Bayer Pharma Biotechnology: 30 years of experience now available to external clients
Wuppertal – Bayer HealthCare Pharma Biotechnology, an integral part of the Pharmaceutical/Chemical Parc in Wuppertal, presents itself as strong partner to external clients. More than thirty years of practical experience in almost all fields of biotechnology are the sound basis for efficient process development and contract manufacturing. „We have an excellent track record covering projects ranging from the production of secondary metabolites secreted by actinomycetes to the cloning and expression of recombinant proteins produced by mammalian cells” says Dr. Hans-Dietrich Hörlein, head of Pharma Biotechnology and he can be proud of his team of more than 90 experts, who have piled up an immense practical know how now offered to outside clients. “We want to use our technical infrastructure for custom development and contract manufacturing for external clients. This allows our customers to speed up their projects by taking advantage of our technical expertise, flexibility and know how”.
Strengths
At present it is not very difficult to find fermentation capacity for contract work in Europe. However, as Dr. Hörlein points out, “there seems to be a need of free capacity for technically more demanding processes, which include for instance the handling of genetically modified organisms (GMO) at large scale, the use of organic solvents as substrates in fermentation or biotransformation processes or the availability of a large flame-proof area on the down stream side to handle large volumes of inflammable organic solvents in order to extract and purify products from fermentation broths, animal organs or transgenic plant material. In our multi-purpose plant we offer our customer a state of the art computer controlled fermentation equipment from lab to 40 m³-scale for ambitious and demanding batch or fed batch processes.” All fermenters and also the down stream equipment are licensed for the use of GMOs on biosafety level 1. On all scales the medium can continuously be UHT-sterilized at e.g. 150 °C, several feeding lines exist to each fermenter, the computer control system is used as flexible tool for more difficult feed strategies, and organic solvents can be fed as substrates or used as an inductor. The downstream processing area allows the use of large volumes of organic solvents and is fully equipped to handle such different projects like the purification of secondary metabolites from fermentation broths, the purification of proteins from recombinant microorganisms, or the isolation of APIs by extraction of animal organs or transgenic plants.
The microbial production plant is backed up by 11 research laboratories ready to develop projects from the initial idea and first concept up to the 10 L scale. This may include the design and optimization of a new biocatalyst for a biotransformation reaction, the improvement of a production strain by mutation and selection or by molecular biological approaches or the cloning and expression of proteins for research and development.
Pharma Biotechnology has full technical support from the Bayer organization, is fully integrated into the Bayer HealthCare QA/QC system to ensure strict compliance to regulations including cGMP. The Pharmaceutical/Chemical Parc is ISO 14001 certified and offers its customers very high safety and environmental standards.
Success stories
There are a number of success stories which demonstrate the efficient development
of biotech processes in Wuppertal throughout the last years. This includes
for instance the fermentation of Acarbose, a secondary metabolite produced
by Actinoplanes spec.. Acarbose is a pseudo-tetrasaccharide (fig. 1) active
as inhibitor of intestinal glucosidases and on the market as potent oral antidiabetic
drug since 1990. The Actinoplanes bacterium was originally isolated from a
soil sample taken in a coffee plantation in Kenia. The biotechnologists in
Wuppertal developed elite mutants by classical mutation and selection methods
and succeeded in increasing the fermentation yield by more than a factor of
500. On the down stream side Acarbose is purified in an effective and high
yielding process which involves a series of chromatography steps leading to
an Acarbose bulk product in superior quality. Dr. Hörlein summarizes:
“Today the fermentative production of Acarbose belongs to the most successful
examples in the field. And still, we have not yet reached the optimum.”
Another interesting example is the large scale biotransformation of the sugar derivative L-aminosorbitol with Gluconobacter oxydans. The biocatalytic production of D-aminosorbose is the central step of the combined chemical/biotechnological synthesis of Miglitol (fig. 2), another highly efficient glucosidase inhibitor being produced at Bayer HealthCare. The researchers at Bayer HealthCare Pharma Biotechnology developed a whole cell biocatalyst for the regioselective oxidation of L-aminosorbitol and arrived at very high yields per volume (up to 500 kg/m³ can be oxidized to more than 99 % in about 24 h). The result is a highly efficient synthesis of the product - short and economic.
