From: Morissette, Rachel

To: Tania Porsgaard Bayer

Subject: memorandum of meeting for osteopontin (OPN)

Date: Thursday, July 11, 2019 2:40:00 PM

Attachments: GPS000010_Memorandum of Meeting_Arla_6.17.19_transmittal.pdf

image002.png

Dear Tania,

Please see attached the memorandum of meeting from our June 17, 2019 discussion on the intended use

of osteopontin in infant formula.

In addition, we discussed providing Arla some potential starting points to consider in its search for

expertise in different fields to address the safety and general recognition concerns for this intended use. I

am providing a list of potential scientific and medical disciplines as a starting point below. Please let us

know if we can provide further assistance.

• Developmental immunology

• Pediatric immunology

• Clinical immunology

• Immunological cell biology and biochemistry

• Developmental toxicology

• Pediatric physiology

• Milk biochemistry

• Gut physiology (especially postnatal)/gut microbiome

• Pediatric gastroenterology

• Biochemistry of osteopontin (from a basic science perspective)

• Food ingredient safety assessment/risk assessment (including familiarity with U.S. legal standards

for food safety)

• Epidemiology

• Biostatistics

Best regards,

Rachel

-------------------------------------------------------------

Rachel Morissette, Ph.D.

Regulatory Review Scientist

 

Center for Food Safety and Applied Nutrition

Office of Food Additive Safety

U.S. Food and Drug Administration

rachel.morissette@fda.hhs.gov
MEMORANDUM OF MEETING (COR2018-4008)

Date: September 19, 2018 

Time: 11:00 a.m. – 12:00 p.m. EST

Location: FDA, Center for Food Safety and Applied Nutrition, Office of Food 

Additive Safety, 5001 Campus Drive, College Park, MD 20740

Participants:

Visitors:

Cathryn Sacra EAS Consulting Group

Robin Guy EAS Consulting Group

Peter Budde Glanbia Foods, Inc.

Angela Walter Glanbia Foods, Inc.

Noreen Hobayan Glanbia Foods, Inc.

Ankur Jhanwar Glanbia Foods, Inc.

Brent Peterson Glanbia Foods, Inc.

Joe Milligan Glanbia Foods, Inc.

CFSAN/OFAS/DBGNR:

Rachel Morissette, Ph.D. HFS-255

Jeremy Mihalov, M.S. HFS-255

Kotaro Kaneko, Ph.D. HFS-255

Jeremiah Fasano, Ph.D. HFS-255

Perry Wang, Ph.D. HFS-717

CFSAN/ONFL/IFMFS:

Andrea Lotze, M.D. HFS-850

Carrie Assar, Pharm.D. HFS-850

Suzanne Wolcoff, M.S., R.D. HFS-850

Subject: Pre-submission meeting for the intended use of bovine lactoferrin (bLf) in 

infant and toddler formulas

In an electronic mail message dated August 13, 2018, Cathryn Sacra requested a meeting 

with FDA/DBGNR to discuss a GRAS conclusion for the intended use of bLf (tradename 

Bioferrin®) as an ingredient in infant and toddler formulas at a use level up to 1 g/L.

Prior to the meeting, Ms. Sacra provided a draft copy of the proposed GRAS notice. 

DBGNR informed her that the notice would not be reviewed in its entirety, but if there 

were specific sections she wanted us to review that we could accommodate that. Glanbia 

Foods, Inc. (Glanbia) stated that their bLf is sourced from cow’s milk whey obtained 

from cheese production and is in accordance with all applicable U.S. Department of 

Agriculture and FDA regulations for the manufacture of dairy products.
Glanbia discussed the identity of its bLf and stated that it has the same chemical 

properties to the subject of GRN 000465.1 Glanbia presented Fourier-transform 

infrared spectroscopy (FTIR) data to support their view that their bLf is structurally 

equivalent to that from GRN 000465. DBGNR pointed out that FTIR is better suited for 

small molecules, not proteins. Therefore, DBGNR suggested that other analytical 

methods could be used and presented in the GRAS notice to support structural 

similarities to other bLf proteins. DBGNR noted that the arsenic specification shown 

was higher than seen in past notices and also suggested specifying limits for lead and 

Cronobacter sakazakii. In support of the intended use level, which FDA noted is up to 

10-fold greater than use levels addressed in prior GRAS notices (e.g. GRNs 000465 and 

0006691), Glanbia stated that human lactoferrin is present in human breast milk and 

colostrum at up to 7 g/L. Additionally, Glanbia stated that bLf is approved for use 

worldwide at levels up to 1 g/L. Glanbia presented the estimated exposures from its

intended uses of bLf for infant and toddler populations and stated that the intended 

uses are self-limiting due to the maximum protein level and quality, as determined by 

the amino acid profile, permitted under 21 CFR 107.100. Additionally, Glanbia stated

that infants may be exposed to bLf from consumption of cow’s milk-based infant 

formulas already marketed in the U.S. containing up to 0.6 g/L bLf.2 DBGNR noted that 

as science evolves, we may have new questions about whether data previously used to 

establish safety continues to be generally accepted as sufficient by qualified experts.

To support a safety conclusion for the intended uses of bLf, Glanbia discussed acute and 

sub-chronic toxicity studies in rats, as well as human clinical trials involving infants and 

toddlers. Additionally, Glanbia discussed bLf in terms of allergenicity and the required 

labeling under FALCPA.

After hearing the safety data and other information presented by Glanbia, DBGNR 

noted that we would have questions on the following points in response to a GRAS 

notice based on that data, including, but not limited to, the following:

x Given that bLf has been reported to exhibit a variety of physiological activities in 

humans, including immunomodulation, we would ask about the basis for 

concluding that the intended use level of bLf would not alter the developmental 

trajectory of the immature infant immune system in potentially adverse ways. 

