SubscribeManufacturing Execution System PAS-X BIOTECH installed in Europe’s largest cell culture plant.
Boehringer Ingelheim is a research-driven group of companies dedicated to researching, developing, manufacturing and marketing pharmaceuticals that improve health and quality of life. With more than 34,000 employees and 152 affiliated companies spread all over the globe, the company's two core businesses are Human Pharmaceuticals and Animal Health.
The former is made up of the business segments Prescription Medicines, Consumer Health Care and Industrial Consumer, which includes Chemicals and Biopharmaceuticals. At the locations in Biberach (Germany) and Vienna (Austria), Boehringer Ingelheim can provide the entire biopharmaceutical process chain from genetic cell development to large-scale commercial manufacturing. In 2003, the Industrial Customer Business of biopharmaceuticals achieved sales of Euro 280 million.
The employment of a Manufacturing Execution System (MES) in production ensures mastery of the complex workflows. The demands in biopharmaceutical production of active pharmaceutical ingredients (API) are particularly high. In the new API facility Boehringer Ingelheim will produce highly innovative biopharmaceuticals.
These advanced products are the result of many years of extensive pharmaceutical research and, without a doubt, represent cutting-edge performance in pharmaceutical production skills. A vital contribution to this process is the MES system by Werum, which has been tailored to meet the very specific requirements of biotechnological production.
Over the last year, no other project in Europe's pharmaceutical industry has gained as much notice as the new active ingredient plant of Boehringer Ingelheim in Biberach. As the largest cell culture plant in Europe, it set a new record in development and construction, and currently surpasses all others in terms of technology. In less than three years, more than Euro 255 million have been invested in this biotech complex.
Just imagine: more than 18,000 cubic meters of concrete, 2,700 tons of steel, 600 huge biotech apparatuses, 70 kilometers of piping, and about 800 kilometers of cable were used in the construction of the building.
Unparalleled Process Reliability
Just as noteworthy is the system for production management and control that keeps the facility's manufacturing process going. "The complexity of this multi-purpose plant with its numerous interfaces to various kinds of equipment, and the automation required for this really makes it a most complicated and intricate matter," explains Mr. Schunk, project manager of Germany-based Werum Software & Systems. "The production management system applied to coordinate all the individual work segments in the overall process of manufacturing active ingredients is unique solely for this reason.
"The production of biopharmaceuticals is one of the most sophisticated of production processes. 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 way from a cell to an active ingredient.
First of all, the cells have to be reproduced under controlled conditions. In the beginning, this is done in the cell bank, then in rather small pre-fermenters and, finally, in huge production fermenters, which can hold up to 12,500 liters. After this, the active ingredient is separated from the cell. By passing it through filtration and chromatography processes, the product is purified and concentrated.
Then, it has to undergo final cleaning and formulation. The stabilized product is filled into vials in an aseptic environment or freeze-dried. Following a visual inspection the vials are packaged for shipping and upon successful completion of quality control they are released for the market. From the aspect of process engineering, the greatest challenge is that the cells handled are live cells.
Even the slightest contamination with external germs, for instance in fermentation, will affect the entire process and usually result in a 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, supplying essential data or carrying out instructions.
Coordinating Complex Processes Safely
"Without a Manufacturing Execution System that interfaces closely with the distributed control system, it would not be possible to run the complex processes in such an optimal way," Mr. Meyer, BIOMES project manager of Boehringer Ingelheim underlines the significance of an MES. "For a smooth flow of production it is essential that the batch record is structured consistently to ensure the manufacturing of products of constant form and stable quality.
"With more than 1,000 processing operations executed in the Biberach plant, any action, i.e. every touch of a button, every temperature reading, and every transfer, is executed according to precise instructions and is subject to complete documentation. The MES system guides the operator safely and step by step through each work segment and prevents errors in operation. The importance of such a system for quality assurance can hardly be over-emphasized - being well aware of this, Boehringer Ingelheim started the BIOMES project as early as May 1999.
Experts in Pharmaceutical and Biotechnological Processing
Werum's PAS-X Manufacturing Execution System (MES) has already been well-established in the processing industry for a number of years. With numerous successful projects in the pharmaceutical industry, Werum ranks among the few providers on the market who are also familiar with biotechnology processing.
"After a decision-making process of several months we came to the conclusion that Werum, with their proven product PAS-X PHARMA and their project experience in biopharmaceutical and fine-chemicals production, was the best qualified of all suppliers," confirms Dr. Carius, Vice President Biopharmaceuticals at Boehringer Ingelheim GmbH & Co. KG. "However, in order to implement our particular requirements the available product functions had to be expanded considerably.
"Werum received the order for the design and implementation of the BIOMES project and prepared the Functional Specification. The requirements of this extraordinary project were defined in detail on about 3,000 pages. By spring 2002, the project team had succeeded in putting the immense paper work into practice.
