New Concepts in Risk Control

Bayer’s Helmut Mothes examines the success of Lean and the development of operational excellence.

“We want to operate the process, the plan and the facility as optimally and as efficiently as possible, which is particularly challenging at the moment”
-Dr. Helmut Mothes

In recent years, the life sciences industry has faced increasing challenges, often due to long development cycles, uncontrolled failure risks and growing competition. As SVP and Head of Process Technology at Bayer, Helmut Mothes is discovering new concepts in the development and manufacturing of drugs to address these issues.

He explains the significant challenges created by the long development cycle for drugs, and the risks produced by the complexity of the tasks, advising the solution for the industry to apply specific concepts proven to speed up the process, containing those risks in its early phases: “If failure happens in an early phase, the risk of having spent too much money already is avoided,” he says.

According to Mothes, there are three major concepts that you could apply to manage that process efficiently. “The first thing is you have to introduce what you could call proof of concept or proof of visibility in the developmental cycle very early, and during the early phases of a developmental project you have to focus on activities that help to lead to the proof of concept.

“You also need workflows, particularly after proof of concept, that are very standardized, very modular, and that allows you with minimum risk to achieve the goal, to break through pre-clinical and clinical development, and then to launch the product. Thirdly, combined with that second concept, it’s necessary to have standardized technology platforms, particularly with respect to manufacturing. So these are the three things that are important to speed up the process and to take the risk of failure into early phases,” says Mothes.

Data management
In terms of improving handling of information, a more efficient creation of data is important to transfer some of that failure risk to earlier phases in the development cycle. Mothes explains that central to this is the development of a drug, whether chemical compound or biological, which will create a huge amount of data. However, this does not come without its challenges.

“The problem arises as to how to manage this data appropriately and also, a challenge even more important in the future, is how to extract the right information out of this data to support decision-making. Essentially, you need efficient ways to manage huge amounts of data, not only for a single-track development project, but also for a variety of projects, because that may create additional information and opportunities. Also, combining data management with modeling and computational tools could allow you to extract further information to create more insights into structures, things you can see by simply handling data.”

In order to shorten the time between target discovery and approval of the active substance, Bayer has implemented many of the standard procedures, from high throughput screening in the early stages of generating small quantities of an active compound, through to efficient ways of managing clinical testing.

“Of course, there are new ways to improve the performance,” explains Mothes. “I would like to describe that with an example, which is not so much related to drug discovery, but to the synthesis of active ingredients and how to get an active ingredient or an active substance from the early stages towards the production scale.”

“For example, when you start a development you generate the first milligram of a product, and the synthesis route you have chosen to do that will affect what you have to invest later on in the production side, it will affect how complex the process development will be, and it will also affect what the risks are. We try to implement a concept so that you generate the first milligrams of a product with technologies that can be easily scaled up and then put into reality in a production plan: micro technology.

“The reaction is done in a single channel and then later on the production is done in a multiple number of channels, but what is happening in a reaction channel doesn’t change. So scaling up is not really a problem. This is very simplified, but it makes clear that it is possible to use the same technology platform when you produce the first milligrams of active substances, and you use the same principles late in production. That of course significantly minimizes the risk of failure and also optimizes the speed of the positive element processes.”

Lean
The move to Lean and towards operational excellence is continuing to dominate discussions within the life sciences industry, and so with it becoming a major topic for biotechnological services, to address topics related to performance and operation. “The idea is to apply operational excellence in an integrated manner. We want to operate the process, the plan and the facility as optimally and as efficiently as possible, so that’s the target, and this objective is particularly challenging at the moment with all the changes in raw materials and global competition,” says Mothes.

“To be really successful in operational excellence you need integrated programs that address three topics. First of all you need an assessment of where you are and where you could go with your performance. This assessment has to be neutral. It should not be biased by beliefs that you carry from the past, so that’s the first element: assessment. Second thing, you need methodology. Very often we get proposals, which we improve, but methodology means you have to have tools, software and handbooks that guide you through the process of implementing operational excellence projects. So assessment, methodology, and the third level that is automatically linked to operational excellence are the topic of sustainable implementation: you need things that allow you to monitor, to steadily improve the key parameters.

“For example, you need online monitoring with respect to key parameters: assessment, methodology and sustainable implementation to bring an integrated approach. At biotechnology services we have put together a package that integrates these three levels and the package actually aims at different targets,” he says.

