Fine Chemicals

A surprising development

Development Chemicals believes that it can make a difference to the way the pharma industry works - and supply life-saving drugs to the poor. We met up with one of the founders, Dr Rob Bryant

For various reasons, the pharmaceuticals industry, as it would readily admit, is very poor at process development. Now two industry veterans want not only to do something about this but also to use their knowledge to build a facility that will supply APIs to treat some of the basic, curable conditions that still cause millions of avoidable deaths in the Third World every year.

Development Chemicals (DCL) basically comprises two Englishmen, one based in the UK and the other in the US and India, both with PhDs in chemistry and over 30 years of experience of process development. They are aided by a network of development partners in the UK, India and South Korea and an office in China.

Dr Peter Nightingale is a synthetic chemist with particular expertise in large-scale operations based on chlorination and hydrogenation. Essentially an applied chemist in the German sense of the term, he began his career as R&D director of Coalite in Chesterfield, after a PhD at UMIST. In 1985 set up SynProTec, a company that, very unusually in those days, specialised exclusively in process development for the agrochemicals and pharmaceuticals industries.

SynProTec expanded to the point where it employed some 50 people. With support from the private equity firm 3i, built a small custom synthesis plant, aiming to become a full-service fine chemicals company. Unfortunately, when Merck cancelled a key development project - the first they ever pulled in Phase III - 3i lost interest and eventually sold the company to Dishman, which still runs it as part of CarboGen Amcis.

Nightingale left in 2005 for the US, where he undertakes consulting projects as well as running DCL with Bryant. For example, he has just agreed to advise the Hikal Group on running its contract R&D facility, Acoris Research in Pune, India.

Dr Rob Bryant is an organic chemist by background. Originally he was with Sterling Organics. It was here, he says, that he first learned "the joy of developing robust, scalable chemical processes". His first project led to the manufacture of a metoprolol intermediate on tonne scale within a few months, which convinced him that developing processes for the fine chemicals industry was what he really wanted to do.

Bryant - Pharma industry has lost its process development skills

For nearly 20 years, Bryant has been mainly a consultant, starting the fine chemicals consultancy Brychem in 1992 and the agrochemicals publishing business Agranova in 1997. During this time, he worked with several major players, notably Farmahispania in Spain from 1992 to 1999 and the chemical R&D group of SK Corporation of Korea - which is not the same as SK Energy & Chemical - from 1999 to 2005.

Here, he worked on chiral intermediates for generic products as the innovator product approached patent expiry and developed many interesting materials. As well as being a fascinating project in its own right, Bryant says, the work gave him a lot of insight into how the generic pharmaceuticals industry could improve its record on process development.

Although still spending much of his time as a consultant and agrochemical publisher, in 2008, he was looking for the chance to do something that would do more than earn him a consultancy fee. Bryant joined DCL, which was at that point a shell company that Nightingale had set up the previous year. "The concept of DCL is to take chemical process development seriously and give companies the opportunity to call our bluff," he says. "Our basic belief is that we can improve most processes."

During the rapid development of new APIs, Bryant points out, chemical processes are not very well developed and are often not even very well optimised. This is in stark contrast to what happens in the agrochemicals industry, which is very price-sensitive. Here, the cost of active ingredients can be critical.

Manufacturers of established pharmaceutical fine chemicals, he contends, need to adopt a similar mindset so as to improve processes and reduce costs. The lower costs of outsourcing to Asia cannot continue do this. And the investment required is modest compared to the potential savings. All this is pretty much undisputable. So why is the pharma industry so bad at process development?

The usual reason is that process development is rushed through in order to get a candidate on the road to market while the patent clock ticks. Timing is more important than cost at this stage and process chemistry is seen as a small cost. Once a project has started, there is simply no time to do exploratory work; the need to make material quickly is paramount. Consequently, the whole industry has lost its process development skill.

DCL founder Peter Nightingale is currently in India consulting for Hikal on Acoris

With the blockbuster model dying, however, Bryant believes that it is time to look at process development earlier on. "The pharma industry grew like mad for years. Now it is at the point of looking at the whole way it does things and people may be ready to listen to us now," he says. "We don't expect to change the world but we are good at taking a process apart and finding a way to improve it."

The means are simple, often echoing the ACS's well-known 12 Principles of Green Chemistry. Chemists and engineers collaborate to develop new processes for both established products and novel targets. Waste is eliminated by using catalysts rather than equimolar reagents, reactions are sped up by using reactive reagents and better equipment, isolations are minimised and unnecessary purifications are eliminated.

