FDA history of safe use definition is ‘arbitrary and unfounded’, says pre/probiotics group

The association, which represents academics and industrial scientists researching probiotics and prebiotics, said it was “concerned about several aspects of the​ [FDA's] draft guidance ​[on new dietary ingredients] as it relates to the science behind the probiotic and prebiotic fields”.​

FDA should use same criteria as in GRAS to establish a history of safe use​

Of particular concern was the FDA’s definition of history of safe use as 25 years of widespread use, said ISAPP, in a formal submission to the FDA filed late last week.

“This seems arbitrary and unfounded. First, the definition of widespread is not clear. Second, some substances might be widely consumed and safety could be reasonably established within months, whereas other substances that might be rarely consumed may not be sufficiently understood from a safety perspective for decades.”​

Instead of a blanket 25 years, ISAPP suggests that the FDA use the same definition as that required for GRAS (generally recognized as safe) notifications for ingredients in foods:

"Substances that are recognized, among qualified experts, as having been adequately shown ... through experience based on common use in food to be safe under the conditions of their intended use."​

Only substantive changes in processing or fermentation conditions with reasonable potential to impact safety should trigger fresh NDI notification ​

As for the FDA’s view that new extraction technologies that could alter the chemical composition of ingredients considered ‘grandfathered in’ should trigger a new NDI notification, ISAPP urges the FDA to “clearly stipulate that in the case of live microbes, only substantive changes in processing or fermentation conditions that have a reasonable potential to impact safety require re-filing.”​

Along with all of the major trade associations, the ISAPP also calls for the FDA to ditch its calls for supplement/end-product-specific NDI filings and instead focus on ingredients for an intended use – as per food-additive and GRAS applications.

Antibiotic resistance​

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Regarding live NDIs, the FDA’s draft guidance stipulates that firms “should document resistance to any clinically relevant antibiotics, and if applicable, the genetic nature of the resistance”.​

It goes on to say that if the microbial NDI is resistant to any clinically relevant antibiotics, firms should also “perform an assessment of the ability of the antibiotic resistance genes to mobilize and transfer to human pathogens under the conditions of use of the dietary supplement”.​

While the presence of transferable, clinically relevant antibiotics is an important factor to consider in the safety of probiotics, noted ISAPP, “methodologies do not exist for conclusive demonstration of lack of transferability”.​

Instead, ISAPP recommends that the FDA “accept a genetic assessment approach whereby the presence of antibiotic resistance genes in proximity to genes that promote rapid transfer be acceptable to establish the absence of a significant likelihood of transferable antibiotic resistance genes”. ​

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In addition, established methods for assessment of phenotypic antibiotic resistance patterns can be used, it argues.

“Strains exhibiting phenotypic resistance outside the norm for the species would warrant further investigation.”​

Strain- vs species-specific information​

ISAPP’s position on whether strain vs species-specification information is needed to prove the safety of probiotics is “consistent with the approach taken by the European Qualified Presumption of Safety of Micro-organisms for Use in Food and Feed (QPS) list​”, says the association.

The QPS list contains microorganisms evaluated by the European Food Safety Authority for which there is sufficient evidence indicating that all strains within a species can be presumed to be safe in the absence of evidence to the contrary.

While ISAPP does not believe safety must be demonstrated at the strain level for QPS species, it should be done at the strain-level for non-QPS species.

However, for the purposes of identification and characterization, all tests must be conducted at the strain-level for all probiotics, it stresses.