Well Thought-Out Strategy New Standards-Setting Sterile Plant

| Editor: Anke Geipel-Kern

The sophisticated design of Hameln Pharma’s new sterile production facility is based on a well thought-out strategy. PROCESS was on site to have a look around.

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Dr. Simone Dahlmanns was the Project Manager with responsibility for construction of the Hameln Group’s new sterile production facility. She and her team seldom had time to take a breather in recent months. However, she put in a relaxed appearance at the news conference where the company presented its end-of-year results. She took the opportunity to share information about the biggest investment project in the history of the company, which was founded more than 100 years ago. “Construction of the new sterile plant was a real fast-track project,” she explained. In June, only 25 months after the authorities granted an operating license, the first production batch was finished while production was still running at the old facility. Final changes to the layout were made after construction got underway, but everything is now ready and transfer of the remaining production equipment was scheduled for September.

This is the first time that the Hameln Group has presented its financial results to the press. Christoph Kerstein, Managing Director/Proprietor, explained that the company decided to invest the effort in an event which is not strictly necessary to increase transparency and generate publicity. Kerstein certainly has no reason to avoid the public eye. On the first attempt in 2007, he made it all the way to the final round of the Entrepreneur of the Year competition. The award is presented each year by Ernst & Young management consultants to an unusually innovative SME. The Kerstein family has owned the company for four generations. 500 employees currently work at the production facility in Hameln and the labs in Modra, Slovakia. Since a restructuring exercise in 2005, three independent entities have been operating under the roof of the holding company: Hameln Pharma, which specializes in contract manufacturing of parenteral pharmaceuticals, Hameln Plus which markets generics, and Hameln Rds, which offers clinical study, contract research and registration services. To raise the profile of these entities, all three companies have their own distinctive logos and corporate design, and Kerstein has handed over operational responsibility to the CEOs.

The company is investing € 35 million in the new sterile plant to support continued growth and significantly expand filling capacity. Dr. Dieter Gothier, CEO of Hameln Pharma, explained that the investment decision was based on an expected capacity shortfall. “We realized that we would reach our capacity limits in 2006. Expansion now gives us the resources we need to increase output.” The company specializes in contract filling of parenteral pharmaceuticals in vials and ampoules which are aseptically filled or terminally sterilized, and Hameln Pharma shares the market with just a few competitors. Gothier pointed out that only a handful of companies have the same narrow focus as Hameln Pharma.

Aseptic filling requires special expertise, highly qualified personnel and heavy up-front investment in production facilities. Gothier believes that narrow specialization combined with high flexibility gives the company a strong strategic position and USP. “We sell flexibility at affordable prices,” said Gothier. This is a totally different scenario compared to contract manufacturing of tablets and other solid drug delivery systems, where markets are highly competitive and margins are small. Gothier pointed out that demand outstrips supply in the sterile filling sector. Market experts are forecasting ten percent annual growth in the contract manufacturing market as a result of outsourcing and the increasing number of biopharmaceuticals which are being pushed out into the market. “We are taking a conservative approach and are basing our forecasts on seven percent growth,” explained Gothier. He expects to see growth primarily in the North American pharmaceutical clusters, and Hameln will simply have to grow to meet its aggressive goals. “We believe that this investment will take the Hameln Group much closer to the € 100 million mark,” said Kerstein.

Form follows function

The new sterile production facility has set the stage for continued business expansion. Customers who visit the plant enter a brightly lit new building with 4000 m2 of cleanroom space which combines functionality and aesthetics. The design is clearly based on the “form follows function” principle. In describing the basic architectural premise, Dahlmanns said that “we designed efficiency into the layout”. A passageway connects the new extension to the existing building. This feature ensures that the mailing address remains unchanged and the regulatory effort does not become unmanageable. Hameln Pharma currently supports 50 customers on 400 projects. If the address had changed, an application for re-approval would have had to be submitted for every project.

The raw materials warehouse is located behind the connecting passageway. Input materials move from the warehouse through a material port to the weighroom. Systems for production and storage of ultra-pure media are located on the ground floor. The water system supplies 5000 l/h of highly purified water (HPW), which is used to produce 2.6 tons of ultra-pure steam per hour. In accordance with the European Pharmacopeia, water for injection (WFI) is distilled from the HPW. WFI is the key raw material for production of parenteral pharmaceuticals, and the plant has capacity to produce 3000 l/h. To prevent growth of microbial contamination and above all to avoid the dreaded formation of biofilm, the water is continually circulated in a loop at a constant temperature of 80 °C. Six kilometers of pipe were installed to handle distribution of ultra pure media.

High visibility

The filling systems are located on the ground floor, and you can easily see where the term “transparent factory” comes from. You see glass everywhere you look. There are virtually no walls to obstruct the view. The general impression is dominated by order and spaciousness. Employees always have eye contact, and the production process is literally transparent. A cleanroom layout with a three-stage gowning procedure keeps walking distances short. Class D rooms are on the outside followed by the C, B and A Class rooms.

The cleanrooms which surround the filling systems all have a similar layout and are all connected by a continuous series of ports. “Standardization creates an additional margin of safety,” explained Dahlmanns. Color coding is a special feature of the plant. The colors red, orange and yellow were chosen for psychological reasons. The underlying principle: the brighter the color, the cleaner the area. The color of the entrance door to a cleanroom indicates the class of the room behind it. An orange door leads to the four weighrooms in the C Class area where the dispensing operations for four batches can be performed in parallel. The rooms which lead to the Class B area are located behind a yellow door.

Batch tanks with a 3500–20 liter capacity provide the necessary degree of production flexibility. “The whole layout is designed to minimize distances for the materials and the employees,” explained the Production Manager. She calls it installed efficiency, and this approach is most evident in the U-shape arrangement of the ampoules and vial filling systems. An employee can load empty glass containers onto the system and subsequently remove the filled and sealed ampoules and vials. The systems which are already installed have an 18,000 vial capacity. With batch sizes between 60,000 and 70,000, product changeover takes a lot of time. Flexibility is more than just a buzzword at this plant. It is a vital necessity every day on the production floor. The aseptic filling zone on the vial system is configured as a restricted access barrier system to reduce Class A cleanroom space to an absolute minimum. “RABS is currently state-of-the-art in the world of aseptic filling,” claimed Dahlmanns. The RABS is opened for product changeover, and glove ports provide access from the Class B area during ongoing production.

A spare room in the production area is dedicated to new technology. The Production Manager believes that installation of a pre-filled syringe line is a logical enhancement to the plant’s production portfolio. The modular design of the plant also facilitates other expansion projects, and the new building could be extended on the west side if necessary.