Keyword MES
A Manufacturing Execution System (MES) represents the electronic interface between staff, equipment automation, orders, logistics, and batch records. Thus, the MES is the linking element between the higher-order ERP system and the distributed control system. In this way, Werum's Manufacturing Execution System PAS-X connects the commercial world (which focuses on sales and production planning as well as controlling) to process automation.
To fulfill its functions, the system breaks down the large manufacturing orders it receives from the ERP system (e.g. SAP) into smaller individual production orders. These are the orders eventually executed on the shop floor. The main tasks of PAS-X BIOTECH in the API plant of Boehringer Ingelheim in Biberach are:
- Warehouse and inventory management for pre-portioned WIP containers.
- In-plant materials management.
- Batch tracking and batch genealogy.
- Recipe creation with version management.
- Recipe control and execution.
- Finite scheduling.
- Computerized weighing.
- Electronic batch recording.
- Integration of in-process control.
- Equipment maintenance, status administration.
- Integration of the economically focused Enterprise Resources Planning System (e.g. SAP R/3) with the Distributed Control Systems supporting shop floor production.
- Data turntable: integrates the data of various external systems (LIMS, DCS, ERP, etc.).
Manual and Automatic Sequences Alternating
The main challenge that MES has to face is that in biotechnological production, automated workflows alternate with manual operations. For this reason, the automated sequences are first filed in the DCS recipe system and transferred to the MES. The MES then links these automated sub functions to the manual operations and consistency checks (e.g. batch or 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. On execution of automated sequences the DCS returns the result parameters to the MES. As the controlling system, the MES continually displays the current status of all processes including DCS. On completion of a manufacturing stage, the MES generates complete associated documentation.
The entire electronic process monitoring is designed to act as an early warning system. Trend calculations are used to detect and report deviations even before they actually occur, so that the operator has enough time to take corrective measures. On-line booking of every process step and every material consumption makes it possible to follow the process flow directly. Another essential task of the MES is the monitoring of cleaning and sterilization status, including expiration dates for all related equipment, such as containers, pipe systems, and set-up parts. The risk of contamination is minimized, since the system would, for instance, issue an alarm as soon as an unsterilised pipe is to be used.
Keyword Biopharmaceuticals
Many seriously ill people are pinning high hopes on biopharmaceuticals. Although biopharmaceuticals still represent a relatively small percentage of all drugs, it is estimated that they will reach a market volume of more than Euro 1 billion, just in Germany. In fact, the average percentage growth of these drugs is expected to reach double figures within the next few years. Even at present, 35 percent of all newly approved pharmaceuticals are biopharmaceuticals. They include recombinant proteins, molecular biological tests, monoclonal antibodies as well as vaccines produced by genetic engineering.
Well known examples are human insulin for treatment of diabetes, growth hormones to treat dwarfism, or Erythropoeitin to treat anemia. According to the association of Pharmaceutical Research and Manufacturers of America (PhRMA), about 400 different biopharmaceuticals are currently in the process of clinical development. Two fifths of them are aimed at various kinds of cancer, like brain tumors, breast and intestinal cancers. Other biopharmaceuticals are being developed for use against cardiovascular diseases, Parkinson's disease, Chorea Huntington disease, or sickle-cell anemia.
Considering Future Requirements: 21 CFR Part 11 Compliance
The MES provides further state-of-the-art features: 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 in a compressed and transparent way.
This procedure is to enable all divisions involved to assess and approve data promptly, safely, and efficiently in electronic form. Furthermore, PAS-X BIOTECH has made it possible for Boehringer Ingelheim to establish a central electronic production management system. This system can be interfaced to all relevant processes even outside the very area of production, such as laboratory information systems (LIMS) or Supply Chain Management systems. The MES serves as a data "turntable" and ensures consistent data flow between SAP and DCS environment.
The fact that a project as complex as this one could be completed within the set time limits first and foremost is due to the effective cooperation with Boehringer Ingelheim. "Nobody denies that 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," Mr. Schunk says looking back. "In the three years of this cooperation we kept very close contact with the project team of Boehringer Ingelheim.
We sent interim reports as often as possible and had detailed discussions about planning and further steps." The fact that the system was running stable at a very early stage shows that this way of dealing with the project was a real success. In the fall of 2002 already, the system was operational. Even system validation - something that usually is awaited full of nervous suspense - and the release for production were managed without major problems in the summer of 2003.
"For the BIOMES validation we drew up mixed teams with Werum," explains the Boehringer Ingelheim project manager. "The smooth and easy cooperation has helped considerably to meet the tight schedule." Boehringer Ingelheim stands by their decision in favor of Werum's production management system. As soon as the start-up phase of the new active ingredient plant has been finished successfully, Boehringer Ingelheim intends to roll out PAS-X BIOTECH in other areas, as well.