Awareness is increasing about the value of nutritional compounds to general good health. However, consumers appear to only be interested in taking so many dietary supplements. Thus, the market is seeing tremendous growth in conventional food and beverage products adding new ingredients that can bolster energy, boost antioxidant capacity or improve cardiovascular health.

“Food manufacturers are increasingly looking to add value to their products, and the functional food sector is growing rapidly,” noted Rakesh Kapoor, Ph.D., director of science and technology at Bioriginal. To help meet that need, Bioriginal—like many other suppliers—has taken one of its dietary ingredients (BioAsteri® borage oil) through the GRAS affirmation process.

GRAS is the acronym for Generally Recognized As Safe. It is a specifically-designated regulatory category for conventional foods. Ingredients added to conventional foods must be approved as food additives or be GRAS, both of which assure “reasonable certainty” of safety. Ingredients commonly used in food prior to 1958, when the Food Additives Amendment was added to the Federal Food, Drug and Cosmetic Act (FFDCA), are automatically GRAS, as are substances for which relative scientific agreement exists as to the safety.

In 1971, the Food and Drug Administration (FDA) promulgated a regulation implementing a public rulemaking process for review of GRAS petitions. The GRAS petition regulation required a review of the dossiers completed by the companies and an approval of the GRAS notification. However, the pre-market approval process took a great deal of time and resources, which FDA found were out of proportion to the public safety benefit.

Therefore, in 1997, the agency proposed a GRAS self-affirmation notification process; while it has not been finalized, FDA is operating under the aegis of the rule with industry buy-in. “The GRAS process is now essentially an independent process with the same safety requirements as food additives, but without FDA approval,” said Melody Harwood, scientific and regulatory consultant with Cantox Health Sciences, one of several industry regulatory consulting firms that provide GRAS determination assistance. “It is more cost- and time-effective to go through the self-affirmation process.”

In the process of self-affirmation, companies work to assemble a comprehensive dossier of scientific substantiation and historical documentation supporting the safe use of the compound. Because of the requirement of “general recognition”, the pivotal data for safety substantiation must be part of the public domain. During the review process, companies work to define particular food categories of interest as well as the usage levels for those categories. “It is important to define the categories and use levels, as safety falls under the dose and exposure that are estimated to come from use of the ingredient,” Harwood added. The final determination by an expert panel includes reviewing technical evidence about the safety of the ingredient for its intended use and common knowledge about the safety of the ingredient, with the data providing “reasonable certainty” of safety.

Interestingly, neither the original 1971 regulation nor the more recent self-affirmation process requires FDA notification. However, if FDA disagreed with a company’s GRAS determination, it could initiate regulatory action, deeming the ingredient an unapproved food additive and/or a food adulterant. “Manufacturers have always been free to deem foods and food components as GRAS in self affirmation and then go straight to market,” said David Seckman, executive director of the National Nutritional Foods Association (NNFA). “But most manufacturers filed petitions under the GRAS process rather than risk FDA disagreeing with the GRAS determination and initiating regulatory action.”

Lou Carson, a spokesman with FDA, confirmed GRAS notification is not currently a requirement, and added notification does not result in “approval” of a GRAS substance. “GRAS notifications are evaluated only as a consultation regarding whether the notice provides a basis for GRAS status,” he said. “If FDA has no questions, the notifier generally feels confident that it can market the product legally. If FDA questions the notice, the notifier may wish to prepare a new notice addressing GRAS status more completely, may decide to submit a food additive petition seeking approval, may decide not to proceed with product development, or may decide to market the product anyway because it believes use is GRAS in spite of the unacceptable notice—risking possible enforcement action.”

While the benefit of affirming an ingredient as GRAS is it can be incorporated into specific food applications, there are continued misconceptions about what GRAS means. The most common misconception concerns the relationship between GRAS substances and dietary ingredients used in dietary supplements. Information provided by FDA’s Office of Nutritional Products, Labeling and Dietary Supplements noted there are two categories of ingredients used within dietary supplements: dietary ingredients (exempt from food additive requirements) as defined within Section 201(ff)(1) of the FFDCA; and other ingredients such as color additives, processing aids, flavors and capsule ingredients, which are regulated like any other food ingredient and must either be GRAS or an approved food (color) additive.

If the dietary ingredient was on the market as a dietary supplement prior to the passage of the Dietary Supplement Health & Education Act (DSHEA) of 1994, it is “grandfathered” for use in such products. If not, it is considered a new dietary ingredient (NDI) and must meet one of two criteria. If the NDI was present in the food supply and used for food in the same form as this NDI, it is exempt from the New Dietary Ingredient Notification (NDIN) process (Sect. 412(a)(1)), and a manufacturer would be free to use it in a dietary supplement provided its use is safe within the meaning of the FFDCA. Otherwise, NDI notification is required (Sec. 412(a)(2) of FFDCA), whereby the supplier provides information to FDA establishing the NDI will be reasonably expected to be safe for dietary supplement use. [For further background and legal interpretation on this issue, see related story, page 56.]

