technologysolutions - Bayersolutions.bayer.com/.../Technology-Solutions-2016-E... · he Bayer Group...

technologysolutionsPhenotyping: Putting Plants in the Picture p. 22

Enzymes: The Catalysts of Success p. 26

Production: A Bull’s-eye Every Time p. 40The role of liver cells in drug research p. 12

Illuminating Insights

T H E M A G A Z I N E F R O M B AY E R T E C H N O L O G Y S E R V I C E S 2 0 16 E D I T I O N

Passion to innovate | Power to change

At Bayer innovation is part of our DNA. But it’s not something that happens exclusively in laboratories. We see it as being open to new and unconventional approaches and perspectives. Our working culture is driven by our passion

and the fascination to think ahead. That is why we encourage you to question the status quo and constantly think beyond the obvious. It takes imagination, ambition and courage to find answers to society’s most pressing questions.


At Bayer innovation is part of our DNA. But it’s not something that happens exclusively in laboratories. We see it as being open to new and unconventional approaches and perspectives. Our working culture is driven by our passion

and the fascination to think ahead. That is why we encourage you to question the status quo and constantly think beyond the obvious. It takes imagination, ambition and courage to find answers to society’s most pressing questions.

3technologysolutions 2016

he Bayer Group is moving into a future as a Life Science company. Its goal: to make a better life possible for people around the world, and to provide solutions for the great

challenges of the future in healthcare and agriculture. At the same time, the company’s internal processes are to be simplified and more closely aligned to our customers. Decision-making channels will be shorter, processes faster.

As the internal Engineering & Technology function, Bayer Technology Services’ primary focus in future will be on full-service, value-creating technologies for the three divisions: Pharmaceuticals, Consumer Health and Crop Science.

The tasks of the new corporate function, however, will not be reduced in any way. On the contrary. As a world-class, innovation company, Bayer is constantly developing new molecules. From these come products and solutions that advance the health of people, animals and plants.

This is exactly where the expertise developed by us proves its exceptional value. In this current issue of “technology solutions,” we present many examples of how our knowledge and experience are called upon and put into practice every single day.

Since January 1, 2016, I have been leading this global team of first-class, dedicated employees. We have decided to continue presenting our readers with exciting instances from within the Bayer world, no longer in an annual magazine format but continually via the Internet – with the already familiar editorial articles, interviews and reports. Because the mission that Bayer has dedicated itself to – Science For A Better Life – remains unchanged. And that is something that will always be worth reporting on.

I hope you enjoy reading this edition.

Dr. Armin Knors

T

Don’t miss out on a single article from technologysolutionsRegister at www.solutions.bayertechnology.com/order or scan the QR code with your smartphone to receive our future articles free-of-charge.

Dr. Armin Knors,Managing Director ofBayer Technology Services

Editorial

4 technologysolutions 2016

The Catalysts of LifeIn the natural world, nothing would happen without them. Researchers at Bayer Technology Services are now using enzymes for chemical syntheses

Bull’s-EyeDeriving optimal production conditions by combing through the available process data is an art

Heading to WuhanFresenius Kabi is building a new production site in the heart of China – planned and supported by Bayer Technology Services

Understanding the Liver Anyone wanting to develop drugs has to know what happens to them in the liver. Experts are developing more and more sophisticated models

Ambassadors for InnovationEvery day, Bayer Technology Services employees are hard at work on inno-vative solutions in the spirit of Bayer’s mission: “Science For A Better Life”

Researchers are on the hunt for the right biocatalysts – Page 26

Researchers are attempting to model processes in the liver (red) – Page 12

WHAT AFFECTS THE WORLD

WHAT INSPIRES PARTNERS

12

40

30

26

44

Contents

technologysolutionsPhenotyping: Putting Plants in the Picture p. 22

Enzymes: The Catalysts of Success p. 26

Production: A Bull’s-eye Every Time p. 40The role of liver cells in drug research p. 12

Illuminating Insights

T H E M A G A Z I N E F R O M B AY E R T E C H N O L O G Y S E R V I C E S 2 0 16 E D I T I O N


03

06

21, 43

50

50

51

Innovation Engineering Optimization

A Home for 600,000 PlantsFully automated, energy saving. Bayer Technology Services helped Bayer Crop Science build an ultra-modern greenhouse

The Dust CatchersSeeds are often coated with plant protection products. Modern technologies help to optimize this process and avoid dust caused by later abrasion

Hard Times for CounterfeitersA new code aims to make every drug package counterfeit-proof and one of a kind. Bayer Technology Services is driving the project forward

Interview: Dr. Thomas Steckenreiter – Page 8

Real or fake? Scan the code to find out – Page 46

The Best and the FastestProduction systems that communicate with each other. Dr. Thomas Steckenreiter explains how Bayer is backing Industry 4.0

No Chance for VirusesBiological material can contain viruses. Bayer Technology Services has developed a process to get rid of them.

Lights, Camera, Action!New imaging technologies allow a wealth of important information to be obtained from pictures of plants

WHAT KNOWLEDGE ACHIEVES

WHAT SUCCESS CREATES

Editorial Close-Up News Knowledge Masthead Sites

SECTIONS

34

08

36

18

COVER: One of the many tasks of liver cells (stained in this image) is

that of filtering and removing for-eign substances from the blood.

This also applies to the active ingredients in pharmaceutical

drugs. For those developing such products, it makes sense to be able to predict the fate of sub-

stances in the liver (p. 12)

22

46


t first glance, the illustration above looks extremely complicated. On second and third glance, too,

most likely – that is, at least, if you don’t happen to be a biochemist. Because if you were such an expert, you would realize immediately that this diagram represents the metabolic

Got it? A

Close-Up


pathways and that it provides an overview of the chemical reactions that take place inside cells. Of special interest to Bayer’s Nimbus Biotransformations Project are the enzymes marked in blue. These particular enzymes demonstrate a unique characteristic: in reactions, they catalyze with exceptional accuracy, even in extremely complex environments. Modern biotechnological methods even allow specific additional

chemical modifications to be made. This can change entire metabolic pathways – and the tiny organisms, invisible to the eye, can be transformed into miniature production plants. Such processes can be particularly useful in the development of new substances in both the pharmaceutical and agrochemical fields. You can read more about the subject in “The Catalysts of Life” on page 26.

technologysolutions 20168

The Best and the FastestSupplying the markets as fast as possible – without a doubt, one of the key factors for future success. To do this, Bayer is backing an increased focus on Industry 4.0: intelligent production systems networked to allow them to communicate with each other. At Bayer, Dr. Thomas Steckenreiter is one of the driving forces behind this.

solutions: Mr. Steckenreiter, at Bayer you’re known as “Mister Industry 4.0.” What’s behind that catch-phrase?Steckenreiter (laughing): Thanks for the compli-ment! But I really should correct that: I’m one of those who advocates for In-dustry 4.0 and wants to push ahead with those kinds of innovations. Broadly speaking, that means using intelligent production systems that are networked with one an-other and thus improve our production efficiency.solutions: Is that possible in the chemical sector?Steckenreiter: Oh, absolute-ly. Let’s take sensors as an example. At Bayer, there are around 250,000 instru-ments in use in the produc-tion areas, measuring tem-perature, pressure, fill level, flow rates, and so on. If we can make use of algo-rithms, models and pro-cess knowledge to build more intelligence into that system, then we can make calculations based on far more information than we can record using standard devices. We not only get

Thomas Steckenreiter was born in 1965 in Offenbach/Main, and stud-ied chemistry at the TU Dortmund University. After submitting his dis-

sertation in 1997, he worked as product manager at Mettler Toledo. In 2001, he moved to Endress+Hauser, working most recently as Director of Marketing. In July 2013, as a member of the Management Committee of Bayer Technology Services, Dr. Steckenreiter took over as head of the Op-eration Support & Safety division. Since then, he has also been a board member of the User Association of Automation Technology in Process In-dustries (Namur). Across all his responsibilities, the focus of his work has consistently been on an integrated approach to processes, with the goal of improving product quality as well as process safety and efficiency.

The Process Expert

more information about processes and the proper-ties of materials, but these so-called smart sensors – at any given moment in any given place – provide us with a comprehensive overview of the status of production, stock and quality.solutions: Can we already call that intelligent?Steckenreiter: Not the actual measuring, no. But Indus-try 4.0 means that the sys-tems communicate with each other, that they think in conjunction with one an-other. And that they get things moving at the right time. For example, autono-mously planning and con-trolling a process so that there is less downtime, or supporting production planning in batch opera-tions, or communicating suggestions for optimizing operations.solutions: To what extent is quality an aspect of Indus-try 4.0?Steckenreiter: A good exam-ple would be the produc-tion of pharmaceuticals; this is an area where quali-ty plays a particularly cru-cial role because it’s di-

rectly connected to human health. The goal here is continuous quality control built directly into the pro-cess, knowing at every point in time exactly what a particular tablet is com-prised of. I would call that something worth striving for. And that is something we can achieve.solutions: You’re talking about individual tablets, not about tons. Has the per-spective shifted with the re-alignment of Bayer and its concentration on the life sciences? Are we more fo-cused on production now?Steckenreiter: Our aspira-tions in terms of quality

and safety have always been extremely high, and that hasn’t changed. But you’re right: We used to be far more involved with the production of mass-pro-duced chemicals, the kinds where we would produce 100,000 tons a year, and now we are looking at far smaller quantities. This applies to drugs just as much as to crop protection products.solutions: So is it the quantities alone that determine the focus on Industry 4.0?Steckenreiter: No, quantity is only one aspect. The glo-balization of markets, their

INTERVIEW WITH DR. THOMAS STECKENREITER

What Knowledge Achieves


The Best and the Fastest

interconnectedness and the individual needs of customers are forcing us to get our products to market as quickly as possible. The key expression here is “time to market.” These days, it’s no longer enough to only be the best. We have to be the fastest and the best. And to achieve that, we need the corre-sponding production envi-ronment.solutions: Where are you already the best?Steckenreiter: In the field of developing new molecules, Bayer can legitimately lay claim to the title. The work being done in this area is one of a kind. And I’m convinced that this will

Better efficiency through better networking: Dr. Thomas Steckenreiter advocates Industry 4.0.

