Every week that goes by the Ebola threat grows worse. A failure to stem the spread of the disease in West Africa has caused checks to be introduced at airports. As the first Westerners die from the disease, politicians begin to talk in terms of a “handful of cases” on home soil and levels of preparedness. The terminology and tone is eerily redolent of the movies we’ve all seen.
When the low-level panic sets in, society turns to the global pharmaceutical companies to provide cures and vaccinations. These companies have done the R&D, they have the vaccinations and therapeutic medicines to deal with Ebola. But they are in experimental form. Questions still remain around how long the clinical trials will take and whether the companies can make enough of the vaccine fast enough to stop Ebola.
The most promising Ebola vaccine is made by UK pharmaceutical giant GlaxoSmithKline (GSK) and was developed by a Swiss biotechnology company it acquired last year. The vaccine is a combination of genetic material from the Ebola virus and a modified chimpanzee cold virus.
Large pharmaceutical companies have previously come under heavy criticism for slow responses to the development and manufacture of treatments for epidemics. But the development of the GSK vaccine has been fast-tracked, with high levels of collaboration between US and UK companies and regulators. Early-stage tests were conducted on volunteers in the UK during August, and the first human trials started in West Africa last month.
The Wellcome Trust and the UK government have provided a £2.4 million grant to kickstart the clinical trials. Vitally, the funding is also enabling GSK to begin manufacturing the vaccine. The company aims to produce up to 10,000 doses while the initial clinical trials are being conducted and make them available to the World Health Organisation for emergency immunisation programmes.
Such initiatives hint at the slow rate at which the pharmaceutical product lifecycle operates. Pharmaceutical manufacturing has not changed significantly for decades, but there are key technology trends shaping its future. New areas of scientific research in biotechnology are creating manufacturing technologies and processes on the plant floor. Greater commercial pressures are causing engineers to look at ways of developing and manufacturing drugs that use increased levels of automation and IT..
Most drugs are still manufactured in batches, restricting the capacities and efficiencies that can be achieved. Batch processing has stuck for a number of reasons. Most importantly, the sector is heavily regulated. The raw materials used to make drugs require a high level of validation. Traceability has to be guaranteed. Another consideration is that the value of the product is often very high. Manufacturing in batches also allows engineers to reconfigure plant and equipment to produce variations of drugs and different drugs faster.
However, last decade most of the larger pharmaceutical companies began pushing towards the goal of continuous manufacturing, as is used in sectors such as food and drink, oil and gas and chemicals. Increasingly, pharmaceutical firms are building and adapting plants to produce an uninterrupted flow of medicines and drug products to meet market needs.
CMAC is the EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation. It was created in 2011 in Glasgow as an academic research centre for the pharmaceutical sector. The centre employs 80 people, most of whom are engineers and scientists. CMAC has £80 million of public and privately funded research projects. The centre’s long-term aim is to help the pharmaceutical industry change from batch processing to fully continuous manufacturing processes and plants.
Craig Johnston, operations director at CMAC, says: “There is less robotics in pharmaceutical manufacturing than some sectors. In some ways it is quite traditional. There’s also a high attrition rate in drug introduction. Some 99% of drugs will fall over during the trial period,” he says.
“But the economics of the industry are changing and companies want to decrease lead time and speed up the development of new drugs. One of the things we aim to do at CMAC is learn from other sectors, from aerospace to fast-moving consumer goods companies, and we’re involved in a number of partnerships with other research centres.”
However, switching to continuous manufacturing after decades of batch processing presents challenges for engineers. The development and installation of plant and equipment in such a highly regulated sector is an expensive and time-consuming endeavour. There are supply-chain issues to address, as the production of most “intermediate” or raw materials that make up drug products is often outsourced.
Technically, there are several main differences between a continuous manufacturing drug plant and a batch one. Johnston says: “The biggest difference is the footprint – a continuous plant is a lot smaller. There are more control systems, more process analytical technology, it’s a more data-rich environment. There’s an increased level of automation.”
Companies such as Emerson and Siemens have developed plant that use SCADA (supervisory control and data acquisition) systems to integrate with each other and with process analytical tools. This enables realtime monitoring and testing of ingredients. For example, on a line making tablets, a tool that measures quality would control an automatic release of the product from one stage of production to the next.
