Latest Compliance Advances of Human Milk Oligosaccharides (HMOs) in the EU and U.S. - Regulatory News - Food & Food Contact Materials

Human Milk Oligosaccharides (HMOs) stands as a unique carbohydrate present exclusively in breast milk, ranking as the third-largest solid component, following lactose and fat. With diverse functions, HMOs plays a crucial role in enhancing the gut microbiota, boosting cognitive function, and alleviating symptoms of irritable bowel syndrome, among other benefits. Currently, there are over 150 known types of HMOs, each with distinct structures, functions, and applications. Several types have initiated compliance efforts globally, with commercialization taking root first in the EU and the United States.

To clarify the compliance advances of HMOs in the EU and U.S., CIRS Group has summarized the detailed approval information as follows.

Supervision over HMOs in the EU and U.S.

Similar to China, where HMOs are required to be applied as nutrition enhancers, HMOs in other countries must undergo a series of approval procedures before being marketed. In the EU, HMOs shall be applied as Novel Foods, while in the United States, it falls under the category of “Generally Recognized as Safe (GRAS)” substances.

In 2015, the first HMO to receive GRAS certification from the U.S. FDA was 2’-Fucosyllactose produced through chemical synthesis submitted by Glycom A/S. Since then, the application of HMOs in the EU and the United States has been on a steady rise. As of December 14, 2023, the HMOs approved in the EU and the United States mainly include the following:

2’-Fucosyllactose (2’-FL)
3-Fucosyllactose (3-FL)
Lacto-N-tetraose (LNT)
Lacto-N-neotetraose (LNnT)
3’-Sialyllactose (3’-SL)
6’-Sialyllactose (6’-SL)
2’-Fucosyllactose/difucosyllactose mixture (2’-FL/DFL)
Lacto-N-fucopentaose I/2’-Fucosyllactose mixture (LNFP/2’-FL)

HMOs approved in the EU and U.S.

According to the publicly available information from the EU and the United States, CIRS has compiled a summary of the various types of HMOs approved as follows:

Approval status of 2’-FL

EU: 1 of chemical source and 3 of microbial source;
U.S.: 1 of chemical source and 11 of microbial source;

Table1: 2’-Fucosyllactose (2’-FL)
Country/Region	Date of approval	Production stain	Applicant
EU	2016.3.16	Produced through chemical synthesis, no production strain involved.	Glycom A/S
	2016.6.23*	Escherichia coli K-12	Glycom A/S
	2017.11.29	Escherichia coli BL21	Jennewein Biotechnologie GmbH
	2023.4.26	Corynebacterium glutamicum ATCC 13032	Advanced Protein Technologies Corporation
	*: It is directly included in the NF list upon its establishment, with no Implementation Regulation being released, as per the modification documents submitted by the applicant.
U.S.	2015.9.16	Produced through chemical synthesis, no production strain involved.	Glycom A/S
	2015.11.6	Escherichia coli BL21 (DE3) #1540	Jennewein Biotechnologie, GmgH
	2016.11.23	Escherichia coli K-12 DH1	Glycom A/S
	2018.4.6	Escherichia coli K12 E638	Glycosyn & Friesland Campina Domo B.V.
	2018.4.23	Escherichia coli K12 MG1655	DuPont Nutrition & Health
	2019.11.15	Escherichia coli Kl2 LU20297	BASF SE
	2020.6.12	Escherichia coli INB000846	DuPont Nutrition and Health
	2021.2.18	Corynebacterium Glutamicum APC199	Advanced Protein Technologies Corp.
	2021.2.26	Escherichia coli BL21 (DE3)	Jennewein Biotechnologie GmbH
	2022.7.15	Escherichia coli BL21 (DE3)	Chr. Hansen A/S
	2022.10.21	Escherichia coli K-12 DH1 MDO	Glycom A/S
	2023.4.4	/	Glycom A/S

Approval status of 3-FL

EU: 3 of microbial source;
U.S.: 3 of microbial source;

