Serie #1 of the article was published in the ‘2022 Biologicals Special’ (August edition). Read it here.
Reliable and robust studies, key point of the dossier
Rules and Authorisation Process
The rules and procedures for the approval of active substances and the authorization of PPPs are defined in Regulation (EC) No 1107/2009. European regulations and several guidance documents from the OECD (or other institutions) guide and assist applicants in preparing, compiling and submitting the data required for approvals. The assessment of biopesticides follows the same process as other active substances (AS) at European level: assessment by the rapporteur Member State (RM), drafting of a DAR (Draft Assessment Report)... It can eventually lead to a classification of the SA biopesticide as a low-risk substance (absence of major toxic effects, non-persistent, non-bioaccumulative, etc.).
In order to assess and characterize the risks, in addition to the general requirements common to all pesticides, specific requirements (for example biological properties or pathogenicity for micro-organisms; chromatic profile for botanical extracts) are mandatory depending on the category of biopesticides. This is why there are specific guidance documents for each of these categories, whether micro-organisms (new requirements from autumn 2022), semiochemicals or botanical extracts. For other natural substances, no specific regulations exist and it is therefore necessary to juggle between the various guide documents available to establish a study program. EU data requirements are listed in Commission Regulations (EU) No 283/2013 and 284/2013 for active substances and products respectively. In these two regulations, Part A applies to chemicals, including natural substances and semiochemicals, while Part B applies to micro-organisms and viruses (it is being revised for implementation). application in autumn 2022).
What data is required?
The data required covers different areas: identity and characterization; physico-chemistry and analysis; efficiency ; human toxicology (operator); residues; behavior in the environment; and finally ecotoxicology. The registration of active substances and approval of products can be difficult due to the low availability of reliable data and the capacities to generate the required studies. Indeed, for each area, all data must be generated according to certain standards of quality, reliability and comparability.
Therefore, studies must be carried out in accordance with recognized guidelines (OECD for example) by following GEP (Good Experimental Practice) or GLP (Good Laboratory Practice) rules as for any substance or product.
In the case of micro-organisms, the design of the dossier, the objective and the design of the studies will be completely revised with the new regulations come into force in the fall of 2022. These new regulations must allow an adapted scientific approach and different from that of the chemical substance dossiers, considered to be ill-suited. This new approach will highlight the question of what is needed to know about the microbial substance (what are the relevant questions to ask?); it will be organized according to a step-by-step approach (mandatory requirements and conditional requirements) and will increase the overall quality of the approval dossier. Accurate characterization of a biopesticide substance can be complex. Because of this difficulty, establishing appropriate and reliable specifications can be seen as the keystone of the case. For micro-organisms, this involves characterizing the strain and having methods to differentiate a mutant or genetically modified micro-organism from the parent strain; but it is also necessary to be able to know the metabolites and secondary toxins which could have an effect.
For semiochemicals, the difficulty lies in their volatility. As for botanical extracts and other natural substances, the obstacles are their natural variability and the availability of specific markers.
Characterization and the possibility of tracking/tracing the active substance during the experimental studies are important and crucial; indeed, the objective is to ensure:
- that the study is conducted with the right substance throughout the experiment
- that the test subjects are well in contact and therefore exposed to the substance at the levels defined in the protocol
For example, for natural substances (especially botanical or animal extracts or lysates of microorganisms), the active substance is often a substance of unknown or variable composition (UCVB).
As it is not possible to follow all the substances contained in the extract, we will only be interested in one or a few key UVCB markers making it possible to follow the fate of the substance in the medium and to ensure that their concentration is maintained throughout the test. Furthermore, due to the natural presence of micro-organisms or similar compounds in the studied matrices, it may be difficult to follow the fate of the substance in the environment. A way around this problem is to carry out an analysis of the natural contents and then to compare the existing level with the level provided by the plant protection product.
Biocontrol Product Registration Puzzle
A common regulatory framework and specific requirements
The diversity of these products as well as the regulations in force lead the applicant to real "tailor-made" work when preparing the approval file for the active substance and the registration file for its reference product or any new product containing it. Due to their differences, the approval of these substances can be a real headache.
Indeed, biopesticides differ from conventional active substances on several points: they are of natural origin; they generally have a low impact for non-target organisms and for micro-organisms, and also reduced negative effects on biodiversity (DG ENV. 8); for natural extracts: they are often less stable and rapidly degradable; for microbials: they are highly specific to the host (e.g. insecticides) and they can proliferate after their release.
