FDA Warns Pharmaceutical Manufacturers of Risk of Benzene in Certain Drugs | King and Spalding

FDA Continues to Focus on Identifying and Controlling Traces of Impurities in Drugs

On December 23, 2021, the United States Food and Drug Administration (“FDA”) alerted drugmakers that the FDA was investigating the root cause of benzene contamination in certain drugs.1 The FDA alert continues the Agency’s increased focus on the identification and control of trace impurities, including nitrosamines,2 per- and polyfluoroalkylated substances (“PFAS”),3 and other potentially toxic substances, in pharmaceuticals. In addition to advances in analytical technology that allow manufacturers to detect impurities at very low levels, increased FDA interest has been sparked, in part, by a series of findings by the Agency for Benzene in products. health care products such as hand sanitizers and aerosol products.4 In addition to the FDA findings, private testing labs have filed citizen petitions with the FDA under 21 CFR § 10.30, which directly lead to personal injury, consumer class actions, and lawsuits. lawsuits against product manufacturers.


FDA, adopting the International Conference on Harmonization (ICH) Q3C Impurities: Guidelines for Residual Solvents, classifies benzene as a Class 1 solvent, which means that it belongs to one of the following three categories: known human carcinogens, strongly suspected human carcinogens or environmental hazards.5 In this classification, the use of benzene in the manufacture of medicaments should be avoided as far as possible. However, if the use of benzene cannot be avoided, the FDA requires manufacturers to put controls in place to ensure that benzene levels do not exceed 2 parts per million (ppm), unless the manufacturer does. justifies it and that the FDA accepts the use of a higher limit.


When benzene is intentionally used during the manufacturing process, drug makers can easily identify the risk and assess whether – and what – controls may be necessary. However, the FDA has identified several potential sources that can result in the presence of benzene even if the solvent is not used intentionally. Specifically, the FDA has identified that ingredients that belong to a chemical class known as “hydrocarbons” or other ingredients made with benzene can be potential sources of benzene. Additionally, the FDA has found that certain ingredients, such as sodium benzoate, can react to form benzene under certain conditions.


The FDA recommends that drug manufacturers perform risk assessments to identify the potential presence of benzene in prescription and over-the-counter (OTC) pharmaceuticals. Although the risk assessment focuses on final pharmaceutical products, manufacturers must also assess whether raw materials can introduce benzene. If a risk of the presence of benzene is identified, drug manufacturers should perform confirmatory testing to assess whether benzene is actually present and at what concentrations. If testing confirms the presence of benzene, the FDA has established how manufacturers should contact the agency about the problem. These options include contacting a dedicated email to share test results and methods (when benzene is below the allowable limit) or contacting the appropriate Regulatory Affairs Division Recall Coordinator (if benzene is detected). above the authorized limit) to discuss initiating a callback. In addition, even though drug manufacturers can rule out the risk of the presence of benzene, they should continue to assess whether the presence of benzene is possible any time there are changes in the raw materials, including changes in the substance. raw material suppliers. The FDA also said the agency intends to issue additional guidance on recommended test methods and appropriate steps to modify formulations to limit and control the presence of benzene.

1US Food & Drug Admin., FDA alerts drugmakers to risk of benzene contamination in certain drugs, (September 2020), https://www.fda.gov/drugs/pharmaceutical-quality-resources/fda-alerts-drug-manufacturers-risk-benzene-contamination-certain-drugs.

2US Food & Drug Admin., Control of Nitrosamine Impurities in Human Drugs (September 2020), https://www.fda.gov/media/141720/download.

3US Food & Drug Admin., Per- and polyfluoroalkylated substances (PFAS), (Current as of October 18, 2021), https://www.fda.gov/food/chemical-contaminants-food/and-polyfluoroalkyl-substances-pfas.

4For example, US Food & Drug Admin., FDA Updates on Hand Sanitizers Consumers Should Not Use, (Current as of December 22, 2021), https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-hand-sanitizers-consumers-should-not-use.

5US Food & Drug Admin., Q3C Impurities: Residual Solvents (Dec. 1997); US Food & Drug Admin., Q3C – Tables and List (August 2018), https://www.fda.gov/media/133650/download.

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