On May 30, 2025, FDA published a draft guidance titled “Replacing Color Additives in Approved or Marketed Drug Products.”U.S. Food & Drug Admin., Replacing Color Additives in Approved or Marketed Drug Products: Draft Guidance for Industry (May 2025) (Draft Guidance). The draft guidance provides industry with recommendations for replacing color additives in approved or marketed drug products under a Section 505(b)(1) new drug application (NDA)FDA’s recommendations in the draft guidance do not apply to drugs approved under Section 505(b)(2) of the FDCA because applicants may not submit supplements to 505(b)(2) NDAs for changes that create a different drug, as described in 21 C.F.R. § 314.70(h). or abbreviated new drug application (ANDA). FDA’s recommendations include how to select a replacement color additive and how to document the change.Id. FDA clarifies in the draft guidance that “applicants” refers to holders of approved NDAs and approved ANDAs, and that “manufacturers” refers to manufacturers of drug products marketed under an NDA or ANDA (including contract manufacturers), drug products not marketed under a drug application (i.e., over-the-counter monograph drug products), compounded drug products subject to Section 503B of the FDCA, and other drug products subject to current good manufacturing practice (CGMP) requirements. Id. at 2.
For drug products subject to an approved Section 505(b)(1) NDA or ANDA, FDA recommends that sponsors notify FDA that they have replaced a color additive in their products through changes being effected in 30 days (CBE-30) supplements.Id. CBE-30 supplements differ from prior approval supplements (PAS), which require prior FDA approval for changes that have a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product. Through a CBE-30, holders of pending or approved 505(b)(1) NDAs or ANDAs may notify FDA of a moderate change they have made to a drug product that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product.Id. at 4. CBE-30 supplements thus streamline FDA’s oversight of changes to a drug product, reducing the regulatory burden on FDA and industry.
The draft guidance describes additional factors for applicants and manufacturers of drug products to consider when replacing a color additive. Most notably, FDA stresses that when companies select a color additive to replace another in their drug products, the replacement additive must conform with the color additive requirements under the Food, Drug and Cosmetic Act (FDCA) and FDA’s implementing regulations.
The draft guidance provides a streamlined pathway for industry to comply with changes to FDA’s color additive framework, which may signal that additional measures to phase out or prohibit the use of other widely used, certified color additives in ingested drugs, such as FD&C Red No. 40 and FD&C Yellow No. 6, may be on the horizon. Indeed, at the press conference announcing the measures that FDA plans to take to phase out the use of widely used color additives in food, Commissioner Makary stated that “FDA is taking action to remove petroleum-based food dyes from the U.S. food supply and from medications” (emphasis added).HHS/FDA Hold Press Event on Intent to Remove Food Dyes, https://www.youtube.com/watch?v=9A3hAR2mBPg&t=864s, at 14:26.
The FDCA and FDA’s regulations define a color additive as any dye, pigment, or other substance that can impart color to a food, drug, cosmetic, or the human body.21 U.S.C. § 321(t); 21 C.F.R. § 70.3. Under Section 721(a) of the FDCA, a color additive cannot be used in a drug product unless FDA has authorized the color additive in its regulations and the color additive and its use conform with the specific authorized use.21 U.S.C. § 379e(a). For drug products, these regulations are codified in Subparts B of 21 C.F.R. Parts 73 and 74. The color additives are further designated as either certified or non-certified, depending on whether they are synthetically produced.Id. § 379e(c). Batches of the color additives listed in 21 C.F.R. Part 74 must be certified with FDA before they are used to color a drug product, while the color additives listed in 21 C.F.R. Part 73 may be used without batch certification. For certified color additives, FDA is required to certify that batches conform with the process outlined in 21 C.F.R. Part 80.
If FDA amends a color additive regulation, drug products containing that color additive must be modified to comply with the amended regulation.Id. § 379e(a). Similarly, if FDA repeals a regulation authorizing a color additive for a specific use, any drug product containing that color additive will be considered adulterated and thus cannot be legally marketed.Id. FDA may accordingly take enforcement action against drug products containing an unauthorized color additive, or FDA may deny importation of such drug products under Section 801 of the FDCA.21 U.S.C. §§ 331(a), 381(a).
