In March 2012, a Draft Guidance proposing to limit the use of certain phthalates as excipients in CDER regulated products was issued and is now open for a 90 day comment period. Depending on how the final version of this guidance document evolves, it could have a major impact on the industry.
Phthalate esters (phthalates) are used primarily as plasticizers in enteric-coatings of solid oral drug products, but can also be found in other dosage forms. The draft guidance focuses on two specific phthalates—dibutyl phthalate (DBP) and di (2-ethyl-hexyl) phthalate (DEHP) in CDER regulated drug and biologic products and their developmental and reproductive toxicities. In the guidance, CDER states that safer alternatives are available and that the use of DBP and DEHP as excipients in drug and biologic products should be avoided. The guidance applies to drug products at all stages of their lifecycle—investigational new drugs, drug products not requiring pre-approval including products marketed under OTC drug monographs, drug products currently under review for marketing consideration (NDAs, ANDAs and BLAs), and currently marketed approved drug products. While it appears that this guidance is applicable only to the aforementioned drug products, we could envision extension of phthalate restriction to dietary supplements, medical foods, medical devices and cosmetics.
Essentially, the agency is hoping to remove DBP and DEHP from the inactive ingredient list (IIG) if possible. Given all of the references to the SUPAC and Changes to an approved NDA or ANDA guidances, it is clear that sponsors are being asked to take heed. If the sponsor cannot identify an appropriate substitute, then a justification for continuing the use of DBP or DEHP should be submitted. Depending on the formulation change involved, additional nonclinical and clinical studies may also be required to support the change, especially since the phthalates may be considered rate-controlling excipients in modified-release drug products.
It is not known just how many products will be impacted by this guidance or when CDER expects sponsors to conform to this change. A quick search of the IIG revealed 4 entries for approved products with DHP, but it can be assumed that many others used DHP based on the levels cited. The guidance is available on the FDA’s website and comments to the guidance may be submitted at https://www.regulations.gov under Docket No. FDA-2012-D-0108. The Docket is open for comment until May 31, 2012.
Posted by Theresa Allio, Senior Consultant and Nick Fleischer, Vice President. For more information, please contact Nick (email@example.com).