This is the third in a series of articles describing the steps necessary to produce a maximally optimal GRAS dossier.
Part 3 – Intractable Risk Mitigation Strategies
Recap
In the first of this series, the prospective product developer urged us to heed the famous IBM sign “THINK AHEAD” by engaging in some preliminary foundational work before commissioning a dossier and encountering delays. The preliminary steps are provided in Figure 1.
Figure 1. Foundational investigational steps to a GRAS
· Regulatory and scientific search · Specifications
· Raw materials/food grade · Detection methodology
· Manufacturing (GAP/GMP) · Stability testing
· Contaminants · Scalability of the process
In the second of this series, we found that determining a safe level of consumption is the first step in determining “hazard” and; for food, the safe level would be nearly any adverse endpoint in an animal test that would not be observed in control animals – this is the No Adverse Effect Level (NOAEL). The NOAEL is commonly divided by a safety factor of 100 to arrive at a safe level of exposure for the consumer (the Acceptable Daily Intake, ADI). In the best of all worlds, aggregate consumption is calculated based on the amount of substance added to food plus the amount of substance from that naturally present in food and other possible sources of the substance. This aggregate consumption yields the Estimated Daily Intake (EDI), which must be equal to or less than the ADI. If, however, there are intractable issues with the substance that cannot be resolved by decreasing the amount in the product, there are other means of managing risk associated with a product and is the subject of this Part 3 of Getting to GRAS.
Introduction: Intractable Risk and Mitigation Strategies
As noted previously, risk is characterized by combining information from exposure and dose-response assessments to determine the likelihood of harm from exposure to a substance. The risk may be assessed by possibly more than one individual, but the final approval to go to market (or not) is made by the Risk Manager (the process is depicted in the flow chart below, Figure 1). If it appears that the substance is a “no go”, it is likely that R&D, Marketing and possibly Regulatory, will appeal to the Risk Manager to find some way to rescue the substance. The Risk Manager is aware that there are no quick fixes, such as fine-tuning consumption by decreasing the amount of substance added to one or more categories or, deleting a category altogether. The decision on how to resolve this dilemma can be especially vexing, if the contributor to the unacceptable risk is one over which the Risk Manager has no control, such as exposure from natural sources, something produced during processing or the Risk Manager’s opinion that the data supporting safety is not as strong as needed.
Intractable Risk and Mitigation Strategies
The government has been in a tug-of-war with itself over what was safe since the 1906 Pure Food and Drugs Act was passed. At first, the Department of Agriculture (the precursor to FDA) enforcers decided that a food must be absolutely safe (i.e., “safety per se”) for all consumers and the presence of any potential toxin was enough to declare a food unsafe. This scenario played out in what resulted in a 1914 Supreme Court decision referred to as “Lexington Mill”,[2] where the justices disabused the federal enforcers of any notion that food was held to a standard of absolute safety; further that for a food to be adulterated, potential “harm” to the consumer must be demonstrated. With the passage of the 1958 Amendment of Food Drug and Cosmetic Act, the standard of safety according to the intended conditions of use – a decision to be made only by qualified individuals – was added to the law and foreclosed any further debates about what is meant by “safe”.
However, in 1975, Commissioner of Food and Drugs Alexander M. Schmidt [3] stated, “The very act of representing a product for food, drug, or cosmetic use constitutes an inherent implied representation of its safety”. This statement was in response to the realization that not everything approved by FDA may actually be absolutely safe for all users in any circumstance, although the item may be commonly present in the marketplace. This opening salvo laid the infrastructure for precautionary language and limitations on various food products and later to intractable risks, that is, risks that in inherent to the product and cannot be eliminated by decreasing the amount added to food. Such intractable risks include food allergens, which were later addressed by the Food Allergen Labeling and Consumer Protection Act (FALCPA) of 2004, and included milk, eggs, fish, etc...
Risk Management
Although the Risk Manager has been handed a food substance which is consistent with the standard of a “reasonable certainty of no harm”, this designation is not the final step in marketing a product, as certain intractable risks could accompany the product, plus the fact the Risk Manager may have other considerations before sending something to market and therefore, may deem the product “unacceptable” in its present state. For these intractable risks, the Risk Manager may then turn to employing certain risk mitigation strategies (see figure below, Figure 2), although these strategies may not address all possible intractable risks.
Label Statement
When Commissioner Schmidt indicated that not everything approved by FDA may be absolutely safe for all users in any circumstance, the door was opened for FDA to place warning labels (i.e., “statements”, as they are referred to by FDA), on the labels of foods, cosmetics or drug products when necessary or appropriate to warn of a hazard that may be associated with use of the product and may be mandated by regulation. Companies cognizant of the potential liability of some products, may voluntarily label a product with a precautionary statement.