Efficiency matters
Mothes notes the importance of efficiency in improving speed and flexibility during drug synthesis in the manufacturing of active substances. He advises the first step in this to be in synthesizing an active substance, starting with the technologies that are easy to scale up, which is often done through the setting up of laboratories that are able to produce very small quantities in a manner that is similar to a later production side.

“Important to this process are modular and standardized concepts, along with being able to prefabricate certain things later on for production. Currently active ingredients are manufactured in multi-purpose, multi-product plants, which require upfront investment, and it’s always difficult to get a high utilization in these plants. These multi-purpose, multi-product plants are very flexible but they are less efficient.

“We try to overcome that problem by moving towards continuous production, and by small but dedicated processes to manufacture active ingredients. This could change the way active substances are manufactured: we move away from a multi-purpose, multi-product chemical plant toward a more automotive kind of production for active substances.

 “Whether that will actually happen, we will see. There are certain challenges in terms of technology that are required, but what I consider to be the most important challenge for us is changing production strategies in such a manner that will require a paradigm change, because you cannot implement a multi-purpose plan in a small, dedicated line. That will not allow you to utilize all the benefits, meaning you have to strategically approach the topic. Therefore Bayer’s biotechnology services, together with other major companies, has started an initiative we call F3 factory.”

Bayer’s F3 factory project is supported by the European Commission, and is set up to allow different companies to put together more flexible concepts, at a faster pace. Since it’s a paradigm change, companies cannot push their individual concepts through. Instead, a consortium of partners must work together to standardize modules and interfaces. The change from a multi-purpose, multi-product bench production toward continuous dedicated production is one of the trends currently being seen in the life science area.

Bayer also recently signed a partnership agreement to use their modeling and simulation software, and as a result has implemented some of the necessary hardware. “These are the first very promising projects running,” explains Mothes. “What are we aiming at? We think that these methods could enhance certain development tasks, such as the area of codings and in the area of formulations and drug delivery systems.

“It’s important to integrate these computational methods with what you do in a standard manner with experiments, and these computational methods allow you to reduce the number of experiments, but they also allow you to challenge your mental models and that creates new knowledge. We have applied these things to two or three actual topics in drug development and we think that these theoretical methods definitely supplement what we do during the normal development cycle.”

Innovation
Bayer follows a strategy that can be described as openly innovative: the complexities of the challenges are only successful if handled without a network of research units, institutes and universities. A single company is not capable of providing all the necessary resources, making it essential to build a network of research collaborations. Mothes names the catalysis centre in Aachen as one example of this: “It’s one element, together with biomaterial signs, biotechnology services and the university, which we have set up. In the centre there are people working from the university but also Bayer people, and in this environment we are carrying out projects that are more long term.

“We are going for what we call dream reactions. Currently, we have a product that you synthesize in plans with five or six steps. It would be very beneficial if you could reduce the steps to get to a polymer from five or six to let’s say two or three, by combining new technologies, new catalysts and ionic liquids, and that will reduce raw material demands and investment.

“Since it’s very long-term research, we also need some time. That’s the reason we’ve supported the center for at least five years, but there are already some developments that indicate there is a potential. There’s still some way to go, but first results show that we are very likely to be successful there,” he says.

Innovation is important to Bayer, especially in terms of economics. “If you look at a product like polycarbonate, then currently you are doing that in plants where you have several steps. You synthesize step-by-step and find the product would be polymer. It is feasible to take two of the main raw materials, carbon dioxide in this particular case, and synthesize that polymer. There have been a lot of efforts in the past to pursue so-called ‘dream reactions’ and in principle they are plausible, but up until now they haven’t been achievable.

“With nanotechnology, new catalysts and new process technologies, like micro technology, there is a good opportunity to be successful.”

Dr. Helmut Mothes has been Head of the Process Technology Division at Bayer Technology Services since January 2002. Prior to this he worked at Bayer’s Animal Health Business Group in Mannheim, where he was responsible for operations (manufacturing, supply chain management, quality assurance. He began his career at Bayer in 1984, working in the Process Engineering Department of the Central Research Division. During his five-year stay in the US, he worked first at Bayer Corp. (formerly Miles Inc.) and then at Haarmann & Reimer as manager of the biotechnology pilot plant and later of citric acid production.