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Cited by 137Probiotics and Fermented FoodsAgricultural safety and regulationsComplementary and Alternative Medicine Studies

Considerations for determining safety of probiotics: A USP perspective

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Roe, Amy L., Boyte, Marie-Eve, Elkins, Chris A., Goldman, Virginia S., Heimbach, James, Madden, Emily, Oketch-Rabah, Hellen, Sanders, Mary Ellen +2 more·2022·Regulatory Toxicology and Pharmacology
DOI 10.1016/j.yrtph.2022.105266PMC PMC10292223
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Abstract

A history of safe use is a backbone of safety assessments for many current probiotic species, however, there is no global harmonization regarding requirements for establishing probiotic safety for use in foods and supplements. As probiotic manufacturers are increasingly seeking to use new strains, novel species, and next-generation probiotics, justification based on a significant history of use may be challenged. There are efforts underway by a variety of stakeholders, including the United States Pharmacopeia (USP), to develop best practices guidelines for assessing the quality and safety of probiotics. A current initiative of the USP seeks to provide expert advice specific to safety considerations for probiotics. Toward this goal, this review provides a helpful summary guide to global regulatory guidelines. We question the suitability of traditional animal toxicology studies designed for testing chemicals for relevance in assessing probiotic safety. This includes discussion of the use of excessive dose levels, the length of repeated dose toxicity studies needed, and the most suitable animal species used in toxicology studies. In addition, the importance of proper manufacturing practices with regard to final product safety are also included. Thus, an outline of essential parameters of a comprehensive safety assessment for a probiotic are provided.

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  • Regulatory authorities and experts require strain characterization, phenotypic MIC determination, and WGS annotated against curated databases to determine whether resistance is innate or potentially transmissible.

    “To exclude such risks, regulatory authorities (EFSA, FDA) and experts explicitly require strain characterization, phenotypic determination of minimum inhibitory concentration (MIC), and whole genome sequencing (WGS) annotated against carefully curated databases of antibiotic resistance/virulence genes (e.g., CARD, ARG-ANNOT, ResFinder) to determine whether resistance is innate or potentially trans”

    From Current Concepts in Probiotic Safety and Efficacy (2026) · cites this paper as [33]

    The Strain identity and Antibiotic resistance sections (page not provided) support strain-level characterization, phenotypic MIC testing, WGS-based resistance-gene analysis, and distinguishing intrinsic from transmissible resistance. The paper attributes the MIC and genotypic requirements specifically to EFSA guidance and discusses databases for gene annotation; the supplied passages do not establish that FDA explicitly requires this entire set of steps or the named databases. The Discussion and conclusions also allows that a well-established history of safe use may make additional testing unnecessary. (LLM, conf=0.84)

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  • This uneven safety assessment weakens the current evidence because probiotic safety cannot be inferred from beneficial functional traits alone and must be supported by strain-level safety evaluation, including assessment of transferable antimicrobial resistance, virulence-associated genes, mobile genetic elements, and toxicological evidence.

    “This uneven safety assessment weakens the current evidence because probiotic safety cannot be inferred from beneficial functional traits alone and must be supported by strain-level safety evaluation, including assessment of transferable antimicrobial resistance, virulence-associated genes, mobile genetic elements, and toxicological evidence. 42”

    From Comparative Genomic Insights into Pangenome Diversity and Functional Adaptation of Akkermansia and Faecalibacterium as Gut-Associated Next-Generation Probiotics: A Systematic Review (2026) · cites this paper as [42]

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Research works printed but not linked: 9

