Susan Aldridge

News of a 'bionic eye' — a device that gives blind people some level of vision — has focused attention on ophthalmic medicine. Most patients with a visual problem won't be getting new eyes, but they do represent the growing market for smarter formulations of existing drugs, such as preservative-free drugs, or reprofiling certain molecules specifically for the eye.  

There is a growing number of specialist pharmaceutical companies searching for opportunities to develop and manufacture new ophthalmic medicines. One of these is Ophthaltec Ltd (UK), which is working towards commercializing research at the UK's University College London (UCL) Institute of Ophthalmology on a project regarding the detection of apoptosing retinal cells, which allows for much earlier detection of glaucoma. The company is also interested in cell therapy for the eye and in reprofiling drugs; these could be compounds that have failed at a late stage of development for their primary indication or that are already successful and have a mode of action that could also be applicable to an eye disease.  

"The challenges in the ophthalmic area largely centre on finding effective therapies for the main ophthalmic diseases that affect people in the Western world — age-related macular degeneration (AMD), glaucoma and diabetic retinopathy," says Peter Adamson, CEO of Opthaltec. "The difficulty in finding effective treatments is that we have such a poor understanding of the disease biology and pathology, particularly in mechanistic terms." 

Adamson explains that when reprofiling an existing drug, or developing a new one, a key issue is formulation; whether an eye-drop or cream is needed or whether the drug can be injected into the eye. The advantage of the topical approach is that systemic exposure is limited and, usually, less of the drug is needed than in an oral dose. However, as the surface of the eye is vascularized, the level of systemic exposure is not zero; for example, eye-drops for glaucoma treatment cannot be used in patients with impaired lung function because systemic exposure can cause bronchospasm. In general, the lower level of systemic exposure reduces the exposure of other organs to the drug substance, limiting side-effects and potential organ toxicity, according to Adamson. "The eye can be regarded as a closed biological location," he says. 

Injecting a drug into the eye may sound risky to most people but is, in fact, routine and the preferred route for antiangiogenic drugs, such as Macugen (pegaptanib) and Lucentis (ranibizumab), which are monoclonal antibodies used for AMD. Also in this category is Avastin (bevacizumab), which is an example of a drug developed for another purpose that has been adopted for ophthalmic use. It is already licensed for colorectal cancer, breast cancer and nonsmall cell lung cancer, but is in clinical trials for AMD, as well as already being prescribed off-licence for the condition. 

The disadvantage of eye drops and creams is that the drug usually has to penetrate the cornea and there is also the problem of low residency time as the drug tends to get washed away by tears. Therefore, the concentration of the drug must be high, and the API must be highly soluble in a non-irritable solvent and must be balanced in terms of salt concentration and pH.

To address these issues, some ophthalmology companies have formed partnerships with hospitals. One example is Opthaltec, which has partnerships with UCL, Moorfields Eye Hospital and Moorfields Pharmaceuticals (UK). The hospital was involved in the bionic eye trials and is also renowned for its work on cell therapy. More information on Moorfields can be found in the July 2007 issue of 

London appears to be a global centre for ophthalmic pharmaceutical companies, but there is significant work going on elsewhere in the world. OphthalmoPharma (OPPH; Switzerland) also focuses on the development of drugs and medical devices for ophthalmology. Richard White, Director of Pharmacology and Toxicology, believes that ophthalmology has been neglected by large pharma as the market size for most of the indications is currently lower than the 'blockbuster' (>$1 billion) potential for drugs in oncology, central nervous system or cardiology. Despite this, profit margins in ophthalmology are very attractive and the market is increasing as the incidence of eye disease grows with the ageing population. Further potential for market growth comes from the significant number of untreated patients and the severity of the diseases, many of which ultimately lead to loss of sight.

OPPH sources, selects and in-licences compounds and technologies close to commercial development. Products are moved across the development phases that add the most value and licensed out to large pharmaceutical companies and ophthalmic specialty firms. OPPH's lead programme is a novel formulation and delivery platform, based on third generation monosubstituted cyclodextrins, for the ocular administration of new molecules and for new applications of established drugs for the treatment of glaucoma, dry eye syndrome, age-related macular degeneration and inflammation. 

Finally, there is news that one of the world's leading eye health companies, Bausch & Lomb (NY, USA) is teaming up with the drug discovery company, Galapagos (Belgium). The research agreement gives the larger company access to a group of small molecules thought to have huge potential in ophthalmic applications. "The molecules come from a programme of ours on a target that could be important in eye disease, which were very effective when tested in animals," explains Galapagos CEO, Onno van de Stolpe. "We want to stay focused as a company on bone and joint disease, but are pleased that these molecules may have another clinical application." 

If Bausch & Lomb find a compound of interest from this partnership, Galapagos will develop it further prior to clinical trials. Such collaborations are likely to become increasingly common as the ophthalmic pharmaceutical market grows. 

www.nxtbook.com/nxtbooks/advanstaruk/pt0707

Articles

... profit margins in ophthalmology are very attractive and the market is increasing as the incidence of eye disease grows with the ageing population.