they also work with very different production condi-tions. In a modern car fac-tory, nine different vehicle models with X-number of equipment configurations can be produced on a sin-gle production line. It is absolutely conceivable that, in the space of one year, you will never see two identical cars roll off the line, which takes in-credibly sophisticated planning and logistics. That would be absolutely impossible without intelli-gent systems and without the complete interconnect-edness of both horizontal and vertical systems, meaning from the mea-surement level to the ma-

continue to be the case in future.solutions: That would seem to suggest that Bayer can’t currently make that claim when it comes to produc-tion.Steckenreiter: I didn’t say that. One has to look at these things with more dif-ferentiation, because envi-ronments vary consider-ably from one industry to another. If we take the au-tomotive industry, for ex-ample …solutions: … they certainly pushed ahead with automa-tion much earlier.Steckenreiter: That’s true. But they not only saw the importance of automation very early in the piece,

chine control level all the way to the SAP system.solutions: But you your-self said that you are now looking at far small-er quantities. How is that different from what takes place in the auto industry?Steckenreiter: For one thing, we are working with fluids, and fluids by their very nature are much harder to work with than individual compo-nents. And you have to keep in mind that Bayer has more than 200 indi-vidual production sites around the world produc-ing more than 5000 prod-ucts. Just introducing the same standards at all of


those sites is a mammoth undertaking. At the same time, I’m not trying to hide the fact that we can learn from other industries. And I am certainly not only thinking about the auto industry when I say that.solutions: But also … ?Steckenreiter: In electrical engineering, too, they’re already well ahead, and al-so in the food industry. We

will be taking a very close look at both of those. No doubt we will be able to translate a number of tech-niques and refine them for our own company.solutions: Concretely speak-ing, what does that mean for Bayer?Steckenreiter: As part of the Bayer reorganization, we will initially be putting special emphasis on the development of technical standards that are applica-ble around the globe, and also on a reduction in the number of certified suppli-ers. These would then be binding for all of Bayer’s production facilities.solutions: Why hasn’t that happened before today?Steckenreiter: To a certain extent, it already has, but on a worldwide scale there hasn’t necessarily been a need to do so. Consider-ation was also given to the particular requirements of individual sites.

solutions: Was that a mis-take, perhaps?Steckenreiter: It was an un-derstandable approach and certainly helped optimize things at a local level. But after several years, you re-alize that you could have done things differently or, where applicable, better, which is in the nature of these kinds of things. These days, however, you

have to optimize on a glob-al level.solutions: What effect will the changes have?Steckenreiter: Superficially speaking, to start with, they won’t have any effect at all. The chemicals won’t change. The machines will still be there. But if you

look more closely, you’ll see that production will become more efficient overall. This will also have enormous repercussions on ware-housing for our products. As a globally operating company, we will therefore be able to supply our customers and patients around the world much faster than before.

solutions: That sounds as if it currently takes a tremen-dously long time for Bayer products to reach their end users.Steckenreiter: Then that’s an impression I have to take issue with, and strongly, because of course there are numerous extremely

positive examples. I’m thinking, for instance, of some of the crop protec-tion products we manufac-ture at our Frankfurt site, and I can tell you this: those products reach our customers’ shelves within a few days of being or-dered. Which is exactly how it ought to be. But it is not like that everywhere. And that is precisely the

situation we are working to improve.solutions: These goals sound very achievable and pragmatic. But when peo-ple talk about Industry 4.0, the discussion quickly turns to scenarios involv-ing virtual factories and corresponding control technologies.Steckenreiter: Don’t worry, we’re not trying to achieve some kind of augmented reality. And we won’t have people running around wearing data gloves – (laughs) at least, not in the production areas. We have completely different chal-lenges that have to be mas-tered first.solutions: For example . . .?Steckenreiter: Considering our growth, the current maxim is that we are work-ing on our organic growth. In the past, that wasn’t the case. Merck, Schering, Roche – when you hear names like those, you im-“Today, we have to optimize globally.”

“We can learn a lot from other industries. No doubt we will be able to translate a number of techniques and refine them for our own company.”



mediately think of success-ful acquisitions. In particu-lar, I have in mind different production systems, where there is still quite a lot to be adapted, integrated and brought up to date. If we were further along with this process and already had the fundamentals in place, we could – in our IT, for example – simply roll out the latest software up-date for our machines and control systems and every-thing would be state of the art tomorrow.solutions: And how are things running today?Steckenreiter: Today, every-thing simply takes a little bit longer.solutions: Your main focus seems to be on speed.Steckenreiter: Because busi-ness success is becoming increasingly dependent on speed.solutions: Because of the fear that someone else will get in ahead of you if

you’re not fast enough?Steckenreiter: Precisely. That’s an important point. But it isn’t the only one. Let’s take crop protection products as an example. In a particular year, there’s only one optimal time-frame in which a farmer can apply the recommend-ed crop protection solution to their fields. There are extremely detailed spray-

vation has to be fast. Ulti-mately, it always comes down to supplying custom-ers in the best possible way.solutions: And you need standardization for that? Doesn’t standardization al-ways mean an off-the-rack solution?Steckenreiter: One shouldn’t confuse these things: this isn’t about standardizing products. It’s about stan-dardizing the production systems and interfaces. Think about the last time

you went away on holiday. Weren’t you annoyed to suddenly discover that you needed an adapter for your old power plug, just be-cause you were away from home? Standardization would help a great deal in situations like that. And in an industrial plant, the re-quirements are naturally far more complex. When machines have to commu-

ing plans, and if our active ingredients are not avail-able at the right time, then we’ve missed the boat for that season. solutions: Has the pace of the competition for cus-tomers really intensified so much in recent years?Steckenreiter: Definitely, and so has the value-cre-ation chain that we want to expand. With plant protec-tion, it’s been a long time since we limited ourselves to only producing out-standing products. Today,

we offer farmers full-ser-vice packages. We serve them in practically all questions relating to their profession and the chal-lenges they face. In future, this will extend to include Digital Farming and in-depth, app-based informa-tion. All of that owes a tre-mendous amount to innovation. And anyone who wants to deliver inno-

nicate with each other, for example, or when you don’t want to have different maintenance processes in place for a single task, just because the pumps are made by different manu-facturers. And believe me, those are just the smaller issues.solutions: Does Bayer have enough market power to be able to demand standard-ized solutions from its sup-pliers?Steckenreiter: We don’t want to use the power we have to push through our inter-ests against the will of our suppliers; for us, it’s more about working with suppli-ers to develop standards that benefit the entire in-dustry.solutions: And what do you say to people who think In-dustry 4.0 is just another new word for more ratio-nalization?Steckenreiter: I can under-stand their concern. How-

ever, I’m convinced that this is not about replacing people with machines; rather, it’s about a new di-mension in the interaction between the two. What has to change is the configura-tion of the work processes, because even intelligent systems have to be imple-mented, maintained and controlled. And that’s what people do.

“Intelligent systems are a must these days.”

“Anyone who wants to deliver innovation has to be fast. Ultimately, it comes down to supplying customers in the best possible way.”


What Affects the World


COMPUTATIONAL LIFE SCIENCES

Understanding the LiverFor five years, more than 200 scientists worked to gain a better understanding of the physiological processes that take place in the human liver. Their aim: to develop new technologies and procedures for pharmaceutical research. The team included systems biology experts from Bayer Technology Services

The liver (left: highlighted in the male body) is geared toward filtering foreign

molecules out of the blood and removing them. This means that, when modeling the behavior of potential new

active substances on the computer, one needs to take their fate in the liver into consideration. Systems

pharmacologists at Bayer have been busy doing precisely that


octor Lars Küpfer has a goal. “Through my work, I’d like to im-

prove the development of therapeutic drugs and their ap-plication for patients,” says the process engineer, a Senior Scientist at Bayer Technology Services. The computer is his most important tool. He uses it to work on models and computer simulations primarily aimed at making one thing possible: to better understand – and perhaps even predict – the behavior of certain molecules in the human body with the aid of virtual patients. These simulations are a valuable supplement to experimental results and clinical studies, without which regulating authorities will not approve any new medication. In these studies, a particular preparation has to demonstrate, among other things, that it really works, and also has to show what constitutes a sensible dosage to achieve its effect. On top of that, a new drug has to prove that it represents a real advantage for patients over existing medications.

Computer models are already capable of reproducing hu-man physiology. And when they are input with the right data, then they allow predictions to be made not only for

D

2 s0,2 s


“Being able to predict the behavior of substances better helps us to optimize our clinical development program.” Dr. Jörg Lippert, Global Head of Clinical Pharmacometrics, Pharmaceuticals

known cases but also for situations that have not been investigated previously.

At Bayer Technology Services, Lars Küpfer works as part of a systems pharmacology group, a special offshoot of systems biology that focuses primarily on the interplay between processes in biological systems – and tries to understand these in as quantifiable a way as possible. Systems pharmacologists investigate the ways in which pharmacological substances are distributed through the human body, and how, as a result of this distribution, an effect occurs that benefits the patient.

This raises the question: why bring a process engineer’s expertise into something like this? Küpfer laughs and ex-plains that it ultimately comes down to using extremely complex mathematical formulae that are interdependent in multiple ways to describe what happens. And this, in princi-ple, is not much different from the classical work of a process engineer, such as modeling the chemical processes in a reactor, for example.

Having said that, Küpfer is quick to stress that systems pharmacology is a young discipline that brings together

Concentration


10 s

How long does a substance, once ad-ministered, remain in the liver? This computer simulation, created as part of a VLN project, demonstrates the progress of the concentration of a

substance in the blood vessels in the liver at three points in time. The

quantity of the substance present in-creases from blue (none) to green to

red (maximum concentration).

many different skills: “Our group includes biologists, chem-ists and physicists working side by side with mathemati-cians, doctors and, as it happens, process engineers.” Only by working together can the complex processes at work in the human body be modeled and simulated. For example, what happens to a substance in the body, and how it is me-tabolized.

In the past five years, the experts have made great strides. A major contribution came from the “Virtual Liver Network” (VLN), a German program funded to the tune of 50 million euros by the country’s Federal Ministry of Education and Research (BMBF). The program focused on the largest and most complex organ in the human body: the liver.

More than 200 scientists from 36 institutions were in-volved in a total of 44 subprojects. Lars Küpfer and his col-leagues from Bayer Technology Services were among them. “Until today, the VLN has been the only program world-wide to focus so comprehensively on one single organ in one

country, and with such a high level of financial support,” says British doctor Adriano Henney, who coordinated the VLN as programme director.

Although the program focused on a single organ, it cov-ered many different subsidiary aspects. Some projects con-centrated on what was taking place in individual liver cells or with the ways cells communicate with each other. Others looked at large sections of tissue or the organ as a whole, while still others looked at the interactions between the liv-er and the rest of the body. Some projects aimed to bring together the different physiological levels, and in particular to make them relevant to clinical practice. This “Vertical Integration” work package ran under the leadership of Bay-er Technology Services.

A few clicks on his keyboard are enough for Lars Küpfer to demonstrate the results of their work. In a video presenta-tion we see how a substance is carried through the blood-stream into the liver. Within fractions of a second, the sub-stance spreads into even the finest blood-vessels, leaving the organ again a short time later via the venous system. It is a computer simulation, developed by Küpfer and his colleagues together with researchers in Bremen and Aachen. “In the model, experimental data move through the vascular structures into the liver,” Küpfer explains. “But at the same time, the mass balances also go in, meaning infor-mation about how and at what speed a substance is metab-olized in the liver. These inputs are specified on the phar-macological side.”

But this is not all that the model can do. It can also be used to predict, for example, how behavior changes in a

In and out again, very fast


damaged liver, or even a dead one. “Ultimately, we were able to show that these simulations cor-respond with experimental data to a very high degree,” Küpfer is pleased to say.

VLN director Adriano Henney believes the various contribu-tions made by Bayer Technology Services to have been “extraordi-narily valuable.” In every form of science, it is vital to make a con-nection between pure theory and practical application. “Because of Bayer Technology Services’ close proximity to the pharmaceuti-cal business, they are well aware of both business demands and actual patient needs. This aligns their developments very much to-ward real-life application, and adds greatly to the value those developments represent.”

