Introduction
Sustainable agri-food systems are essential for ensuring resilient food supplies while reducing the exploitation of natural resources and minimizing environmental harm. Advancing such systems is also critical for achieving the United Nations Sustainable Development Goals (FAO, 2025). A key driver in realizing these sustainable systems is the development of alternative protein feedFootnote 1 products enabled by recent advancements in cellular and agricultural technologies. Recognizing this potential, the European Union has directed Horizon Europe funding toward initiatives that advance the goals of its Farm to Fork Strategy, a comprehensive effort to build a fair, healthy, and environmentally sustainable agriculture system (European Commission, 2020). The Horizon Europe funding program has allocated EUR 1 billion to support research projects in food and feed, agriculture, bioeconomy, and natural resources. A significant portion of this funding is dedicated to exploring the potential and accessibility of alternative protein products derived from plant, animal, and microbial sources (European Commission, 2020). Similarly, China’s 14th National Five-Year Plan for the Development of Bioeconomy highlights the transformative potential of synthetic biology, calling for increased research into the development of ‘artificial proteins’ to mitigate environmental degradation and reduce pressure on natural resources (NDRC, 2021). These efforts underscore a global commitment to advancing alternative protein solutions as an essential component of sustainable agri-food systems.
Precision fermentation is an advanced cellular biotechnology that can show considerable promise for the production of sustainable animal feed products. It relies on inexpensive and readily available raw materials, making the overall production process highly efficient and environmentally friendly. Although fermentation techniques have long been used to enhance the flavor and shelf life of food products, recent advancements in modern biotechnology, such as genetic profiling and omics techniques, have expanded their potential dramatically. These technologies enable the identification and selection of microbial strains with high productivity and other desirable properties, laying the foundation for large-scale production of novel feed products (Graham and Ledesma-Amaro, Reference Graham and Ledesma-Amaro2023). Through sophisticated genetic modification, microbes can be engineered to produce proteins and other high value compounds, a process characterized as ‘precision fermentation’ (Graham and Ledesma-Amaro, Reference Graham and Ledesma-Amaro2023; Hilgendorf et al., Reference Hilgendorf, Wang, Miller and Jin2024). Precision fermentation involves ‘engineering of optimized metabolic pathways and assembling the genes involved in a microbial chassis’, drawing multi-disciplinary expertise in microbiology, synthetic biology, and computational science to decode microbial genomes and metabolic functions and to enable niche designs in microbes (Teng et al., Reference Teng, Chin, Chai and Chen2021).
In the 1980s, scientists combined genetic engineering and fermentation techniques to develop therapeutical products, with one notable example being the use of recombinant DNA technology in Escherichia coli to increase the production of insulin for human use (McElwain et al., Reference McElwain, Phair, Kealey and Brady2022). Currently, the environmental and health benefits of precision fermentation technology, along with its capacity for tailored product design, have driven continued capital investment in its applications within the feed industry (Choudhury, Reference Choudhury2024). Efforts are underway to advance the use of precision fermentation in the production of microbial protein animal feed (hereinafter referred to as ‘MPF’). In particular, selected genetically modified (GM) microbes can utilize waste feedstocks in fermentation processes to produce animal feed, thereby reducing waste disposal, such as food waste and carbon- or nitrogen-rich substrates, conserving natural resources, and supporting the circular bioeconomy (Jach et al., Reference Jach, Serefko, Ziaja and Kieliszek2022).
MPF derived through precision fermentation is a promising approach for advancing agricultural sustainability as it can reduce the considerable use of natural resources in traditional feed production (Graham and Ledesma-Amaro, Reference Graham and Ledesma-Amaro2023; Augustin et al., Reference Augustin, Hartley, Maloney and Tyndall2024). It has been demonstrated that producing sufficient feeding stuff for human consumption in traditional husbandry requires the input of 40% of arable land and around one third of the water used in all agricultural production, with numbers expected to increase with the global population growth (Mekonnen and Hoekstra, Reference Mekonnen and Hoekstra2012; Govoni et al., Reference Govoni, D’Odorico, Pinotti and Rulli2023). Additional benefits associated with MPF include improving animal welfare and decreasing greenhouse gas emissions, water depletion and pollution, soil contamination, and deforestation, etc. (Ran et al., Reference Ran, van Middelaar, Lannerstad, Herrero and de Boer2017; Woern and Grossmann, Reference Woern and Grossmann2023).
Although MPF is far from becoming a complete substitute for plant- and animal-derived feed protein, the global fermented feed market is expected to grow from USD 19.9 billion in 2024 to an estimated USD 42.1 billion by 2034, at a projected Compound Annual Growth Rate (CAGR) of roughly 7.8%. The United States and China currently represent the largest markets for fermented animal feeds, valued at USD 7.7 billion and USD 4.7 billion, respectively (Choudhury, Reference Choudhury2024). Given the anticipated growth of MPF in the coming years, supportive regulatory frameworks will be essential to accelerate market entry while ensuring the safety of human, animals, and environment (Mbaya et al., Reference Mbaya, Lillico, Kemp, Simm and Raybould2022).