Eyeing up opthalmic opportunities

Once famous for coal and steel, Wales now aims to make its mark in the life sciences sector. The recent BioWales 2008 (UK) conference demonstrated how much the region has progressed, thanks to the support of the Welsh Assembly government, the EU and the enthusiasm of the Welsh biotech community. The country's bioscience sector, which comprises approximately 200 companies, grew by 18% last year and is now worth £1.3 billion (€1.6 billion) in annual turnover, employing 15–20000 people. 

Addressing more than 400 delegates at the conference, Dr John Patterson, Executive Director for the development of AstraZeneca's new medicines, spoke of the patents that are expected to expire on many of the world's best-selling drugs by 2011, the increasing frequency of patent challenges and the limits of data exclusivity. "Generic erosion is steeper and faster each year," he said. Added to this, the public is increasingly critical of the pharmaceutical industry, while having ever higher expectations. People seem to have bought into an instant gratification mentality; as soon as a gene is discovered, a cancer cure is expected to swiftly follow.  

"So why do we bother?" Patterson asked. The answer is that there are so many unmet medical needs — some of them clearly related to aspects of modern life, such as stress, pollution and obesity. Then there is the problem of antibiotic resistance and the demands of an ageing population. Pharma must try to grab these opportunities, but how can the industry boost its flagging success rate? 

Patterson noted that academia and small companies are very good at discovering new therapeutic molecules, but they are unable to turn them into medicines. Biotech companies are flexible and innovative but, unlike big pharma, they cannot fund failure or scale-up. Pharma has the global reach, the manufacturing standards, the track record and the ability to withstand failure, but it is just too big?  

"You are now seeing the whole of the pharmaceutical industry undergoing a revolution," Patterson said. In the future, he believes the winners will be the companies who access both big and small molecules — a blend of biotech and traditional pharma, although where the balance between the two will lie is debatable. The winners will be those who use translational medicine, meaning closer collaboration between the research and clinical sides, and those who leverage emerging markets. 

Many of these lessons are being put into practice in one of Wales's leading biopharmaceutical companies, Ipsen BioPharma, which is headquartered in France, but has a manufacturing facility in Wrexham that opened in 2000. Ipsen has five products in oncology, endocrinology and neuromuscular disorders, including Dysport, which competes with Botox, and Decapeptyl, a GnRH analogue. The Wrexham facility is dedicated to the manufacture of these therapeutic proteins and others that are moving through Ipsen's pipeline.  

According to Mike Harvey, VP of Manufacturing Supply Operations for Ipsen, design is the key to pharma success. "We so often hear of a discovery being stillborn because of a factor like dosage or distribution," he says. "Design must be thought through right at the beginning if you are to be successful in this industry." Although neither easy nor cheap, earlier commitment and decision making are needed to assure product quality in its broadest sense. "Product form and presentation must be thought of early, and early analytical development is vital for biologics," he adds. "Quality by design is here to stay and it is important for proteins too. It must be used." 

Design is what keeps a company competitive as 85% of the cost of goods is set by how a product or process is designed. Harvey believes that the key to Ipsen's manufacturing success in Wales is "a constant drive, a burning desire to improve, with focused teams in manufacturing with a mixture of skills, including those with commercial awareness." This is particularly important when products are manufactured far from the site where they were developed; for example, by a contract manufacturer. 

Wales is famous for its sheep — so maybe it is suitable that it is also home to two companies that make therapeutic antibodies raised in sheep (even if one of them uses Australian sheep). Protherics, a leading biopharmaceutical company, has its main manufacturing operations in Llandysul, where it produces three commercial products: CroFab, ViperaT and DigiFab, as well as a new product in

clinical development. These are all polyclonal antibody fragments (also known as Fab fragments) for the critical care market, based on antibodies raised in sheep sourced from Australia. CroFab and ViperaT are for treating poisonous bites from North American rattlesnakes and European vipers, respectively, while DigiFab treats overdoses of digoxin, a heart drug with a narrow therapeutic index. CytoFab, also a Fab fragment for severe sepsis is being groomed for blockbuster status with AstraZeneca.  

Meanwhile MicroPharm, which is located in Newcastle-Emyln in West Wales, uses local sheep to raise a range of antisera and antivenoms for contract manufacture, and offers Wales's only contract sterile filling service. The company has a deal with the Nigerian government to supply antivenom against the Carpet Viper, which is responsible for approximately 2000 bites a year, meaning that the MicroPharm product has likely saved hundreds of lives. The company also helps Nigeria save money because it has a liquid rather than freeze-dried formulation contained in cheaper vials. They also reduce cleaning costs by using disposables in their manufacturing plant. 