It was no coincidence, therefore, that the experts at Bayer Technol-ogy Services also led the “Clini-cal Translation” work package. Their goal: to put the knowledge garnered from research (some of which was purely theoretical) in-to a useful clinical form – i.e. into a form that could be used directly with patients.

In one project, Bayer Technol-ogy Services researchers, work-ing with partners from the In-stitute of Clinical Pharmacology in Stuttgart and the University Hospital in Dresden, investigat-ed how quickly six different sub-stances could be broken down in the liver when all of them were introduced into the body at the same time. This substance cock-tail was chosen with deliberate care so that, in breaking down each substance, a different liver enzyme would come into play. For the researchers, it was particularly interesting to find out whether the individual substances would be bro-ken down at different speeds by different patients. “Any dissimilarities might then be traceable to variations in the genes of the enzymes involved, which would make them dependent on the so-called genotype,” Küpfer explains. “We then used the computer model to investigate wheth-er relationships of this kind between the genotype and the breakdown rate exist.”


The process engineer has a clear goal in mind: “It is con-ceivable that, one day, we will be able to customize the dosages of a particular substance to match each specific genotype.” In this way, the very best therapy could be de-termined for each individual patient.

The work also has practical relevance in terms of the inter-activity of different drugs. “If two drugs are broken down by the same liver enzyme, it can lead to interactions,” Küp-fer says. The extent of such interactions can then be evalu-ated using computer modeling to determine how great they

Capturing events in the body in formulae and curves: systems pharmacologists Dr. Jörg Lippert and Dr. Lars Küpfer at work.


stances. “We can represent these kinds of things with our software platform extremely well,” says Küpfer.

This technology solution is utilized by Bayer and by other pharmaceutical companies to establish the dosage limits for clinical studies as effectively as possible, for example. Ide-ally, the result will be to reduce the cost of the studies and speed up development of new drugs. But the platform also serves to run through such concrete scenarios as the extent to which a substance accumulates in the body if it is unable to be eliminated by the kidneys.

Küpfer and his colleagues have continued to push ahead with the development of PK-Sim and MoBi in the course of their VLN projects. “With the current version, we’re in a position to be able to make even better predictions about individual patients,” the process engineer is pleased to say. For instance, the experts were able to gain a good under-standing of individual data from clinical studies by taking into account the specific physiology of each of the patients taking part.

For pharmaceutical companies involved in research, such a tool is invaluable. “Being able to better predict the behavior of substances for specific patient populations or even for individual patients helps us to plan clinical stud-ies more effectively, and thus to optimize our clinical development program,” explains Dr. Jörg Lippert, who is responsible for the Clinical Pharmacometrics depart-ment at Pharmaceuticals. Adriano Henney would agree: “During my career, I’ve seen a lot of candidate substanc-es fail during phase II and III clinical studies. If theoreti-cal models can help us avoid those kinds of misguided de-velopment efforts at an early stage, we will be able to save valuable resources – and put them to use elsewhere, in the interests of patients.”

The VLN coordinator is happy with the results of the immense five-year program in other ways, too. “We have achieved a lot in that time, and learned a great deal,” Hen-ney says. “Many processes can now be modeled.”

Ultimately, this also opens up new possibilities in pharmaceu-tical research, but there is still much to be done. Regard-less, Lars Küpfer takes a long-term view of his work. Why shouldn’t we one day be able to model the human body so well that we can accurately foretell the effects of particular substances using complete virtual patients? Is that going too far? “Why?” Küpfer asks, then points to the develop-ment of the airplane. “There was a time when hardly anyone could even conceive of the possibility that airplanes might one day be designed largely on computers. And today, that’s exactly how it’s done.”

could be in an extreme case, taking into account the dif-ferent genetic and physiological co-factors of the particu-lar patient.

For their differentiated approaches, the systems biologists at Bayer Technology Services make use of a software plat-form that includes the PK-Sim and MoBi programs; the plat-form was developed in-house and has been expanded con-tinuously over the last ten years. The abbreviations stand for the simulation of the pharmacokinetics of substances, and the modeling of biological systems, respectively. And in fact, based on very little experimental data and a num-ber of fundamental individual physiological values, it is now possible to predict how a drug could circulate through the body in, for example, young children or older people. “By using this program, we are able to take into account such circumstances as the fact that, in younger children, the liv-er makes up a larger proportion of their body weight,” Küp-fer explains. Among older people, by contrast, both body fat as a percentage of weight and the speed of blood flow are reduced. Both factors influence the metabolization of sub-

W ithout the liver, nothing works. Weighing in at around two kilograms, the organ produces im-

portant messenger substances and proteins – used in the blood clotting process, for example – and plays an important role in metabolizing carbohydrates and fat. Some substances are also stored in the liver, while oth-ers are eliminated by it, especially foreign substances such as medications. If this happens too fast, the drug does not have enough time to be completely effective. If it happens too slowly, then it can lead to an increased risk of side effects. For this reason, the liver plays a key role in the development of therapeutic drugs. With blood flow of around 90 liters per hour, the organ is well supplied, with blood coming from both the venous and arterial systems. In modeling the liver, these complex and often interrelated functions represent a very special challenge.

90 liters per hour

“The developments made by Bayer Technology Services are extremely practical and valuable.”Dr. Adriano Henney, Programme Director, Virtual Liver Network


e 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 atmo-sphere and makes it down to the earth’s surface. If it did, UV-C 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 employ-ing artificially generated UV-C light. Bayer Technology Servic-es, in turn, has developed a system that, based on UV-C radia-tion, 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 Sar-torius, Bayer Technology Services’ distribution partner (see also technology solutions 1/2010).

Among the first users was Biotest, based in Dreieich in Hes-sen, 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 pro-portion of its products are based on materials from biological sources, for example blood plasma, that can potentially con-tain viruses. To render such pathogens harmless, the plasma has to go through at least two completely independent clean-ing stages, a requirement of the regulatory authorities.

The battle against viruses includes chemical attacks – for ex-ample 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 process-es, on the other hand, become correspondingly less effective the closer the virus and product molecules approach one an-other 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-im-pact, effective process,” confirms Dr. Udo Große-Westermann, Product Manager for Bayer Technology Services, whose port-folio includes UVivatec.


BIOTECHNOLOGY

W

No Chance for VirusesMore 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).


Ultimately, that was also the reason that Biotest was inter-ested 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 prob-lems of earlier UV systems,” says Michael Rodemer, who was involved with testing the system at Biotest from the very be-ginning. Early attempts with UV-C light suffered from an in-ability to eradicate all of the viruses present in a liquid com-pletely. 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 en-thuses. What’s more, the system is easily scalable, meaning that the results obtained from tests with the small laboratory

S cientists 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 spi-ral 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 correspond-ing number of turns.

The developers chose Polytetrafluorethylene (PTFE) – aka Teflon – for the material for the spiral flow path, be-cause 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 special trick: A vortex named Dean

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.


“UVivatec works so gently that we are able to achieve high product yields.”Michael Rodemer, Director Technical Project Management, Biotest


system can easily be transferred to the larger UVivatec pro-cess 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 prob-lematic 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 devel-opment. Both are part of Biotest’s extraordinarily dedicated development program. Half a dozen different candidate sub-stances are currently going through clinical testing simulta-neously. 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 im-

mediately bring in more money than all of their current products put together.

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 pro-cess, too, has to be officially approved be-fore production can actually begin.

Product Manager Udo Große-Westermann is enthusiastic about the future, because apart from Biotest, the innovative anti-viral tech-nology has already found other buyers. Al-most 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 require-

ments. 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 cus-tomer’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 main-tenance 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 pre-cisely into a corresponding recess in the customer’s clean-room 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.


News

NEW CLINICAL SAMPLE PLANT In 2015, a new plant for the production of clinical samples went in-to operation in Leverkusen. The building, where Bayer now produc-es powders, granulates, pellets, tablets and capsules for use in clin-ical studies, was planned and built by Bayer Technology Services. It encompasses a clean-room area of around 630 square meters. Bay-er Technology Services also took part in establishing the associated IT infrastructure.

EXPANDED CAPACITYBayer is currently registering increas-ing demand for herbicides that ef-fectively combat weeds that are oth-erwise resistant to such controls. Because of this increasing demand, the company is investing in expand-ing its related production capacities at several different sites – and is sup-ported in this by Bayer Technology Ser-vices. In July, the foundation stone for a new glufosinate-ammonium plant was laid in Frankfurt; the substance is used in such herbicides as Liber-ty and Basta, which are used around

the globe. The project, headed by Bay-er Technology Services, is proceed-ing at an estimated cost of 100 mil-lion euros and should be completed by 2017.

By then, a new plant in Knapsack for the production of an important pre-liminary stage should also be finished (see page 50). For this project, Bayer is investing more than 150 million eu-ros – and has also entrusted man-agement of the construction to Bayer Technology Services. The two invest-ments form part of a 2.4 billion euro expansion program covering research, development and production capaci-ties. By the start of 2017, the work in Knapsack will include the laying of 48 kilometers of pipes; more than 4300 electronically controlled components will also be installed.

21

YOUNG TALENT IN DORTMUND

Theresa Westhuis (2nd from left) and Christian Schwarz (2nd from right) were the pick of this year’s graduates in bio and chemical en-gineering studies at TU Dortmund University. With final grades of 1.4 and 1.2 respectively, they are now not only Masters of Science, but also received the annual award from Bayer Technology Services. This was conferred by INVITE director Dr. Armin Schweiger (left) and the dean of the Bio and Chemical Engineering faculty at TU Dortmund University, Prof. Dr. Oliver Kayser (right). Bayer Technology Services currently runs numerous joint research projects with TU Dortmund, including the INVITE GmbH research center, and also gains many young, talented recruits from the university.

EMINENT VISITORS TO CHINAOn a 2015 trip to China, German Minister for Economics Sigmar Gabriel paid a visit to Bayer in Beijing. A highlight of the visit by the 80-strong delegation was a tour of the production site. It is currently being expanded to become the largest packaging operation for pharmaceuti-cals in Bayer’s global production network; Bayer Technology Services is managing the expansion project. The transfer to a fully automated warehouse system was also implemented by the experts from Bayer Technology Services.


ly the most promising candidates from the CPL are tested further in the field.

Now, digital sensory and image processing systems repre-sent a new element in the early evaluation of plants. Images of the plants are created, and these images, in turn, are au-tomatically assessed in great detail.

With these digital technologies, a wide range of parame-ters can be derived, on the basis of which the specialists can precisely determine the condition of a plant: How big is the plant? What proportion of it is green? What stress fac-tors are visible? Which metabolites have collected on the surface? How does the water balance look? And how does the thermal transfer function? In short: everything that de-scribes the appearance of the plant is measured. To the ex-perts, this is known as phenotyping.

With the assistance of phenotyping technologies, plants can be characterized throughout their development more ac-curately and in far more detail. The technologies allow, for

example, better assess-ment of the effectiveness of treatment with a partic-ular substance, or wheth-er the time at which the treatment was applied was actually the optimal point.

