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

By Erika L. Roberts, ELR Lab Services LLC

Despite regulatory efforts, benzene contamination in pharmaceuticals has led to product recalls and increased scrutiny in recent years. In 2021, over-the-counter drug products Odor-Eaters spray products, Lotrimin AF and Tinactin spray products, and Coppertone and Neutrogena/Aveeno sunscreens were recalled due to the detection of elevated levels of benzene. These incidents prompted regulatory agencies to reevaluate their monitoring and testing protocols, emphasizing the need for stringent quality control measures throughout the pharmaceutical supply chain.

In December 2023, the FDA announced the publication of a final guidance for industry titled Reformulating Drug Products That Contain Carbomers Manufactured With Benzene. In order to understand the context of the final guidance, I will share background on benzene and related existing guidances that have influenced why the final guidance has been developed, before delving into the recommendations in the final guidance itself.

A Background On Benzene

Benzene, a six-carbon aromatic hydrocarbon, is a well-known industrial chemical widely used in the production of various goods, including plastics, synthetic fibers, and rubber. While it plays a crucial role in these industries, its presence in pharmaceutical drugs has raised concerns due to its potential health risks.

Benzene exposure is a significant concern due to its well-established carcinogenic properties, and its production and use are subject to strict regulations to mitigate environmental and health risks. Long-term exposure to high levels of benzene has been linked to the development of various cancers, including leukemia and other hematologic malignancies. The International Agency for Research on Cancer (IARC) has classified benzene as a Group 1 human carcinogen, emphasizing its potential to cause cancer in humans. The risks associated with benzene exposure depend on the duration and intensity of exposure. Occupational exposure in industries where benzene is used as a solvent or in manufacturing processes poses a higher risk, but even low levels of benzene in pharmaceutical drugs could potentially contribute to long-term health risks for patients.

In recent years, concerns have arisen regarding the unintended presence of benzene in certain pharmaceutical drugs. Benzene can find its way into drugs through various routes, with one common source being the manufacturing process. Some drug manufacturing processes involve the use of carbomers in the form of fillers, emulsifiers, gelling agents, and binding agents, polymerization solvents, or chemicals that may contain benzene, and despite strict quality control measures, trace amounts of this compound may remain in the final product. Additionally, benzene can form as a byproduct during the synthesis of certain drug ingredients. For example, the interaction of two or more chemicals during the manufacturing process may lead to the inadvertent production of benzene. The challenge lies in identifying and mitigating these sources to ensure the safety of pharmaceutical products.

Manufacturers have responded to these concerns by reviewing and adjusting their production processes to minimize the risk of benzene contamination. Additionally, the pharmaceutical industry has been exploring alternative solvents and manufacturing methods to reduce the reliance on chemicals that may contribute to benzene formation.

The New Guidance’s Relation To Previously Existing Benzene-Related ICH And USP Guidance

Both the International Conference for Harmonization (ICH) guidance for industry titled Q3C — Tables and List and USP General Chapter <467> Residual Solvents designate benzene as a Class 1 solvent (i.e., solvents that should be avoided) and recommend that benzene should not be employed in the manufacture of drug substances, excipients, and drug products. However, several grades of carbomers that are manufactured using benzene as a solvent are still being used in pharmaceutical products even though alternative grades of carbomers that are manufactured without the use of benzene are available.

At the time of publication of the guidance, carbomers manufactured with benzene may fall under the United States Pharmacopeia-National Formulary (USP–NF) monographs Carbomer 934, Carbomer 934P, Carbomer 940, Carbomer 941, or Carbomer 1342. These monographs permit benzene levels as high as 5,000 parts per million (ppm), which is significantly higher than the limit of 2 ppm on benzene as an impurity in the USP–NF Carbomer Homopolymer, Carbomer Copolymer, and Carbomer Interpolymer monographs. These monographs have been industry standards for documenting and testing of carbomers manufactured with the use of benzene.

To avoid confusion, and because of the safety concerns associated with these unacceptable levels of benzene permitted by these monographs, FDA has asked the USP to remove (or “omit”) the Carbomer 934P, Carbomer 940, Carbomer 934, Carbomer 1342, and Carbomer 941 monographs from the USP–NF compendium.

The FDA’s proposed USP monograph omissions are consistent with the concerns described by FDA in a communication titled FDA alerts drug manufacturers to the risk of benzene contamination in certain drugs, released on June 9, 2022, in which FDA provided a list of products, mostly hand sanitizers and aerosol drug products (sunscreens, deodorants, and antiperspirants), that “have been recalled due to benzene contamination” and asked USP to omit the above-mentioned carbomer monographs that “allow for levels of benzene of 100 ppm or greater.”