Table 2: 3-Fucosyllactose (3-FL)
Country/Region	Date of approval	Production stain	Applicant
EU	2021.11.22	Escherichia coli K12 MG1655	DuPont Nutrition & Biosciences ApS
	2023.1.5	Escherichia coli BL21 (DE3)	Chr. Hansen A/S
	2023.10.23	Escherichia coli K-12 DH1	Glycom A/S
U.S.	2021.2.8	Escherichia coli BL21 (DE3)	Jennewein Biotechnologie GmgH
	2021.8.12	Escherichia coli K12 MG1655	Danisco
	2022.11.7	Escherichia coli K-12 DH1 MDO	Glycom A/S

Approval status of LNT

EU: 2 of microbial source;
U.S.: 4 of microbial source;

Table 3: Lacto-N-tetraose (LNT)
Country/Region	Date of approval	Production stain	Applicant
EU	2020.4.3	Escherichia coli K12 DH1	Glycom A/S
EU	2023.1.4	Escherichia coli BL21 (DE3)	Chr. Hansen A/S
U.S.	2019.10.7	Escherichia coli K-12 DHl	Glycom A/S
	2021.2.2	Escherichia coli BL21 (DE3)	Jennewein Biotechnologie GmgH
	2022.8.23	Escherichia coli BL21 (DE3)	Chr. Hansen A/S
	2023.6.5	Escherichia coli K-12 MG1655	Inbiose N.V.

Approval status of LNnT

EU: 1 of chemical source and 2 of microbial source;
U.S. 1 of chemical source and 5 of microbial source;

Table 4: Lacto-N-neotetraose (LNnT)
Country/Region	Date of approval	Production stain	Applicant
EU	2016.3.16	Produced through chemical synthesis, no production strain involved.	Glycom A/S
	2016.9.1*	Escherichia coli K-12	Glycom A/S
	2021.6.7	Escherichia coli BL21 (DE3)	Chr. Hansen A/S
	*: It is directly included in the NF list upon its establishment, with no Implementation Regulation being released, as per the modification documents submitted by the applicant.
U.S.	2015.10.2	Produced through chemical synthesis, no production strain involved.	Glycom A/S
	2016.11.23	Escherichia coli K-12 DH1 (Crystallization)	Glycom A/S
	2020.10.30	Escherichia coli BL21 (DE3)	Jennewein Biotechnologie GmgH
	2020.12.3	Escherichia coli K-12 DH1 (Optimized process，powder)	Glycom A/S
	2022.12.2	Escherichia coli K-12 DH1 MDO (Crystallization)	Glycom A/S
	2023.4.4	Escherichia coli K-12 MG1655	Inbiose N.V.

Approval status of 3’-SL

EU: 2 of microbial source;
U.S.: 1 of chemical source and 5 of microbial source;

Table 5: 3’-Sialyllactose (3’-SL)
Country/Region	Date of approval	Production stain	Applicant
EU	2021.1.29	Escherichia coli K12 DH1	Glycom A/S
EU	2023.1.17	Escherichia coli BL21 (DE3)	Chr. Hansen A/S
U.S.	2018.9.26	Produced through chemical synthesis, no production strain involved.	GeneChem, Inc.
	2020.2.21	Escherichia coli K-12 DH1	Glycom A/S
	2020.10.30	Escherichia coli BL21 (DE3)	Jennewein Biotechnologie GmgH
	2022.7.15	Escherichia coli BL21 (DE3)	Chr. Hansen A/S
	2023.4.5	Escherichia coli K-12 MG1655	Inbiose N.V.
	2023.4.18	Escherichia coli W (ATCC 9637)	Kyowa Hakko Bio Co., Ltd.

