The regulation of biotechnology products is a complex process involving various institutions with different protection goals to ensure their safety and efficacy (Wolt and Wolf, 2018). Therefore, it is essential to have a sound regulatory framework to monitor and evaluate biotechnology developments and their applications (Xue and Shang, 2022).

This study presents a compilation of Paraguay’s current regulatory framework for biotechnology focusing on recombinant DNA-derived products, vaccines, and biopharmaceuticals. It examines the country’s efforts to create a regulatory environment that aligns with international standards while accommodating rapid biotechnological advancements. Even though any attempt to summarize and analyze regulations runs the risk of being incomplete and outdated, we are confident that it can serve as a resource for policymakers, researchers, and other stakeholders working to understand and navigate this complex regulatory landscape. We aim to provide an analysis of this regulatory framework, focusing on the roles and responsibilities of the various government bodies involved (Table 1). Finally, we aim to highlight potential areas for improvement and collaboration among stakeholders.

Paraguay has signed several international treaties related to modern biotechnology which emphasize the conservation of biological diversity, the sustainable use of resources, the equitable sharing of the benefits of genetic resources and the safe handling of genetically modified organisms (GMOs). They also address intellectual property rights and plant variety protection (Table 2).

In South America, the Southern Common Market (Mercosur) has been actively developing and implementing regulations for biotechnology products (Figure 1). Mercosur countries recognize the importance of cooperation and harmonization in biotechnology regulation which aim to establish consistent regulations across member states and facilitate trade, while maintaining safety and effectiveness standards (Dellepiane and Pagliusi, 2019). For each of the following sections, we have included Mercosur regulations that address these efforts.

Mercosur Common Market Group (GMC) Resolutions have the goal of setting standards for the harmonization of regulations within the group, namely, once a GMC Resolution is incorporated into a country’s regulatory framework, said country must adjust its internal regulation to fit the standards set by that Resolution, and thus facilitate mutual recognition. To that end, GMC has also passed Resolutions on the procedures to elaborate, revise and revoke technical regulations (Mercosur GMC, 2017), and for mutual recognition of control systems (Mercosur GMC, 1998).

Mercosur’s GMC has long been incorporating Codex Alimentarius guidelines for the harmonization of food safety standards (FAO, 1995; De F Toledo, 2014). However, as of the date of submission of this paper, no Codex guidelines referring specifically to products of biotechnology have been incorporated into the Mercosur framework, and thus the use of said guidelines is left up to each member state.

MAG plays a central role in authorizing regulated trials, pre-commercial releases, commercial releases, and other proposed uses of genetically modified (GM) crops based on the opinion issued by CONBIO (Figure 2).

Submissions for approval of both regulated field trials and commercial release of plant GM events are received by MAG, and derived for analysis to CONBIO. MAG Resolution No. 27/2015 (MAG, 2015) contains both Form 1, for submission of regulated field trial applications; and Form 2, for submission of commercial release applications for GM crops (Fernandez Rios et al., 2018). Different treatments are established for events submitted for approval, based on their characteristics (Benitez Candia et al., 2020; Fernandez Rios et al., 2024).

In the case of the differentiated procedure established for events previously approved by sound and experienced regulatory systems (MAG, 2019a; MAG, 2019b), it is worth noting that Paraguay has not established a formal definition of an “experienced” regulatory system. However, the country recognizes that such a system employs scientifically sound methodologies for risk assessments to evaluate the safety of GMOs as food and feed and to assess their potential environmental impact. These systems are typically accompanied by several key features (McHughen, 2016), such as regulations that are commensurate with the level of risk and are based on a comparative risk analysis; the development of a rational risk hypothesis; the requirement of scientifically valid data of sufficient quality and quantity to inform on relative safety; and a clear distinction between scientific, political, ethical, and economic considerations.

