This is the first in a series of articles describing the steps necessary to produce a maximally optimal GRAS dossier.
Part 1- The Substance
Introduction
This article is the first of three articles on the process of compiling a GRAS dossier. This series is not instructions for a DIY for a GRAS dossier, but a description of common problems encountered in generating a dossier. For the sake of brevity, much of the detail in dealing with various problems has been left out.
For each new substance to be GRAS, focus is on the functionality of the substance, not the substance itself, until some critical questions are raised. In this first part of the series, eight critical attributes must be resolved before progressing towards a GRAS or food additive petition (see figure). These attributes are all, to one degree or another, interrelated and are therefore depicted as interconnected in a cycle. Importantly, these issues must be resolved regardless of the fact that the substance may be produced by the entity wishing to make the substance compliant or even if the substance is produced by a third party.
Regulatory and Scientific Assessment
In the spirit of “why be defeated before you even begin”, the seasoned investigator will conduct a search of the regulatory constraints (if any) on the candidate substance. This is necessary because some substances are prohibited outright from addition to food or require a food additive petition (such as having a step involving irradiation) or have limitations on them, such as some GRAS substances cannot have an additional use added to their domain (as a GRAS), but each additional use must be the product of a food additive petition. Also, some substances may have restrictions on them by local regulations such as California’s Proposition 65.
A search of the scientific literature is useful as toxicity issues with the substance may be revealed that could severely restrict or even preclude the use of the substance such as an indication the substance or a close structural analog is a carcinogen. Alternatively, it could be found that the substance has a toxic effect at the level of exposure projected for humans or, provide an idea of the extent of testing that would be necessary to support the safety of the substance, such as performance of a two-generation reproduction study or a carcinogenicity study.
Raw Materials (Food Grade)
A primary consideration is of the raw material out of which the substance will be synthesized or produced/processed from a natural source. The indication of “food grade” stipulates that the starting materials, although not necessarily food grade themselves, must be theoretically eligible for this designation. For example, if lecithin is to be used, it could not be produced from bovine neural tissue as the result of a prohibition against using products potentially contaminated with bovine spongiform encephalopathy (BSE). Likewise, grains contaminated with mycotoxin and otherwise not suitable for use or chemicals that would otherwise fit the criteria for the Food Chemicals Codex criteria with known origin, levels of contaminants, such as heavy metals or microbiological load, etc., that would make it a candidate for GRAS itself, but not necessarily as such (i.e., GRAS). In general, nothing that is “…in whole or in part of any filthy, putrid, or decomposed substance, or is otherwise unfit for food…”’
Manufacturing (GAP/GMP)
The substance must be produced, if of agricultural origin, according to Good Agricultural Practice (GAP) or if not, such as that produced in subsistence agriculture, the product be tested for its suitability for human consumption, including but not limited to heavy metals, pesticides, microbiological load, etc. If the substance is produced under Good Manufacturing Practice, the principals of which are well known and should also be addressed by the Food Safety Modernization Act (FSMA).
Manufacturing and production are critical aspects, and the process is weighed heavily by FDA for this phase is the potential origin of contamination or a change in manufacturing technique can produce unwanted and potentially harmful substances. In each submission for a GRAS notification or FAP, the agency will require enough of a description of the details of the process such that a person knowledgeable of the production of a similar substance(s) might determine that even a minor change in time/temperature, solvent, etc., could substantively affect the outcome of the final product.
Verification of the outcome of any synthetic process is required and traditionally, FDA has required testing of five batches, three of which cannot be consecutive.
Contaminants
Changes in the conditions of synthesis, processing or extraction may lead to an unacceptable level of contaminants, including similar isomers of the same substance but with a different effect on the consuming organism. For example, instead of producing a racemic mixture, a reaction may produce an imbalance of isomers, one of which may have different physiologic effects than the other or the racemate. Likewise, in the extraction of a natural substance, it may be that there is co-elution with a toxic substance, such as tomatine from tomatoes (normally present in very small amounts and not injurious to health) but becomes concentrated during the production of lycopene. In this case, the tomatine normally present in the tomato (not being an added substance), the tomato is not considered adulterated, if the quantity of tomatine does not render the tomato injurious to health, but if concentrated in the extractant, the product is adulterated.