Research on pre-market regulation of precision fermentation products has mostly addressed regulatory issues related to human food. For instance, a recent study on the regulation of precision-fermented dairy products in the EU used a cheese product as a case study and concluded that the current legal regulations are restrictive and present considerable challenges to commercialization (Ronchetti, Springer and Purnhagen, Reference Ronchetti, Springer and Purnhagen2024). Similarly, an analysis of the Australian legal regimes governing food derived through precision fermentation indicated that complex domestic legal requirements and the regulatory bodies’ overlapping mandates could impede the commercialization of such products (Jolieke van der et al., Reference Jolieke van der, Pedro, Fiona, Nhat, Xianxian, Lisa, Robin, Mathias, Marcellin, Bansal, Ebert, Gumulya, Johnson, Peng, Turner and van der Pols2024). However, there remains a notable gap in research examining the pre-market legal regulation of precision fermentation for feed production and the associated legal challenges. This gap highlights the need to investigate how MPF is governed across different jurisdictions and, more importantly, to assess whether existing regulatory frameworks support a favorable legal environment for advancing sustainable agri-food systems and aligning national efforts with the Sustainable Development Goals (SDGs).
Our analysis considers both the technological attributes of MPF production methods and the characteristics of their end-products. We examine relevant regulatory regimes in four key jurisdictions, namely, the United States, the European Union, China, and Australia, which collectively represent major global trends in the governance of MPF products. The United States, a longstanding advocate for emerging biotech-driven products, has adopted a comparatively permissible regulatory approach. This is illustrated by its 2022 approval of products derived from GM beef cattle for market entry (Harrison, Reference Harrison2022), suggesting potential openness to proteins produced by GM microorganisms. In contrast, the EU maintains a markedly restrictive and precautionary stance toward novel biotechnologies. Its regulatory model, often cited as an embodiment of the ‘Brussels Effect’, has significantly shaped agricultural safety standards worldwide, including those applicable to feeds produced by advanced technologies (Bradford, Reference Bradford2012; Sinopoli and Purnhargen, Reference Sinopoli and Purnhargen2016). China, with its vast population and growing demand for protein, presents a distinctive case. Its legal framework increasingly reflects efforts to facilitate emerging agricultural technologies as part of broader strategies to enhance food security. Meanwhile, Australia, known for its high-quality agricultural products and consistent investment in biotech-manufactured innovations, has emerged as the fourth-largest global market for cellular agriculture (Eassom, Reference Eassom2024). In 2023, Australian plant-based meat manufacturers accounted for 56% of the 300 alternative protein products available on major supermarket shelves worldwide, underscoring the country’s rapid growth and leadership in this sector (Eassom, Reference Eassom2024). Together, these jurisdictions illustrate the diverse regulatory landscapes shaping the future development and market readiness of MPF products.
Our initial investigation explored two key issues: the pre-market safety assessment processes and the labeling procedures. In addition to an in-depth analysis of existing regulatory pathways, we identified legal challenges that could impede the future commercialization of MPF products. Although the legal context and challenges vary across the four jurisdictions, insights from our comparative analysis could support efforts by national regulatory bodies to develop or re-align regulations in accordance with best practice in the governance of MPF. Well-structured governance frameworks will not only support the development of more sustainable domestic agri-food systems but can also contribute to a broader alignment toward the United Nations’ SDGs. The study could also enhance the MPF developers’ understanding of legal challenges in different jurisdictions and support more efficient planning for the commercialization of their products.
Legal materials
To enable precise legal searches and cross-jurisdictional analysis, all authors first engaged in discussions to identify the characteristics of precision fermentation technology and the specific features of MPF products. One author, with an academic background in biotechnology, was primarily responsible for clarifying scientific concepts and ensuring the accuracy of technical aspects in research and writing. Based on the technological characteristics clarified, a search for relevant legal documents was completed by two authors, each responsible for two jurisdictions, followed by a process of cross-checking to ensure accuracy and to minimize, to the greatest extent possible, the risk of omission of important legal materials. During this process, we assessed the relevance of the collected documents to the key characteristics of the MPF technology while confirming the effectiveness and official source of each entry in the data set. The legal materials we analyzed included legislation and other documents that apply across the entire jurisdiction under consideration. This approach excluded legal instruments applicable exclusively to individual regions such as a state in the United States, a state or territory in Australia, a province in China, or a member state of the EU.
Legal regulation and challenges for pre-market safety assessment
The manufacture of MPF through precision fermentation involves the use of various biotechnologies, including fermentation and genetic modificationFootnote 2 (Thygesen, Reference Thygesen2024). The end-products mostly include (1) proteins without detectable modified genetic substance after purification; (2) proteins containing endogenous or exogenous genetic substance, which will then be deactivated; and (3) proteins retaining endogenous or exogenous genetically modified microbes (living microbes), which serve as nutritional supplements to achieve antioxidant, digestive, and other health-promoting functions for the feeding animals. Considering these technologies and end-product types, the following section discusses the legal requirements of pre-market safety assessment procedures applicable to MPF in the four selected jurisdictions.
The United States
The 1986 Coordinated Framework for the Regulation of Biotechnology (hereinafter referred to as ‘1986 Regulatory Framework’) stipulates that the United States will not enact specialized legislation for products manufactured using emerging biotechnologies but rather rely on existing legal regimes and regulatory agencies (OSTP, 1986). At the same time, the U.S. Food and Drug Administration (the FDA) claims that the product-based regulatory framework on end-products derived from the novel biotechnologies requires potential assessment or approval ‘in essentially the same manner for safety and efficacy as products obtained by conventional techniques’, unless the ‘risk posed by the introduction “of a new product” is unreasonable’ and needs special oversight (OSTP, 1986). The Federal Food, Drug, and Cosmetic Act (21 USC 321, hereinafter referred as to the ‘FD&C Act’) has categorized food to include food for human and for animal, and an animal food product will only be subject to pre-market approval when it is considered a food additive. According to the 1986 Regulatory Framework, ‘substances that are used in animal feeds and are produced by GM technology are considered to be food additives and require approval in a separate food additive petition (FAP) procedure, even though a similar substance is currently approved as a food additive’ (OSTP, 1986). Therefore, whether MPF should undergo a pre-market approval process under these legal provisions seems to depend on the clarification of the final product’s attributes. Specifically, if the final product is purified and presented as protein without detectable GM substance involved, it is highly likely to be recognized as an ordinary feed product needing no pre-market assessment and regulation. By contrast, once the final product remains GM substance that is used to enhance the feed properties and functionality, it is likely to be classified as a food additive, warranting appropriate pre-market regulation.
