Trial and replication

When multinational pharmaceutical company Leo Pharma needed a new semi-solids production unit for its Dublin plant, the company turned to existing supplier Romaco FrymaKoruma.

This is a project with a difference, however, as the two companies have devised a strategy aimed at making the new plant effectively 'plug-and-play'. Leo Pharma is a global leader in the manufacture and marketing of dermatological products. The company concentrates its skills and facilities in specialist production centres, one of which is based in Dublin, Ireland, where products in cream and ointment forms are manufactured under high sterility conditions. To increase capacity in line with market demand, Leo now has a requirement for the design and manufacture of a complete plant for the production of a low-volume active dermatological ointment. In accordance with the high sterility conditions at the Dublin site, the plant must be compatible with the highest standards of Clean-in-Place/Sterilise-in-Place (CIP/SIP). A further requirement is a high level of automation, to minimise personnel involvement in the manufacturing operation and to keep running costs low. Leo's choice to handle the core operation – the actual manufacture of the product – was Romaco, a global supplier of process and packaging lines for the pharmaceutical industry. Romaco has installed a variety of equipment at Leo's Dublin plant, including a FrymaKoruma DisHo V230/5500 vacuum disperser/homogeniser in 1998. The largest DisHo ever built, at 5.2 metres tall and with a batch capacity of four tonnes, the V230/5500 was chosen by Leo at the time based on the clear advantages it offered over the competition in terms of productivity and user-friendly operator interface software.

Specific challenges Ancillary equipment for the installation included premix and trituration vessels, as well as a 150-litre pilot plant to enable Leo to scale up from trial size batches to full production. A feature of the advanced aseptic processing technique employed in FrymaKoruma mixing vessels is its ability to produce absolutely homogeneous, highly stable end product. In the case of Leo's product range – where a low volume of high potency APIs needs to be evenly distributed through a large mass of product – this is fundamental. Other specific challenges associated with the latest project include precise temperature regulation during the heating and cooling phases to maximise product stability, rapid sterilisation of the plant at the end of each batch and maximising the yield of high value products. Romaco FrymaKoruma is addressing these respectively by incorporating highly sophisticated valve technology, automated online filter integrity testing and an Ethernet control system to monitor every aspect of the operation.

Control system CIP/SIP performance will be optimised by the incorporation of an integral clean steam generator, separation of the plant into four discrete CIP/SIP zones, real-time temperature monitoring and adjustment, and a plant design that eliminates blind spots in vessels and dead legs in pipework. The Ethernet control system is a PC/PLC-based integrated plant management system encompassing storage and management of product formulations, trend analysis and system alarms and diagnostics. Although the requirements described thus far position the new plant at the higher end of the performance spectrum, none of them is particularly out of the ordinary for a supplier of pharmaceutical production equipment. What is unusual, however, is the way in which the two companies are managing the project: this approach – described below – is certainly a first for Romaco FrymaKoruma, and possibly in the industry as a whole.

Service planning A major installation such as this brings with it a deal of planning for services and the connection of ancillary equipment, much of which in the traditional scenario has to be dealt with on-site during and immediately following the installation of the main plant. In this case, however, Leo Pharma and FrymaKoruma are working to minimise this element of the project by building a replica of the plant at FrymaKoruma's factory in Neuenburg, Germany. The plant was specifically designed to meet the requirements of the customer and the product. It consists of four rooms, of which two are dedicated to production. In the first of these is a vacuum processing unit dedicated to the manufacture of a premix suspension, while in the second there is a further unit used for sterilisation of the batch and the introduction of the active. The relevant cleanroom standards are class D for the first room and class B for the second, with the addition of a laminar flow unit to create class A conditions for the area immediately around the processing unit. The third room contains buffer tanks for the finished product, split into two identical groups of three tanks each. The logic for this is that two full batches can be stored at any time but that batches are released for filling only one third at a time. In this way, any problems on the filling line do not result in the loss of the entire batch. Finally, the fourth room is the technical area, where the complete CIP/SIP system is located, along with a control system for all valves and all filters, which are automatically checked and monitored. Additional equipment includes the heating system for the water to be pumped into the double jacket of the vessel and the steam group essential for the highest standards of CIP and SIP. Evidently, this is a major installation and the decision to build a replica unit has considerable attendant costs. However, Leo Pharma believes that these are justifiable on the basis that all planning for the positioning of equipment and services can be completed in parallel at the two sites, meaning that when the plant reaches its ultimate destination, its installation will be essentially 'plug-and-play'. Validation procedures such as installation qualification (IQ) and operational qualification (OQ) can also be planned in advanced, using the replica plant as a model, and Leo will also have the benefit of an ideal trial plant available to them ahead of the final installation.

Future handling In terms of project strategy, this will significantly reduce the time from delivery to start-up of the plant, and this in turn will enable the company to see a return on its investment at a far earlier stage than in the traditional project scenario. To remain competitive in today's business environment, the pharmaceutical industry and its suppliers must be able to respond quickly, efficiently and in a streamlined manner. This installation epitomises the spirit of partnership necessary to succeed and is an excellent model for the way in which major processing projects might be handled in the future.