Key Takeaways
- Color additives used in drug products must conform to FDA regulations and be properly listed and approved for the specific use.
- While a qualitative or quantitative change in inactive ingredients is generally considered a major change, the FDA's guidance generally considers the replacement of one approved color additive with another to be a moderate change that can be submitted via a "Changes Being Effected in 30 Days" (CBE-30) supplement.
- Products containing unlisted or improperly used color additives risk being deemed adulterated or misbranded, with potential regulatory consequences including enforcement actions or refusal of entry.
On May 27, 2025, the Food and Drug Administration (FDA) released a new draft guidance, "Replacing Color Additives in Approved or Marketed Drug Products" (Guidance), that outlines regulatory expectations for manufacturers and applicants seeking to replace color additives in drug products. The Guidance applies to drug manufacturers and applicants and to a broad range of products, including those marketed under approved New Drug Applications, Abbreviated New Drug Applications, over-the-counter monograph drugs, and compounded drugs under Section 503B of the Food, Drug, and Cosmetic Act (FD&C Act). It does not apply to drug products where the color additive is the active ingredient, to Section 505(b)(2) of FD&C Act applications where a change would create a different drug, or to biologics (unless a color additive is used as an inactive ingredient). Comments on the draft Guidance are due within 60 days of its publication in the Federal Register.
Under the FD&C Act, color additives used in drug products must conform to FDA regulations and be properly listed and approved for the specific use. If the regulation governing a color additive is repealed or amended due to safety concerns or other reasons, the additive must be removed or replaced. The Guidance clarifies that such replacements may also be made proactively for business or formulation purposes, provided that the substitute additive complies with applicable listing, certification, and use restrictions. The Guidance further provides a framework for ensuring that such replacements comply with applicable requirements and do not adversely affect product quality, safety, or efficacy.
Notably, while a qualitative or quantitative change in inactive ingredients is generally considered a major change, the Guidance generally considers the replacement of one approved color additive with another to be a moderate change that can be submitted via a CBE-30 supplement. This is a departure from prior guidance, which treated most qualitative or quantitative changes as major changes requiring prior approval. To qualify for the CBE-30 pathway, the substitution must not involve a change in other inactive ingredients beyond 5 percent of the unit dose or otherwise rise to the level of a major change under FDA regulations. Removal of a color additive without replacement may be treated as a minor change suitable for reporting in an annual report.
Applicants and manufacturers must update labeling, drug product specifications, master batch records, and composition statements to reflect the change. They are also expected to generate and retain supporting documentation, including pharmaceutical development data, stability studies, batch release data, and in vitro test results, to demonstrate continued compliance with Current Good Manufacturing Practice and product specifications. In some cases, especially where the colorant serves a functional role beyond aesthetics, additional testing may be necessary to ensure that the replacement additive maintains the drug's integrity and performance. Updated labeling must accurately reflect the identity of the new color additive and any changes in product appearance.
Manufacturers must retain all records at the production site and ensure they are available to FDA during inspections or upon request. Firms planning to use a color additive not already listed for the intended use must first petition FDA for approval. Importantly, products containing unlisted or improperly used color additives risk being deemed adulterated or misbranded, with potential regulatory consequences including enforcement actions or refusal of entry. Applicants and manufacturers should review current formulations and procedures to ensure that all color additives are appropriately listed, certified if required, and used in accordance with their approved conditions.
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