Microorganisms are being increasingly recognized for their benefits in animal feed, enhancing animal health and productivity. A new draft of EFSA’s guidance on microorganisms introduces significant regulatory changes, including new categories and testing considerations. While these changes offer opportunities for innovation, they may pose challenges for those unprepared.
By Argenta with the participation of Flavia De Marta, Business Development Manager and Andrew Bell, PhD, Regulatory Affairs Manager
Microorganisms as feed additives are being increasingly recognized for their role in enhancing gut function and productivity. Under EU regulation 1831/2003, ‘microorganisms’— which include bacteria, yeasts, and other microbial species — are primarily classified as zootechnical feed additives, although they can also be grouped under technological feed additives (as preservatives and silage additives). Within the zootechnical category, microorganisms can have a range of functions (Table 1) but are most commonly approved as gut-flora stabilizers. Additionally, microorganisms can be used as production strains for the manufacture of other feed additives such as enzymes, amino acids, vitamins, etc.
Beyond their technological functions and animal gut health benefits, microorganisms also offer advantages for developers. Zootechnical feed additive authorizations, including those for microorganisms, are holder-specific, meaning that, for ten years, only the applicant (and those they license the feed additive to) can place the feed additive on the market, ensuring better protection of revenues and profits.
While microorganisms have demonstrated clear benefits in feed applications, the regulatory pathway to approval for microorganisms has remained complex and challenging. Now, a significant regulatory shift is approaching, with new draft guidance from the European Food Safety Authority (EFSA) set for public consultation until February 7 and final implementation by June 2025.
“This revision represents more than just procedural updates, it fundamentally expands the scope of microorganism regulations while simultaneously introducing more rigorous assessment criteria,” says Flavia De Marta, Business Development Manager at Argenta. “For developers navigating this evolving landscape, understanding these imminent changes is crucial for ensuring compliance.”
Here, we examine the critical updates in EFSA’s draft guidance, their implications for product development strategies, and steps developers should take to better prepare for the new requirements.
UNDERSTANDING THE EFSA EVALUATION PROCESS
There are three main bodies involved in the microorganism approval process: EFSA, the EU reference laboratories for feed additives (EURL-FA), and the European Commission (EC).
EFSA’s role is to provide scientific advice to support the authorization of feed additives. It examines the efficacy and safety data of the additive to determine whether it has harmful effects on humans, animals, or the environment. The EURL-FA evaluates testing methods to ensure they are fit for official controls. If EFSA’s opinion is favorable, the EC prepares a draft regulation to authorize the additive, which is then discussed and endorsed by Member states.1
When submitting a request to EFSA for evaluation of a microorganism, there are four main stages:
1. Pre-submission phase
• Notification of studies: applicants must provide EFSA with details of relevant studies, including the type of study and start date, before they conduct them. The penalty for not doing so is a six-month delay in the application process.
• EURL-FA samples: applicants must send samples to the EURL-FA and arrange a fee-payment following their administrative guidance.
2. Dossier preparation and submission
In the dossier, applicants must provide detailed information supporting the characterization, safety and efficacy of the microorganism. A dossier comprises three sections:
• Identity and Characterization: Information about the quality of the product, impurities, stability and methods of analysis must be provided, alongside detailed descriptions of the manufacturing processes to demonstrate batch consistency.
• Safety: The safety of the microorganism strain needs to be evaluated for animals, humans and the environment. If the strain qualifies for Qualified Presumption of Safety (QPS) status, meaning there is already an existing knowledge of the safety profile, then a full assessment won’t be required, streamlining the process. User worker safety data also needs to be provided.
• Efficacy: All relevant information must be provided for all studies, including detailed descriptions of study designs and evidence of compliance with appropriate animal welfare regulations. All studies must follow current EFSA efficacy requirements.
Additionally, according to article 39 of EU regulation 2019/1318, applicants must create both a confidential and non-confidential version of each annex of the dossier with proper justification for each confidentiality request.
3. Risk assessment
After the full dossier is submitted and validated by EFSA, the scientific assessment starts. During this, scientific officers can request additional information, stopping the clock until the applicant submits responses and outstanding data.