Although the trend towards continuous manufacturing has accelerated over the last two years as competitive pressure has increased, Johnston admits that the technical and supply-chain challenges mean it is still at “early adopter” stage. Nevertheless there are some leading examples in the UK, he adds, where the adoption has been driven by “business benefits”, notably the Sanofi plant at Haverhill, Suffolk. The plant, which makes ingredients for a product used in kidney dialysis as well as “small therapeutic products”, is one of only a few in the world to go from manufacturing only in batches to being entirely continuous.
“The challenge is getting the systems from the lab into everyday use,” says Johnston. “You need a fundamental understanding of the processes, the particles and the polymorphs of the same material. A key thing is then designing the technologies to cope with the demands of the commercial environment. Then the technical challenge is to put the unit operations together so they flow. To run six or seven units and not mismatch the rates and have the right scale is difficult.”
Comprehensive research, including the use of simulation and modelling software and practical experiments, can help to overcome these challenges, adds Johnston. Companies are pursuing continuous/batch manufacturing hybrid manufacturing models to deal with the complexity and variety in their products.
Some technologies have also been widely adopted already. The uptake of flow chemistry using micro-reactors has been high in primary manufacturing, the half of pharmaceutical manufacturing where ingredients are made and combined. In secondary manufacturing, where tablets or liquids are formed and packaged, the introduction of continuous granulation machinery has had a high impact.
Granulation machines dry and extrude a drug material before it is tableted and packaged. In particular, the uptake of a continuous granulation machine by GEA Technologies called the Consigma has been high, says Johnston.
Bright sparks: GlaxoSmithKline is investing tens of millions of pounds into new research centres around the UK
Global pharmaceutical firm GSK has been experimenting with continuous manufacturing, including micro-reactors, since 2003. David Lynch, head of engineering for GSK, says that batch processes are equipment and energy intensive and can involve using large volumes of solvents. In contrast, continuous manufacturing can make the same volume of finished product on plants a fraction of the size and use less energy and solvents.
He says: “To give a feel for the scale, some of the reactors we use are the size of a pen. And because production is continuous, we don’t need to have the steps associated with the batch process where we need to stop, cool, or clean the reactor. Running machines 24 hours a day also reduces waste.”
Continuous processes will be adopted first in niche applications as well as telescoped processes, where multi-stage processes are consolidated into one stage, he says. For secondary manufacturing, he agrees that the key trend is a switch to continuous “oral solid dose” manufacturing using continuous blending, granulation and coating to make tablets. “As pharmaceutical manufacturing moves to continuous processing, automation will play a key role. We have a strategy group looking at advanced automation and we’re positive about the opportunities,” he says.
Elsewhere GSK is investing R&D funding into synthetic biology, an area Lynch believes will have a “significant” impact on the development and manufacture of active pharmaceutical ingredients. Active ingredients are the parts of the drug that produce the desired effect on the body. Synthetic biology applies engineering principles to the development and manipulation of molecules, cells and biological systems to make new organisms such as enzymes, genetic circuits and cells. For example, pharmaceutical compounds are cultivated in plants and harvested, instead of chemically produced through reactions. Earlier this year the government invested £40 million in three new synthetic biology research centres, one of which is in Bristol and will develop new antibiotics, vaccines and anti-cancer drugs.
The other area of investment for GSK, like many other large pharmaceutical companies, is the development of manufacturing processes and plants for biopharmaceuticals. GSK is building a biopharmaceutical plant at Ulverston, Cumbria, its first new plant in the UK for 40 years. Work on the £350 million plant is expected to start next year and to be complete by 2021. Its development is complex and expensive, primarily because it involves dealing with living cell cultures. The main difference with organic cell cultures is that they are larger molecules that require careful handling, with a significant number of separation and purification steps. However, the result is medicines that have a more targeted action, which helps increase efficacy, says Lynch.
Continuous manufacturing and new biological-based processes and technologies mean engineers within the pharmaceutical sector are facing an unprecedented period of change. It is a massive challenge to meet both the market and society’s demands for medicines while innovating sufficiently in product development and manufacturing. The importance of this challenge is made all the more urgent when diseases such as Ebola afflict thousands of people.