For both US and international companies, obtaining GRAS status involves strategic steps. James Heimbach, PhD, explains what's important and why FDA approval may not be necessary.

In the US food regulatory system, the designation GRAS (generally regarded as safe) provides market differentiation between manufacturers. It closes the market to people who are taking shortcuts and makes the market available only to companies with high standards.

What exactly is the GRAS safety standard? It is that there must be a reasonable basis to conclude that a substance does not present a significant or unreasonable risk of illness or injury under the conditions for which its use is suggested.

To demonstrate safety and prepare a GRAS dossier, the following information must be supplied: a complete description of the substance; the proposed use of the substance; a method for detecting and quantifying the substance in foods; and safety and toxicology of the substance. The document must include any unfavourable information, including safety studies, adverse-reaction reports and any known consumer complaints.

Obtaining GRAS approval for a functional food involves significant challenges. On one hand, there are drugs, which are bioactive materials that are given under medical supervision. The duration of exposure varies and the clinical evidence of safety is based on human clinical standards. Overall, GRAS approval is based on proof of a positive risk:benefit ratio, and approval will certainly err on the side of safety.

On the other hand, traditional food additives are used for a functional effect in food and are expected to be fairly innocuous. Consumption is unregulated over a potential lifetime of exposure, and usually the safety of the food additives has been based on animal toxicology studies. There is no risk:benefit ratio, and there are usually large safety margins.

What about functional food ingredients? From a safety standpoint, it's the worst of both worlds. They are bioactive ingredients with a potential for lifetime exposure and unregulated consumption. Clinical evidence of safety must be based on a combination of animal studies and clinical evidence, and working with humans costs more than working with rats. There is usually some level of risk:benefit to be factored because many of these substances are potentially harmful at exaggerated levels. The therapeutic index has an approximate 10,000:1 safety margin.

It is critical that suppliers and manufacturers of functional foods know the mechanisms of action for active ingredients, the safety factors, and the phamacokinetics, which refers to absorption, distribution, metabolism and excretion (ADME) of the substance.

Labelling issues challenge the manufacturer because the following items cannot be placed on food labels: dosage recommendations/limits, drug interactions, food interactions, disease contraindications, population subgroups at risk, populations not studied and side effects.

Optional FDA Notification
How do you obtain a GRAS determination? First, the above information is placed in a dossier, which must be reviewed by an expert panel. The final and optional step is US Food and Drug Administration notification. The following three factors help determine if FDA notification is needed: if customers and key clients request the FDA's "no objection" letter; if the FDA has already reviewed the product and expressed concerns; and if something has an unusually long peptide sequence, or a problem with an allergy induction or autoimmune response. If the FDA is notified and there are no objections, the FDA submits a letter stating that there are no questions and that the product is GRAS.

When considering whether an ingredient is GRAS, it is important to follow a strategic sequence. Here are some important questions to ask about an ingredient. Botany: What is the genus? Agronomy: Where and how was it raised? Technology: What parts of the plant are being used? Other considerations include chemistry, animal toxicology, human safety and efficacy. Careful attention to these areas ensures that ingredients can stand up to the test for GRAS.

James Heimbach, PhD., FACN, is principal of ENVIRON Int'l, 4350 Fairfax Dr., Arlington, Virginia 22203, USA, Tel: +1 703 516 2300, www.environcorp.com.