Exploring Red No. 3 ban reformulation strategies for Rx, OTC drugs

Behind the ban

Despite the growing concern for public safety, the ban on Red No. 3 is not based on any new human safety data. Instead, Schoneker clarified that the FDA's decision was a result of the "legal nuance, related to the outdated Delaney clause," a 1958 provision of the Food, Drug and Cosmetic (FD&C) Act.

Under the Delaney Clause's precautionary zero-tolerance rule, the FDA is required to ban any food or color additive if any "credible study" demonstrates carcinogenicity in humans or animals, regardless of dose or real-world risk to health.

Technically, that bar was met in a 1980s study in which male rats fed a high-dose (4%) diet of Red No. 3 (2,464 mg/kg/body weight per day; ~123,000× higher than the average adult daily intake of 0.02 mg/kg/body weight) for 30 months showed increased thyroid follicular cell changes and adenomas.

"I saw pictures of what the rats looked like at the lab. The rats' skin turned bright red," Schoneker recalled. "That's how much of this dye was being fed to these rats. In no way would humans ever be exposed to anything like this."

Though the study findings satisfied the Delaney Clause, the FDA concluded the thyroid tumors were caused by a hormonal mechanism that is rat-specific, leaving the dye's authorization status unchanged.

"None of the lower-dose studies that were more reasonable showed any issue[s]," Schoneker added. "The FDA didn't believe there was any [human] safety concern from this study."

Regulatory compliance timeline

The Center for Science in the Public Interest and 23 co-petitioners filed a color additive petition (CAP) on Nov. 15, 2022, asking the FDA to rescind the approval of FD&C Red No. 3 in all foods, dietary supplements and ingested drugs, citing the Delaney Clause.

Bound by the decades-old amendment, the FDA issued its final action on Jan. 15, 2025, withdrawing authorization of Red No. 3, requiring manufacturers of the following products to comply by these dates:

• Jan. 15, 2027. Foods and dietary supplements.
• Jan. 15, 2028. Prescription and over-the-counter medications.

According to the agency, all U.S. drugs containing Red No. 3 must be reformulated or pulled from the market by the 2028 deadline. However, Schoneker warned that increasing political and advocacy pressure could push organizations to act sooner.

"The FDA has talked in some public forums about trying to move that date up… [but for now] it's simply voluntarily asking the industry to try to do it quicker," Schoneker clarified.

Reformulation considerations

As Schoneker mentioned before, a ban on synthetic dyes, like Red No. 3, and the broader push toward natural colors present substantial technical and regulatory challenges for pharmaceutical manufacturers.

Industry experts recommend that companies be proactive in exploring possible reformulation opportunities and develop a strategy to determine how and when to make changes, if necessary, by considering the following:

• Regulatory acceptance. Verify that the potential replacement colorant has gone through the FDA's CAP process and is approved for specific use in drugs. Just because a color is approved for use in certain foods, it doesn't mean it is approved for drugs, Schoneker warned. For example, riboflavin, also known as vitamin B2, is approved as a food colorant but isn't listed as an approved drug color additive.
• Technical performance. Compared to synthetics, natural pigments are more sensitive to light, heat and pH, making it challenging to achieve the 2–3-year shelf life required for medications. Many natural colorants also contain components that differ with season and supplier, creating potential interactions with active pharmaceutical ingredients that are difficult to foresee or control.
• Shade and taste matching. Matching natural alternatives to synthetic colors can be tricky because they are generally less bright, have weaker tinting strengths and often require larger quantities to match existing colors, which can affect taste, palatability and other formulation properties.
• Supply chain and cost. The global natural color supply chain is not currently equipped to meet the demand if the entire industry shifts away from synthetic colors. Schoneker cautioned that a sudden increase in demand would undoubtedly lead to "significant shortages of certain colors" and could have "a dramatic impact on pricing" for both colorants and products.
• Allergenicity. Natural dyes can cause allergic reactions. For instance, carmine, a red dye extracted from female cochineal beetles, triggers an allergic response in 1–2% of children.

Navigating the regulatory process

The FDA has issued a draft guidance document on "Replacing Colors in Drug Products" to assist companies in navigating the reformulation process for Red No. 3. The guidance offers some flexibility for companies that can meet specific criteria, potentially allowing for a simpler submission process (CBE 30) instead of a prior approval supplement.

However, Schoneker noted that many reformulations are unlikely to meet the criteria because replacing synthetic colors often requires adjusting the levels of other excipients, since natural colors are generally weaker, shaded differently and rarely one-to-one replacements.

Schoneker also advised that global drug makers should be cautious about moving too quickly, adding that Red No. 3 and "other synthetic colors are still used in medicines in Europe." Although U.S. products using Red No. 3 will ultimately require reformulation, other FD&C synthetic colors are not banned and remain permitted, with no substantiated safety or hyperactivity concerns to date, he said.

In the meantime, he encouraged companies to "start doing investigations" into potential alternatives and work with trusted suppliers to understand what is physically possible and what will be available for future use. While the Red No. 3 drug compliance deadline might not be as immediate as it is for foods and dietary supplements, exploring viable options now can prepare organizations for these regulatory changes.

And since finding appropriate replacements that work in each application can be challenging, it's best to start the process sooner rather than later, Schoneker advised.

Alivia Kaylor is a scientist and the senior site editor of Pharma Life Sciences.

Editor's note: This article was updated on Aug. 13, 2025, to incorporate several clarifications provided by the speaker, Dave Schoneker.