In November of 2022, the Complex Excipients Expert Committee (EC) posted notice that it intends to omit the USP-NF monographs for Carbomer 934, Carbomer 934P, Carbomer 940, Carbomer 941, and Carbomer 1342, with a targeted official date of Aug. 1, 2025.

The New FDA Guidance

The FDA’s notice states that:

“the Agency (FDA) is implementing this guidance without prior public comment because it has determined that prior public participation is not feasible or appropriate (§ 10.115(g)(2) and (3)). FDA made this determination because benzene is a known human carcinogen, and the Agency seeks to facilitate the transition away from using carbomers manufactured with high levels of benzene. Publishing this guidance without prior public comment addresses the immediate public health need to expedite the discontinuation of the use of these carbomers and provides a less burdensome risk-based approach to applicant submissions, relative to existing guidances on SUPAC. Although this guidance document is immediately in effect, it remains subject to comment in accordance with FDA's GGP regulation.”

Due to the FDA’s request for omission of the previously mentioned USP monographs, applicants and manufacturers may need to reformulate their drug products to avoid use of these carbomers. The FDA’s final guidance for industry provides recommendations to applicants and manufacturers on what tests should be performed and what documentation should be submitted or available to support the reformulation of drug products that use carbomers manufactured with benzene.

For testing, the FDA recommends utilizing the ICH Q3 guidelines for testing of benzene. The ICH classifies solvents into three classes: Class 1 solvents are known or strongly suspected carcinogens (such as benzene) and environmental hazards; Class 2 are non-genotoxic animal carcinogens and possible causative agents of other irreversible toxicity; and Class 3 solvents are solvents with low toxic potential with no health-based exposure limits needed. Since benzene is a Class 1 solvent, its limits are preset by the ICH guidelines at a concentration limit of 2 ppm and it is noted that it should be avoided in pharmaceutical products.

Residual solvents are typically determined using chromatography techniques, with gas chromatography (GC) being the most common. Gas chromatography offers high sensitivity and resolution, making it suitable for the analysis of complex mixtures with a wide range of compounds. The technique is particularly adept at analyzing volatile and semi-volatile compounds, including benzene.

The majority of quality laboratories that were testing for benzene using USP monographs should consider reevaluating the testing and validations for those USP tests utilizing the carbomer monographs or the USP <463> residual solvents testing monograph. If benzene is being used in current production, testing will still need to be completed per the ICH guidelines. This requirement of a limit of 2ppm for benzene will still need to be documented and tested for in the quality testing process. The deleted monographs can still be used as a guideline or starting point for which to evaluate your current GC capabilities and to accurately assess whether your GC procedures can demonstrate that the benzene concentration is 2 ppm or less; however, the FDA is highly recommending removing all benzene from any part of the production process to discourage use and need of testing for benzene Residual solvent testing in the quality laboratory can be tough to achieve low ppm results accurately due to the ease in which trace amounts of other solvents found in the common chemistry laboratory can cross contaminate your sample. Any changes to testing schemes or validations needed in the laboratory will also need to be submitted to the FDA to show that if solvents are to be tested for benzene, the lab can consistently deliver quality test results to ensure the 2-ppm limit is met.

You can submit public comments about this guidance via the Federal eRulemaking Portal or by following the instructions at the bottom of the FDA webpage here. There is no stated deadline for submitting comments.

Applications for reformulation can be submitted to the FDA via https://www.regulations.gov.

Moving Forward

Benzene contamination in pharmaceuticals is a complex issue that requires ongoing collaboration between regulatory agencies, pharmaceutical manufacturers, and other stakeholders. While the risks associated with benzene exposure are well established, addressing this issue without compromising the availability of essential medications is crucial.

One factor that helps is that the pharmaceutical industry is increasingly embracing sustainable practices that prioritize environmental and human health. This includes developing greener manufacturing processes that minimize the use of hazardous chemicals, reducing the likelihood of benzene formation during drug synthesis.

Regulatory bodies play a pivotal role in setting and enforcing standards to ensure the safety of pharmaceutical products. Manufacturers, in turn, must adopt advanced testing methodologies and sustainable practices to minimize the risk of benzene contamination. As the pharmaceutical industry continues to evolve, a proactive and collaborative approach is essential to protect public health and maintain the integrity of the drug supply chain. Integrating sustainability into drug development and manufacturing will likely become a key focus.

About The Author

Erika L. Roberts, MFS, is principal consultant and owner of ELR Lab Services LLC. Having more than 15 years of experience working in many different areas of the pharmaceutical/biotech manufacturing quality environments, she has particular expertise in sterility testing, microbial identification training, HPLC analysis, cGMP training, analytical chemistry, and pharmaceutical regulations. Roberts obtained a master’s in forensic science in 2006 with an emphasis in document examination.