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 hand sanitizers and aerosol drug products have been recalled due to benzene contamination. This contamination may be related to inactive ingredients such as carbomers (thickening agents), isobutane (a spray propellant), or other drug components made from hydrocarbons.
FDA reminds drug manufacturers 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 they have the appropriate specifications, test methods, and controls to ensure drugs are free from contamination. FDA has discussed with manufacturers conducting 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 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. The guidance 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.
What drug manufacturers should do
Drug manufacturers are required to ensure the safety and quality of their drugs. As FDA works to better understand the potential sources of benzene in 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. Consistent with the recommendations of the ICH Q3 guidance, manufacturers should not use benzene in the manufacture of drugs. Ingredients that are hydrocarbons or are manufactured with benzene or other hydrocarbons may indicate a higher likelihood of benzene contamination.
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.
Drug manufacturers with a risk for benzene contamination should test their drugs accordingly and should not release any drug product batch that contains benzene above 2 ppm, consistent with the recommendations described in the ICH Q3C guidance. If any drug product batches with benzene above 2 ppm are already in distribution, the manufacturer should contact FDA to discuss the voluntary initiation of a recall by contacting the appropriate Division of Pharmaceutical Quality Operations in the Office of Regulatory Affairs.
We note that 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 email@example.com. 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.
FDA reminds manufacturers of NDA and ANDA products of their obligation to submit a Field Alert Report (FAR) if testing reveals their drug products contain benzene above 2 ppm (21 CFR 314.81(b)(1)(ii)). FDA’s guidance Field Alert Report Submission: Questions and Answers Guidance for Industry addresses how to submit a FAR. Manufacturers of NDA and ANDA drug products whose testing reveals their drug products contain benzene below 2 ppm should contact FDA at CDERfirstname.lastname@example.org.
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 below chart summarizes 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:
|Drug product batches already in distribution with benzene impurities above 2 ppm||Contact appropriate ORA 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 above 2 ppm||Contact appropriate ORA 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 above the limit of detection but below 2 ppm||Contact FDA at CDERemail@example.com||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|
Benzene limits in drug products
As FDA evaluates the root cause of benzene contamination in certain drugs, the agency is taking 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 will review any Field Alert Reports from drug manufacturers that identify the presence of benzene, in addition to other available information. This information will help inform further updates to FDA’s approach to limiting benzene levels in drug products, as appropriate.
We note that certain United States Pharmacopeia – National Formulary (USP-NF) carbomer monographs allow for levels of benzene of 100 ppm or greater. To eliminate 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.
In order to ensure their products conform to appropriate quality specifications (21 CFR 211.84, 21 CFR 211.160), and consistent with the recommendations in the ICH Q3C guidance, 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 intends to issue 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 CDERfirstname.lastname@example.org.