It is recognized that methods of production may affect the safety assessment of food ingredients (FDA, 2012). Flavoring substances may be produced in a variety of ways and the FEMA Expert Panel’s assessments to determine the status of flavor ingredients as “generally recognized as safe” (GRAS) includes a review of the method of production for the ingredients. This statement addresses how recent developments in new methods of production of flavoring substances are addressed within the FEMA GRAS program.

FEMA GRAS Status and Methods of Manufacture
It is long-standing FEMA policy that significant changes in the use or production of FEMA GRAS flavoring substances require that their GRAS status be reevaluated by the Expert Panel. The Expert Panel states its policy in GRAS determination letters.

Significant changes in use levels within an approved category, or use in new food categories, require a re-evaluation of this material by the Expert Panel. Re-evaluation may also be required if there is a significant change in the composition or production method of the product in commerce. (emphasis added). The Expert Panel reserves the right to re-evaluate the GRAS status of this substance if new relevant data becomes available or if there is a significant increase in the annual volume of use of this substance.

The Expert Panel’s policy is consistent with guidance issued by the Food and Drug Administration (FDA, 2012) which indicates that methods of production for new food ingredients and new methods of production for food ingredients already in commerce should be reviewed to assure that they do not result in potential safety concerns.

The Regulation of Flavors in the United States
The vast majority of flavoring substances are added to food in the U.S. under one of three legal authorities (Hallagan and Hall, 2009) - as GRAS substances or food additives under FDA regulation (approximately 1,000 flavoring substances), or as GRAS substances through the FEMA GRAS program (approximately 3,000 flavoring substances). Nearly all flavoring substances listed by FDA as GRAS or as approved food additives in the Code of Federal Regulations also have FEMA GRAS status.

With respect to new methods of production for flavoring substances currently in commerce, both FEMA and FDA (2012) are consistent in their guidance that as a condition of maintaining regulatory authority to use a substance, significant changes in production processes should be reviewed to assure that no safety concerns result.

Biotechnology Methods of Manufacturing Flavoring Substances
In the 1990s significant exploration began of new methods of producing flavoring substances applying techniques of modern biotechnology. These new production methods focused largely on fermentation processes employing genetically modified organisms. A process for performing a safety assessment for flavoring substances produced by these new methods was published (Hallagan and Hall, 1995). As noted by Smith et al. (1996), the issues evaluated by the Expert Panel in such a safety assessment are consistent with FDA policy. However, this safety assessment process has seldomly been applied by the FEMA Expert Panel because the production of flavoring substances using biotechnology has only recently become economically and practically viable.

FEMA Policy and Guidance
The FEMA Expert Panel explained its process for evaluating flavoring substances produced through biotechnology production methods in the “GRAS 17” publication (Smith et al., 1996).

The FEMA Expert Panel uses a decision tree approach to assess the safety of flavor ingredients produced using genetically modified organisms (GMOs). This approach consists of several levels (Hallagan and Hall, 1995). The first level consists of an evaluation of the identity of the substance, including an examination of regulatory status, i.e. is it currently permitted for use in food? If so, what are the specifications for the substance, and are they met by the material produced through the use of a GMO? If the substance produced through a GMO is the same as the conventionally produced substance the assessment is greatly simplified. In fact, if the substance is currently permitted for use in food by virtue of an appropriate prior safety assessment, the evaluation would be essentially complete. In addition to determining the identity of the substance, the first level consists of evaluating the method of production employing a GMO, specifications for the substance produced using a GMO, and the safety of constituents produced using a GMO compared to conventional methods of production.

It has been long-standing FEMA policy that significant changes in the production of FEMA GRAS flavoring substances, such as the new use of biotechnology production methods, result in the requirement that GRAS status be reevaluated by the Expert Panel. If a FEMA GRAS flavoring substance is to be produced using biotechnology methods, or other significant new methods of production, producers must contact the Scientific Secretary of the FEMA Expert Panel, Sean Taylor, Ph.D. ([email protected]; 201.331.2328) to determine if an evaluation of the new production method is necessary in order to maintain the FEMA GRAS status of the substance.

For More Information
Please contact John Hallagan, FEMA Senior Advisor and General Counsel ([email protected]; 202-293-5800) or Sean Taylor, Ph.D., Scientific Secretary for the FEMA Expert Panel ([email protected]; 202-293-5800).

Food and Drug Administration. Guidance for industry - Assessing the effects of significant manufacturing process changes, including emerging technologies, on the safety and regulatory status of food ingredients and food contact substances, including food ingredients that are color additives. 2012.

Hallagan J.B. and Hall R.L. Safety assessment of flavor ingredients produced by genetically modified organisms. In Genetically Modified Foods-Safety Aspects. Engel, Takeoda and Teranishi, Eds. American Chemical Society. Washington, D.C. 1995.

Hallagan J.B. and Hall R.L. Under conditions of intended use – New developments in the FEMA GRAS program and the safety assessment of flavor ingredients. Food and Chemical Toxicology. 47, 267. 2009.

Smith R.L., Newberne P., Adams T.B., Ford R.A., Hallagan J.B. and the FEMA Expert Panel. GRAS flavoring substances 17. Food Technology. 50(10), 72. 1996.