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Postbiotics: A global perspective on regulatory progress

September 13, 2024/in ISAPP Science Blog /by KC

By Dr. Gabriel Vinderola PhD, CONICET, National University of Litoral, Argentina

While the conceptualisation of postbiotics varies among scientists, some recent actions may suggest that regulatory agencies around the world are starting to align with the ISAPP definition (Salminen et al. 2021), understanding postbiotics as preparations of inanimate microorganisms able to confer a health benefit.

Before the May 2021 publication of the postbiotic consensus definition by an expert panel convened by ISAPP, a search in www.pubmed.com using the term postbiotics rendered around 320 entries in the period 1975-2021. Three years after the ISAPP publication, by August 2024, almost 1200 entries could be found. However, it is still to be examined how many of these entries use the term postbiotics to refer to (1) administered metabolites, (2) metabolites produced by the gut microbiota or (3) inanimate microbial preparations, the three most prevalent conceptualizations of the term. A future bibliometric analysis of the literature could be performed to shed light on this. Meanwhile outside academia, the discrepancy in postbiotic definitions continues: some companies market specific metabolites as postbiotics whereas other companies use the term postbiotics to refer to heat-inactivated lactobacilli.

The first movement I noticed towards potential regulatory adoption of the term was made by Health Canada, as suggested in a presentation by an officer at Probiota 2023 in Chicago last year. The presentation shared the ISAPP definition, stating that postbiotics would fall under the Natural and Non-Prescription Health Products Directorate (NNHPD), that some probiotic specifications may apply (strain specification, antibiotic resistance, etc,), and that quantification, in principle would be based on milligrams, expecting that more sophisticated and accurate methodologies would arise over time. This issue was addressed further in a Discussion Group in the recent ISAPP meeting at Cork (Ireland) – see the annual meeting report here. Presently, there is only one entry for the word postbiotics in the Health Canada webpage, where it is stated that “gut modifiers as livestock feed are products that, once fed, have a mode of action in the gastrointestinal tract of an animal. The gut modifier category can encompass a variety of feed ingredients, these ingredient types may include, but are not limited to viable microbial strains, prebiotics, postbiotics, enzymes, organic acids and essential oils”. However, no further indications of the meaning of the term postbiotic are stated on the website.

In January 2024, the trade journal Nutraingredients announced that the China Nutrition and Health Food Association (CNHFA) had decided to draft industry standards for quantifying postbiotics or inactivated cells and were rallying industry players and the public to take part in the draft process through a public consultation. The National Institutes for Food and Drug Control (NIFDC) was leading the process and it had drafted flow cytometry standards to measure postbiotics composed of inactivated cells of lactic acid bacteria. In addition, a fluorescent quantitative PCR detection method had been drafted for inactivated Bifidobacterium lactis cultures. In correspondence with the NIFDC, it was discussed that a direct counting method using a standard microscope for single culture postbiotics was being explored.

The TGA (Therapeutic Goods Administration) is the Australian body that regulates medicines, medical devices and biologicals. The TGA recently published a guidance to provide information for applications relating to microorganisms as active ingredients for use as new substances in listed medicines (the category which includes the majority of dietary supplements marketed in Australia), or as active ingredients in registered complementary medicines (RCM). Listed medicines and RCM containing microorganisms as active ingredients are generally referred to as probiotics or postbiotics. For the purpose of this guidance, microorganisms are whole and intact cells of bacteria and fungi (including yeasts) that are live or non-viable. This guidance is intended for the premarket assessment of new live and whole/intact non-viable microorganisms potentially used as probiotics and postbiotics. Interestingly, the guidance does not include cell fragments, which have different pharmacokinetics within the gut. It is worth noting that Australia is part of the ACCESS Consortium, consisting of Australia’s TGA, Health Canada, the UK’s MHRA, Swissmedic from Switzerland and Singapore’s Health Sciences Authority. However, it’s not yet known whether the ACCESS Consortium will take inspiration from the Australian guidance.

Which scientific publications may be influencing these regulatory directions? At the beginning of this blog I discussed the possibility of conducting a bibliometric analysis of the literature in order to find out how the term postbiotic has been used so far in relation to the different conceptualizations it may have. Surprisingly to me, a bibliometric analysis was published as a preprint last February at www.preprint.org and entitled “Who is qualified to write a review on postbiotics? A bibliometric analysis”. Authors indicated that between November 2021 and December 2023, 76 review articles were published on postbiotics, with a mean of almost 3 reviews per month. Authors concluded that a portion of this collection of work was written by first authors with no previous engagement with related research and lacking colleagues or mentors involved with microbiome/probiotics research to support them as senior authors. Our article “The Concept of Postbiotics”, in collaboration with Dr. Mary Ellen Sanders PhD and Prof. Seppo Salminen PhD ranks in third place among the top 10 publications according to the number of citations received.

While the academic and scientific sphere still debate the proper meaning of the term postbiotics, it seems the regulatory landscape for postbiotics is progressing to consider them to be preparations of inanimate microorganisms able to confer a health benefit, as proposed by ISAPP.

Definition of postbiotics: A panel debate in Amsterdam

December 5, 2022/in ISAPP Science Blog /by KC

By Dr. Gabriel Vinderola, PhD, Associate Professor of Microbiology at the Faculty of Chemical Engineering from the National University of Litoral and Principal Researcher from CONICET at the Dairy Products Institute (CONICET-UNL), Santa Fe, Argentina.

A panel debate titled “Postbiotics, definition and scopes” was convened at the 9^th Beneficial Microbes conference in Amsterdam on November 14, 2022. The aim of this panel was to advance the discussion about postbiotics in the aftermath of some published disagreement (see here and here) about the definition of postbiotics produced and published by ISAPP: “a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”. The debaters included Prof. Seppo Salminen and myself (Dr. Gabriel Vinderola), both members of the board of directors of ISAPP and co-authors of the ISAPP postbiotics definition, supporting the ISAPP definition, and Prof. Lorenzo Morelli (in attendance virtually) and Dr. Guus Roeselers challenging the ISAPP definition. The debate was attended by around 150 persons, and consisted of 15-minute opening arguments on both sides, followed by a 30 min open discussion guided by the conference chair, Dr. Koen Venema.

I introduced ISAPP as a non-profit organization dedicated to advancing the science on probiotics, prebiotics and related substances. Among many other activities, ISAPP has produced 5 different consensus definitions: probiotics, prebiotics, synbiotics, postbiotics and fermented foods. Each consensus panel was composed of academic scientists with different backgrounds, expertise and perspectives, comprising at least 11 authors from 4 – 10 countries, who came together to incorporate broad perspectives and engage in thoughtful debate. To date, all 5 consensus papers have had almost half a millon accesses at Nature Reviews Gastroentetology and Hepatology, the journal where all of the definitions are published.

The discussion within ISAPP about the need for a postbiotic definition dates back to our 2019 annual meeting. Emerging research on the health benefits conferred by non-viable microbes, their fragments and metabolites was discussed at the meeting, and this planted the seed for a definition that would cover this area. Many different terms such as heat-killed probiotics, heat-treated probiotics, heat-inactivated probiotics, tyndallized probiotics, paraprobiotics, ghost probiotics, cell fragments, cell lysates and postbiotics had been used to encompass these substances.

