Bipha Human Serum Albumin Plant, Japan
The Chitose project was the world's first human serum albumin plant, using genetic biologic recombination process. It is located at the Chitose factory (Hokkaido) of Bipha, a wholly owned subsidiary of Yoshitomi Pharmaceutical (now Mitsubishi Pharma Corporation).
Due to the risk of infection by HIV or other viruses and agents, and associated screening costs, there is enormous pressure worldwide to develop alternatives to using donor blood to obtain pure human serum albumin (HSA). This is especially true in Japan since it suffered a scandal in which some public blood supplies were infected. Quantitatively, HSA is the world's most used intravenous protein, estimated at around 500 tonnes per year. Clinical applications include stabilising blood volume during surgery and during the treatment of shock or full thickness burns.
Japanese demand for human serum albumin is estimated at 5.9 million vials a year. The albumin used is derived from blood with the majority 3.9 million vials coming from Japan and the additional two million vials made from imported blood plasma. The company as expected concentrated on the sizeable domestic market. Yoshitomi Pharmaceutical's initial aim was for the sales of the new serum product to reach ¥1bn ($9.5m) within a three-year timescale.
The main problem is whether the artificial serum albumin can be produced as inexpensively as the product obtained from genuine blood. There are two areas which must be overcome in the development of a recombinant human serum albumin process. The first is purity; the second is cost. To control production costs, maximum quantities of albumin must be produced from the minimum volumes of cell culture, followed by a high-efficiency, high-yield purification method.
Amersham Pharmacia Biotech, the plant's process technology provider, had developed a manufacturing process to make human serum albumin by genetic manipulation of Pichia pastoris (yeast) on a commercial scale. The methylotrophic yeast, Pichia pastoris, is widely used as a host strain for the production of a variety of heterologous proteins.
Application for government approval of the process was lodged in 1997. The application was made was made under the brand name Albrec. Cellastim 8482 is a more recent competitor human albumin product from the biotech Ventria Bioscience, alongside Recombumin from Delta Biosciences of the UK.
HSA PLANT CONSTRUCTION
Construction of the new serum plant was started in 1998 and was completed in the last quarter of 1999. The plant then went into trial operation, and full scale commercial production began in the middle of 2000. The cost of construction was ¥14bn ($134m).
The new plant uses the 'Streamline' process, which was developed by the Sweden-based Amersham Pharmacia Biotech. In addition, the plant uses 'Chromaflow' technology from the same company. Amersham Pharmacia Biotech also supplied other downstream equipment and chromatography media. The Swedish company wanted to expand its precision chemical engineering side and was pleased with the Japanese order as the Chromaflow and Streamline columns are the biggest it has ever supplied.
Streamline technology improves productivity by roughly 50% in terms of processing time and 45% in terms of yield. In addition the life time of the gel and the column itself are very long. Even after running more than 1,000 process cycles, performance remains unchanged, making the process more cost effective.
Construction was handled by Niigata Engineering Corporation Ltd, one of Japan's foremost pharmaceutical industry engineering companies. The new plant will commence with the production of 1 million vials a year. This is equivalent to a capacity of 12.5t a year of pure rHSA. Capacity can be raised to 1.5 million vials within three years, after the addition of two cultivation tanks.