The agri-food regulatory system is structured around a problem formulation approach, where protection goals are identified and plausible risk hypotheses are formulated. These hypotheses are tested with robust testing methodology. Such tests are conducted either in the laboratory or in confined field trials and follow a tiered-testing approach. For example, for non-target organisms (NTOs) the process starts with highly conservative early-tier tests in the laboratory and progresses to more complex, higher-tier experiments when necessary. Risk assessors must select data that can evaluate potential effects by translating policies and protection goals into risk assessment operational goals (Garcia-Alonso and Raybould, 2014; Wach et al., 2016). Experience has taught local regulators that most countries where GM crops have already been approved have protection goals that apply to a common set of valued ecological functions. One of the key elements that enabled Paraguay to develop a differentiated procedure for GM crops already approved in third countries was the utility of early tier tests using surrogate species for predicting field effects (Wach et al., 2016). The choice of appropriate surrogates for the assessment of NTOs is influenced by scientific factors, such as understanding the mode of action and spectrum of activity, and protection goals based on ecosystem services, including biological control, pollination, and decomposition of organic matter. Furthermore, the Paraguay agri-food regulatory system considers that the results from the use of surrogate species in tiered testing are transportable, as such testing can be replicated in other laboratories (Wach et al., 2016).

When Paraguay updated the regulatory framework for GM crops in 2015, it incorporated the concept of data transportability, which became a useful tool for avoiding redundant confined field trials (CFT). Through collaboration with the regulatory agency from Argentina, risk assessors learned that CFTs’ site selection with a focus on the diversity of environments tested within the production zone of the crop of interest is a key element. At the same time, the appropriate methodology and agronomic management of the studies and the measured endpoints are relevant (Vesprini et al., 2020; Vesprini et al., 2022). If these conditions are met, and if through the application of problem formulation there were no risk hypotheses related to Paraguay’s agro-climatic conditions, not only the data (as informative studies), but also the conclusions of the CFT are transportable, and applicable to risk assessments for Paraguay, without the need to generate additional CFT data.

If a relevant risk hypothesis related to Paraguay’s agro-climatic conditions is formulated, risk assessors scientifically assess the need (or not) for a new specific confined field trial that provides necessary unavailable data and answers that specific risk hypothesis. If a new confined field trial is required, risk assessors need to identify putative agro-climatic zones (Melnick et al., 2023) where this specific confined field trial could be conducted (e.g., where the production of that crop is common, and understanding the importance of any particular agro-climate for the production of a specific crop). This contributes to providing only relevant data that answer a specific risk hypothesis that persists even when all available data are analyzed.

Since 2014, SENAVE has maintained a registry of companies operating with regulated GMOs in the agricultural sector. To apply for registration, companies must fill Forms DBA-01 and DBA-02 (SENAVE, 2014b), whereby they declare relevant data about their legal representatives, technical advisors, and location where the companies operate. SENAVE has also approved a procedure for the risk management of activities with regulated GMOs in the agricultural sector, through Resolution SENAVE No. 283/2014 (SENAVE, 2014a) (Supplementary Table 1). Meanwhile, a Mercosur GMC Resolution has been incorporated into Paraguay’s regulatory framework which approves a mechanism to reduce the low-level presence of unapproved GMOs (Mercosur GMC, 2019; Presidencia de la República del Paraguay, 2021).

The regulation of genetically modified microorganisms (GMMs) in the agri-food system is governed by the same norm as crop biotechnology and subject to analysis by CONBIO, which includes conducting case-by-case risk assessments of activities involving GMMs and identifying potential environmental risks or safety concerns to human and/or animal health resulting from the use of GMMs and their byproducts (Presidencia de la República del Paraguay, 2012a). However, the differentiated mechanism for events previously assessed in third countries is not currently applicable. Paraguay has approved the use of several GM yeasts for ethanol production (OECD, 2023). Because yeast-derived products and distiller’s dried grains with solubles (DDGS) can be used as animal feed, a CONBIO safety assessment is required.

GM animals have a wide range of applications, from laboratory research to agriculture and public health. The regulation varies depending on these applications. In the context of the agri-food system, an assessment by CONBIO is necessary, and genetically modified animals are regulated according to the same standards as crop biotechnology.

Paraguay has recently granted the first commercial release of a GM insect, Spodoptera frugiperda, containing a self-limiting gene which allows for the production of male-only insects (MAG, 2024). Once released into the environment, these modified males will seek out and mate with wild females. The self-limiting gene will be transmitted to offspring, preventing female offspring from reaching maturity and reproducing. By continuously releasing GM males in a specific area, there will be a decrease in the number of wild females and consequently a reduction in the overall population of these insects (Reavey et al., 2022).

For applications related to public health, an evaluation by the MSPyBS may be required in some cases. However, there are currently no established guidelines outlining the assessment process in the public health context.