The panel discussed these different terms and previously published definitions. Those opposed to the ISAPP definition preferred the Tsilingiri and Rescigno (2013)¹ definition of postbiotics, which focuses on metabolites produced by probiotics. I reviewed the limitations of that definition, which were outlined in Salminen et al. (2021)². One concern is that requiring a postbiotic to be derived from a probiotic creates an unnecessary burden of first meeting the criteria for a probiotic before developing a postbiotic.

Morelli emphasized the importance of definitions for regulatory bodies and stated that researchers should provide guidance on criteria to meet a definition. He quoted the first published definition of postbiotic by Tsilingiri and Rescigno in 2013¹: “any factor resulting from the metabolic activity of a probiotic or any released molecule capable of conferring beneficial effects to the host in a direct or indirect way”. Morelli stated that one value of this definition was that it was clear to regulators; metabolites are measurable and produced by microbes already accepted as food components with a long history of safe use. He considered this of paramount relevance as otherwise, the novel foods path would be required. He challenged the ISAPP approach as defining a substance that was unclear how to measure. Morelli showed pictures depicting the deterioration of the biomass of freeze-dried cultures during storage, to underscore the challenges of controlling the quality of products based on biomass of non-viable microbes. He added, “If we don´t know which are the components responsible for the health benefits, then it is challenging to determine what to measure.” He questioned the ability to establish the shelf life of such a product. The need to be precise in terms of how to quantify the active components of non-viable cells was essential to his criticism of ISAPP’s definition of postbiotics. Prof. Morelli concluded that researchers must address this issue of quantification methods, both to advance research and to provide regulatory bodies needed approaches to regulating non-viable microbes.

Conclusions from the debate were that the flaws of definitions previous to the ISAPP definition are apparent, and that the substance defined by ISAPP was useful to delineate, but that clear approaches to measurement of the active component(s) of non-viable microbes are needed to make the ISAPP definition workable in scientific and regulatory circles. The debate was very worthwhile, since science advances through respectful debates such as this.

It is clear that characterization of postbiotic products may be challenging, especially with increased complexity that arises by use of multiple inanimate strains, inclusion of metabolic endproducts, and the presence of whole and fragmented cells. But these challenges are not unique to postbiotics. Probiotic products can comprise complex mixtures of multiple strains as well as metabolic products (as the biomass during industrial production is harvested for freeze-drying, but not washed), along with significant amounts of non-viable microbes, which all may contribute to the overall health benefit. These facts are usually overlooked when relying just on viable cells for quantification.

Many commercial products carrying inanimate microbes and metabolic fermentation products, that potentially fit the ISAPP definition of postbiotics, are already available in the market. These are diverse products such as a mixture of two lactobacilli aimed at treating infant and adult diarrhea³ or a fermented infant formula to support pediatric growth⁴. Similar products also target animal nutrition⁵. A tightly controlled manufacturing process may be the path forward to warrant reproducibility of health benefits. Suitable characterization methodologies such as flow cytometry for non-viable microbes and mass spectrometry for metabolites seem to be relevant to sufficient postbiotic product characterization.

In brief, the ISAPP definition itself seemed well accepted by the meeting participants, but concerns were raised about how to quantify postbiotics according to the definition. We intend to address this point through consultations with experts, proposing scientific paths to help conceptualize factors that need to be considered for postbiotic quantification.

Panel debate about ISAPP’s definition of postbiotics held at Beneficial Microbes conference in Amsterdam on November 14th, 2022. On the stage, from left to right: Koen Venema (conference chair), Gabriel Vinderola, Seppo Salminen, Guus Roeselers and Lorenzo Morelli (on screen).

References

Tsilingiri, K. & Rescigno, M. Postbiotics: What else? Benef. Microbes (2013) doi:10.3920/BM2012.0046.
Salminen, S. et al. The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics. Nat. Rev. Gastroenterol. Hepatol. (2021) doi:10.1038/s41575-021-00440-6.
Malagón-Rojas, J. N., Mantziari, A., Salminen, S. & Szajewska, H. Postbiotics for Preventing and Treating Common Infectious Diseases in Children: A Systematic Review. Nutrients 12, (2020).
Béghin, L. et al. Fermented infant formula (with Bifidobacterium breve C50 and Streptococcus thermophilus O65) with prebiotic oligosaccharides is safe and modulates the gut microbiota towards a microbiota closer to that of breastfed infants. Clin. Nutr. 40, 778–787 (2021).
Kaufman, J. D. et al. A postbiotic from Aspergillus oryzae attenuates the impact of heat stress in ectothermic and endothermic organisms. Sci. Rep. 11, 6407 (2021).

Additional reading:

Follow up from ISAPP webinar – Probiotics, prebiotics, synbiotics, postbiotics and fermented foods: how to implement ISAPP consensus definitions

Postbiotics: The concept and their use in healthy populations

Watch / listen to the debate here: https://youtu.be/pATNfhQY4P4

Decoding a Probiotic Product Label

February 11, 2022/in Consumer Blog /by KC

By Mary Ellen Sanders, PhD

Interested in knowing what’s in your probiotic product? Unfortunately, there are many ways that probiotic product labels can fall short.

First, not all items labeled as “probiotic” truly meet the scientific criteria for a probiotic product. See here for information on what qualifies as a probiotic. Some fermented foods are marketed today claiming to be ‘probiotic’. But these products often have undefined microbial content and lack any studies documenting health effects, criteria that are required for a probiotic. Instead, such products could legitimately be labeled as containing ‘live, active cultures’. Dietary supplement products formulated with untested microbes should similarly not be labeled as probiotics.

Also, a label might not provide adequate information on what types of microbes are contained in the product. Genus and species may be listed, but no strain designation. Maybe only “bifidobacteria” or “lactobacilli” are listed.

They might not disclose the potency of individual strains in the product. Some may provide a total count of colony forming units (cfu)/dose or serving, which in the case of a single strain product is informative. But in the case of a multi-strain product – products may contain a couple or up to 30 strains – you don’t know if equal amounts of all strains are included, or perhaps the bulk of the count is made up of the strain in the formulation that is least expensive to manufacture rather than the one that will make the probiotic more effective. Some products may provide one count for “Lactobacillus” and another count for “Bifidobacterium”, a slightly more informative approach than just total count, but still lacking in detail. Many challenges exist for multi-strain products, including the lack of robust methods to quantify different strains once combined, especially viable ones. This topic was one that was covered in an ISAPP webinar, Current issues in probiotic quality: An update for industry.

The label may state that the count is “at time of manufacture”, a number that is no doubt inadequate if you purchase the product close to the end of its shelf-life. Most probiotic strains suffer cell count decline over the course of shelf-life, with some strains more susceptible than others. This situation almost guarantees that by the pull-by date for a multi-strain product, the ratio of cfu of strains to each other is likely much different than at the time of formulation.