Traditional toxicological study endpoints do not provide meaningful information 

on this point. Evidence of general acceptance in the scientific community on the 

lack of adverse consequences from the intended use of bLf, particularly among 

experts qualified to assess postnatal development of the human infant immune 

system, would be extremely helpful in addressing this question.

 

1 Cow’s milk-derived lactoferrin was the subject of GRNs 000465 (use level 130 mg/L ) and 000669 (use 

level 130-140 mg/L). We evaluated these notices and responded in letters dated February 18, 2014, and 

March 9, 2017, stating that we had no questions at that time regarding Morinaga Milk Industry Co., Ltd.

and Synlait Milk, Ltd.’s GRAS conclusions, respectively.

2 FDA has not evaluated a GRAS conclusion through the GRAS Notification Program for the intended use 

of bLf in infant formula at a use level higher than 140 mg/L.
x Given the intended population, intended use level, and properties of bLf, we 

would ask questions about the evidence that the scientific data relied on by 

Glanbia is generally available and generally accepted at the present time by 

experts with the appropriate expertise. The significance and utility of published 

scientific literature and of GRAS panels in providing evidence of general 

recognition was discussed. FDA noted that a GRAS panel is only one strategy that 

can be employed as evidence of general acceptance. However, if used, a GRAS 

panel is only effective in generating such evidence when the appropriate expert 

disciplines are represented on the panel. In this case, representative expertise in 

infant immunology and immunomodulatory proteins would be important if the 

panel’s conclusion were being used to support the contention that bLf used at 1 

g/L is recognized by qualified expert communities as safe for its intended use.

x Considering the focus of our questions, we would consider evidence for the 

intended use of bLf based on the previous conclusions of authoritative bodies as 

supportive given that such bodies did not consider and dismiss the issues we had 

raised above. This is also true of current uses of bLf in infant formula above 130

mg/L.

x To the extent that Glanbia’s GRAS conclusion incorporates a comparison of 

lactoferrin levels in bovine and human milk, we would have questions about the 

basis for concluding that these proteins are comparable in biological activity in 

humans, and the significance of any known differences in this activity.

x While bLf in infant formula at lower use levels has been the subject of several

GRAS conclusions for which FDA had no questions at the time, we emphasized

that science evolves over time. Therefore, the data and information used to 

support a conclusion that an intended use is safe and accepted by qualified 

experts may also evolve over time. We would have some questions about bLf’s 

immunomodulatory activities and the basis for concluding it was consistent with 

GRAS status in infant formula in response to a new notice regardless of use level,

although the extent of our questions would differ depending on the specific use 

level.

In addition to the points discussed above, DBGNR attendees provided the following 

recommendations:

x Specify the category of infant formula and the intended infant population (e.g. 

non-exempt infant formula for term infants, milk or soy-based).

x Glanbia stated that the final product is specified to contain up to 5% “other 

proteins.” In the notice, provide a discussion on the identity of the other proteins 

present in the final product.
x When presenting studies done in a pre-term infant population in the notice, 

provide a discussion bridging this information to full-term infant populations.

x Glanbia could submit a FOIA request for the amendments to GRAS notices they 

intend to incorporate into the current notice so that the full-breath of the review 

process for those notices is available for reference.

Ms. Sacra sent a follow-up email on October 10, 2018 with an attached memorandum of 

meeting that she and the Glanbia participants wrote to share their understanding of the 

outcome of this pre-submission meeting. Based on the contents of this memo, DBGNR 

will recommend a follow-up meeting to clarify the points discussed and options for 

moving forward.

________________________________

Rachel Morissette, Ph.D.

ATTACHED:

1. Meeting Request (email dated August 13, 2018)

2. Email dated September 18, 2018

3. Email dated October 10, 2018

4. Powerpoint Presentation 

5. Draft GRAS notice dossier

Rachel 

Morissette -S

Digitally signed by Rachel Morissette -S 

DN: c=US, o=U.S. Government, ou=HHS, 

ou=FDA, ou=People, 

0.9.2342.19200300.100.1.1=0014346356

, cn=Rachel Morissette -S 

Date: 2018.10.23 08:15:10 -04'00'
R/D:HFS-255:RMorissette:9/25/18, 10/2/18, 10/18/18, 10/23/18

Edit/Comment/Init:HFS-255:JFasano:10/1/18, 10/2/18, 10/17/18

Edit/Comment/Init:HFS-255:JMihalov:9/26/2018

Edit/Comment/Init:HFS-255:KKaneko:9/25/18

Discussion:HFS-255:RMorissette,JFasano,PGaynor,SCarlson:10/17/18

Edit/Comment:HFS-255:PGaynor:10/17/18, 10/22/18

F/T:HFS-255:RMorissette:10/23/18
From: Cathryn Sacra

To: Morissette, Rachel

Cc: Robert Martin

Subject: RE: GRAS Pre-submission Meeting Request

Date: Monday, August 13, 2018 2:58:04 PM

Attachments: image002.png

Pre-Submission Letter8-13-18.pdf

Dear Dr. Morissette,

I am attaching a letter requesting a pre-mission meeting. Please let me know if any of the dates we

propose will work for you and your team.