Nonetheless, there are uncertainties involving the classification of MPF products containing deactivated GM substance, prompting feed developers to seek clarification from the FDA. The scope of (animal) food additive has been interpreted in 21 CFR 170.3(e)(1) to encompass any substance that directly or indirectly constitutes a component of a feed product and that, if not a component, affects the characteristics of the feed, for example, when used to ‘prepare an ingredient of the feed to give it a different flavor, texture, or other characteristic’. As such, deactivated GM strains included in feed products align with the definition of the ‘component’ and are subject to pre-market regulation. However, considering the product-based regulatory approach established in the United States, it is possible for feed developers to make the case for compliance with the non-food additive regulation. In negotiations with the FDA, they could argue that the deactivated GM strains are minor in quantity and have lost biological activity to be unjustifiably categorized as additives, further referencing the regulation of the use of substance in food contact articles. For the food contact articles, such as food-packaging or food-processing equipment, their minor migrations into foodstuffs becoming ‘components’ could be deemed below the threshold to trigger pre-market regulation, given the absence of: (1) a (suspect) carcinogen in humans or animals; (2) health or safety concerns; (3) technical effect in or on the food to which it migrates; and (4) significant adverse environmental impacts (21 CFR 170.39). Feed developers’ communication with the FDA should, at a minimum, establish that such deactivated strains would not affect the characteristics of the feed and justify logically the necessity or technical unavoidability of not removing these strains.
It is worth noting that the U.S. regulation on substances used for animal feed is evolving. Currently, there are two regulatory pathways that feed developers could opt for to ensure market access for feed additives: either submitting a food additive petition (FAP) or self-affirmation under the Generally Recognized as Safe (GRAS) procedureFootnote 3 (FDA, 2024). In the past, an alternative pathway for feed developers to bring their products into the market was Association of American Feed Control Officials (AAFCO) Ingredient Definition Request Process (hereinafter referred to as ‘Request Process’), which operated under the Joint Regulatory MOU 225-07-7001 between the AAFCO and FDA (2019b). The AAFCO serves as an independent third-party organization with a wide voluntary membership of U.S. federal and states agencies, including the FDA, which provided technical support in assisting the AAFCO to review feed ingredient definition (FDA, 2019b). The AAFCO annually released an Official Publication (OP) with a list of substances that have been approved via FAP, deemed GRAS, and established through the Request Process (CVM, 2024). With ‘most States having adopted the ingredient definitions listed in the AAFCO OP under their State laws’ (CVM, 2024), feed developers had the option for market placement of their feed products by completing a Request Process.
The FDA decided not to renew the Joint Regulatory MOU after its expiration in October 2024 and ceased cooperating with the AAFCO in providing technical support for the Request Process. The Agency is reviewing the FAP and GRAS procedures to consider ‘any changes […] to better serve public health and improve the path to market for new […] ingredients’ (Federal Register, 2024). For substances that have been previously included in the OP as a result of the Request Process, the FDA plans to introduce interim measures, namely the Animal Food Ingredient Consultation (AFIC), that feed developers could use to accelerate official assessment and approval of the substance (CVM, 2024, 2025). The rollout of the AFIC is partly grounded on the premise that ‘the conclusion of Request Process does not bind the FDA’, although the substances may have been marketed in interstate commerce, and the completion of AFIC could enable the FDA’s enforcement action on these substances in an accelerated manner (CVM, 2024, 2025). Therefore, feed developers need to confirm whether the microbial substances they are using for producing MPF fall into this category and whether the AFIC procedures apply. It is still unclear, however, if there are any additional regulatory requirements for those substances that have been included in the OP and have subsequently been genetically modified. A further concern could be raised about whether the FDA’s non-renewal of the MOU signifies a step forwards narrowing administrative regulation through FAP, especially considering the limited GRAS recognition that the Agency has only issued around 40 no-question letters for animal food GARS conclusion since December 2011 (FDA, 2025b).
The European Union
According to article 15 of the EU Regulation No 1829/ 2003, any feed should be categorized as a GM feed and be subject to pre-market assessment, if it constitutes genetically modified organisms (GMOs), contains GMOs or consists of GMOs, or is produced from GMOs. Hence, MPF is highly likely to be recognized as a GMO due to the genetic modifications involved in its production. Even if the MPF product is purified or deactivated, it appears to meet the definition of being ‘produced from GMOs’. It is important to note that the EU considers exemptions for mandatory pre-market approval of GM products, given that the feed products are produced with rather than from GM strains under specific conditions (Preamble (16) of Regulation No 1829/ 2003). The EU has clarified in 2004, and reiterated in 2019, the boundary of recognizing GM strains as ‘processing aid’ with which the feed is produced, provided that ‘no GM substance can be detected in the final product, totally or partially, whether alive or not’ (Standing Committee on the Food Chain and Animal Health, 2004; Standing Committee on Plants, Animals, Food and Feed, 2019). Feed products being purified may fall under this regulatory exemption; however, it still depends on whether the purified technology can sufficiently achieve the level of removal endorsed by the EU regulatory authority.
