Bushu Pharmaceuticals, Japan's largest dedicated contract manufacturer, has been going from strength to strength as Japan's pharma outsourcing industry awakens.
As the outsourcing trend has taken off in the country since 2005 when a law change made it easier for companies to outsource drug manufacturing, Bushu has seen its sales nearly double, from 4.1bn Yen a year in 2003 to 7.8bn Yen in 2006. Similarly, its customer base has followed the same trajectory, rising from 27 to 46. At the moment revenue is almost evenly split between Japanese and international clients, but Bushu is making a concerted effort to attract more business form around the globe. "Because of the projection that the Japanese market is on a downward trend with shrinking pipelines, we see international markets as very important to our long term strategy," said Kamphuis. The company specialises in the manufacturing of solid dosage forms, as well as reformulation and packaging especially for the Japanese market. Most of the solid dose work comes from within Japan. The clinical trials manufacturing component of this is steadily growing, as more trials are being conducted in the country by foreign firms, although still a very small proportion compared to domestic commercial. Most of the company's international work is in relation to contract packaging, as it is extremely difficult for foreign manufacturers to package products appropriately for the Japanese market. In terms of drug dosage forms, Japan's market requirements are different form many other countries. Granules are a preferred dosage form, with around 10 per cent of all drugs on the Japanese market being sold in this form. Large sized tablets are also a no no, as are coloured tablets. White and perhaps yellow are the colours that are acceptable to consumers, said Bushu president Takayuki Kasai. "These colours look clean and minimalistic to consumers - that's what Japanese people like," he said. Because of these requirements Bushu undertakes a lot of work with pharma firms form around the world who wish to successfully sell their product on the Japanese market but first of all need to reformulate them into an acceptable dosage form. Meanwhile, the firm also carries out high potency production and primary packaging in a dedicated facility built for a client, as well as 2-8 degree cold chain storage and packaging of biologics, a growing area in Japan, along with the rest of the world. Kamphuis said that Bushu is only one of a few contract manufacturers that he knows of in the area that has such a facility, and so demand is high for this service. Moreover, although still only small, Bushu's clinical trials manufacturing business is "growing steadily," and is an area that the company regards as "very important" as the majority of work is currently coming from international clients. It is key to helping the firm build relationships with international clients early on, which can eventually lead to commercial manufacturing deals and an expansion of the company's global presence, as per its goal. As Outsourcing-Pharma.com witnessed on a recent site inspection, cleanliness is key in the factory - the facility has an abundance of "clean processes," many of which go beyond those employed by other manufacturing facilities around the world - right from the point of first entry. The warehouse has high speed shutters to keep insects and other particles out, coupled with an air shower to blow particles out as the door opens. Wood palettes have been phased out as they have been in the US and only plastic and aluminium palettes are now used. Everything that enters the warehouse is either individually wiped down or vacuum cleaned to remove any particles.
Insects that are caught in insect exterminating machines are regularly counted and classified as to their species so as to keep an eye on any trends of note. Each manufacturing building is separate and has its own air handling facilities so there is no mixing of air in different rooms. The workers of each separate segment are also required to wear different colour coded uniforms so as to eliminate possible contamination this way. A unique feature of pharmaceuticals manufactured in Japan is that wherever possible, 100 per cent of the raw material ingredients undergo a sieving process to remove any foreign material that should not be there. Bushu uses two types of sieve, depending on the type of material, an oscillating sieve, or a brush-type sieve. "You will be surprised what the sieving process reveals," said Yoshiaki Taniguchi, another Bushu spokesperson. "We find stones, sticks, fibres, metal particles, hair and insects among other things, especially in raw material that is derived from the earth, such as talc," he said. Prior to sieving, all the bulk material delivered is subject to an acceptance test and any material found to be "substandard" according to Japan's stringent expectations, is returned to the supplier. As a rule of thumb, the particle classification in Japan is class 100,000 (meaning 100,000 particles per cubic feet) for solid dosage form manufacturing areas as opposed to class 1,000,000 class in other countries. Air is filtered substantially more in the manufacturing areas in Japan producing a much cleaner environment. Another difference of note that is unique to Japan is that for storage purposes, the ambient temperature is considered as between 1 and 30 degrees Celsius, where as in Europe and the US ambient temperature is classed as 15-25 degrees Celsius. "This difference sometimes causes problems with international customers because the Japanese ambient temperature range does not fit in with their global policies," said Kamphuis, who went on to explain the significance of the differences. According to Japanese law, product can be stored between 1-30 degrees Celsius if stability data has been taken at 25 degrees Celsius with a relative humidity of 60 per cent. EU and US companies perform stability testing at the same conditions but their laws stipulate that product can then only be stored at 15-25 degrees with some exceptions. "The Ambient Temperature definition is a little different in meaning. If international companies abide by Japanese law and practises there are no issues," said Kamphuis.
"However, in reverse when sending clinical trial product to overseas markets, there could potentially be some issues with the difference in ambient storage temperatures. To date, we have only supplied product to the EU and have managed to do so using Japanese temperature storage conditions. We have not supplied product to the US."