In early March, the Food and Drug Administration (FDA) issued draft guidance recommending that the “pharmaceutical industry avoid the use of [dibutyl phthalate (DBP)] and [di(2-ethylhexyl) phthalate (DEHP)] in [Center for Drug Evaluation and Research (CDER)]-regulated drug and biologic products,” including prescription and nonprescription products, because of “potential human health risks associated with exposure to DBP and DEHP.” This draft guidance does not address the use of these phthalates in other types of FDA-regulated products “or exposure to DBP or DEHP due to the presence of any of these compounds as an impurity–including as a result of leaching from packaging materials.” In issuing this guidance, the Agency has noted that “[a]lthough the currently available human data are limited, the Agency has determined that there is evidence that exposure to DBP and DEHP from pharmaceuticals presents a potential risk of developmental and reproductive toxicity,” which, according to the FDA, justifies the recommendation that the industry “avoid the use of DBP and DEHP as excipients in CDER-regulated drug and biologic products.”
The FDA’s draft guidance provides a number of steps that entities should take if they manufacturer covered products containing DBP and DEHP. This includes the following: (1) for currently marketed products, entities should use the FDA’s Scale-up and Post-Approval Changes (SUPAC) guidance to determine the level of change for a formulation and the information that should be submitted to FDA to support the change; (2) manufacturers of currently marked products approved under an NDA or ANDA should refer to the Changes to an Approved NDA or ANDA guidance to determine the reporting category associated with a change in DBP and DEHP use; and (3) if a manufacturer determines that there are no viable alternatives to DBP or DEHP, the manufacturer should provide justification to FDA regarding why the substances should be used, including submitting data supporting why a safer alternative cannot be used and a risk/benefit analysis demonstrating that the benefit to the intended population outweighs potential safety concerns. For over-the-counter drugs, the FDA generally does not consider DBP or DEHP to be safe or suitable inactive ingredients in these products. The FDA has also recommended that entities refer to the Inactive Ingredient Database to help identify substitutes for DBP and DEHP.
While comments regarding FDA guidance can be submitted at anytime, the FDA recommends that interested parties submit comments regarding this draft guidance by May 31, 2012 to have these comments considered by the FDA before it begins working on the final version of the guidance.