Surveys of probiotic product labels

Additionally, it is difficult for consumers to know what products are backed by studies documenting a health benefit. If a product is not labeled sufficiently, it is impossible to link it to evidence. Two studies surveyed commercial probiotic products in the Washington DC area, Retail Refrigerated Probiotic Foods and Their Association with Evidence of Health Benefits and More Information Needed on Probiotic Supplement Product Labels. Results showed that 45% of retail dietary supplement products did not provide strain designations and an equal number did not provide a measure of potency through the end of shelf-life. Only 35% of products could be linked (based on strain and dose) to evidence of a health benefit. Food products fared a bit better, with 49% of refrigerated probiotic food products being linked to evidence of a health benefit. One clear indication from this study was that if your food product discloses the strain designation, it is likely to have evidence of a health benefit. An overall conclusion was that product labeling – at least in this region – needs improvement.

Historical context on guidelines for probiotic product labels

According to the FAO/WHO 2002 Working Group on Guidelines for the Evaluation of Probiotics in Food (page 39 of this combined document), the following information should be on probiotic labels:

– Genus, species and strain designation for each probiotic strain in the product.

– Minimum viable numbers of each probiotic strain at the end of the shelf-life, typically expressed in colony forming units (or cfu).

– The suggested serving size (or dose) must deliver the effective dose of probiotics related to any health benefit communicated on the label.

– Health claim(s) (as allowed by law and substantiated by studies)

– Proper storage conditions

– Corporate contact details for consumer information

These principles are developed and reiterated in “Best Practices Guidelines for Probiotics” (2017) developed by the Council for Responsible Nutrition and IPA.

Additional information

ISAPP created an infographic to explain the information on a probiotic labels. Our example portrays an imaginary dietary supplement for sale in the United States. Labels on foods containing a probiotic or a probiotic produced in another country would be labeled differently from this example to comply with applicable regulations. For those interested in probiotic labels in the EU, see the infographic ISAPP created for a probiotic product in the European Union. Also of interest, USP.org created an infographic on “How to Read a Dietary Supplement Label” for U.S. products.

Can dietary supplements be used safely and reliably in vulnerable populations?

July 8, 2021/in ISAPP Science Blog /by KC

By Dr. Greg Leyer, Sr. Director – Scientific Affairs, Chr. Hansen, Inc., Madison, WI and Prof. Dan Merenstein, Department of Family Medicine, Georgetown University Medical Center, Washington DC

What is it that doctors look for when recommending or prescribing therapies to patients? If it is a drug, a supplement, a new diet, or even a new exercise regimen, they look for safety and efficacy. There are of course other things to consider, including cost, ease of administration, and patient compliance, among others. But safety and efficacy are their foremost concerns.

A recently published clinical report from the American Academy of Pediatrics (AAP) (Poindexter 2021) examined the evidence for probiotics to prevent morbidity and mortality in preterm infants. They concluded that probiotics could not be recommended. This differs from conclusions of the American Gastroenterological Association (AGA) (Su et al. 2020), which recommended specific probiotic strains for preterm (less than 37 weeks gestational age) and low birth weight infants. The AAP report also differs from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) (Van den Akker et al. 2020), which recommends specific strains for this use, although their recommendations are not fully aligned with AGA’s (see What’s a Clinician to do When the Probiotic Recommendations from Medical Organizations Do Not Agree?).

The AAP report does a thorough job of reviewing data on use of probiotics in the NICU, including conflicting studies, lack of confirmatory studies of efficacious strains, and safety and cross contamination inside the NICU. However, the overriding theme of the report is “clinicians must be aware of the lack of regulatory standards for commercially available probiotic preparations manufactured as dietary supplements and the potential for contamination with pathogenic species.” Therefore, at the heart of the AAP failure to recommend probiotics is the concern that the quality of available products is insufficient. Because of the absence of a pharmaceutical-grade probiotic product for use in the United States, they posit, they cannot recommend usage. It is noteworthy that the trials performed on premature infants resulting in multiple conclusions of safety and efficacy have thus far utilized probiotic products manufactured as dietary supplements.

Probiotics can be marketed as drugs if they follow that regulatory pathway, but generally in the US they are sold under the regulatory classification of dietary supplements. Is the AAP correct that no dietary supplement is of sufficient quality to recommend for use in preterm infants?

Quality of probiotic dietary supplement probiotics. Dietary supplements were a category of product developed to supplement the diet of the generally healthy population, not to treat or prevent disease. In practice this is an important distinction, because while the safety standard is high for dietary supplements for healthy individuals (see comments by food safety expert Jim Heimbach here), such supplements do not need to be established as safe for patient populations. But in the case of probiotics, many clinical trials have evaluated safety and efficacy for prevention or treatment of disease, more aligned with drug uses. Yet probiotic products supported by these data are not marketed in the US as drugs.

It is a common misperception that dietary supplements are “not regulated”. However, the FDA has clear good manufacturing practices (GMP’s) and regulations dedicated to dietary supplement manufacturing. The onus is on manufacturers to establish appropriate product specifications based on intended use and risk. Reputable manufactures establish rigorous purity, strength, and identity quality standards consistent with the intended population and sufficient for that use. Products intended for infants, including premature infants, should be manufactured under quality standards more rigorous than those intended for a healthy adult population. For example, Chr. Hansen bases the enhanced specifications for products aimed at infants, and preterm infants, on elements of Codex standards for infant formula, amongst other stringent microbiological criteria. This would include manufacturing the probiotic strain to an “infant” grade, employing stricter environmental monitoring, sanitation, and airflow control throughout the process, careful selection of raw ingredients for infant compatibility, and enhanced testing and purity standards using validated methods at every step. The internal manufacturing standards that Chr. Hansen applies for products intended for infants, and preterm infants, are much stricter than typical dietary supplement standards, and are appropriate for their intended use.

Therefore, there are high quality, safe probiotic products produced under dietary supplement regulations even though such products do not carry any label statement claiming this added level of quality. However, products sourced for hospitals to stock in formularies could work with the supplier to demand this extra level of product testing specifications. Pharmacies can institute quality agreements with vendors that would delineate their expectations for the strains present, the levels of live microbes acceptable in the final product, etc. This agreement could also mandate that any product change – as defined in the agreement – would require the vendor to notify the customer. Such an agreement might be burdensome for a hospital pharmacist, but a sophisticated dietary supplement company should be able to assure the hospital formulary of their quality.

Products made using strict specifications, geared towards infant and premature infant applications, are on the market and are safely being used in this patient population in many NICUs and as part of infant formulas. We disagree with AAP’s position that a pharmaceutical approach is needed, as long as a product of sufficient quality can be provided. To deny preterm infants probiotics, which have a significant chance of improving their clinical outcomes, is not in line with other medical recommendations. Instead, the hospital formularies should stock products that have been scrutinized for sufficient evidence of safety and efficacy. Suppliers of stocked products should provide product testing results, a description of the quality standards employed during production, and a rationale for the suitability of the standards for preterm infants. Third party verification of adherence to these quality standards would assure medical professionals regarding the safety of these products for use.

