Building for the future

Looking at future drug development capacity requirements enabled AstraZeneca to set the parameters for its new UK pharmaceutical development facility. Stuart Nathan outlines some of the features of this major technological achievement

Designing process plants and manufacturing facilities that use process principles is always a juggling act. But when the facility is being built for an industry that is one of the largest in the world, as well as the most technologically advanced and the most heavily regulated, it becomes the equivalent of juggling a mixture of flaming torches and sharp knives – not to be attempted except by experts. So when AstraZeneca decided to design and build a new pharmaceutical development facility (PDF) at its research and develolpment site in Charnwood, Loughborough, UK, the stage was set for a major technological feat.

Designing and building the PDF was a response to a review of AstraZeneca's drug development pipeline and future needs, says an AstraZeneca spokesman. 'We looked a few years down the line and decided that we wanted to have a certain number of new chemical entities coming to development each year.

'The number of compounds would build up as time went on, as further compounds came into development.

'Taking that into account, along with the development time for a new compound, showed us that we needed a new facility to achieve this capacity – and told us how big it would be.'

The PDF integrates with a cluster of AstraZeneca facilities at the Charnwood site, all built over the past decade. The chemistry and biochemistry laboratories opened in 1993, the safety assessment laboratory in 1995; the process r&d pilot plant in 1998, and the pharmaceutical and analytical laboratories in 1999 – which, among other functions, monitor the adherence of PDF operations to GMP standards. Later this year, another new facility, a process r&d laboratory, will open. In all, the facilities cost some £250m (US$360m), and house 1,200 employees – more than 10% of AstraZeneca's r&d staff. All the facilities are interlinked by design, and people and processes pass freely from one to another.

flexibility

The speed of consolidation in the pharmaceuticals industry has meant that the PDF was conceived and designed under one company, Astra, and opened by a second, AstraZeneca. But with flexibility one of the main requirements of the concept, the design did not change throughout the merger, says the spokesman. 'Amec Construction carried out a year-long front-end study for us, and was awarded the contract in 1997,' he explains. 'After that, the design was locked in.'

Construction took three years and involved a variety of subcontractors – a total of 53 in all. The largest of these were Crown House for electrical and mechanical services and Galloways for ventilation. Satchwell provided the Building Management Systems. The facility was then validated by Eutech, the former ICI engineering management subsidiary that is now part of ABB, using results and documentation provided by End Systems, the commissioning subcontractor. In all, the project cost £45m (US$65m).

And that buys you a lot of plant. The design encompasses a total of 14,170m² of floorspace, spread over four levels, each dedicated to process and plant. The sharp end of the development is 40 clean rooms, all of which are free from supporting columns. This is due to the design of the building itself — the roof and plantroom are supported by exceptionally large trusses, measuring 6 metres high by 42 metres long. Because of the huge amount of flexible space, there is capacity to carry out process development alongside the manufacture of drug formulations to supply clinical trials.

large scale processing

The management didn't arrive at this design out of thin air,' says the spokesman. 'During the front-end work, we went around the development facilities of most of the other large companies in the sector. We utilised some of their good ideas, integrated some of our own and this is what you see. No doubt when they come to develop their own facilities they will visit us and do the same.

Consultation also took place with the various regulatory bodies to ensure that the facility met or exceeded anticipated standards for quality and safety in Europe and the US.

The role of the PDF is to take the drug development process from the benchtop level all the way through to pilot scale (approximately one tenth of industrial production scale). By the time a candidate drug reaches production scale or the largest scale in the PDF, it will already have undergone several years of laboratory studies, and the chemical makeup of the compound, its crystalline form and so on, will be established. The reaction stages needed to synthesise the compound will also have been determined.

So the job of the PDF is both to scale-up the manufacturing process for the formulation to a degree representative of industrial scale and to ensure that enough product is available to carry out the clinical trial stages. If these are successful, AstraZeneca will be able to put the drug product into production almost immediately. The PDF is the most up-to-date facility of its type within AstraZeneca r&d.

mobile equipment

Most of the process equipment within the PDF is mobile, and can be wheeled into the process rooms from an equipment store, explains the spokesman. 'Each clean room has a service panel which provides access to compressed air, purified water, nitrogen, oxygen, propane, single and three phase electricity etc. This means that we can move a process into pretty much any room in the facility. The only exceptions are those that require very large pieces of machinery like blenders or fluidised-bed dryers — these are too big to move around, so they have dedicated rooms. But basically, it's a giant plug-and-play system.'

The control system for the PDF operates on a similar flexible basis. 'Each process room is linked into an environmental management system, so that all the scientists have to do is plug into the data system by means of their laptop, and they can then receive a readout on all the conditions in that room.'

The facility can produce drug formulations in batches up to 50kg. It has facilities for producing products for use in Phase I to III clinical trials, and injectables for Phase I and II. Primarily, it is geared up for producing sterile solutions, oral dosage forms (tablets, capsules and liquids) and pressurised metered dose inhalers (pMDIs). The last of these is a particular speciality of AstraZeneca r&d at Charnwood, tying in with its development programmes for asthma, rhinitis, emphysema and chronic bronchitis. The PDF can manufacture a batch large enough for around 15,000 pMDI units, using automated production lines.

For solid dosage forms, the facility's equipment includes particle size control and reduction equipment along with granulation, drying, tableting, capsule fillers and film coating equipment.

The sterile solutions facilities include equipment for manual and automated filling of solutions, lyophilisation to remove water from unstable drugs, and equipment for making radio-labelled and sterile infusion products.

pilot plant upgrade

The design philosophy continues throughout the complex. Adjacent to the PDF, the pilot plant facility has also been upgraded recently. The facility has four process modules and one common services module, providing the batch plants with compressed air, nitrogen, hydrogen and solvents. The machinery is controlled by a distributed control system (DCS), but the software that runs the control system had reached its limits, and needed to be replaced urgently.

The control system was struggling with various additions to the pilot plant suite. 'We had to expand the system now, as our applications had grown so large they would not fit the memory of the existing controllers,' explains Mike Baker, associate principal scientist with AstraZeneca, who is responsible for the pilot plant DCS. 'We were experiencing problems because we were running the controllers close to the maximum capacity.'

The solution was to return to the DCS supplier, Swiss engineering giant ABB, for a system upgrade. This includes replacing workstations with systems based on Windows NT, which have faster performance and, crucially, higher data storage capability on hard disks. A PC duo system allows remote connections to be made to any workstation on the network.

Other new features include the installation of a fibre-optic link for data communication, which is much faster than conventional networks and has higher bandwidth. The speed is further enhanced by allowing the system's sensors and instrumentation to communicate with the software over a Profibus fieldbus network. The system upgrade will also allow more capacity for background data logging, and speed up program download and instruction execution times. 'It will allow us to continue to expand our facilities in the pilot plant,' says Baker.