One particular case is that of synthetic beef (and plant-based meat substitutes). The use of the word “meat” (carne) is regulated by Law No. 6916/2022 (República del Paraguay, 2022), and is reserved for the edible muscular part of animals slaughtered and declared fit for human consumption by the official veterinary inspection, consisting of the soft tissues surrounding the skeleton, including their fat covering, tendons, vessels, nerves, aponeurosis, the skin of swine and poultry (except that of the order Struthioniformes) and all those tissues not separated during the slaughter operation. The diaphragm is also considered meat. At the time of submission of this paper, a draft bill is being studied in Congress to ban synthetic meat altogether (Franco Alfaro, 2023). These laws were promoted by the agribusiness sector as a way to combat market competition for conventional meat, claiming that by calling alternatives ‘meat’, competitors are fooling consumers (La Nacion, 2022). France has a similar policy against using meat-related terms for plant-based products (Carreno, 2022). However, research suggests that labeling these products as “meat” does not inherently cause confusion (Gleckel, 2020; Profeta et al., 2021; Tosun et al., 2021).

Several Mercosur GMC Resolutions have been integrated into the Paraguayan regulatory framework, focusing on animal health requirements for importing various types of animal genetic materials. This includes frozen semen and embryos from bovines, bubalines, porcines, equines, caprines, and ovines (Supplementary Table 2).

The registry of biologics for human use ¹ is made by DINAVISA, following public health policies from MSPyBS and is regulated by the Presidential Decree No. 6611/2016 (Presidencia de la República del Paraguay, 2016b; Presidencia de la República del Paraguay, 2016a). DINAVISA’s webpage makes available all forms required for the registry of biologics (DINAVISA, 2023).

Decree No. 6611/2016 categorizes requirements into two segments: general requirements (Table 3); and additional requirements (Table 4) for the registry of vaccines, hemoderivatives, innovative biologics, biosimilars, biologics for orphan diseases, and biologics obtained through recombinant DNA technology. Paraguay does not have specific regulation for biotechnological pharmaceutical products; their regulation is established within that of biologics.

The registration of all products requires preclinical and clinical trial information, and in the case of biosimilars, said studies must be done in a comparative manner. Paraguay does not require the performance of local clinical trials. The biosimilarity study seeks to rationally predict the same safety and clinical efficiency between the innovator product and the biosimilar. The process must define the quality and safety attributes necessary for comparison and must include preclinical and clinical studies. The scope of this study shall be defined based on the characteristics of the product and the differences in the production and purification mechanisms, and the results obtained may determine the need for additional studies for biosimilarity testing. The World Health Organization (WHO) has recently issued a new guideline on biosimilars (Kurki et al., 2022; WHO, 2022), thus we can expect local regulation instruments to be updated soon.

Vaccines present different situations. In the case of novel vaccines, preclinical and clinical studies are required; while for conventional and combined vaccines developed by new manufacturers, the demonstration of non-inferiority with marketed vaccines of proven efficacy and safety is required. When new vaccination schedules or new indications are proposed, they must be accompanied by the corresponding clinical trials.

Good Manufacturing and Control Practices are required in all cases. The guidelines for the certification of compliance of Good Manufacturing and Control Practices were approved through MSPyBS Resolution No. 020/2015 (MSPyBS, 2015a; MSPyBS, 2015b).

Sanitary registries are valid for 5 years, and can be renewed for similar periods. The renewal of sanitary registries for biologics necessitates compliance with the requirements specified in article 6 of the Decree, ensuring that there have been no changes in the production process from the active ingredient to the final product, modifications of the therapeutic indications, change of manufacturer, and other changes that DINAVISA considers essential to maintain the quality, safety, efficacy and immunogenicity of the biologic ² . If there have been changes in the production process from the active ingredient to the final product, modifications of the therapeutic indications, change of manufacturer and other changes that DINAVISA considers essential to maintain the quality, safety, efficacy and immunogenicity of the biologic, a new application for sanitary registry must be submitted.

Regarding pharmaceutical products in Mercosur, several important resolutions have been incorporated into the Paraguayan regulatory framework. These include standards for registering pharmaceutical products across member states (Mercosur GMC, 1995; Presidencia de la República del Paraguay, 1997), criteria for company registration (Mercosur GMC, 1996c; Presidencia de la República del Paraguay, 1997), and detailed requirements for documentation and information necessary for registration (Mercosur GMC, 1996d; Presidencia de la República del Paraguay, 1997). In addition, standards for good manufacturing practices have been established to ensure product quality and safety (Mercosur GMC, 2009; Presidencia de la República del Paraguay, 2012b).