Based on this categorization of MPF as a GMO, feed developers intending to bring any such products into the market are required to apply for authorization (see Fig. 1). Upon receiving the application, the respective agency of the Member State forwards it to the European Food Safety Authority (EFSA), which then informs the other Member States and the EU Commission of the application and releases the application information to them (article 17 of Regulation No 1829/ 2003). The EFSA has formulated a detailed guidance to assist feed developers in preparing a ‘risk assessment for GM microorganisms and their derived feed products’ (EFSA, 2011). Pursuant to article 18 of Regulation No 1829/ 2003, the EFSA carries out a technical assessment and grants an opinion within 6 months (which may be extended due to incomplete information submitted). If the feed product seeking market placement is recognized as GMOs, contains GMOs, or consists of GMOs, the feed developer is required to submit to the EFSA additional information on environmental risk assessment completed in accordance with Directive 2001/ 18/EC and a monitoring plan for environmental impacts. Within another 3 months, the EU Commission considers the EFSA’s opinion in conjunction with the relevant legal provisions and consults the Standing Committee on the Food Chain and Animal Health (the Standing Committee) to make a decision on whether to grant authorization to MPF (article 19 of Regulation No 1829/ 2003).
The approval process for GM feed in the European Union.
The EU has adopted a process-based regulatory model for GM feed products, extending its regulatory authority to every aspect of the production process (Ishii, Reference Ishii2018; Smyth, Reference Smyth2020). As such, feed developers need to engage with multiple authorities when undergoing the authorization procedure, which means that each step in the process may affect the outcome. For example, although the EFSA has been tasked with the technical assessment of feed products, it may, according to Regulation (EC) No 178/ 2002, entrust specific technical tests or/and environmental risk assessments to specific organizations in the Member States. Although the EU Commission takes responsibility for deciding whether to approve the product based on the EFSA’s opinion, the Committee procedure guarantees the authority of the Standing Committee and the Council of the EU to object to the decision made by the Commission (article 35 of Regulation No 1829/ 2003). Another legal challenge for feed developers is the complexity of the administrative procedures, as demonstrated by the authorization process for feed additives. When categorized as feed additives for marketing, the MPF product is subject to the parallel authorization procedures for feed additives and GM products. Although technical assessments under both procedures are undertaken by the EFSA, the EU articulates in Preamble (29) of Regulation (EC) No 1831/ 2003 that the two processes hold different regulatory objectives and warrant concurrent applications. Subsequently, feed developers should submit their feed additives applications directly to the EU Commission (article 7 of Regulation No 1831/ 2003), while the GM product applications go first to the respective agencies of Member States. All these complex procedures and onerous legal requirements impose considerable compliance pressures on the industry, raising doubts about the possibility for accelerated commercialization of MPF in the EU (Davison and Ammann, Reference Davison and Ammann2017).
China
According to article 2 of the Administrative Measures for Novel Feed and Novel Feed Additives (Novel Feed Administrative Measures), MPF and feed additives produced by precision fermentation fall within the scope of novel feeds (additives), which are defined as substances that are ‘newly developed in China and not yet approved for use’. As per the Measures, the presentation of novel feed subject to pre-market approval should be ‘single feed’, that is, ‘feed derived from one kind of animal, plant, microbe or mineral and used for the production of feed products’ (article 49 of Regulation on the Administration of Feed and Feed Additives). This rule indicates that if the final product blends various proteins or additives that originated from different organisms, an approval process must be sought for each single feed component, rather than treating the blended feed product as a single unit for regulatory purposes. There is a possibility that feed developers would face a prolonged process for securing market approval, especially when their products include multiple components, which adds more procedural complexity and uncertainty.
China’s Ministry of Agriculture and Rural Affairs (MARA) is responsible for the validation of novel feeds (additives), and developers are required to seek approval from the MARA prior to starting the production of such feeds (articles 5 and 6 of Novel Feed Administrative Measures). The National Feed Review Committee of MARA is responsible for the technical review, which aims to address safety and effectiveness issues related to novel feed products as well as their potential impact on the environment (article 5 of the Novel Feed Administrative Measures). The Committee forwards the technical review results to the MARA within 9 months (with the possibility of up to 3-month extension subject to additional experiments needed), and the MARA shall make a decision on whether to issue a certificate for the novel feed (additive) within 10 working days upon the receipt of the review results (articles 15 and 16 of Novel Feed Administrative Measures). However, the Novel Feed Administrative Measures only generally outlines the type of materials that should be prepared for the declaration and the reviewing procedure. It remains unclear how exactly the generality of these legal requirements affects the commercialization of novel feed.
Notably, the Novel Feed Administrative Measures fails to address how the production of MPF involving the use of GM technology should be regulated. Products developed with GM technology and components are subject to a concurrent review by both the Novel Feed Administrative Measures and other GM-related laws. The primary legislation on GM used in agriculture, the Administrative Regulations for the Safety of Genetically Modified Organisms in Agriculture, applies to ‘[…] microorganisms […] whose genomic structures have been modified by genetic engineering technologies for the use in agricultural production or processing’ (article 3). The Chinese government monitors the entire process of GM technologies utilization, from the research phase to pre-market evaluation and post-market supervision. The marketing of GM products is subject to administrative approval (see Fig. 2) and inclusion in the GM product catalog, with relevant safety evaluation under the purview of the National Biosafety Committee on Agricultural Generically Modified Organisms under the MARA. As such, although the MARA is the primary authority for pre-market approval of MPF, dedicated committees are designated for reviewing the safety of novel feed and GM feed. Moreover, feed developers, after receiving regulatory approval by the MARA, are still mandated to apply for ‘License for Agricultural Genetically Modified Organisms Processing’ from China’s provincial agricultural authorities to legalize their production activities in each province (article 3 of Measures of the Examination and Approval for Agricultural Genetically Modified Organisms Processing). These overlapping assessment procedures complicate legal compliance through onerous requirements for application material preparation and submission, potentially impairing process transparency. Besides being burdensome, continuous engagement with regulatory agencies largely increase compliance expenditures for feed developers.
