FDA is evaluating the root cause of benzene contamination in certain drugs and alerting drug manufacturers to the risk of benzene contamination from drug components and other potential risk factors. Benzene is a known human carcinogen that causes leukemia and other blood disorders. Certain drug products, including hand sanitizers, benzoyl peroxide products, and aerosol drug products have been recalled due to benzene contamination. As discussed in further detail below, this contamination may be related to inactive ingredients, such as carbomers (thickening agents), isobutane (a spray propellant), or other drug components made from hydrocarbons, or to degradation of certain active ingredients in drug products.
FDA reminds drug manufacturers that they are required to establish scientifically sound and appropriate specifications and test procedures to assure drug components (active and inactive ingredients) and finished drug products conform to appropriate quality specifications (21 CFR 211.84, 21 CFR 211.160). This includes testing of raw materials and finished product batches (21 CFR 211.165) prior to release to ensure they meet appropriate specifications for identity, strength, quality, and purity.
One way manufacturers can meet the requirements of 211.84, 211.160 and 211.165 is by using tools such as risk assessments to determine that they have the appropriate specifications, test methods, and controls to ensure drugs are free from contamination. FDA has discussed with manufacturers the need to conduct risk assessments to evaluate the possible presence of benzene in their drug products and components, including active ingredients and inactive ingredients. In particular, FDA has also discussed with manufacturers the need for a special focus on ingredients that are hydrocarbons or are manufactured with benzene or other hydrocarbons.
Drug manufacturers should avoid using benzene in the manufacturing process
Manufacturers should not use benzene in the manufacture of drugs. The International Conference on Harmonization (ICH) Q3C Impurities: Residual Solvents guidance and companion document Q3C Tables and List provide provide guidance on limited cases where the presence of benzene may be tolerated. Specifically, the ICH Q3C guidance explains that Class 1 solvents such as benzene should not be employed in the manufacture of drug substances, excipients, or drug products because of their unacceptable toxicity unless their use can be strongly justified in a risk-benefit assessment. The Q3C Tables and List document notes that if benzene use is unavoidable to produce a drug product with a significant therapeutic advance, then its levels should be restricted to 2 parts per million (ppm), unless otherwise justified. This 2 ppm limit is designed to avoid consumer exposure to more than 20 micrograms (mcg) per day of benzene1 from a product (and assumes a 10 g per day dose of the product).2
As FDA evaluates the root cause of benzene contamination in certain drugs, the agency has taken a stepwise approach to address the potential for benzene contamination in marketed drug products by first identifying products that should be immediately recalled or not released for distribution based on a benzene level in the products above 2 ppm, consistent with the considerations described in ICH guidance. Concurrently, the agency has conducted proactive testing, worked with manufacturers to address the presence of benzene in their drug products, and reviewed new information that has become available about benzene. This information has helped inform further updates to FDA’s approach to limiting benzene levels in drug products.
While the ICH Q3C guidance is applicable to cases involving residual solvents (where benzene is present as an impurity), FDA applies similar risk assessment principles to those described in the ICH guidance to circumstances where benzene is present for other reasons (for example, where it is present in a drug product as a degradant). Accordingly, if the presence of benzene is unavoidable in a finished drug product, benzene levels should be limited so that consumers are not exposed to more than 20 mcg per day of benzene from the product.
Based on the characteristics of a particular product and how it is used (for example, how much of the body the product is applied to, the frequency of application, and the route of administration), this 20 mcg per day exposure limit will be reached through a product-specific benzene concentration limit. As an example, the ICH Q3C guidance provides that, for products with a 10 g per day dose, this 20 mcg per day exposure limit is reached through a product concentration limit of 2ppm. For products that have a dose different than 10 g per day, however, the 20 mcg per day exposure limit will be reached by a different concentration limit. FDA intends to issue guidance with additional detail about the calculation of product-specific concentration limits for benzene.
What drug manufacturers should do
Drug manufacturers are required to ensure the safety and quality of their drugs. FDA reminds manufacturers of drugs marketed under approved applications and manufacturers of other drugs, including over-the-counter monograph drug products, of their obligation to ensure their products conform to appropriate quality specifications. As noted above, benzene contamination may be related to inactive ingredients, such as carbomers and isobutane, or to degradation of certain active ingredients. Drug components that are hydrocarbons (or are manufactured with benzene or other hydrocarbons) may indicate a higher likelihood of benzene contamination.
Benzoyl peroxide, a commonly used active ingredient in acne treatment drug products, may degrade into benzene under certain conditions (such as extreme temperatures). FDA is also aware of ingredients, such as the antifungal preservative sodium benzoate, that in combination with chemicals, such as antioxidants in a drug formulation, may yield benzene under certain conditions. The formation of benzene from benzoate can lead to an increase in benzene content over a drug’s shelf-life and should be considered when determining the appropriate timing for benzene testing, e.g., testing at release and on stability (21 CFR 211.165, 211.166), and establishment of an appropriate expiration date (21 CFR 211.137). FDA reminds manufacturers that changes in raw materials throughout the lifecycle of the drug, including changes in raw material suppliers, warrant additional scrutiny for the potential risk of benzene contamination.