Meanwhile, Wrexham is the location of one of India's leading generic companies, Wockhardt UK, which is the second largest producer of hospital generics in the UK. "The Welsh experience encouraged us to grow our business in Europe," says Sirjiwan Singh, Managing Director of the company. "When we located here, people thought we were fools for not going East."  

But Wockhardt has earned $450 million (€284 million) in Europe, mainly through mergers and acquisitions, since moving. Currently, Europe accounts for 60% of revenues of the companies, while those from India have declined. In Wales, Singh says he likes: the good infrastructure, a supportive business environment and a good support structure. "We are now moving to value-added niche products. We want to build an entrepreneurial and risk-taking ability in our managers."  

It seems to work, for Wockhardt is now growing at a rate of 14%, which is twice the rate of UK pharma. "I've learned that we must improve at a rate greater than the competition," he concludes. "What has happened in the computer industry in the last 15 years will happen to pharma in the next 15." There is going to be a lot of change and evolution, and only those companies that can keep up will survive. 

Meanwhile, Ortho-Diagnostics, which is part of Johnson & Johnson, will open a facility for the manufacture of diagnostic kits for heart disease, HIV and hepatitis B virus in the new Pencoed Industrial Park in July. In the UK, locations outside of London, Cambridge and Oxford struggle to get the attention they deserve from the rest of the world, but Wales is developing connections with Israel. For instance, MaimoniDex RA of Tel Aviv, which develops monoclonal antibodies for rheumatoid arthritis, is intending to establish a facility in Swansea. Addressing BioWales, Gil Erez, Minister for Commercial Affairs at the Embassy of Israel in London, commented that Israel and Wales are actually the same size. His country is a fast growing, high-tech economy, which scored high on the Global Competitiveness Report. It is an EU partner in Framework Programme 7 and has 50 ongoing projects with the UK. Israel has 466 life science start-ups and is fourth in the world for molecular patents and second for medical device patents. The UK is seen as an expensive place to locate a biopharma facility, and Israeli companies still do not know enough about life beyond London. However, Erez believes Wales is going in the right direction, by sending delegates to BioIsrael, for example, and encouraging companies to come here.

Once famous for coal and steel, Wales now aims to make its mark in the life sciences sector. The recent BioWales 2008 (UK) conference demonstrated how much the region has progressed, thanks to the support of the Welsh Assembly government, the EU and the enthusiasm of the Welsh biotech community. The country's bioscience sector, which comprises approximately 200 companies, grew by 18% last year and is now worth Â£1.3 billion (â‚¬1.6 billion) in annual turnover, employing 15–20000 people.

Building bioscience in Wales?

Insulin is one of the world's oldest and most well-known biological drugs, and the need for it is not going to go away as the number of patients diagnosed with diabetes continues to increase. A wealth of clinical evidence shows that good, long-term glucose control in diabetes is key to avoiding complications such as kidney disease, blindness and heart problems. 

The way insulin is delivered plays a vital role in helping patients manage their condition. As with all peptide or protein drugs, insulin cannot be administered orally because it is degraded by gastric fluids, and pharma companies have long been searching for more convenient and acceptable ways of delivering insulin as opposed to the conventional syringe and needle. Pen injectors are now well-established, but other routes under investigation include inhalers, eye drops, needle-free injections, nose drops, patches and even oral formulations.  

Inhaled insulin has had a tough time recently. In February this year, Novo Nordisk (Denmark) announced it had ceased clinical development of its inhaled insulin, AERx iDMS, in Phase III. The news came only a few months after Pfizer (NY, USA) dropped its own inhaled insulin, Exubera. The reasons had nothing to do with safety, although some physicians do have reservations about the long-term impact of delivering an active drug to the lungs on a chronic basis; the Exubera inhaler was rejected by patients and doctors because it was too bulky, complicated and inconvenient.  

But these setbacks do not herald the end for inhaled insulin. Eli Lilly (NJ, USA), who worked with Frederick Banting and Charles Best at the University of Toronto (ON, Canada) in the 1920s to make insulin first available as a drug to diabetics, now has an inhaled insulin in Phase III. MannKind (Valencia, CA), a company focused on medical devices, is also developing an inhaled insulin. Novo is still in the game too, committed to developing long-acting inhaled insulin in liquid and powder form.  

Mads Thomsen, CSO at Novo, outlines the challenges in developing pulmonary drugs. According to him, there is plenty of experience in inhaler technology for asthma where the drug acts locally in the lung, but for diabetes, the lungs are a vehicle for transporting insulin into the blood, and this is an important difference. "The ideal insulin inhaler would look like an asthma inhaler," says Thomsen, "but it must perform much better. The amount of drug delivered in asthma is highly variable, but this doesn't matter as the patient can just take another puff. For insulin, exactly the same dose must be delivered every time." 

Bioavailability is another issue, as only 10% of the inhaled drug makes it from the lungs to the blood compared with 100% for an injection. "We need to improve both the half life and the bioavailability of insulin in the inhaled form," says Thomsen.  