Therefore, GRAS status does not impact whether an ingredient is subject to NDIN requirements. GRAS covers the use of substances in conventional foods, and for specific food applications. While many GRAS substances can be used in dietary supplements, GRAS or food additive status does not necessarily mean an NDI is safe for use in dietary supplements. Carson noted, “While information that providesthe basis of GRAS/food additive status may assist in determining whether use as a dietary ingredient is safe, it is not de facto evidence that the NDI is safe under the new dietary ingredient standard.”

Some of the concern about NDINs stems from the fact that the NDIN process is seen as setting a higher bar for companies. “Many NDINs are being rejected by FDA, despite the fact that Congress set up a different threshold for safety of supplement ingredients— reasonable expectation of no harm,” said George Burdock, Ph.D., with the Burdock Group, a regulatory consulting firm. “FDA is essentially taking dietary ingredients to the higher GRAS threshold— reasonable certainty of no harm, which is the reason many NDINs are being turned down.”

The differences in the safety threshold have come into play for some ingredient suppliers. “Obtaining GRAS status is much more difficult than obtaining approval for an NDI,” said Bob Capelli, vice president of sales with Cyanotech Corp., which self affirmed the GRAS status of its Hawaiian Spirulina Pacifica®.

Scott Backman, market development manager for the functional food and food technology group at Cognis Nutrition & Health, noted meeting the different regulatory requirements for NDIs and GRAS substances pose specific challenges. However, he said, “Ingredients that have achieved GRAS status are likely to have adequate safety information to also pass the safety requirements of an NDIN.”

So why do companies go through the process? The most obvious reasons are to tap into a growing market and to assure customers of an ingredient’s safety. “GRAS status is an important safety assurance for manufacturers, so it makes an ingredient more desirable from a sales standpoint,” said Manashi Bagchi, Ph.D., senior scientist, research and development, with InterHealth Nutraceuticals. “Many large manufacturers require it as a matter of course.”

Ronald R. Martin, vice president of sales and marketing with Polyphenolics, said his company has found many food and beverage companies require both GRAS self-affirmation and FDA notification before considering using a new ingredient. “It is important for companies to know the GRAS status so they are aware there is no risk in using the ingredient in that application, as well as the maximum use level,” he said. Polyphenolics underwent self-affirmation and notification for its MegaNatural® Gold grape seed extract and MegaNatural GSKE grape pomace extract.

In addition, as manufacturers are expanding into the functional food/beverage market, suppliers see a chance to bring the benefits of established dietary supplement ingredients to a new audience. Lonza, for example, aimed to bring the benefits of its L-carnitine product to consumers. “Dietary intake contributes to about 75 percent of the body’s L-carnitine stores, and maintaining these stores can be considered vital to optimal health and well-being,” said Kevin Owen, Ph.D., associate director of nutrition with Lonza. “As opposed to relying on red meat consumption, American consumers can choose from convenient, healthy food sources of L-carnitine in the form of L-carnitine-enriched conventional foods.” Lonza worked with Cantox Health Sciences to obtain self-affirmation on its L-Carnipure® L-carnitine for several categories including beverages, grain products and plant protein products.

Nutrition 21 took a different route for notification; after completing its self-affirmation GRAS process with Environ for its Chromax® chromium picolinate, the company submitted the details with its petition for a qualified health claim. Jim Komorowski, vice president of technical services and scientific affairs with Nutrition 21, said the company sought GRAS affirmation not only to meet increasing demands from food companies for safe, efficacious fortificants, but also to provide safety documentation if questions came up about the use of chromium.

That documentation is one of the key items that regulatory consultants suggest manufacturers request when incorporating GRAS substances into new foods. “Manufacturers should ask for the documentation, specific use levels and applications,” Harwood suggested. “Generally, out of a GRAS determination, a supplier receives a letter signed by the expert panel that includes a summary of the data they used to come to the safety conclusion, product specifications, and the ingredient food categories and usage levels.”

Because GRAS determination applies to specific usage levels and ingredient categories, it is important to ensure the new usage will be legal. “Formulators should ask about a company’s GRAS status to ensure their intended application has been included in the GRAS evaluation,” Backman said. Cognis self-affirmed its XANGOLD® lutein esters as GRAS for a number of food and beverage options; it has also undergone the self-affirmation process for its Vegapure® phytosterols and Tonalin® conjugated linoleic acid (CLA).

In addition to opening up new markets, undergoing the GRAS process can provide ingredient suppliers with a leg up on the competition. Self-affirmation and notification procedures cover only the indicated ingredient, and for the uses and dosages specified. While there is allowance for an abbreviated affirmation procedure if a compound can be shown to be substantially equivalent to an existing GRAS compound, there are requirements involved. “GRAS is particular to a single ingredient, with the manufacturing process and specifications taken into account,” Harwood noted. “It may make the process easier if another company supplying a similar ingredient has gone through self-affirmation, but that second company still has to go through the determination on its ingredient.”

