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Bespoke Services

Tony Flinn at Onyx Scientific Ltd explores custom synthesis, its challenges and how to get the most out of the partnership it requires

Custom synthesis is the generic term for a range of services whereby a supplier company makes, under contract, a specific chemical compound or class of compounds for a sponsor company. This usually includes quantities from a few milligrammes to multiple kilos. Sponsor companies are very diverse but pharmaceutical and agrochemical companies have a more mature history of outsourcing custom synthesis projects. Often, custom synthesis is employed to obtain compounds that have previously been made at a small scale in a research programme and are needed in greater quantities as the product moves through development. Researchers are best at research and repeat synthesis is unlikely to be the greatest use of their talents; hence outsourcing to specialist suppliers is often favoured. Moreover, specialist suppliers are more likely to have the appropriate facilities for scaling up a process, and as a result are better suited to making larger quantities.

CUSTOM SYNTHESIS

As an example of a custom synthesis programme, consider a pharmaceutical company that screens thousands of compounds against a specific biological target. Typically 20,000 chemicals are made or screened in order to produce one commercial drug. During the discovery phase a few milligrammes are needed. If the compound shows initial promise gramme quantities are produced and, if good enough to enter preclinical development, the compound might be needed in the 100g range. Clinical Phase I needs about one kilogramme of the drug, Phase II needs about 10kg and Phase III about 100kg. Commercialisation of course could require substantially more and, although commercial production is occasionally classified as custom synthesis, this article will concentrate on small scale.

Custom synthesis also includes the manufacture of impurities, metabolites and competitor compounds, as well as radio- and stable-labelled compounds. A process or ‘recipe’ may be provided by the sponsor, or alternatively, a reference to literature on synthesis of the specific molecule or a related one. Alternatively, only the chemical structure is supplied with the assumption that the supplier company will come up with its own method of synthesis. Clearly, the more information supplied by the sponsor, the more precise the supplier can be about prices and timing. If little information is supplied, or the compound has never been made before, or reference is made only to patents, the supplier’s alarm bells begin to sound. As any chemist will know, producing compounds that have never been made before can take a long time. If a proposal is made based on the assumption of, say one month’s work, and the initial route used is unsuccessful, alternative routes have to be tested. This will prolong the project and the customer, having been promised a specific delivery date, soon begins to lose patience and the supplier starts making losses.

Research chemists often use the most convenient method available to make a compound – as their prime focus is the compound itself, not its route of synthesis. Scaling up the original process might not be possible on safety or cost grounds so the scale-up chemist invariably has to look at alternative methods to employ. Even scaling up a process that has been run successfully on a small scale can be fraught with problems, as scale impacts on the results. For example, impurities are often higher at a larger scale as it takes longer to heat and cool a reaction, and side reactions have more time to occur.

The primary aims during process development and scale-up are to increase yields and throughput, and to make the task practical. Process development makes processes robust and reproducible, of course, an absolute requirement is that the processes are safe. Moreover, by eliminating expensive reagents, costs can be minimised. The supplier will try to eliminate toxic reagents, avoid chromatography and minimise waste. Solvents will be chosen with regard to their residual effects and for new drugs, ICH guidelines are followed. A good supplier will try to convert stoichiometric processes to catalytic processes.

RISKS INVOLVED

When making a proposal the supplier company needs to fully consider the risks involved. How confident are they in the chemistry? Are there backup methods available if the preferred route doesn’t work? Is the repeat scale considerably larger than previously run? For example, a 10-fold increase calls for a caution approach; 100-fold increase in scale needs even more caution and the difference becomes more acute the larger the scale operated. Experienced scale-up and process development chemists will have a good feeling for the risks of a project and if these seem too high it is not unusual for the supplier company to decline the offer. In these circumstances, a sensible sponsor should be willing to fund a full-time equivalent (FTE) arrangement where the supplier company works for a specified time with no guarantee of producing the goods.

Working from patents is extremely dangerous for supplier companies as patents often deliberately obscure the real methods or are purely figments of the imagination and have never actually been made. Sometimes an obvious analogue cannot be made by the method used for a similar compound. The sponsor company must also consider their risks. They might wish to split supply between two suppliers. If the synthesis is on a critical path, delays in receiving the compound can be problematic. Therefore it is in their own best interests to provide as much information at possible. Despite this, it is often the case that suppliers reinvent the wheel, or reinvent the fact that the square wheel doesn’t work: the sponsor has missed sending a crucial piece of information that would have prevented the supplier from wasting their time. Nevertheless the customer is always right, aren’t they?

There are many custom synthesis companies operating worldwide, ranging from a small laboratory-based company in a university environment, to multi-service companies operating at a range of scales. University-derived companies can do the basics but process development and scaleup are beyond their experience. Genuinely experienced companies with strong technical ability are available in most developed and developing nations. A linear custom synthesis of multiple steps can easily mean that the early steps are of a much larger scale and beyond the capabilities of some companies. By way of illustration, a 15-step synthesis to make 10g of a product with a molecular weight of 400 and a 60 per cent yield for each step needs to start with at least 10kg of the starting material with a molecular weight of 200, and if research dilutions are used, in about 1,000 litres of solvent. Clearly it is important for the supplier company to spend some time developing the process. However, there is often great pressure to simply reproduce earlier chemistry and carry on with inefficient processes. It takes a mature company to resist the pressure of a sponsor company and (in effect) add to their costs, in the short term at least.

WESTERN OR OFFSHORE SUPPLIERS?

Cost is always an issue. Business analysts tell us that cost is not a driver for certain industrial applications. Do not believe them. Cost is the prime reason why the dye manufacturing industry has almost completely disappeared from our shores and the reason why all manufacturing moves to a cheaper supply base. Western suppliers are more expensive than companies based in developing nations, although the gap is getting smaller and, when productivity is taken into account, the gap narrows even more. The principle countries in this analysis are India and China. Salaries are the major cost in a custom synthesis business and are much lower in developing countries. Some sponsors are rightly concerned about putting valuable IP to companies in developing countries because of confidentiality and IP protection. Moreover, communication can be a problem. Infrastructure can inhibit productivity as delays in securing raw materials’ impact on timelines.

In the west we are proud of our safety and environmental record. The overused phrase ‘a level playing field’ often doesn’t exist between east and west, particularly where safety and environmental costs are concerned. Without acting with the necessary due diligence, it is advisable to deal only with those larger and more established companies in order to ensure best safety practices are in place and that waste is treated responsibly.

ADDING VALUE

Real custom synthesis isn’t just about paying a few dollars for a compound; the better companies will add considerable value. Some process development done alongside the synthesis, including perhaps new process and safety information, can save you time and money and add real value. An unofficial partner is a valuable asset and a natural extension of your facilities whichever industry you are in.


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Tony Flinn is Chief Executive Officer of Onyx Scientific Ltd. He is a trained scientist with a BSc and PhD in Chemistry, and has worked for several companies in various roles. Starting as a research chemist, he then moved to development chemistry and technical management roles. Thereafter he held several sales and marketing positions, before founding Onyx Scientific Ltd in 2000. Tony has written in over 25 scientific publications and has one patent to his name.
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