Regulatory Update: The IPEC Novel Excipient Safety Evaluation Procedure - Pharmaceutical Technology

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Regulatory Update: The IPEC Novel Excipient Safety Evaluation Procedure
The authors, representing the International Pharmaceutical Excipients Council, propose a new evaluation procedure, including tiered toxicology testing for excipients.


Pharmaceutical Technology
Volume 33, Issue 11, pp. 72-82

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 robust database.

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.


Table II: Estimated costs of a proposed tiered-testing toxicology program.
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 toxicological surprises.


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