Breast cancer drug Herceptin is effective. It prolongs the life of breast cancer sufferers and prevents the cancer's return when in remission.
But Herceptin is expensive. A year’s treatment in the US costs around £35,000. In the UK it's £21,800, in China its £38,000
So, Herceptin is only effective if you can afford it. If you have breast cancer in a poorer region of the world, you probably one of a large amount of people that can’t afford Herceptin. The result is a substantial increase in the mortality rates for a cancer that many are successfully treated for elsewhere in the world.
Herceptin and breast cancer is just one example of such an imbalance in the availability of drugs worldwide. It’s a similar story for many other treatments which are developed and manufactured in the West and diseases, which afflict people worldwide. The problem is worsening as the rate of so-called “lifestyle” diseases like cancer rises in developing countries.
For example, in the world’s most populous country, China, someone is diagnosed with cancer every 6 minutes. Some 312 million people a year diagnosed with cancer in China, resulting in 2.7 million deaths. Brazil has 20 million people who need access to insulin. Both China and Brazil are among the world's top ten economies. The Brazilian government does not need to depend on other nations for the supply of an important drug, as much as the Chinese Government does not want millions of its citizens dying of cancer.
There is therefore massive growing demand for biopharmaceuticals from emerging economic regions such as Brazil and China, who want to be self-sufficient, have security of supply and reduce the cost of these drugs. These places are attempting to create entire biopharmaceutical industries from scratch, very quickly. This creation process is spurring leaps of innovations in manufacturing and process technology.
Key to the treatment of lifestyle diseases like cancer and diabetes are biopharmaceuticals. These are drugs which are not synthesised using chemical reactions like other drugs, but are created by living organisms that have been changed to produce the drug. Biopharmaceuticals are proteins such as antibodies, nucleic acids, such as DNA or RNA.
Herceptin, like most biopharmaceuticals, is expensive because it’s really difficult to make. It’s a monoclonal antibody, a protein that is normally made inside the body by the immune system. To make biopharmaceuticals you have to cultivate the antibody’s growth outside of the body, from a living organism, in a clean manufacturing environment, repeatedly. In contrast to the relatively “small” molecules manipulated to produce chemically based drugs, biologically based drugs involve “large” complex molecules. It’s a tough manufacturing job that requires a lot of technology and expertise to perform. Notwithstanding the large research and development costs required to initially develop the treatments.
However, biopharmaceuticals are a lucrative business. Since the first biopharmaceutical, Humulin, was introduced in 1982, more than 200 biopharmaceutical products have been launched. It’s estimated there are more than 500 in development. According to healthcare analysts IMS Health, pharmaceuticals are one of the fastest growing segments of the market - 16% of all medicines sold in 2010 were biopharmaceuticals.
In common with all drugs, once a biologically based pharmaceutical has been developed, the pharmaceutical firm owns the exclusive rights to produce it for up to 25 years. Dr Racho Jordanov, chief executive of biopharmaceutical developer JHL Biotech, says: “When big pharmaceutical companies register products, the technology and processes remain unchanged for years because the profit margins allow lousy techniques and no innovation.”
Once the patent runs out, the original innovator of the drug loses exclusivity, opening the door for other companies to manufacture copies of the drug. Copies of established biopharmaceuticals are called “biosimilars”, because the copied drugs cannot be identical replications of the original due to their biological nature. A recent study by consultancy Frost and Sullivan estimates that $100bn of biopharmaceuticals will come “off patent” by 2020.
JHL Biotech is one of a cadre of small biotech companies that is attempting to help developing countries in regions such as Asia and South America build the biopharmaceutical plants capable of producing biosimilars. Despite the potential size of the markets, Dr Jordanov insists that the driving force behind JHL Biotech isn’t profit. Rather, after being diagnosed with cancer himself and surviving thanks to the medication, it is “to make affordable medicines that can be distributed all over the world.” He says: “A lot of Asian countries wish to manufacture their own medicines, a lot have national-scale health problems and can’t afford the Western drugs.”
JHL Biotech has created a “biopharmaceutical centre of excellence” in Taiwan, which Dr Jordanov says is the first step in addressing the lack of availability of expensive medicines in Asia. The first plant in Taiwan is being used for developing manufacturing equipment and processes. It can produce oncology, other high value drugs and is also being used for training.
The company’s first commercial scale plant is being built in Wuhan province in China and will be commissioned at the start of 2015. According to Dr Jordanov, it will be the largest single use bioreactor plant in the world and will produce mainly oncology drugs, metabolism drugs such as insulin and biosimilairs. After Wuhan, the company plans to build plants in Vietnam, Indonesia and the Philippines.
However, there are some considerable engineering challenges to overcome. JHL Biotech must first simplify and reduce the cost of what is one of the most complex and highest value manufacturing processes in the world. Dr Jordanov says there are two main aspects to the manufacturing innovations at JHL Biotech is developing for biopharmaceutical plants: “The manufacturing process for this type of drug typically takes two and a half months for one batch. Cells grow, there is a chromatography process and quality control tests.”
“We are changing the centrifugation process, which is quite destructive to proteins, to depth filtration. We are developing media that grows cells that are specific to a specific cell line. On the chromatography and purification side we are developing new technology with Japanese companies to improve the processes.
“All our processes are automated and computer controlled. The process control schemes are remotely operated from Taiwan, so we can observe results and change flow rates to achieve the quality we need.”
The second aspect of innovation will be to take advantage of a trend in the biopharmaceutical sector to use disposable, pre-sterilised plastic parts, such as tubes, bags and filters in the manufacturing process. Once a batch has been manufactured, the parts are simply thrown away. New plastic parts are fitted before the next batch is produced. The main advantage is a large reduction in the risk of contamination. It takes just one errant cell out of billions to grow and kill an entire batch. With a typical process including 1000 control points to clean and sterilise the chance of error is high. Typically in the West, says Dr Jordanov, with a 70 day proess a company would be happy with an 80% success rate.
