The demanding criteria required to obtain novel protein ingredient regulatory approval in the U.S. were explained at the 2022 Protein Trends & Technologies Seminar. The U.S. is one of the few jurisdictions that regulates new food ingredients as food additives unless the substance is concluded Generally Recognized as Safe (GRAS) among scientific experts. So stated Ray Matulka, Ph.D., Director of Toxicology, Burdock Group Consultants in his presentation, “Novel-Sourced Protein Ingredients: Critical Scientific Components for Regulatory Compliance.”
A food additive regulation or GRAS status is based on the intended conditions of use, not the ingredient itself. For example, Matulka noted that “the dose is the poison.” An amino acid may be safe at specific use levels, but a novel source could introduce toxic contaminants that would be an issue when the ingredient is used at a higher level.
It is best to meet with the FDA initially to determine a roadmap to approval. But many companies want to rush their product to market ASAP, waiting until the last step for approval, said Matulka.
Completing a Dossier for GRAS
Matulka described the information required when completing a dossier for GRAS for new protein ingredients. Identification, specifications, and manufacturing methods for the component must be
detailed. Potential contaminants must be identified, and stability, safety, and consumption patterns must be presented. Additionally, claims must be substantiated, and proper labeling with intended use must be provided.
“One of the biggest data challenges posed by the FDA is not only the source, but modifications and chemical changes to the raw ingredient,” explained Matulka. In addition, “the manufacturing process, safe use of technical additives and processing under current Good Manufacturing Practice (cGMP) standards” are all critical to GRAS assessments.
Represent the Whole Ingredient
The manufacturer must demonstrate a complete understanding of the whole ingredient, not just the “active” components. All components of the final ingredient—“to nearly 100%”—must be understood. Also, the company must be able to describe the component within the raw material that explains why the novel ingredient should be added to food.
Stability data under typical storage conditions are required for the ingredient when isolated and used in food/feed. “Does the oil content of a protein obtained from an oilseed introduce rancidity?” posed Matulka. “If so, will an antioxidant be needed, especially if high protein levels will be utilized in a product?”
Proteins contained in ingredients that can be supported through a history of safe use, such as soy, oat or almonds, are good candidates for GRAS. While introducing novel ingredients is important, some new sources may have antinutrients that could present a nutrient absorption issue, so processing for safe use is essential.
Defining the traits of source organisms is a critical part of a regulatory evaluation, such as whether the ingredient is microbe- or enzyme-based; whether the production organism is native or genetically
modified; whether there will be up-regulation or deletion of native genes in the source organism; and whether the production microbe will be viable in the finished product, noted Matulka. Genetically engineered proteins may yield potential allergens.
Other variables to consider when working toward novel protein ingredient regulatory approval include the gene source, amino acid sequence of the protein and the stability of the protein to digestion.
“Fermentation may result in metabolites that may not be safe for humans or animals,” explained Matulka. FDA expects a thorough safety assessment. All media components must also be “food grade” and “safe and suitable” for the intended use.
The FDA is very concerned with the amount of an ingredient that may be consumed when it is used as a sole food in a diet, such as high-protein shakes. Other key questions include whether the protein-based ingredient amino acids enter the bloodstream intact; whether the ingredient will replace other nutrients or increase some nutrients over others; and whether ingredient consumption could lead to imbalances in amino acids.
Claims substantiation must include literature-based documentation of the mechanism of action and clinical trials with statistically significant outcomes from a control group. Moreover, “structure or function of the body” statements must be based on nutritive value.
Matulka concluded with a summary of four key takeaways FDA
requires for GRAS:
• Naturally sourced isolates from known or novel sources must be shown to be safe—no presumption of safety.
• A precise product characterization is a key step in reaching compliance.
• Safety must be established and may be completed in parallel with claims studies.
• Claims must be based on the product or the clear identification of the component that substantiates a claim.
“Novel-Sourced Protein Ingredients: Critical Scientific Components for Regulatory Compliance,” Ray Matulka, Ph.D., Director of Toxicology, Burdock Group Consultants
TEXT CHART:
Studies to Support the Conclusion of Safety
• Repeat-dose/dietary toxicity study in rodents
— Conducted according to FDA/OECD protocol—typically 90 days in length
— 14-day palatability study prior to the main study
— Safety-related endpoint parameters should be included
— Test substance should meet commercial specifications
• Genotoxicity studies
— Typically, both in vitro and in vivo genotoxicity studies
— Conducted according to FDA/OECD protocols
• Assessment of potential allergens may be necessary
— Human tolerability studies
— Quantitative risk assessments for potential allergenicity
— Adverse-event reports on similar products or components
SOURCE: RAY MATULKA, PH.D., DIRECTOR OF TOXICOLOGY, BURDOCK GROUP CONSULTANTS/2022 PROTEIN TRENDS & TECHNOLOGIES SEMINAR
Chart caption: For novel protein ingredient regulatory approval, an FDA dossier must be completed. Much research must be conducted to support GRAS determination.
Click on the phrases below to see related articles on these topics at FoodTrendsNTech.com.