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Great To Be GRAS

Albion Minerals®

With increased ingredient safety concerns and an exploding global functional food and beverage market, ingredient suppliers and experts talk about the importance and process of attaining GRAS status, and the role it could potentially play with NDIs.

According to the U.S. Food and Drug Administration (FDA), under sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act (the Act), any substance that is intentionally added to food is a food additive, that is subject to pre market review and approval by the FDA, unless the substance is generally recognized, among qualified experts, as having been adequately shown to be safe under the conditions of its intended use, or unless the use of the substance is otherwise excluded from the definition of a food additive. 

Under sections 201(s) and 409 of the Act, and FDA’s implementing regulations in 21 CFR 170.3 and 21 CFR 170. 30, the use of a food substance may be GRAS (generally recognized as safe) either through scientific procedures or, for a substance used in food before 1958, through experience based on common use in food.

“Prior to 1997, the FDA had to be petitioned to ‘affirm’ that a substance is GRAS, and was getting backed up with reviewing GRAS petitions,” said John R. Endres, ND, CSO with AIBMR Life Sciences, Inc. (Puyallup, WA), a consulting firm that has been working with the natural products industry since its founding in 1978, and significantly increased its services to the functional foods industry in 2007. “On April 17, 1997, the FDA proposed a voluntary procedure whereby the Agency could be notified of a determination (the self-affirmation) that a substance is GRAS.” While this proposed rule is yet to be finalized, all ingredients added to foods must have GRAS or Food Additive status.

Self-Affirmed GRAS 

GRAS notification to the FDA is a voluntary process and not required, according to Endres. “Self-affirmation is accomplished according to the aforementioned FDA proposal. Companies hire a firm, such as AIBMR Life Sciences, to prepare a safety dossier generally based upon scientific procedures and corroborated by a history of human exposure. Finally, a panel of experts is assembled,” he said, adding that AIBMR usually has two to three staff physician scientists as panel members, and the chair being a PhD toxicologist retired with 40 years experience with the FDA and EPA. “The expert panel must be qualified by training and experience to evaluate the safety of food ingredients, and must agree with the basis of the determination that the intended use of the ingredient is GRAS.”

This was a route began in earnest in 2009 by Trace Minerals Resources International, Inc. (TMR, Ogden, UT).“We wanted to continue gathering scientific data giving validity to our trace mineral ingredient, Concen Trace Trace Mineral Drops,” said Ryan Fisher, the company’s general manager. “As our company has grown over the last decade, we have had more international interest as well as larger food companies inquire about our minerals as a method to improve their products and add significant mineral claims to their products supplement facts. GRAS affirmation was required by some of them and encouraged by all of them. We wanted to make our product available to new markets and increase the availability of our product throughout the world.”

TMR first looked at working individually with the required experts, but later decided to use the services of AIBMR.The estimated cost for GRAS affirmation is $75,000 and the time frame was approximately two years to complete, which was a completely worthwhile investment, according to Fisher.

“We saw an immediate impact with our potential client list after the process was complete,” he said. “Companies who had interest in our products before but had held off purchasing from us began to bring our products in. Other current customers expanded the amount of business they were doing with us because of the extra level of confidence that they gained with us.”

Another company that has seen markets open up after securing self affirmed GRAS in late summer 2011 for its patented cognitive health ingredient Magtein™ is City of Industry, CA-based AIDP, Inc. “This compound has large market potential for a broad number of conditions,” said Kathy Lund, director of business development. “By securing self-affirmed GRAS, AIDP can assure customers of Magtein’s safety. It indicates an investment behind the product and a commitment to market development. GRAS helps to open several market channels that would not otherwise consider a non-GRAS ingredient, such as beverages, which require a GRAS status.”

Suzanne McNeary, president of NutraGenesis LLC (Brattleboro, VT), shared that her company’s choice, as with many companies, for self-affirmed GRAS was deliberate. “Our company has always preferred self-affirmed GRAS and we are not alone—the majority of GRAS determinations are self-GRAS in order to protect the proprietary information of an ingredient from competitors,” she said, adding that NutraGenesis has worked with RS McQuate & Associates and GRAS Associates attaining GRAS self-affirmation for the company’s Wellberry®, Wellberry® Trim, WellBody•365™ and Capros® ingredients. “We like working with those firms because the principals of both are former FDA safety officers and FDA toxicologists. Working with a firm or firms that have former FDA officers on staff can provide a company undertaking GRAS with a higher degree of confidence because these individuals know the inner workings, culture and mindset of the FDA, and they know what the information requirements will be in order to truly satisfy the FDA standard of GRAS.”