FDA states that, while changes to the formulation of a drug product’s inactive ingredients are generally considered major changes, in many cases, replacing a color additive with another listed in its color additive regulations is unlikely to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product.Id. at 4. For drug products subject to an approved NDA or ANDA, FDA accordingly recommends notifying FDA of such changes through a CBE-30.Id. FDA clarifies that a CBE-30 would not be appropriate for changes in the levels of other inactive ingredients that exceed 5% of the target unit dose weight, and for a major change that would require FDA approval before the change is implemented and the product is distributed.Id. at 4-5. To determine whether changes are minor or major, FDA recommends that applicants refer to 21 C.F.R. § 314.70 and FDA’s “SUPAC” guidances, which it identifies in Footnote 29 of the Draft Guidance. See id. at 4 n.29.
When selecting a replacement additive, FDA advises industry to consult its color additive regulations. As noted above, the color additive regulations must list the additive in either Subpart B of 21 C.F.R Part 73 or Subpart B of 21 C.F.R. Part 74. If the additive is listed in the latter subpart, batches of the additive must be certified with FDA before use. Additionally, use of the replacement additive must conform with the specifically authorized use in the listed regulation. FDA notes, for example, that 21 C.F.R. § 73.1200(c) restricts the total amount of synthetic iron oxide that may be used to color ingested drugs to 5 milligrams per day.
FDA says in the draft guidance that it expects sponsors to support a color additive replacement through development of in vitro data and stability data.Id. at 8, Table 1. FDA recommends that this information be retained at the manufacturing site, and that sponsors include such information in a CBE-30.
FDA also recommends that sponsors update their products’ labeling to accurately reflect the color additive replacement, although FDA acknowledges that 21 C.F.R. § 201.100(b) does not require that inactive ingredients — including most color additives — be disclosed in product labeling for oral drug products.Id. at 6 n. 44. Certain color additives such as FD&C Yellow No. 5 and FD&C Yellow No. 6 must be disclosed on labels. See 21 C.F.R. § 201.20.
To ensure that the post-change drug product continues to meet established specifications through the product’s expiry date, FDA provides a series of recommendations for sponsors to evaluate the change. These include the following, which range in regulatory burden and complexity:
FDA also provides detailed recommendations for updating manufacturing records, all of which should be retained at the manufacturing facility. These include updating the replacement color additive’s name (using the name listed in its color additive regulation), its level, and the regulation or regulations with which it complies; the statement of ingredients in the drug product labeling, including the DESCRIPTION section of the Prescribing Information and the container label or labels; and the specifications for drug product release and stability if the replacement color additive changes the description of the drug product, such as its appearance from red to pink.Id. at 8.
Aside from FD&C Red No. 3, FDA has not banned the use of other widely used color additives in ingested drugs, such as FD&C Yellow No. 6. The draft guidance does not alter the regulatory framework for color additives, and it does not expressly indicate that FDA plans to take such a step. But the timing of its publication — coupled with a recent statement from Commissioner Makary and FDA’s scrutiny of color additives in foods — suggest that drug product companies should be prepared for changes on the horizon.
The draft guidance provides a framework for companies to comply with the recent ban of Red No.3 and any further prohibitions on the use of color additives. By recommending that color additive replacements be documented in a CBE-30 as opposed to a PAS, FDA has signaled its willingness to facilitate the transition. Nevertheless, selecting a new color additive and following FDA’s recommendations for evaluating the post-change drug product could prove burdensome. Given FDA’s specific focus on certified color additives, sponsors might want to consider a transition to certification-exempt color additives when making changes. Replacing one certified color additive with another may prove a short-lived solution if FDA eventually takes action against them as a class.
Latham will continue to monitor for additional updates on FDA’s plans regarding the use of color additives in drug products.