The approval process of the agricultural GMOs in China.Footnote 4
Australia
The Australian Pesticides and Veterinary Medicines Authority (APVMA) is responsible for the regulation of animal feeds. The AMPVA states in general terms that their approval of novel products will be based on the satisfaction of ‘full assessment against all statutory criteria’ (APVMA, 2023a). Product developers are obligated to attest to the safety and efficacy of their products. Regarding MPF, feed developers should comply with both the general feed regulation and the GM-related laws.
In order for feed to be exempt from registration, it ‘must look, smell and taste like feed, be freely consumed as part of the animal’s natural feed intake’, and should not contain any active constituents or be used for treatment purposes (APVMA, 2024a). The APVMA further states on its official website that ‘inactivated fermentation by-products that do not contain any viable fermentation organisms (although they may contain minute levels of specified permissible contaminant microorganisms)’ need not be registered (APVMA, 2024a). Hence, feed developers having their MPF purified and living strains of MPF deactivated would likely be allowed to bypass registration. When living microbes are retained as nutrients in feeds, they are likely to be deemed feed supplements. The APVMA clarifies that feed supplements do not need to be registered if two conditions are met: (1) when they are ingested voluntarily by the animal, ‘as opposed to being administered in water or as a paste or drench, or by stomach tube’; and (2) when they are labeled as ‘supplement diets where levels may be low’ or with similar statements (APVMA, 2024a). Based on this clarification, the living microbes contained in MPF may also not be subject to registration.
Nonetheless, these general regulations applicable to all feeds have not adequately addressed whether the involvement of GM in producing MPF would require a differential regulatory approach. The APVMA regulates agricultural chemical products (encompassing the agricultural chemical product and veterinary chemical product)Footnote 5 or actives constituentsFootnote 6 on a case-by-case basis by requiring the developers to specify in the registration application if genetic manipulation was used in the production process (APVMA, 2023b, 2024b). When determining whether to approve certain active constituents and register chemical products, the APVMA is required to consult with the Gene Technology Regulator, the agency responsible for GM products, and consider the advice it provides (Part 2, 8A of the Agricultural and Veterinary Chemicals (Administration) Act 1992). While the regulation of MPF could potentially be exempted from a pre-market registration, it is unclear whether the involvement of GM elements would prompt a compulsory registration or a different regulatory path altogether. Hence, although feed developers are allowed to make preliminary self-assessment on whether their products meet certain standards and require pre-market registration (APVMA, 2022), it seems important that they inform the APVMA about the use of any GM technology and seek advice on how to meet all regulatory requirements.
Meanwhile, the commercialization of new feed products using GM microbes is governed by the Gene Technology Act of 2000. According to Part 2, Division 2 (10) of the Act, feed developers should submit application to Office of the Gene Technology Regulator for a license allowing the ‘making, developing, producing or manufacturing the GM organism’, and ‘the use of GM organism in the course of manufacture of a thing that is not the GM organism’. Hence, MPF retaining living GM microbes should undergo licensing procedures to be legitimately placed in the market. Even though the Act’s process-based definition likely enables a wide recognition of GM feed, regulatory exception could be granted to ‘organisms derived from GMOs but with no traits from gene technology’ (OGTR, 2021). As such, feed products presented as protein or protein containing deactivated GM microbes may meet the conditions for regulatory exception. Determining eligibility primarily depends on whether the purification or inactivation techniques that feed developers use on their products can gain acknowledgment from regulatory authorities. However, a previous study has shown that Australia generally applies a similar safety assessment scheme for both GM food and GM feed products. The study called for the creation of a distinct assessment scheme aimed at addressing biosafety issues specific to GM feedstuff (Giraldo et al., Reference Giraldo, Shinozuka, Spangenberg, Cogan and Smith2019). Given the uncertainties regarding regulatory exceptions, feed developers should seek additional clarification from the regulatory authorities on the interpretation of technical details.
Similarities and differences between jurisdictions
Based on the considerations outlined above, all four jurisdictions are likely to assess the GM technology utilized in the production of MPF and the presence of GM substances in the final product to determine specific regulatory pathways. The EU, China, and Australia tend to regulate MPF based on established pre-market assessments procedures for GM products. However, for feeds not containing GM substances in the final product, feed developers can make the case to the EU and Australian regulatory authorities for potential exemption from GM regulation. Notwithstanding, there are gray areas, and many aspects of the regulatory process remain to be clarified. In addition to GM pre-market assessment, feed developers in China would still need to follow the existing compliance procedures for their products to be recognized as ‘novel feed’. The United States has not yet developed specific legislation on GM feed that distinguishes it from regular feed products. MPF may be considered a (animal) food additive under the FD&C Act due to the involvement of GM technology. On this basis, feed developers can opt for either a FAP declaration or a GRAS procedure to meet the pre-market compliance obligations. However, it is still unclear whether the feeds containing inactivated strains could be exempt from regulation, and more clarification is needed as to whether and how the AFIC process, which is being newly developed by the FDA, can be applied to MPF.
