Read about a New Database to Keep Track of GRAS Self-Determinations

Last November, our company, natural products consulting firm AIBMR Life Sciences Inc. (Puyallup, WA), announced the launch of the first-ever GRAS Self-Determination Inventory Database (GSID). The purpose of this searchable database is to make available in one place all of the GRAS (Generally Recognized as Safe) self-determinations that either AIBMR was able to find mentioned in the public domain or determinations that manufacturers themselves brought to our attention. The database is funded solely by AIBMR and is available free of charge at www.aibmr.com.

As discussed ahead, FDA’s GRAS self-determination process has had its share of critics. AIBMR hopes that its database plays a role in making information on the numerous self-determinations by various companies more readily accessible, transparent, and easily tracked.

History of the Self-Affirmed GRAS Process

The 1958 Food Additives Amendment to the Federal Food, Drug and Cosmetic Act (FFDCA) defined that any substance intentionally added to food is a “food additive” and requires premarket approval by FDA in the form of a food-additive petition. There is one exception: substances that are generally recognized as safe for their intended use, among experts qualified by scientific training and experience to evaluate their safety, are exempt from definition as a “food additive” and hence from FDA premarket approval requirements. To specify which substances are considered GRAS, FDA created a list of GRAS substances-ingredients with a safe history of use prior to 1958 (referred to as the GRAS List). This list, however, was not intended to be all-inclusive, and manufacturers would often request FDA’s opinion about other ingredients they believed to be GRAS.

In the 1970s, after FDA began a more formal review process of GRAS substances under the direction of President Nixon (via the Select Committee on GRAS Substances), FDA established a voluntary petition affirmation process whereby companies could petition FDA to affirm that a substance was generally recognized as safe. After review and a public comment period, if FDA affirmed a substance as GRAS, a final rule would be issued. However, in reality, FDA took years to bring GRAS petitions to closure and publish final rules. Because of this, manufacturers would often market a substance while it was still under review by FDA. It was considered legal to do so because, as mentioned, the FDA GRAS petition affirmation process was voluntary. In other words, as long as qualified experts agreed that an ingredient is GRAS (a “self-determination” or “self-affirmation” of GRAS status), the ingredient was legally GRAS. Ultimately, the responsibility of safety fell upon the manufacturer, supplier, or distributer of the ingredient. Of course, FDA always has the authority to investigate the use of an ingredient that it believes may be of public health concern.

In 1997, FDA proposed a new GRAS rule, in order to help reduce the backlog of voluntary GRAS petitions. The proposed rule has yet to be finalized but is currently the rule that is followed. In contrast to the voluntary GRAS petition program, the new, proposed voluntary GRAS notification program eliminates the requirement that FDA issue final rules for GRAS substances. This saves FDA a large amount of time. FDA stated that the lengthy rulemaking process (publishing a filing notice, requesting public comments, drafting detailed responses, publishing final rules, etc.) provided limited public health benefit, especially because manufacturers were often marketing the substances prior to an FDA decision.

Instead, companies that have self-determined their ingredient as GRAS, most often with the help of industry expert consultants, have the option to notify FDA of their determination. FDA encourages, but does not require, that companies notify the agency of their self-determinations and to consult with FDA about the safety of ingredients. As opposed to the voluntary GRAS petition process, the voluntary GRAS notification process involves submitting just a detailed summary of a determination. It takes FDA approximately 180 days to review and respond to these notifications. Rather than issuing a final rule, FDA responds to a manufacturer’s FDA GRAS notification by a letter that states one of three things:

• FDA has no questions: If FDA cannot find any reason to disagree with the GRAS self-determination’s conclusion that the ingredient is reasonably expected to be safe for its intended use, the agency issues what is commonly referred to in the industry as the “no objection” letter. The “no objection” response is highly valued in industry. While a “no objection” letter is not legally required in order to sell an ingredient, many multinational food corporations strongly encourage the companies they work with to notify FDA of their self-determinations and obtain a “no objection” letter before the corporation will accept an ingredient for use in its food products. Receiving a FDA “no objection” letter gives a company additional marketing power for its ingredient.
   

