Interest in steviol glycosides has been steadily building over the past 10 years or so, and there doesn’t appear to be a downturn anytime soon. First identified in Stevia rebaudiana (Bertoni), a plant native to South America, steviol glycosides are non-nutritive sweeteners that can be up to 450 times sweeter than sugar. They belong to a family of diterpene glycosides that all contain a steviol backbone.
Steviol glycosides extracts can have a bitter or metallic aftertaste, so many manufacturers have developed methods to purify specific steviol glycosides with preferred taste profiles from a stevia leaf extract or improve the organoleptic properties of the extract through enzyme modification. Most recently, manufacturers have begun preparing high-purity steviol glycoside products via fermentation reactions.
In 1991, an import alert was issued to ban the import of stevia leaves, stevioside, and food containing steviol glycosides into the United States. In 1995, the import alert was modified to allow the import of stevia leaves, stevioside, and steviol glycosides intended for use as a dietary supplement or as an ingredient in dietary supplements.
In 2007, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) published a monograph on steviol glycosides, establishing a safe level of intake and specifications that required a minimum purity of not less than 95% of stevioside, rebaudioside A, rebaudioside C, dulcoside A, rubusoside, steviolbioside, and rebaudioside B. Shortly thereafter, FDA filed, reviewed, and issued a “no questions” letter for high-purity rebaudioside A. JECFA has since issued a revised monograph which includes specifications for a minimum purity of not less than 95% of all naturally-occuring steviol glycosides.
While FDA often declines to file GRAS Notices (GRNs) for substantially similar ingredients that include the same manufacturing process, supporting safety data, and/or proposed uses, an exception is usually made for steviol glycosides preparations due to the existing import alert. In 2018, Perrier et al. published an article outlining FDA’s regulatory approach to steviol glycosides, which provides an in depth overview of the history of steviol glycosides regulation and GRAS Notice review process.
According to FDA’s GRAS Notice Inventory as of September 16, 2019, 64 GRNs have been filed for a variety of steviol glycosides-containing ingredients, including: stevia leaf extracts, high purity steviol glycosides, and enzyme-modified steviol glycosides. Of these, 60 GRNs have received a “no questions” letter from FDA; the remaining 4 GRNs are currently under review.
Steviol Glycosides Ingredient Compositions
Based on the most recent data available on FDA’s GRAS Notice Inventory website as of September 16, 2019:
Steviol glycosides leaf extracts (comprised of multiple steviol glycosides in varying concentrations) and high-purity rebaudioside A preparations are the subject ingredient for just over 60% of the filed GRNs.
Enzyme-modified steviol glycosides (EMSG)—steviol glycosides leaf extracts that have been treated with glucosyltransferase enzymes to increase the glucosylation of the steviol glycosides, which increases sweetness and decreases bitterness—account for nearly 16% of the submissions.
The remaining GRNs are for high-purity single steviol glycosides.
Manufacturing Methods
There are four general categories of manufacturing methods currently used to produce steviol glycosides:
Extracting highly purified steviol glycosides from S. rebaudiana leaves (40 GRNs)
Producing enzyme-modified steviol glycosides from highly purified S. rebaudiana leaf extract (9 GRNs)
Producing highly purified individual steviol glycosides from bioconversion of one or more steviol glycosides, facilitated by enzymes produced by genetically engineered microorganisms (6 GRNs)
Producing and isolating highly purified steviol glycosides from genetically engineered microorganisms (5 GRNs)
Manufacturing processes involving genetically engineered microorganisms have undergone a surge of interest since 2016, when the first “no questions” letter was issued by FDA for GRN No. 626. Steviol glycosides produced in Saccharomyces cerevisiae. Since then, half of the GRAS Notices submitted for steviol glycosides preparations have been manufactured using genetically engineered yeasts (Saccharomyces cerevisiae, Pichia pastoris), fungi (Yarrowia lipolytica), or bacteria (Escherichia coli).
The Future of Steviol Glycosides
As long as the import alert remains in place, it’s expected that FDA will continue to file GRAS Notices for steviol glycosides. The inclusion of all naturally-occuring steviol glycosides in the most recent JECFA monograph will likely result in the manufacture of high-purity minor-steviol glycosides (in addition to rebaudiosides C, D, M, which have already undergone GRAS review), either through advanced extraction techniques of S. rebaudiana leaves, or produced by microorganisms via fermentation or bioconversion processes. Advancements in selective breeding and enzymatic-modification processes will also allow manufacturers to produce an array of steviol glycosides blends with preferred organoleptic properties.
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Perrier, J.D., Mihalov, J.J., Carlson, S.J. (2018) FDA regulatory approach to steviol glycosides. Food Chem. Toxicol. 122, 132-142.
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