EU regulatory support approaches for microbials
In this Q&A, our senior Regulatory Project Managers introduce Eurofins Agroscience Regulatory (EAR) and address some of the typical questions that manufacturers / producers of biocontrol / biostimulant products based on micro-organisms, might ask when aiming to enter the European market
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Eurofins Agroscience Services is well known as a global provider of regulatory testing for agrochemicals including biopesticides for over two decades. In contrast, the consulting business is perhaps less well known. What services do you offer and what is your track record?
Joachim: We provide the complete range of regulatory consulting services to facilitate the approval of active substances and related products for use as plant protection products. Depending on the individual needs of our clients, it could be support from initial regulatory assessment through to approval, or on a “pick-and-choose” basis. In recent years we have been engaged in an increasing number of biopesticide projects, mainly for existing and new active substance approvals. We have been able to deliver this service thanks to several senior professionals having joined Eurofins Regulatory. Our team has grown in terms of size and expertise and now, in addition to biopesticides, we have also offered a full service for biostimulants since the end of 2019.
Are you as a consultant within EAR actively participating in the regulatory decision making process in Europe? And if so, what does your involvement look like?
Hans Ulrich: For four years now, Eurofins Agroscience Regulatory and Eurofins Agroscience Services have been an associated member of the IBMA (International Biocontrol Manufacturers Association). We are taking part in country level meetings of IBMA and thereby are in close contact with the manufacturers of biopesticides (e.g. in Germany/Austria and in France). We have also taken the opportunity to actively participate in scientific working groups for biopesticides at IBMA, including the Microbials Professional Group as well as the steering committee of the Professional Group for Natural Substances. We think that it is important to play a part in bringing the regulatory process for biopesticides forward in the EU.
Morgane: For biostimulants, we will be joining mirror groups very soon to constantly follow the implementation process for the new Regulation (EC) No 2019/1009
It is a common approach for microbials used as biopesticides to address certain data requirements via scientific literature and data waivers/statements. Are you at EAR following the same approach?
Joachim: Indeed, for the registration of a new as well as of an existing active substance used for biocontrol in the EU, this is the default approach. At first, we perform a thorough search in literature data bases for available scientific literature as well as information and data that the client has already generated. As a next step, we propose to conduct a data gap analysis in order to identify where the data requirements can be fulfilled with a) the abovementioned information, or statements / justifications for non-submission of data. Only when available information and waivers are not considered sufficiently robust, we advise the client to generate additional experimental data in accordance with the latest regulatory guidance. Giving a sustainable proposal, which includes published literature, statements and studies conducted by contract research organisations, is a matter of correctly interpreting the data requirements, the application of good (regulatory) science and experience.
The advantage of being part of Eurofins Agroscience Services is that this is a CRO that has been part of the development of biopesticides for more than two decades and therefore can offer the required technical expertise. This unique situation means we are able to cooperate very closely with our colleagues from the experimental units, providing the best conditions for us as consultants to design and realize exactly those studies that our clients actually need.
You indicated that in the EU biopesticides are registered under the same regulatory framework as chemical pesticides although some special provisions have been developed. The legislation provides for measures that favour the registration of products defined as ‘low risk’ and it appears that most of the biocontrol microbials would qualify but this process has not worked very well in practice. Do you see any improvement going forward?
Joachim: It is true that the EU regulatory process remains complex and cumbersome. This situation is discouraging product developers from applying for registration in Europe, and that’s not only for small and medium-sized enterprises. But we can also see that the market for microbials is growing and will continue to grow as a result of the Farm-to-Fork Strategy as a building block of the European Green Deal. This market growth should make the decision easier for applicants to face the elaborate EU regulatory processes.
At a country level, the picture is mixed with some countries clearly leading the way while others are lagging behind. Nevertheless, there are some clear examples of regulatory innovation at Member State level. Moreover, enhanced training activities for risk assessors dealing with micro-organisms will be implemented from 2021 on.
What future developments do you see regarding the registration of microbials as PPP in Europe?
Hans Ulrich: Currently, a lot of effort is being made by the International Biocontrol Manufacturers Association (IBMA) and several regulatory authorities to overcome the regulatory obstacles that are currently causing the most problems for microbials. This includes a revision of the data requirements for micro-organisms as well as the preparation of new guidance documents, e.g. how to address the subjects of microbial metabolites or antimicrobial resistance. We are confident that the situation for applicants will improve as a result of these efforts.
In a more general sense, the situation for an individual applicant will also depend on the microbial species to be registered. If it is a new strain of a species that has already been registered before or one that is commonly accepted to be presumably safe (e.g. QPS micro-organisms [1]), registration can be straightforward. However, if a completely new species comes into play, the situation may be different and registration will become more challenging. Many evaluators in the EU are risk-adverse and do not want to compromise in terms of safety. Nevertheless, we believe that good science and good regulatory strategies will always prevail!