  1. Agencia Nacional de Vigilancia Sanitaria (ANVISA), 2018. Resolution of the Collegiate Board RDC No. 241. RESOLUTION of the COLLEGIATE BOARD RDC No. 241. OF JULY 26, 2018 - National Press (in.gov.br). (Accessed 20 May 2022).
  2. Bulletin of the International Dairy Federation (IDF), 2012. Safety Demonstration of Microbial Food Cultures (MFC) in Fermented Food Products. 455/2012. Bulletin of the IDF N◦ 455/2012: Safety Demonstration of Microbial Food Cultures (MFC) in Fermented Food Products – FIL-IDF (Accessed 20 May 2022).
  3. Bulletin of the International Dairy Federation (IDF), 2018. Inventory of Microbial Food Cultures with Safety Demonstration in Fermented Food Products. N◦ 495/2018. Bulletin of the IDF N◦ 495/2018: Inventory of Microbial Food Cultures with Safety Demonstration in Fermented Food Products – FIL-IDF. (Accessed 20 May 2022).
  4. Bulletin of the International Dairy Federation (IDF), 2022. Inventory of Microbial Food Cultures with Safety Demonstration in Fermented Food Products: Update of the Bulletins of the IDF N◦377–2002, N◦455–2012 and N◦495–2018. N◦514/2022. Bulletin of the IDF N◦ 514/2022: Inventory of Microbial Food Cultures with Safety Demonstration in Fermented Food Products – FIL-IDF. (Accessed 20 May 2022).
  5. IDF, 2002. Bulletin No. 377: Inventory of Microorganisms with a Documented History of Use in Food. https://store.fil-idf.org/product/health-benefits-and-safety-evaluation-of-certain-food-components-inventory-of-microorganisms-with-a-documented-history-of-use-in-food-trans-fatty-acids-milk-lipids-in-diet-and-health-med/. (Accessed 19 April 2021).
  6. IDF, 2012. Bulletin No. 455, Safety demonstration of microbial food cultures (MFC) in fermented food products. https://store.fil-idf.org/product/safety-demonstration-of-microbial-food-cultures-mfc-in-fermented-food-products-2/. (Accessed 19 January 2021).
  7. IDF, 2022. Bulletin No. 514, Inventory of microbial food cultures with safety demonstration in fermented food products. https://store.fil-idf.org/product/bulletin-idf-n-495-2018-inventory-microbial-food-cultures-safety-demonstration-fermented-food-products/. (Accessed 19 January 2021).
  8. vonWright A, Axelsson L, 2019. Chapter 1: lactic acid bacteria, microbiological and functional aspects. In: Lactic Acid Bacteria, Microbiological and Functional Aspects, fifth ed. Gabriel Vinderola, Arthur Ouwehand, Seppo Salminen, Atte von Wright, CRC Press. Published. (Accessed 5 April 2019).
  9. United States Pharmacopeia (USP), 2022b. Chapter 64 probiotic tests. Available at: https://online.uspnf.com/uspnf/document/1_GUID-804A3FF9-39F3-4C5D-A4B0-2A387EF95F96_2_en-US. (Accessed 20 May 2022).

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Authors
Roe, A. L., Boyte, M.-E., Elkins, C. A., Goldman, V. S., Heimbach, J., Madden, E., Oketch-Rabah, H., Sanders, M. E., Sirois, J., & Smith, A.
Affiliations
  • Procter & Gamble (United States) (US)
  • United States Pharmacopeial Convention (US)
  • Consumer Healthcare Products Association (US)
Corresponding author
Roe, Amy L.
ORCID
Venue
Regulatory Toxicology and Pharmacology
Publisher
Elsevier BV
Published
2022-12
Volume
136
Pages
105266
ISSN
0273-2300 (ISSN-L)
DOI
10.1016/j.yrtph.2022.105266
PMC
PMC10292223
OpenAlex
W4300981179
Cited by
136
References
93
Citations by year
2026: 53 · 2025: 45 · 2024: 23 · 2023: 15
FWCI
1.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Regulatory Toxicology and Pharmacology (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc)
Funders
National Institutes of Health (CC999999)
Topics
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Agricultural safety and regulations
  • Health Sciences › Medicine › Complementary and alternative medicine › Complementary and Alternative Medicine Studies
Keywords
probiotics, probiotic safety assessment, regulatory guidelines, United States Pharmacopoeia, veterinary toxicology, repeated-dose toxicity, dose levels, animal species selection, manufacturing practices, international harmonization
MeSH terms
Animals, Dietary Supplements, Probiotics

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