Addressing benzene contamination, FDA issues guidance for reformulating products containing certain carbomers
In response to a series of alarming studies and citizen petitions regarding benzene contamination, the FDA requested removal of five specific United States Pharmacopeia (USP) monographs for carbomer ingredients containing high amounts of benzene. Now, the FDA has released guidance laying out the tests and regulatory submissions needed for the reformulation of products containing these ingredients.
Background: Benzene impurities
- The U.S. Pharmacopeia (USP) defines impurities as “any component of the drug substance that is not the chemical entity that is defined as the drug substance” or, “any component of a drug product that is not the drug substance or an excipient in the drug product.” For regulators, there are two primary concerns associated with impurities – that they may cause a drug substance to degrade (thereby reducing its efficacy or safety) and that the impurities (or their effects on the drug substance) may be harmful to patients.
- To help control impurities, the FDA requires all starting materials used in drug manufacturing and final pharmaceutical products to be evaluated for “identity, strength, quality and purity.” The agency has adopted the International Council on Harmonisation (ICH) Q3C guideline that provides recommendations on acceptable amounts of residual solvents in pharmaceuticals. [Read AgencyIQ’s analysis of the ICH guideline here].
- One impurity of concern to regulators is benzene, which the Q3C guideline classifies as a Class 1 impurity, or a solvent that should be avoided due to its carcinogenic and environmental hazard properties. Per the FDA, “In small amounts over long periods of time, benzene can decrease the formation of blood cells. Long term exposure to benzene through inhalation, oral intake, and skin absorption may result in cancers such as leukemia and other blood disorders.” If the use of benzene is unavoidable, the ICH guidelines recommend that benzene be present at less than two parts per million (2 ppm).
- Benzene may occur in some products from the degradation of other ingredients, increasing the risk for unintentional contamination. The FDA states that the presence of benzene in many products “may be related to inactive ingredients such as carbomers (thickening agents), isobutane (a spray propellant), or other drug components made from hydrocarbons.” Thus, certain ingredients may warrant scrutiny throughout the life cycle of the drug because of the potential risk of benzene contamination during the manufacture process or through degradation.
Citizen petitions have raised the alarm regarding benzene in recent years, leading to FDA action
- Valisure, an analytical pharmacy that first alerted the FDA to concerns associated with nitrosamine impurities, recently set its sights on benzene impurities. The company submitted four separate citizen petitions to the FDA from March 2021 through October 2022 regarding benzene impurities. These citizen petitions alleged the presence of benzene in various consumer products, which ultimately resulted in voluntary recalls of many popular and recognizable products, including hand sanitizers, sunscreen and after-sun care products, antiperspirant and deodorant body sprays, and dry shampoo. [ See AgencyIQ’s in-depth analysis of these petitions here.].
- In response, the FDA announced in late 2021 that drug manufacturers are advised to ensure appropriate quality testing to avoid benzene contamination. If benzene is detected, the FDA provides a chart on how manufacturers should contact the FDA based on the results. The agency said it will be “taking a stepwise approach” by identifying and recalling products with a benzene level at or above 2 ppm.
- In late 2022, the FDA also announced it was working with USP to remove certain monographs from their compendium. Per the FDA, certain carbomer monographs published by USP allow for unacceptable levels of benzene. The FDA has requested that USP remove five specific monographs which allow for “residual benzene levels that are significantly higher than the 2 ppm” permitted by ICH Q3C. USP posted a notice of intent to omit these monographs, with a targeted official date of August 1, 2025.
- The agency also seems to be shoring up its own regulatory science capabilities, as evidenced by two recent contract notices. A consumer-oriented FAQ on Benzene Contamination in Drugs states that the FDA is evaluating the root cause of benzene contamination and that the agency “continually gain[s] additional knowledge about drugs which allows us to identify and quickly address previously unknown risks to consumers.” In July 2022, the FDA issued a contract notice in search of a “contract laboratory [to] test ~200 drug product samples for benzene, using validated test method(s)” in order to evaluate root cause and risk factors for contamination. According to the FDA, this contract was awarded and is nearing completion. In August 2023, the agency issued an additional contract notice seeking a laboratory to test ~150 OTC drug products for benzene, specifically “aerosol products consisting of sunscreens, antiperspirants, foot sprays and foam-based hand sanitizers.”
Now, a new guidance provides clear instructions for reformulating products containing certain carbomers
- On December 28, 2023, the FDA released an immediately-in-effect guidance titled “Reformulating Drug Products That Contain Carbomers Manufactured With Benzene.” The document was featured for the first time on the 2023 CDER Guidance Agenda, suggesting a relatively quick turnaround. The FDA explains in the document that prior public comment was not obtained because the document “addresses the immediate public health need to expedite the discontinuation of the use of these carbomers.”