References

CAC/RCP 66-2008. Code of hygienic practice for powdered formulae for infants and young children. Codex.

Poindexter, B. 2021. Use of Probiotics in Preterm Infants. Pediatrics 147 (6): e202 1051485.

Su et al. 2020. AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders. Gastroenterology 159:697-705.

Van den Akker et al. 2020. Probiotics and Preterm Infants: A Position Paper by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Committee on Nutrition and the European Society for Paediatric Gastroenterology Hepatology and Nutrition Working Group for Probiotics and Prebiotics. Journal of Pediatric Gastroenterology and Nutrition. 70(5):664-680.

A roundup of the ISAPP consensus definitions: probiotics, prebiotics, synbiotics, postbiotics and fermented foods

May 11, 2021/in ISAPP Science Blog /by KC

By Dr. Mary Ellen Sanders, PhD, ISAPP Executive Science Officer

ISAPP has long recognized the importance of precise definitions of the ‘biotic’ family of terms. As a scientific organization working to advance global knowledge about probiotics, prebiotics, synbiotics, postbiotics and fermented foods, we believe carrying out rigorous scientific studies—and comparing one result to another—is more difficult if we do not start with a clear definition of what we are studying.

Over the past 8 years, ISAPP has endeavored to bring clarity to these definitions for scientists and other stakeholders. ISAPP board members have met with other top experts representing multiple perspectives and specialties in the field to develop precise, useful and appropriate definitions of the terms probiotics, prebiotics, synbiotics, postbiotics and fermented foods. The definitions of these first four terms have all entailed the requirement that the substance be shown to confer a health benefit in the target host. Fermented foods have multitudes of sensorial, nutritional and technological benefits, which drive their utility. A health benefit is not required.

The problem with health benefits

The definitions provide significant advantages for the scientific community in terms of clarity but complexity arises when the same definitions are accepted by regulatory agencies. This requirement for a health benefit as part of the probiotic definition has been rigorously implemented in the European Union. Currently, with the exception of a few member states, the term probiotic is prohibited. The logic is that since a health benefit is inherent to the term probiotic and since there are no approved health claims for probiotics in the EU*, the term ‘probiotic’ is seen to be acting as a proxy for a health claim. This has frustrated probiotic product companies who believe they have met the scientific criteria for probiotics, yet cannot identify their product as a probiotic in the marketplace because they have not received endorsement of their claims by the EU. This is not an issue resulting from an unclear definition, since probiotics surely should provide a health benefit, but rather from a lack of agreement as to what level of evidence is sufficient to substantiate a health benefit.

ISAPP remains committed to the importance of requiring a health benefit for the ‘biotic’ family of terms (outlined in the table below). It’s clear that all of these definitions are meaningless unless the requirement that they confer a health benefit is considered as essential by all stakeholders. One could reasonably discuss whether the required levels of evidence for foods and supplements are too high in some regulatory jurisdictions, but the value of these substances collapses in the absence of a health benefit.

Summary of ISAPP consensus definitions

With the publication of the most recent ISAPP consensus paper, this one on postbiotics, I offer a summary below of the five consensus definitions published by ISAPP. Each definition is part of a comprehensive paper resulting from focused discussions among experts in the field and published in Nature Reviews Gastroenterology and Hepatology (NRGH). These papers are among the top most viewed of all time on the NRGH website and are increasingly cited by scientists and regulators.

Table. Summary of ISAPP Consensus Definitions of the ‘Biotics’ Family of Substances. Probiotics, prebiotics, synbiotics and postbiotics have in common the requirement for a health benefit. They may apply to any target host, any regulatory category and must be safe for their intended use. Fermented foods fall only under the foods category and no health benefit is required.

	Definition	Key features of the definition	Reference
Probiotics	Live microorganisms that, when administered in adequate amounts, confer a health benefit on the host	Grammatical correction of the 2001 FAO/WHO definition. No mechanism is stipulated by the definition.	Hill et al. 2014
Prebiotics	A substrate that is selectively utilized by host microorganisms conferring a health benefit	Prebiotics are distinct from fiber. Beneficial impact on resident microbiota and demonstration of health benefit required in same study.	Gibson et al. 2017
Synbiotics	A mixture comprising live microorganisms and substrate(s) selectively utilized by host microorganisms that confers a health benefit on the host	Two types of synbiotics defined: complementary and synergistic. Complementary synbiotics comprise probiotic(s) plus prebiotic(s), meeting requirements for criteria for each. Synergistic synbiotics comprise substrate(s) selectively utilized by co-administered live microbe(s), but independently, the components do not have to meet criteria for prebiotic or probiotic.	Swanson et al. 2020
Postbiotics	Preparation of inanimate microorganisms and/or their components that confers a health benefit on the host	Postbiotics are prepared from live microbes that undergo inactivation and the cells or cellular structures must be retained. Filtrates or isolated components from the growth of live microbes are not postbiotics. A probiotic that is killed is not automatically a postbiotic; the preparation must be shown to confer a health benefit, as well as meet all other criteria for a postbiotic.	Salminen et al. 2021
Fermented Foods	Foods made through desired microbial growth and enzymatic conversions of food components	Fermented foods are not the same as probiotics. They are not required to have live microbes characterized to the strain level nor have evidence of a health benefit. Types of fermented foods are many and are specific to geographic regions. Compared to the raw foods they are made from, they may have improved taste, digestibility, safety, and nutritional value.	Marco et al. 2021

*Actually, there is one approved health claim in the EU for a probiotic: Scientific Opinion on the substantiation of health claims related to live yoghurt cultures and improved lactose digestion (ID 1143, 2976) pursuant to Article 13(1) of Regulation (EC) No 1924/2006

Further reading: Defining emerging ‘biotics’

Video Presentation: Behind the scenes of the consensus panel discussion on the definition of fermented foods

January 18, 2021/in ISAPP Science Blog /by KC

Numerous misunderstandings and questions exist around the concept of fermented foods. For example:

If a food does not contain live microorganisms, can it still be a fermented food?
Should the live microbes in fermented foods be called probiotics?
Do fermentation microbes colonize the human gut?

The first step in answering these questions is for scientists to come to agreement on what constitutes a fermented food. A new global definition of fermented foods was recently published by 13 interdisciplinary scientists from various fields—microbiology, food science and technology, immunology, and family medicine. In their paper in Nature Reviews Gastroenterology & Hepatology, fermented foods are defined as: “foods and beverages made through desired microbial growth and enzymatic conversions of food components”.

The panel discussion and the definition of fermented foods are covered in this video presentation by the paper’s first author Prof. Maria Marco, from the Department of Food Science and Technology at the University of California, Davis. This presentation was originally given at the virtual ISAPP 2020 annual meeting.

The new definition is intended to provide a clearer conceptual understanding of fermented foods for the public and industry, with the authors expecting that in the years ahead, scientists will undertake more hypothesis-driven research to determine the extent that various fermented foods improve human health and precisely how this occurs. More studies that address fermented foods in promoting health will be useful for establishing the importance of fermented foods in dietary guidelines.