No Objections 

As soon as an ingredient is self-affirmed as GRAS it can be added to foods according to the GRAS dossier, said AIBMR’s Endres. “For most companies, this is fine up to the point that they discuss selling the ingredient to the larger multinational companies. These larger companies most often require the manufacturer to get the ‘no objection letter’ from the FDA before they will buy the ingredient to add to their products.”

Healthco (Bloomingdale, IL), the raw material and private label division of NOW Foods, made the decision to seek self-affirmed GRAS status for its enzyme treated stevia, brand named Stevia- FSE™, about three years ago. Once that was successfully done, the company began the process for FDA-notified GRAS status. “We made the decision to go through the process because we felt our full spectrum whole leaf extract was an extraordinary product, with potential in many food and beverage applications,” said Peter Sokoloski, the company’s private label manager. “We submitted a GRAS notification for Stevia-FSE to the FDA voluntarily. We made the business decision to do this because we believe that this product will have many food and beverage applications and thus having a no objection from the FDA would be very valuable.”

Sokoloski explained that while the process was significant, preparation and actively asking questions made a great deal of difference. “We hired consultants familiar with this process and developed a scientific strategy for the information required. The big piece initially was complete characterization of the product. This took us into the most sophisticated chemical analytical technologies available today,” he said. “We then met with the FDA and they suggested that we also complete a metabolic study, which we then did. With all this information we prepared a self affirmed GRAS and also submitted to the FDA.

“The FDA process was straightforward, especially since we met with them early on and knew what was required.They had minor questions, which we answered,” Sokoloski added. “The frustration was that it took a long time; longer than it should.” 

Beyond the consultants and direct interaction with the FDA, Sokoloski said that having the right internal resources didn’t hurt. “Because of Healthco’s access to NOW Foods’ technical staff with their testing and regulatory expertise, as well as some of the most sophisticated labs in the business, we had a good understanding of what was required and the capacity to do it,” he said.

“Although there are two different pathways for GRAS—self-affirmation and FDA no objection—and both pathways end up in an ingredient legal for food use, many food manufacturers will not accept a self-affirmation; they want an opinion from the FDA,” added Michael Lelah, technical manager with NOW Foods. “This further protects them from the FDA disagreeing with a self-affirmation at some future date, which could happen.” 

AIBMR’s Endres acknowledged this line of thinking, but offered another side. “There is the perception that the FDA ‘no objection letter’ is the best that can be obtained,” he said. “GRAS selfaffirmations, if properly prepared and reviewed, should be thorough enough to cause the FDA to not question the basis of the GRAS determination.” 

One company confidently banking on this is Kemin Health L.C. (Des Moines, IA), which began its GRAS self-affirmation review in October 2010 for AssuriTEA Wellbeing™ and worked steadily on the review up through the time the Expert Panel was convened in September 2011.

“If a company makes a self-determination, FDA may challenge that determination on the basis that the product is an illegal food additive,” said Debbie Trinker, Esq., vice president of regulatory and legal affairs with Kemin.

“However, Kemin is not aware of any situation where FDA has challenged the GRAS status of a substance that has been self-affirmed after a thorough, documented scientific finding of GRAS status was confirmed by an qualified and independent scientific experts, such as was done for AssuriTEA.”

The company’s confidence is well placed, according to Trinker, as Kemin has carefully followed FDA regulations at 21 CFR 170.30 on GRAS status that require “common knowledge about the substance throughout the scientific community knowledgeable about the safety of substances directly or indirectly added to food …” “The GRAS determination of the proposed uses of AssuriTEA Wellbeing was based upon ‘scientific procedures’ as described in the regulation, as corroborated by history of safe Use of green and black teas,” Trinker explained. “Kemin was able to rely upon the history of safe use of tea, because its ingredient is a water extract that qualitatively and quantitatively compares compositionally to brewed tea. Unlike some commercial tea ingredients, AssuriTEA Wellbeing is not extracted with alcohol and its green tea component is not concentrated to EGCG or any other constituent, making reliance upon the history of safe use of tea appropriate.”

Kemin’s Assuri TEA Wellbeing review has taken a year and cost tens of thousands of dollars in external consulting fees, as well as required extensive use of the company’s internal resources.Other discussions on the GRAS process estimate $75,000 in fees from external consultants, and six months of review time. “The amount of time and money a company will spend will depend on the ingredient, the proposed food applications and usage levels,” said Trinker.“Based on Kemin’s experience with a number of ingredients, companies can easily expect to pay in the six figures and for the GRAS review process to take considerably longer than six months.”