Our review of pertinent laws and regulations highlights that regulatory mechanisms for novel MPF products are insufficient in these jurisdictions, especially when compared to the regulatory approaches to novel food products derived from new biotechnologies. For instance, the EU and China have already implemented novel food regulations focusing on novel proteins used for food production. These regulations consider and alleviate the potential overlap of regulatory procedures by designating novel foods produced using GM elements to fall under the purview of GM laws and associated GM technical assessments (Wang, Wang and Du, Reference Wang, Wang and Du2024). However, as previously illustrated, the EU has yet to establish specific novel feed regulations. In China, despite the enactment of the Novel Feed Administrative Measures, the regulatory process has not optimally integrated the approval procedures for GM products and novel feeds. With the continued reliance on the 1986 Regulatory Framework, the United States is less likely to introduce dedicated legislation for novel biotechnology-derived products. Still, since 2019, the FDA and the United States Department of Agriculture (USDA) have collaborated to jointly oversee human food products derived from animal cell-culture technology, strengthening their ability to manage potential biosafety risks (FDA, 2019a). However, the FDA has not yet developed dedicated regulatory procedures for novel feed products, such as MPF. It merely stipulates that feed developers should contact the FDA Centre for Veterinary Medicine if they intend to market animal cell-cultured feed (FDA, 2023). Therefore, there is no clear and comprehensive legal regulation of novel feeds in these major jurisdictions, and the regulatory uncertainties could present challenges for feed developers seeking compliance with the existing laws and contribute to a largely unregulated industry for novel feeds.
Legal regulation and challenges of feed labeling
There are no specific labeling requirements for MPF products derived from precision fermentation in any of the jurisdictions we examined. Rather, the general labeling requirements for feedstuffs also apply to MPF products. These requirements primarily focus on the need to clarify the nature of animal feed. For instance, in accordance with 21 CFR Part 501, the FDA urges feed developers to provide information about the identity of the feed, ingredients, manufacturers, directions for use, batch number, expiry date, and other related details (FDA, 2013). In addition, the Agency requires that the language used for labeling is clear, without ambiguous or misleading statements (FDA, 2013).
All four jurisdictions mandate a clear distinction between animal feed and animal therapeutic drugs, as the latter require a stricter approval process and more rigorous scientific documentation. For instance, according to the United States FD&C Act, any claims about preventing, treating, or affecting body functions will position the product as an animal drug, thus submitting the product to animal drug approval processes (FDA, 2025a). Similarly the APVMA requires that any therapeutic claims made about feed products undergo rigorous scientific evaluation before the products can be registered in Australia (APVMA, 2024c). Nonetheless, these jurisdictions seem to allow certain health-promotion or nutritional claims on the label. For example, the FDA permits claims about the feed products being supportive of intestinal and urinary tract health, given that the Agency is satisfied with the evidence behind such claims (FDA, 2025a). The EU allows claims about ‘feed intended for particular nutritional purposes’, given that product developers complete the procedures for including the desired nutritional claims into ‘a list of intended uses of animal feeding stuffs for particular nutritional purposes’ as established under Directive 2008/ 38/EC.
As discussed above, MPF products could be recognized as GM feeds in some cases and would require corresponding GM product labeling. According to article 24 of EU Regulation No 1829/ 2003, GM feed should be clearly labeled. However, compulsory labeling is not required when the presence of GM materials or residues does not exceed 0.9% and is accidental or technically unavoidable. On this basis, all GM feed labels should indicate with sufficient clarity GM attributes and should disclose the differences between GM feeds and those produced in a conventional way or, if a conventional counterpart does not exist, the label should detail the nature of such GM feeds (article 25 of the Regulation No 1829/ 2003). In addition, the EU urges feed developers to ensure that labeling does not raise ethical and religious concerns, and this requirement needs to be met at the pre-market assessment stage (articles 17 and 25 of the Regulation No 1829/ 2003). China has established a catalog for agricultural GMOs under the Administrative Measures for the Labeling of Genetically Modified Organisms in Agriculture, and all GM feed products approved for marketing are incorporated in this catalog for mandatory labeling (articles 2 and 3). It requires that the labeling is visible, with the law providing examples of how to label various GM products (articles 5–9). Even when GM substances are no longer detectable in the final product, their presence in the processed raw materials must still be indicated on the product label (article 6). Additionally, the labeling requirements of China’s Novel Feed Administrative Measures also apply to MPF, demanding that the proposed label format be submitted for administrative assessment and approval. However, further guidance is needed on how to label such novel feed products, as the law does not clarify the distinction or intersection between novel feed labeling and GM feed labeling.
The United States and Australia have not instituted clear requirements as to whether and how GM substances should be labeled when they are used in the manufacturing process of MPF or are contained in the final feed product. In the United States, the USDA has introduced the National Bioengineered Food Disclosure Standard, which has established national-wide and mandatory standards for the labeling of bioengineered food. However, the definition of food used in this Standard applies only to bioengineered food for human consumption, unlike the broader definition in the FD&C Act that covers both human and animal food (Federal Register, 2019). This leaves a significant loophole regarding the labeling of the MPF. Given the lack of clear guidelines, feed developers may need further engagement with the FDA to clarify how the existing GM labeling regulations apply to MPF in the pre-market phase. This is especially important considering that the FDA would not ‘pre-approve labels for food products’; however, it aims to ensure the appropriateness of labeling by rigorous post-market surveillance (FDA, 2013). There are also gray areas in the Australian regulations regarding the specific labeling requirements for MPF involving GM elements. The APVMA has not declared detailed requirements for labeling MPF with GM characteristics. Even for chemical products that should be registered for commercialization, the APVMA merely requires inclusion of labeling information in the application files for review (APVMA, 2023b).
