When it comes to the pharmaceutical industry, the old adage "if you want something done right, do it yourself" doesn't necessarily apply. Big Pharma, as well as biotech and drug development companies, rely on an intricate network of partnerships in the academic, business and technical realms to get drugs through the extensive clinical trial process and into the market.
Custom synthesis is one of the options open to drug developers in need of the active pharmaceutical ingredients (APIs) to make their products effective. If it is impossible or impractical for a company to make these molecules and compounds in-house, a chemical specialist that offers custom synthesis will often be brought in to do the job. For the most part, these contracts are carried out under strict confidentiality agreements and strict delivery deadlines are part of day-to-day operations.
Onyx Scientific is a UK-based pharmaceutical service company that specialises in chemical synthesis for customers in the pharmaceutical industry. We talked to the company's CEO Tony Flinn about the trials, techniques and technology involved in operating in this high-pressure market.
Chris Lo: Could you give a short introduction to custom synthesis?
Tony Flinn: Custom synthesis is where a company requires a molecule to be made exclusively for them, at a certain scale. It's custom in the sense that it's dedicated for them, and it's almost invariably done under confidentiality agreements.
Usually the customer defines the quantity and the quality that they need. They may provide a recipe or a process, or alternatively we may have to design our own synthetic route to make it. Custom synthesis can be as low as a few milligrams, or it could be as high as 10 kilos or more. When you go above that sort of scale, it's normally called contract manufacturing.
CL: What are the advantages of a pharmaceutical company contracting an external supplier for a compound?
TF: There are several advantages, potentially. We may have some expertise in a particular area of chemistry or some facilities that the pharma company may not have. With a big pharma company, they obviously have their own synthesis teams in-house; they might well be better served doing research and development work rather than just making something that has been made before. So it's a matter of pharma companies prioritising what's best for their own chemists.
Custom synthesis houses can be less expensive than pharma companies. As you can imagine, the rates of pay at pharma companies are considerably higher than the supplier base. And if they have their own resources in-house, they may have peaks and troughs; when they have peaks they might not have the in-house resources to do the chemistry, so they can look at external suppliers to help them. There are also a number of virtual pharma companies and small biotechs who don't have their own chemistry facilities, and it's a necessity for them to get companies like ourselves to make products for them.
CL: Where does custom synthesis slot into the larger drug development process?
TF: In our company, our major niche is in pre-clinical Phase I. But there are others who get more involved in the earlier stages. If you're in the drug discovery arena, you might only want a few mg of the material for testing. And there are companies who specialise in doing what are called libraries of compounds. That's still custom synthesis, but it's more specialised, small volumes and a large number of molecules. We tend not to do that, we generally focus on slightly larger scale. The scale we naturally operate at fits in with pre-clinical development pretty well.
CL: What are the main challenges of scaling up production from grams to kilos?
TF: Very often, we will get a process or a recipe from either the company or from the literature. Usually it has been done at a relatively small scale, and it has very often been done by a medicinal chemist who has been making the compound for their research efforts. They're not worried about the chemistry that's used, all they're interested in is getting the molecule and testing it to see if it has the right biological effect. They might, for example, use expensive reagents or a root that was quite convoluted as long as it gave them the product in the end.
So very often it's not possible to scale up a medicinal chemist's process, because it might be unsafe to do so. For example, a lot of medicinal chemists will do what's called "all on board" reactions, where you add all of your agents in a pot, and then you heat it up. If you get an exotherm heat generated in that reaction, it's such a small scale they can usually manage it. But you can't do that on a large scale – if you put all your molecules together and generate a large amount of heat it can be very dangerous. So you have to look at the chemistry that's been done and see if that can be scaled up.
It's usually thinking about making things safe, robust and repeatable. One of the things we tend to do is not use the latest reagents. Very often, something more traditional is the better approach than the latest trendy reagent, which has perhaps caught the medicinal chemist's eye. So we'll tend to try and make things as efficient as possible. Quite often a medicinal chemist will use things on a stoichiometric basis, so they'll use one reagent for one molecule on a one-to-one basis. When you scale it up, you try where possible to use a catalytic amount of one material, so you tend to use catalysis more than you do in med chemistry.
CL: In your experience, what do pharma companies expect from providers of custom synthesis?
TF: Speed and reliability are two important drivers. Flexibility is another, as well as strong technical ability. The savvy customers will know that when you're scaling things up, you're always coming across problems and you need good chemists and good scientists to overcome those problems. You need a strong technical company. We have preferred supplier status with a number of our customers, including four of the world's top seven pharma companies. They know they can trust us to deliver on something that might be quite difficult. I guess the downside for us is we tend to get the more difficult projects. It's a double-edged sword, I'm afraid; it would be nice occasionally to get some of the very simple projects where we can just turn the handle and not have any problems. But unfortunately, we've made our bed and we've got to lie in it.
CL: Are you often contracted to deliver a compound at very short notice?
TF: That's the niche that we're occupying. Speed is absolutely crucial, particularly with the biotech companies where we don't want to be on the critical path for their drug development. They very often have very tight timelines and it can be quite a pressure to achieve something. We'd never compromise safety, but we do have a reputation for being able to start quickly and finish on time.
CL: How important is communication when collaborating with your customers?
TF: Communication is vital, and we do tend to over-communicate, but that's not a great problem because the customers know exactly where we are and when they can expect the product. What they won't find from us is if we've said five weeks to deliver a compound, we won't phone them up in five weeks and say, "Oh, by the way, we're going to be late." They will know exactly how we're getting on at every stage. Every week, our customers are informed; whether they want it or not, we inform them as to progress. So there are never any shocks.