Approval status of 6’-SL

EU: 3 of microbial source;
U.S.: 5 of microbial source;

Table 6: 6’-Sialyllactose (6’-SL)
Country/Region	Date of approval	Production stain	Applicant
EU	2021.1.28	Escherichia coli K-12 DH1	Glycom A/S
	2023.5.15	Escherichia coli BL21 (DE3)	Chr. Hansen A/S
	2023.10.24	Escherichia coli W (ATCC 9637)	Kyowa Hakko Bio Co., Ltd
U.S.	2020.2.24	Escherichia coli K-12 DH1	Glycom A/S
	2021.4.23	Escherichia coli BL21 (DE3)	Jennewein Biotechnologie GmgH
	2022.7.15	Escherichia coli BL21 (DE3)	Chr. Hansen A/S
	2023.3.22	Escherichia coli K-12 MG1655	Inbiose N.V.
	2023.5.12	Escherichia coli W (ATCC 9637)	Kyowa Hakko Bio Co., Ltd.

Approval status of mixed HMOs

2’-FL/DFL: All are applied by Glycom and granted approval;
LNFP/2’-FL: Applied by Glycom, it has been granted GRAS status in the United States and has passed the safety assessment by EFSA in the EU. It is expected that the Implementing Regulation will soon be published (See Table 8).

Table 7: 2’-Fucosyllactose/difucosyllactose mixture (2’-FL/DFL)
Country/Region	Date of approval	Production stain	Applicant
EU	2019.11.29	Escherichia coli K12 DH1	Glycom A/S
U.S.	2019.8.20	Escherichia coli K-12 DH1	Glycom A/S
Lacto-N-fucopentaose I/2’-Fucosyllactose mixture (LNFP/2’-FL)
Country/Region	Date of approval	Production stain	Applicant
U.S.	2023.1.19	Escherichia coli K-12 DH1	Glycom A/S

HMOs under approval in the EU and the United States

Several HMOs are currently undergoing the approval process in both the EU and the United States. Details are as follows:

Table 8: HMOs under approval in the EU and the United States
Substance	Country/Region	Date of application	Status	Applicant
2’-FL	U.S.	/	Pending	Kyowa Hakko Bio Co., Ltd.
		/	Pending	Inbiose N.V.
		/	Pending	Synaura Biotechnology (Shanghai) Co., Ltd.*
3-FL	U.S.	/	Pending	Chr. Hansen A/S
3’-SL	EU	2021.8.6	Passed the safety assessment	Kyowa Hakko Bio Co., Ltd.
LNFP-I / 2’-FL	EU	2021.3.24	Passed the safety assessment	Glycom A/S

In addition to new substances, there are applications for modification of multiple HMOs that have been authorized. The modifications generally include the production strains, quality specifications, scope of use, and use levels:

Table 9: Application for modification of authorized HMOs
Substance	Date of application	Status	Applicant
2’-FL	2021.7.8	Passed the safety assessment	Kyowa Hakko Bio Co., Ltd.
	2021.11.3	Passed the safety assessment	Chr. Hansen A/S
	2023.9.21	Dossier Received	Synaura Biotechnology (Shanghai) Co., Ltd.*
LNT	2023.10.16	Dossier Reveived	Inbiose N.V.
6’-SL	2023.10.30	Dossier Received	Inbiose N.V.

* Synaura Biotechnology (Shanghai) Co., Ltd., a synthetic biology company invested and incubated by Mengniu Venture Capital Fund, has received approval for its independently developed 2’-FL, as announced in the National Health Commission (NHC) Notice No. 8 of 2023. Currently, its application for modification of the 2’-FL has been accepted by the European Food Safety Authority (EFSA), and the GRAS certification is also under approval process.

Fierce competition in the international market

Statistics reveal that the applicants of HMOs in the EU and the United States are mainly the world’s major suppliers of HMOs raw materials, including Glycom A/S (Denmark), Jennewein Biotechnologie GmbH (Germany), and Inbiose NV (Belgium), among others. In recent years, overseas industry giants have actively engaged in collaboration through acquisitions, mergers, and joint research and development, partnering with HMO raw material suppliers to secure a leading position in the field.

