Chemicals & raw materials

The FDA announced a pilot programme for a separate regulatory process for excipients in 2019, and an update is expected in the summer of 2021.

excipients: they can be naturally occurring, synthetic or semi-synthetic, and sourced from, among other things, mines, plants or animals. The profile of castor oil, for example, could differ depending on the region from which it’s sourced. That variability, Sheehan says, “can cause a lot of issues for formulators if they do not understand that it is very critical to select, and understand your sourcing and your composition”. That complexity is part of the reason that developers tend to shy away from experimenting with inactive ingredients that could improve their products’ performance, but it’s far from the whole story. At least as important is the FDA requirement that applications for novel excipients be made as part of the approval process for new drug products.

Risk against risk

The lack of an independent pathway for the regulation of novel excipients acts as a brake on innovation, says Brian Shoichet, professor of pharmaceutical chemistry at the University of California, San Francisco. “The regulations involving excipients make developing new excipients very expensive, and that’s meant that excipient development is a dead field or, at least, moribund,” he explains.

Adding a novel excipient to a new drug creates a “lot of added risks”, says Sheehan. The main one is “the risk of rejection of the drug if it’s going through the drug application process”. Sheehan points out that the cost of a drug application can be up to $1bn, so any potential delay caused by adding a novel excipient, which is only a small part of the investment in drug product development, is hard to justify. Most drug developers would prefer to wait for someone else to go through the approval process first.

The impacts of this are wide-ranging. In an online survey of 264 drug formulators carried out by USP in 2019, 84% of respondents said that currently used excipients have imposed limitations on drug development. In over half the cases, the reason was because the chosen excipient wasn’t currently used in any FDA-approved drug at the selected dosage – in

World Pharmaceutical Frontiers /

other words, it would have to go through an approval process. Faced with that, many manufacturers choose to try and reformulate their entire product for the US market. Other reasons included the inability of available excipients to maintain stability or to overcome bioavailability, solubility or permeability issues in the final drug product. Some fixes for these issues are obvious.

“The bar to using a novel excipient is high,” wrote one survey respondent. “It would be helpful if the agencies could more explicitly differentiate between truly new excipients and those which are already used in other products (for example, foods, consumer products) but are just new to drug product use.” The deterrent to innovation is particularly strong in drugs that have a riskier route of administration, such as injections, says Sheehan. In such cases, there is much greater burden on the formulator to carry out additional safety and toxicological reviews, which translates directly into extra costs and longer development timelines. Occasionally, a drug manufacturer will introduce a novel excipient to address an unmet need. Sheehan cites Pfizer, which incurred a lot of additional expense in toxicological and safety evaluation for the approval of a new excipient for use in an otic drug. Otherwise, however, manufacturers must draw on the limited set of approved excipients in the United States Pharmacopeia National Formulary (USP-NF), not all of which will meet the precise needs of a particular drug and, given their limitations, could actually prevent developers from bringing new therapies to market. “If you’re using the same excipient over and over to solve stability and solubility problems – using the same excipients and expecting a different outcome – there’s no innovation there,” points out Sheehan. “There’s no thinking outside the box in terms of what other types of excipients could be better.” Established excipients can still be functional in new therapies, but the speed of development in the latter category is increasing the need for innovation in the former. “With these old excipients, traditionally some


Excipients in FDA’s inactive ingredients database that have been found to interact with enzymes and receptors in the human body. Science



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