4. Post-adoption phase
EFSA adopts a scientific opinion and, if positive, the draft authorization is discussed by the Standing Committee on Plants, Animals, Food and Feed. The authorization is then published in the EU Official Journal and the feed additive is listed in the EU Register of feed additives.
In the best-case scenario, microorganism approval will take around 2-4 years, but it can be much longer if applicants don’t adopt a strategic and well-informed approach from the outset.
CHANGES IN THE MICROORGANISMS EFSA GUIDANCE
EFSA’s previous guidance on microorganisms, released in 2018, provided a foundational framework for assessing microorganisms used in feed additives, focusing primarily on bacteria, yeasts, and filamentous fungi. The guidance highlighted key principles such as the need for thorough characterization of microorganisms, rigorous safety evaluations for both animals and humans, and comprehensive environmental risk assessments.
While this framework has served the industry well, it had certain constraints. Notably, the scope of the guidance was somewhat limited, primarily addressing established microorganism categories without fully accounting for emerging groups. As demands for new and diverse microorganisms in animal feed have grown, these gaps in the regulatory framework have become more apparent. In response, EFSA has updated its draft guidance:
Scope Expansion
One of the most notable updates to the regulations is the inclusion of new microorganism categories. For the first time, viruses (including bacteriophages) and microalgae are now specifically included. Additionally, the new draft guidance introduces updated protocols for evaluating genetically modified microorganisms (GMMs) and production strains.
Standardization of Characterization Methods
EFSA has now standardized the approach to characterizing microorganisms. Whole Genome Sequencing (WGS) must be used to identify bacteria, yeasts, filamentous fungi, and viruses at the species level. For microalgae and other protists, taxonomic identification should combine morphological and DNA sequencing information.
ANTIMICROBIAL RESISTANCE
Antibacterial Resistance
EFSA has introduced new workflows to distinguish between intrinsic and extrinsic resistance. Intrinsic resistance, which is naturally present in a microorganism’s species, is not considered a risk. However, extrinsic resistance, which arises from incorporation of DNA from external sources, requires additional evidence to evaluate risk to human and animal health. This is established through assessment of phenotypic susceptibility to confirm bacteria are still killed by the antibiotic at levels below the cutoff value.
Antimycotic Resistance
This category is a new addition that applies to yeasts and filamentous fungi. As horizontal transfer of resistance genes is uncommon in fungi, genomic analysis isn’t relevant. Instead, for active agents, phenotypic testing should be used.
TOXIGENICITY AND PATHOGENICITY
Yeasts and Filamentous Fungi
To assess the potential pathogenicity of yeast and filamentous fungi and their ability to produce harmful metabolites, applicants should carry out a literature search on the species, and other closely related species. In addition, applicants should use WGS analysis to identify known metabolic pathways involved in toxigenicity and compare the data against at least one up-to-date curated database. The WGS database search must be no older than two years from the date of application submission.
If either of the searches indicate potential harmful metabolites, the following should be conducted:
• For active agents: phenotypic testing under relevant conditions
• For production strains: quantitative analysis of hazardous metabolites
Microalgae and Protists
Microalgae and protists are another new addition to this section of EFSA’s guidance, which states that a literature search should be conducted to identify the capacity of the species to produce known harmful metabolites. If the search suggests potential risks, applicants should perform quantitative analyses of the relevant metabolites.
Viruses and Bacteriophages
Viruses and bacteriophages are a new addition to the EFSA guidance. For viruses, the infectivity and absence of adverse effects should be demonstrated using representative species. Plant virus assessments must confirm target specificity and lack of adverse effects on non-target plants.
For bacteriophages, testing should be conducted on a representative set of strains for the target and closely related species. WGS-based analysis is required to interrogate the presence of genes coding for toxins, virulence factors, lysogeny, and genetic elements involved in transduction. As is the case with yeasts and filamentous fungi, the WGS analysis of bacteriophages should be conducted using a curated, up-to-date database, and the search should be no older than two years from the date of submission.
