiation, renders viruses in liquids harmless – a requirement for the manufacture of many pharmaceutical products. The initial concept goes back to the 1990s, but it took years to overcome all of the technical obstacles and to clarify issues relating to materials. The result was called UVivatec, a laboratory version of which has already been marketed for several years by Sartorius, Bayer Technology Services’ distribution partner (see also technology solutions 1/2010).

Among the first users was Biotest, based in Dreieich in Hessen, Germany, which received UVivatec Lab in 2008. Among its products, Biotest manufactures therapeutic substances for diseases of the blood and the immune system. A large proportion of its products are based on materials from biological sources, for example blood plasma, that can potentially contain viruses. To render such pathogens harmless, the plasma has to go through at least two completely independent cleaning stages, a requirement of the regulatory authorities.

“UVivatec works so gently that we are able to achieve high product yields.”

Michael Rodemer

Director Technical Project Management, Biotest

The battle against viruses includes chemical attacks – for example heat treatments or reduction of the pH values – as well as such physical methods as filtration and chromatography. All of these processes, however, have their drawbacks. In some cases, heat or low pH values damage the product itself or reduce its effectiveness. The physical separation processes, on the other hand, become correspondingly less effective the closer the virus and product molecules approach one another in size. This is where treatment with ultraviolet light comes in as the perfect adjunct to existing technologies. “Irradiation with UVivatec precisely targets only the DNA, making it a low-impact, effective process,” confirms Dr. Udo Große-Westermann, Product Manager for Bayer Technology Services, whose portfolio includes UVivatec.

Ultimately, that was also the reason that Biotest was interested in utilizing an ultraviolet system as the ideal anti-virus approach. And ongoing tests with the laboratory version over several years have made believers of the company. “We have seen for ourselves that UVivatec exhibits none of the problems of earlier UV systems,” says Michael Rodemer, who was involved with testing the system at Biotest from the very beginning. Early attempts with UV-C light suffered from an inability to eradicate all of the viruses present in a liquid completely. They also damaged proteins, thus reducing the yield of the product itself. “UVivatec works in such a gentle way that we are able to achieve high product yield,” Rodemer enthuses. What’s more, the system is easily scalable, meaning that the results obtained from tests with the small laboratory system can easily be transferred to the larger UVivatec process module. This is important, for example, when examining the performance of the system with aggressive test viruses such as HIV. Test liquids that contain certain viruses are run through the UVivatec process; they are then tested to find out to what extent the viruses have been neutralized. With problematic viruses in particular, researchers are reluctant to carry out such tests on a large scale.

Biotest has now ordered two UVivatec process systems for its production line. Compared to the laboratory version, these are somewhat larger, have a higher radiation density and allow throughput six times higher, all of which are requirements for using the process in series production. The two systems are to be used for the production of two different compounds, both of which are currently in the early stages of clinical development. Both are part of Biotest’s extraordinarily dedicated development program. Half a dozen different candidate substances are currently going through clinical testing simultaneously. This represents a huge number for a company that has previously had turnover of around 600 million euros a year. And any one of these development candidates could immediately bring in more money than all of their current products put together.

A special trick: A vortex named Dean

Scientists have known for a long time that microbes and viruses can be fought using ultraviolet light. Using the principal to effectively treat biological fluids, however, means employing a number of technical tricks and using suitable materials. One problem is that UV-C radiation is highly scattered – and does not necessarily reach every particle in the liquid. It would therefore be insufficient to simply transport the process solution past an ultraviolet light source.

The developers at Bayer Technology Services had an idea that had previously been put to use in optimizing a heat exchanger: why not simply guide the flow in a spiral along an elongated UV source? When fluids flow along curved pathways, they form Dean vortexes – named after William Reginald Dean, who researched the phenomenon nearly 90 years ago. Experts can calculate precisely how long a path needs to be so that, at the end, practically every particle in the solution will have been exposed to the area of influence of the UV-C light. Bayer Technology Services did just that, then equipped UVivatec with the corresponding number of turns.

The developers chose Polytetrafluorethylene (PTFE) – aka Teflon – for the material for the spiral flow path, because it is UV stable and otherwise completely inert. But it took the very special expertise of a supplier to be able to apply the hard-to-manage material in a perfect spiral to the long quartz tubes in which the UV source is enclosed.

a test system at Bayer
When the light is blue, UVivatec (left: a test system at Bayer) is in action. The ribbed sides (right) show how the liquid is moved in a spiral around the ultraviolet source.

Biotest is currently investing 200 million euros at their headquarters in Dreieich to build up the necessary infrastructure for the future production of their new compounds. This includes the production environment for the two products that are to be treated with UVivatec. While these two compounds are still a few years away from regulatory approval, Biotest – even at this early stage – is taking the necessary steps to secure future production: the manufacturing process, too, has to be officially approved before production can actually begin.

Product Manager Udo Große-Westermann is enthusiastic about the future, because apart from Biotest, the innovative anti-viral technology has already found other buyers. Almost at the same time as Biotest, an order came from New Zealand based Thermo Fisher Scientific.

The larger industrial version of Bayer Technology Services’ UVivatec process has long been developed to series-production readiness. However, every new application brings with it its own particular requirements. As a result, for the past few months the experts from Bayer Technology Services have been occupied with tailoring the two Biotest systems to perfectly correspond to the customer’s needs – and to integrate them into the future overall process.

Biotest, for example, asked for the UV irradiation to take place inside a clean room. Everything else – supply lines, pumps, valves and controls – is to be housed in a separate control room. The advantage is that all parts requiring maintenance are easily accessible, for example for the obligatory annual changing of the valve membranes.

Still, the changes required a degree of resourcefulness on the part of the team. The experts finally settled on a divided housing in place of the usual steel cabinet. This now fits precisely into a corresponding recess in the customer’s cleanroom wall. Once fitted, it only needs to be sealed.

The last technical intricacies were clarified by the end of 2015, and meanwhile construction has startet. If everything goes according to plan, fitting of the system in Dreieich could start in the second half of 2016. Biotest could then commence test operations and initial production in 2017.

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