A bitter pill to swallow – the excipient approval process

1 October 2014



The current practices for new excipient approval by regulatory agencies are grossly inefficient and hinder innovation. As many drugs’ patents expire, the excipient market is growing, and yet excipients lack independent approval processes separate from the drug. Natalie Healey asks Dr Chris Moreton from IPEC Americas what changes are necessary, and he discusses how investment in novel excipients may solve drug delivery challenges in future.


Excipients are a curious subject. Once the most neglected segment in the pharmaceutical industry, interest in these inert carriers of active pharmaceutical ingredients has recently picked up pace. Forecasters at BCC Research predict a 6.9% annual growth rate for the market over the next five years.

It's partly due to the trend for new drug candidates to possess larger molecular weights, which in turn reduces their solubility. In order to get these novel pharmaceuticals to their sites of action, more sophisticated formulation approaches are needed. After all, what good is an efficacious drug if it can't reach where it's required?

A few decades ago, this pharmacokinetic conundrum wasn't so relevant, but now, with around 70% or more of new chemical entities requiring some help to increase their bioavailability, the spotlight is on excipients.

Empty vessels

"Excipients have always been assumed to be inert carriers, so why would anyone worry about them?" poses Dr Chris Moreton, a board member of the IPEC Foundation, who has over 30 years' experience in the pharmaceutical industry. "Well, I think we're learning that they're much more than that. Without them, sometimes the drugs just don't get absorbed."

Take potent immunosuppressant ciclosporin, for example. Originally available from Sandoz and marketed as Sandimmune, it was formulated as a self-emulsifying drug-delivery system that just about got the drug absorbed. But the results were highly variable and ultimately unsatisfactory for patients. Eventually, Novartis introduced a self-microemulsifying system called Neoral, which gave it more consistent absorption properties. An alternative formulation (and excipients) was game-changing in this instance.

"It’s a pharmaceutical catch 22. Drug companies will not use excipients in their products that haven’t been approved. But the FDA will not approve an excipient unless it’s been included in an approved drug product."

Lipid-based drug-delivery systems like these aren't bad options for some APIs, but they're not suitable for every drug, and the industry desperately needs alternatives in the formulation sphere. With many blockbuster drugs due to come off patent in the next few years, Big Pharma should be looking to novel excipients to accompany the born-again generics. But despite this trend, and the role excipients play in getting drugs to patients, Moreton believes there are many roadblocks for companies that would otherwise look towards developing them.

"New excipients are still a quandary," he reveals. "A lot of people would be interested in developing them, but it's a major issue for people to accept them without some kind of approval from the regulatory authorities."

"And the pharmaceutical industry is so conservative that if it's not been approved by the FDA, you can't use it, which puts a considerable block on the introduction of novel excipients," he adds. "That's part of the problem. Everybody's in a rush to be second. Nobody wants to be the first."

It's a pharmaceutical catch 22. Drug companies will not use excipients in their products that haven't been approved. But the FDA will not approve an excipient unless it's been included in an approved drug product. Consequently, there's no incentive for organisations to invest in what's not the active ingredient. Development pipelines for new excipients are too lengthy when considered on top of the development timelines for the drug. And, depending on the type of pharmaceutical, the excipient could well be out of patent life before it reaches commercial sales.

Copy capsules

"The sincerest form of flattery is imitation, and people will imitate," says Moreton. "Generic copies will come out before you've made any money."

One exception seemingly worth the risk however was Captisol by Cydex, he reveals. Sulphobutylether beta-cyclodextrin, its chemical name, was invented in the University of Kansas Higuchi Bioscience Center. Pfizer was the first to use the compound for its anti-fungal drug Vorivonazole, which the company desired in an IV formulation.

"Pfizer took a big risk, but they wanted an intravenous form of the drug, and this was the only thing they found that worked. So they had an overriding technical need," points out Moreton.

Unfortunately for patients, scenarios likes Captisol are rare; but some organisations are working towards an excipient approval system, which could give pharmaceutical companies a reason to invest in new formulations in future.

A major player in this initiative is the International Pharmaceutical Excipients Council (IPEC) Federation, the industry association that develops, implements and promotes global use of appropriate quality, safety and functionality standards for pharmaceutical excipients and drug-delivery systems.

