As biotechnology companies develop new proteins and functional ingredients through engineered microorganisms, questions about finished ingredient composition, residual fermentation materials and the scope of safety assessments are drawing greater attention.

Precision fermentation is expanding the range of proteins, fats, enzymes and other compounds available to food manufacturers. By programming microorganisms to produce substances traditionally obtained from animals or plants, companies are developing alternatives for dairy, eggs and other conventional ingredients. But the intended output is only one part of the manufacturing process. The composition of the finished ingredient, the effectiveness of purification and the scope of its safety assessment are equally important.

A microorganism engineered to produce a milk protein does not produce that protein alone. It also generates other proteins, metabolites and cellular materials as it grows. Some are removed during purification. Others may remain in the finished ingredient.

What Happens Beyond the Fermentation Tank?

Precision fermentation uses genetically modified microorganisms, including yeast, bacteria and fungi, as production platforms. Scientists introduce genetic instructions that enable these organisms to manufacture a specific compound, such as a protein with an amino acid sequence matching one found in animal milk or eggs.

Following fermentation, manufacturers use downstream processing to recover, separate and purify the desired substance. Depending on the production system, the fermentation broth may contain host-cell proteins, nucleic acids, cell fragments, fermentation metabolites, spent growth media and processing aids alongside the target protein.

A 2026 review in the Annual Review of Food Science and Technology, by researchers J.K. Keppler and R.M. Boom, examines the challenges of recovering food proteins through precision fermentation. The authors explain that when a protein is secreted into the fermentation medium, the resulting liquid can contain other proteins, extracellular compounds and residual processing aids. Additional purification is necessary to separate the desired ingredient from these materials.

The degree of purification is also an economic and technical consideration. Highly purified proteins may require additional processing, increasing production costs and material losses. For some food applications, manufacturers may prioritize functional performance and an appropriate ingredient specification over achieving the highest possible purity.

This does not mean that every residual compound represents a safety concern. It means that the finished ingredient’s composition, rather than the intended protein alone, is relevant to evaluating its quality and safety.

A Closer Look at a Commercial Milk Alternative

A study published April 3, 2026, in Scientific Reports, titled “Multi-omics profiling finds synbio milk differs nutritionally from bovine milk and contains 93 uncharacterized fungal metabolites and 236 fungal proteins,” brought these questions into sharper focus.

Researchers Ravikishore Velamuri, Thejaswi Yertha and John Fagan examined a commercially available milk-replacement product containing recombinant bovine beta-lactoglobulin, a whey protein produced using the filamentous fungus Trichoderma reesei.

Using mass spectrometry, proteomics, immunoassays and amino acid analysis, the researchers investigated the product’s protein composition and small-molecule profile, comparing it with conventional, organic and biodynamic bovine milk.

They identified 236 fungal proteins and reported that fungal proteins accounted for 75.1% of the measured protein in the product using shotgun proteomics. An alternative calculation based on ELISA and conventional protein analysis estimated the fungal-protein share at 86.5%. The researchers also identified 93 small-molecule compounds that could not be matched to their mass-spectrometry reference libraries.

The researchers reported substantial differences between the analyzed product and bovine milk in their measured nutritional profiles. Of 69 small-molecule nutrients identified in bovine milk, only seven were detected in the precision-fermented product in smaller amounts. Differences in amino acid composition were also reported.

The findings raise questions about the relationship between the intended protein, the fermentation process and the composition of a finished food product. However, the study has important limitations. The researchers examined a particular commercial formulation, not every precision-fermented ingredient or production platform. Most small-molecule analyses relied on one product lot, although a second lot was included in subsequent proteomic testing. The study did not conduct human clinical trials or direct toxicity testing.

Furthermore, compounds that cannot be identified through existing reference libraries are not automatically toxic or necessarily novel. Their identities and biological effects would need to be established before conclusions about health risks could be drawn.

The authors disclosed funding from the Organic and Natural Health Association, the Non-GMO Project, Abby Rockefeller and the Foundation for Agricultural Integrity, as well as their institutional roles at Health Research Institute.

An additional distinction is important when interpreting these findings. In GRAS Notice 863, submitted to the FDA in 2019, Perfect Day described a purified fermentation-derived beta-lactoglobulin ingredient with at least 90% beta-lactoglobulin as a proportion of protein. Analyses of three non-consecutive production lots reported values between 99.5% and 100%.

The notification describes a purified ingredient, whereas the 2026 study analyzed a commercial beverage containing this type of fermentation-derived protein. These are not identical sample types, and the results should not be treated as a direct batch-to-batch comparison. Nevertheless, the distinction illustrates why ingredient specifications, finished-product composition and the actual materials tested must be considered separately.

What Does a Safety Assessment Actually Cover?

