Toxicology program considerations.
In the developmental toxicology program, in vitro assays are used to screen for potential toxicity before undertaking more expensive toxicity tests. In this process, a compound
that causes an undesirable toxicity can be eliminated from consideration. This "discovery" program leads to less cost and
allows for a more rapid screening of multiple compounds to select those that represent potential utility as an excipient.
In addition, the discovery program can be developed into different tiers of testing (i.e., as the compound is developed, additional
testing is undertaken to further determine the potential safety of the compound).
In the first tier, a compound is subjected to different in vitro assays to determine the potential genotoxicity, cytotoxicity, and metabolism and the ability of the compound to be absorbed
across biological membranes. At the outset, however, it is recommended that a quantitative structure-activity relationship
(QSAR) model be developed. A QSAR model enables the prediction of various toxicities based on structural similarity to existing
chemicals. Hence, compounds can be easily limited from consideration if structural alerts for certain endpoints are revealed
(e.g., carcinogenicity). There are several QSAR models that have been developed over the years, each with its own advantages
and disadvantages. The model overall is useful for predicting potential toxicity for potentially allowing the use of short-term
bridging studies that could be used to determine the toxicity of the new excipient compared with an excipient that has a more
Following QSAR, it is recommended that the compound be subjected to in vitro genotoxicity and cytotoxicity assays. These studies are comparably inexpensive to the longer-term in vivo toxicity studies. A cytotoxicity assay is valuable to determine the potential for the compound to cause cell disruption, and
such a study is particularly useful if the compound would be administered intravenously. In addition to these in vitro studies, an in vitro metabolism study can be done as a screening assay to determine the extent of metabolism and whether potential reactive metabolites
would be formed. Finally, membrane penetration studies would be conducted. Ideally, the excipient would not be absorbed across
biological membranes, but may enhance the penetration of API. Immunotoxicity studies would be done only if there is an important
structural alert or the compound is from a class of excipients that may be known to induce an immunotoxic effect.
If the data developed in this first phase of the program reveals limited or no concern for toxicity, then the compound is
tested in repeat-dose toxicity studies with the idea that these additional tests will be compliant with FDA guidance for excipient
testing. In the second phase, data could be developed that would allow the sponsor to "bridge" to existing, structurally related
compounds. In this case, for example, a repeat-dose toxicity study would be conducted with a new pegylated substance based
on the extensive toxicity data that exists for PEG-400. In this manner, the sponsor would not necessarily need to conduct
studies if the data demonstrate a similar toxicity profile. In addition, in the repeat-dose study, groups of animals (rats)
could be included to examine for potential reproductive and developmental toxicity following the Organization for Economic
Cooperation and Development's Guideline 422. Finally, as part of the subchronic study, a micronucleus assay can be incorporated
rather than conducting a separate study.
One issue that arises as part of this second phase is conducting the studies in a rodent and non-rodent species. Indeed, it
would be recommended that a separate study in, for example, the dog, be conducted. If long-term toxicity studies in the non-rodent
species have not been conducted with the structural analog, then the sponsor will need to conduct at least a 90-day study.
Based on the results of the second phase of the program, the sponsor would then conduct studies in a third and final phase
of the program. In this final stage of excipient development, many of the studies outlined in FDA's excipient testing guidance
would be conducted (e.g., safety pharmacology). More thorough metabolism studies also would be conducted in this phase. These
studies can be complex depending on the compound. For polymeric materials, these studies may not be possible although a consideration
for undertaking metabolism studies with the monomer or oligomers of the polymer would provide useful data on absorption and
distribution. Based on the outcome of testing in phase two, definitive developmental and reproductive toxicity studies may
be warranted. For developmental studies, a second species (e.g., rabbit) would be necessary.
Undertaking a toxicology program in accordance with FDA's excipient guidance leads to significant costs (see Table I) compared
with the costs associated with alternative paradigm (see Table II). Because of the absence of a regulatory process, the timing
to gain FDA acceptance can be very prolonged, particularly if the sponsor of a drug product uses a new excipient in the formulation
and in nonclinical testing of the drug product. Although the process described here is no panacea for approval, this tiered
process will permit the excipient sponsor to plan a program in conjunction with the drug product sponsor and thereby avoid
Table II: Estimated costs of a proposed tiered-testing toxicology program.