Dr. Nina Schwalb, for many years the head of the Bio-Im-aging Group at Bayer Technology Services, concludes that: “With the technologies available today, the growth and de-velopment of plants can be observed significantly more ob-jectively and systematically than ever before.” It goes with-out saying that not every single plant has to be recorded and assessed individually. In the CPL, everything runs completely automatically, including taking pictures of the plants. For this, the entire spectral range is used, includ-

hen you think of a greenhouse, what do you see? A lot of glass, a lot of light

and many thriving plants? “See what I mean?” says Dr. Gitta Erdmann, “And that’s why ‘greenhouse’ is a completely in-adequate expression for what we operate here in Frankfurt.” A more accurate term might be climatic chamber. Or per-haps the more contemporary Crop Performance Lab (CPL).

Nothing here is left to chance. Everything is measured with great precision and digitalized. All of the plants grow under specified, controlled environmental conditions. In the Crop Performance Lab, different climatic zones can be sim-ulated. Erdmann, who heads the Crop Efficiency Biology group at Crop Science, explains the background to the proj-ect: “In the Crop Performance Lab, we carry out research into new technological possibilities for better analyzing dif-ferent substances, aiming to safeguard yields in the most optimal way possible, even when environmental influenc-es cause problems.” In the controlled conditions inside the

CPL, corresponding consequences for the plants – as mini-mal as they may be – can be made visible.

The CPL, however, cannot replace field testing. Such test-ing remains an indispensable tool. But tests outdoors, in the field, require a great deal of time and are expensive. To judge whether a particular treatment has been successful, the specialists are sometimes left with no more than the har-vest as an indicator. More concretely, this means constantly having to wait for the completion of a growth period.

The great advantage of the climatic chamber in Frank-furt, compared to field tests, lies in the opportunity to easily carry out experiments and tests in winter – and, of course, the harvests in the Crop Performance Lab are not tied to the actual seasons either. With the aid of this tech-nology, one can see very quickly whether a particular sub-stance, strain or seed treatment has potential or not. On-

IMAGING TECHNOLOGIES

W


Lights, Camera, Action!

“With digital technologies, the health of a plant can be assessed very precisely.”Dr. Gitta Erdmann, Crop Efficiency Biology, Crop Science

Dr. Nina Schwalb and Benjamin Kolb are experts in bio-imaging. Assisted by digital technologies,

they are able to differentiate a wide range of parameters that allow a plant’s condition to be determined

with precision.

How big a harvest can we expect? What kinds of grain and which plant protection products allow us to achieve a particular yield? What effect does an extended dry spell have? New digital imaging technologies can make a valuable contribution to getting more detailed, accurate answers to these questions.


Lights, Camera, Action!



are supplied for every single plant, and these can then be assessed and broad-er correlations extracted. This sub-sequently allows the identification of those approaches that are worth pur-suing further.

Suitable phenotyping screening and analysis systems are supervised, op-timized and subject to ongoing devel-opment by Bayer Technology Services, the division thereby fulfilling its obli-gation to develop technological solu-tions that are then used by other Bay-er divisions in their own research and development endeavors. At the same time, Bayer Technology Services en-sures that the technologies under de-velopment are tailored to the spe-cific needs of the different partners. This also means that these solutions embody the robustness and maturi-ty needed to guarantee problem-free, long-term deployment in an industrial environment.

In Frankfurt, Benjamin Kolb shows how this obligation is put into prac-tice in the Crop Performance Lab. Ev-ery day, Kolb is involved with phe-

ing not only the visible spectrum, but also the ultraviolet and infrared ranges.

These processes make it possible to put together a com-prehensive picture of the growth and health of plants. But because the assessment of such traits is contingent upon the subjective perceptions of the observer, automated im-age analysis – comparing and evaluating a wide range of parameters against one another – plays a decisive role. “To obtain a precise assessment of the plants, it’s necessary for all of the required information to actually be contained in the digital images,” says Schwalb, explaining the chal-lenge the specialists face. And she points out that, most im-portantly, “this information also has to be subsequently made available.”

This is where the expertise of Bayer Technology Services once again comes to the fore. Schwalb goes on: “We ensure that the digital information is evaluated and put into a us-able form.” More precisely, this means that digital datasets

“For research and development at Bayer, we deliver customized technological solutions that have the robustness and maturity needed for long-term, problem-free industrial deployment.”Dr. Ingo Gaida, Head of Enabling Technologies at Bayer Technology Services

Mobile image processing using a smartphone provides researchers with far-reaching potential for a wide range of new operations and applications. The prerequisites for this were tailored to the requirements of Crop Science.

Imaging technologies are employed not only in the controlled conditions of a climatic chamber,

but also out in the fields. To do this, Bayer Tech-nology Services has developed a multisensor system with a high-resolution camera, spectrom-eter and laser scanner. The system records the number, size and condition of the plants, and sys-tematically assesses the results. The system is thus equipped to provide precise information about the plants at individual stages of development.

From the lab to the field


notyping assisted by digital images. The engineer began focusing on automation technologies and image process-ing during his studies. These days, his expertise is primar-ily put to work in research and development at Crop Sci-ence: “Here in Frankfurt, I collaborate very closely with the biological research areas. But the results we come up with are also taken over into chemical research, where the molecules under investigation are then optimized and developed further.”

But before that can happen, all of the extensive informa-tion gathered from the experiments has to be evaluated. “We prepare the collected data systematically, putting it into a useful form for our colleagues at Crop Science,” says Kolb. To do this in the past, one would have had to rely far more on the existing substance library. But the number of potential candidates stored there numbers in the millions.

If one wanted to put all of those to the test out in the open field, complete with corresponding repetitions, “then you

How big is the plant? What proportion of it is green? What stress factors are visible? Which metabolites have collected on the surface? How does the water balance look? And how does the thermal transfer function? Intelligent image processing extracts a range of parameters that make the condition of the plant visible, allowing researchers to draw conclusions about the plant’s performance.

would need to have more than half the globe available as a testing ground,” Nina Schwalb points out. She has no doubt whatsoever that the significance of phenotyping and the possibilities it offers will continue to become more and more important.

Kolb agrees with her: “The development is happening tremendously fast. In future, with new imaging technolo-gies and sensors, higher levels of automation, larger data quantities and ever-improving networking, we will have a considerably wider range of opportunities available to us in research and development, and be able to deliver corre-spondingly more valuable contributions and results.”

And Dr. Ingo Gaida, head of Enabling Technologies at Bayer Technology Services, adds that, “The collaboration in Frankfurt is an outstanding example of how it is possible to successfully adapt new digital technology solutions to meet industrial requirements, and to work in a fully integrated way with the research sites.“


ENZYME RESEARCH

What Inspires Partners

The Catalysts of LifeThey keep humans, animals and plants alive: As biocatalysts, enzymes play a key role in every cell. And it is this characteristic that makes them so fascinating to an interdisciplinary team searching for biocatalysts beyond the boundaries of the divisions – and finding them.

technologysolutions 2016 27

Biocatalysts in the brewery: Enzymes are created in germinated malt, and these transform the starches contained in the grain into maltose during the brewing process. Malt is what gives the beer its fullness of flavor and color.


hen we first started,” recalls Dr. André Pütz, “we waited and waited

for the enquiries to come.” While the advantages of using enzymes were indeed already known, centralized contact persons, people ready to help out in both word and deed, were lacking. “When the first calls came in, we rejoiced inwardly. Finally, we would be able to show that it really worked!” Over the course of the project, the number of en-quiries grew steadily, and the requirements with them. “Now, we have to pay careful attention to the order in which the enquiries come through, because we have more than we can deal with simultaneously.”

There is a very good reason for the demand for the services offered by the Biotransformation Platform: the project team has been extremely successful. The collaboration, through Nimbus, between colleagues from Pharmaceuti-cals, Crop Science und Technology Services was thus greatly simplified and correspondingly intensified. The result: all enquiries can be processed rapidly and straight-forwardly. And in almost 80 percent of cases, the team is able to come up with an enzyme that can work as a catalyst for the reaction in question. Pütz, who heads the Biochem-istry & Biocatalysis group of Bayer Technology Services, also points out that, “These days, we are pretty fast.” And

W


that is also important for the team. “When our colleagues come to us, they know they can save time – which also means saving money.”

The colleagues he is talking about work for Pharmaceu-ticals and Crop Science, and are constantly on the lookout for new chemical compounds in new areas of application, both for the development of alternative substances for ani-mal and human medicines, and for active substances for use in plant protection. However, the molecules that the researchers deal with are becoming increasingly complex. And this complexity puts ever-growing demands on the requirements for catalysts, as well. This is where enzymes, as “reaction helpers,” can play a pivotal role.

This role is often associated with what are known as ste-reocenters. These are found in practically all new sub-stances – sometimes more than once. If a stereocenter is present, then the molecules of the substance, despite having the same structure, exhibit diametrically opposite behavior relative to one another. This means that they are non-superposable. Basically, says Pütz, you can think of the two molecules as being like two hands: at first glance, they are the same, but they are not identical.

What makes this particularly challenging is that the mirror-image molecules can have different effects. Thus –

The task that Dr. André Pütz and his colleagues share is to find, isolate and characterize new biocatalysts. Their success has been impressive. For almost 80 percent of all enquiries, the team is able to find an enzyme that catalyzes the desired reaction.


when developing a new active substance, for example – it is crucial to be able to produce only one of these so-called enantiomers. The other has to be separated out as soon as possible. “And that,” says Pütz with a smile, “is where en-zymes come in.”

These biological catalysts can differentiate between the left hand and the right. So, if one wants to alter only one of the two hands, enzymes can carry out the task with extreme precision. “Of course, we’re not doing anything that our colleagues in the chemical sector can already do well,” Pütz explains. For especially complex molecules – synthe-sizing hormones, for example – biocatalysts are indispens-able. “There are many reactions that are only possible at all by us-ing biocatalysis.”

But how can enzymes that might be used in a chemical synthesis be identified? To answer this ques-tion, and to be able to use biocata-lysts throughout the entire Bayer Group, an interdisciplinary team has been working to es-tablish an enzyme collection. They have been doing this since 2013 as part of the cross-company Biotransforma-tion Platform, part of the larger Nimbus initiative, which gives the Bayer Technology Services experts a clear over-view of exactly what the divisions require. At the same time, they keep a constant eye on their ultimate goal: to ensure that enzymes are employed as standard tools for chemical syntheses. And together with their colleagues in the divisions, they can already look back on many successes.

This is also confirmed by Dr. Daniel Götz, who works in substance development at Pharmaceuticals. By using en-zymes in his project, he was able to benefit from the expe-rience of the project team. More specifically, a purely chemical step in a synthesis was replaced by an enzymatic step. The result: the desired reaction took place with sig-nificantly higher specificity and better yield. Götz was pleased with the result: “The people at Bayer Technology Services made a decisive contribution to our success.” And they did so all the way from identifying the right enzyme to implementing it on a 400-litre scale. “In the end, every-thing worked, despite a very challenging schedule.”

It is these successes that make the entire team proud. What’s more, the specified goals have all been achieved, some even over-achieved. Pütz sees the close, trusting col-laboration between the participants as an important factor in their mutual success. Dr. Olaf Queckenberg, head of Global Chemical & Pharmaceutical Development at Phar-maceuticals, backs him up, concluding that, “The experts from Bayer Technology Services bundle our expertise and the available enzyme libraries – and have taken it well beyond the boundaries of the divisions. That’s where the added value lies.”

