Pharma groups suggest changes to FDA’s guidance on replacing color additives

Industry groups representing drugmakers have expressed support for a US Food and Drug Administration’s (FDA) draft guidance that would make it easier to replace color additives in drugs, though they sought further changes to simplify the process. Pharmaceutical excipient groups have raised several issues with the guidance.

The draft guidance, issued in July, would allow changing the color of a tablet through a changes being effected in 30 days (CBE-30), rather than requiring a prior approval supplement (PAS), under certain conditions. (RELATED: FDA proposes downgrading drug color additive changes to CBE-30, Regulatory Focus 30 May 2025)

This document would replace the an guidance issued in February 1997, titled "SUPAC-IR Questions and Answers about SUPAC-IR Guidance." SUPAC stands for Scale-Up and Post-Approval Changes. In the previous guidance, changing the color of a product was considered a major change. The deadline for public comment closed on July 29.

The Association for Accessible Medicines (AAM) and the Pharmaceutical Research and Manufacturers of America (PhRMA) largely supported the draft guidance.

AAM said that it “appreciates the issuance of the draft guidance clarifying the steps that an applicant must take when replacing color additives in approved or marketed drug products. We also appreciate the recognition in the draft guidance that replacing a color additive with one that is listed in the color additive regulations is unlikely to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product and, as a result, the draft guidance takes a less burdensome approach than is generally taken with regard to a change in the qualitative (“Q1”) or quantitative (“Q2”) formulation of a drug product.”

PhRMA concurred that the draft guidance “marks an important shift from prior guidance.” The group states that “in making this shift, FDA will reduce undue regulatory burdens on sponsors seeking to change color additives. Doing so also will achieve an important deregulatory effect consistent with the Administration’s deregulatory initiatives.”

Yet the groups said that certain changes are needed to improve the guidance.

AAM said that its members “feel that more needs to be done to authorize the disclosure of Q1/Q2 information and remove unnecessary barriers and delays for generic drugs. As you know, if FDA determines that a proposed generic formulation does not satisfy Q1/Q2 sameness, the agency only informs the generic applicant of that determination and does not disclose the ingredient at issue or any details about deviations in concentration. Generic applicants must continue to submit proposed formulations to FDA until Q1/Q2 sameness is demonstrated.”

In pharmaceutical development, Q1/Q2 sameness refers to the qualitative and quantitative similarity of inactive ingredients compared to the reference-listed drug (RLD).

This issue is particularly pronounced for complex generics such as injectables, otic preparations, ophthalmic drugs, and topicals. AAM noted that for these products, demonstrating Q1/Q2 sameness is notably challenging.

AAM also indicated a disconnect between the draft guidance, which states that demonstrating comparability when replacing color additives generally does not require an in vivo bioequivalence (BE) study, and some of FDA’s product-specific guidances (PSGs), which do requires these studies.

As an example, the group cites FDA’s PSG guidance for nitazoxanide, which states that if the test product formulation cannot demonstrate Q1/Q2 sameness to the RLD, bioequivalence should be established by conducting in vivo BE studies with clinical endpoints and pharmacokinetic endpoints and in vitro comparative dissolution testing.

AAM said that “we encourage FDA to clarify in PSGs that, based on the same scientific principles that it is applying to replacing color additives, it may be possible to conduct in vitro studies rather than in vivo BE studies to support approval of a product with a different color additive than the RLD.”

Another shortcoming cited by AAM is the guidance does not take into effect upcoming changes to the National Drug Code (NDC). FDA’s regulations require a new NDC for changes in the drug’s distinguishing characteristics such as color, but the guidance does not address the NDC.

“The guidance should address whether every color additive change would necessitate a new NDC or only those that change the color. For regulatory efficiency, the guidance should address scenarios when, for example, the color is only slightly changed due to a color additive replacement. More broadly, FDA should take steps to address potential consumer confusion over changes in color, particularly given that the original and new formulations may be on the market concurrently.”

In July 2022, FDA proposed an update to the NDC, replacing the existing 10-digit format with a 12-digit format in anticipation of a looming exhaustion of these codes within the next ten to 15 years. In an interview with Focus, Tish Pahl, an attorney with Olsson Frank Weeda Terman Matz PC, said that a final rule is expected sometime next year, said Pahl. (RELATED: FDA announces plans to revamp national drug code, Regulatory Focus 26 July 2022)

In its comments, PhRMA also suggested greater clarity on the situations where FDA would expect a prior approval supplement (PAS) instead of a CBE-30 to replace a color additive.

“The draft guidance is ambiguous about which types of changes would qualify as having ‘the potential to adversely affect the safety or effectiveness of the drug product.’”

PhRMA also recommended revising the draft guidance to say that FDA cannot disclose proprietary information about inactive ingredients.

The group also recommends the draft guidance clarify the process for delisting color additives. “The draft guidance does not address the statutory requirements for delisting a color additive, nor does it specify the process FDA plans to use to delist a color additive from the agency’s color additive regulations,” PhRMA wrote.

Still other groups took issue with the guidance. The International Pharmaceutical Excipients Council of America (IPEC-America) said that only Immediate Release (IR) dosage forms were referenced in the draft guidance and recommended the guidance address other dosage forms such as modified-release (MR) drug products.

Colorcon, an excipient manufacturer, stated that it is unclear why the FDA issued this guidance, given that flexibility already exists in the FDA's March 2014 guidance regarding chemistry, manufacturing, and controls (CMC) for documenting post-approval manufacturing changes in annual reports.

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Pharma groups suggest changes to FDA’s guidance on replacing color additives

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