Controlling the giant
Advanced software keeps Europe’s largest cell culture plant on track

Boehringer Ingelheim chose Werum’s PAS-X Biotech manufacturing execution system for its new biopharmaceuticals plant at Biberach. Controlling production in such a large and technically-demanding plant was never going to be easy, but the project ran smoothly and the company is well satisfied with the results.

Over the last year, no other project in Europe’s pharmaceutical industry has gained as much notice as Boehringer Ingelheim’s new active pharmaceutical ingredients (API) plant in Biberach, Germany. As the largest cell culture plant in Europe, it has set new records in development, construction and technology. In less than three years, Boehringer Ingelheim has invested more than s255 million in this huge biotech complex. Used in the construction of the building were more than 18,000 cubic meters of concrete, 2,700 tonnes of steel, 600 pieces of biotech equipment, 70 km of piping and about
800 km of cable. A vital part of the new plant is the manufacturing execution system (MES) developed and supplied by
German specialist company Werum Software & Systems.
The new plant produces highly innovative biopharmaceuticals. Technical demands in the biopharmaceutical production of APIs are particularly high, and require cutting-edge pharmaceutical production skills. An advanced MES is essential to provide mastery of these complex workflows. Werum’s PAS-X Biotech MES system has met all of Boehringer Ingelheim’s needs, having been tailored to the very specific requirements of biotech production.

Unparalleled process reliability
“This multi-purpose plant is really complex, with many interfaces to various kinds of equipment,” explains Mr. Schunk, project manager at Werum. “This alone means that the production management system needed to co-ordinate all the individual work segments in the overall manufacturing process is unique.”
Cleanliness and sterility are the watchwords in pharmaceutical production, but for biopharmaceuticals, the demands on reliability and safety are twice as high. It is a long and difficult route from a cell to an active ingredient.
First of all, the cells have to be grown under controlled conditions. At first this is done in the cell bank, then in small pre-fermenters, and finally in huge production fermenters holding up to 12,500 l. After this, the active ingredient is separated from the cells and the product is purified and concentrated by filtration and chromatography. Then it undergoes final purification and formulation, before filling, final inspection and packaging. After successful completion of quality control, the product is released for sale.
From a process engineering point of view, the greatest challenge is that the cells handled are alive. Even the slightest contamination by external micro-organisms, for instance during fermentation, will affect the entire process and usually result in the loss of the whole batch. This is why process reliability must come first. The monitoring process in the active ingredient plant involves about 10,000 sensors and actuators distributed over 150 pieces of equipment.
Experts in pharma and biotech
Knowing that the MES would be vital for the success of the new plant, Boehringer Ingelheim started the MES project, codenamed Biomes, back in May 1999. “Without a manufacturing execution system that interfaces closely with the distributed control system (DCS), it would not be possible to run our complex processes optimally,” says Mr. Meyer, Biomes project manager at Boehringer Ingelheim. With more than 1,000 separate processing operations carried out in the Biberach plant, the new MES would have to ensure that every action is executed according to precise instructions and fully documented.
Werum’s PAS-X Manufacturing Execution System (MES) has been established in the process industries for several years. With numerous successful projects in the pharmaceutical industry, Werum ranks among the few MES providers who are familiar with biotech processing. “After several months we concluded that Werum, with their proven PAS-X Pharma product and their experience in biopharmaceuticals and fine chemicals, was the best-qualified of all the suppliers,” confirms Dr. Carius, Vice President Biopharmaceuticals at Boehringer Ingelheim GmbH & Co. KG. “However, to implement our particular requirements Werum had to considerably expand the software’s functions.”
Werum received the order to design and implement the Biomes project and prepared the functional specification, which ran to about 3,000 pages. By spring 2002, the project team had succeeded in turning this immense pile of paper into a working system.
First manual, then automatic
The main challenge facing an MES in biotech production is that automated workflows alternate with manual operations. For this reason, the automated sequences are first filed in the recipe system of the DCS and transferred to the MES. The MES then links these automated sub-functions to the manual operations and checks for consistency, such as batch and equipment status. Finally, target values are assigned to these manufacturing specifications.
The MES handles all the manual sequences and triggers the automated procedures in the DCS. After executing each automated sequence, the DCS returns the result parameters to the MES. As the controlling system, the MES continually displays the current status of all processes, including the DCS. On completion of a manufacturing stage, the MES generates the associated documentation.
The entire electronic process monitoring is designed to act as an early warning system. Trend calculations are used to predict and report deviations before they actually happen, so that the operator has enough time to take corrective measures. On-line booking of every process step and every use of materials makes it possible to follow the process flow directly. Another essential task of the MES is monitor cleaning and sterilization status, including expiry dates for all related equipment such as containers, pipe systems and set-up parts. The system minimizes the risk of contamination by, for instance, issuing an alarm whenever the production plan would call for an non-sterile equipment item to be used.
Future requirements: 21 CFR Part 11 compliance
PAS-X Biotech is also qualified for paperless documentation on the basis of electronic batch recording (EBR). The system ensures compliance with 21 CFR Part 11 for the handling of electronic records and electronic signatures (ER/ES), and guarantees GxP/FDA-compliant archiving of process data. The PAS-X deviation report, which is part of the electronic manufacturing report, shows deviations and events concisely and transparently. Furthermore, the MES has made it possible for Boehringer Ingelheim to establish a central electronic production management system. This can be interfaced to processes outside production, such as laboratory information systems (LIMS) or supply chain management systems. The MES serves as a data “turntable”, ensuring consistent data flow between, for instance, SAP and DCS environments.
The fact that a project as complex as this could be completed in the time available is first and foremost down to the effective
co-operation between Werum and Boehringer Ingelheim. “Really high demands were placed on the MES, but they were clearly defined and we knew about them early enough. So we had a good chance to cope,” says Mr. Schunk. “For three years we kept in very close contact with the project team at Boehringer Ingelheim.” The system was operational by the fall of 2002, and system validation — a task that is usually full of suspense — and release for production were managed without major problems in the summer of 2003. “For the validation step we formed combined teams with Werum,” explains project manager Meyer. “Smooth co-operation was a great help in meeting the tight schedule.”
Boehringer Ingelheim stands by its decision to choose Werum’s production management system. As soon as the start-up phase of the new API plant has been completed successfully, Boehringer Ingelheim intends to roll out PAS-X Biotech in other areas.