SmartTox and Bioacting: Faithful Partners in QSAR Analysis, Agrochemical Data Generation and Registration

Quantitative Structure-Activity Relationship (QSAR) is not only an important tool for predictive toxicology of agrochemicals, it is also a solid bridge connecting SmartTox and Bioacting, two companies that serve the Agro-regulatory field with considerable expertise. AgroPages spoke with Alexandre Quesada, Executive Director of SmartTox, Pedro Guivisdalsky, CEO of Bioacting, Hernan Grobly, Scientific Director of Bioacting to understand the meaning of QSAR and why it is the current core business of both companies.

Please give us a brief introduction of SmartTox, including its history and scope of business.

Alexandre Quesada: Sure! I am Alexandre Quesada, founder and CEO of SmartTox, with 20 years of experience in the AGRO market. In 2017, I created SmartTox - an international HUB of solutions for agribusiness that connects the best professionals worldwide.

Our current core business is the evaluation of Quantitative Structure-Activity Relationship (QSAR). We count on a strategic expert partner, Bioacting S.A, to perform such solution for the market.

Alexandre stated that Bioacting is their partner. Please give us a brief introduction of Bioacting?

Pedro Guivisdalsky: Bioacting offers a comprehensive and multidisciplinary service within the Agro-regulatory field. Our services aim at reducing possible risks during the registration process, generating a substantial cutback in costs and times.

At present we stand out in conducting in silico studies; we analyze, in a theoretical and computational way, the toxicological impact that the presence of certain non-relevant impurities may have on technical products.

We have vast experience in QSAR studies in more than 50 agrochemical products; additionally, we have not received any requirement from the authorities, and all of our studies have been accepted as well as the toxicological equivalence demonstrated.

Today we offer an accurate and robust QSAR solution to the market, comprising a multidisciplinary knowledge to cover all interpretation on the data retrieved from the software systems.

Under this partnership and with your expertise in the regulatory toxicology of agrochemicals, what specific services do SmartTox and Bioacting offer to clients?

Alexandre Quesada: As aforementioned, QSAR is our core business. According to Cronin (2010), “(Q)SAR is the study of the correlation between chemical structure and associated biological activity, with the ultimate goal of predicting the activity of untested chemicals based on structurally related compounds with known activity”.

This analysis is generated using various public and private domain software, through which the quantitative relationship between the structure of a compound and its biological activity is analyzed. This relationship is closely linked to the functional groups present in the molecule, as certain structural fragments generate alerts that are directly associated with mechanisms that trigger biological activity, in this case toxicity.

Once these alerts are being detected using specific algorithms to each platform, a quantitative relationship between structure and biological activity can be obtained, thus generating an estimate of the toxicological potential for each endpoint.

Boscalid Alertas QSAR Toolbox

It is important to highlight that this type of analysis is in full swing, not only because of its applicability but also because it is a great tool to reduce the number of studies with animal experimentation. Although in silico studies do not replace traditional tests at the moment, they are considered a great preliminary tool to detect possible relevant toxicological impurities.

Great! Based on this, could you please explain what a QSAR analysis is and detail your expertise and experiences in the agrochemical market?

Hernan Grobly: In the equivalence registration processes, the product’s chemical profile to be registered must be equivalent to the reference profile. If the new source presents new or the same impurities, yet above a certain amount stipulated by FAO (3 g / kg or 50% the most restrictive value), the chemical equivalence is compromised, and hence the toxicological equivalence must be demonstrated. This is here where QSAR studies take a great relevance, as they are used to solve this problem. Moreover, they are mandatory in certain countries, such as Brazil, USA, Australia, Europe, and Mexico.

Knowing the impurity structure, a software can estimate its toxicological potential, although some of the programs may yield values with low reliability or deviations. Also, it can detect when it is fundamental to analyze the active ingredient or molecules of similar structures and / or modes of action, through the comparison and critical theoretical analysis and experience in reaction mechanisms. It can be inferred from these analyses how accurate, or not, the results are.

Critical analysis of the results is essential and not just based on the results predicted by the software.

Compared to other similar companies, what do you think are your company's advantages? Can you give us some examples to illustrate your strengths?

Pedro Guivisdalsky: QSAR studies are about relationships between certain functional groups or fragments with their possible toxicity. However, this relationship is not always entirely correct, and a critical analysis of the data must be performed.

There are two different types of approach but with the same purpose, to be able to detect potentially relevant impurities. At first instance, when the product profile is analyzed, it is advisable to carry out an exploratory study and promptly detect impurities that can increase the toxicity of the technical product, and thus improve the production process to be able to eliminate them before carrying out all the studies required by international guidelines.

If the preliminary analysis has not been performed and the authorities require proof of toxicological equivalence, it is necessary to conduct a more complete study and with a totally different approach.

For instance, it is very important to analyze the applicability domains of each model, to understand the calculations used in the algorithms, to study each acceptance parameter, to detect possible deviations, to understand and analyze the chemical reactions involved in each proposed mechanism, and to analyze in detail the alerts detected – in sum, its reliability, selectivity, and predicted / real value ratio.

