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New plant for bulk production and purification of insulin

1st April 2013


A new E300 million plant in Denmark combines advanced control, three dimensional design,clean-in-place technology, water purification and sterilisation in one insulin production and purification plant. eLab takes a look inside.

When IBP decided it wanted a new insulin plant in Kalundborg, Denmark, it pulled together suppliers from around the world.

In charge of the project was the Danish design and engineering contractor Novo Nordisk Engineering (NNE), which used its own amodular plant' construction concept.

The plant's main 200-metre long production hall has nine auxiliary plants located as side buildings feeding the central dual stream production lines. These auxiliary facilities include a CIP cleaning plant, a cooling/refrigeration plant, an HPLC column and a high capacity water purification plant ­ prior to ozone sterilisation ­ plus laboratories and workshops.

All these services are supplied to the required points on the main fermentation, purification and crystallisation production lines, which can mean up to 300 separate connection circuits.

The factory computer system co-ordinates, controls and records the production process, according to any of the 800 recipes established, selecting from 17 000 operations. During the process, extensive quality data is gathered and used to generate a batch report for each processing area, an essential requirement for pharmaproduction.

"Managing such a project, involving800 workers on site, and 500 NNE staff, has been an enormous challenge,“ said Ole Regnar Hansen, project director. "All of the many NNE skills and know-how have been utilised. NNE also undertook 90 per cent of the huge task of qualifying this large pharmaceutical plant. NNE md Hans Ole Voigt added: "This project has been a unique catalyst for growth, providing us with invaluable know-how and skills thatenhance our capabilities for future pharma projects.“

Advanced control and records

Hundreds of instructions and procedures that must be followed to the letter have been drawn up to ensure that all the processes used in the Insulin production are carried out correctly. In order to document that this has indeed been done, numerous items of data must be gathered routinely, and many tests and checks made as part of each batch report.

"Most of that kind of work used to be done on paper, but the bulk of it will be handled electronically in the new factory,“ said Leif Poulsen, department manager for automation. "The factory computer system is designed to coordinate and control the complex production process and automatically generate the necessary batch documentation. This eliminates a lot of the routine work and lets operators concentrate on making sure that production is carried out optimally.“

The computer system helps make daily work more interesting and is also an effective way of ensuring that production is carried out in accordance with the procedures in force ­ procedures for processing, quality control and cleaning. Technically, the procedures are defined as electronic recipes in a database, where they are maintained and approved electronically by the quality assurance department before being used in production. When production starts, the relevant information is sent from the recipes to the processing system, which ensures that the individual steps in the process are carried out in the right order.

During the production process, a lot processing and quality data are gathered and used as the basis for generating a batch report for each processing area. The batch report is as important as the product being made, because the product cannot be released without documentation. The system contains an enormous amount of data: 600 recipes have been drawn up with related reports covering more than17 000 different operations with a total of about600 000 associated parameter values.

In the past, recipes and reports were often programmed as part of the processing management system, but this solution was not viable for IBP due to the huge volume of data.

"We have implemented a data-driven solution that defines recipes and reports as data, which users can easily change as needed. That provides great flexibility in terms of future changes and also reduces the need for subsequent revalidation. Italso gives the factory a agold mine' of easily accessible processing data that can be used foron-going optimisation of operations,“ explained Poulsen.

HPLC columns, 3D design

Column processes are a known purification stage in Insulin manufacture. The large HPLC column facilities in the IBP plant are a good example of the value of project recycling, modular engineering, and external construction of modules parallel withon-site building work.

"The HPLC columns could largely be constructed on the basis of existing columns by copying substantial parts of the design and the efficient process technologies, thereby minimising development work,"" said Jim Knudsen, the engineer responsible for this part of the project. The HPLC columns were modularised with a view to further recycling in future projects, and also to reduce overall construction time by enabling parallel activities such as machine and instrument installation to be carried out as building work progressed.

"We took the flat, 2D pipe design from an earlier project and, using the AutoPlant program, literally superimposed a new and smarter 3D model on top of it. We then did the necessary redesign work, which also included process and health andsafety improvements,“ he added. Construction of the modules, both steelwork and instrumentation assembly, took place outside the plant building.