Novo is using its background in medical device manufacture to develop a new insulin inhaler. The company has made 100 million pen injectors for insulin, which is a great advance compared with the traditional syringe, but it is, in fact, only one of many pain-free or needle-free approaches to systemic drug delivery. One of the most novel of these devices coming to market is the Solid Dose Injector (SDI) being developed by Glide Pharma (UK). 

The SDI is a tiny rod of solid dose form drug — smaller than a grain of rice — with a point at the end that is pushed gently into the skin. "This pushing action is very important," claims Charles Potter, Glide's CEO. "Other needle-free systems fire the drug at the skin and the drug penetrates to a varying depth because each patient's skin is different. The push is more accurate and reaches the same depth each time." 

Use of a solid dosage is important too because it is more stable and has a longer shelf life than solution formulations. "The SDI, with its pen-sized, spring-powered actuator, is simple to manufacture and use", Potter adds. Glide will apply it for mass vaccination, in both industrialized and developing nations, and in emergencies (i.e., pandemics). "We can address all three vaccine markets because we have moved away from needles and cold storage, which make it very cheap for high volumes," Potter explains. The SDI can also be used for home use of proteins and peptides, such as insulin and interferon.  

Glide is already working with big pharma and has recently signed an agreement with a leading company to evaluate the SDI technology for the delivery of a branded peptide product. It is Glide's third deal involving a biological product, and further agreements will be announced in the near future. 

Meanwhile, Medgenics (Israel) is developing a drug delivery system for proteins that combines drug production and delivery in a single 'biopump', where a piece of the patient's own tissue is programmed to produce a therapeutic protein in the body. "We are taking a tiny biopsy — the size of half a toothpick — processing it outside the body and then replacing it beneath the dermis," explains Medgenics CEO Andy Pearlman. "This is truly personalized medicine. The patient receives a miniprotein production plant made of their own skin."  

Medgenics's bioprocessing unit introduces a gene that transforms the required protein into the tissue, or 'micro-organ' as it is known. The resulting biopump then releases the protein drug into the patient's body. Although it may sound like gene therapy, it's not; in gene therapy it is hard to control where the virus carrying the therapeutic gene will be delivered, but with the biopump, you know exactly where the device has been implanted, and where it will produce and release the drug. The amount released to the patient can be controlled by implanting the required number of biopumps. For a higher dose, more biopumps are implanted and, to reduce the dose, they can be ablated. This gives a steady level of therapeutic protein with time as opposed to an injection that provides an initial peak concentration that falls during the days that follow at a rate dependent on its half life.  

The company is developing the biopump for erythroprotein, which is used for treating chronic anaemia in kidney disease, and for interferon-alpha, used in the treatment of hepatitis C, where conventional injections are linked with severe side effects that the biopump may be able to alleviate. As far as regulation of this new therapy is concerned, it has been likened to a drug-eluting stent, and Medgenics is working closely with FDA to have it approved under the Centre for Biologics and Evaluation Research. 

Pearlman believes that the field of drug delivery is becoming increasingly more 'patient-friendly' as it moves towards smart pills and needle-free injections, but he believes that what Medgenics has to offer goes even beyond this, representing a new paradigm in drug delivery. "This is really different — the protein is being produced fresh in the patient's body each time," he says.  

Commenting on drug delivery trends during the next 10 years, Novo's Thomsen thinks pulmonary delivery will be important, and there is also room for improvement in drug delivery pumps, which are currently heavy, inconvenient and untidy. Innovation may come in the form of prefilled 'patch' pumps, which are mini-pumps in the form of patches. In the end, drug delivery may come full circle and there could be 'magic pills' — enhanced forms of oral delivery that allow biologic drugs to enter the blood without being degraded. Many such programmes are already underway for insulin. "This is a long-term ambition for us, and others," says Thomsen.  

All of this should improve the quality of life for patients. Living with a chronic disease and managing it with medication is difficult and patients are right to demand better drug delivery techniques, but, of course, there is something in novel drug delivery for the companies as well. Beset by generic competition, and with productivity down, packaging an old drug into a new delivery system makes good business sense. 

Insulin is one of the world's oldest and most well-known biological drugs, and the need for it is not going to go away as the number of patients diagnosed with diabetes continues to increase. A wealth of clinical evidence shows that good, long-term glucose control in diabetes is key to avoiding complications such as kidney disease, blindness and heart problems.

Dawning of a new drug delivery era?

Clean water is an increasingly precious resource, and there are huge inequities in water use around the world; for example, 700 L for domestic use per individual per day in the US, compared with 7 L a day in Senegal. Meanwhile, according to the World Water Council, more than 1 billion people lack access to clean drinking water while 2.6 billion do not have access to adequate sanitation. However, the main consumers of water are industry and agriculture. The amount of water used by industry, including pharma and biotech manufacturing, amounts to 23% of the world's supplies on average, which ranges from 5% to as much as 80%, depending on the nation and its level of development. 

