The US Food and Drug Administration has approved a substantially lower number of drug formulations containing new molecular entities (NMEs) in the past decade (1). In 2008, the agency approved formulations containing 21 NMEs and four biologics, slightly higher than the 2007 total of 17 NMEs and two biologics. The growth between 2007 and 2008, however, was not enough to counter the marked downward spiral of drug approvals during the past 10 years (1). Behind the trend may be tightening safety standards, the complexity of clinical trials that have escalated drug-development costs, and even perhaps a shift in emphasis as pharmaceutical companies move away from truly innovative solutions toward more complex therapeutic profiles.

An additional barrier to the development of new drug formulations is that, in some cases, active pharmaceutical ingredients (APIs) that show promising activity in animals or in vitro biologic systems fail to show sufficient efficacy in human clinical trials. In some cases, this discrepancy may be due to a lack of bioavailability and desired effect at the target site in the human body—properties potentially linked to the specifics of the formulation.

The choice of excipients also can be a critical factor for developing clinically efficacious drug formulations. The current regulatory environment both inside and outside the United States, however, strongly discourages development of new excipients, limiting the choices to those already approved. The International Pharmaceutical Excipients Council of the Americas (IPEC–Americas) has proposed specific regulatory changes to encourage new excipient development which, if adopted, could expand options for API formulation, potentially removing this formidable barrier to drug development. IPEC–Americas also developed an independent excipient review procedure, the IPEC Novel Excipient Safety Evaluation Procedure, which can serve as a temporary solution to this issue until the council's proposals are implemented. These efforts resulted in the evaluation of at least one novel excipient, Solutol HS 15 [Polyoxyl (Macrogol) 15 hydroxystearate manufactured by BASF, Ludwigshafen, Germany). The development of procedures for independent safety evaluation and its application to Solutol HS 15 are described in subsequent sections of this article.

In the long term, new paradigms are needed to evaluate excipient safety. The FDA guidance on the safety evaluation of excipients details safety tests generally required to establish safety of a novel excipient, which are strikingly similar to those required for a new drug (4). However, unlike drugs, excipients are designed to be pharmacologically inactive and these tests may be excessive for safety evaluation, thereby representing a potential barrier to innovative development of new excipients.

Current regulatory status of new excipients

Under the current paradigm, even though excipient innovators are able to adapt to new procedures and are willing to invest in development and safety-evaluation costs, novel excipients are not finding their way into drug products. Understandably, drug-product manufacturers are risk-averse because of the large investments required for drug development. Despite these challenges, the expanding FDA Inactive Ingredient Database (IID) suggests that the demand for new excipients is strong. The IID lists excipients used in approved drug products, their route of administration, and their maximum dosage (i.e., maximum potency per dosage unit). A regulatory system with a strong, predictable excipient safety and efficacy evaluation could potentially lead to an explosion of new choices for drug formulators.

Under current drug approval processes, novel excipients are not independently evaluated; they are only reviewed in the context of the first drug application containing the excipient. There is no regulatory approval process specifically for a new excipient as a unique molecule. Globally, the International Conference on Harmonization (ICH) does not have specific excipient safety evaluation guidelines, but FDA guidance on excipient safety evaluation cites several ICH safety-testing guidelines (e.g., ICH S1A, S2B, S3A, S5A, S7A and M3) as reference materials for the conduct of safety tests (4).

According to FDA and ICH definitions, an excipient is considered "novel" if it is used for the first time in a human drug product. Although FDA maintains the IID, none of the US nor ICH standards distinguish between new chemical entities and minor modifications of approved excipients, coprocessed mixtures of existing excipients, approved excipients proposed for a new route of administration, or excipients approved for use in foods or cosmetics. Some of these excipients may not require the full battery of tests listed in the FDA guidance on excipient safety evaluation (4). In these cases, excipient and pharmaceutical manufacturers must predict what the reviewing agency will require upon review of the drug application. If the manufactuer is wrong, the consequence could be significant delays in drug approvals or rejection of the drug application. Most drug manufacturers are wary of this process and therefore rely on excipients already used in approved drug products for their formulation needs.

In 2007, the IPEC–Americas Safety Committee proposed and developed the IPEC Novel Excipient Safety Evaluation Procedure, which is an independent excipient review procedure. This process was anticipated to reduce the cost and uncertainty related to the use of novel excipients in pharmaceutical formulations, thereby encouraging their use in drug-development programs and providing a needed boost to drug formulation innovation.

The Aclairo Pharmaceutical Development Group (Aclairo PDG, Vienna, VA) manages the Novel Excipient Evaluation Committee (NEEC), an independent expert group of IPEC charged with conducting the safety evaluations of new excipients. The committee has successfully evaluated one excipient, Solutol HS 15, and is in the process of reviewing others. Two authors of this paper (R. Osterberg and W. Brock) serve on this expert committee.