Boscalid LD50 QSAR Toolbox

In addition, it is important to analyze the molecule in question, its reactivity, the presence of bulky groups, steric hindrance, reaction mechanisms, and activation / deactivation of the alert due to chemical or physical issues.

On the other hand, and making use of the values provided by the expert systems, it is possible to analyze the impact of toxicological impurity on the matrix by calculating the "Impurity Relative Hazard". This analysis allows us to determine, according to each quantitative endpoint, the relevance of the impurity and the maximum concentration acceptable in the matrix in question.

Then, it is a multidisciplinary analysis in which factors that seem to be separate are totally related. This method is known as “Read across” and is the cornerstone of in silico studies, providing robustness, reliability, and credibility for the results.

When is QSAR testing required to be performed by the industry?

Hernan Grobly: Authorities require these types of studies when the profile to be registered contains new or the same impurities in a higher concentration than that in the reference profile.

QSAR analysis is required when the technical product profile contains a new impurity that is relevant from the Toxicology and Ecotoxicology point of view.

In the vast majority of cases, new impurities are organic compounds that are not deeply characterized, so it is necessary to carry out an in silico study (QSAR) to evaluate the impurity toxicological potential and its impact on the matrix (technical product to be registered by equivalence).

There is a preliminary and merely preventive approach that must be carried out in early experimental stages. When the manufacturer analyzes the technical product profile through a pre-screening and identifies the impurity structures, it is advisable to conduct an exploratory QSAR study in order to estimate whether these impurities could be toxicologically relevant, i.e., If they present toxic functional groups and / or if they present new alerts that are absent in the active ingredient.

When concerning results are found, it is ideal to eliminate this impurity from the technical product for two fundamental reasons: to decrease toxicity and to increase the probability of being equivalent to the reference.

This is where we offer another of our most important services: to analyze, modify, and improve the production process in order to eliminate the impurity in question and improve the quality of the products.

What are the recent changes in Brazil's policy on toxicological regulation of agrochemicals? How has SmartTox adapted its business to these changes and worked with customers to respond quickly?

Alexandre Quesada: The most recent toxicology regulation was the adoption of IATA process into the toxicology evaluation dossier.

The requirements made by IATA (Integrated Approaches to Testing and Assessment) were already in the DNA of SmartTox before their publication, as we had already been performing in silico testing and evaluating in vitro studies since our opening.

Some of our clients request exploratory evaluation, in order to guide their research & development department to better results. Also, as informed before, Bioacting has made a great work with some clients of ours evaluating the synthesis process to avoid any relevant impurity. And so far, it has been a great payback to our clients.

As a consultancy company, what do you think is the most critical factor in gaining the trust of customers in your companies?

Alexandre Quesada: I believe that commitment would be the most critical factor in a relationship. Business is done every day, but not all of them are sustainable, because the main goal of a business needs to be the relationship, which creates engagement with team and clients. The Business is a consequence of a good, clear, respectful, and trustable relationship.

Our process makes clients comfortable, once they give a clear view of their projects, which are customized for each client’s reality, always with a technical and an administrative support.

About SmartTox

SmartTox is operating in the product registration market as HUB, bringing clients to partner registration consultancies in Brazil and Latin America, in order to enable the portfolio that SmartTox offers to the market, as described below:

QSAR

Differentials:

1) Use of public and private domain software

The studies are carried out with public and private software, according to the requirements of each country. In addition to Brazil, SmartTox studies have already been successfully submitted for Europe, Mexico and the United States, without additional requirements by the respective regulatory agencies.

2) Convenience & Economy: customized studies to serve several countries

It is possible to contract a single study to simultaneously meet demands from two or more countries, generating agility and savings for the client.

Additional Services

Aiming to meet specific and long-term needs, SmartTox offers support services for several stages of the registration process, including:

• Risk Assessment

• In-vivo and in-vitro Toxicology Assessments, 5-Batch, Ecotoxicological and Physical-Chemical studies

• Labelling

• MSDS

• PATE / FLORA (ANVISA)

• Market evaluation

Website: https://smart-tox.com.br 

Contact: Alexandre Quesada

Tel: +55 11 99232-1816 (tel/whatsapp) // 61 99135-9901 (tel/wechat)

Email: alexandre.quesada@smart-tox.com.br  

About Bioacting

Biaocting S.A. is a company founded in 2012. We have represented a large number of clients globally. Our main objective is to provide innovative solutions to problems generated in the regulatory field and in sustainable products development. We are characterized by our professionalism, commitment, respect and understanding of the customer's needs. Our team has extensive experience in the regulatory field, a deep knowledge of the regulations of each country and excellent academic training. Our work is focused on reducing registration times by detecting and avoiding potential problems from an early stage and / or proposing solutions to existing problems.

We have developed innovative formulations either by formulation type or by the identity of the active principles used. We advise and assist companies along each stage of the customer registration process. We carry out QSAR studies under various regulations. Five Batches analysis, training and implementation, dossier follow up, manufacturing process solutions and impurity genesis.

Website: http://bioacting.com.ar/en/hompage-english/ 

Contact: Dr. Pedro Guivisdalsky and Hernan Grobly

Tel: (+54-11) 4857-0950

Email: info@bioacting.com.ar

This article was initially published in AgroPages' '2021 Latin America Focus' magazine.