The pressure is on to save water in all areas of life. This means not only fixing that dripping tap, but making sure that industries use the smartest technologies and best designs possible to optimize water use.   

These efforts could learn from a relatively new concept known as water footprint, which has been introduced by Arjen Hoekstra and Ashok Chapagain of the University of Twente (The Netherlands). Water footprint is similar to the idea of carbon footprint, and the two are connected because energy is used to produce purified waters, such as those used in pharma and biotech manufacturing, and to process wastewater effluents. The water footprint is defined as the amount of freshwater a nation uses in production of goods and services, including its medicines. The total global water footprint is, on average, 7450 Gm

/year per head in China. These figures include the volume of industrial water drawn both within and outside the nation.  

Water footprint is closely linked to the concept of 'virtual water', which is the water used to produce a good or service (according to Hoekstra and Chapagain, the virtual water content of a microchip is 32 L, and 8000 L for a pair of shoes).

  So far, this concept of water 'price' has mainly been applied to agriculture. Industrial products are said to have an average virtual water content of 80 L per dollar used in their production, which varies from 100 L in the US, to 50 L in Germany and The Netherlands, and only 10–15 L in Japan, Australia and Canada. These concepts have not been widely applied to the pharma and biotech industry. 

Pharma and biotech industries rely on water — and expensive purified sterile water at that — for processing, as their products are intended for human consumption. Biologics manufacturing relies on water even more because microbial and mammalian cell culture require a carefully controlled aqueous medium for productivity, and water quality and availability are key issues. If this industry is to grow, it must get the water it needs, and this can be a major contributing factor in determining the location of a plant. A large facility uses millions of litres a day and cannot afford to be affected by interruptions in supply. For instance, Amgen (CA, USA) had extensive discussions with the local water authority in 2004 regarding whether enough water would be available to manufacture its drug Enbrel at its Rhode Island plant in the US. The talks resulted in the company introducing many water conservation measures in-house to safeguard its supplies. This was not just, the company said, self-interest, but about trying to set an example as a corporate citizen. 

Water is also a necessity for biotech industries for downstream processing, formulation and cleaning, with the latter application accounting for approximately 60–80% of water usage in a manufacturing plant. Energy and costs of producing the different grades of water, which are used in the operations that go into making a biological medicine, must also be considered. According to Simon Routledge, cGMP production manager at the UK's National Biomanufacturing Centre in Speke, the water requirements of a plant largely depend on the dosage form and purity requirements of the final product, and this is also true for pharma. If the product will be introduced orally, water quality requirements are not as high as those required for a parenteral product, Routledge explains.  

Water used in manufacturing ranges from simple, reverse osmosis-treated water, which has undergone one filtration pass through a membrane, to highly purified water for injection (WFI). Different types are classified according to their level of microbial contamination (colony forming units [CFU] per mL). United States Pharmacopeia purified water is subject to various purification processes, such as filtration, reverse osmosis and ultraviolet (UV) treatment, and has less than 100 CFU/mL.  

Drinking water is often the source of purified water for manufacture, but chlorine content interferes with cell culture and corrodes stainless steel. Therefore, the UV stage is used to kill bacteria, which grow more rapidly once the chlorine has been removed. WFI is the purest water used in manufacturing and should be fit for the purpose that the name implies. It is virtually sterile, with fewer than 0.1 CFU/mL, and is free of bacterial endotoxins, which is a key requirement of regulatory authorities. It is then kept at 80°C, preventing microbial contamination. It is used in downstream processing operations, in the formulation of parenteral products, and in the final rinse of the washing of stainless steel pipes and vessels in the plant.  

The middling grade of water is known as 'highly purified water' and can sometimes be used in certain cleaning operations. In many respects it is equivalent to WFI, but is cheaper to produce because it does not have to be distilled. 

Water quality requirements tend to increase for the purification stage of a manufacturing process as you near the final dosage form of a product, says Routledge. This is because impurities have a bigger impact on product quality at these later stages.  

The demand for WFI is increasing, partly because of more stringent regulatory demands for purity in the final pharmaceutical product. As WFI is so costly to produce, manufacturers are looking at ways of optimizing its use in manufacture.  

There are many ways to decrease water consumption in biopharma manufacturing. Smart engineering and design can create plant water supply systems that can easily switch between grades of water for different operations. Where a lower grade is acceptable, it can rapidly be supplied by such a system. PAT, with its emphasis on a deeper and better understanding of the whole manufacturing process, will also make a big contribution by revealing the optimum use of water in the various operations involved.  