The production of natural flavors like vanillin, gamma-decalactone or 2-methylbutyric acid is another example of well established processes in the multipurpose fermentation plant in Wuppertal. As Dr. Hörlein points out there are some special aspects to these fermentations. One is that the production is run under kosher conditions as the product is a food additive sold in part on the US market. “Once or twice a year, our production facility is inspected by a rabbi who controls in detail the compliance to the kosher regulations.” The second important aspect is that the production of organic acids requires the feeding of alcohol substrates into the fermentation. “This poses no special problem to us”, says Dr. Hörlein “as we are able to handle and prepare organic solvents in our flame-proof down stream processing area if needed in large volumes and transfer it from there into the fermenter. We think that the capability to handle inflammable organic substrates e.g. in biotransformation reactions is of special interest to our customers“.
The use of organic solvents in large volumes is of central importance in the production of many products, particularily when they have to be isolated and purified from animal organs or transgenic plants. This was a very classical task in biotechnology in the past but regains great importance as more and more products are produced in genetically modified organisms. The Wuppertal plant has just recently established a contract with a large pharmaceutical company to prepare a protein of animal origin involving a multistep process containing organic solvent extraction steps. Production is carried out under full cGMP.
High cell density fermentations e.g. of E. coli is another important topic which is gaining more and more importance for the production of biocatalysts or proteins using GMOs. “We have the necessary equipment in place on all scales” says Dr. Hörlein “to carry out such fermentations with cell dry weight yields of 70 to 80 g per liter (fig. 3).” A recent example was the production of recombinant E. coli biocatalyst. Dr. Hoerlein is very proud “as we managed to obtain a specific catalytic activity at large scale which was even slightly higher as in the optimized lab scale process which we took over from our customer.”
The future
As highlighted by many successful projects carried out in the past in BayerHealthCare
Pharma Biotechnology in Wuppertal, the know-how and the technical equipment
now available to external clients covers the whole range of classical and
modern biotechnology. Dr. Hörlein points out: “Our aim is to offer
custom development and contract manufacturing to clients being faced with
technically very demanding processes. We see a market for processes at pilot
scale or medium sized production scale with special requirements regarding
process control, sterility, use of inflammable substances, handling of GMOs
on all scales, or a flame-proof down stream processing area. What we do not
intend is to compete with established companies in the production of low priced
bulk products. Our offer is more on the side of specialized processes requiring
the appropriate fermentation and down-stream equipment. In this segment we
can offer a full range of capabilities.”
Box:
Bayer HealthCare Pharma Biotechnology: Strengths· 30 years of experience in all fields of biotechnology· 11 research laboratories
- Pilot and production plant with scales of 30 L, 300 L, 3000 L and 40 m³
- Flame-proof downstream processing area, handling of organic solvents on the large scale
- Use of recombinant microorganisms on biosafety level 1 from lab to 40 m³ scale
- State of the art equipment for technically demanding batch or fed-batch processes· Development of biocatalysts and biotransformations from lab to production scale
- Full integration into the Bayer HealthCare Pharma QA/QC system
Further information on the “Pharma und Chemiepark Wuppertal”
can be obtained by visiting our website:
www.pharma-und-chemiepark.de
November 2004
Please address all enquiries to:
Dr. Bernd von der Linden
Phone: +49 (0)202 / 36-75 87
E-Mail: herbert.stillings@bayerhealthcare.com
Forward-looking statements
This news release contains forward-looking statements based on current assumptions
and forecasts made by Bayer Group 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 our public reports filed with the Frankfurt Stock Exchange and with the
U.S. Securities and Exchange Commission (including our Form 20-F). The company
assumes no liability whatsoever to update these forward-looking statements
or to conform them to future events or developments.
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