FDA Provides New Industry Recommendations for the Reformulation of Drug Products Containing Carbomers Manufactured With Benzene

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The US Food and Drug Administration (FDA) recently released new guidance recommendations for drug product applicants and manufacturers on what tests should be performed and what documentation should be submitted or available to FDA to support the reformulation of drug products that use carbomers manufactured with benzene. According to the FDA, some United States Pharmacopeia (USP) carbomer monographs permit unacceptable levels of benzene, which raises safety concerns.¹ Benzene, a known carcinogen, has been detected in many personal care products in recent years, including sunscreen and aerosolized dry shampoo.

The FDA now requests that the USP remove monographs, and drug product applicants and manufacturers “may need to reformulate their drug products to avoid using these carbomers.”

“First and foremost, the big picture here is that the FDA is clearly stating to the public that ‘benzene is a known human carcinogen,’ and that several manufacturing building blocks (called carbomers) for health and personal care products are contaminated with cancer-causing benzene. The FDA specifically states, ‘certain US Pharmacopeia carbomer monographs currently allow for unacceptable levels of benzene,’ (some as high as 5,000 parts per million). This means the manufacturing process of many everyday products, from sunscreens, after-sun care products, antifungal sprays, anti-perspirants, hand sanitizers, dry aerosolized shampoos, benzocaine topical anesthetic spray, and others, needs reform to avoid benzene-containing carbomers,” said Christopher Bunick, MD, PhD, associate professor of dermatology and physician-scientist at the Yale School of Medicine in New Haven, Connecticut, in an interview with Dermatology Times.

Bunick added, “I view this FDA update as its formal acknowledgment to the public that benzene is a very dangerous carcinogen, it is in fact contaminating multiple products being used by the public, and that it is not acceptable this is occurring. For the FDA to publicly affirm what Valisure, myself, and others have been saying for the past ~3 years regarding benzene contamination is reassuring that the FDA intends to fully correct this problem. This update to drug manufacturers does exactly that - it lays out a plan for eliminating carbomers with high benzene levels and provides manufacturers guidance on what testing will be required for products that must be reformulated with new/different carbomers.”

In its guidance announcement, the FDA lists carbomers as a group of polymers composed of acrylic acid that are often used as inactive ingredients in drug products such as fillers, emulsifiers, gelling agents, and binding agents. The FDA also states that there are currently carbomers used as inactive ingredients and manufactured using benzene as a polymerization solvent. Despite the 2018 ICH Q3C guidance and USP General Chapter <467> Residual Solvents recommendations against the use of benzene when manufacturing drug products, multiple grades of carbomers manufactured using benzene as a solvent are still used in pharmaceutical products, “even though alternative grades of carbomers manufactured without the use of benzene are available.”

According to the FDA, carbomers manufactured with benzene that are used in FDA-regulated drug products 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 allow benzene levels as high as 5,000 parts per million (ppm). Unlike these monographs, the USP-NF Carbomer Homopolymer, Carbomer Copolymer, and Carbomer Interpolymer monographs cover carbomers that are manufactured without benzene and limit benzene as an impurity to no more than 2 ppm. Therefore, the FDA has asked USP to remove the Carbomer 934P, Carbomer 940, Carbomer 934, Carbomer 1342, and Carbomer 941 monographs from the USP-NF compendium.

“Under section 501(a)(2)(b) of the FD&C Act (21 U.S.C. 351(a)(2)(B)), a drug that is not manufactured, processed, packed, or held in conformity with current good manufacturing practice to assure that the drug meets requirements for safety, and quality and purity characteristics, which it purports or is represented to possess, is considered adulterated. Manufacturers should not use benzene in the manufacture of drugs,” wrote the FDA in the new guidance.