Best regards,

Cathryn

Cathryn W. Sacra

Director of Labeling and Cosmetic Services

EAS Consulting Group, LLC

1700 Diagonal Road

Suite 750

Alexandria VA, 22314

877-327-9808 (toll free) +1 571-447-5500 (main) +1 571-447-5505 (direct) 703-548-3270 (fax)

csacra@easconsultinggroup.com

www.easconsultinggroup.com

From: Cathryn Sacra 

Sent: Friday, August 03, 2018 12:47 PM

To: Morissette, Rachel <Rachel.Morissette@fda.hhs.gov>

Cc: Robert Martin <rmartin@easconsultinggroup.com>

Subject: RE: GRAS Pre-submission Meeting Request

Dear Dr. Morissette,

Thank you. Once I have some new dates from our team for your consideration, I will reach out to

you with our meeting request.

Best regards

Cathryn

Cathryn W. Sacra

Director of Labeling and Cosmetic Services

EAS Consulting Group, LLC

1700 Diagonal Road

Suite 750

Alexandria VA, 22314

877-327-9808 (toll free) +1 571-447-5500 (main) +1 571-447-5505 (direct) 703-548-3270 (fax)

csacra@easconsultinggroup.com
www.easconsultinggroup.com

From: Morissette, Rachel <Rachel.Morissette@fda.hhs.gov> 

Sent: Friday, August 03, 2018 11:29 AM

To: Cathryn Sacra <csacra@easconsultinggroup.com>

Subject: FW: GRAS Pre-submission Meeting Request

Dear Ms. Sacra,

Please feel free to contact me when you are ready to move ahead with a pre-submission meeting for this

GRAS notice.

Best regards,

Rachel Morissette, Ph.D.

Consumer Safety Officer

Center for Food Safety and Applied Nutrition

Office of Food Additive Safety

U.S. Food and Drug Administration

rachel.morissette@fda.hhs.gov

From: West-Barnette, Shayla 

Sent: Friday, August 03, 2018 10:55 AM

To: Cathryn Sacra <csacra@easconsultinggroup.com>; Morissette, Rachel

<Rachel.Morissette@fda.hhs.gov>

Cc: Robert Martin <rmartin@easconsultinggroup.com>

Subject: RE: GRAS Pre-submission Meeting Request

Hello Ms. Sacra,

Thank you for your message.

I am asking Dr. Rachel Morissette to set up your meeting (she is copied on this message). She

will reach out to you shortly.

Regards,

Shayla West-Barnette, Ph.D.

Supervisory Consumer Safety Officer

Center for Food Safety and Applied Nutrition

Office of Food Additive Safety

U.S. Food and Drug Administration

Shayla.WestBarnette@fda.hhs.gov
From: Cathryn Sacra [mailto:csacra@easconsultinggroup.com] 

Sent: Friday, August 03, 2018 10:40 AM

To: West-Barnette, Shayla <Shayla.WestBarnette@fda.hhs.gov>

Cc: Robert Martin <rmartin@easconsultinggroup.com>

Subject: RE: GRAS Pre-submission Meeting Request

Dear Dr. West-Barnette,

I had sent an email in July requesting a pre-submission meeting with FDA with some proposed dates

in August. We are still working on the last stages of the draft dossier and would like to withdraw the

request for the proposed dates. We will send a new request for a pre-submission meeting when we

have finalized the draft dossier.

Thank you,

Cathryn Sacra

Cathryn W. Sacra

Director of Labeling and Cosmetic Services

EAS Consulting Group, LLC

1700 Diagonal Road

Suite 750

Alexandria VA, 22314

877-327-9808 (toll free) +1 571-447-5500 (main) +1 571-447-5505 (direct) 703-548-3270 (fax)

csacra@easconsultinggroup.com

www.easconsultinggroup.com

From: Cathryn Sacra 

Sent: Thursday, July 12, 2018 9:32 AM

To: Shayla.WestBarnette@fda.hhs.gov

Subject: GRAS Pre-submission Meeting Request

Dear Dr. West-Barnette,

With the attached letter, I am requesting a pre-submission meeting with you and your colleagues to

discuss a GRAS Notice for the use of bovine lactoferrin in term infant formula. Please let me know if

any of our proposed dates are acceptable to you.

Best regards,

Cathryn Sacra
Cathryn W. Sacra

Director of Labeling and Cosmetic Services

EAS Consulting Group, LLC

1700 Diagonal Road

Suite 750

Alexandria VA, 22314

877-327-9808 (toll free) +1 571-447-5500 (main) +1 571-447-5505 (direct) 703-548-3270 (fax)

csacra@easconsultinggroup.com

www.easconsultinggroup.com
August 13, 2018

Shayla West-Barnette, Ph.D. 

Supervisory Consumer Safety Officer 

Office of Food Additive Safety 

Center for Food Safety and Applied Nutrition, FDA 

5001 Campus Drive 

College Park, MD 20740 

240-402-1262 (direct) 

Shayla.WestBarnette@fda.hhs.gov

Dear Dr. West-Barnette:

On behalf of Glanbia Nutritionals, we are requesting a pre-submission meeting with you and your 

colleagues to discuss a GRAS Notice for the use of bovine lactoferrin (Bioferrin®) in term infant 

formula and toddler foods. This request is in accordance with FDA’s guidance on pre-submission 

meetings intended to solicit FDA’s input on the draft GRAS document where FDA’s scientists, 

Glanbia Nutritionals, and EAS can discuss the draft document to obtain agreement on the 

sufficiency of the document before formally submitting the GRAS Notice to FDA.

The dates that we are proposing for this meeting are: August 27, August 28 and August 29. After the 

meeting date has been agreed upon, we will send you copies of the draft GRAS Notice for your use in 

preparation of our meeting. 

Bioferrin® is substantially equivalent to the bovine lactoferrin that was the basis of GRAS Notices 465 

and 669 for the same uses. We have relied heavily on the data and information in those documents to 

support this GRAS determination. 

