It has become common practice in developing drug formulations to consult the FDA’s Inactive Ingredient Guide (IIG) to obtain information on "acceptable levels" of excipients used in previously approved products. The rationale behind this practice is the understanding that the FDA will accept experience associated with prior use of a particular ingredient at the level specified in the IIG as adequate qualification of an inactive ingredient. It is important, however, to remember that the FDA analysis of the adequacy of evidence from the IIG goes beyond simply confirming that a specific amount of the ingredient has been used in a particular dosage form. The FDA also considers whether the conditions of use of the inactive ingredient in the previously approved product are comparable to (or greater than) those of the proposed new product. Additional factors that the FDA considers in this analysis are the route of administration, duration of exposure, patient population, and level of exposure.
Route of Administration – This criterion is the one for which the FDA allows the greatest flexibility. Data on levels of inactive ingredients can generally be used interchangeably when the route of administration of the drug product is the same (e.g., data from oral tablet formulations can be used for oral capsules, data from topical gel formulations can be used for topical creams). However, there are formulation considerations beyond simply the route of administration. For example, an excipient used in a topical cream may not have the same safety profile if used in an occlusive topical patch. Therefore, additional safety information may be needed to qualify the use of the excipient in a different formulation even if the route of administration and all other factors affecting usage are the same.
Duration of Exposure – In considering prior experience with an inactive ingredient, the FDA evaluates whether the prior use in the approved product is at least of a similar duration as the use of the proposed formulation. For example, experience with an excipient level deemed acceptable in a product used sporadically or for only very short periods would not be considered sufficient to adequately qualify levels in a product used chronically.
Patient Population – The patient population is also an important factor that is considered when assessing whether prior exposure at a level cited in the IIG is adequate to qualify that inactive ingredient in a proposed formulation. Excipients necessary for the delivery of lifesaving therapies may be acceptable to the FDA at higher levels or with less of a safety database than if the excipients are used in products intended for patients with more benign conditions. Also, patient populations differing in age or disease status may also differ in their ability to tolerate certain excipients (e.g., benzyl alcohol, an antimicrobial preservative, is not tolerated in neonates because their ability to metabolize the excipient is incompletely developed.
Level of Exposure – Although the IIG provides information on the level of an excipient present per dosage unit (i.e., per tablet, per patch, per unit volume, etc.), it does not provide information on the level of exposure of the patient who uses the product. Additional information on the total daily dose and, in some cases, the rate of administration is also considered by the FDA when evaluating the adequacy of the IIG information. The rate of administration is particularly important in considering parenteral formulations. An inactive ingredient considered safe when infused slowly may not be considered equally safe when injected rapidly.
The factors described above place an additional burden of proof on Sponsors for establishing inactive ingredient safety. However, the IIG remains a valuable source for Sponsors to begin the process for establishing the safety of the levels of inactive ingredients in a proposed formulation.
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