David Light, CEO

“This new guidance is a particularly strong action from the FDA, and we applaud the agency for taking the threat of carcinogenic benzene contamination seriously. Unlike previous measures, this directive goes beyond monitoring and urges the reformulation of affected drug products, which is a substantial undertaking for manufacturers. This a major step towards fundamentally weeding out the problem as it requires manufacturers to remove a raw material, ‘carbomer,’ that Valisure identified in its March 2021 FDA Citizen Petition as a likely source of benzene contamination. Carbomer is a gelling agent that can be used in gels, creams, lotions, suspensions, and oral tablets, all of which are affected by this new FDA reformulation guidance,” said David Light, chief executive officer of Valisure, an independent laboratory that chemically tests drugs and consumer products in New Haven, Connecticut, in an interview with Dermatology Times.“Since Valisure’s March 2021 FDA Citizen Petition on benzene in hand sanitizers, numerous products have been recalled for benzene contamination through December of 2023. We need this type of action to address the fundamental root causes of benzene contamination, in addition to the testing and recalls we've seen for over 2.5 years.”

Reformulation Requirements

Based on the FDA’s update, for drugs that are recognized in an official compendium, manufacturers that use Carbomer 934P, Carbomer 940, Carbomer 934, Carbomer 1342, and Carbomer 941 as solvents will be required to reformulate to eliminate these carbomers in their products once the USP monographs have been removed. The FDA recommends that manufacturers select an alternative grade of carbomer with a similar chemical composition and one that is manufactured without benzene.

According to the FDA guidance, when switching to non-benzene-containing grades of carbomers, drug applicants and manufacturers should consider the following information regarding chemistry, manufacturing, and controls; in vitro release or dissolution testing; and in vivo bioequivalence documentation.

• Applicants are responsible for evaluating the effects of any postapproval compositional change on the identity, strength, quality, purity, and potency of the drug product as they relate to the safety or effectiveness of the drug product before the distribution of the drug product made with the change. Applicants must submit proposed formulation changes through supplements to their applications.
• For applicants and manufacturers (including manufacturers of OTC monograph drugs) making such a formulation change, information to support compliance with current good manufacturing practice requirements must be documented and made available for the FDA to review during an inspection under section 704(a)(1) of the FD&C Act (21 U.S.C. 374(a)(1)) or when requested by FDA in advance or in lieu of an inspection as described in section 704(a)(4) of the FD&C Act (21 U.S.C. 374(a)(4)).
• The studies that should be conducted following the reformulation of drug products with alternative carbomers include tests for critical quality attributes for drug products (e.g., applicable comparative physicochemical and structural characterizations), and in some cases, additional bioequivalence studies depending on the dosage form, route of administration, intended use, and the scope/level of the proposed change as determined by the principles described in the applicable SUPAC guidance.

Different Dosage Forms

The available dosage forms to submit to the FDA include:

• Semisolid dosage forms
  • Applicants and manufacturers should follow the recommendations in the guidance for industry Nonsterile Semisolid Dosage Forms: Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation (May 1997) (SUPAC-SS guidance) for the appropriate tests and studies to be conducted and documented, as well as for the recommended submission type, if applicable.
• Immediate-release solid oral dosage forms
  • Applicants and manufacturers should follow the recommendations in the guidance for industry Immediate Release Solid Oral Dosage Forms: Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (November 1995) (SUPAC-IR guidance) for the appropriate tests and studies to be conducted and documented, as well as for the recommended submission type, if applicable, except as otherwise noted in this guidance.
• Modified-release solid oral dosage forms
  • Applicants and manufacturers should follow the recommendations in the guidance for industry SUPAC-MR: Modified Release Solid Oral Dosage Forms: Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation (September 1997) (SUPAC-MR guidance) for the appropriate tests and studies to be conducted and documented, as well as for the recommended submission type, if applicable, except as otherwise noted in this guidance.

Additional requirements for each form can be found here.

Benzene Contamination in Recent Years

Major news of benzene contamination in personal care products began in 2021 with Valisure’s discovery of detectable levels of benzene found in certain sunscreen and after-sun products. Since then, benzene has been detected in numerous other products including antifungal products, aerosolized antiperspirants, aerosolized dry shampoo, and more.

What concerns researchers and physicians the most is that these benzene-contaminated products are absorbed through the skin, and benzene has been associated with blood cancers such as leukemia. Now, all eyes are on the FDA as it takes the necessary steps toward requiring the reformulation of drug products containing carbomers manufactured with benzene.