Attending the meeting, in person,will the individuals listed below>

Glanbia

Noreen Hobayan, Director, Regulatory Affairs

Ankur Jhanwar, Senior Manager, Technical Services

Brent Peterson, Senior Director, Research and Development

Joe Milligan, Plant Manager, Richfield

Angela Walter, Senior Product Manager, Product Management

Second Science, Inc.

Jeanne Hoskins
EAS Consulting Group, LLC

Cathryn Sacra, Director Labeling and Cosmetics

Robin Guy, Independent Expert Consultant

Robert Martin, Independent Advisor, Food Additive Safety

Should you have questions regarding this request, please feel free to contact me. Thank you for your 

cooperation and prompt attention to this request.

Sincerely, 

Cathryn W. Sacra

Director, Labeling and Cosmetics
From: Cathryn Sacra

To: Morissette, Rachel

Cc: Robert Martin; Robin Guy

Subject: FW: GRAS Pre-submission Meeting Request

Date: Tuesday, September 18, 2018 1:07:47 PM

Attachments: image001.png

image007.png

image013.png

image019.png

image025.png

image031.png

image037.png

image043.png

Importance: High

Rachel,

The two main points that we would like FDA to consider are:

1. Compare the specifications in table II-14 and infrared spectra in figures II-3a - II-3f listed on pages

34-38 that show Bioferrin is identical to the bLfs that have been approved by FDA. 

2. That use levels up to 100 mg/L is safe for use in infant formula as established by the opinions of

other international regulatory bodies and FDA’s reviews of other bLf GRNs and is supported by the

draft GRAS dossier.

Thank you

Cathryn W. Sacra

Director of Labeling and Cosmetic Services

EAS Consulting Group, LLC

1700 Diagonal Road

Suite 750

Alexandria VA, 22314

877-327-9808 (toll free) +1 571-447-5500 (main) +1 571-447-5505 (direct) 703-548-3270 (fax)

csacra@easconsultinggroup.com

www.easconsultinggroup.com

From: Morissette, Rachel <Rachel.Morissette@fda.hhs.gov> 

Sent: Tuesday, September 18, 2018 8:10 AM

To: Cathryn Sacra <csacra@easconsultinggroup.com>

Subject: RE: GRAS Pre-submission Meeting Request

Thank you. Are there specific sections of the dossier that you would like to us to take a look at? We will

not be able to review the entire dossier at this time, but if there are specific questions that you have we

can try to address them at the meeting.

Best,

Rachel

From: Cathryn Sacra <csacra@easconsultinggroup.com> 
Sent: Monday, September 17, 2018 3:55 PM

To: Morissette, Rachel <Rachel.Morissette@fda.hhs.gov>

Subject: RE: GRAS Pre-submission Meeting Request

Dear Rachel,

I am attaching the dossier that is the subject of the pre-submission meeting on Wednesday. I will

follow with the slide deck. 

Best regards,

Cathryn

Cathryn W. Sacra

Director of Labeling and Cosmetic Services

EAS Consulting Group, LLC

1700 Diagonal Road

Suite 750

Alexandria VA, 22314

877-327-9808 (toll free) +1 571-447-5500 (main) +1 571-447-5505 (direct) 703-548-3270 (fax)

csacra@easconsultinggroup.com

www.easconsultinggroup.com

From: Morissette, Rachel <Rachel.Morissette@fda.hhs.gov>

Sent: Monday, September 17, 2018 1:15 PM

To: Cathryn Sacra <csacra@easconsultinggroup.com>

Subject: RE: GRAS Pre-submission Meeting Request

You’re welcome!

Rachel

-------------------------------------------------------------

Rachel Morissette, Ph.D.

Consumer Safety Officer

Center for Food Safety and Applied Nutrition

Office of Food Additive Safety

U.S. Food and Drug Administration

rachel.morissette@fda.hhs.gov

From: Cathryn Sacra <csacra@easconsultinggroup.com> 

Sent: Monday, September 17, 2018 1:14 PM

To: Morissette, Rachel <Rachel.Morissette@fda.hhs.gov>

Subject: RE: GRAS Pre-submission Meeting Request
Thank you!

Cathryn W. Sacra

Director of Labeling and Cosmetic Services

EAS Consulting Group, LLC

1700 Diagonal Road

Suite 750

Alexandria VA, 22314

877-327-9808 (toll free) +1 571-447-5500 (main) +1 571-447-5505 (direct) 703-548-3270 (fax)

csacra@easconsultinggroup.com

www.easconsultinggroup.com

From: Morissette, Rachel <Rachel.Morissette@fda.hhs.gov>

Sent: Monday, September 17, 2018 1:12 PM

To: Cathryn Sacra <csacra@easconsultinggroup.com>

Subject: RE: GRAS Pre-submission Meeting Request

Ok, thanks. The official address of our campus is 5001 Campus Drive, College Park MD. However,

there’s two buildings on campus, and we are located in the smaller of the two. You might tell the Uber

driver to put in 4300 River Rd. as the address, because our building (University Station) is actually on

River Rd, not Campus Drive. The security entrance for the parking lots is located closer to our building

and is on River Rd, so I would suggest having the driver let you off at the security station and then letting

the guards direct you to the correct entrance of the building. Make sure they know you’re looking for

University Station and not the Wiley building. Unfortunately in the past, the guards have directed some

visitors to the larger Wiley building by mistake and then they had to walk all the way back. My desk

number is 240-402-1212 if you have any issues.

Best,

Rachel

-------------------------------------------------------------

Rachel Morissette, Ph.D.

