As Prescribed


FDA’s Office of Pharmaceutical Quality (OPQ) issued a new Manual of Policies and Procedures (MAPP) in June explaining the agency’s internal procedures for evaluating color additives and flavors in an oral drug product submitted as part of an investigational new drug application (IND), new drug application (NDA), and Type IV drug master file (DMF).[1] The goal of the MAPP is to “(1) identify the information on color additives and flavors to be documented by product quality assessors for Type IV DMFs, INDs, NDAs, and NDA supplements; and (2) delineate when a request for an [Office of New Drugs (OND)] evaluation of a flavor would become necessary during a quality assessment.” Based on the latest MAPP, companies should be prepared to provide FDA with additional information regarding color additives and flavors included in drug products as inactive ingredients.

Color additives and flavors play an important yet understated role in oral drug products, helping patients distinguish between products, providing a way for manufacturers to brand products, and helping to mask drug bitterness and enhance palatability. The regulation of these ingredients in the drug space, however, is quite complex, involving both the Center for Drug Evaluation and Research (CDER) and the Center for Food Safety and Applied Nutrition (CFSAN).  Moreover, it is important for drug manufacturers to understand the regulation of these ingredients, as noncompliance with FDA’s laws and regulations can result in product adulteration and application approval delays. Given the importance of these ingredients and the complicated nature of the area, greater transparency in how FDA evaluates color additives and flavors in drug products is a welcome development.

Color Additives. Under the new MAPP, OPQ will confirm that a color additive is listed in FDA’s regulations, that its use complies with regulatorily prescribed conditions, and that the additive is used within permissible levels, which levels may be listed in a regulation or may be based on historical use levels, as set forth in FDA’s Inactive Ingredient Database. Moreover, OPQ will also ensure that, if applicable, color additive batch certification requirements are included in the drug product’s component specifications.

Flavors. OPQ will review flavoring ingredients to determine if the ingredient is identified in the Code of Federal Regulations (CFR), a successful GRAS notification, or the Inactive Ingredient Database. In its safety evaluation, OND may also consider flavor substances used in food on the basis of self-determined GRAS status (whereby industry makes a GRAS determination that is not reviewed by FDA), but OND may have additional questions about such substances or about the GRAS self-determination for a particular application at a particular use level. (The MAPP states that OND “considers — but is not bound  by — food additive status, GRAS determinations, history of safe use in food, and other relevant safety information as it reviews the safety of flavor preparations . . . and individual flavoring substances . . . .”) If the flavor preparation previously was reviewed by FDA, OPQ will determine whether the proposed use exceeds any limits on the levels of use. On the other hand, if the flavor preparation is either new to FDA or its newly proposed use exceeds levels of use that FDA previously reviewed, then pharmacology and toxicology reviewers will evaluate the safety of the flavor preparation. Given the new MAPP, drug product applicants, including IND sponsors and DMF owners, should ensure that proper justification and support for use of color additives and flavorings in drug products are clearly set forth in the applicable FDA submissions. Moreover, companies with pending submissions that currently do not include this information should be ready to receive and respond to information requests as the agency works through the chemistry, manufacturing, and control section of the filing under the MAPP.

[1] The new MAPP does not apply to abbreviated new drug applications or their supplements because the Office of Generic Drugs already evaluates color additive and flavor acceptability.