Complex regulatory pathways
Our comparative analysis indicates the absence of clear regulatory pathways across the four jurisdictions, as the countries have not enacted specific laws and regulations for cellular agriculture that support the commercialization of MPF. Presently, developers must navigate complex regulatory landscapes, where determining the appropriate course of action for each novel MPF product often depends on its purely technical characteristics. The degree to which the existing regulatory environments could expedite market approval will likely influence where innovators choose to commercialize their products.
The current regulatory frameworks in the EU, Australia, and China present distinct challenges for market approval of MPF products. The EU employs a broad, process-based regulatory approach to novel biotechnology products within a comprehensive framework that mandates strict oversight. There are protracted authorization delays and an overall distrust toward GM foods, illustrated by the fact that only one GM plant has been approved for cultivation in the EU since 2000 (Vanderschuren et al., Reference Vanderschuren, Chatukuta, Weigel and Mehta2023; Lubieniechi, Van Eenennaam and Smyth, Reference Lubieniechi, Van Eenennaam and Smyth2025; Ludlow, Falck-Zepeda and Smyth, Reference Ludlow, Falck-Zepeda and Smyth2025). Similarly, Australia’s strategy of adapting pre-existing legal frameworks, rather than creating new regulations specifically addressing novel products like MPF, creates a fragmented system. This forces developers to navigate a complex interplay between general feed regulations and stringent rules for GM organisms, a problem compounded by safety assessment requirements for feed that lack specificity and approximate standards developed for GM food (Giraldo et al., Reference Giraldo, Shinozuka, Spangenberg, Cogan and Smith2019). An Australian government-backed report has established that the current approach is inefficient as it imparts onerous obligations and multilayered oversight, creating a rigid regulatory environment that discourages innovation (Jolieke van der et al., Reference Jolieke van der, Pedro, Fiona, Nhat, Xianxian, Lisa, Robin, Mathias, Marcellin, Bansal, Ebert, Gumulya, Johnson, Peng, Turner and van der Pols2024). China subjects MPF to parallel regulatory oversight under both its GM and novel feed legislation. This dual-track system does not streamline the process; rather, it creates additional regulatory gaps and legal ambiguity regarding intersecting laws, resulting in an environment that does not support timely market introduction (Yang, Zheng and Yao, Reference Yang, Zheng and Yao2024). Regardless of their different legal approaches and procedures, all three jurisdictions currently have restrictive regulatory regimes that would hinder, rather than advance, the development of sustainable feed solutions like MPF.
In contrast, the United States has developed a more supportive environment for biotechnology development and commercialization. While it lacks omnibus legislation for advanced biotechnological products, its regulatory system tends to be more dynamic and flexible. The FDA, for instance, continuously adapts its regulatory guidance documents by closely tracking new technological advancements and incorporating knowledge and experience it has gained over time. A notable example of this approach is the U.S. consideration to change the voluntary notification of GRAS status of products to the FDA as self-determined by the feed manufacturers in current practices. Following a directive by the Department of Health and Human Services (HHS), the proposed reform to the GRAS would make the public notification to the FDA of ‘the intended use of relevant ingredients, along with underlying safety data’ a mandatory requirement for feed developers, before the market entry for such new human or animal food substances (HHS, 2025). The intended reform seeks to close a loophole in the current system that developers could exploit to commercialize products without fully disclosing the complete safety dossier, which could undermine the scientific validity of the safety claims (HHS, 2025). Notably, although the final rulemaking remains undecided, reports suggest that a potential overhaul of the self-affirmed GRAS procedures could pose significant challenges to the fermentation industry. This is due to the sector’s heavy reliance on this pathway for commercializing products, particularly within the precision fermentation segment (Mridul, Reference Mridul2025a, Reference Mridul2025b).
In summary, the global regulatory landscape for MPF is rather complex and fragmented. The significant divergence in regulatory approaches, ranging from comprehensive and strict legal systems in the EU, Australia, and China to a more adaptive, risk-based approach at the federal level in the United States, warrants that feed developers conduct thorough assessments of target markets, as the choice of jurisdiction may be a critical determinant of commercial viability.
Recommendations for future MPF regulation
While MPF offers a promising pathway toward more sustainable agricultural systems, its potential is currently hindered by regulatory gaps and complex legal environments. Our analysis of four major jurisdictions indicates that there are no clear pathways for commercialization of novel MPF products. Technological convergence constitutes a major challenge in this process as products derived from advanced biotechnologies often integrate multiple techniques that place them under the purview of overlapping and, often, conflicting regulatory regimes (Tyczewska, Twardowski and Woźniak-Gientka, Reference Tyczewska, Twardowski and Woźniak-Gientka2023; Wang, Wang and Du, Reference Wang, Wang and Du2024). This legal ambiguity significantly constrains the application of existing laws (Tyczewska, Twardowski and Woźniak-Gientka, Reference Tyczewska, Twardowski and Woźniak-Gientka2023; Wang, Wang and Du, Reference Wang, Wang and Du2024).
The regulatory debate in the United States over cell-cultured meat, as previously explored, clearly illustrates this problem. The introduction of this technology quickly triggered a jurisdictional dispute between the FDA, which is the primary regulatory agency responsible for all human food safety and nutritional oversight, and the USDA, the primary federal entity specifically tasked with the regulation of agricultural and meat products (POLITICO, 2018). This case underscores how new biotechnologies often challenge traditional legal definitions of agricultural products by creating entities that transcend the mandates of any single regulatory authority (Johnson, Reference Johnson2019; Wang, Wang and Du, Reference Wang, Wang and Du2024). This is a fundamental issue that also complicates the regulation of MPF across different jurisdictions.