- The purpose of this new guidance is “to help facilitate and expedite the reformulation of drug products that use carbomers manufactured with benzene.” As mentioned above, once the USP monographs have been removed, reformulation will be required. In the meantime, the FDA is asking manufacturers to begin moving in that direction. The guidance explains that “pending the USP’s removal of the monographs for these carbomers that contain unacceptable levels of benzene, the FDA recommends that manufacturers select an alternative grade of carbomer that is manufactured without the use of benzene and has similar chemical composition (e.g., carbomer homopolymer) and physical properties (e.g., viscosity, rheology).” The carbomers that will need to be discontinued are Carbomers 934P, 940, 934, 1342 and 941.
- According to the FDA, this guidance “provides a less burdensome risk-based approach to applicant submissions, relative to existing guidances on SUPAC [scale-up and post-approval changes].” A quick background on SUPAC: As most drug products are made in relatively small batches during the development program, the FDA maintains SUPAC guidances for companies to utilize as they either expand production capacity or make other changes, such as using a new facility. The company must notify the FDA of all manufacturing changes, while certain changes also require prior FDA approval. The existing SUPAC guidances, which cover immediate-release and modified-release solid oral dosage forms, as well as nonsterile semisolid dosage forms, were published in the late 1990s.
- In general, manufacturers are responsible for evaluating the effects of any reformulations on the “identity, strength, quality, purity, and potency of the drug product.” Studies supporting drug product reformulation include tests for critical quality attributes (CQAs) to compare the physicochemical and structural characterizations of the product before and after the change. Additional bioequivalence studies may sometimes be required depending on the dosage form and route of administration, according to risk-based SUPAC principles.
- To assist manufacturers with assessing the impact of reformulation on a given product, the guidance outlines recommendations and requirements according to dosage form, route of administration and scope of change. Semisolid dosage forms, as well as immediate-release and modified-release solid oral dosage forms, are subject to the testing recommendations in the associated SUPAC guidances. For the purposes of those guidances, level 2 changes will be considered those in which the benzene-manufactured carbomer is substituted with “an alternative carbomer that has similar chemical composition and physical properties and in a similar quantity.” This should be documented through submission of a changes being effected in 30 days (CBE-30) supplement. When the new ingredient does not meet these qualifications, the changes will be considered level 3. Here, applicants and manufacturers should follow the SUPAC recommendations for level 3 changes and submit a prior approval supplement (PAS).
- Given that oral suspensions are not addressed in current SUPAC guidances, the guidance document outlines expectations for stability testing, which should be performed “according to an established stability protocol.” This should involve three months of accelerated stability data for one batch, with one batch placed on long-term stability studies. For other dosage forms or routes of administration not addressed in the document, the guidance instructs applicants to seek recommendations from the FDA through formal communication methods.
- In a concluding note, the agency states that “the above recommendations generally apply to premarketing changes as well as postmarketing changes. However, in the event of premarketing changes, applicants should contact FDA for recommendations.”
- The sole Appendix provided in the guidance document offers an especially useful resource – a table summarizing the recommended test documentation and filing documentation for each formulation type.
- This guidance provides key information to applicants and manufacturers that formulate products with the five carbomers scheduled for USP monograph removal. The document lays out the tests that must be conducted, as well as the information that must be submitted for successful reformulation, providing a concise and straightforward path for navigating the decades-old SUPAC guidances. Manufacturers now have a roadmap that will allow them to address the use of these carbomers prior to the removal of the USP monographs – targeted for August 2025.
- The FDA may begin to take a more proactive approach related to benzene contamination, which could include surveilling for benzene content during facility inspections. In April of this year, the FDA released a warning letter for failure to adequately investigate benzene contamination. This warning letter, directed to Accra-Pac, Inc (dba Voyant Beauty) in Indiana, was sent after an on-site inspection of the facility, which manufactures OTC drugs and cosmetics. The letter states that FDA investigators collected samples of three drug products during the inspection, all of which were found to contain benzene when tested. According to the FDA’s Warning Letters database, this appears to be the first benzene-related warning letter that is not associated with hand sanitizer products.
- As AgencyIQ has previously discussed, this guidance and other recent agency actions show an overall trend toward increased scrutiny of product contamination. The agency has recently released a string of warning letters to companies that did not adequately test product components for possible contamination with the toxic ingredients diethylene glycol (DEG) or ethylene glycol (EG) [See AgencyIQ’s analysis of FDA’s activities related to DEG/EG here.]. And just one day prior the publication of this benzene guidance, the FDA released a revised draft guidance on topical ophthalmic drug product quality, adding additional microbiological considerations in the wake of a spate of recalls and warning letters related to actual and potential contamination [ Read AgencyIQ’s analysis of the guidance here]. When considered together, this means that the agency now has a very broad range of products and ingredients that are expected to be adequately tested to prevent contamination – and all of this is without even touching on the FDA’s participation in a globally harmonized effort to detect and mitigate nitrosamines in medicinal products.
Key Documents and Dates
- Reformulating Drug Products That Contain Carbomers Manufactured With Benzene
- FDA Docket No.: FDA-2023-D-5408