Commonly inert pharmacologically inactive ingredients, excipients are added to the active pharmaceutical ingredient (API) to act as diluents, stabilising and bulking agents, disintegrants, colouring agents, solubility agents and, increasingly, to manage bioavailability issues such as ensuring a biocompatible dosage form.
However, their very ubiquity and the reliance of the industry on them as one of the bedrocks of product formulation may, somewhat counter-intuitively, be acting as a drag on pharma’s ability to innovate and ultimately achieve full commercial and formulation potential.
According to Keith Horspool, vice-president of pharmaceutical development at Boehringer-Ingelheim, there are a number of problems at play here which, increasingly, the pharmaceutical industry and regulators are going to have to debate and solve.
"First, we need to go beyond using just what is available to further the availability of new excipients; some are being under-utilised and there is an issue around collaboration and sharing of knowledge," explains Horspool. "But an even bigger issue is that we do not have enough excipients, and manufacturers that are developing excipients are struggling to get them approved.
"There are some key reasons for this: a combination of the regulatory environment and the economic climate, and a resulting reluctance among pharmaceutical companies to take the risk or make the investment required. Excipients do not have any independent regulatory status; they have to be approved as part of new product registration. So that, of course, can mean a long development time. When you consider you are developing a new chemical entity, it can take 12 years or more."
Managing the excipient problem
Some excipient providers are working with partners independently and some are being creative, for example, working with generic providers to develop generic versions of compounds and then underwriting the excipient, but it is a tough problem.
"A lot of people are still trying to figure out what the best forum is," Horspool explains. "Some excipients have been in development for 12 years and they are still only in phase III. So you can naturally get providers turning around and asking: ‘Yikes, is this a good business model for us to be in?’"
Financial constraints make it very difficult now for any company to take it on. Excipient providers themselves cannot fully fund it, given the time frames. It is a new chemical entity and it is a new material so a very risky bet when it is all on one product.
"It’s the contrast between a firm looking to make a lot of money from another blockbuster versus an excipient provider that has to put in millions and then wait for years to make a profit," Horspool explains.
The issue of collaboration and knowledge sharing is also becoming increasingly critical. Excipients have a pivotal role in a deeply competitive, commercial environment as, essentially, they are often the difference between an expensive drug becoming viable for market or not.
To that end, it is not hard to see the value – monetary and otherwise – that gets attached to excipients and, therefore, the reluctance on the part of many pharma companies to share information and knowledge, even if that sharing, ultimately, will be to their collective benefit.
"As an industry, we need to work together and identify what is needed to share information about new materials. The Vitic Excipients Database, for example, tends to be for existing materials," Horspool says. "We need more collaboration and more collective lobbying about the regulatory side and then more load sharing around some of the information that is generated and some of the costs. Then we can really move this forward to get more materials coming through.
"Looking at biologics. You would not have a certain range of treatments for conditions such as prostate cancer if you did not have new materials and polymers. The whole biologic space, in fact, could do with a lot more materials within it. The bottom line is we have to put an emphasis on working together and trying to enable more materials to be developed and more open innovation; we need to see more companies working together rather than individual companies always taking the risk.
Pharma’s competitive advantage
This is a sensitive landscape, and there will always be commercial and competition issues to take into account. But, at the end of the day, many research organisations already work together and even develop new targets together. In chemistry, too, there always has to be a lot of sharing and openness.
"If they can do it, why can’t we do it with excipients, which are, after all, enabling and enhancing?" Horspool asks. "We need a different database to The Vitic Excipients Database, one that has more analysis in terms of current availability. But, more widely, what we really need is to drive more partnership between pharma companies and vendors. It is about people coming together and looking at where the gaps are and working collectively to develop new materials."
Things have moved forward in the past decade but, if the industry is going to drive the next generation of new materials, it has to keep evolving from where it is right now.
"We need to be sitting down and figuring out where there are opportunities for creativity, for collaborative effort, so that we can develop strategies that can bring forward new materials," Horspool says.
"On top of that, we need to work to change the regulatory environment so that we can get independent status for these materials; that has to be one of the most important ultimate goals. At the moment, there is just not the incentive for companies to drive these materials.
"There needs to be more collaborative effort between pharma and providers to develop the next generation of excipients; things need to be less retrospective. We can, of course, use the knowledge and expertise that we currently have, but on top of that I think there is a real opportunity to work differently, work together, to develop close partnerships and change how we approve and adopt new exipients."