There are also alternatives to water, such as ozone, for cleaning and the trend towards disposables promises to cut water use dramatically. Wherever a disposable component replaces stainless steel — be it in a pipe, valve or vessel — cleaning is eliminated, along with resulting wastewater, which must also be considered as it involves further energy costs. Typically, more water will be used in steam injection to decontaminate the water used in a biotech process. Chemical content must be neutralized so it is harmless and the water will then, perhaps, enter public drains. Recycling wastewater is increasingly an option for many companies. The water can be used for cooling to save drawing more water for this purpose from the local supply.  

Hoeskstra and Chapagain suggest many ideas for reducing water footprint that could be applied to pharma and biotech. First, adopt production techniques that use less water per unit of product. Second, raise awareness across the board about the water requirements involved in manufacturing and, finally, consider locating production in areas of higher water productivity.  

Biotech products can be lifesaving, but so too can access to clean water. Minimizing water use in production will not only cut the costs of these medicines, but make a small, yet significant, contribution to easing the global water crisis.  

Water footprints of nations: Water use by people as a function of their consumption pattern

The amount of water used by industry, including pharma and biotech manufacturing, amounts to 23% of the world's supplies

Water, water everywhere?

My personal experience of lab automation is limited to supervising a peptide synthesiser back in the late 1980s. The machine was eye-wateringly expensive — but it was soon paying its way in terms of productivity and research publications. So if I were a stake-holder in a company pondering whether to invest in a well-designed gadget that could automate a routine operation, I'd say: 'go for it'. 

Pharmaceutical manufacturing, by its very nature, is well-suited to some degree of automation, with process control of batch reactions now being well-established throughout the industry. Those operations that lend themselves to standard off-the-shelf equipment such as automated liquid handling, which is good for compound storage and high-throughput screening, are becoming widespread too. Testing is also becoming increasingly automated, whether in R&D or quality control. 

According to Tony Moran, sales and marketing director of Astech Projects (UK),

which specializes in automation for drug delivery testing, it is the pharmaceutical companies themselves, rather than the suppliers, that have been driving the shift towards automation.  

There are many advantages to automation, and relatively few drawbacks. Higher throughput and productivity, with the ability to operate 24/7, are the most obvious benefits — and these are of particular significance to an industry under ever-increasing timeline and cost pressures. Consistency in process control is another advantage while repeatability of test methods provides more reliable data for the regulatory authorities. "A machine is very accurate and precise compared with a person," says Moran. Companies can also look forward to a reduction in overall costs through labour saving and a reduction in lost batches. 

Moran provides an interesting example of labour saving and productivity improvement in a typical stability study of a metered dose inhaler (MDI) new drug application. Using 1000 samples as baseline, full automation can achieve the job using the input of less than one full-time employee. Semi-automation of MDI testing would require four to six employees for the job, while fully manual firing would take 12–18 employees. 

And let us not forget the human advantages of automation, which "frees up clever chemists to use their brain, instead of their hands," according to Stephen Fleck, consulting business manager at TTP LabTech (UK), a company with 20 years experience of providing custom automation solutions in both development and production environments. There are also health and safety advantages in automation as personnel are exposed to less hazardous equipment and chemicals. 

The main drawback of automation is the cost, particularly for a GMP environment. Pharma investors are only going to vote for cost-effective systems with the shortest possible payback time, and it is up to suppliers to develop and deliver these. Moran acknowledges that customers can be conservative when it comes to bespoke automation. Therefore, Astech takes the approach of scaling-up automation by building it gradually with key modules. In this way, with time, they will have a fully automated platform. They also offer proof of concept modules and loan modules to allow for a limited risk trial of the concept. 

The other challenge is to make automation more innovative to meet the needs of the biotech industry, and to make it more flexible in the context of medicinal chemistry and process development. Cell culture (the way biological medicines are produced) is both manually tedious and notoriously tricky to get right. It presents a different type of challenge to large-scale synthetic chemical synthesis, which is the basis of small molecule drug production. Fleck recalls how TTP LabTech developed a project for Amgen's (CA, USA) manufacture of its anaemia treatment, recombinant erythropoetin (EPO). A manual cell culture process had to be scaled up and its location moved. TTP LabTech's system involved setting up 40000 roller bottles, all of which had to be rotating and visible. The project required a novel approach to roller bottle storage and handling, as there was no available off-the-shelf equipment. The system, perhaps the biggest project ever in biotech manufacturing automation, took 25 man-years to complete, and contains more than 1 million components. A huge investment, but putting it into context, the cost was less than a day's EPO revenue. 

There are now many products on the market to streamline biotech research, process development and manufacturing, such as automated cell culture systems from The Automation Partnership (UK) and the ClonePix FL from Genetix (UK), which uses imaging and robotics to pick out high-producing clones that manual methods might miss. 

When it comes to medicinal chemistry and process development, systems must generally be more flexible than for manufacturing operations. Fleck says: "On the chemistry side, we are finding an increasing need for automation among graduate and PhD chemists who used to spend a lot of their time in the lab working on new formulations and reactions. There is now a driver towards increasing their productivity, without increasing headcount — so they are doing more in parallel using automation." 