Manufacturers of drug products at risk for benzene contamination should test their drugs accordingly and should not release any drug product batch that would expose consumers to more than 20 mcg per day of benzene from the product. For products that have a 10 g daily dose, this means that benzene levels should be limited to no more than 2 ppm. For products that have a daily dose above 10 g, manufacturers should determine the appropriate concentration limit for their product that ensures consumers are not exposed to more than 20 mcg per day of benzene from the product. If any drug product batches containing benzene above this level are already in distribution, the manufacturer should contact the appropriate Division of Pharmaceutical Quality Operations in the Office of Inspections and Investigations (OII) at FDA to discuss the voluntary initiation of a recall.
Assessing Supply Disruptions
If decisions to not release a drug product or to initiate a recall are likely to disrupt the drug supply, manufacturers should contact CDER’s Drug Shortages Staff immediately at drugshortages@fda.hhs.gov. Contacting the Drug Shortages Staff in writing allows manufacturers of certain covered drug products to meet applicable obligations to report discontinuances or interruptions in drug manufacture under 21 U.S.C. 356C(b) and FDA’s associated regulations. This also allows FDA to evaluate the market and determine if additional steps are needed to avoid a supply disruption that may impact public health.
Submitting Field Alert Reports
NDA and ANDA holders are required to submit a Field Alert Report (FAR) if testing reveals that one or more distributed batches of a drug product fails to meet the specification established for it in the application (21 CFR 314.81(b)(1)(ii)). For products at risk of benzene contamination, this would encompass products for which testing reveals benzene above 2 ppm, or, for drug products that have daily doses of more than 10 g, if testing reveals benzene above the level that would expose consumers to more than 20 mcg per day from the product. FDA’s guidance Field Alert Report Submission: Questions and Answers Guidance for Industry addresses how to submit a FAR.
Contacting FDA
- Manufacturers of nonapplication products, including over-the-counter monograph drug products, should contact FDA using the information in the table below when testing reveals benzene in a product.
- Manufacturers should also be prepared to provide FDA with test results and any information available on the potential source of the benzene to assist in FDA’s analysis.
The following chart explains when and how manufacturers should contact FDA if testing reveals the presence of benzene and the information FDA may request from drug manufacturers when following up:
| Finding | Contact Method | Notes |
|---|---|---|
| Drug product batches already in distribution with benzene levels above 2 ppm (or, if the product has a daily dose of more than 10 g/day, with benzene above a level that would expose consumers to more than 20 mcg/day of benzene) | Contact appropriate OII Division Recall Coordinators | Field Alert Reports are required for ANDAs and NDAs with such findings for distributed drug products (21 CFR 314.81(b)(1)). Application holders notified of benzene results from the manufacturer of an API used in their product are required to submit FARs. |
| Active pharmaceutical ingredient lot with benzene levels above 2 ppm (or, if the product has a daily dose of more than 10 g/day, with benzene above a level that would expose consumers to more than 20 mcg/day of benzene) | Contact appropriate OII Division Recall Coordinators | FDA will advise on appropriate next steps, such as notifying any entity that received contaminated API. |
|
Any drug product or active pharmaceutical ingredient with benzene levels above the limit of detection but below 2 ppm (or, if the product has a daily dose of more than 10 g/day, with benzene below a level that would expose consumers to more than 20 mcg/day of benzene). Any drug product or active pharmaceutical ingredient with benzene levels above 2 ppm but with a daily dose of less than 10 g, which would expose consumers to less than 20 mcg per day of benzene. |
Contact FDA at CDER-benzene@fda.hhs.gov | The manufacturer should also be prepared to share with FDA the methods used and any available information on the potential source of the benzene to assist with FDA’s analysis. |
USP Carbomer Monographs
Certain United States Pharmacopeia – National Formulary (USP-NF) carbomer monographs allow for levels of benzene of 100 ppm or greater. To minimize confusion and because of the safety concerns associated with these unacceptable levels of benzene, FDA has asked USP to remove (or “omit”) these monographs from their compendium. On November 18, 2022, in response to FDA’s request, the USP issued a Notice of Intent to Revise, stating that it intends to omit the Carbomer 934, Carbomer 934P, Carbomer 940, Carbomer 941, and Carbomer 1342 monographs. These updates have a targeted date of August 1, 2026. In December 2023, FDA issued a guidance that provides recommendations to applicants and manufacturers on what tests should be performed and what documentation should be submitted or available to FDA to support reformulation of drugs products that use carbomers manufactured with benzene.
In order to ensure their products conform to appropriate quality specifications (21 CFR 211.84, 21 CFR 211.160), applicants and manufacturers who identify risks of benzene contamination from drug components or confirm the presence of benzene in a drug product should also take steps to use ingredients without benzene, or, if justified, use suppliers that minimize risk of unacceptable benzene impurity levels. FDA has issued a guidance for manufacturers on recommended test methods and appropriate steps for manufacturers needing to modify their formulation or manufacturing process for a legally marketed drug product. For additional questions, contact CDER-benzene@fda.hhs.gov.
1. 20 mcg per day of benzene exposure is associated with a lifetime excess cancer risk of 10-5 (see, e.g., ICH Q3C guidance, Appendix 4).
2. Product concentration limits for benzene in the ICH Q3C guidance are generated from the following equation: Concentration (ppm) = (1000 × PDE) ⁄ DOSE
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