Consumer Safety Officer

Center for Food Safety and Applied Nutrition

Office of Food Additive Safety

U.S. Food and Drug Administration

rachel.morissette@fda.hhs.gov

From: Cathryn Sacra <csacra@easconsultinggroup.com> 

Sent: Monday, September 17, 2018 1:03 PM

To: Morissette, Rachel <Rachel.Morissette@fda.hhs.gov>

Subject: RE: GRAS Pre-submission Meeting Request
Thank you. At the moment, we are planning on Uber, but if that changes, I will send the

information. As Dr. Martin will not be able to attend, do you have any additional information on the

address? I confess I was counting on Bob to get us there as he knows the location so well and I have

not been to your offices.

Thank you

Cathryn W. Sacra

Director of Labeling and Cosmetic Services

EAS Consulting Group, LLC

1700 Diagonal Road

Suite 750

Alexandria VA, 22314

877-327-9808 (toll free) +1 571-447-5500 (main) +1 571-447-5505 (direct) 703-548-3270 (fax)

csacra@easconsultinggroup.com

www.easconsultinggroup.com

From: Morissette, Rachel <Rachel.Morissette@fda.hhs.gov>

Sent: Monday, September 17, 2018 1:00 PM

To: Cathryn Sacra <csacra@easconsultinggroup.com>

Subject: RE: GRAS Pre-submission Meeting Request

Hi Cathryn,

Thanks for the update. Just a reminder to send the make, model, and license numbers of any vehicles

that will be parking on site at least an hour before the start of the meeting so we can get that info to the

security office.

Thanks,

Rachel

-------------------------------------------------------------

Rachel Morissette, Ph.D.

Consumer Safety Officer

Center for Food Safety and Applied Nutrition

Office of Food Additive Safety

U.S. Food and Drug Administration

rachel.morissette@fda.hhs.gov

From: Cathryn Sacra <csacra@easconsultinggroup.com> 

Sent: Monday, September 17, 2018 12:49 PM

To: Morissette, Rachel <Rachel.Morissette@fda.hhs.gov>

Subject: FW: GRAS Pre-submission Meeting Request
Dear Rachel,

I have updated our attendee list for our meeting on Wed, September 19 at 11:00. Dr. Martin is

unable to attend the meeting because of a death in his family. I will be sending a copy of the dossier

and our slide deck later this afternoon.

Glanbia:

Peter Budde, Senior Director, Product Management

Angela Walter, Senior Product Manager, Product Management

Noreen Hobayan, Director, Regulatory Affairs

Ankur Jhanwar, Senior Manager, Technical Services (Foreign National – from India)

Brent Peterson, Senior Director, Research and Development

Joe Milligan, Plant Manager, Richfield

EAS Consulting Group:

Robin Guy, Expert Consultant

Cathryn Sacra, Director, Labeling and Cosmetics

Best regards,

Cathryn

Cathryn W. Sacra

Director of Labeling and Cosmetic Services

EAS Consulting Group, LLC

1700 Diagonal Road

Suite 750

Alexandria VA, 22314

877-327-9808 (toll free) +1 571-447-5500 (main) +1 571-447-5505 (direct) 703-548-3270 (fax)

csacra@easconsultinggroup.com

www.easconsultinggroup.com

From: Cathryn Sacra 

Sent: Thursday, August 23, 2018 3:18 PM

To: Morissette, Rachel <Rachel.Morissette@fda.hhs.gov>

Subject: RE: GRAS Pre-submission Meeting Request

Dear Rachel,

Thank you for confirming the date. We look forward to the meeting. We will have a slide

presentation and will forward them to you when they are completed. Please let me know if I can
forward them as an attachment in an email. The attendees are listed below and will be participating

in person. There is one foreign national attending. Please let me know what additional information

you will need from him.

Glanbia:

Peter Budde, Senior Director, Product Management

Angela Walter, Senior Product Manager, Product Management

Noreen Hobayan, Director, Regulatory Affairs

Ankur Jhanwar, Senior Manager, Technical Services (Foreign National – from India)

Brent Peterson, Senior Director, Research and Development

Joe Milligan, Plant Manager, Richfield

EAS Consulting Group:

Robin Guy, Expert Consultant

Cathryn Sacra, Director, Labeling and Cosmetics

Cathryn W. Sacra

Director of Labeling and Cosmetic Services

EAS Consulting Group, LLC

1700 Diagonal Road

Suite 750

Alexandria VA, 22314

877-327-9808 (toll free) +1 571-447-5500 (main) +1 571-447-5505 (direct) 703-548-3270 (fax)

csacra@easconsultinggroup.com

www.easconsultinggroup.com

From: Morissette, Rachel <Rachel.Morissette@fda.hhs.gov> 

Sent: Monday, August 20, 2018 2:09 PM

To: Cathryn Sacra <csacra@easconsultinggroup.com>

Subject: RE: GRAS Pre-submission Meeting Request

Dear Cathryn,

Thank you for your email. I scheduled your meeting for Wednesday Sept. 19, 2018 from 11 am -12 pm

EST. I just have a few questions for you below.

1. How many people will be attending the meeting? Please provide their names and affiliations.

2. Will you or others be attending in person or will you require a WebEx remote meeting access?

3. Will any non-U.S. citizens be attending the meeting in person?
4. Will you be showing PowerPoint slides or require any other computer or technical

accommodations? If you are giving a presentation and would like to send the slides ahead of time,

I can circulate them to the review team. Please note that any materials provided to FDA prior to the

meeting may be releasable under the Freedom of Information Act. Therefore, please do not

provide any confidential or trade secret information in the materials you provide to us.

Best regards,

Rachel

-------------------------------------------------------------

Rachel Morissette, Ph.D.