ENVIRONMENTAL RISK ASSESSMENT
When it comes to environmental risk assessment, the regulations now have a specific focus on microbiome interactions and the potential for horizontal gene transfer between microorganisms. QPS strains are excluded from additional environmental assessments, streamlining the process for microorganisms that have already been deemed safe.
For GMMs, a comparative analysis with their non-modified parental strains is required to ensure that the modifications don’t introduce environmental risks.
IMPACT ON THE GUT MICROBIOMES
A significant new addition to the draft guidance is the need to assess microorganisms’ potential adverse effects on gut microbiomes. EFSA now stipulates that developers should assess for potential risks such as dysbiosis (a disruption in the gut’s microbiota) and the shedding of pathogens, acknowledging that microorganisms used in feed additives could influence the overall health of animal microbiomes.
KEY TAKEAWAYS: PRACTICAL IMPLICATIONS OF EFSA’S NEW DRAFT GUIDANCE
The updates in the new draft guidance will have several important practical implications for applicants:
Opportunities and Challenges for Innovative Products
Different microorganism product categories, such as viruses, bacteriophages, and microalgae, now feature more prominently in the framework, offering new opportunities for innovative feed additives. However, pioneer products may still face challenges due to their novelty.
Enhanced Regulatory Scrutiny in Antimicrobial and Antimycotic Resistance
Clearer guidance on how to interpret antimicrobial and antimycotic resistance could help to better predict regulatory outcomes.
Time to Perform Studies
The regulations now require additional testing in several areas, where some tests need to be conducted within a specific time window. For example, WGS must now be carried out within two years of the application submission date, which demands more careful planning and can add complexity to existing programs.
Susceptibility Testing
In cases where some references — such as cut-off values for susceptibility testing — don’t apply across all bacterial, yeast, and fungal species, applicants may justify deviations from the guidance that EFSA will assess on a case-by-case basis. Since this leaves room for the interpretation of the authority, applicants need to clearly understand where deviations are and are not appropriate to ensure alignment.
PREPARING FOR THE CHANGES: KEY STRATEGIES FOR REGULATORY SUCCESS
While the new guidance updates may present challenges, with the right approach, applicants can avoid missteps and maximize the chance of a successful application.
Proactive Planning
By preparing early for the upcoming changes and aligning studies with the draft guidance as soon as possible, developers can reduce the risk of needing to revisit or repeat studies further down the line, preventing unnecessary and costly later-stage disruptions.
Leveraging Regulatory Expertise
Experienced regulatory partners can offer valuable support, providing in-depth knowledge of the current regulatory landscape to help applicants interpret and apply the guidance effectively. By engaging a regulatory partner early in the process, applicants can ensure that the right types of data are being generated and compiled into a robust dossier, reducing the risks of clock-stops and streamlining the path to approval.
Staying Informed
Tracking the draft guidance as it evolves and moves towards implementation is essential, as it will help developers to better understand exactly what will change and have more time to plan for and accommodate those changes.
SHAPING THE FUTURE OF FEED AND FOOD ADDITIVES
The draft guidance represents a significant change for microorganism feed additive developers. While these changes open the door to new opportunities, they also bring new challenges and complexities.
With the final guidance expected to be published in June 2025, industry stakeholders must act decisively to align to the updates. By proactively planning, leveraging the expertise of regulatory partners, and keeping track of the guidance as it evolves, developers can ensure compliance and avoid unnecessary delays to their applications for a smoother journey to market.
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References
1 https://www.efsa.europa.eu/en/topics/topic/feed-additives
About Flavia De Marta
Flavia De Marta, Business Development Manager at Argenta Barcelona, brings extensive experience guiding organisations through the EU approval process for feed additives. She has been a key liaison with EFSA and the European Commission (EC) in previous roles in the animal health and nutrition industry.
About Andrew Bell
Andrew Bell, Regulatory Affairs Manager at Argenta Barcelona, with over a decade of experience in analytical microbiology and regulatory affairs, he supports clients from project inception to EU authorisation for feed additives and novel foods.