The panel acknowledged that regulations on fermented foods from country to country are mainly concerned with food safety — and that, when properly made, fermented foods and their associated microorganisms have a long history of safe use.

‘Probiotic’ on food labels in Europe: Spain adopts a pioneering initiative

December 9, 2020/in ISAPP Science Blog, News /by KC

By Silvia Bañares, PhD in commercial law, attorney Barcelona Bar Association, Spain; and Miguel Gueimonde, Departamento de Microbiología y Bioquímica de Productos Lácteos, IPLA-CSIC, Villaviciosa, Asturias, Spain.

The word ‘probiotic’ has been absent from food products in most countries in Europe for years. Authorities there concluded that the word is an implied health claim, which is a reasonable position based on the probiotic definition: live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. The argument proceeds: since there are no health claims approved for probiotics by the European Union, the word is not allowed on food labels. However, the logic fails since in 2010 ESFA actually did approve a health claim for probiotics – although they didn’t use the term ‘probiotic’. This claim was for yogurt cultures improving lactose digestion. But nonetheless, restrictions on using the word ‘probiotic’ have endured.

Recently, akin to positions taken by Italy (here and here) and ostensibly the Czech Republic (as stated here), Spanish authorities have determined that the term ‘probiotic’ may be used.

In October 2020 the Spanish Health Authority (AESAN) delivered a new decision related to the use of the term “probiotic” in foodstuffs. According to it:

“until a uniform criterion is generated on the part of the Member States of the European Union, it is considered that it could be accepted that the term probiotic/s on the label of foodstuffs, both of national manufacturing as well as from other countries of the European Union. In all cases, these products must meet the safety requirements. However, it should be noted that the use of this term cannot be accompanied by any health claim, unless expressly authorized under the Regulation of the European Union -Regulation EC 1924/2006–” [1]^, [2]

This new decision completely differs from the previous one (February 2020), which forbade the use of “probiotic/s” term in food products. Surprisingly, both documents are extremely similar in their reasoning.

However, the new Guidance contains some points that might be relevant for the future:

First, there is a clear statement related to the EU Commission Guidance of 2007 [3]; such Guidance had always been invoked as the rationale in order to forbid the term probiotic in foodstuffs, since according to it, the reference to “probiotic/s implies a health benefit”[4]. But the AESAN communication points out for first time that such Guidance is not binding since it has no legal force.
Secondly it recognizes the lack of harmonization at the EU level regarding the “probiotic” term:

“From the discussions that have been held within the European Commission’s group of experts on nutritional and health claims, it is found that there are different interpretations by State Members regarding the use of the term “probiotic”, which, in turn, implies a non-harmonized situation in the European Union market”[5].

Third, there is a clear reference to mutual recognition principle; that is to say, any product legally marketed and sold in any EU country might be, in its turn, marketed in any other European Union Member State. For instance, any foodstuff labelled as “probiotic” in Italy might be legally sold in Spain as far as it fulfils the aforementioned criterion in its country of origin. The AESAN communication recognized such fact, pointing out that:

“In this sense, infant formulas and follow-on formulas are marketed which, as a voluntary added ingredient, contain different live microorganisms. The presence of these live microorganisms is indicated on the product label in the ingredient list. In the field of food supplements, it has been found that there are a large number of food supplements on the market, which include the term “probiotic/s”. These products come from different EU countries, where they are allowed to be marketed under this name and, therefore, they could not be prevented from being marketed in Spain, in application of the “principle of mutual recognition” established in the European Union Treaty”[6].

This statement is clearly aligned with Regulation EU 2019/515 [7] (related to mutual recognition principle) and a recent Commission Regulation (Implementing Regulation 2020/1668), which develops the previous one [8]. According to these dispositions, any competent authority suspending market access should notify the legitimate public interest grounds for such suspension. Therefore, Spain would find quite difficult to reject a foodstuff labelled as “probiotic” in another EU country when it is legally sold as such. Hence, it can be said that Spain has adopted a pioneering initiative that maybe could be followed by other EU Member States.

Italy and the Czech Republic have allowed use of the term ‘probiotic’ on foods – perhaps simply because they considered it to be the right thing to do – but they did not make the convincing legal argument made by Spanish authorities. The rationale presented by Spain could likely be easily adopted by other EU countries as well. Perhaps the Spanish initiative will motivate the EU Commission and EFSA to reach a consensus about this word.

Two decades ago, with a rapidly growing list of probiotic-containing products reaching the market worldwide, there was increasing concern by consumers about how to distinguish among the different probiotic strains available and how to know which products have evidence for different health benefits. This, together with the interest of scientist and industry for clear rules and fair competence, prompted the EU Commission to regulate the area and the Regulation EC n° 1924/2006 on nutrition and health claims made on foods was developed. In its preamble this Regulation states, “to ensure a high level of protection for consumers and to facilitate their choice, products put on the market must be safe and adequately labelled” and recognises that “general principles applicable to all claims made on foods should be established in order to ensure a high level of consumer protection, give the consumer the necessary information to make choices in full knowledge of the facts, as well as creating equal conditions of competition for the food”. Therefore, consumer protection and facilitating informed purchase choices was in the forefront of the Regulation, in an attempt to satisfy the concerns and demands that consumers had leveraged.

Subsequent interpretation of the Regulation EC n° 1924/2006 led to the conclusion that the term “probiotic” was a health claim and, as a consequence, should not be used in product labelling. Different countries, such as Italy or the Czech Republic, reacted to this by developing national regulations allowing the probiotic food labelling. Now Spain, on the basis of mutual recognition principle, accepts its use as well.

However, this new situation makes relevant again the challenges that consumers had identified two decades ago: how to differentiate among the different available probiotic products and make an informed, purposeful purchase. This unsolved issue should now be addressed. In this context, we advocate for the development of easy-to-use guidelines targeted to regular consumers, not to clinicians or scientists, to provide consumers with the necessary tools to make their choice.

References:

[1] https://www.aesan.gob.es/AECOSAN/web/seguridad_alimentaria/subdetalle/probioticos.htm

[2] Translation by the authors

[3] https://ec.europa.eu/food/sites/food/files/safety/docs/labelling_nutrition_claim_reg-2006-124_guidance_en.pdf

[4] Guidance on the implementation of Regulation n° 1924/2006 on nutrition and health claims made on foods conclusions of the Standing Committee on the Food Chain and Animal Health /14/12/2007

[5] Translation by the authors

[6] Translation by the authors

[7] Commission Implementing Regulation (EU) 2020/1668 of 10 November 2020 specifying the details and functionalities of the information and communication system to be used for the purposes of Regulation (EU) 2019/515 of the European Parliament and of the Council on the mutual recognition of goods lawfully marketed in another Member State.

[8] Regulation (EU) 2019/515 of the European Parliament and of the Council of 19 march 2019 on the mutual recognition of goods lawfully marketed in another Member State and repealing regulation (EC) nº 764/2008

Safety and efficacy of probiotics: Perspectives on JAMA viewpoint

April 16, 2020/in ISAPP Science Blog /by KC

By Mary Ellen Sanders PhD, executive science officer, ISAPP, and Daniel Merenstein MD, Department of Family Medicine, Georgetown University School of Medicine

The Journal of the American Medical Association (JAMA) recently published a short viewpoint that called into question the safety and efficacy of probiotics. After careful review, we concluded that some opinions expressed were not consistent with available data. We share our perspectives here.