It goes almost without saying that such results are the con-sequence of hard work. But for Pütz, the fun he has in the process is almost as important. “For me, that’s a major part of my motivation.” The same sentiment is expressed – re-peatedly and conspicuously – by the other biocatalysis ex-perts at Bayer Technology Services.

To maintain a regular exchange of ideas and information, the specialists have set up their own community, comprising mainly chemists, biochemists, biologists, biotechnologists, molecular biologists and bioprocess engineers spread across seven different Bayer sites.

Twice a year, they meet to discuss the current state of their work. Pütz is convinced that this community is also an impor-tant success factor. “We share a common goal, and that cre-ates a connection.” And as relaxed as they may be with one another personally, they take their work very seriously in-deed. “So far, we have been able to identify new ideas and fields of application at every meeting,” he says. “And togeth-er, we are looking for – and discovering – the right solutions.”

It may be that this strong interaction is the true secret of their success, Pütz suggests. Then he quickly adds, “And, of course, the very great desire that it really will work out.” But it is “incredibly satisfying to come up with and demonstrate applicable, practicable solutions together with one’s col-leagues: See, it really works!”

Science thrives on the exchange of experiences. And there are plenty of opportunities for this

when it comes to the health of people, animals and plants. The Bayer Group is now focusing more close-ly on these interfaces, and launched the Nimbus ini-tiative to this end back in 2012.Aiming to interlink the life sciences more closely, the company has provided 30 million euros for new re-search projects. The researchers are working on such issues as epigenetics, high-throughput screen-ing for drug discovery, and biotransformations. Their objective: to more intensively exchange acquired knowledge beyond the boundaries of location and technical specialization, and to further improve the quality of research.

Research Success with Nimbus

“Biotransformation is a great example of how life science synergies at Bayer stimulate

both R&D and our innovation culture.”Kemal Malik, Bayer AG Board Member responsible for innovation



“Researching and developing active pharmaceutical ingredients is one of the most important tasks in our company. But just as important is producing them safely. Right now, I’m developing a concept for a production plant for biologi-cal active ingredients. These bind selectively to cancer cells and kill them. For patients, this increases the possibility of a cure.” Stefan Sievers, Bioengineer, Germany


cience For A Better Life – the mission of the Bayer group goes to the heart of its

ambitious goal. For the great challenges of the future – a grow-ing, aging society – the employees of Bayer Technology Servic-es, working together with the different divisions of Bayer, devel-op solutions and products that fulfill the goal of improving the quality of life of people. Our employees thus see themselves as competent ambassadors for innovation – and for “Science For A Better Life,” as well.

But what does this mean in concrete terms? What contri-butions do our employees make that benefit both the com-pany and wider society? How does every individual, day af-

EMPLOYEES

S

“We run a plant where waste water, with special processes, is cleaned so well that it can flow out into a lake in the middle of a recreational area. This is environmental protection at its most advanced.”Rodrigo Miranda, PCT Engineer, Mexico

“One of my tasks is to make connec-tions among the huge amount of da-ta that comes from production. Like this, I contribute to the highest level of capacity and product quality.”Tingting Li, MES Engineer, China

Ambassadors for InnovationOur employees are more than just workers at a life-science company that focuses on health and nutrition. In their work, they help to make the Bayer mission a reality every single day, and give a face to our common goal – “Science For A Better Life.”


“Varroa mites threaten bee populations worldwide. A Bee Gate helps to protect the bees from these parasites. The gate is the entry to the hive; every time the bees enter, they are brushed with an active ingredient and carry it inside, where it kills the mites. Through the microscope, I check the distribution of this substance.”Brigitte Mosbach-Wetzka, Laboratory Technician in Physical Characterization, Germany


ter day, contribute to achieving that greater goal?

A few examples will serve to illus-trate just how different the tasks at Bayer Technology Services can be. But as fragmentary and random as this se-lection may appear, the common goal unites them all: a better life for people, wherever they are in the world.


“Together with my team, I optimize process control systems, making sure that they fulfill exactly the require-ments for safe, reliable and efficient facilities.”Corrina Liu, PCT Engineer, China

“Our innovative IT systems safe-guard the packaging, storage and transport of our drugs. They guaran-tee high protection – especially from counterfeit products.” Klaus Würschinger, IT Project Manager, Germany

“My most crucial task is to sup-ply production plants with reliable power. In an earthquake, emergency generators take over. I ensure that production continues – all the time.”Jim Engan, Electrical Engineer, USA

“As a manager, I ensure that projects run smoothly – which concerns time and budget – and that our custom-ers have access to quality products when they need them.”

Bing Bao, Project Manager, China


presidents later, the chemical engineer can look back on countless engineering projects. He knows practically ev-ery Bayer site in North America, and depending on the par-ticular project, has spent months or even years working at each of them.

2011, however, was a year in which even the experienced Liberati moved into uncharted territory. When he landed at Memphis International Airport for the kick-off meeting at Crop Science, there was more waiting for him than just his first project in Tennessee. The content of this particular en-terprise offered something new, as well. “Up to that point, I’d never had anything to do with cotton, seeds or green-

houses,” Liberati re-calls with a smile.

But that didn’t matter, because the engineer knew that the relevant ex-perts would con-

tribute their specialist knowledge wherever it was need-ed. As project manager, Liberati’s main job was to dovetail all of the other participants in the 18 million dollar project together seamlessly. At the same time, he had to ensure that the technical execution stayed on time and within budget, and above all was carried out safely and accident-free.

The comfortable working conditions for the employees, how-ever, are only one advantage of the automated greenhouse. Another is that the automated system offers more space and, because of that, a significant boost in efficiency, cou-pled with better resource conservation. This was also the initial inspiration behind the project, because the demand for cotton seed is growing. And not only for the quantity, but also in terms of the properties exhibited by the plants themselves.

Bit by bit, new properties make their way into the genetic material of the seed by way of a complex cycle of defined crossbreeding steps. To put it more simply: step by step, over many generations, certain characteristics are cross-bred into the plants. And this continues until plants grow that, in their pods, contain seeds with exactly the desired

nyone who works in a greenhouse has to be able to endure a lot. The

high humidity and temperatures in excess of 40 degrees Celsius (over 100°F) represent a special challenge for those working inside. These are also the kind of conditions in-side Crop Science’s new greenhouse for cotton in Mem-phis, Tennessee. The difference is that, in the new con-struction, no one needs to be exposed to these conditions for very long, because a large part of the day-to-day opera-tions is carried out fully automatically. Watering, fertiliz-ing and lighting are all computer-controlled, which adds up to an important contribution to the health of employees.

And when the staff really does have to work manually with the growing cotton plants, remote-controlled roll-ing tables transport the relevant greenery to an adjoining building, which has a climate controlled workspace much more agreeable to human beings. Re-potting, sowing new beds, sorting out seedlings with undesired qualities, sam-pling and testing, pollinating other plants, harvesting ripe seeds, and checking resistance to a particular herbicide – these are all typical tasks in the production of cotton seed. All of these activities, with the exception of pollinating and harvesting mature plants, can now be done without the need for personnel to enter the greenhouse.

With its FiberMax and Stoneville cotton seed brands, Crop Science is the market leader in many important farm-ing countries, including the United States, Brazil, Tur-key and Greece, and part of the seed supply originates in Memphis.

One man who has played a major role in getting Crop Sci-ence’s new greenhouse up and running is Ernie Liberati, a project manager with Bayer Technology Services. Liberati is an old hand: he started his career with Bayer when Ger-ald Ford was in the White House. Forty years and six U.S.

A

SEED PRODUCTION

What Success Creates

A Home for 600,000 PlantsTo meet the demand for seeds with improved characteristics, Crop Science depends on innova-tive concepts. To this end, and with the support of Bayer Technology Services, a fully automated greenhouse that uses forty percent less energy has now been constructed.

“We want to improve our competitiveness – and Bayer Technology Services is helping us do it.”Bernd Nowack, Head of Global Engineering, Crop Science


the greenhouse proper, the plants now grow side by side over the entire area, because there is no need for people to get to them directly. “That allowed us to cut the required space by half,” Liberati explains. Which translates into en-ergy savings and lower operating costs. “We calculate that Crop Science uses 40 percent less gas and power than they would with an off-the-shelf solution,” says Liberati. An im-portant result.

But that is not the only reason for Crop Science’s satisfaction with the new building. “This greenhouse puts us in a posi-tion to develop highly efficient seed lines with new proper-ties, both today and in the future. That’s a crucial contri-bution to our competitiveness,” says Bernd Nowack, at that

time head of Global Engineering at Bayer Crop Science. Nowack is also thrilled at how professionally the partners completed the project on schedule. “Our Bayer Technology Services colleagues have shown once again that they are a team to rely on for innovative projects.”

While Bayer Crop Science is producing the first seeds in the new greenhouse, Ernie Liberati moved on long ago. Today, he is at the helm of another project for Crop Science, this time in Kansas City. Unlike Memphis, Libe-rati knows the Midwest city well, because it was in Kan-sas City that he completed his very first project for Bay-er, in 1978. Back then, he still had his entire working life ahead of him.

genetic traits. It is a long process, and it takes time. And a lot of space. At a certain point, the old greenhouse in Mem-phis, covering around 1,500 square meters, was no longer big enough. To be adequately equipped to handle the grow-ing demand, a bigger one was needed. But how big, exact-ly? To answer this question, Liberati turned to a colleague in the Operational Excellence and Logistics area at Bayer Technology Services in Baytown: Brijesh Rao.

“Once you know how many seed projects are supposed to run simultaneously within a given period, and how many generations are required to breed for a particular charac-teristic, you’re able to develop a very accurate model,” Rao explains. In his calculations, the expert had to take into ac-

count that cotton plants need to grow for about 16 weeks before their seeds can be harvested and the process con-tinued. He also calculated with between 100 and 200 seeds per plant, and realized that he could count on only around one percent of the seedlings possessing the desired char-acteristics to be used for further pollination or as a seed supplier. The final result was clear: the new greenhouse would need to be extensive enough to house 600,000 seed-lings each season. This translated into an area of 7,400 square meters – or almost five times the area of the older building.

The fact that the new greenhouse actually only covers 3,700 square meters can be attributed to automation. In

Cotton plants on the move – fully automatically, in Bayer Crop Science’s new greenhouse.


Bees have to be safeguarded from direct contact with plant protection products. Together with Crop Science, Bayer Technology Services has developed an array of solutions to keep dust generation to a minimum during seed treatment.



BEE HEALTH

The Dust CatchersTreating seeds is an art. Under no circumstances should the substance used to dress the seeds – which protects the plant from pests at germination and in the early growth phase – be allowed to enter the environment as dust when the seeds are sowed. A tough goal, but an ambitious project is aiming to achieve just that. Its name is its aim: “Zero” Dust.


“You can compare how much of the seed hasn’t yet found its way into the spray zone within a given period of time,” says Conzen, explaining what we are seeing on the screen. “You can see exactly where certain zones haven’t yet been mixed.” Even the transfer of the dressing product from one seed to another can be visualized.

These different seed-dressing machines, however, only exist on the computer. And although we are only looking at virtu-al seeds, we know precisely what effect a particular apparatus design will have on the quality of the dressing. “The computer modeling, when coupled with the depth of experience brought to the table by Crop Science, allows us to understand the dress-ing process inside out, and to optimize it by making changes at the right places,” Conzen explains. From the scaling of planned treatment facilities to changes to existing machines – with the computer, all sorts of questions can be answered.

