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When success inflates costs

The production of therapeutic proteins and peptides is a success story for biology and engineering. Red biotechnology became commercially successful because process engineering succeeded in expressing foreign genes in microorganisms and got a grip on cells: tissue cells were not only cultivated using technical methods but also purified for medical application on an industrial scale. However, the biopharmaceutical industry is now facing rising costs.

A look back at the beginnings of bio and technology clearly shows the rapid development of the two sciences: in 1989, Amgen used to culture EPO using tissue cells in “roller bottles” with several hundred of such bottles next to each other in incubators. Nowadays, the drugs are produced in huge stirrer tank reactors 10 to 50 cubic metres in size.
The product yield also increased considerably: ten to 15 years ago, E. coli cultures resulted in a yield of only a few milligrammes per litre culture medium, said Jürgen Hannemann, founding dean of the biopharmaceutical biotechnology course at Biberach University of Applied Sciences. Nowadays, manufacturers are able to produce a thousand times more drugs – in the best case up to ten grammes per litre.

Biologists and engineers need to talk with each other a lot earlier

The earlier biologists talk with process engineers the better, says Jürgen Hannemann. © Biberach University of Applied Sciences
During the initial stages of biopharmaceutical production, the biological part is dominant – numerous cloning steps are required to find the most effective production strain, establish a master cell bank and cell banks for the daily experiments. When it comes to transferring the production process from Erlenmeyer flasks or laboratory fermenters to large-scale fermenters containing thousands of litres, then the impact of process engineering gradually increases. Hannemann is convinced that this is the point at which biologists and engineers should establish a closer dialogue. Hannemann’s conviction seems to imply that this has not previously been the case.

The fermentation step is the latest stage at which the interplay between biologists and process engineers should come into effect. In order to be able to understand this necessary interplay, Biberach students are taught how a stirrer is formed, how quickly the medium has to be stirred for the sensitive cells to be effectively and carefully transported by the stirrer, and which type of reactor is required for which types of cells. They also learn how gas is introduced to the nutrient solution to prevent the cells from floating upward at the same time as making sure that the gas dissolves optimally in the culture medium. The culture medium requires a specific pH, which has to be kept constant by adding either sodium hydroxide (high pH) or hydrochloric acid (low pH).

Engineering creates a feeling of well-being

The task of process engineers is to create the perfect growth conditions for cells in a technical environment. According to Hannemann, the maintenance of such conditions requires both process engineering and biological knowledge. Process engineers use technical means to set up the climatic conditions for the cell cultures. This again requires detailed knowledge of fluid mechanics, the correct adjustment of heat supply and removal, pressure control or stirring techniques, said Annette Schafmeister, professor of process engineering at Biberach University of Applied Sciences.

Communication accelerates solution finding

The chemical engineer, Annette Schafmeister, is well aware of the different ways in which engineers and scientists deal with problems. While biologists tend to favour the trial and error principle, engineers want to calculate everything and have full control over biological systems. In the end, the result is the same, but Hannemann is sure that the synergy of biology and process engineering accelerates the finding of solutions.

In Biberach, Schafmeister is teaching future pharmaceutical bioengineers about fluid mechanics, mechanical and thermal process engineering. This also includes materials science. Sterile technologies are very important in pharmaceutical processes. Schafmeister explains that the materials have to be able to cope with sterile conditions and the production process has to take all this into account.

Standardised processes “outwit” the variable biology

A female lab worker is connecting a thin flexible tube to a cell culture device.
The biopharmaceutical production process has made huge progress in the last few years. The picture gives an insight into parts of the cell proliferation process. © Boehringer Ingelheim
Has it been possible to effectively build a bridge between biology and the engineering sciences? Have complex biological processes been translated into calculable processes? Yes, Hannemann is nodding, but makes it clear that cells can only be reliably reproduced to a certain extent. He also says that big traditional pharmaceutical companies find it easier to cope with this variability than smaller biotech companies.

In big industry, these variable processes have to a large degree been standardised and it has become possible to render the production of antibodies 95 reproducible, for example. As part of Good Manufacturing Practice, there is a specified range within which the process is allowed.