In 2016, Glycosyn and Friesland Campina signed a technical cooperation agreement. In 2017, they jointly submitted the application for a microbial fermentation-produced 2’-FL, and successfully obtained GRAS certification the following year;

In 2020, DSM acquired Glycom A/S (Glycom) for an enterprise value of 765 million euros. The collaboration between the two in the early life nutrition field significantly accelerated the development of the HMOs product line. Currently, DSM is equipped with the production capacity for more than a dozen HMOs, and several of them have been successfully introduced to the market, making DSM a major driving force behind the commercialization of HMOs.

(Source: Official website of DSM)

Within the same year, Chr. Hansen A/S acquired Jennewein Biotechnologie GmbH, marching into the HMOs market, strategically positioning itself and successfully obtaining market approvals multiple HMOs in the EU and the United States.

(Source: Official website of Chr. Hansen A/S)

The entry of major players in the HMOs industry have intensified industrial competition and differentiation. Research and development enterprises aiming for breakthroughs must establish their own technological advantages, upgrade processes, and achieve large-scale production. An important part of the technological barriers are the patents related to HMOs synthesis. Industry giants such as Chr. Hansen and Glycom have previously engaged in multiple disputes over HMOs patents, resorting to legal proceedings.

The synthesis methods for HMOs can be divided into three main categories, namely, chemical synthesis, enzymatic processes, and microbial fermentation. Chemical synthesis involves complex steps and high costs, making it unsuitable for large-scale production, resulting in a limited number of approvals. HMOs of microbial source mainly use Escherichia coli (E. coli) as the production strain, and the strains used by different companies vary. CIRA has compiled the following information on the production strains of HMOs that have been approved in the EU and the United States :

Table 10: List of production strains of HMOs
Production strain	Strain	Company
Escherichia coli	K12 DH1	Glycom A/S
	K-12 MG1655	Inbiose NV; DuPont Nutrition & Health; Danisco
	K12 E638	Glycosyn & Friesland Campina Domo B.V.
	Kl2 LU20297	BASF SE
	INB000846	DuPont Nutrition and Health
	BL21 (DE3)	Jennewein; Chr. Hansen A/S
	W (ATCC 9637)	Kyowa Hakko Bio Co., Ltd.
Corynebacterium Glutamicum	ATCC 13032	Advanced Protein Technologies Corporation

Domestic market gearing up for further development

In October of this year, China HNC released Notice No.8 of 2023, officially approving 2’-FLand LNnT as nutrition enhancers, sparking a wave of excitement within the infant formula industry. Although, compared to the EU and the United States, the approval of HMOs in China came a bit later, it is worth noticing that as early as 2016, the former National Health and Family Planning Commission (NHFPC) had collected public opinions on 2’-FL as a new food additive. Currently, there are 8 applications for 2’-FL, 1 for 3-FL, 2 for 6’-SL, and 2 for 3’-SL in the application process, reflecting the enthusiasm of enterprises.

For approval information of HMOs in China, click here to refer to our previous article.

Comparison of HMOs approval status in both domestic and international markets:

Substance	EU	U.S.	China
2’-FL	√	√	√
3-FL	√	√	Pending
LNT	√	√	×
LNnT	√	√	√
3’-SL	√	√	Pending
6’-SL	√	√	Pending
2’-FL/DFL	√	√	×
LNFP/2’-FL	Pending	√	×

In light of the regulatory constraints on “Three New Foods” in China, formulations such as 2’-FL/DFL and LNFP/2’-FL do not align with the application requirements. The approval progress for 3-FL, 3’-SL, and 6’-SL is still pending, while LNT is currently in a phase where no applications have been filed.

Currently, top enterprises are rushing to launch infant formula with added HMOs to seize an early advantage in the highly homogeneous market and capture consumer awareness. It is believed that, with more sophisticated research and development in the future, HMOs may evolve into a pivotal technological force in the differentiating competition.

Note: The data presented is accurate as of December 14, 2023. The information is sourced from publicly available platforms and is for reference only.

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