Yesterday, the FDA issued a draft guidance titled “Replacing Color Additives in Approved or Marketed Drug Products” (here). We all know that removing or partially removing a color from a product was an easy annual reportable change, and this remains unchanged in the draft guidance. However, changing a color by replacing it with another color additive was classified as a level 3 change requiring a prior approval supplement (see questions 1 and 2 under SUPAC-IR Questions and Answers about SUPAC-IR Guidance (here). With the issuance of this new draft guidance, in most cases the changing of a color additive will be down-regulated to a Changes Being Effected in 30 days supplement (CBE-30).

There are (of course) limitations as to what color additives (defined by the FDA “as any dye, pigment, or other substance that can impart color to a food, drug, cosmetic, or the human body”) may be incorporated into a drug product under this guidance. For instance, FDA requires that “color additives used in approved or marketed drugs must be listed in the color additive regulations.” Thus, this guidance addresses both drugs that are approved by the FDA, marketed over-the-counter drugs, and prescription drugs that may be marketed without FDA approval.

The FDA expects full documentation which is defined in the guidance for manufacturers and applicants and requires changes to be made in accordance with current good manufacturing practices and record-keeping requirements.

Replacement of a color additive may be required by the FDA when they determine that a particular color additive is no longer safe (as is the case for Red Dye #3) or just for business reasons. This guidance will provide a down-regulated approach to accomplish such changes.

The FDA discusses its rationale for the changes in filing requirements by stating “Although changes to the ‘qualitative or quantitative formulation of the drug product, including inactive ingredients,’ are generally considered major changes, in many cases, replacing a color additive with one that is listed in the color additive regulations is unlikely to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product. Therefore, for a drug product marketed under an NDA or ANDA, replacing a color additive can generally be considered a moderate change that applicants can submit in a CBE-30. However, if changes are made other than replacing a color additive and making the associated adjustments in excipient levels described in this section, a CBE-30 may not be appropriate, and a prior approval supplement may be warranted. A CBE-30 must be submitted at least 30 days before distribution of the postchange drug product. To submit a CBE-30 for a color additive replacement, the change should NOT (emphasis added) include:

  • Changes in the levels of other inactive ingredients that exceed 5 percent of the target unit dose weight.
  • A major change that would require FDA approval before the change is implemented and the product is distributed. This includes changes that the FDA determines to have the potential to adversely affect the safety or effectiveness of the drug product. This could occur when factors associated with the change (e.g., diluents in the color mixture) necessitate a more extensive assessment because a specific population uses the drug product (e.g., neonates).”

The draft guidance includes sections that address the documentation expected, including but not limited to, stability requirements (at least three months of stability studies conducted at accelerated and room temperature conditions to confirm previous expiration dating periods), pharmaceutical development and in vitro dissolution studies, batch size requirements, updating and validating analytical methods as appropriate, updated labeling to reflect the new color as well as, the change in ingredients and updating specifications. There is also a table that outlines a summary of recommended documentation for replacing a color additive.

Please read the document carefully to best understand the requirements as they apply to your situation. The unanswered question in this draft guidance is when can these changes be implemented, given this guidance is still in draft, even though the draft expresses the Agency’s current thinking on this issue! We will have to wait and see.