However, as IBMA points out in its communication of 30 March 2022 (IBMA, 2022), no specific European legislation exists for the approval of biocontrol substances and the registration of products. Thus the marketing authorization (MA) of these products follows the common approval process for all active substances in Europe: the first step is the approval of the active substance at European level and the second step is the MA of the product at national level once the substance has been approved at European level. Therefore, biopesticides must comply with common regulatory requirements that are not always appropriate (for example for stability, this will be difficult to monitor if no specific marker is found to monitor over time; this is the case for lysates of micro-organisms where the only markers are very common organic molecules) and specific requirements related to specific guidance documents. In addition, various concerns may be raised in the form of additional requests during the European assessment:
- for chemical substances and botanical extracts, they concern the environment and ecotoxicology, as well as reproductive toxicity and carcinogenesis;
- for living organisms, concern relates to environmental multiplication, infectivity, secondary metabolites, and then antibiotic resistance.
Micro-organisms: a specific dossier model to be used
For the submission of the authorization dossier for products containing micro-organisms, a specific dossier template must be used, unlike the other types of biopesticides (semiochemicals and natural substances) which follow the classic format. The OECD has also published specific guidance documents for the submission or generation of data (studies, risk assessments). All of these documents guide and assist applicants in preparing, compiling and submitting the data required to support planned approvals of active substances and registration of products containing these active substances. But on the other hand, the diversification of regulatory tools complicates the readability of the requirements.
Adapting to the variability of national rules
Another difficulty lies in the variability of national rules, as each country has its own criteria for distinguishing biopesticides, sometimes different from those established at EU level.
Indeed, according to regulation 1107, only plant protection products containing low-risk substances (according to com. reg. (EU) 2017/1432) benefit from certain advantages: approval up to 15 years (instead of 10 years) ; Decision of the Member States within 120 days (instead of one year); data protection up to 13 years... For the majority of other biopesticidal substances, these legal advantages are not applicable; however, the majority of countries have promoted their expansion by issuing specific non-harmonised rules.
For example, in Denmark or Sweden (northern zone), only micro-organisms are promoted by the application of assessment fees lower than those of conventional products. The other categories are considered as conventional products. In Austria (central area), reduced fees apply for assessment, but only for micro-organisms and semiochemicals; botanical products are not included. To submit a biopesticide in the Netherlands, the applicant must follow a specific assessment manual with specific data requirements and risk assessment. Fees are also reduced. In France (southern zone), comprehensive legislation has been developed to promote biocontrol products (art. L. 235-5,6,7 of the Rural Code and Marine Fisheries). This legislation grants reduced fees for all categories of biocontrol products according to the criteria of art. L.235-5. The legislation also grants reduced evaluation periods. For Italy, only reduced fees are granted for micro-organisms, semiochemicals and substances of natural origin not chemically defined.
These non-homogeneous rules show the complexity of the registration of biopesticides in Europe. However, in countries that have adopted specific measures, since the approval of substances and the registration of products are facilitated and encouraged due to reduced taxes and/or adapted and accelerated processes, these incentive measures lead to limiting the financial risk for industrialists while encouraging scientific innovation.
What budget should be foreseen to register a biopesticide?
To develop a biocontrol product, the budget for the required studies can be excessively reduced if data can be extrapolated from the "substance" data. Thus, the main share will go to efficiency trials as well as ecotoxicological studies (effects on bees and non-target arthropods). Toxicology and residue trials are generally limited or non-existent when considering a low-risk substance with very limited effects on humans. Finally, the physico-chemical characterization of the product as well as the cost of drafting and risk assessments represent an intermediate cost (Figure A).
Fig. A Regulatory development cost of a biopesticide product excluding registration fees
A regulatory challenge
The registration of biopesticides is therefore a challenge due to the lack of suitable guidelines, the variability of national criteria, the difficulties in characterizing them, demonstrating efficiency and assessing the risks for humans, the environment and non-target organisms. In its communication, the IBMA also underlines the urgency of giving a legal European definition to biocontrol as well as an adapted European legislative framework as it may already exist across the Atlantic. But these difficulties do not prevent the expansion of these alternative crop treatment methods thanks to fruitful discussions between applicants and national and European authorities.
For more information or any support in your biologicals products developement, please contact Staphyt team: firstname.lastname@example.org
This article was initially published in AgroPages' '2022 Market Insight' magazine.