FDA alerts drug manufacturers to the risk of benzene contamination in certain drugs

The FDA is investigating the root cause of benzene contamination in certain drugs and informing drug manufacturers about the risks associated with benzene contamination from drug components and other potential factors. Here's a summary of the FDA's alert to drug manufacturers regarding the risk of benzene contamination in certain drugs: Key Concerns:

• Benzene Contamination: The FDA is alerting drug manufacturers to the potential risk of benzene contamination in drug products. Benzene is a known human carcinogen.
• Root Cause Evaluation: The 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.
• Recalls: Certain drug products, including hand sanitisers, benzoyl peroxide products, and aerosol drug products, have been recalled due to benzene contamination.

Manufacturer Responsibilities:

• Testing: Drug manufacturers 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. This includes testing of raw materials and finished product batches prior to release.
• Risk Assessments: Manufacturers should conduct risk assessments to evaluate the possible presence of benzene in their drug products and components, especially those containing hydrocarbons or manufactured with benzene or other hydrocarbons.
• Avoid Benzene: Manufacturers should avoid using benzene in the manufacturing process. The International Conference on Harmonization (ICH) Q3C guidance provides guidance on limited cases where the presence of benzene may be tolerated.
• Benzene Levels: If benzene use is unavoidable, levels should be restricted to 2 parts per million (ppm) to avoid consumer exposure to more than 20 micrograms (mcg) per day.
• Quality Control: Manufacturers must ensure the safety and quality of their drugs and ensure they conform to appropriate quality specifications.
• Ingredient Scrutiny: Manufacturers need to pay special attention to inactive ingredients (like carbomers and isobutane) and the potential degradation of active ingredients (like benzoyl peroxide).
• Raw Materials: Changes in raw materials, including suppliers, warrant additional scrutiny for benzene contamination.
• Testing and Release: Drug products at risk should be tested accordingly, and batches that would expose consumers to more than 20 mcg per day of benzene should not be released.

The following chart explains when and how manufacturers should contact FDA if testing shows the presence of benzene and the information FDA might request from drug manufacturers during follow-up.

FDA's Actions & Guidance:

• Stepwise Approach: The FDA has taken a stepwise approach to address potential benzene contamination in marketed drug products.
• Proactive Testing: The agency has conducted proactive testing, worked with manufacturers, and reviewed new information to limit benzene levels in drug products.
• Risk Assessment Principles: The 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).
• Concentration Limits: If the presence of benzene is unavoidable, benzene levels should be limited so that consumers are not exposed to more than 20 mcg per day. The FDA intends to issue guidance with additional detail about the calculation of product-specific concentration limits for benzene.
• Guidance Documents: 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.

Supply Chain & Reporting:

• Supply Disruptions: If decisions not to release a drug product or initiate a recall are likely to disrupt the drug supply, manufacturers should contact CDER's Drug Shortages Staff immediately.
• 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.
• Contacting FDA: Manufacturers of non-application products should contact FDA when testing reveals benzene in a product and be prepared to provide FDA with test results and information on the potential source of the benzene.

USP Carbomer Monographs:

• Monograph Revisions: The FDA has asked USP to remove (or "omit") these monographs from their compendium to minimize confusion and because of the safety concerns associated with these unacceptable levels of benzene
• Targeted Dates: These updates have a targeted date of August 1, 2026.

Summary: The FDA is actively working to address the risk of benzene contamination in drugs and has issued guidance to manufacturers on how to test for and prevent contamination. Manufacturers must conduct risk assessments, test raw materials and finished products, and report any concerning findings to the FDA. The goal is to ensure that drug products are safe and do not expose consumers to unacceptable levels of benzene.

FDA document here