• At the notifier’s request, FDA has ceased evaluation: In some cases, FDA may have more questions about the basis for the determination of safety than the manufacturer is prepared to answer in a reasonable period of time. In these cases, it is prudent for a company to ask FDA to cease evaluating its notification at present. However, it should be noted that even if this occurs, all of the information submitted will still be made publicly available on the FDA’s GRAS Notice Inventory website (this is true for all notifications). Of course, the GRAS notification can be rewritten and resubmitted to FDA at a later date.
   

• The notice does not provide a basis for a GRAS determination: This response indicates that FDA does not agree with the self-determined conclusion that the ingredient is GRAS. This could occur because FDA believes that an ingredient is unsafe for its intended use or because the notification was inadequately prepared and does not provide adequate information to show that the ingredient is safe for its intended use. FDA is generally quite clear in articulating to the notifier the agency’s questions about the safety of an ingredient and how reasonably it predicts that the questions could be answered in a relatively short period of a few weeks. If answers to FDA questions will take a long period of time to prepare, notifiers generally opt to request that FDA cease evaluation of the notification (#2 above) and will resubmit a revised notification at a later date.

Recent Criticisms of the GRAS System

In February 2010, the U.S. Government Accountability Office (GAO), in its report (GAO-10-246) to Congress, and more recently the Pew Health Group, expressed concerns about the current GRAS process. The GAO concluded that FDA should strengthen its oversight of self-determined GRAS ingredients. The GAO suggested that FDA finalize the GRAS rule, taking into consideration experiences with the process to date, and that the agency issue guidance about how to perform self-determinations, require companies to provide FDA with basic information about their self-determinations, and systematically reconsider the safety of GRAS substances.

Pew recently voiced similar criticisms during its evaluation of FDA’s process to ensure that substances added to food are safe. Pew noted that because notifying FDA of a self-determination is voluntary, FDA is unaware of many substances that are added to food and can’t ensure that self-determinations of GRAS status were properly made.

The GSID

AIBMR Life Sciences Inc. has a long history of guiding dietary supplement and functional food companies through FDA and FTC regulatory frameworks. In particular, the company specializes in GRAS self-determinations and FDA GRAS notifications and believes in the need for ongoing critical, scientific evaluation of the GRAS process.

AIBMR believes that the GSID addresses some of the concerns about the GRAS process. As a unique, publicly available database of ingredients that have been self-determined GRAS, the GSID provides a certain degree of transparency to both industry and government agencies about the number and types of substances that are being marketed as GRAS. It also functions as a searchable list for companies seeking novel ingredients that have GRAS status.

AIBMR is committed to maintaining the GSID database. As stated above, the information listed in the database is sourced from the public domain and also stems from direct requests by manufacturers to be added to the GSID. Currently, the database contains the following information: the trade and generic names of the substance; a brief description; the date that the self-determination was announced in the public domain; the name, country (if known), and hyperlink to the manufacturer; and a link to the article or press release announcing the GRAS status. Currently, the GSID contains self-determined ingredients from 20 different countries. It’s important to note that AIBMR has in no way evaluated the quality of the GRAS self-determinations.

It should also be noted that critical information such as the intended conditions of use and estimated daily exposure are not listed, in part because that information is not usually found in the public domain. It is extremely important that food manufacturers read and critically review GRAS determinations prior to adding these ingredients to the foods they produce. If companies feel they are not qualified to make such assessments, they should engage an independent organization that can on their behalf.

Some of the safety assessments for ingredients found in the GSID were later submitted to FDA in the form of voluntary FDA GRAS notifications and received the FDA “no objection” letter; in these cases, the FDA notification number is listed in the GSID as well. FDA maintains a separate database of all GRAS notifications (called the FDA GRAS Inventory) that the agency has received and filed.

AIBMR strongly encourages industry to participate in this effort by keeping AIBMR updated on any existing or future GRAS self-determinations. This is easy to do by sending the information by email to gras@aibmr.com.

When the 1997 proposed rule is finalized, we expect that FDA will take into consideration many of the criticisms of the GRAS process and recommendations from various organizations, in order to have a better handle on the safety of ingredients being added to food. At some point, FDA may require that if a company opts not to submit a GRAS notification, that it will at least need to submit basic information about its GRAS self-determinations and intended uses for the substances. Until that day, AIBMR hopes its investment for the good of the industry and public health will provide the public, industry, and government with an increased awareness of GRAS self-determined ingredients.