Benzoyl Peroxide is the active ingredient in many acne creams, ointments, gels, and combination semi-solid products for the treatment of acne. These products are sold either by prescription or over the counter. Valisure is the same testing lab that uncovered the nitrosamine impurities in Ranitidine products that developed over the expiration dating life of drug which may increase in part over time in higher storage temperatures. As you well know, many other products were implicated regarding these nitrosamine impurities.  The FDA has been trying to address the nitrosamine impurity issue for a number of years and, while they are getting close and have made recommendations for a fix, the issue is still not fully resolved and remains somewhat unsettled.

Now, Valisure is claiming in a petition (here) filed with the FDA on March 5, 2024, that benzoyl peroxide-containing acne products stored at higher than recommended temperature develop benzene, a known carcinogen, as an impurity and in some instances, benzene gas was released and noted around the product that could “create inhalation exposure”.

The Valisure petition states “Benzoyl peroxide is known to thermally decompose to form two (2) molecules of benzoic acid radicals that can further decompose to benzene radicals with liberation of carbon dioxide. The benzene radicals can then produce benzene.”  While benzene is permitted when its use cannot be avoided, the FDA permits a very low level and “is restricted under such guidance to two (2) parts per million (“ppm”)”. The Petition requests the Agency to take action on nine issues (see petition for all nine) but I find the two most interesting requests are:

  • “request a recall and suspension of sale of products containing benzoyl peroxide. Given the drug’s propensity to form the known human carcinogen benzene, the drug is misbranded under Section 502 of the FDCA (21 U.S.C. § 352);”
  • “promulgate regulations requiring robust independent chemical testing and verification of pharmaceuticals and, while these regulations are pending, issue guidance requesting such testing and verification.”

Valisure cited the recently published FDA guidance, “Reformulating Drug Products That Contain Carbomers Manufactured with Benzene” as an indication of the FDA’s concern regarding benzene impurities. The firm further goes on to provide background on the historical actions on benzene taken by the EPA and FDA and describes the methodology it used in its testing of the benzoyl peroxide-containing products. They also tested a number of different benzoyl peroxide (BPO) brand and generic products at 50º C and 70º C for 18 days, and while these temperatures are extreme, they represent what Valisure says are conditions that could be reached in a hot car for a period of time. And in one test, a single day at these temperatures resulted in one product with a benzene level of approximately 29 ppm of benzene in a 5.5 oz tube of BPO. At the 50º C storage temperature, levels were seen up to about 1800 ppm and were somewhat higher at the 70º C storage condition exceeding 2000ppm. While these temperatures are certain significantly higher than the recommended storage temperature for BPO products which are generally 20-25º C (68-77º F) (see the USP definition of controlled room temperature which allows certain small excursions) benzene levels seen in the Valisure testing were somewhat alarming.

This petition raises an interesting question regarding approved labeled storage conditions and patients’ failure to adhere to the recommended conditions and the danger it could pose. Can this be remedied by stronger warnings on the need to strictly adhere to the recommended storage conditions? Just exactly what rabbit hole will this newly submitted petition take the FDA and the industry down? Please read the petition and let us know what you think!