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Ingredient Specifications, Stability, and Safety Assessment: Putting the Cart Before the Horse

Updated: Feb 4, 2022

The importance of specifications

Often, when starting the process of gathering safety data for a Generally Recognized as Safe (GRAS) ingredient or new dietary ingredient (NDI), people are anxious to get started, designing animal studies and getting bids from labs, but this is putting the cart before the horse. There is a tendency to overlook the importance of establishing substance specifications and stability prior to any animal or genetic toxicity testing.  If the substance specifications are not nailed down prior to safety testing, any data produced may not be valid if the specifications are subsequently changed – even the smallest “tweak” in specifications could invalidate the safety data, as safety is determined based on the substance tested, not on something similar to the substance tested.  Likewise, stability under the conditions of storage and use must be established.  If a substance is not stable and changes composition post-manufacture, there will always be some question as to the composition of the substance used for animal testing and exactly what is being added to food.  If the substance is only stable frozen or under refrigeration, then the consumer product to which it is added must also be kept frozen or refrigerated.  You must establish conditions of storage and use (e.g., time, temperature, type container in which it may be stored and other critical variables) to share with your customers.  Further, the customer must be able to take samples for his quality control and compare the sample to the advertised specifications.  If the results of quality assurance testing indicate something other than the specifications, there is no way the customer can conclude he has been shipped the correct product and/or if the substance has deteriorated to the point where now potentially undesirable substances have formed.

It is important to recall from the GRAS final rule (published in August 2016[1]) that the Food and Drug Administration (FDA) states that the standard of safety needed for a GRAS determination is identical to the safety data needed for a food additive petition (FAP).  This requirement would include supportive data, such as specification data and feeding study data. Additionally, the GRAS final rule also emphasizes the importance of specifications by highlighting that specifications are relevant to both the identity of a substance (i.e., a food ingredient) and the safe use of that substance in food. For a food additive petition (FAP), the FDA recommends that five lots of ingredient, three of which are non-consecutive, be tested to demonstrate conformity to the specification. By being held to the same standard of safety as a FAP, the demonstration of conformity to specifications extends to the GRAS process as well. Likewise, stability testing should be conducted to ensure that the product remains stable under the intended conditions of use and for a set amount of time.

While some ingredients may have certain specifications established by either prior use or from governing bodies, other ingredients may not have specifications established and will require you to determine them for your ingredient. The specifications established for your ingredient should characterize the key components of the ingredient and should be used to establish a chemical identify for your ingredient. Additionally, specifications should also identify potential contaminants in your ingredient and establish tolerance levels for those potential contaminants.  For example, if the specific manufacturing technique that was used to create your ingredient involves an extraction step, it will be necessary to establish a specification for the solvent used for the extraction to ensure that the residues are below a threshold level in the final product. Further, it is important that there are no contaminants (e.g., heavy metals, microbials, etc.) in the ingredient that may impact the integrity of the substance, especially if the ingredient is obtained from a natural source.

Verifying stability of your ingredient is also an important step in the safety assessment process.  Stability testing will be used to assess how stable your ingredient is over the anticipated shelf life under specified storage conditions. It is important to document that the specific characteristics of your product that make it a unique ingredient remain stable for the anticipated shelf life.  If your ingredient is attractive because of, for example, a high nutrient content, then you will have to establish that there is no innate activity that would degrade the nutrient during the shelf life. Additionally, it is important to demonstrate that no chemical decomposition occurs in the ingredient.  This degradation can be attributable, in part, to an increase in moisture content of the packaged ingredient during storage, which can be caused by environmental conditions.  An increase in moisture can also result in other effects on your packaged ingredient such as the possibility that an increased moisture content may provide a favorable environment for the proliferation of bacteria.   A decrease in the key constituent, the formation of degradation products, or an increase in contaminants above the established specifications will be seen by FDA as impacting the safe use of the ingredient.

So why is it important to establish specifications and stability early on? If you are proceeding down a path where you will be determining the GRAS status of your food ingredient and you are planning safety studies to support the safe use of your ingredient, but don’t verify specifications and establish stability at the onset, you could be forced to repeat the safety testing and thus delay the completion of a GRAS assessment or NDI and ultimately, the ability to sell your product.  Below are a few situational examples to illustrate where issues may arise if you do not address specifications and stability before beginning safety studies or composition of the GRAS dossier:

  1. If you are conducting animal safety testing with a sample of your ingredient and the product fails to meet specifications, then you are not really testing the product you intend to sell. Further, if a contaminant is identified in the batch used in a study, the interpretation of the results may be complicated by the possibility that the contaminant effected the outcome.

  1. If you are unable to show that your product is stable for at least the duration of the study, or frequent dietary mixes are made with fresh test substance, the data gathered from the safety studies may not meet the strict criteria of a study conducted according to Good Laboratory Practices (GLP), as required by FDA.

  1. If you have established specifications for your product based on your intended target, but testing reveals that your manufacturing process failed to meet your specifications, it could cause delays in making the GRAS determination while you determine where the issue may be and produce more of the ingredient for testing. This could have an impact on the sale of your ingredient to vendors, if the sale hinges upon meeting a certain minimum characteristic (e.g., a certain amount of fiber content).

While it is a requirement to have specification and stability data available to support the safety of your ingredient, waiting until you are far along in the process to test for these requirements could hinder your ability to sell your product by a target date.  Proactive preparation in the beginning can help ensure that delays are minimized during the safety assessment process and can aid in achieving your ultimate goal.

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