FDA’s recent focus on potentially harmful color additives in food products has expanded to the pharmaceutical sector. In May 2025, FDA issued a draft guidance titled Replacing Color Additives in Approved or Marketed Drug Products. This guidance signals FDA’s increasing attention to the use of colors in all consumable products, including both prescription and over-the-counter (OTC) drugs. In doing so, the guidance outlines FDA’s expectations for selecting suitable replacements for color additives and providing appropriate documentation in regulatory filings when drug formulation changes are planned.
FDA’s Growing Concern Over Color AdditivesThe recent draft guidance comes on the heels of several state actions to restrict the use of color additives in food to varying degrees, as documented in our Well Done blog. The guidance also follows FDA’s action to phase out all petroleum-based synthetic dyes from food and ban the use of Red Dye No. 3 (erythrosine) in food and ingested drugs. Notably, though, the recent draft guidance is not specific to drug products containing these synthetic dyes, but applies broadly to any proposed drug reformulation that seeks to replace a color additive—that is, any dye, pigment, or other substance that can impart color. The draft guidance thus demonstrates FDA’s active encouragement of voluntary changes to drug formulations that contain color additives, consistent with its other color-safety initiatives.
Broad Applicability in the Pharmaceutical Sector
The draft guidance has broad applicability to prescription and OTC drugs alike, regardless of market entry pathway. The recommendations apply to approved new drug applications (NDAs), abbreviated new drug applications (ANDAs), drug products subject to the OTC monograph system, and compounded drug products under Section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA). However, the draft guidance does not apply to drug products in which the color additive is the active pharmaceutical ingredient (e.g., methylene blue) or to biologics subject to approved biologics license applications (BLAs).
Replacement of Color Additives Triggers CGMP Activities
For applicable products, formulations that include color additives not listed in FDA’s color additive regulations are adulterated. Consequently, the draft guidance states that drug applicants and drug manufacturers should ensure that any replacement color additives are listed in FDA’s regulations and meet all specified use criteria and restrictions. The draft guidance also reminds industry to consult FDA’s inactive ingredients database for reference levels in particular dosage forms of approved products, and to conduct pharmaceutical development studies and stability testing. FDA further recommends updating manufacturing records, labeling, batch records, and product specifications to document any changes in color additives, as required under Current Good Manufacturing Practices (CGMP).
Easing of Post-Approval Regulatory Filing Pathway
A key part of the draft guidance is FDA’s recommendation that color additive replacements can sometimes be submitted via a Changes Being Effected in 30 Days (CBE-30) Supplement rather than a prior approval supplement (PAS), the latter of which requires significant product quality testing and a lengthy FDA review timeline under various user fee programs. Under the draft guidance, FDA suggests that changes to color additives could be regulated as moderate manufacturing changes in certain cases. Replacing a color would involve a moderate change if (1) the new color additive is already listed in FDA’s color additive regulations, (2) the change does not involve increasing other inactive ingredients by more than 5% of the target unit dose weight, and (3) no other associated changes would potentially impact product safety, identity, strength, quality, purity, or potency. Outside of these parameters, a PAS would be required, since a major change includes use of a color additive that introduces a new safety concern or dictates other formulation changes beyond the color additive replacement that could impact the product’s critical attributes.
By lessening the regulatory burden for applicants and manufacturers in this way, FDA smooths its own path for revoking the authorization of color additives in the future. Nevertheless, many potential formulation changes would still trigger a PAS.
Moreover, other longstanding laws and policies are implicated by these drug reformulation plans, such as the generic drug “sameness” requirement under FDCA Section 505(j), the 505(b)(2) NDA prohibition on post-approval changes that create a “different” drug, and the product design requirement to assess potential impacts on patient safety, such as medication error avoidance, dosing regimen adherence, adequate differentiation for a multiple strength dosing regimen, and the protection of vulnerable pediatric and geriatric patient populations.
Therefore, manufacturers should carefully assess the overall scope of any changes when determining a color replacement strategy and the appropriate regulatory filing category.
Key Takeaways
The draft guidance reflects FDA’s current thinking on color additive changes to drug product formulations and the agency’s intent to align oversight of color additives across product categories and its supervisory centers. Drug manufacturers should review current product formulations, identify “at-risk” excipients, monitor the regulatory status of color additives, and ensure that robust change management and regulatory submission processes are in place when evaluating potential changes to product formulations to address color additive concerns. The draft guidance is currently open for public comment until July 29, 2025.