Consumer Safety Officer

Center for Food Safety and Applied Nutrition

Office of Food Additive Safety

U.S. Food and Drug Administration

rachel.morissette@fda.hhs.gov

From: Cathryn Sacra [mailto:csacra@easconsultinggroup.com]

Sent: Monday, August 20, 2018 1:42 PM

To: Morissette, Rachel <Rachel.Morissette@fda.hhs.gov>

Subject: RE: GRAS Pre-submission Meeting Request

Dear Rachel,

I apologize for the delay in responding as I was waiting for several people to respond on available

dates. 

We would like to request a meeting on September 18, 19th or 20th.

Best regards,

Cathryn

Cathryn W. Sacra

Director of Labeling and Cosmetic Services

EAS Consulting Group, LLC

1700 Diagonal Road

Suite 750

Alexandria VA, 22314

877-327-9808 (toll free) +1 571-447-5500 (main) +1 571-447-5505 (direct) 703-548-3270 (fax)

csacra@easconsultinggroup.com

www.easconsultinggroup.com
From: Morissette, Rachel <Rachel.Morissette@fda.hhs.gov> 

Sent: Monday, August 20, 2018 9:16 AM

To: Cathryn Sacra <csacra@easconsultinggroup.com>

Subject: RE: GRAS Pre-submission Meeting Request

Dear Cathryn,

I’m following up on my email from last Monday. Are you still interested in scheduling a pre-submission

meeting?

Best regards,

Rachel

-------------------------------------------------------------

Rachel Morissette, Ph.D.

Consumer Safety Officer

Center for Food Safety and Applied Nutrition

Office of Food Additive Safety

U.S. Food and Drug Administration

rachel.morissette@fda.hhs.gov

From: Morissette, Rachel

Sent: Monday, August 13, 2018 3:03 PM

To: 'Cathryn Sacra' <csacra@easconsultinggroup.com>

Subject: RE: GRAS Pre-submission Meeting Request

Dear Cathryn,

Thank you for your request. Unfortunately, we will not be able to accommodate the dates that you

requested in your letter. Please provide three potential alternate dates and times starting in September or

October that might also work, and I will try to accommodate your schedule as best as possible.

Best regards,

Rachel

-------------------------------------------------------------

Rachel Morissette, Ph.D.

Consumer Safety Officer

Center for Food Safety and Applied Nutrition

Office of Food Additive Safety

U.S. Food and Drug Administration

rachel.morissette@fda.hhs.gov
From: Cathryn Sacra

To: Morissette, Rachel

Subject: RE: pre-sub meeting memo on bovine lactoferrin

Date: Wednesday, October 10, 2018 5:13:26 PM

Attachments: image007.png

Glanbia - Memorandum of Meeting with CFSAN FINAL 10-10-2018.docx.pdf

Rachel,

Thank you for the update. In the meantime, we have put together a Memorandum of Meeting with

our understanding of the issues that were raised in the meeting, which I have attached. Please let

me know if you or the team have any comments or questions.

Best regards,

Cathryn

Cathryn W. Sacra

Director of Labeling and Cosmetic Services

EAS Consulting Group, LLC

1700 Diagonal Road

Suite 750

Alexandria VA, 22314

877-327-9808 (toll free) +1 571-447-5500 (main) +1 571-447-5505 (direct) 703-548-3270 (fax)

csacra@easconsultinggroup.com

www.easconsultinggroup.com

From: Morissette, Rachel <Rachel.Morissette@fda.hhs.gov> 

Sent: Thursday, October 04, 2018 9:15 AM

To: Cathryn Sacra <csacra@easconsultinggroup.com>

Subject: pre-sub meeting memo on bovine lactoferrin

Hi Cathryn,

I just wanted to let you know that I haven’t forgotten about sending you the meeting memo. We’re waiting

on a staff member to weigh in on the memo before I can finalize and send it to you. Hopefully within the

next week or so I should have it to you.

Best,

Rachel

-------------------------------------------------------------

Rachel Morissette, Ph.D.

Consumer Safety Officer

Center for Food Safety and Applied Nutrition

Office of Food Additive Safety

U.S. Food and Drug Administration

rachel.morissette@fda.hhs.gov
Memorandum of Meeting

On Wednesday, September 19, 2018, representatives from Glanbia Nutritionals and EAS Consulting 

Group met with officials from CFSAN to discuss a draft GRAS notice for the use of bovine lactoferrin 

(bLf) in infant formula and toddler foods. The meeting took place at the CFSAN Office of Food Additive 

Safety, College Park, MD from 11:00 a.m. – 12 noon. The individuals attending the meeting are listed 

below.

Visitors

Glanbia Nutritionals 

Angela Walter, Senior Product Manager, Lactoferrin

Noreen Hobayan, Director of Quality Assurance, Specialties

Peter Budde, Senior Director Product Management, Lactoferrin

Brent Peterson, Senior Director, Ingredient/Bioactives R&D

Ankur Jhanwar, Senior Technical Services Manager

EAS Consulting Group

Cathryn Sacra, Director of Labeling and Cosmetic Services

Robin Guy, MS, DABT, RQAP-GLP

CFSAN Attendees

NOTE: A sign-in sheet was maintained. Regrettably, we did not get a copy of the sign-in sheet. Based 

on the introductions, we understood that the CFSAN representatives were from OFAS and the Infant 

Formula Group.

After introductions of the meeting attendees, Ms. Hobayan thanked the CFSAN representatives for 

arranging this meeting to allow Glanbia Nutritionals (Glanbia) and EAS to discuss their draft GRAS 

Notice for its use in infant formula and toddler foods and to seek advice and input from CFSAN as

Glanbia planned to go forward on this project. This was followed by a brief introduction of Glanbia by 

Ms. Hobayan. Glanbia’s bLf (Bioferrin) was then discussed by Glanbia and EAS representatives to 

include: its formula, regulatory status, chemistry, exposure, and safety information. 