Advancements in precision fermentation are expected to yield increasingly complex and tailored feed products, which will further challenge existing regulatory categories such as ‘feed’, ‘GM feed’, or ‘novel feed’. The sophistication of these products necessitates a rigorous and proactive assessment of their associated risks. Key concerns include the alteration of functional properties and nutritional value during separation and purification (Malila et al., Reference Malila, Owolabi, Chotanaphuti, Sakdibhornssup, Elliott, Visessanguan, Karoonuthaisiri and Petchkongkaew2024), as well as significant safety issues such as the presence of allergens, toxic metabolites from microbial hosts, and contamination from heavy metals, pesticides, or pathogens due to unhygienic production (Alves et al., Reference Alves, Díaz-Ruiz, Lisboa, Sharma, Mussatto and Thakur2023; Malila et al., Reference Malila, Owolabi, Chotanaphuti, Sakdibhornssup, Elliott, Visessanguan, Karoonuthaisiri and Petchkongkaew2024). To mitigate these risks, regulatory frameworks must explicitly mandate a set of core protocols, including rigorous, product-specific nutritional and toxicological assessments, stringent hygiene controls to prevent contamination, and comprehensive allergen management and labeling. Furthermore, regulators should require long-term post-market monitoring and surveillance to track any unforeseen health impacts, ensuring that safety evaluation continues after commercialization.
Building upon these essential safety protocols, we recommend that regulatory authorities develop clear and transparent pathways for the commercialization of MPF. This includes establishing well-defined guidelines for pre-market applications that also incorporate the necessary safety requirements. Streamlining application procedures and standardizing documentation would minimize regulatory inconsistencies and eliminate redundant reviews across authorities, and, ultimately, lower compliance costs for developers. Additionally, given the rapid evolution of the underlying biotechnologies, regulators should proactively utilize pre-submission consultation mechanisms (Wang, Wang and Du, Reference Wang, Wang and Du2024). Early engagement would provide regulators with sufficient time to consider product-specific technical characteristics and associated safety concerns prior to the formal approval processes, enabling the timely identification of potential risks and development of mitigation strategies. These stakeholder engagement practices are crucial for fostering an adaptive regulatory environment and ensuring responsible commercialization of MPF products.
Streamlined administrative procedures, however, should never come at the expense of nutritional value and safety. Instead, the regulatory focus must remain on scientifically grounded and rigorous testing, earlier assessment of substantial safety issues, and long-term monitoring for unforeseen risks. Determining the appropriate scope and intensity of regulatory oversight should be guided by the accumulation of scientific evidence and regulatory experience, while long-term monitoring of commercialized products will serve as a crucial reference for future regulatory improvements (Ludlow, Falck-Zepeda and Smyth, Reference Ludlow, Falck-Zepeda and Smyth2025). If scientific and management risks remain unaddressed by an adaptive and forward-looking regulatory framework, the commercial development of MPF will continue to face compliance burdens, extended approval timelines, and delayed market entry, ultimately undermining bio-innovation and progress toward a more resilient and sustainable global agri-food system.
Conclusion
This study investigated the pre-market regulation of MPF produced by using precision fermentation and GM technologies, identifying legal challenges concerning pre-market safety assessment, and labeling requirements for MPF products. All four jurisdictions we reviewed currently lack dedicated and comprehensive regulations in place for such novel feed products. As a result, the regulatory process in each jurisdiction greatly relies on general feed regulations, along with specific GM-related laws applicable to MPF. The approach to legal regulation of MPF products is frequently determined by the use of GM technology in the manufacturing process of the feed and/or the presence of GM substances in the final product. China appears to be the only jurisdiction that has enacted a law specifically for newly developed feed products without consumption history (novel feed), but requirements in this law are general and may not provide sufficient guidance to practice.
We identified specific legal challenges that can hinder the commercialization of MPF products. The legal regimes in the EU and China appear to be highly restrictive, with feed developers facing multiple administrative approval procedures by different regulatory authorities. These complex procedures present obstacles for accelerated commercialization of MPF and raise compliance costs for product developers. The United States follows a product-oriented approach to the regulation of feed products, regardless of whether any advanced biotechnologies are involved in their production. However, the United States is currently contemplating the deployment of the FAP and GRAS systems traditionally used to approve feed additives and plans to introduce the AFIC process to facilitate the market entry of certain products. Many details of the pre-market regulation of MPF still need to be further clarified by the FDA, especially in the context of an evolving regulatory environment. Regulatory uncertainty in Australia primarily concerns the APVMA’s regulation of feed products. Although the APVMA generally does not require feed products to undergo pre-market registration, it is still unclear whether the GM factors involved in the MPF manufacturing process and in the final product would warrant a different regulatory practice.
In conclusion, efforts to overcome the existing challenges in the jurisdictions under consideration should prioritize the adoption of pragmatic regulatory pathways that facilitate administrative review and approval of MPF products. Pre-market consultation with feed developers should become an integral aspect of the regulatory process, as it could significantly improve the regulators’ understanding of novel MPF products and how potential safety risks could be mitigated. Ultimately, striking a good balance between calls to advance technological innovation and the need to ensure food safety through science-based regulatory strategies is the key for realizing the benefits of MPF.
Acknowledgments
DeepL (version: 25.3.31833266) was used for language editing during the initial stage of drafting this manuscript in December 2024.
Open access