Claim 1: The paucity of high-quality data supporting the value of probiotics.

The authors speak to the “paucity” and “lack” of data supporting probiotic use. They criticize probiotic meta-analyses in general, even though there are many well-done ones, which describe clear PICOS, assess the quality of studies included, and assess publication bias. Many conclude that there is evidence that certain probiotics may be beneficial for several clinical endpoints. In the case of treatment of colic, an individual participant data meta-analysis was conducted on a single strain, and concluded “L reuteri DSM17938 is effective and can be recommended for breastfed infants with colic” (Sung et al. 2018). For necrotizing enterocolitis (NEC), a change in practice is recommended by a Cochrane meta-analysis (AlFaleh et al. 2018), which is consistent with draft American Gastroenterological Association (AGA) recommendations posted last month. In some cases, conclusions are qualified as being based on low quality data, which is also the case with many standard-of-care medical interventions. Other benefits supported for certain probiotics by evidence are shown in Table 1 of Sanders et al. 2018. But an evidence-based review of available data would not support a general statement that “data are lacking.”

Instead, we think a discussion of what evidence is actionable is reasonable to have. For this discussion, different people or groups can reasonably set the bar at different levels for what constitutes actionable evidence. But several medical organizations, including the European Society for Paediatric Gastroenterology, Hepatology and Nutrition, World Gastroenterology Organisation, American College of Gastroenterology, AGA (proposed, for antibiotic-associated diarrhea, NEC and pouchitis), European Crohn’s and Colitis Organization, and European Society for Primary Care Gastroenterology have actionable recommendations for probiotic use for one or more indications. For those indications, any individual physician may judge that the available evidence as not convincing to him or her, but many qualified healthcare experts did find the evidence convincing and have made recommendations accordingly. We recognize that the JAMA viewpoint was limited in the number of words and references allowed, but to impugn an entire field, the authors are obliged to explain why their views differ so much from established organizations.

The authors also criticize the inclusion of small, single-center trials in probiotic meta-analyses. They state such studies have less oversight, are more susceptible to misconduct and are at greater risk of bias than larger, multicenter trials, and thereby skew conclusions of meta-analyses in favor of probiotics. They state, without evidence, that small trials are more likely to show large effects and are more likely to be published. They advocate for meta-analyses that only include multi-center trials, thereby ignoring much available evidence on the basis of unsubstantiated preferences. There are a number of reasons why some trials are multi-center, but improved quality or closer monitoring are not among them (see here, here and here). Multicenter trials may be necessary to study a rare medical endpoint, a condition with an expected small effect size but significant health implications, or to accelerate the time course for a study. In fact, an analysis of 81 meta-analyses of RCTs in 2012 concluded:

“Our results do not support prior findings of larger effects in SC (single-center) than MC (multi-center) trials addressing binary outcomes but show a very similar small increase in effect in SC than MC trials addressing continuous outcomes. Authors of systematic reviews would be wise to include all trials irrespective of SC vs. MC design and address SC vs. MC status as a possible explanation of heterogeneity (and consider sensitivity analyses).” [Emphasis ours]

In our experience, the size of a study does not inevitably minimize risk of bias. We have directly witnessed private physicians enroll for large multi-site trials without such oversight or professionalism. As the great David Sackett said in his paper from 20 years ago, “The more detailed the entry form and eligibility criteria for ‘somebody else’s’ RCT, the greater the risk the criteria will be ignored, misunderstood or misapplied by distracted clinicians who regard them as further intrusions into an overfull call schedule.” Further, due to often being underpowered, taken alone smaller studies are less, not more, likely to generate positive findings than larger trials. But when they are included in a meta-analysis, these studies contribute to the total body of evidence. We have personally worked on many single-center randomized controlled trials on probiotics. These often have monitors from the U.S. Food and Drug Administration and/or the National Institutes of Health, they are all registered with both primary and secondary outcomes listed, they utilize a data safety monitoring board, they undergo true allocation concealment, and otherwise are conducted to minimize risk of bias. To criticize probiotic studies for being single-center vs multicenter seems unjustified and baseless.

It is quite true that many of the studies conducted on probiotics were done 15 or more years ago, and the quality standards do not meet what we expect today. We wholeheartedly agree but would ask the authors to review studies conducted on drugs 15 years ago, and they will see the same issues. So we agree that more trials using modern quality standards are needed in the field of probiotics, as is the case for any interventions with a long history of being studied.

Claim 2: Potentially biased reviews of probiotic efficacy

In trying to explain why physicians might recommend probiotics, the authors speculate that some professional societies and some journals may be insufficiently critical in reviewing probiotic studies due to financial conflicts of interest. We have no doubt that there is bias in the scientific realm, which is not just limited to financial conflicts of interest, but question if there is any evidence that this occurs any more or less frequently with probiotics compared to any other realm of science. To leverage this accusation at the probiotic field specifically implies it is especially egregious, but no data supporting this accusation were provided. Also there is no face validity for this accusation. There is much more money to be made by pharmaceuticals and medical interventions than probiotic supplements and yogurts.

Claim 3: Complex framework in which probiotics are regulated and sold

The regulatory framework for probiotics can be difficult to navigate and is not always in the best interest of stakeholders, but we don’t think it’s reasonable to criticize the probiotic field for this situation. In the USA, probiotic products are bound by law that was enacted by Congress and the rules/guidance developed by the FDA for allowable product claims, levels of required regulatory oversight, and lack of requirements for premarket approval. It is fair to criticize Congress and the FDA for these circumstances surrounding the category of dietary supplements, but doing this in the context of an article on probiotics unfairly maligns probiotics.

Drugs vs dietary supplements. Most probiotics are sold as foods or dietary supplements. Since probiotics were first described as fermenting microbes in soured milk, this makes historical sense. Companies and consumers do not view these products as drugs, and in most cases they are not used as drugs. Outside a regulatory mindset, it makes perfect sense for foods to be useful for promoting health and managing symptoms, and this is what has driven 30 years of research and marketing of probiotics. Forcing all probiotics into a drug rubric would deprive consumers of access, would greatly increase their cost, and would preclude responsible food/supplement manufacturers from producing them. Drugs are drugs primarily to protect the safety of the patient. All drugs are assessed with a risk/benefit balance, and in some cases, the risk is significant. In the case of probiotics, we agree with the authors that most probiotics are likely safe for the general population. We see no reasonable justification to advocate that these products must all be researched and sold as drugs.

