Reopening the Public Consultation: Why Do Previously Approved HMOs Keep Reappearing in the Public Eye? Is Further Application Required When Production Strain Information Remains Consistent?

In 2023, 2’-fucosyllactose (2’-FL) and lacto-N-neotetraose (LNnT) were officially approved as new food nutrition enhancers in China, marking a regulatory milestone regarding human milk oligosaccharides (HMOs), a globally recognized category of essential nutrients. Since then, several other HMOs continue to progress along the compliance pathway: on May 10, 2024, the Center for Food Safety Assessment (CFSA) issued the draft and reopened the period for public consultation for 2’-FL and LNnT.

Accelerated Regulatory Progress and Surging Applications for HMOs in China

Various categories of HMOs have made regulatory progress in China, with 2’-FL seeing the most significant number of applications. To help companies stay updated on the latest developments, CIRS Group has compiled a detailed summary of the regulatory status of 2’-FL in China.

As of May 10, 2024:

• Approved 2’-FL (4 types): All are of microbial source, each with same standards and different production strain information;
• 2’-FL issued for public comments and not yet approved (5 types): 1 of chemical source and 4 of microbial source. The production strain information of 1 product in the latest draft for public consultation is consistent with that stated in the previous approval announcement.
• 2’-FL accepted and still in the process of technical review (12 types): 7 have been issued an extension notice, 1 have been accepted, and 4 have been issued a non-approval decision.

Details are as follows:

Approved 2’-FL (4 types)

Nutrition enhancer	Source	Donor	Announcement
2’-fucosyllactose	E. coli K-12 DH1 MDO	Helicobacter spp. a	National Health Commission (NHC) Announcement No. 8 of 2023 issued on October 7, 2023
	E. coli K-12 MG1655	Helicobacter spp. a
	E. coli BL21 (DE3)	Neisseria spp. a
	E. coli BL21 (DE3)	Helicobacter pylori a	NHC Announcement No. 2 of 2024 issued on March 13, 2024

^a: donor of α-1,2-fucosyltransferase

2’-FL issued for public comments (5 types)

S.N.	Date of issue	Remarks
1	2021.10.21	Synthesis method
2	2023.08.23	Microbial source. Production strain information: Source: Corynebacterium glutamicum ATCC 13032; Donor: Pseudopedobacter saltans a
3	2024.03.13	Microbial source. Production strain information: Source: E.coli BL21 star (DE3); Donor: E.coli O126 a
4	2024.05.10	Microbial source. Production strain information: Source: E.coli K-12 GI724; Donor: Bacteroides vulgatus a
5	2024.05.10	Microbial source. Production strain information: Source: E.coli K-12 MG1655; Donor: Helicobacter spp.a Note: Consistent with the production strain information given in HNC Announcement No. 8 of 2023.

^a: donor of α-1,2-fucosyltransferase

2’-FL at the stage of acceptance and additional materials submission (12 types)

S.N.	Acceptance date and No.	Review status
1	2023/07/14 衛食添新申字(2023) No. 0045	2024/03/07 Delivered an extension notice
2	2023/09/20 衛食添新申字(2023) No.0061	2024/04/15 Delivered an extension notice
3	2023/11/01 衛食添新申字(2023) No.0065	2023/12/12 Delivered an extension notice
4	2023/11/21 衛食添新申字(2023) No. 0074	2023/12/12 Delivered an extension notice
5	2024/01/11 衛食添新申字(2024) No. 0002	2024/04/15 Delivered an extension notice
6	2024/01/16 衛食添新申字(2024) No. 0005	2024/02/08 Delivered an extension notice
7	2024/01/18 衛食添新申字(2024) No. 0009	2024/02/08 Delivered an extension notice
8	2021/05/07 衛食添新申字(2024) No. 0042	/
9	2023/11/30 衛食添新申字(2023) No. 0076	2024/02/08 Issued non-approval decision
10	2023/11/01 衛食添新申字(2023) No. 0064	2024/02/08 Issued non-approval decision
11	2023/09/19 衛食添新申字(2023) No. 0058	2024/02/08 Issued non-approval decision
12	2022/11/15 衛食添新申字(2022) No. 0085	2024/03/25 Issued non-approval decision

Source: HNC Government Service Hall

It can be observed that after the official approval of 2’-FL in 2023, many companies continue to submit new applications. In fact, several other typical HMOs substances also have multiple records of being accepted.

Even If the Product Information Complies with the Official Announcement, It Still Needs to be Applied as a “New Variety”

Many may wonder: why there are such a large number of applications? Do products that comply with the official announcement need to be re-applied? The answer is: yes. CIRS will analyze it from the following two perspectives.

Consumption safety

HMOs approved both internationally and domestically are mainly prepared via genetically engineered microorganisms fermentation. In China, the application process for such additives is rather complex and requires assessment or approval from the following two regulatory authorities:

• Ministry of Agriculture and Rural Affairs of the People’s Republic of China (MARA): Responsible for conducting safety assessment of the genetically engineered microorganisms used in additive production;
• National Health Commission of the People’s Republic of China (NHC): Responsible for the review and approval of fermented end products (i.e. new food additives).

For genetically modified microorganisms (i.e., production strains), although their origin and donor may align with the official announcement, the genetic engineering techniques and product synthesis pathways used by each company are unlikely to be entirely identical. Therefore, from both a food safety perspective and due to the uniqueness of processes, these substances require “case-by-case” approvals from both MARA and NHC.

Official announcements and regulations

Take the latest approval announcement and draft for public comments regarding 2’-FL as an example. It’s worth noticing that:

• As specified in NHC Announcement No. 8 of 2023, production strains need to undergo safety assessment. (CIRS remarks: Simply meeting the requirements outlined in the announcement is insufficient; assessment by relevant regulatory authorities is still required.)
• In the latest draft for public consultation draft regarding 2’-FL, the production strain information is completely consistent with the previous approval announcement. (CIRS remarks: Even if the production strain aligns with the announcement and passes safety assessments, it is still necessary to file an application and issue the draft.)

Meanwhile, CIRS Group, after consulting regulatory authorities and multiple experts, confirms that for food ingredients produced using synthetic biology techniques, such as HMOs substances, even if the production strain information meets the requirements outlined in the official announcement, it is still necessary to undergo safety assessment by MARA and apply for new food additives to NHC.

Furthermore, we kindly remind users of such ingredients that compliant procurement of qualified raw materials is a crucial factor in ensuring the safety of the final products.

HMOs are gaining momentum in the Chinese market, and it is believed that the regulatory approval and nutritional innovation research in this field will remain popular in the coming years. CIRS Group will keep following closely on the approval status and policy changes on such substances.

About us

Established in 2012, the Food Business Division at CIRS Group boasts a professional technical team and has provided one-stop food compliance services for over 1,000 domestic and international companies. With extensive experience, we have made a track record of successful cases in the fields of “three new foods”, synthetic biology foods, US FDA GRAS application, health foods, infant formula and foods for special medical purposes (FSMP). Currently, CIRS Group has carried out the application of dozens of GMM new food additives on behalf of our clients, positioning us at the forefront of the industry in terms of project experience and successful cases. We warmly welcome inquiries or visits to learn more about our technological expertise.

If you need any assistance or have any questions, please get in touch with us via service@jianzaoshiwang.cn.

Further Information

Latest Compliance Advances of Human Milk Oligosaccharides (HMOs) in China