How much more complex is the registration of a product based on only one microorganism, in comparison with a mixture of them, e.g. mixtures of several different bacterial species or mixtures of bacteria and fungi?
Hans Ulrich: This is a good example where innovation and regulation may be perceived as not going perfectly hand in hand! Microbial consortia, working as a team, may have better efficacy than one single strain alone. However, the current regulatory situation for plant protection products in the EU is that each strain of the consortium would be considered as an individual active substance and would have to be registered separately. This is most likely not feasible for most applicants as costs would multiply. So, one option is to avoid consortia and rather, to focus on screening for one singular strain that will exhibit similar properties or efficacy to the consortium.
Knowing that microbials can be registered both as PPP and as plant biostimulants, how do you see possible interaction between both regulations as today, the data requirement and risk assessment processes are rather different?
Morgane: Indeed, it is possible to place a plant biostimulant based on bacteria or fungi on the market in the EU via a less complex and cumbersome route than would be the case for a microbial pest control agent. With the adoption of the new EU Fertilising Products Regulation (FPR) [2], a clear definition was provided with regard to what will be within the scope of plant biostimulants and what will be classed as plant protection.
Taking into account that a microbial used as PPP could also work as a biostimulant at the same time (or vice versa), a decision has to be made by applicants whether to go for PPP or biostimulant status. Products with one or more functions, one of which is covered by the scope of Regulation 1107/2009, are plant protection products falling within the scope of that Regulation and should be excluded from the scope of Regulation 2019/1009.
How can we distinguish between the direct pesticidal effect of microbials and an indirect effect as a plant biostimulant, making the plant less vulnerable to abiotic stress or improve plant nutrition?
Morgane: For a micro-organism, it might not always be possible to draw a clear line between pesticidal and biostimulant traits. In theory, a bacterium could of course have the ability to produce a specific pesticidal substance and at the same time have the ability to increase nutrient use efficiency of plants, e.g. if present in the rhizosphere.
To be able to make this distinction in a regulatory sense, it is in our view crucial to elucidate and describe the mode of action of a microbial as clearly as possible. Furthermore, the label claim and the intended uses that are derived from the active principle will determine whether a microbial will be regarded to be within the scope of plant protection products or plant biostimulants.
According to the EU definition for plant biostimulants, only those microbials that have the sole aim of improving one or more of the following characteristics of the plant can be regarded as biostimulants: nutrient use efficiency; tolerance to abiotic stress; or crop quality traits. In the light of this definition, if a description of a mode of action includes something like “making the plant less vulnerable to attack” and/or “stimulating the plant to make native pesticidal compounds”, the active principle could be interpreted as inducing tolerance to biotic stress, e.g. by stimulating plant defense mechanisms. In this case, even if it was an indirect effect (as it is also in the case of elicitors), the microbial agent would be viewed to be within the scope of plant protection products.
Eurofins Agroscience Regulatory offers an initial regulatory feasibility check to find the suitable regulatory strategy based on the properties of the microbe and the label claim.
References:
[1] Qualified Presumption of Safety; see Update of the list of QPS‐recommended biological agents intentionally added to food or feed as notified to EFSA 11: suitability of taxonomic units notified to EFSA until September 2019; EFSA Journal 2020;18(2):5965
[2] Regulation (EU) No. 2019/1009
About Morgane, Hans Ulrich, and Joachim:
Morgane Salaun (Senior Regulatory Expert – Biostimulants / Biofertilizers) is part of the EAR team since January 2020. Morgane has a PhD in Plant Physiology (University of Angers – INRA), 20 years of experience in plant nutrition, and 12 years in regulatory affairs in fertilizer industry (with a focus on innovation and biostimulants). She manages registration projects, supports product compliance and advises clients on regulatory strategies for biostimulants & fertilizing products at EU and national levels.
Hans Ulrich Rexer (Regulatory Project Manager – Microbials) joined the EAR team in 2016. He has a degree in biology, PhD in microbiology (University of Tuebingen). Hans Ulrich gained 9 years of experience as a study director for ecotoxicology field studies for plant protection products at Eurofins Agroscience Services. He manages registration projects on active substances and formulated products (biopesticides), and advises clients on technical / scientific matters for the registration of microbials.
Joachim Rumbolz (Regulatory Project Manager – Biopesticides & Regulatory Team Leader) joined Eurofins in 2012. Joachim has a PhD in Biology (Plant Pathology; University of Konstanz). He has been engaged in EU regulatory for 18 years, working as a consultant in several functions to support industry in the registration of active substances and formulated products based on chemical substances including natural extracts (botanicals) and micro-organisms as well as biocidal products. He manages registration projects on active substances and formulated products (biopesticides & conventional agrochemicals) and advises clients on regulatory strategies.