Probiotic product quality.The authors seem to prefer the drug model for probiotics based on a perceived need for improved product quality and oversight. Yet all foods and dietary supplements in the USA are required by law to be manufactured under good manufacturing practices. This includes most every product bought at the grocery store and served for dinner as well as probiotic foods and supplements. Further, companies are required to label their products in a truthful and not misleading fashion, including representations of contents and claims. Companies that fail to meet these standards are in violation of the law. Yes, there are products – of all types – that fall short of these requirements. The many responsible probiotic manufacturers and probiotic scientists decry such occurrences. However, these cases do not define the probiotic field any more than medical errors define physicians. It is not fair to impugn the entire probiotic industry based on the ‘bad apples’ that participate in it. A 2017 ESPGHAN review cites surveys of probiotic products from different regions globally, most of which report examples of probiotic products falling short in some quality attribute. Such surveys highlight quality problems, but due to sampling and methodological approaches, their results do not provide a reliable estimate of the extent of problem among commercial probiotic products. Many probiotic products are produced responsibly and are subjected to third party quality audits. The absence of such third party documentation is not evidence of poor quality, but we agree that it serves to improve consumer and healthcare provider confidence (see Jackson et al. 2019), and if more fully adopted, would weed out irresponsible probiotic manufacturers.

Oversight of probiotic research. The authors state, “If a manufacturer claims that any product, including a probiotic, cures, mitigates, treats, or prevents disease, the product is classified as a drug, thereby triggering a costly Investigational New Drug (IND) application process.” However, they seem to conflate the regulatory approach to product claims and the regulatory oversight of biologic drug research. In the case of product claims, if a product claims to cure, treat, prevent or mitigate disease, it is by definition a drug. If it has not undergone appropriate drug approval process, it is an illegally marketed drug and is subject to FDA action, including recall. Probiotics not destined for sale as drugs should not have to be researched under a drug rubric. This does NOT mean that such studies will de facto be substandard studies. We all understand the importance of conducting and reporting trials according to well-established guidelines. Studies on foods and supplements can and should follow those same principles.

Claim 4: Possible concerns about probiotic safety

Medical professionals balance potential harm with potential benefit for any intervention they recommend. Regarding safety of probiotics, the authors acknowledge that most probiotics are likely safe, but we would qualify that statement with “for their intended uses.” The use of probiotics in critically ill patient populations needs to be done with caution, proper oversight and a justification that the potential benefit will outweigh risk. The authors cite two examples to support their concern about probiotic safety, both in critically ill patient populations. One was a retrospective study looking at bacteremia in critically ill children (see the report here and responses to the report here and here). The second was a RCT that reported higher mortality in patients with pancreatitis (see the report here, with additional perspectives on interpreting safety outcomes here and here). We are not aware of any probiotics that are marketed for such uses, and if they were, they would be marketed as drugs, requiring drug-level safety and efficacy evidence. These studies are not an indictment of safety of probiotic foods and supplements, which in most cases are intended for the generally healthy population.

The authors further state that studies identifying adverse events from probiotics are the “tip of the iceberg” – creating an image of a huge number of unreported adverse incidents poised to be revealed. We have personally studied the most widely used Bifidobacterium strain, and in well over 30,000 pediatric patient days have not seen any serious adverse events and no more adverse events than placebo. The article cited by the authors states that our trials adequately reported harm. Obviously, no intervention is harmless, and no one claims as much for probiotics. It is true that older probiotic studies can rightly be criticized for not rigorously collecting and reporting data on adverse events (Hempel et al. 2011). However, a reasonable assessment of all available data, including data from well-conducted clinical trials, including trials in vulnerable populations, history of safe use, FDA notified assessments for GRAS use of certain probiotic strains, European Food Safety Authority QPS list, and others support that commonly used probiotics have a strong safety record for use in the general public.

Transferable antibiotic resistance. Regarding the risk that probiotics may transfer antibiotic resistance genes, this is a hypothetical concern – there is no documented case of this. Further, one pillar of probiotic safety assessments is that strains with antibiotic resistance genes flanked by mobile genetic elements are excluded from commercialization. As stated by Ouwehand et al. 2016, “Probiotics are specifically selected to not contribute to the spread of antibiotic resistance and not carry transferable antibiotic resistance.” The current approach to probiotic safety is that complete, well annotated genome sequences are available for commercial strains. This information is typically included in GRAS notices submitted to the FDA, and all the major probiotic suppliers require this level of safety assessment. This is the expected standard by the European Food Safety Authority as well, a standard that we enthusiastically and unreservedly endorse. Transferable antibiotic resistance is not a lurking threat of probiotics use, but is a well-considered issue adequately addressed by responsible probiotic manufacturers.

Conclusion

We believe that this JAMA viewpoint misrepresents the totality of data on probiotics and can potentially do harm by dissuading use of probiotics in an evidence-based manner. Important points have been raised by the authors, especially with regard to the use of probiotics in vulnerable populations, but this does not characterize most of probiotic use. We agree, as we expect the majority of scientists working on probiotics would, that additional, well controlled human studies are needed. That was why we were pleased to see the authors’ studies assessing the impact of L. rhamnosus R0011 and L. helveticus R0052 or L. rhamnosus GG on acute pediatric gastroenteritis, even though the results of both studies were null (see blog post regarding these studies here and here). But as we await additional trials, we have a responsibility to consider available evidence. The authors raise many good points that the entire medical field could learn from, but there are clear indications for probiotics and they should continue to be used for these indications, likely benefitting many while harming few.

Acknowledgements

MES and DM are grateful for the critical review of this perspective by probiotic safety expert Dr. James Heimbach, biostatistician Dr. Daniel Tancredi, and gastroenterologist and probiotic expert Dr. Eamonn Quigley.

The FDA’s view on the term probiotics, part 2: Further down the rabbit hole

April 4, 2020/in ISAPP Science Blog, News /by KC

By James Heimbach, Ph.D., F.A.C.N., JHEIMBACH LLC, Port Royal, VA

A number of weeks ago I wrote on the ISAPP blog about US Food and Drug Administration (FDA) declining to file Generally Regarded As Safe (GRAS) notices that described the subject microorganism as a “probiotic” or “probiotic bacterium” (see The FDA’s view on the term “probiotics”). Now the FDA’s response to such GRAS notices has developed additional ramifications. Let me put them into two categories: Class 1 misdemeanors that will cause FDA to reject the notice, and Class 2 misdemeanors that will probably not prevent filing, but will cause FDA to raise questions. I should note that these thoughts are based on both my own direct experiences and my repeated telephone conference calls with FDA.

Class 1 Misdemeanors

Using the term probiotic in any way in describing or characterizing the subject microorganism or its past, present, or intended use.
Extended discussion of benefits derived from ingestion of the microorganism in animal or human research.
Any mention, however brief, of the potential for the microorganism to be used in dietary supplements.