Paraguay’s regulation of veterinary products, supervised by SENACSA, is characterized by a multilayered approach aimed at ensuring the safety and efficacy of veterinary biologics. The foundational legal framework, established by Law No. 667/1995 (República del Paraguay, 1995) and amended by Law No. 2426/2004 (República del Paraguay, 2004a), mandates the registration of all veterinary products and entities dealing with such products.

Meanwhile, Decree No. 6991/2017 (Presidencia de la República del Paraguay, 2017) entrusts SENACSA with exclusive jurisdiction over the authorization, operation, and supervision of entities dealing with veterinary products. The registration of all activities related to veterinary products is managed through SENACSA’s SIGOR (Regional Office Management Information System) online platform (SENACSA, 2021b; SENACSA, 2021c).

Resolution SENACSA No. 2803/2011 (SENACSA, 2011) outlines the criteria for the registration and licensing of importers. In addition, Resolution SENACSA No. 199/2012 (SENACSA, 2012a; SENACSA, 2018a) sets operational standards for vaccine-vending houses and distribution centers, while Resolution SENACSA No. 785/2012 (SENACSA, 2012b) sets comprehensive guidelines covering a wide array of operational aspects of laboratories including personnel management, facility layout, and quality control processes.

Biosafety information requirements for the registration of veterinary biologics include biological and chemical composition, specifications and methods of control for components of the formula and for culture media, substrates and other biological materials used, methodology of product manufacturing, method of control of the finished product, and evidence of safety and efficacy (literature review and clinical trials, when applicable) (SENACSA, 2020; SENACSA, 2021b).

The registration process for subunit immunogens produced via biotechnological processes mandates comprehensive control of the components and final product, ensuring their safety, quality, and efficacy. This encompasses chemical and biological characterization, manufacturing processes, and quality control protocols. The registration process focuses specifically on managing biological risks, emphasizing the prevention of public, animal, and environmental health hazards during production (SENACSA, 2021b; SENACSA, 2021a).

Disease control is another critical aspect addressed. Resolutions SENACSA No. 687/2017, No. 1641/2017, and No. 124/2018 focus on foot-and-mouth disease vaccine production standards, while Resolution SENACSA No. 690/2017 outlines standards for Brucella abortus vaccine production. These standards include infrastructure requirements for the manufacturers, dosage and specific strains to be used in production, and quality control (SENACSA, 2017b; SENACSA, 2017c; SENACSA, 2017a; SENACSA, 2018b).

Mercosur GMC Resolutions scaffold the harmonization of regional regulatory frameworks for veterinary products. In particular, vaccines against diseases such as symptomatic anthrax and gas gangrene are addressed, along with vaccine production in poultry. The adoption of Mercosur resolutions into Paraguay’s regulatory framework indicates an effort to align veterinary health standards and promote a unified strategy for animal healthcare (Table 5).

Patents are regulated in Paraguay through Law No. 1630/2000 (República del Paraguay, 2000), which establishes the requirements for the obtention of a patent, types of patent, matters excluded from patent protection, duration of the patent, and other relevant regulations. In particular, article 5 states that plants and animals (except microorganisms), and processes that are essentially biological for the production of plants or animals, are excluded from patent protection.

In addition, article 16 determines that during the application for a patent, when the invention refers to a product or procedure related to some biological material that is not available to the public and cannot be described in such a way that the invention can be implemented by a person skilled in the matter, the description shall be complemented by the deposit of said material in a deposit institution recognized by the General Directorate of Industrial Property. Such deposit shall not be required if it has already been made in any state member of the World Trade Organization or if the examination of novelty has already been carried out by the authority of any such country. The executing body of intellectual property policy is the National Directorate of Intellectual Property (República del Paraguay, 2012).

In compliance with article 27 section 3.b of Law No. 444/1994 (incorporation of TRIPS agreement) (República del Paraguay, 1994b), Law No. 385/1994 (República del Paraguay, 1994c) establishes several instruments for the protection of plant varieties, which apply to GM crops. Its implementing authority is SENAVE since the passing of Law No. 2459/2004 (República del Paraguay, 2004b). Further specifications on the use of these instruments can be found in Decree No. 7797/2000 (Presidencia de la República del Paraguay, 2000).