The meeting revolved around a PowerPoint presentation prepared by Glanbia and EAS that had been 

submitted to CFSAN in advance of the meeting. In advance of the meeting, Glanbia and EAS had 

indicated to CFSAN that there were two questions that they hoped to resolve and confirm at the meeting: 

1. Bioferrin is substantially equivalent to the bovine Lf’s that were previously reviewed by FDA for use 

in IF. Comparison of the specifications in table II-14 and infrared spectra in figures II-3a - II-3f listed on 

pages 34-38 of the draft GRN establish that Bioferrin is identical to the bLfs that have been approved by 

FDA.
2. That use levels up to 1000 mg/L is safe for use in infant formula as established by the opinions of 

other international regulatory bodies and FDA’s reviews of other bLf GRNs and is supported by the draft 

GRAS dossier.

There was good discussion related to the product. The CFSAN representatives essentially agreed that 

Bioferrin is equivalent to the bLfs that FDA had previously evaluated. Among the questions/issues raised 

by an OFAS toxicologist were:

x The FDA Toxicologist stated that the Agency has changed the way that they consider GRAS 

since GRN 669 for bioactive molecules. The Toxicologist stated that they want to make sure that 

there is a reasonable certainty of no harm, especially since this is for infants who inherently have 

an underdeveloped immune system. We note that Bioferrin in this GRN is intended for use in 

term infants who are presumed to be healthy at birth. Clarification is needed as to exactly what 

the toxicologist was referring to here.

x Most of the studies conducted have specific normal toxicological endpoints, especially with the 

studies conducted in adult rats. He implied that he didn’t know how these types of studies would 

be appropriate with regard to infant endpoints. He stated that he had not read the dossier; 

however, since the clinical trials were set up to address specific endpoints, we need to address 

how this relates to the infant, and how does this effect the preterm and VLBW infants. Again, as 

noted above, this is confusing as the GRN use is intended for term infants and not VLBW infants 

or premature infants, etc.

x He stated that even if EFSA found this use to be okay, we don’t know if they did the correct 

evaluations. 

x He wants the GRAS document to address:

The functionality of the protein

Intended population

Studies not looking at more subtle safety endpoints such as immunological effects.

As this was not clear to us, it was suggested that we contact the toxicologist and request any pertinent 

references that may have led to his concerns in this area.

The meeting ended at 12 noon. The visitors thanked the CFSAN representatives for their input.

Cathryn W. Sacra

Director, Labeling and Cosmetics

EAS Consulting Group

Agenda

• Introduce Participants

– Glanbia

– EAS

– FDA

• Introduction to Glanbia Nutritionals

• General Introduction and Overview

2
Agenda (continued)

• Dossier Highlights

– Bioferrin® Background Information

– Dietary Exposure

– Self Limiting Levels of Use

– Regulatory Assessments 

– Current Uses

– Safety Related Information

• Summary and Conclusions

3
Participants

4

• Glanbia Nutritionals

• Angela Walter

• Noreen Hobayan

• Brent Peterson

• Ankur Jhanwar

• Peter Budde

• EAS Consulting

• Edward Steele

• Robert Martin

• Robin Guy

FDA/CFSAN/OFAS


General Introduction

• The name of the substance under consideration is 

bovine lactoferrin (bLf) also referred to as 

lactotransferrin. The tradename for Glanbia’s bLf is 

Bioferrin®.

• The purpose of this notice is to substantiate the GRAS 

determination for Glanbia’s bovine lactoferrin (bLf) at 

intended use levels up to 1 g/L (1000 mg/L) in infant or 

toddler formula.

• The statutory basis for this GRAS determination is 

scientific procedures in accordance with 21 CFR 107.30 

(a) and (b).

7

Overview

• Lactoferrin is present at levels ranging from 1-3 g/L in human breast milk to 6-7

g/L in colostrum (Montagne et al., 2001).

• Bovine lactoferrin is approved in the EU at maximum use level in infant formula 

at 1g/L (Annex II of 2012/725/EU) after EFSA safety assessment (17 July 2012).

• Per the Food Safety Authority of Ireland, Glanbia’s Bioferrin® is substantially 

equivalent to bLf authorized to Morinaga (2012/725/EU), the latter of which is 

GRAS in US (GRN 465) .

• Currently in US, bLf is GRAS at less than the approved EU level (GRAS Notices 

GRN 465 [Morinaga 2014]) - at 130 mg/L); and GRN 669 (Synlait 2017) - at 130-

140 mg/L infant formula.

• There is history of use of lactoferrin in US infant formula at levels exceeding the 

current US GRAS levels e.g., Mead Johnson’s ENSPIRE infant formula in US has 

lactoferrin at 600 mg/L.

• This GRAS notice is for Glanbia’s bLf at intended use levels up to 1 g/L (1000 

mg/L) in infant or toddler formula. 

• This GRAS notice gives examples of growth and safety and other clinical data in 

infants up to 1g/L in infant formula.

9
Background Information

• Bioferrin is bovine lactoferrin (bLf) which occurs naturally in cows’ milk.

• Bovine lactoferrin, manufactured by various processes and manufacturers, 

has previously been determined to be GRAS for specific uses including 

infant formula.