DCL has already contributed to several projects. These include: a key chiral intermediate for a developmental API that has reached Phase III, with 50 kg being made in India using DCL technology; meeting the process cost target for making the API for R-praziquantel with WHO funding; a chiral version of a known drug with a manufacturing process that cost much less than the commercial racemate; and, producing a small volume API for a major drug company in an Indian GMP plant from chiral starting material sourced in China, both using DCL technology.

The network of collaborators came together through personal contacts. It begins with Creative Chemistry, another recently formed two-man operation that works on early stage chemistry development with clients from across the pharmaceuticals industry. Dr William Jackson and Dr William Hems are very talented chemists and it was the combination with them that gave us the confidence to say that we can usually reduce the costs of a process by at least 20%, often much more" says Bryant.

Drs William Jackson and William Hems of Creative Chemistry have worked with DCL on early stage chemistry

Also involved at the development stage are Knowchem Laboratories, which makes basic non-GMP intermediates in Pune, India, CLS Laboratories of Korea makes intermediates, notably for anti-cholesterol APIs, for impending generics using highly sophisticated chiral chemistry, and High Force Research of Durham, UK, a CRO specialising in chemical synthesis and R&D for the pharmaceuticals, biotech and fine chemicals industries.

Nightingale knew High Force founder Bob Redfern well and took a small-scale GMP project there. This is expected to be scaled up by Acoris, which was originally founded as a GMP R&D centre for Hikal by former Höchst and Clariant executive Dr R. Helmut Rupp. Mumbai-headquartered Hikal is one of the network's two potential API partners.

A more recent addition in China has been Porton, which is based in Shanghai and manufactures in Chongqing. Bryant, who also organises workshops on agrochemical process technology as part of the summit that Chinese market consultancy CCM International organises alongside the China Agrochemical Conference every March, sees China as pivotal. "The low manufacturing cost 'buck' stops with China. There is really nowhere else to go now," he says.

Most fine chemicals of over 1,000 tonnes/year volume could equally well be made in the West, Bryant contends. Labour is a small element of the cost - barely 2-3% in the case of paracetamol. Curiously, however, production of steroids and prostaglandins, where labour costs are more like 40-50% of the total, has been coming back to Western Europe.

The longer term dream is of building a plant to make a small range of key APIs for malaria and other serious tropical diseases which are currently neglected. This grew out of experience in working with agencies that develop and supply medicines for the poorest regions of the world, notably the Swiss-based Medicines for Malaria Venture, for whom DCL managed to develop a 60% cheaper process to make racemic mefloquine hydrochloride. It aims to be making this by Q1 2012.

The company has now put together a business plan for setting up a low cost API unit and is hoping to secure funding from an agency with a long charitable record. The facility would carry out the final cGMP stages, with regulatory starting materials coming from the existing network - and hopefully also becoming a centre of excellence in process development. It would take a radically different approach to costing.

DCL aims to fund a low-cost API facility to treat common diseases in poor countries

"Sustainably reducing API costs to their absolute minimum requires a combination of two things: the most cost-efficient technology and a cost-plus API production unit," says Bryant. Where fine chemicals companies produce on a 'cost plus' basis, existing API producers, like pharma, tend to operate on a 'market price minus' basis of what the market will stand and so is not financially structured to do this.

Morally, the case is unarguable. In the Third World, for lack of affordable drugs - among other things - malaria alone avoidably kills thousands of people every day. Meanwhile, the pharmaceuticals industry continues to operate on a model that makes it more worthwhile to treat the conditions of the 'worried well' of the developed world. This - and the underlying problem, the grotesque, rapidly growing gulf between rich and poor - is the worst scandal of our time.

The pharmaceuticals industry's patchy record at reducing the cost of existing products is a big part of the problem. This is partly, of course, because the blockbuster model meant that it never had any incentive to improve process chemistry, though also partly because the way the patent system works means that generics companies gain more by being first off the blocks and fighting legal battles than by developing better manufacturing processes.

But can DCL, a two-man operation with a small, if global, network of contacts, actually put something on the ground that can address the issue? Bryant believes that it might. The current situation in the Western pharma industry is favourable, given the huge availability of high quality used manufacturing plant and, just as importantly, the motivated and talented people who have fallen victim to restructuring as Big Pharma sheds them by the thousand.

"We firmly believe that such a venture will be worthy of financial support and will be in effect an attempt to use enlightened market forces by using the standard manufacturing model of sales price equals cost plus margin," he says. "The current pharma model of 'what will the market stand?' works well for the industry and the developed world but is a disaster for poor individuals and countries, where the market will 'stand' a child dying of malaria every 45 seconds."

 

 

From Online Issue: December 2011