Class 2 Misdemeanors

Including brief mentions of the microorganism serving as a probiotic. E.g., if you cite a study of the microorganism that you might previously have reported as “a study of the probiotic benefits” of the microorganism, change it to simply “a study of the benefits” of the microorganism. This same caution is advised when reporting opinions from the European Food Safety Authority (EFSA) or other authoritative bodies.
Using the word “dose” in describing intended use. Also see #4 below.
Virtually any use of the term “dietary supplement,” including in reporting past, current, or intended uses of the strain or the species in Europe or elsewhere, by anyone.
Even relatively brief mentions of benefits. The recommended way of handling reporting of human studies of the species or strain is to avoid any narrative at all. Simply summarize the studies in tabular form, listing the citation, study design (RCT, open-label, etc.) and objective, study population (number, sex, age, characterization such as IBS patients, malnourished children, preterm infants), test article (microorganism binomial and strain), dose (but call it “administration level”—“dose” can be seen as indicating a drug or dietary supplement), duration, and safety-related results. Include methods used to ensure that any adverse events or severe adverse events would have been reported—medical examinations, self-report questionnaires, parental questionnaires, biochemical measures, etc.—and at what time points during or after the in-life portion of the research. Avoid ANY discussion of improvements seen in the test group.

Good luck!

The FDA’s view on the term probiotics, part 1

January 24, 2020/in ISAPP Science Blog, News /by KC

By James Heimbach, Ph.D., F.A.C.N., JHEIMBACH LLC, Port Royal, VA

James Heimbach, food and nutrition regulatory consultant

Over the past 20 years as a food and nutrition regulatory consultant, I have filed about 40 GRAS notices with the United States Food and Drug Administration (FDA), including 15 strains of probiotic bacteria and 5 prebiotics. This fall I submitted notices dealing with 4 strains of bacteria and on January 16 received a telephone call from FDA that surprised me and initially infuriated me, but which I have come to understand.

The essence of the call was that FDA was declining to file my probiotic notices because the notices had identified the subject bacteria as “probiotics” or “probiotic bacteria.” FDA suggested that I resubmit without calling the subject microorganisms “probiotics.”

As I said, I was surprised and frustrated, and I still would prefer that when FDA makes a policy swerve they would do it in a way that does not make extra work for me and delay my clients’ ability to get to market in a timely manner.

What I have had to do here is remove my advocate’s hat and put on my regulator’s hat. (I worked for FDA for a decade . . . long ago [1978 to 1988], but I still remember how to think like a regulator.) And here is the issue. Recall that GRAS is concerned with safety, not efficacy (generally recognized as safe, or GRAS), and the information provided in a GRAS notice is focused on safety (although benefits may be more-or-less incidentally covered). The reviewers at FDA are charged with assessing whether the notice provides an adequate basis to conclude that there is a reasonable certainty that no harm will result from the intended use. They are not charged, and they are not equipped, to evaluate what benefits ingestion of the substance or microorganism might provide. So they are not in a position to say whether the subject microorganism will “confer a health benefit on the host,” which is to say, they are not in a position to say whether or not it may be regarded as a probiotic. Remember, probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (Hill et al. 2014).

Given that the FDA reviewers cannot say whether the notified microorganism is rightly called a probiotic, they are reluctant to sign off that they have no questions about a notice that calls it one. Regulatory agencies have to be careful; things sometimes come back to haunt them. Those who have been following FDA’s GRAS-notice response letters for a couple of decades will be aware that the agency is putting more and more disclaimers into the letters—about standards of identity, about potential labeling issues, about benefits shown in clinical trials, and about Section 201(II) of the FD&C Act.

One concern that FDA likely has is that if some issue comes up in the future regarding a claim made for benefits from use of a product containing the subject bacterium, someone may make the argument that FDA had accepted that the strain is indeed a probiotic and so it presumably confers probiotic benefits. In the case of probiotics, there are also some internal FDA politics. As ISAPP meeting attendees may already be aware, FDA’s Center for Biologics Evaluation and Research (CBER) would like to claim jurisdiction over all administration of live microorganisms, and the Center for Food Safety and Applied Nutrition (CFSAN) does not seem willing to have a confrontation.

I suspect that a similar situation obtains with the term “prebiotic.” Although I have filed a number of GRAS notices for prebiotics, they haven’t been called that; they have been called fructooligosaccharides, or tamarind seed polysaccharide, or polydextrose, or 2’-O-fucosyllactose. I don’t know how FDA would respond if a GRAS determination were filed with the substance labeled as a prebiotic.

So, I’ve decided that my sympathies lie with FDA. Until and unless a microorganism has been confirmed by competent authority to have probiotic properties when used as intended in a GRAS notice, FDA is probably correct in rejecting its right to be labeled a probiotic. If it’s any consolation, this new position by the FDA has its origin in their acknowledgment of the official scientific definition of the word “probiotic”.

When Mary Ellen Sanders (ISAPP’s Executive Science Officer) reviewed my first draft of this note, she asked what I had in mind by “competent authority,” to which I don’t have a good answer at the present time except to insist that it is not FDA’s Division of GRAS Notice Review. Thirty years ago, when I was at FDA, I was in the Office of Food Science and Nutrition, and that office was charged with making determinations of that type (although I don’t recall anything about probiotics coming before us). But FDA no longer has such an office. Until it does, or until it agrees on another source of authority on designation of microorganisms as non-CBER-domain probiotics, I suspect that CFSAN will continue to be very cautious in this area.

Read part 2 of this blog series here.

Minimum criteria for probiotics: ISAPP perspectives

October 9, 2018/in featured, News /by Mary Ellen Sanders

By Mary Ellen Sanders PhD, Executive Science Officer, ISAPP

During its 2018 annual meeting (June 5-7), ISAPP convened a group of 30 participants from 13 countries to address issues associated with global harmonization of regulations for probiotics and prebiotics. This topic was of interest due to the broad international presence at this meeting, ISAPP’s first in Asia. The goal of this group was to provide regulators guidance derived from this assemblage of experts regarding the minimum criteria a probiotic food or supplement should meet. Drs. Seppo Salminen, Yuan-Kun Lee, and Gabriel Vinderola, who chaired this group, recently completed a summary titled “ISAPP position statement on minimum criteria for harmonizing global regulatory approaches for probiotics in foods and supplements”.

In December of 2017 the International Probiotic Association (IPA) presented a proposal to Codex Alimentarius – a recognized body that develops global standards and guidelines related to foods – regarding establishment of guidelines for probiotic foods. Codex Alimentarius accepted this proposal and requested that Argentina prepare draft guidelines to be considered in the 2018 session of the Codex Alimentarius Committee on Nutrition and Foods for Special Dietary Use. ISAPP representatives and group coordinators (Sanders, Salminen and Vinderola) took part along with IPA in a scientific meeting in Argentina to present the ISAPP views to local authorities and experts. IPA hopes that these efforts will lead to harmonized regulations since “this lack of harmonization in industry practice and legislation remains and often leads to serious issues and concerns for the probiotics industry, regulators, and even consumers in regard of quality, safety and labelling.” (Page1 of the proposal)

As the efforts of harmonization of regulations for probiotic foods through Codex progresses, ISAPP offers – through this summary document – its perspectives on minimum criteria for probiotics. The ISAPP group’s conclusions echo the principles outlined in the IPA proposal. Our hope is that this ISAPP document will provide useful perspective to local regulators. As of this writing, Prof. Salminen has delivered this document to the Codex representative at the Finnish Ministry of Agriculture and Food. We hope that further dissemination of the perspectives in this document will contribute to a science-based approach to global harmonization of regulations for probiotics.

See the document for the list of minimum criteria.