One of the primary difficulties in Paraguay’s regulatory framework for biotechnology is the absence of a centralized database of regulations. Currently, these regulations are scattered across various platforms, which often leads to accessibility issues, and some are entirely unavailable online, meaning interested parties must make a written request of a physical copy at the respective government office, resulting in extended waiting periods.

This decentralization impedes the ability to monitor the development of regulations, thereby complicating the process of determining whether a norm is currently in effect, or has been repealed, replaced, or modified. Paraguay has a unified online portal of public information (Portal Paraguay - Acceso a la Información Pública, 2023) where such requests can also be made, but they are not always answered in a timely manner. Additionally, the absence of official signatures or letterheads on digitally available documents necessitates additional verification steps, which further diminishes the efficiency of the system. We gathered the regulations analyzed for this work and deposited them in a repository to ensure their availability to our readers (in Spanish) (Benitez Candia et al., 2024).

Mercosur GMC Resolutions present a specific challenge. We were unable to find a local incorporation instrument for Resolution GMC No. 33/00 (Table 5), which results in uncertainty about its domestic status.

The biotechnology framework in Paraguay is closely aligned with Mercosur, yet the regulatory agencies of the member states exhibit distinct characteristics that may result in variations in their approaches (Magnuson et al., 2013; Mukherjee et al., 2022). Cooperation within the region is primarily sustained by the exchange of information and a certain level of harmonization of legal and regulatory requirements. However, effective harmonization necessitates the acceptance of common values and objectives, shared interests and challenges, mutual economic and other advantages, avoidance of disputes, collaboration on other concerns, and streamlining of procedures (McLean et al., 2002). Unfortunately, achieving this level of harmonization is a daunting task.

Moreover, regulatory systems have often been implemented on a “piece-by-piece” basis (McLean et al., 2002) in response to the urgent needs of the moment, and are more reactive than preventive systems. An inventory and evaluation of priorities, policies, existing regulatory regimes, and scientific and technical means is ideally a prerequisite to the development and implementation of policies and regulations (McLean et al., 2002; Schoemaker et al., 2020). However, building such a system and making it operational is complicated by the fact that there is no single best approach nor standard that reflects cultural, political, financial, and scientific heterogeneity. When establishing a regulatory framework, considerable attention must be paid to factors such as regulatory triggers, transparency, public involvement in policy-making and regulatory decision-making processes, and proportionate methods for assessing and managing risk.

While Paraguay has made efforts to improve its regulatory framework, the triggers for regulatory review are not adequately defined in several current norms. The country has recently implemented science-based approaches to assessing and managing risks in relation to GMOs. However, there is a deficiency in terms of public consultations and participation. Current processes for public engagement are lacking, resulting in a disconnect between regulatory bodies and the broader community. Establishing an effective public consultation process would not only enhance regulatory decision-making, but also promote a more transparent approach to biotechnology governance. It is essential to involve stakeholders and the public in discussions about biotechnology to ensure informed policymaking and foster trust.

Several regulations have proven particularly challenging in their interpretation. An example is article 10 of Law No. 3283/2007 (República del Paraguay, 2007b), which addresses the validation of evaluations for sanitary registration from specific countries. The wording of the law presents a challenge to understanding whether the procedure involves automatic acceptance from third-country assessments, and the extent of this provision. At the very least, interpretations are manifold. In addition, articles 4 and 5 of Decree No. 6611/2016 determine that for biologics with a sanitary registry from the regulatory agencies specified in the aforementioned law, therapeutic indications “can be recognized and expanded”, which makes interpretation of both regulations together even more challenging.

These difficulties have significant ramifications for a range of stakeholders, including researchers, industry experts, and policymakers; and can impede the development, authorization, and commercialization of biotechnology products, consequently affecting scientific progress. At minimum, the process and criteria for risk assessment and risk management must be widely published to instill trust in the system as credible and predictable among developers, stakeholders, and the public (Crow et al., 2016; Wolt and Wolf, 2018).

We suggest the evaluation of current scientific and technical capacity in Paraguay in order to facilitate the development of a more fit-for-purpose system. A sound regulatory system necessitates continuous updates on the latest scientific advancements; without such updates, the regulator’s knowledge base will have a limited lifespan. We hope that this initial assessment of current legislation will be the starting point for determining and implementing appropriate, scientifically sound regulations.