Chemists have long been able to set 10 or 20 syntheses in motion and walk away from the equipment, but such systems are inflexible, as they generally allow the variation of only one parameter at a time. They now want to explore more parameters such as solvent, temperature or process time in parallel. "We are seeing more demand for automation in organic syntheses, and in crystallization for polymorph screening and solid state development work," says Fleck. TTP LabTech has developed a 'batch-of-one' approach, where parallel synthesis allows the testing of many different reaction parameters in the one experiment. "This design of experiment approach provides a very efficient way of exploring experimental space," he says. 

 pharmaceutical operation be automated? And are we now moving towards a fully automated lab or production plant? If the demand is there, then it may be possible to push automation a very long way forward. "Engineers will often rise to the challenge and do what was previously thought impossible," says Fleck. In the future, he believes there will be an increasing role for 'intelligent automation' where an element of artificial intelligence is applied to a chemist's decision-making process. At TTP LabTech they are looking at how they might get computers to capture and mimic what a chemist really does. 

Fleck also predicts a shift towards more continuous production in pharma and biotech (as has been the case in the chemical and food industries) because there is less down time with equipment laying idle. Flow chemistry also gives improved yield because of better control of reaction conditions, particularly temperature control and mixing. A further advantage of continuous over batch production is better accommodation of unstable intermediates. Automation companies will have to provide the corresponding automation technology — a challenge that lies not so much in the engineering, but more in the corresponding regulatory requirements of FDA and GMP because continuous mode requires a different set of process control data for validation. 

Greater scrutiny of all aspects of pharmaceutical technology may also lead to new automation challenges, Fleck adds. For example, formulation development in pharma, healthcare and skincare tends to involve gels, pastes and viscous liquids. Until now, there has been a need to hand mix these products, but, given the demand to explore formulation more quickly, there will be increased pressure to automate, which will require technological innovation. 

According to Moran, advances in technology have allowed automated platforms to become far more productive through greater computing power, allowing multifunctional parallel processing on fully integrated systems. The amount of data that can be stored and interrogated has also increased dramatically. This pleases the regulatory authorities and provides new opportunities for designing and improving processes. 

The future for automation in the pharmaceutical industry looks exciting, providing the right people who can really put it into practice are found. "It is difficult to find scientists who understand engineering and 

," Moran admits. In other words, we need creative engineers who understand the science they are automating, such as the intricacies of growing cells, the way medicinal chemists think and the need for sterility. The success of companies has much to do with attracting people who can offer the balance of science and engineering that makes automation work.

My personal experience of lab automation is limited to supervising a peptide synthesiser back in the late 1980s. The machine was eye-wateringly expensive - but it was soon paying its way in terms of productivity and research publications. So if I were a stake-holder in a company pondering whether to invest in a well-designed gadget that could automate a routine operation, I'd say: 'go for it'.

Automation works

Deciding where in the world to locate a new plant is a key decision for any pharma or biotech company — and there has never been more choice. Europe and the US now compete with the Far East and India, and what about the new EU states? Might Lithuania or Estonia turn out to offer advantages compared with France or Germany when it comes to finding the best place to take a new drug forward to the market place? 

Late in 2007, Merck&Co. Inc., the world's seventh largest pharmaceutical company, announced its decision to build a €200 million strategic vaccine facility at Carlow Town in South-East Ireland. The facility will support the company's expanding global business in human vaccines and biologics, and will create 170 jobs by 2011. It will be the first, stand alone human vaccine project in Ireland, and will have a formulation and sterile filling operation, as well as an R&D team to support recently launched vaccines and new product. Merck will also collaborate with Irish academia in biologics production. 

Ireland won the deal after an international site study by Merck, which already has two existing operations in the country employing more than 450 people. The facility at Ballydine, County Tipperary, produces APIs, while the site at Leopardstown, County Dublin, is a corporate platform for Merck's strategic activities in the country. 

Merck is one of several companies that make up Ireland's lively pharma and biotech cluster. At a recent meeting in London to discuss the future of Ireland's pharmaceutical industry, Barry O'Dowd, manager of pharmaceuticals and biotechnology for IDA Ireland (the country's foreign investment agency), pointed out that Irish pharma exports were €33 billion in 2006 compared with €18 billion in 1999. Nine of the top ten global pharma/biotech companies are located in Ireland — besides Merck, there is Wyeth, Genzyme, GlaxoSmithKline, Pfizer, Johnson&Johnson, Novartis, Schering-Plough and Bristol-Myers-Squibb (BMS). Looking further down the rankings, 17 out of the top 20, and 28 out of the top 50, pharma companies have a facility in Ireland too. Seven out of ten pharmaceutical blockbusters are made in Ireland, including Enbrel, the revolutionary new fusion protein tumour necrosis blocker treatment for rheumatoid arthritis, which is made at Wyeth's €1.3 billion plant at Grange Castle near Dublin, the world's largest biopharmaceutical production facility. O'Dowd also adds that Ireland is attracting companies from India and the Far East. "We are also in the generic space — for instance, Teva is located in Waterford with a six sigma operation with worldscale PAT." 