The biologist and the process engineer agree that exploding levels of knowledge in molecular biology have led to increasing protein yields: more and more details about the genetic mechanisms are known; it is known which regulatory elements have to be included in the vector for the cell to produce even greater amounts of protein. However, Schafmeister and Hannemann have different views on whether the biologists have been more successful than the process engineers or vice versa.

Production is not the problem

Prof. Dr. Hans Kiefer. © Biberach University
Both agree with their colleague, the biochemist Hans Kiefer who holds one of two German professorships for protein purification: it is not production that is the problem but rather the isolation and purification of the proteins. During this downstream process, the desired proteins are isolated and separated from the damaged cells using chromatography.

And this is where pharmaceutical producers experience the greatest problem. Since the upstream process has led to a thousand-fold increase in protein yield, the chromatography columns are becoming bigger and bigger. They often have a diameter of two to three metres. Hannemann: “The production capacity per litre of culture medium has increased enormously, not so the purification capacity. The effectiveness of the purification process has not been technically improved.” However, the process engineer, Dr. Schafmeister, does not agree, pointing to improved sterile technologies, better apparatus and other technologies as examples.

What is technically feasible is not always profitable

Biopharmaceutical proteins (dyed red) are purified in a chromatography column - alaboratory technician is checking the separation process. The complex control system is located on the left hand side.
Chromatography drives the costs. © ratiopharm
The gist of the matter is not the technology but the costs involved. The purification of the proteins is no problem with available methods, said the Biberach chemist Hans Kiefer. However, protein purification accounts for up to 80 per cent of the entire production costs; in any case, the purification accounts for considerably more than 50 per cent of costs. Kiefer believes that upstream processing has become considerably cheaper due to higher production rates. High initial concentrations enable the use of completely different processes, for example those used in chemistry such as crystallisation or fluid-fluid extraction. But these methods are new and have not yet been used. Kiefer also reports on batch methods in which magnetic particles are used in suspension. The particles have surfaces that are similar to those of chromatography columns.
Cell harvest using microfiltration
Cell harvest using microfiltration. © Boehringer Ingelheim

Biosimilars as technology drivers?

According to Kiefer, the high costs related to the purification of proteins appeared not to be a problem for biopharmaceutical producers for a long time. The situation changed with the advent of biosimilars, which forced pharmaceutical companies to reduce the price of the original drugs, hence necessitating a reduction in production costs. Politicians are also concerned that production is being relocated to low-wage countries. That is why the BMBF has launched a funding programme for protein purification, in which companies from the Ulm BioRegion are working together with scientists. The cooperative project is being coordinated by the Biberach University of Applied Sciences.

Chemical process engineering as model

Experts believe that expensive chromatographic processes will always be necessary; the only possibility of reducing costs might be the reduction of the process from three to two chromatography steps. Economising one step in the process would lead to considerable cost savings. However, Schafmeister does not believe in the big success and can imagine the use of continuous production methods instead. This would enable a better control of production quantities, would not lead to system downtimes of several days due to maintenance work. She considers it important to optimise individual process steps, such as for example the extraction step where specific filters are used. Schafmeister also alluded to the example of diffusion-controlled nanofiltration which takes a long time and requires different strategies. Hannemann envisages the possibility of using salt to precipitate the proteins, i.e. the possibility to roughly separate the constituents without the traditional chromatographic step.

Sources:
Dirk Weuster-Botz: Bioverfahrenstechnik im Jahrhundert der Biologie. In: Mücke, Wolfgang/Gröger, Gabriele (Eds.): 2. Reisensburger Umweltbiotechnologie-Tag: Anwendungen der Biotechnologie in der chemischen Industrie, p. 25-35

John Curling: Process Chromatography: Five Decades of Innovation, in: Biopharm International, February 2007, p. 10ff.

Eric S. Langer: Managing Biopharmaceutical Manufacturing Capacity, in: BioProcess International, (3/2007, p. 20-26) 4th annual Report and Survey of Biopharmaceutical Manufacturing and Capacity and Production).

Nina Forsberg: 30 Jahre Höhepunkte des Downstream-Processing, in: Bioforum 1/2008, p. 52f.



wp - 31.03.2008
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