The modules were delivered to the plant almost complete and installed in place immediately prior to closure of the building exterior. Once the last cables and pipes were installed, final qualification of the columns could start. This was a considerable job of work as it involved some of the most advanced equipment on the IBP plant. "I would estimate that we saved around four months using modular engineering rather than conventional procedures, a saving that is directly reflected in the final completion date,“ noted Knudsen.

The many other pipe systems in the IBP project were also constructed using smart, 3D design principles to create a three-dimensional pipe and equipment model to predefined specifications. This enabled parts lists and working drawings to be generated for direct use in the pipe installation.

A 3D model of building structures, ventilation, cable trays and other major components was also created, enabling potential clashes to be identified as early as the design stage.

This was hugely important for the project construction phase when sorting out problemscan rapidly impact on the completionschedule.

The 3D model made it possible to introduce a degree of modularisation by enabling well-defined process units to be isolated from the rest of the plant, put out to tender, and completed by a subcontractor.

CIP cleaning

Equipment cleaning is fully automated via a sophisticated, centrally managed cleaning in place (CIP) facility. CIP means that cleaning is carried out by permanently connected units ­ in this case, located at more than 300 points in the process, right from fermentation, to insulin ready to be filled into pens.

How could such a massive job have been done in such a short space of time? "Instead of designing more than 300 tailored CIP solutions, our challenge was to build one large system with so many abuttons' that all 300 operators could use it. This was a whole new approach to CIP,“ said Dirk Anthonisen, automation coordinator, who has been involved since the start of the project.

The CIP process was divided into three phases: preparing cleaning fluids, mixing, and collecting used fluids for online measuring. A single program manages the 24 local depots where users can collect cleaning fluids.

"Some liken the new CIP facility to a piece of furniture with lots of drawers to open as needed,“ says Claes Bloch Larsen, CIP project manager.The system is considerably more flexible than traditional CIP solutions, because the individual user recipes can easily be changed and modifications made to apply everywhere. Novo Nordisk is so satisfied with the new CIP plant at IBP inKalundborg that it plans to install a similar set-upat its next large factory.

The equipment was produced and tested with water offsite at the supplier's premises to ensure the highest possible efficiency. The same software module is used throughout the plant, a major advantage for reporting and cleaning validation because the batch reports and their data are compiled to the same standards, regardless of location in the production process.

NNE and GEA Liquid Processing Scandinavia established the joint venture company GEANNE I/S, which supplied the full solution, from theseven-metre high preparation tanks to the last little test tap, including all design, management and validation work.

"We supplemented each other's strengths and gained a sense of shared responsibility for the project. We had a common interest in coordinating the work as well as possible and solving problems underway,“ added Claes Bloch Larsen.

Water purification and sterilisation

Insulin production requires huge amounts of water, both raw water for fermentation and recovery and purified water for the subsequent processing stages and CIP.

For IBP, a team of employees designed what was to be one of the world's largest water purification plants. Anders Kofoed Nielsen, project manager,saw coordinating with all the other subprojects as a major challenge: "All production areas need water, so we had to be ready first. In order to meet the delivery deadline for this type of facility, we were also the first team to alock' our design. As we didn't yet know the exact operational requirements forthe finished factory, we had to rely on calculated estimates.“

The estimates were obviously fairly accurate, since after the first year of testing, only a few adjustments have been necessary relative to the actual pattern of consumption. As something completely new, the raw water plant is prepared for ozone sterilisation ­ a technology previously unknown in Denmark. Not only are ozone sterilisation systems cheaper and moreenvironment-friendly than heat sterilisation, theyput less strain on the plant as it is not subjected to thermal stress. As the water purification plant was one of the first systems up and running, it was also a guinea pig for many of the other systems thatwere added later, such as the factory management system, automation, and the entire qualification apparatus.

More about NNE is available on tel 0045 4444 7777, fax 0045 4444 3777, email contact@nne.dk, www.nne.dk





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