GRAS and NDIs 

With the door closing on the FDA’s acceptance of comments regarding its New Dietary Ingredient (NDI) Draft Guidance, NIE asked: “Might GRAS status negate a company’s need to submit an NDI notification (NDIN)?”

“Technically, GRAS is a higher standard than NDI because the standard for safety is higher for GRAS than for the NDI. GRAS can negate the need for an NDI, but the regulatory landscape is quite complex,” said NOW Foods’ Lelah.

“GRAS status is typically considered to require an ingredient to meet a higher standard of safety than the standard that applies when obtaining an NDIN,i. e., that the ingredient does not present an unreasonable risk of illness or injury when used under its intended conditions of use,” explained Kemin’s Trinker. “Also, FDA’s ‘acknowledgment’ letters to an NDIN expressly state that FDA is merely accepting the notification for filing and the acknowledgment is not a finding by the FDA that the NDI or supplement that contains the NDI are safe or not adulterated. The Draft Guidance recognizes that new dietary ingredients may be exempt from an NDIN submission if the GRAS substance has been used in the food supply.According to the Draft Guidance, a GRAS substance (including substances self-affirmed as GRAS) can be used as new dietary ingredients without notification if the intake levels of the new dietary ingredient recommended are the same or lower than the intake level reviewed in the GRAS determination. So, if there is adequate information to provide reasonable assurances that the use of the GRAS substance as a NDI in a dietary supplement will not present a significant or unreasonable risk of illness or injury, then yes, the GRAS status could ‘negate’ the need for an NDIN submission.”

A point concurred by NutraGenesis’s McNeary: “I think it remains to be seen as to what will ultimately come out of the NDI Draft Guidance, but in the short term I believe that many companies may pursue GRAS status if they are at all unsure as to their ODI/NDI situation.My understanding of the current law is that GRAS status does indeed negate the need for an NDI.”

“The FDA’s recent guidance on NDIs allows companies to use an ingredient in their supplement without filing for NDI if that ingredient has GRAS status,” said Wendi Reymore, director of quality and regulatory affairs with Bergstrom Nutrition (Vancouver, WA), producer of OptiMSM®. “GRAS requires that pivotal information be published and in the public domain, whereas information to support the safety of an NDI need not be published. GRAS also requires an expert panel to review safety data, whereas the proof for NDI safety only need be provided by the company filing for the NDI.”

In closing, AIBMR’s Endres has been working closely with the FDA and had this to offer: “It is difficult to anticipate what the FDA may be thinking. I have been asked a few times in meetings with the FDA in person regarding GRAS notices how I felt the voluntary program is working. My opinion is that it is working well.”


Bergstrom Nutrition (Vancouver, WA), producer of OptiMSM®, started considering GRAS status in 2003. According to Rodney Benjamin, director of technical development, “We saw GRAS status as a natural progression for MSM. GRAS requires a higher level of toxicology and safety data on an ingredient than what is required for the dietary supplement market. We felt that GRAS would accomplish two goals, a stronger safety profile for our ingredient and allow entry into the additional market of functional food and beverage.”

Bergstrom’s final decision to proceed was in late 2004, early 2005, after an acute and sub-chronic toxicity study had been completed and an additional data gap analysis had been performed on OptiMSM.“This identified the additional studies that would be needed and gave us a rough idea of costs,” said Benjamin. “I say rough because we actually exceeded initial Estimates by about 50 percent. The entire process cost several hundred thousand dollars and took about three years.” 

In addition, Bergstrom made the choice to submit the dossier and expert panel opinion to FDA-CFSAN and received the FDA’s no-objection letter.

Afterwards, the company took it a step further in deciding to follow the Global Food Safety Initiate (GFSI) program, which provides a framework for a system of independent certification that a supplier’s food safety and quality management system complies with international and domestic food safety regulations.

“(GFSI) was pursued in part because of the need to be able to ensure to customers that all precautions are being taken to ensure the safest product possible is being made.The process for obtaining the GFSI certification was a lengthy one, which started with the implementation of the ISO 9001:2008 program And subsequent registration. Once that benchmark was achieved, the building of the FSSC22000 program was simpler than it would have been had we not established the ISO 9001:2008 program,” said Wendi Reymore, Bergstrom’s director of quality and regulatory affairs, adding that the reason for that was because the GFSI program the company chose, FSSC22000, takes many requirements right from the ISO 9001:2008 standard and adds a requirement for a HACCP plan and a few other in-depth programs to ensure product safety. “And since Bergstrom Nutrition had many of the controls already in place, it was relatively simple to write the program and put the required documentation into the daily practices.

“Going forward we see this as an opportunity to prove to our customers that we are dedicated to making a high quality and very safe product,” Reymore concluded.

Albion Minerals®