The questions raised by the study are not entirely new to food regulators. The UK’s Food Standards Agency (FSA) identified several recurring challenges in its 2025 review, “Review of Precision Fermentation Applications to Identify Common Challenges for Safety Assessment.”

The review examined precision-fermentation applications that had entered or passed through the agency’s novel-food assessment process. It identified insufficient information about production microorganisms, genetic modifications, protein digestibility, nutritional quality and allergenicity as recurring obstacles to completing safety assessments.

Characterizing the production organism is one important consideration. Regulators need information about the microorganism’s identity, genetic modifications and genetic stability to assess whether it could produce toxins or other substances of concern.

The FSA also emphasized the importance of evaluating what remains in the final product. If a microorganism can produce secondary metabolites, applicants may need to analyze those compounds and demonstrate that they are not present at concerning levels. Manufacturers must also provide evidence that the production organism has been adequately removed when its presence is not intended in the finished ingredient.

A recombinant protein may have the same amino acid sequence as its naturally occurring counterpart but differ in its three-dimensional structure because of differences in how the production organism folds or modifies the protein. These differences can affect biological function, digestibility and potentially allergenicity.

A September 2026 review in Foods, “Allergenicity Assessment of Precision Fermentation-Derived Food Proteins,” by Jun-Hyeok Ham and colleagues, further examines this issue. The researchers explain that residual host-cell proteins, differences in protein folding and host-dependent modifications can make fermentation-derived proteins imperfect replicas of their naturally occurring counterparts.

This is particularly relevant when manufacturers produce milk or egg proteins through fermentation. Producing a milk protein through a microorganism does not automatically eliminate its potential to trigger reactions in people with milk allergies. Its allergenic properties and appropriate labeling must still be evaluated.

What Does a GRAS Determination Establish?

In the United States, many novel food ingredients enter the market through the Food and Drug Administration’s (FDA) Generally Recognized as Safe (GRAS) framework.

Under the Federal Food, Drug, and Cosmetic Act, substances intentionally added to food generally require premarket approval as food additives unless an exemption applies. One exemption covers substances whose safety under their intended conditions of use is generally recognized among qualified experts through scientific procedures or, for substances used in food before 1958, through experience based on common use in food.

The FDA operates a voluntary GRAS notification program through which manufacturers can submit the scientific basis for their conclusions. After reviewing a notification, the agency may issue a letter stating that it has no questions regarding the notifier’s GRAS conclusion. However, a no-questions letter is not formal FDA approval, nor does every GRAS conclusion necessarily involve an FDA review.

A GRAS conclusion applies to a particular substance under specified conditions of use. It does not automatically establish the safety of every formulation containing that substance, every production process or every possible exposure level.

Perfect Day’s GRN 863 illustrates how these assessments are structured. The notification describes the production strain, genetic modifications, fermentation and recovery process, ingredient specifications, batch analyses, proposed uses and allergenicity considerations. FDA issued its no-questions letter on March 25, 2020.

An August 2026 FDA proposal could increase transparency surrounding these determinations. Published August 11, the proposed rule would require manufacturers to submit GRAS notifications for covered substances they determine are safe under their intended conditions of use. It would replace the current voluntary notification framework with mandatory submissions for qualifying uses, subject to specified exceptions.

However, mandatory notification would not mean mandatory independent premarket approval. Manufacturers would remain responsible for establishing the scientific basis for their GRAS conclusions. The proposal is intended to give FDA and the public greater visibility into substances entering the food supply.

The comment period runs through December 9, 2026.

Sources:

1. Velamuri, R., Yertha, T., and Fagan, J. (2026). “Multi-omics profiling finds synbio milk differs nutritionally from bovine milk and contains 93 uncharacterized fungal metabolites and 236 fungal proteins.” Scientific Reports, 16, 16029. https://doi.org/10.1038/s41598-026-38994-7
2. Keppler, J.K., and Boom, R.M. (2026). “Downstream Processing of Food Proteins from Precision Fermentation.” Annual Review of Food Science and Technology, 17, 459–474. https://doi.org/10.1146/annurev-food-060424-091647
3. Food Standards Agency. (2025). “Review of Precision Fermentation Applications to Identify Common Challenges for Safety Assessment.” FSA Research and Evidence. https://doi.org/10.46756/001c.147356
4. Ham, J.H., Jung, H., Hong, C., and Kim, H.Y. (2026). “Allergenicity Assessment of Precision Fermentation-Derived Food Proteins.” Foods, 15(17), 3153. https://doi.org/10.3390/foods15173153
5. U.S. Food and Drug Administration. (2020). “GRAS Notice (GRN) No. 863: Non-Animal Whey Protein from Fermentation by Trichoderma reesei.” FDA.
6. U.S. Food and Drug Administration. (2026). “Substances Generally Recognized as Safe.” Federal Register, 91 FR 51834, August 11, 2026. Docket No. FDA-2025-N-3262.