And this knowledge goes directly to Crop Science and to its own manufacturer of seed treatment equipment in the United States. “Our recommendations, of course, draw a great deal of attention there, because the specialists can immediately see which solution is the best, and how they can most easily achieve the desired result,” says Conzen. “All of it without having to put a lot of time and expense into building test machines.”

All of this, however, really comes as no surprise, because the software that makes this kind of modeling possible already

exists, though it comes from a completely different field: Bay-er Technology Services original-ly used it to optimize the feed behavior of polymer extrusion equipment. As Conzen points out, “That’s what is so remark-able, that so much knowledge is available in this company.

You just have to use what’s already there.” This is happen-ing not only with plans for new seed treatment machines – so-called “tuning kits,” also computer generated, will al-so be made available. These allow significant optimization of existing machines.

Precise knowledge of the processes at work in a seed dress-ing machine also leads to significant improvements in terms of reducing dust: “We are now able to assess exactly what forces are at work and whether they will lead to avoidable abrasion and dust.”

Independently of the seed dressing itself, improving the drying process has also been a focal point for the experts. The idea of drying the seeds during the dressing process was proposed.

This is known among experts as In-Bowl-Drying and involves hot air being directed into the bowl of the seed dressing ma-chine. It causes the evaporation of large amounts of water and increases the space available for the dressing substance itself. Mairata: “Like this, we are able to increase throughput sub-stantially.” A big part of the challenge was ensuring that the hot air was passed through the seed perfectly evenly. This was achieved using a special metal plate with specially designed

ne of Dr. Carsten Conzen’s favorite films doesn’t have much of a plot. It is an

animated film that shows a bowl in which grains of rice move. Some of them are sprayed with dye. Some aren’t. This goes on for a few minutes, then the film comes to an end. “Well?” says Conzen. “Isn’t that fantastic?”

For those who know this material, what may seem to be rather mundane to the untrained eye actually represents a great leap forward on the path to optimized seed dressing. Dressing means that the seeds are coated with a plant protection agent prior to sowing. This keeps both seeds and plants safe from the very start. And the specialists agree that very little of an active sub-stance is needed to have a very big impact.

They are similarly in agreement that treated seeds have to be handled with extreme care, because the layer of active sub-stance coating the seeds has to stay in place and not be rubbed off. Otherwise there is a danger that the substance could be released into the environment in an uncontrolled way, and that is something that has to be avoided because it could potentially have a negative impact on bees and other beneficial insects.

For Bayer, this was the starting point for a comprehensive project comprising a large number of individual measures: “Ze-ro” Dust. Under this rubric, a wide variety of possibilities for large-scale dust reduction were put forward, analyzed, tested

and finally put into practice: from “SweepAir” – a kind of “field vacuum cleaner” – to the use of polymers to improve the adhe-sion of the seed dressing. “The various ideas are certainly at dif-ferent stages of maturity,” observes Dr. Antoni Mairata, who is leading the project on the Bayer Technology Services side. “But with some of them, we have come a long way forward.”

With the modeling of the entire seed dressing process, for example. Which brings us back to Dr. Conzen’s favorite film. The expert, who is responsible for polymer technology and modeling at Bayer Technology Services, now has a large col-lection of very similar films. But if you look closely, you begin to notice crucial differences. Sometimes the grains move around in the bowl with practically no disturbance at all, and other times they are stirred up quite considerably. Sometimes the grains are colored immediately, sometimes the process takes place rela-tively slowly.

This is largely dependent on the design of the seed-dressing machine: With one, the plates that break up the evenness of the motion are attached near the top. With another they are at-tached at the side. Sometimes there are many of these “spoil-ers,” sometimes only a few. And when the design changes, so does the dressing of the seeds.

O


“Because we promote bee health, we are grateful for all the solutions that Bayer Technology Services delivers.”Martin Gruss, Head of SeedGrowth, Crop Science


ronment that generally tends to be very loud, putting this idea into practice was no easy task. Two years have now passed since the inception of the project: the problem has been solved and a patent issued.

“For us, however, it was clear from the start that we were fo-cused only on the issue at hand,” Dr. Mairata explains. The aim was also to come up with a technology that Bayer’s competitors would also use. At the end of the day, it comes down to ensur-ing that less active substance enters the environment, not just for Bayer, but across the board. Still, Mairata admits, “It is par-ticularly satisfying to work for a company that does so much to reduce abraded dust.”

Will it ever be completely avoidable? The separate effects of the individual parts of the “Zero” Dust project can’t simply be added together, stresses Dr. Jens Uhlemann, who heads the Formula-tion & Crystallization group at Bayer Technology Services. But he has no doubts: “I am convinced that we still have some good ideas to present in this area.” After all, Bayer Technology Ser-vices has such a broad base of expertise it can draw on “that we really can tackle all aspects of the subject,” says Uhlemann. And how many firms can claim that? “Frankly, off the top of my head, I can’t even think of one.”

gaps. And again, it’s no coincidence that a similar apparatus has already been used in the past – for a pharmaceutical in the field of tablet drying.

But how do you know, exactly, when you have reached the right point to end the dressing process? This point is influential in determining how much dust is likely to be produced when the seed is sowed. If the seed is too moist, the individual grains can stick together and can’t be sowed as desired out in the field. But if they are treated for too long, it can lead to an increase in the amount of abraded dust.

For this reason, a specially qualified employee constantly stands beside the basin in which the seed is being dressed. This person, because of their long experience, can hear the precise moment when the sound changes, and that is the signal for the drying to stop. This results in the dressing adhering to the seed as optimally as possible. Tests have shown that stopping the process ten seconds too late can mean up to 30% more dust.

But, according to the experts in process analysis technology at Bayer Technology Services, this process could be improved even further. This was a job for application engineer Reinhard Gross and his team. Gross proposed relying on a sensitive mi-crophone rather than trusting the human ear. But in an envi-

Seed treatment specialist: Dr. Carsten Conzen. The glass containers display brightly colored seeds.



Bull’s-EyeThe “Golden Batch” is the name given by chemists to a perfect result, a batch in which every-thing comes together, from the specifications to the energy consumption. But hitting such a bull’s-eye can be a difficult task. A team of experts from Bayer Technology Services and Crop Science is making it easier – with the intelligent analysis of process data.

MANUFACTURING INTELLIGENCE


A confusing array of possibilities:In chemical and pharmaceutical

production, many variables can be modified in the search for gold.

obby chefs know it well: sometimes a meal works brilliantly – sometimes

it’s a flop. There can be many reasons why the results are not always identical: the size or type of the potatoes, for ex-ample, or the temperature of the water, the amount of salt. Each of those variables can change, and each has its corre-sponding effect on the outcome. Of course, you could keep a tally of all of the factors involved, and that, of course, would lead to a perfect result every time. But how many amateur chefs do that?

In the chemical and pharmaceutical industries, a per-fect result is called a “Golden Batch.” Needless to say, all of the other batches that are delivered to the customer fulfill all of the necessary specifications. Purity, melting point, moisture content – everything complies precisely with the specifications. But it is still entirely possible to differenti-ate batches from one another. In terms of manufacturing time or energy consumption, for example. These are only tiny differences, to be sure, but in the long run, even tiny differences can make themselves felt.

But how do you turn a product into a “Golden Batch”? Does it come down to stirring for an extra minute before heating, so that the source material is better mixed? Or does opening valve X only at point Y, thus maintaining the high pressure just a little longer, make the difference?

There are countless possible adjustments in a chemical process. Plant operators with training and a lot of experi-ence are well aware of that. And it is precisely their ex-pertise – and also their gut feeling – that is so valuable to any operation. And, of course, it would be wonderful to be able to ensure optimal process management based on ob-jective criteria. For this purpose, Crop Science is currently putting together a central process data archive, the Pro-duction Information Center (PIC). The project team, under the leadership of Dr. Karsten-Ulrich Klatt, is supported by experts from the Manufacturing IT (MIT) area at Bayer Technology Services.

One of these is Martin Schmitz. He works in a field within MIT known as Manufacturing Execution Systems (MES). For Schmitz, it is not particularly important to know which chemicals are present in a reactor or how they react with each other. Schmitz is a computer scientist. His inter-est lies in data. “Data is a treasure trove,” Schmitz knows. Assuming that one can analyze it properly and glean infor-mation from it that is not immediately obvious. And this is exactly what the PIC aims to make possible in future for the process experts who work in the production areas of Crop Science. Karsten-Ulrich Klatt is currently one of Schmitz’s most important customers.

As in other areas of life, a tremendous amount of data is pro-duced in the chemical production field. Every pump, ev-ery valve, every temperature sensor, every pressure gauge – all of them supply a continuous stream of information. Normally, the control system that regulates the particu-lar process works with this data. In future, the data will be stored at Crop Science in the PIC, where the experts in the

H


quence and, for example, prevent a tempera-ture increase in a reactor – ideally fully auto-matically via the process control system.

Experts like Klatt and Schmitz call this ap-proach “Manufacturing Intelligence” – infor-mation is harvested from data and, in turn, is used to come up with concrete instruc-tions for appropriate action. They talk cheer-fully about “Smart Data,” meaning a further development of “Big Data.” The “smart” tag points to the fact that the data is not merely gathered, but also intelligently (or smartly) evaluated. In production optimization, this approach is still very new, although it has al-ready proven its worth in subdisciplines such as the life cycle management of plants or in-dividual components. Its capabilities can be shown with one example from a Bayer opera-tion in which pressure sensors were break-ing down with unusual frequency, but for no easily identifiable reason. It was only when the plant data was subjected to exhaustive analysis that the cause was discovered: pres-sure fluctuations in a pipe system, triggered by frequent opening and closing of valves, were responsible.

The project team, which also includes Dr. Carsten Welz from Crop Science, is thinking far beyond the applications for individual plants. The Manufacturing In-telligence approach at Crop Science is intended for global use from the very start. In the PIC, process and other data is gathered from around 30 sites worldwide. This is no triv-ial matter. For one thing, the local site systems from which the PIC draws its data are very different. For another, the global data transfer has to work securely at all times. In a year, all of the data in the PIC should be available and ana-lyzable with the tools available there.

Then the process experts in every connected production operation of Crop Science will be in a position to optimize the process conditions step by step toward the “Golden Batch.” “Thanks to smart data, Bayer will definitely hit a few bull’s-eyes,” says Schmitz. “And if our treasure trove of data really translates into Golden Batches in the end, then we’re talking about real money.” Karsten-Ulrich Klatt for-mulates his expectations more soberly: “We’re aiming for optimal production at all times. Together with Bayer Tech-nology Services, we are constantly getting closer to achiev-ing that goal.”

“We want optimal production at all times. Together with Bayer Technology Services, we are constantly getting closer to that goal.”Dr. Karsten-Ulrich Klatt, Manufacturing Systems Technology, Crop Science

project team aim to conflate it with data from batch sys-tems and quality control. “In this way, bit by bit, we want to get closer to the process conditions for the production of Golden Batches.”