“The old fashioned plant is all made out of stainless steel, which requires two layers of equipment and the cleaning and sterilisation of all the lines and equipment including the tanks and the pathways, plus miles and miles of pipes and vessels. In new plants, disposable plastic takes the place of much of the steel,” he says.
Olivier Loelliot is general manager of Enterprise Solutions for GE, a part of the large US engineering company which supplies plant and equipment to the biopharmaceutical sector. He says the industry started to transition to plastic parts about ten years ago: “Normally it would take two weeks of turnaround time to change batches. With disposable plastic parts it takes two days. The reduction of downtime has great value in these high value manufacturing plants.”
According to Loelliot, for the last ten years the cheapest biopharmaceutical plants have been built for between $150 to 200 million. But now there is growing recognition amongst manufacturers that these investments have to be around $30 to $50 million to make biopharmaceutical plants suitable for countries in Asia and South America.
GE's Kubio modular plant concept for pharmaceutical production
To help achieve this cost reduction, GE has introduced its Kubio modular concept. Kubio progresses the idea of supplying plant and equipment bespoke to providing entire biopharmaceutical plants off-the-shelf. Pre-made boxes are manufactured in Germany that include equipment, fittings, HVAC and piping. In total 85% of the plant is made off-site. The boxes are then shipped to the customer and fitted together on site to construct the plant. Including meeting regulations, GE says a Kubio plant will take just 18 months from ordering to commissioning to build. A typical Kubio plant comprises of 50 modules, around 2200m2.
“The only thing to do at the site is dig the foundations,” says Loelliot. “We compare it to Lego. But, by the time the plant is assembled you cannot recognise you are in a modular building.
“Emerging markets may not have any knowledge about how to develop a biopharmaceutical plant. If you are a big pharmaceutical firm and want to put a plant in Vietnam, then one in Thailand one year later, then one in Brazil one year later, you need a system you can repeat from one country to another without reinventing the wheel and worrying about the local knowledge.
“There is a huge demand and this is exactly the type of solution people are looking for.”
During the last couple of years growth in the biopharmaceutical sector has slipped because of the global economic slow-down. However, in terms of investment, Loelliot says the market is still growing at between 5 and 7% in Europe and the US. In emerging economies it is growing at 25% a year.
“They have been struggling to develop the local biopharmaceutical industry on their own, but they are now working with a lot of big pharamaceutical companies, who have big plans to invest,” Loeillot says. “Globally there is a need to make medicines more accessible to everyone. More than 50% of our customer pipeline is big pharmaceutical companies in emerging markets. For growth they need to tackle these markets and the product has to be half the cost as it is in the US and Europe. You have to be very competitive and produce at a much cheaper price.”
Even so, once built, the challenges to running a biopharmaceutical plant in some countries are not restricted to which type of filters and vats you have specified in the build. There can be problems connected to infrastructure that many in the West would take for granted. Having a constant supply of steam and pure water to clean and sterilise is a challenge in some places. Power outages can also cause havoc with production processes. “Just one blackout and everything is lost, it could put you out of business,” says Dr Jordanov of JHL Biotech.
Another key challenge is skills. A typical biopharmaceutical plant requires between 40 and 60 highly skilled and qualified people around the clock. The staff for JHL Biotech’s first Chinese plant are being trained at the demonstration plant in Taiwan so they are ready from day one. A further challenge is to overcome the regulatory hurdles. The standards and regulations for biopharmaceuticals are much stricter than for pharmaceuticals. Biopharmaceutical plants have to be licenced alongside the product, unlike chemical based pharmaceuticals.
Considering all these challenges, Dr Jordanov still sees the most effective route to market for biopharmaceuticals in emerging economies as being outside of the big established pharmaceutical companies. Instead he sees a future of smaller firms operating with local government and industry in a collaborative way. He says: “Big pharma are trying to create medicines in the East and lower the prices, but they are not doing it effectively and the market could move a lot faster. The generic drug association says that biopharmaceuticals could be a third of their current cost with the right development.”
Ibio - A tobacco plant technology
The global biopharmaceutical sector is perhaps the number one place where biology and engineering clash and create innovation.
Earlier this year GE signed an agreement with the biggest public vaccine maker in Brazil to design a yellow fever vaccine manufacturing plant based on Ibio technology.
The Brazilian plant in the city of Eusebio will be the first commercial Ibio plant in the world and produce the world's first vaccine from a plant.
Ibio and GE formed a global alliance in 2012, after the former had developed what it says is a radically cheaper way of manufacturing vaccines and monoclonal antibodies.
The typical way of producing these drugs is by using mammalian or microbe based cell cultures. Instead the Ibio technique uses 20cm high tobacco plants, into which the DNA of the protein or virus you want to produce is injected.
The plant is then encouraged to rapidly grow by placing it under a strong source of energy for three to six weeks. The plants are then harvested, cut into millimetre small pieces and the virus or protein recovered through processing to produce the drug.
The use of materials extracted from plants to produce medicines is one of the oldest forms of industry known to man. “To this day, there are a lot of products where you take the active ingredients from plants,” admits Olivier Loelliot, general manager of Enterprise Solutions for GE. “But there is nothing like this exact technology on the market yet, where you grow the protein you want inside the plant. We think it will be a very important technology in the next 10-20 years.”
The big advantage of Ibio is the new vaccines and proteins it will enable, but the technology also has the potential to reduce R&D costs “tremendously” adds Loelliot. This will be achieved if the Ibio platform is able to reused for the production of five or six different vaccines.
Construction on the Ibio plant starts next year and is due to complete in 2016.