Table 1. Label statement on consumer products | ||
Label Origin | Item | Label Statement |
21CFR 101.17(a) | Self-pressurized containers | Warning - Avoid spraying in eyes. Contents under pressure. Do not puncture or incinerate. Do not store at temperature above 120°F. Keep out of reach of children. |
21CFR 101.17(b) | Self-pressurized containers with halocarbon or hydrocarbon propellants | Warning - Use only as directed. Intentional misuse by deliberately concentrating and inhaling the contents can be harmful or fatal. |
21CFR 101.91 | Gluten-free labeling of food | [The label may bear] the claim "no gluten ," "free of gluten ," or "without gluten " |
21CFR 74.1705 | FD&C Yellow No. 5 | "This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons….” |
21CFR 172.170(b)(3) | Sodium nitrate | If in a retail package intended for household use, the label of the additive or of a mixture containing the additive, shall bear the statement "Keep out of the reach of children". |
21CFR 172.175(b)(3) | Sodium nitrite | If in a retail package intended for household use, the label of the additive, or of a mixture containing the additive, shall bear the statement "Keep out of the reach of children". |
21CFR 172.804(d)(2) | Aspartame | The label of any food containing the additive shall bear, either on the principal display panel or on the information panel, the following statement: PHENYLKETONURICS: CONTAINS PHENYLALANINE. |
21CFR 172.841(e) | Polydextrose | The label and labeling of food a single serving of which would be expected to exceed 15 grams of the additive shall bear the statement: "Sensitive individuals may experience a laxative effect from excessive consumption of this product". |
21CFR 180.25(e) | Mannitol | The label and labeling of food whose reasonably foreseeable consumption may result in a daily ingestion of 20 grams of mannitol shall bear the statement "Excess consumption may have a laxative effect". |
21CFR 184.1835(e) | Sorbitol | The label and labeling of food whose reasonably foreseeable consumption may result in a daily ingestion of 50 grams of sorbitol shall bear the statement: "Excess consumption may have a laxative effect." |
Safe Drinking Water and Toxic Enforcement Act of 1986, (Proposition 65) |
| [Substance is] ”known to the state to cause birth defects or other reproductive harm” |
Voluntary? | Lactose | Lactose free, milk free, dairy free |
Voluntary? | My Salt Substitute [4] | “Persons on a potassium restricted diet should consult their physician before using any salt substitute.” |
Voluntary? | Morton Salt Sodium Free Salt Substitute – for Sodium-Restricted Diets [5] | “Consult a physician before using any salt substitute.” |
Voluntary? | Ensure Plus® nutrition shakes | “Not for people with galactosemia” |
Processing Requirements
Some regulatory agencies in a few other countries try to exert control over the process of producing a product during its manufacture. For example, these agencies may mandate limits on time, temperature and other parameters to avoid formation of harmful substances during the production process, whereas FDA will require only that these possible toxic substance are not present in the final product.
Exceptions to the general rule of looking at final product only are those actions left up to the consumer, such as “keep refrigerated”, or “cook products to certain a certain temperature” (e.g., pork products), or “wash before consuming”.
Tolerances Imposed
The terms “specification” vs “tolerance” are similar, but are distinguished in the FDA lexicon. “Specification” is defined by FDA as “A specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which a drug substance or drug product should conform to be considered acceptable for its intended use.”[6] Therefore a specification may refer to a specific substance, toxic or not. On the other hand, a tolerance, as used by FDA, refers to a specific toxic substance that may be present in any number of substances or foods, such as a toxin in several species of seafood; that is, independent of a specific fish, but refers to a category of fish that may have the toxin.
Contaminants for which a tolerance may be set are those associated with synthesis, growth, production or storage and are regarded by FDA as unavoidable. Because they are unavoidable, the FDA sets limits rather than bans them. Contaminants regarded as avoidable or of such hazard that a safe level cannot be set, FDA has determined that food containing such substances is banned or; are beyond the control of FDA and cannot be regulated. Paralytic shellfish poisoning (PSP or saxitoxin) is the only seafood toxin for which a tolerance is set; other toxins such as domoic acid, ciguatera, etc., do not have a tolerance set.
Tolerances for the unavoidable presence of contaminants in food include, but are not limited to pesticides, heavy metals (e.g., lead, arsenic, cadmium), nitrosamines and related substances, food-borne molds and mycotoxins (aflatoxin, fumonisins, zearalenone, ergot alkaloids), trans-fatty acids and furan.
The Risk Manager, once having determined a contaminant is unavoidable according to the criteria set by FDA (i.e., contaminants associated with synthesis, growth, production, or storage) may apply to FDA for a tolerance level, although FDA may require the GRAS be converted to a food additive petition.
Exposure Adjustment
Conceivably, although the Risk Manager has received approval from FDA (as a food additive) or from Experts conferring GRAS status, a very conservative Risk Manager may feel an extra layer of protection is required. Circumstances for wanting this extra layer of protection would be marketing to a particularly vulnerable group such as women of child-bearing age or children or, something that may conceivably be subject to abuse or an item that attracts litigants such as a tobacco additive. Alternatively, the Risk Manager may feel the “harm” or “hazard” was based on a NOAEL of a particularly egregious endpoint such as a birth defect, which GRAS or “safe” at a particular level of use and having a safety factor of 100 or more, the Risk Manager may feel imposition of an “uncertainty factor” is justified. Uncertainty factors are used as multipliers of the safety factor, moving it from 100 to 1000 or more. Ultimately, the extra layers of protection demanded by the Risk Manager may exceed the ability of the product to show no harm.
Conclusion
Someone must make the final decision on whether a product will be marketed or not – this responsibility falls to the Risk Manager and even though the substance has been vetted and deemed “safe according to its intended use,” the risk manager may take a broader viewpoint as to the risk of marketing the product. Beyond the finding of safe according to intended use, is the prospect of an intractable risk. The intractable risk mitigation may involve the use of a warning label, a processing requirement (either for the manufacturer or the consumer), the setting of a tolerance or an extra layer of safety through the use of uncertainty factors.
[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.
[2] US v. Lexington Mill & Elevator Company 232 U.S. 399 (1914)
[3] Schmidt, A.M. (1975) Cosmetics. Warning Statements/Package Labels. Federal Register. Washington, D.C. Volume 40. p. 8912.
[6] https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q6a-specifications-test-procedures-and-acceptance-criteria-new-drug-substances-and-new-drug-products (site accessed 17Oct2024)
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