But that’s not all: the experts also have the process con-ditions that could lead to noncompliant batches in their sights. In practice, it happens again and again that, for ex-ample, a reactor temperature briefly exceeds the normal range. “If luck isn’t on your side, the formulation has had it, and has to be thrown away,” explains Schmitz. To avoid this, one looks for indicators that precede an undesired in-crease in temperature. A pattern in the temperature pro-file, for example. Or it might be a particular mixing setting, a striking raw material characteristic, a certain external temperature: that is, correspondences that only become apparent when one looks more deeply into the data.

Mastering such a complex evaluation requires intelligent methods. “So we provide IT-based solutions which we can use to discover characteristic patterns even in enor-mous quantities of data,” says Schmitz. If such a pattern is known, then in future one can intervene in the process se-

An experienced team: Martin Schmitz (left) from Bayer Technology Services and his project partner Dr. Carsten Welz from Crop Science.



News

BIOLOGICS IN FOCUSBayer is investing heavily in its biolog-ics business in both Germany and the United States. At their site in Berkeley, California (photo), a 7,500 square me-ter, three-story laboratory building is currently being constructed. The new laboratories will focus on quality con-trol for future generations of hemophilia products. Bayer is currently developing two new preparations for the treatment of hemophilia A, the most common form of the blood disease. Colleagues from both Pharmaceuticals and Bayer

Technology Services are collaborating closely on the planning and implemen-tation of the project.

Similar work is going on in Leverku-sen and Wuppertal, where Bay-er will be making total investments of around 500 million euros by 2020 to expand its global capacity for he-mophilia products. Bayer Technology Services is acting as principal developer and is also taking care of the technolo-gy transfer from Berkeley to Wuppertal. A high-bay warehouse was completed at the site in 2015. In addition to the lab facilities, the new premises will al-so house production areas and facilities for sterile filling and packaging.

43

EXPANDED COLLABORATION Bayer Technology Services and the East China University of Science and Technology (ECUST) are strengthening their collaboration, and an agree-ment has now been signed between ECUST Vice President Prof. Dr. Changsheng Liu (left) and Wolfgang Eickhoff, Head of Bayer Technology Services Asia. Since 2007, Bayer Technology Services has been working with the renowned university in Shanghai, for example with the develop-ment of more environmentally friendly technologies. The company also draws talented recruits from the university. Around ten percent of the workforce in China studied at ECUST, and in the Technology Development area, one in two has done so. Eickhoff believes that cooperating with top universities is crucial, especially with Bayer’s life science focus.

MINISTER VISITS INVITEIn October, Rainer Schmeltzer (left) visited Bayer’s INVITE research cen-ter. The visit by the Minister for Labor for North Rhine-Westphalia was personally conducted in part by Dr. Thomas Bieringer (right), the former Managing Director of the Leverkusen center. Schmeltzer was impressed at “how quickly universities, industry and politic develops new technologies that are both highly efficient and economically viable” at the center. The INVITE center was set up in 2011 as a joint venture between Bayer Tech-nology Services and the TU Dortmund University. Its goal: to develop re-source-friendly, flexible and modular production concepts for the “fac-tory of the future.” Its mandate also includes Industry 4.0 concepts for the chemical sector.


uhanrong. In the local vernacular, Huhanrong is the name for the high-

speed train that, for the last few years, has linked Shang-hai on China’s eastern seaboard with Chengdu in the west. In the name, “hu” stands for Shanghai and “han” for Wu-han, a city of millions that lies along the line at the conflu-ence of the Yangtze and Han rivers. Previously, going by train between the two major cities took ten hours or more. Since the completion of the high-speed connection, how-ever, it’s possible to do the 800 kilometer journey in five.

For Eric Sun and a dozen of his colleagues from Bayer Technology Services in Shanghai, that turned out to be a good thing. In 2014, they spent many months working in Wuhan, the capital of Hubei province, and most of them traveled back and forth every weekend, commuting with the Huhanrong.

The Bayer experts made the regular journey in the service of Fresenius Kabi. The company, headquartered in Germany, was in the process of building its sixth Chinese site in Wu-

han, focused primarily on producing cancer medication for the growing Chinese market.

The company leased a building in the newly constructed Wuhan Biopark to set up a plant, and the four-story con-struction required customizing to meet Fresenius Kabi’s requirements. Floors and stairwells needed to be rein-forced to meet load-bearing requirements and its “U” shape made fitting a production line difficult – but not im-possible. To make the necessary changes and adapt the site to its needs, Fresenius Kabi went in search of an engi-neering partner. They found Bayer Technology Services.

Initially, a comprehensive restructuring concept had to be developed. Under the project leadership of Eric Sun, a team of thirty experts came up with a detailed proposal within two months. For a number of the Bayer employees, this was their first engineering experience in the pharma-

ceutical field, and it was a project with a number of very special requirements. Among other compliance require-ments, the strict standards set by Good Manufacturing Practices (GMP) had to be adhered to.

In Wuhan, this meant constructing clean rooms in line with the particularly stringent Class A standards. All fill-ing areas had to comply with these specifications. The Class A standard stipulates, for instance, that particles larger than five micrometers can occur no more than 20 times per cubic meter of air. In the classical chemical pro-duction areas in which many of the Bayer employees had previously worked, the rules are not as strict.

And another aspect is different – in the pharmaceutical field, the entire HVAC (heating, ventilation, air condition-ing) system is far more crucial than in plants designed to process petrochemicals. A heating system like the one planned for Wuhan is not at all what one would usually ex-pect to find in the chemical production field.

GMP also affects the arrangement of devices and equip-ment. For example, the distance between a component and the nearest wall has to be sufficient to allow the space between to be ad-equately cleaned to ful-

fill hygiene requirements. And such things need to be tak-en into consideration very early, which is where Yang Lu comes in. An experienced healthcare engineer, she knows the demands faced by engineering in pharmaceutical ar-eas, and led the development of the concept.

Other aspects, however, are easier when it comes to plan-ning a pharmaceutical production facility. “As a rule, ev-erything is an order of magnitude smaller, because phar-maceutical products are manufactured in much smaller quantities,” explains project leader Sun. The daily pro-duction of a petrochemical site, for example, can exceed the entire annual output of a pharmaceuticals facility.

Once Sun’s team had submitted a persuasive, workable concept, Fresenius Kabi immediately awarded Bayer Technology Services two subsequent contracts. Under these, Bayer Technology Services would be responsible


PHARMA-ENGINEERING

H

Heading to WuhanBayer Technology Services is active in central China, as well. The company recently completed the planning for a production site in Wuhan for healthcare company Fresenius Kabi, for exam-ple, and also provided support during construction.

“We were impressed by the abilities and high standards of the Bayer project team.”Yueyun Chen, Plant Manager Wuhan, Fresenius Kabi


for part of the procurement as well as project management during the construction phase. As a result, around fifteen of Sun’s staff spent six months mostly on site in Wuhan, and were regular passengers on the Huhanrong high-speed service.

In September 2014, the first part of the three-phase con-struction project was completed. The client was especially satisfied that the project was able to stay completely on schedule despite facing a number of technical hurdles along the way. Yueyun Chen, Plant Manager Wuhan for Fresenius Kabi, says, “Our company was impressed by the abilities and high standards of the Bayer project team.

They were extremely diligent, actively providing solutions to unavoidable technical issues during the project’s imple-mentation phase, helping to keep it on schedule.” The local plant manager was also very pleased with the high safety standards set by the Bayer employees, avoiding all poten-tial incidents throughout the entire construction period. “This will certainly not be the last joint project we work on in China,” Chen adds.

The Bayer Technology Services employees in Shanghai would certainly be pleased with a new collaboration. And who knows? Maybe they’ll get to acquaint themselves with a different high-speed train.

800 kilometers in five hours: for their project, Bayer Technology Services employees spent several months commuting by train from Shanghai to Wuhan (above).


DRUG SAFETY

Hard Times for CounterfeitersIn future, a complex packaging code aims to make life difficult for the makers of counterfeit drugs. Experts from Bayer Technology Services are behind the implementation, conceptu-ally and technically.



ou had to look very carefully. Even then, you would only be able to see it with

the help of ultraviolet light. Something just didn’t seem right about the paper of the package insert and the packaging itself. It wasn’t up to the usual quality. But for a long time, no one noticed. The whole thing only came to light because someone stumbled across tiny irregularities in the instructions inserted with the stomach medicine. But by then, the counterfeiters had already slipped the sham packages into German pharmacies in large quantities – and had earned good money by doing so.

That case happened just a few years ago. At that time, no health concerns were caused by the fakes, because the pills had been correctly produced by a contract manufacturer. Even so, every patient who buys his or her medication from a pharma-cist has to be certain that they are getting the genuine product. That means a product that comes from the manufacturer shown on the packaging, a product that fulfills strict quality standards.

Around the world, authorities and manufacturers are working on solutions that provide this certainty. Dr. Stefan Artlich is also part of this. For many years, on behalf of Bayer Technology Ser-vices, the mathematician has been part of an expert team of the European Federation of Pharmaceutical Industries and Associ-ations (EFPIA), whose goal it is to come up with an appropriate

Y

Practical and safe: A comparison between the scanned code and the data-base instantly shows whether the pack is from an original manufacturer.

coding plan that covers the European Union, Norway, Liechten-stein, Switzerland and Iceland.

Artlich and the other experts involved have long had a clear idea of what the solution will look like: Every drug package would carry a unique data-matrix code – a one-of-a-kind grid of small black and white squares. The two-dimensional code looks similar to the well-known QR code, which can be scanned us-ing a smartphone, and is a further development of the barcode. The barcode, however, runs into problems when confronted by the small dimensions of medication packaging: the sequence of bars, by itself, is not enough to encode all of the important infor-mation. The code is supposed to include the product number, batch number, expiration date, and an individual serial number up to 20 figures long – each of these, therefore, represents a long sequence of digits.

“Before the pharmacist hands over a package to a customer, all the staff member has to do is scan this code,” Artlich ex-plains. “Because each code is unique, if anything is not as it ought to be then it would instantly show up, for example if the scanned code has ever been passed across a counter some-where else.”

But to guarantee that this actually happens, it has to be pos-sible to carry out a code query in real time. The prerequisite for


But a simple trick prevents this from being successful. “Not every number is also a valid serial number,” explains Artlich. On the contrary, in fact: of 10,000 consecutive numbers, on-ly one, on average, will actually be used as a serial number. As a result, the chances of a counterfeiter actually hitting on a real code by using a randomly chosen number falls to one in ten thousand. And to make things even more difficult: deciding which numbers are used as serial numbers at all is a decision made by the BayCoder. BayCoder is a special program devel-oped personally by Artlich and his colleagues (see box), which Bayer Technology Services markets worldwide, also to compa-

this, of course, is that all pharmacies have to be connected to a central database in which all codes that have ever been printed on a package are stored.

A few years ago, a pilot project involving 25 pharmacies in great-er Stockholm confirmed that the process works. In that pilot, too, Bayer Technology Services played an important role (see technology solutions 1/2010).

Over the past few years, however, Stefan Artlich and his colleagues have not only been concerned with the technical questions of coding. “We have also travelled extensively throughout Europe to promote the concept to the authorities and manufacturers associations in each country,” Artlich ex-plains. By “we,” he means the four experts in the EFPIA core team, three of whom are specialists from Bayer Technology Services – from the Operational Excellence & Logistics depart-ment, to be exact. “Bayer Technology Services’ contribution to this project has really been exceptional,” underscores François Bouvy, who heads the Market Access working group at EFPIA. “Their commitment was a decisive factor, both for the technical realization as well as the acceptance of the system in the Euro-pean countries.”

