The FDA’s recent draft guidance proposing a streamlined path for color additive changes in drug products has generated significant attention across the pharmaceutical industry. While many trade organizations support the agency’s move toward regulatory flexibility, several have called for further revisions to address lingering challenges related to formulation transparency, bioequivalence expectations, and National Drug Code (NDC) implications.
A Shift Toward Regulatory Flexibility
The FDA’s draft guidance, issued in July 2025, would allow certain color changes in drug products to be submitted as a “Changes Being Effected in 30 Days” (CBE-30) rather than requiring a Prior Approval Supplement (PAS). This would apply only when specific conditions are met and is intended to replace the 1997 SUPAC-IR guidance that previously categorized color changes as major modifications.
Industry groups including the Association for Accessible Medicines (AAM) and the Pharmaceutical Research and Manufacturers of America (PhRMA) welcomed the proposal. AAM stated that the new guidance reflects a more balanced regulatory approach and acknowledged the FDA’s recognition that replacing one approved color additive with another generally does not impact a drug’s safety, efficacy, or quality.
PhRMA also applauded the shift, calling it consistent with broader deregulatory initiatives and a necessary step to ease burdens on sponsors.
Calls for More Transparency in Q1/Q2 Sameness
Despite overall support, AAM raised concerns about how the FDA handles Q1/Q2 sameness determinations, especially in the context of complex generics. Under current policy, the FDA does not disclose which ingredient failed to meet Q1/Q2 standards when rejecting a formulation. This lack of transparency can create costly and time-consuming delays for sponsors attempting to develop therapeutically equivalent generics.
Q1/Q2 sameness refers to both the qualitative and quantitative alignment of excipients with the reference-listed drug (RLD), a standard often difficult to meet in complex formulations such as injectables, topicals, or ophthalmics. AAM urged the FDA to provide more clarity on this process, especially when color additives are the only variable.
Inconsistencies with Product-Specific Guidances
AAM also flagged a disconnect between the general principles in the draft guidance and requirements in some product-specific guidances (PSGs). For example, FDA guidance for nitazoxanide requires full in vivo bioequivalence studies when Q1/Q2 sameness is not demonstrated, even if only the colorant differs. AAM recommended that PSGs be revised to align with the scientific principles underpinning the draft color additive guidance, including acceptance of in vitro data where appropriate.
NDC Changes and Market Confusion
Another issue not fully addressed in the draft guidance is the potential need to update National Drug Codes when a color change occurs. FDA regulations require a new NDC if a distinguishing feature of the product—such as color—changes. However, the draft guidance does not specify whether this applies in all cases, including minor or barely perceptible changes.
AAM emphasized that such changes could confuse consumers and healthcare providers, especially when original and modified versions are available simultaneously. They urged the FDA to clarify when a new NDC is required and to consider public education strategies to prevent confusion.
Additional Industry Perspectives
PhRMA echoed the need for clarity around when a color change would still require a PAS and recommended that the guidance outline FDA’s process for delisting color additives. Other commenters, such as the International Pharmaceutical Excipients Council of America (IPEC-America), suggested expanding the guidance to include modified-release dosage forms.
Meanwhile, the excipient manufacturer Colorcon questioned the necessity of the new guidance, citing existing regulatory flexibility provided by the 2014 FDA guidance on post-approval chemistry, manufacturing, and controls (CMC) documentation.
Preparing for Future Changes
As the FDA reviews these comments and considers next steps, drug developers should monitor how this guidance evolves. EMMA International continues to support clients navigating formulation changes, regulatory submissions, and Q1/Q2 strategies. Our experts are available to assist with pre-submission planning, regulatory impact assessments, and CMC documentation.
For more information on how EMMA International can assist, visit www.emmainternational.com. Contact EMMA International at (248) 987-4497 or by email at info@emmainternational.com to learn more.
References
Eglovitch, J. (2025, August 4). Pharma groups suggest changes to FDA’s guidance on replacing color additives. Regulatory Focus. Retrieved from https://www.raps.org/news-and-articles/news-articles/2025/8/pharma-groups-suggest-changes-to-fda-s-guidance-o
