Preclinical studies have linked the two phthalate excipients with reduced fertility in male and female animals. Human data is limited but the US Food and Drug Administration (FDA) wants to phase out use of the two ingredients, dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP).
In draft guidance the FDA wrote: “While it is recognised that drug products may carry inherent risks, DBP and DEHP are used as excipients, and safer alternatives are available. Therefore, the Agency recommends avoiding the use of DBP and DEHP as excipients.”
DBP is used in oral controlled and extended release formulations, as well as enteric coated products that encase the active ingredient until it reaches the small intestine. The FDA inactive ingredient database lists DBP in four formulations.
Companies should now consider reformulating. “Manufacturers with products that contain DBP or DEHP should consider alternative excipients and determine if the alternative excipient they plan to use has been used in similar CDER-approved products and at what level”, the FDA wrote.
When switching from DBP and DEHP to other excipients the FDA wants companies to consider scale-up and post-approval changes guidance. These documents will help companies decide the data, such as bridging studies, which they should submit to the FDA to justify the change of excipient.
It is possible the FDA will let some manufacturers continue to use DBP and DEHP if they can justify the decision. “Such justification should include data to support why a safer alternative cannot be substituted, as well as a risk/benefit analysis”, the FDA wrote.
Across the European Union companies are banned from using DBP in cosmetics and children’s toys. In 2006 the European Medicines Agency told governmental questioners that no centrally authorised medicinal product contains DBP.
A 90 day draft guidance comment period is now open.