Winning acceptance was also the focus at the European Commission in Brussels, where the concrete implementation of the system ultimately had to be decided. As a result, Artlich and his fellow campaigners made many trips to the Belgian capital. “Again and again, we presented the technical possibili-ties and our own progress in developing an overarching con-cept for all of Europe to the employees concerned with the topic at the European Commission, all with the goal of guaranteeing an efficient solution for supplying patients with safe medicinal products,” Artlich explains.

As simple as the coding idea seemed at first glance, the pre-cise organization of a schedule for implementing the proj-ect in some 30 countries turned out to be extremely compli-cated. A lot of questions needed to be answered: Where was the central database supposed to be set up? Who would be responsible for its operation? How could the elaborate in-frastructure be put in place in countries like Estonia or Mal-ta? From time to time, alternative technologies, too, entered the discussion; for example, using a chip built into the pack-aging that could be read wirelessly. But because of technical hurdles with RFID technology, the data matrix approach won out in the end.

But what happens if the data matrix code is forged? At the end of the day, one has to assume that will happen. Artlich nods: “It’s definitely conceivable that criminals will get their hands on a package and simply combine the product and batch numbers with different serial numbers.”

One million packages of a particular product are to be given a serial number. In a classical scenario,

they would simply be numbered consecutively from 1 to 1,000,000. The problem with doing it this way is that coun-terfeiters who already know the product and batch num-ber have it easy, because every serial number lower than 1,000,000 actually exists on a package.However, things would be different if you were able to se-lect your serial numbers from a larger range. And exactly that is what the BayCoder software does. Specially devel-oped by Bayer Technology Services, BayCoder starts with a selection that is 10,000 times as large as the number of packages. In this particular example, that means ten billion numbers. Then the program generates a random sequence of these numbers. The first million numbers in this com-pletely unsorted sequence would then be used as serial numbers for the one million packages. On average, there-fore, only one number in ten thousand from the selected range is an actual serial number. As a result, counterfeit-ers who attempt to integrate a serial number into their da-ta matrix code take the risk that 9,999 out of 10,000 fake products will be identified as such as soon as the code is scanned and compared with the database, because most of the numbers in the range simply don’t exist there. Even armed with the knowledge of several existing serial num-bers, the BayCoder algorithm remains uncrackable.

One in Ten Thousand

“At our projects on sites all over the world, I’m glad I can rely on Bayer Technology Services’ experience.”Thomas Hendrischke, Program Head 2D Matrix Code, Product Supply, Pharmaceuticals



been completed successfully: In Berlin, Berkeley (USA), and in Segrate in Italy, the first product packaging bearing the new code rolled off the production line at the end of 2014. And more sites will be added this year, including Leverkusen and Weimar in Germany, Ansung in South Korea and Turku in Finland.

At Bayer, they know to appreciate the support provided by Artlich and his team. “I’m happy to be able to fall back on Bayer Technology Services’ experience, also with the projects taking place at other sites,” says Thomas Hendrischke, who heads the corresponding program on the Product Supply side.

Some countries, with their security concept, go even fur-ther than the European Union does. In addition to the secu-rity code, they require complete traceability for every single package along the entire supply chain. In concrete terms, that means knowing when a particular package was loaded onto a certain ship or a certain truck, and where – all of this infor-mation has to be recorded in the database by the manufactur-er and distributor. For Artlich and his colleagues, this pres-ents an additional challenge. They are currently working to ensure that Bayer fulfills this requirement for the fifth largest pharmaceutical market in the world: Brazil. A test phase with selected products is already running. And time is pressing: the South American country is planning the introduction of the matrix code for 2016.

nies outside the Bayer Group. The code concept has now found acceptance, and the European Commission has made a firm commitment to the data matrix approach for recognizing coun-terfeit medicines. The Europe-wide rollout is planned to take place by the end of 2018.

In several non-EU countries, the data matrix code is already in day-to-day use. Turkey, for instance, has stipulated the use of such a security measure since 2010. And in Argentina, China, Saudi Arabia and South Korea, medicines also have to carry a 2D code. Other countries, including Brazil, are about to intro-duce a corresponding system. For Stefan Artlich and his fel-low data matrix advocates, all this global activity has brought with it more work, because it means they have to support their colleagues at Pharmaceuticals and Consumer Health in adding the required code to the product packaging for each of those countries.

“For imported products, an initial solution provided for add-ing the codes for the respective countries retroactively,” says Artlich. But in the mid-term, the products will need to come off the production line already fully encoded. “Bayer is currently in the process of integrating this step-by-step into the respective production lines at all sites around the world.” Bayer Technol-ogy Services employees are involved in all local site projects; in some, Artlich himself is on site. The first projects have already

Very happy with the high security standard set by the data matrix code solution: Dr. Stefan Artlich.

BAYER TECHNOLOGY SERVICES IN FIGURES

MASTHEAD: publisher: Bayer Technology Services GmbH; responsible for the contents: Dr. Arnold Rajathurai; editor-in-chief: Birgit Neumann; concept and editing: Widera Kommunikation, Cologne; editorial team: Dr. Ralph Herbst, Dr. Martin Gerlach, Dr. Wilfried Kopp, Dr. Jörg-Rainer Schmitz; design: Dietmar Suchalla; final editing: Wilm Steinhäuser; reproduction: Reprostu-dio Kroke; production: Das Druckteam Berlin (Europe), Yingli Print House (Asia); editorial address: Bayer Technology Services GmbH, Corporate Communications, Building K9, 51368 Lever-kusen, Germany; email: [email protected]; www.bayertechnology.com

BRAND NAMES: Basta, BayCoder, Liberty, Teflon, UVivatec

PHOTOGRAPHS: p. 1: VLN; p. 3: Bayer; p. 4: fotolia, Matthias Sandmann/Bayer; p. 5: Matthias Sandmann/Bayer, Bayer; p. 6/7: Roche; p. 8–11: Matthias Sandmann/Bayer (3); p. 12/13: fotolia; p. 14/15: Fraunhofer MEVIS, Bayer; p. 16: Sabine Bungert/Bayer; p. 17: privat; p. 18/19: Rick Fischer/Masterfile/Corbis; p. 20: Bayer, private; p. 21: Bayer (2); p. 22/25: Bernhard Moll/Bayer (4); p. 26/27: fotolia; p. 28: Matthias Sandmann/Bayer; p. 29: Bayer; p. 30–33: Bernhard Moll/Bayer (3), Bayer (5); p. 34/35: Bayer (2); p. 36–39: Bayer (3); p. 40/41: Pau Molas/ ImageZoo/Corbis; p. 42: Jutta Jelinski/Bayer; p. 43: Bayer, Bernhard Moll/Bayer, Peter Ginter/Bayer; p. 44: Fresenius Kabi; p. 45: Joseph K. K. Lee; p. 46–48: Bayer (2); p. 49: Matthias Sand-mann/Bayer; p. 50: Bayer (3); p. 51: fotolia

FORWARD-LOOKING STATEMENTS: This publication may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at http://www.bayer.com/. The company assumes no li-ability whatsoever to update these forward-looking statements or to conform them to future events or developments.

Would You Believe It?

48 kilometers of pipes are to be laid at Bayer’s site in Knapsack, Ger-many, by 2017. The pipes, equivalent to the distance between Co-logne and Düsseldorf airports, will service a new Bayer production

plant. The company is investing 150 million euros to increase its production capacities of methane phosphonous acid n-butyl ester (MPE). MPE is an im-portant precursor for the increasingly in-demand herbicide active substance glufosinate-ammonium (see page 21). Bayer Technology Services has been en-trusted with construction management of the project; building work started in April 2015, with the foundation stone being laid in August (pictured). The proj-ect also includes 4300 electronically controllable components.

0.15 is the number of recordable incidents leading to lost working time per 200,000 employee working hours reported at Bayer Techno-logy Services in 2015. This figure, known as the LTRIR, is below

the ambitious target of 0.21 set by the Bayer Group for 2015. For many years, the frequency of work-related accidents at Bayer has been dropping steadily. In 2008, for example, the LTRIR was still at 0.44. Since then, the rate has fallen by more than half. The constant improvement in safety is partly the result of Bayer’s many successful safety campaigns (pictured). Among these is a global program which is currently still running, and which aims to improve the safety-related behavior of every individual employee.

60000000000 tablets at 50 milligrams each. That’s how many tab-lets have been made from

the 3000 tons of acarbose produced by Bayer at its Wuppertal site up to 2015. Demand for the acarbose-based, type-2 diabetes drug has been increasing for years. To meet this de-mand, Bayer expanded its production capacities at its Wuppertal site between 2004 and 2012. Biotechnology experts from Bayer Technology Services played a key role in the con-ception and design of three new fermenters (pictured). The operations in Wuppertal have been producing acarbose since 1997.

Knowledge


1

3

55

6

7

8

9

9

9

2 4

7

8

1 BRAZIL: BELFORD ROXOMarkets: BrazilRegional Head: Roberto SalvadorPhone: +55 21 2189 0464

CHINA: SHANGHAIMarkets: China and East AsiaRegional Head: Wolfgang EickhoffPhone: +86 21 61465100

3

5 INDIA: MUMBAI, VAPIMarkets: India and South AsiaRegional Head: Balaram KhotPhone: +91 22 2531 1949

GERMANY: BERGKAMEN, BERLIN, DORMAGEN, FRANKFURT, KREFELD, LEVERKUSEN*, WENDELSHEIM, WUPPERTALMarkets: Europe and Africa Managing Director: Dr. Armin Knors Phone: +49 214 301

4

2 CANADA: SASKATOONMarkets: CanadaRegional Head: Dr. Gerd DahlhoffPhone: +1 306 385 8007

RUSSIA: MOSCOWMarkets: CISRegional Head: Dr. Evgeny BelovPhone: +7 495 234 2000

MEXICO: MEXICO CITYMarkets: Mexico and Central AmericaRegional Head: Jan-Peter SchmelzPhone: +52 55 5728 3016

6

SINGAPOREMarkets: Southeast Asia, Australia and New ZealandRegional Head: Samme WangPhone: +65 6496 1888

* global headquarters

USA: BERKELEY, KANSAS CITY, MORRISVILLEMarkets: USARegional Head: Helmut EngelsPhone: +1 919 549 5600

The entire world of Bayer Technology Services

Sites


9


At Bayer we encourage you to question the status quo and constantly think beyond the obvious. We foster open discussions, sharing knowledge across our community and partnering with external networks. We always start by

listening – because our customers are at the heart of everything we do. At Bayer you have the opportunity to be part of a culture where we value the passion of our employees to innovate and give them the power to change.

EB_Ad_Image_210x280_Portrait_Diver_EN_RZ.indd 1 28.08.14 12:00

technologysolutions - Bayersolutions.bayer.com/.../Technology-Solutions-2016-E... · he Bayer Group...

Documents

Transcript of technologysolutions - Bayersolutions.bayer.com/.../Technology-Solutions-2016-E... · he Bayer Group...