One critical point is the extent of differences in composition or characteristic properties. “There are different processes used by different companies to produce the same ingredient,” Capelli noted. “Some companies take extra care and expense to produce ingredients with higher quality. If a company affirms its ingredient as GRAS, that does not apply to other ingredients across the entire category.”

Juliana Zeiher, new ingredient and technologies manager for GTC Nutrition, agreed that GRAS status provides a competitive advantage in the food market. “Using GRAS ingredients ensures the safety for consumption will be attained,” she said. “Most manufacturers do not use non-GRAS ingredients, because they are concerned with the safety of the finished products they develop.” GTC’s NutraFlora® and Aquamin™ have been the subject of GRAS notifications, while CalciLife™ is self-affirmed GRAS.

Komorowski said while the GRAS affirmation process does take time and money, it has significant benefits in the market. “GRAS determination by qualified experts applies to the company’s specific ingredient,” he said. “And that helps reward suppliers who move ahead to ensure the safety and applications of their product.”

Classification of Ingredients for Use in Dietary Supplements
by Anthony L. Young, Esq.

A driving force behind the dietary supplement industry’s push for enactment of the Dietary Supplement Health and Education Act of 1994 (DSHEA) was the Food and Drug Administration’s (FDA) use of the 1958 Food Additive Amendments to the Federal Food, Drug, and Cosmetic Act (FFDCA) as an enforcement tool.FDA’s approach was to sue a company marketing a product claiming that an ingredient in the product was an unapproved food additive. The company would then have the “burden of proof” to show the ingredient was GRAS (generally recognized as safe), and thus exempt from the food additive approval requirement.To counter whatever a company proffered, FDA would put up scientists who would review the information and conclude the ingredient was not GRAS, and the courts would generally rule in FDA’s favor. Evening primrose oil was an ingredient FDA pursued under this legal theory.

DSHEA addressed FDA’s use of the Food Additive Amendments by exempting dietary ingredients used in dietary supplements from their reach. In addition, DSHEA created a new definition of “adulteration” that defines when dietary supplements, and not foods, are deemed to be adulterated.That provision [21 U.S.C. Sec. 342(f)] contains the significant caveat, addressing FDA’s past practice, that states: “In any proceeding under this subparagraph, the United States shall bear the burden of proof on each element to show that a dietary supplement is adulterated. The court shall decide any issue under this paragraph on a de novo basis.”

Through DSHEA, FDA’s past practice of using the Food Additive Amendments of 1958 as an enforcement tool against dietary ingredients was put to an end. It also made the use of GRAS self-affirmations, GRAS notifications, GRAS regulation petitions or food additive approvals irrelevant and of no legal consequence with respect to the marketing of new dietary ingredients (NDIs) for use in dietary supplements;except, if an ingredient meets the standard of GRAS for food, it might also meet the requirements applicable to NDIs.

Under DSHEA, there are two classes of dietary ingredients: “old” dietary ingredients and “new” dietary ingredients. The term NDI means a dietary ingredient that was not marketed in the United States before Oct. 15, 1994 [21 U.S.C. Sec. 350b(c)], whereas an “old” dietary ingredient is one that was marketed prior to that date. In 1995, the dietary supplement industry trade associations prepared lists to memorialize the principal ingredients used in dietary supplements at that time, but the FDA does not recognize these lists as authoritative.

Under DSHEA’s NDI provision, a dietary supplement that contains a NDI is deemed adulterated unless one of two conditions is met. The first condition is that the NDI has been present in the food supply as an article used for food in a form in which the food has not been chemically altered. In this case, the legislative history of this provision describes chemical alteration as not including the following:“minor loss of volatile components, dehydration, lyophilization, milling, tincture or solution in water, slurry, powder, or solid in suspension.” If an NDI meets this definition, there is no requirement that FDA be notified in advance of marketing.

If the first condition for an NDI cannot be met, then an NDI notification is required to be made to FDA that must include evidence that there is a history of use or other evidence of safety establishing that the NDI, when used under the conditions recommended or suggested in the labeling of the dietary supplements to which it will be added, is reasonably be expected to be safe. Such a notification must be made at least 75 days before the NDI is introduced into U.S. commerce. The notification must include the information, including any clinical—not non-clinical—studies and any citation to published articles, which is the basis on which the company has concluded a dietary supplement containing the NDI will reasonably be expected to be safe when used as labeled. If a product containing an NDI is marketed without the required notification, FDA may take the position that the product is adulterated as a matter of law.

Anthony Young has practiced food and drug law for over 30 years. He is a partner at Kleinfeld, Kaplan and Becker, LLP (www.kkblaw.com).