Biotech is very big in Ireland too — with Lilly, Elan, Genzyme and Wyeth. O'Dowd is particularly proud of Centocor's new facility in Cork, a €500 million investment that has been completed ahead of schedule and under budget. It is now in the validation phase prior to producing four biologic drugs. BMS, Organon and Allergan are also making biologics and new therapeutics in Ireland. "As biotech grows we expect more investment and we will be competing for this," says O'Dowd. Meanwhile, Lilly is building a new plant in Kinsale and Pfizer's new development centre in Cork is an investment of more than €100 million. On the small molecule side, Ireland has Servier, Wyeth, and Takeda. "Small molecules are not all heading to India," he comments. "We are still winning projects in these areas."  

Pharma is the biggest contributor to corporation tax in Ireland. In fact, it is the low tax that draws companies there in the first place, as Ireland is famous for having the lowest corporation tax in EU, and this is something the Irish Government is strongly committed to keeping. The country also has tax credits for R&D and, according to Jim Ryan from the consultancy CIRCA Group Europe, there has been a range of other initiatives too. For those starting out, there is financial support to purchase consultancy and innovation vouchers worth €10000. Universities and research centres are also expected to conduct R&D and can get Government support to do so. "Within the next 3 years, we're hoping for 55 companies with an R&D spend of over €2 million. That's an ambitious target, but the initiatives are being managed quite well and are well-coordinated."  

However, Ireland has really had to build up its infrastructure to support the pharma and biotech industries. The National Development Plan (2000–2006), an investment programme supported by private, public and EU money that was set up to focus on areas of the Irish economy, placed a large emphasis on R&D and invested €2.5 billion. This led to the Programme for Research in Third Level Institutions, which has built up university infrastructure, with 33 new research centres and 97000 m

  of dedicated space — half of this investment being for life sciences. Meanwhile, Science Foundation Ireland (SFI), founded in 2000, has been charged with the task of building up the quality and scale of basic R&D. It has also funded 118 principal investigators and a number of centres for science, engineering and technology that bring together academia and industry. These include the Alimentary Pharmabiotic Centre at University College, Cork, the Regenerative Medicine Institute at the National University of Ireland, Galway, and the Biomedical Diagnostics Institute, Dublin City University.  

Regarding industry, IDA brings in foreign investment, while Enterprise Ireland funds and encourages the indigenous industry. The country now has 65 biotech companies in drug discovery, pharmaceuticals or diagnostics, which employ more than 2000 workers and have a turnover of approximately €300 million. The biotech start-up rate has been approximately 18 companies a year — five of which are from the higher education sector.  

Ireland has a distinct competence in development and manufacturing while discovery research is beginning to happen, although, according to O'Dowd, the country has traditionally not been strong in this area. "The development and manufacturing model, with collocation of the two, is the model we are trying to promote — taking compounds from research units into Phase I with smooth technology transfer. Merck has done this, for example, and this plays to our knowledge agenda with our new graduates coming through." 

Of course, there will always be competition from elsewhere. Singapore is focused on very similar sectors. "We are always looking at them and them at us," says O'Dowd. The populations, GDP and employment levels are similar for both countries, but laboratory costs and inflation are greater in Ireland. In Singapore, you can negotiate zero tax for the short term and it has a very strong infrastructure, especially since it built its giant science city, Biopolis, but Ireland is catching up. It is much more politically stable, and has cheaper power and a more streamlined planning system. The Irish climate is also good for biotech (which needs water!). O'Dowd also adds that there are fewer local engineering personnel in Singapore and, once you start to subcontract work, you lose accountability. Accordingly, safety can be an issue in Singapore, while the Centocor plant in Cork has just gone for one million hours without an accident. 

Both countries are winning projects — Ireland got the Merck vaccine project, but Novartis opted for Singapore when it needed a new facility. IDA is trying to increase R&D in Ireland by understanding company needs, facilitating collaborations and working closely with SFI. "A lot of it is about personal relationships," O'Dowd concludes. "Ireland is coming at this in a joined up way, with people, tax breaks and a shared agenda." 

"Collaboration is a very important element," Ryan agrees. "We have got the infrastructure for this collaboration now — we had a poor infrastructure until the 1990s — and we are now spending to create what others already have. In the next 5 years, our indigenous and multinational companies will be developing in parallel."

Deciding where in the world to locate a new plant is a key decision for any pharma or biotech company - and there has never been more choice. Europe and the US now compete with the Far East and India, and what about the new EU states? Might Lithuania or Estonia turn out to offer advantages compared with France or Germany when it comes to finding the best place to take a new drug forward to the market place?