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 Delaney clause," a 1958 provision of the Food, Drug and Cosmetic (FD&C) Act.

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

And technically, that bar was met in a 1980s study in which male rats fed a 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."

Though the study findings satisfied the Delaney Clause, the FDA concluded the thyroid tumors were caused by a mode of action that is largely rodent-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 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 and heat, making it difficult to achieve the 2–3-year shelf life required for medications.
• Shade and taste matching. Matching color with natural alternatives can be difficult because they're generally less bright and often require large amounts that risk affecting palatability.
• 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 lead to "significant limitations" 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 changing the levels of other excipients, as natural colors are generally much weaker.

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."

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 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.

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