Christopher Bunick, MD, PhD

“The current FDA update formally and publicly acknowledges the dangerous problem of benzene contamination in products. It comes after numerous products were found to have high levels of benzene and underwent some level of recall. Importantly, companies performing their own quality control of products recalled have validated the high benzene findings. The FDA has made the critical step of explicitly calling for a move away from manufacturing ingredients contaminated with high benzene (such as high benzene carbomers). What else needs to happen? I think in 2024 the manufacturers now need to respond publicly, identifying what products are built off the contaminated carbomers, and release their plan for how they will transition their manufacturing process away from those carbomers according to the FDA-provided guidance. Many manufacturers may have to re-formulate and re-test their products, which is not convenient, but it is the right thing to do for the long-term good of public health,” said Bunick.

Calling Attention to Other Carcinogens Found in Personal Care Products

In October 2023, the FDA released a proposed ban on formaldehyde or formaldehyde (FA)-releasing chemicals, another known carcinogen, found in hair smoothing or straightening products. In its proposed ban, the FDA stated, “Use of hair smoothing products containing FA and FA-releasing chemicals is linked to short-term adverse health effects, such as sensitization reactions and breathing problems, and long-term adverse health effects, including an increased risk of certain cancers.” According to the FDA, when hair smoothing products are heated during a hair treatment, formaldehyde is released into the air as a gas. If a hair salon does not have proper ventilation, both the hair stylist and client are at risk of inhaling the harmful gas.²

When asked about the correlation between benzene and FA and why additional FDA action is needed overall, Bunick provided the following analysis:

“Benzene and formaldehyde are similar in that they are both Group 1 carcinogens according to the American Cancer Society and many other agencies. Benzene is most commonly linked with leukemias, whereas evidence connects the use of formaldehyde and formaldehyde-releasing chemicals with the risk of uterine and breast cancer. One study showed 2.4% higher rates of uterine cancer among women 70 or older who used hair straightening products with formaldehyde in the previous 12 months compared to no use.

The fundamental difference between the two is that formaldehyde and formaldehyde-releasing chemicals are purposeful ingredients put into products and can be found on the product label, whereas benzene is a contaminant from the manufacturing process and cannot be found on the package label. Thus, in the case of benzene, consumers have no ability to know the level of benzene in any of the products they are using. Unlike in the case of benzene contamination, formaldehyde and methylene glycol should be listed on the product ingredient label. Consumers can check labels and avoid products with formaldehyde or formaldehyde-releasing chemicals. However, formaldehyde and methylene glycol have synonyms, and product labels may differ between manufacturers making quick identification of problem ingredients on the label difficult. For example, formaldehyde may be listed as formalin or formaldehyde monohydrate, or methylene glycol listed as methanal or methanediol.

Public health and safety are of paramount importance. Therefore, more FDA action is needed in order to ensure proper manufacturing processes and guidelines are actually followed by drug manufacturers. Unfortunately, quality control measures have not been sufficient when left to self-regulation; FDA government oversight provides a layer of urgency and officialness to the problem and hopefully forces manufacturers to truly do what is best for the patient, not for profit.”

Continuing Improvement

When looking ahead to future changes and improvements, Light stated, “We at Valisure hope to see manufacturers quickly implement this new guidance to weed out carbomers and reduce the risk of benzene contamination. We also hope to see the FDA continue to take strong action on the ongoing problem of benzene in drug and cosmetic products. There are other major sources of benzene contamination, like propellants in aerosol spray products, which are often contained in products like spray sunscreens, body sprays, and dry shampoos. Valisure continues to investigate this serious issue of benzene in drug and cosmetic products, including with new technologies like SIFT-MS that can detect benzene directly from the air, and hopes to work with FDA, manufacturers, and major health systems to minimize benzene exposure and enhance public health.”

References

1. Reformulating drug products that contain carbomers manufactured with benzene: guidance for industry. US Food and Drug Administration. December 27, 2023. Accessed January 5, 2024. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/reformulating-drug-products-contain-carbomers-manufactured-benzene

2. Use of formaldehyde and formaldehyde-releasing chemicals as an ingredient in hair smoothing products or hair straightening products. Department of Health and Human Servies. October 16, 2023. Accessed January 5, 2024. https://www.reginfo.gov/public/do/eAgendaViewRule?pubId=202304&RIN=0910-AI83