The IPEC-Americas Safety Committee published proposals for the rational safety and toxicity testing of pharmaceutical excipients in 1996 (Steinberg et al).

"That wasn't official; it was voluntary. But I do think that Cydex and Pfizer used it as part of their discussion with FDA to get Captisol approved," reveals Moreton.

In 2007, the same group proposed and developed the IPEC novel excipient evaluation procedure. The goal was to provide an independent evaluation of the safety and regulatory acceptance of a new excipient before a regulatory filing. The independent review process is meant to mirror that of the regulatory agencies and provide confidence to pharmaceutical manufacturers that the excipient-safety data package would be acceptable to the FDA and that the excipient will be acceptable in their formulations. However, again it is not official and thus does not overcome such objections.

Moreton reveals that there is an initiative from the IQ Consortium in the pipeline, supported by IPEC Americas. It's an excipient approval process that would actually be overseen by the FDA and have associated user fees. They're still discussing, he says. However, it would require approval by the US Congress for the proposal to be introduced.

This may sound a cumbersome undertaking, but the US is way ahead compared with much of the world. Take Europe, for example. The EU and national regulatory authorities are doing even less to encourage innovation, according to IPEC. The organisation is continuing to press for the introduction of an excipients master file system, the absence of which is putting the EU regulators out of line with the US and other developed countries. The use of master files allows manufacturers to protect their confidential know-how, processes and methods, and manage their own product information.

Help the medicine go down

Despite the immense difficulties for novel excipients, manufacturers have some reason to be optimistic. Patent expiry will bring innovation in one category of the chemicals: co-processed excipients. Here, two or more existing excipients are combined or particle-engineered in special ways. The regulatory hurdles are much reduced, compared to their novel counterparts. And in the last two decades, a lot of coprocessed excipients have appeared on the market.

"If I were to be asked by excipient manufacturing companies, whether they should go with a co-processed excipient, or a brand new one, I would have to tell them, even today, that they should go with the co-processed excipient."

"If I were to be asked by excipient manufacturing companies, whether they should go with a co-processed excipient, or a brand new one, I would have to tell them, even today, that they should go with the co-processed excipient," he says.

"The cost of development and the timeframe is so much shorter. And that's exactly what we're seeing. Co-processed excipients tend to get accepted because they can use the safety data from the individual excipients that have been around for much longer."

But it's worth noting that co-processed excipients do not solve all of the issues. Novel excipients that meet stability and compatibility challenges will still be required. Essentially, their co-processed counterparts are only a small step in the right direction.

While a big change won't be on the cards soon, what could the industry expect if an FDA-approved system finally does get the nod in the near future?

"I won't say it will open the floodgate, but it'll certainly open up a small spillway for novel excipients," says Moreton.

Lots of companies have good ideas already, he says. But it's unlikely they'll get their novel excipients to market, because it's just going to take too long. If FDA had an acceptable system that companies were able to adopt, the situation could dramatically alter.

But if there's a catalyst for change, it could well be an unfortunate one. Excipients tend only to raise eyebrows when disaster strikes, such as the adulterated over-the-counter medicine sold in Panama in 2006 where cheap glycerine had been tainted with toxic diethylene glycol with deadly consequences.

"I think it would take some form of crisis to get things moving," admits Moreton. "What that crisis might be, I really wouldn't like to say, and I really don't want it to happen because it would mean patients suffer, and I'm not looking for that, believe me."

In the meantime, patients need novel drugs that are convenient and reliable. And with new drug candidates lacking in drug-delivery power, excipients will play a major role. The pharmaceutical industry can only hope regulators stop underestimating the importance of innovation in this field.

Dr Chris Moreton is a formulation scientist, with experience in innovator, generic and over-the-counter projects as well as working in QA/QC, regulatory affairs and technical support for an excipient and drug-delivery company.


Privacy Policy
We have updated our privacy policy. In the latest update it explains what cookies are and how we use them on our site. To learn more about cookies and their benefits, please view our privacy policy. Please be aware that parts of this site will not function correctly if you disable cookies. By continuing to use this site, you consent to our use of cookies in accordance with our privacy policy unless you have disabled them.