Specifications
Specifications can be modeled on those used in the Food Chemicals Codex and should include but not limited to Chemical Abstracts Service Registry Number, chemical composition and further characterizing information (e.g., melting point, boiling point, specific gravity, refractive index, optical rotation, pH, solubility, and reactivity). For substance of natural origin, information on the source (e.g., systematic name, genus, species, variability based on climate or other geographical factors). Unavoidable but undesirable substances accompanying the desired substance can be limited through the use of a limiting specification.
It is important to be as pragmatic as possible; that is, to provide specifications that can be easily met using your manufacturing or production process. Too narrow a specification limit can result in a reduced amount of product acceptable for use. Also, keep in mind that your claim of safe use of the substance was based on a substance with certain specifications and marketing a substance that does not comply with specification, is adulterated. Also, it is advisable that if the substance is purchased from a third party, the specification be generic enough such that if the third party no longer offers the substance, a substitute supplier may be found,
Detection
Any GRAS or FAP includes a method of quantitative detection of the substance, this is obvious for verifying specifications for each batch, but also for verifying the presence and quantity of the substance in the final food product. A practical method of detection is also required for stability studies and for verification of the substance in the various dose levels in feed or water for animal safety studies. The method should be easily reproduced and economical to conduct.
Stability
Because your clients, manufacturers of the end product to which your substance will be added, will need to know the stability of your substance and under what conditions of storage and use. Stability studies can be conducted relatively easily by sampling the substance following storage under the suggested conditions (e.g., cool, dry place), or using accelerated conditions. Because stability studies require multiple samples be taken, emphasis on development of an economic detection methodology pays dividends at this point. Also, if there is a particular break down product of concern (e.g., one effecting the integrity or toxicity of the substance), detection of this breakdown product might also be employed; however, because you must ultimately report how much substance remains over a period of time (e.g., the shelf-life of the product), the quantitative presence of the substance must be determined.
Scalability
A bedeviling situation occurs when synthesis or extracting a natural substance cannot be scaled up to economic levels. At the bench level, production of the substance will remain prohibitively expensive, but sometimes scaling up to pilot plant, then later full scale production may require a reassessment of specifications and contaminants. Scalability becomes a question early on because animal testing often requires several kilograms, a level of production often unobtainable at the bench top; further, stability testing will require substantial amounts of substance.
Utility
Also called technical effect or functionality, it is assumed the manufacturer already had the functionality in mind when first thinking about the GRAS, so utility is not listed in the eight concepts in the figure. The previously accepted 32 technical effects are listed in 21CFR 170.3(o), but most date back to 1977 when this regulation was first written; new technical effects have been devised since then and the new effects are acceptable to the human food side of FDA, if accompanied with an understandable explanation. Although the human food side will likely not require proof of the technical effects efficacy, the animal side of FDA (the Center for Veterinary Medicine), may require proof of efficacy and publication of the proof in a scientific journal. A word of caution here – FDA is very aware of attempts at Trojan horses; that is, claiming an acceptable utility while actually performing another function such as a color additive claiming to be an antioxidant.
Conclusion
Unfortunately, many of the steps cited above are not undertaken until the process of compiling the GRAS dossier or FAP is underway. Delays at this point guarantee a domino effect, ultimately missing windows of opportunity and delayed or reduced ROI.
Part 2 – Risk Characterization – Coming Soon
[1] Caution - this series of articles is not meant to be instructions for a DIY GRAS dossier; in addition, if read closely, the article describes what must be done, but not how to do it. For the “how to” contact Burdock Group.
At Burdock Group, we combine unparalleled expertise with meticulous attention to detail in every GRAS notification we handle. Our team of seasoned professionals brings decades of scientific, regulatory, and industry knowledge to the table, ensuring that each submission meets the highest standards of accuracy and compliance. By staying at the forefront of regulatory developments and tailoring our approach to each client's unique needs, we deliver consistently successful results, earning us the trust and respect of clients and regulators alike.
