FDA Guidance Breakdown: Reformulating Drug Products That Contain Carbomers Manufactured With Benzene

The FDA just finalized its guidance to expedite the reformulation of drug products that use inactive ingredients made with benzene, which the agency called a “known carcinogen.”

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The FDA has finalized its guidance to speed up the reformulation process of drug products that contain inactive ingredients manufactured with benzene.

The guidance applies to new drug applications (NDAs), abbreviated new drug applications (ANDAs), marketed drugs, and non-prescription drugs. It includes topical liquid and semi-solid forms such as creams, gels, lotions, and ointments, immediate-release solid oral forms, modified-release solid oral forms, and oral suspensions.

In its announcement, the FDA has urged manufacturers to implement reformulation “as soon as possible.” The guidance will become effective immediately without prior comment, as it is considered a high priority for public health.

The FDA noted that the current USP carbomer monographs allow benzene levels of 100 parts per million (ppm) or higher. Due to safety concerns associated with these unacceptable levels of benzene, the FDA has asked USP to remove or "omit" these monographs from their compendium with a target effective date of August 1, 2025.

Background

In 2023, FDA’s Francis Godwin expressed concern about the increasing number of recalls and warning letters associated with drug products containing benzene, which is a known carcinogen.

In 2022, the FDA issued a warning letter to Mirfeel in South Korea for contaminated hand sanitizers containing benzenes. Last year, the agency issued another warning letter to Voyant Beauty, a division of Accra-Pac, which makes OTC topical drug products. After inspecting the firm’s site in Elkhart, Indiana, investigators said the firm failed to investigate products for benzene contamination.

In December 2022, the FDA issued a statement expressing concerns about the presence of benzene in certain drugs. According to regulators, any drug containing more than 2 ppm benzene is considered adulterated and should be recalled. The statement was updated on December 27, 2023 — and regulators laid out a number of direct suggestions for manufacturers:

1. Avoid Using Benzene in Drug Manufacturing: Manufacturers should not use benzene in the manufacture of drugs, aligning with the recommendations of the ICH Q3 guidance.

2. Monitor Ingredients for Benzene Risk: Ingredients that are hydrocarbons or manufactured with benzene or other hydrocarbons should be scrutinized for potential benzene contamination.

3. Be Aware of Benzene Formation Risks: Understand that certain ingredients, like sodium benzoate, can form benzene under specific conditions. This possibility should be considered in benzene testing schedules and in setting expiration dates.

4. Conduct Thorough Benzene Testing: Test drugs for benzene contamination at release and during stability, adhering to 21 CFR 211.165 and 211.166.

5. Respond to Benzene Levels Above 2 ppm: Do not release any drug product batch containing benzene above 2 ppm. If such batches are already distributed, contact the FDA to discuss potential recall actions.

6. Report Supply Disruptions: If withholding a product or initiating a recall affects drug supply, contact CDER’s Drug Shortages Staff immediately.

7. Submit Field Alert Reports (FARs): For NDA and ANDA products with benzene levels above 2 ppm, FARs are required as per 21 CFR 314.81(b)(1)(ii). If benzene levels are below 2 ppm, contact FDA at CDER-benzene@fda.hhs.gov.

8. Contact FDA for Nonapplication Products: If testing reveals benzene in nonapplication products, including over-the-counter monograph drug products, contact the FDA and be prepared to provide test results and information on the potential benzene source.

9. Follow Specific Contact Protocols:

   • For drug product batches in distribution with benzene above 2 ppm: Submit FARs for ANDAs and NDAs, and contact appropriate Office of Regulatory Affairs (ORA) Division Recall Coordinators.

   • For active pharmaceutical ingredient (API) lots with benzene above 2 ppm: FDA will advise on next steps, including notifying entities that received contaminated API. Contact appropriate ORA Division Recall Coordinators.

   • For any drug product or API with benzene above the limit of detection but below 2 ppm: Be prepared to share methods and information on the potential source of benzene with the FDA. Contact FDA at CDER-benzene@fda.hhs.gov.

In the background of the guidance, the FDA discusses the risk associated with carbomers manufactured using benzene, outlines the regulatory stance on benzene levels in drug products, and asserts the need to switch to non-benzene-containing carbomer grades.

Overview

The guidance recommendations are in line with the ICH Q3C guidance on residual solvents, which was released in December 1997, and its companion Q3C document, which was issued in August 2018.

• According to the Q3C guidance, if benzene use is necessary to produce a drug product that has significant therapeutic benefits, its levels should be limited to 2 parts per million (ppm).

• Additionally, the guidance is aligned with the FDA's scale-up and post-approval changes (SUPAC) guidelines.

The FDA advises that when transitioning to non-benzene-containing grades of carbomers, drug manufacturers and applicants should assess the impact of these changes on the strength, quality, purity, and potency of the drug product.

The final guidance provides recommended reporting categories and documentation requirements for reformulating with different dosage forms. For instance, for semisolid dosage forms, the guidance specifies that applicants and manufacturers should adhere to the recommendations in the May 1997 SUPAC guidance for nonsterile semisolid dosage forms.