Excipient safety evaluation: a new paradigm
Excipients received a great deal of notoriety in the early 1930s. At that time, a chemist at the Massengill Company used diethylene
glycol (DEG) as a sweetening agent for elixir of sulfanilamide as the "teaspoon of sugar to help the medicine go down" because
the elixir was somewhat sour for use in children. A principle in toxicology introduced by Paracelsius about 500 years ago
was "Omnia venenum sunt, nec sine veneno quicquam existit; dosis sola fcit ut venenum non sit," which, literally translated, states that "all substances are poisons; there is none which is not a poison." This concept
continues to be a basic tenet in the field of toxicology. The Massengill Company at the time had not completely investigated
the potential toxicity of DEG. Hence, many children fell ill to the kidney toxicity associated with this compound, and many
of those children unfortunately died (8).
Based on this tragic incident, the 1938 amendment to the Food, Drug, and Cosmetic Act was promulgated, essentially requiring
that the safety of a drug be demonstrated before marketing. In spite of this regulation in the US and the incident that occurred
in the 1930s, additional incidents of DEG contamination occurred internationally in the 1980s and 1990s. An important consideration
with regard to these incidents, however, is that the safety of the drug substance was not in question, but rather the safety
of the excipient had not been demonstrated before use in the drug-product formulation.
Indeed, the regulatory environment for the approval of excipients has not kept pace with the innovations observed in the pharmaceutical
industry. Except as associated with the submission of an NDA for a new pharmaceutical that contains an innovative excipient,
there is no regulatory process for the independent approval of the excipient.
During the past two decades, regulatory allowance of an excipient occurred only through the use of the material in a drug-product
formulation. Hence, with approval of the drug product came acceptance of the excipient (excipients are not approved but their
use is allowed). That excipient could be used subsequently in other drug products up to the concentration and duration used
in the previously approved drug formulation. Moreover, the excipient could be used in a new drug product for a different route
of administration only if toxicology data generated via that route was accepted by FDA. P. Baldrick proposed that a guidance was urgently needed for excipients, and further suggested
that this would be a useful topic for ICH consideration (9). This suggestion was not a new concept as several years before,
Steinberg et al. proposed a testing scheme for the evaluation of new excipients and that testing scheme was ostensibly similar
to that used in the evaluation of a new drug substance (5). In that paper, the authors described a nonclinical program for
excipients based on the oral route of administration because most drugs are approved for oral use.
Baldrick's paper was followed by several publications, each further indicating the need for a regulatory process for excipients
as well as a proposal for how to manage new excipients. In 2003, G. Pifferi and P. Restani suggested that new excipients be
evaluated much in the same way as food additives (i.e., by the International Toxicological Committees such as the Joint Expert
Committee on Food Additives, a committee of the World Health Organization) (10). The authors demonstrated that there are a
large number of substances that can be used as excipients with a very diverse chemical profile, sources, technological functions,
and so forth. The Pifferi/Restani paper of 2003 followed a 1999 paper describing the need for standards of characterization
and quality review, just one more aspect needed for a regulatory framework for excipients (11).
Also in 2003, at the American College of Toxicology annual meeting, a symposium on issues associated with food and excipient
safety was presented (12). M. Steinberg and I. Silverstein reviewed several concepts for addressing the regulatory status
of new excipients but clearly noted that there was no regulatory process in the US compared with what had been established
in Europe and Japan (13). Osterberg and N.A. See subsequently described the testing paradigm of what had been recently published
draft guidance from FDA on excipient testing. In that guidance, which was subsequently approved (14), the various toxicity
studies needed for a new excipient are outlined.
Overall, the guidance is similar to what Steinberg et al. had proposed several years earlier in 1996 (5), although the provision
for safety pharmacology studies was included in the FDA guidance. Regardless, a provision for a stand-alone regulatory process
remained elusive. As described above, IPEC–Americas established an expert working group to review the safety of new excipients
based on testing, and proposed to FDA that the studies represent good science and excipients should be allowed in drug products
without going through a regulatory process in conjunction with a drug approval. Because of the absence of a regulatory process,
the innovation of new excipients has been restricted. Moreover, because of the costs associated with a standard toxicity
program for a new excipient, innovation and development have been limited (see Table I).
Table I: Estimated costs of a typical toxicology program.
The IPEC program described is a typical toxicology program with costs based on 2009 pricing of studies within the contract
research organization (CRO) industry. Moreover, the costs reflect a basic study design and do not include toxicokinetic assessment
which could add about 5–10% of the total cost. In addition, to initiate the 90-day studies, shorter-term repeat-dose studies
would be needed to assist in setting dose levels. The added costs for these studies could approach $200,000. Finally, the
costs associated with this program do not include discovery, development, and manufacturing costs for the new excipient.
The undertaking of a toxicology program represents a risk to a business, but in the current regulatory environment, such a
program is needed. There remains an option to the excipient development process that does not require such an outlay of resources
early in the development phase. Lessons learned from the drug discovery and development process may be helpful in toxicological
screening of excipients for use with active pharmaceutical substances.