iOn December 28, 2023, the U.S. Food and Drug Administration (FDA) announced the availability of a new guidance document that provides recommendations for drug manufacturers on the reformulation of drug products that contain carbomers manufactured with benzene.
Carbomers are a class of synthetic polymers commonly used as thickeners, suspending agents, gel bases, emulsifiers, and binding agents. They are used in personal care products, cosmetics, and pharmaceuticals. United States Pharmacopeia (USP) monographs exist for several carbomers as inactive drug ingredients, including Carbomer 934, Carbomer 934P, Carbomer 940, Carbomer 941, and Carbomer 1342. Some carbomers are manufactured using benzene as a polymerization solvent, and in those cases, the USP monographs permit residual benzene levels as high as 5000 parts per million (ppm). Other USP monographs cover carbomers produced without benzene, and in those cases, benzene is generally limited to no more than 2 ppm as an impurity.
FDA states in its new guidance that certain USP carbomer monographs allow for unacceptably high levels of benzene and that FDA has asked the USP to remove those monographs. FDA also notes that if the use of benzene is unavoidable to produce a drug product with a significant therapeutic advance, then its level should be restricted to the level recommended in the International Council for Harmonisation (ICH) guidance for industry Q3C Impurities: Residual Solvents (December 1997) and the companion ICH guidance for industry Q3C — Tables and List (August 2018) and USP General Chapter <467> Residual Solvents, unless otherwise justified.
FDA’s guidance recommends that drug manufacturers using carbomers manufactured with benzene switch to an alternative grade of carbomer manufactured without the use of benzene. The guidance also reviews the responsibility of application holders (i.e., holders of approved New Drug Applications and Abbreviated New Drug Applications) and other manufacturers, including manufacturers of over-the-counter monograph drug products, to evaluate the effects of a formulation change. The guidance recommends test documentation and submission type (prior approval supplement (PAS) or Changes Being Effected in 30 days (CBE-30)), for application holders.
In addition to issuing the guidance, FDA has posted information on its website alerting drug manufacturers to the risk of benzene contamination in certain drugs as well as frequently asked questions about benzene contamination in drugs.