GRN NO. SUBSTANCE CLOSURE DATE APPLICANT PURPOSE / USE

669 Bovine milk-derived 

lactoferrin Mar 9, 2017 Synlait Milk Ltd

New Zealand

For use as an ingredient 130-140 mg/L infant formula 

(ready-to-feed (RTF) or prepared for consumption from 

powder or liquid concentrate and in follow-on formula at 

a level of 150 mg/L RTF or prepared for consumption 

from powder.

465 Cow’s milk-derived 

lactoferrin Feb 18, 2014 Morinaga Milk Industry Co. Ltd

For use as an ingredient at a level of 130 mg/L of 

formula (ready-to-feed or prepared for consumption from 

powder or liquid concentrate)

464 Cow’s milk-derived 

lactoferrin Feb 18, 2014 Morinaga Milk Industry Co. Ltd

For use as an ingredient in cow’s milk-based products 

[yogurts (100 milligrams (mg) per 100 grams (g)), 

powdered milk (400 mg/100 g), and milk-based frozen 

desserts (200 mg/100 g)] and in chewing gum (30 mg/g)

77 Milk-derived lactoferrin Aug 14, 2001 DMV International Sports and functional foods at 100mg / serving

10
Property Typical Value Method 

Moisture less than 4.5 % AOAC 927.05 

17th Ed.

Ash less than 1.5 % AOAC 945.46 

Gravimetric

Arsenic less than 2 mg/kg EPA 7010 GFAA

Iron less than 350 mg/kg Glanbia Method

Protein

of which is

bLf

other proteins

>93 %

>95 %

< 5 %

SMEDP 17th Ed., 

Chapter 15 Ion 

Exchange –

Glanbia Method

pH (2 % solution, 20 °C) 5.2 to 7.2 pH Meter

Solubility (2 % solution, 20 °C) complete Glanbia Method 

Identity

• bLf is an iron-binding glycoprotein of approximately 77 kDa and consists 

of a single polypeptide chain of 689 amino acids.

• It is isolated from cow’s milk whey via ion exchange and subsequent 

ultra-filtration steps. Finally it is dried by spraying and large particles are 

sieved out.

Physical-chemical properties of bovine lactoferrin

11
Property Value Reference

Molecular Mass (Da)

Sedimentation co-efficient (aqueous) 77,100 ± 1,500 Castellino et al. (1970) 

SDS-Page 76,400 ± 2,400 Castellino et al. (1970) 

Iron Titration 78,000 Aisen and Leibman (1972)

Isoelectric Point (pH)

Chromatofocusing 8.2-8.9 Shimazaki et al. (1993) 

Isoelectric focusing 9.5-10.0 Yoshida and Xiuyun (1991)

Absorption Spectra Aisen and Leibman (1972)

Apo-form at 280 nm 12.7

Holo-form at 470 nm 0.400

Protease sensitivity Relatively low Brines and Brock (1983)

Iron-binding Aisen and Leibman (1972)

Equilibrium dialysis (K1 x 10-4) 3.73

Thermal Denaturation Paulsson et al. (1993) 

Apo-Lf denaturation (Tmax: °C) 71 ± 0.3 and 90 ± 0.3

Apo-/I HQWKDOS\ ǻ+cal: J/g) 12 ± 0.4 and 2 ± 0.5

Holo-Lf denaturation (Tmax: °C) 65 ± 0.3 and 93 ± 0.3

Holo-/I HQWKDOS\ ǻ+cal: J/g) 2 ± 1 and 37 ± 1

• Bovine lactoferrin is well characterized. Chemical Abstracts Service Registry Number (CAS Reg. 

No.) 146897-68-9 is a 689 amino acid glycoprotein, with five potential glycosylation sites (Mead 

and Tweedie, 1990; Pierce et al., 1991). 

• It contains N-glycosidically-linked glycans possessing N-acetylneuraminic acid, galactose, 

mannose, fructose, N-acetylglucosamine, and N-acetylgalactosamine (Coddeville et al., 1992). 

The generally accepted physical and chemical properties of bLf are outlined in Table 2 (GRN 669, 

page 000026)).

Identity

Physical and Chemical Properties of Bovine Lactoferrin 

12
(b) (4)
Bioferrin® bLf FTIR

14


Dietary Exposure

• The highest concentration of human lactoferrin (hLf) is found 

in milk and colostrum (5-7 g/L) (Trend et al., 2016; Rodriguez 

et al., 2005). 

• Mean hLf concentration in breast milk of mothers of VLBW 

infants at various time points in the lactation cycle were 

determined (n=104 to 277): colostrum: 14.92 g/L, milk at one 

month of lactation: 10.34 g/L, milk at two months of lactation: 

8.52 g/L (Turin et al., 2017). 

• The purpose of this notice is to provide to the FDA the 

determination of GRAS of Bioferrin® bLf for use in infant 

formula and toddler formula in the U.S. at levels of use up 

to 1 g /L.

17
Bioferrin® Exposure

Estimated Daily Intake (EDI) of bLf from proposed use of 1g/L in Infant Formula and Toddler 

Formulas 

Age Group

bLf Intake of added bLf4

mg/day mg/kg bw/day

Mean 90th Percentile Mean

90th Percentile

0 - 6 months1 1023 1484 179 269

7 - 12 months2 963 1420 111 162

13-36 months3 770 1373 92 152

1. Formula fed infants (all-user) 0-6 months consumed an average of 799.1 g of formula per day (129.1 g/kg/BW/day; 6.3 kg BW) and 1220.0 g/d

(203.3 g/kg/BW/d; 6.0 kg BW) for heavy users (90th percentile) as calculated using data from U.S. NHANES 2007-2008 survey and cited in

GRN 669, Pages 57-58.

2. Formula fed infants (all-user) 7-12 months consumed an average of 679.7 g of formula per day (76.7 g/kg/BW/day; 8.9 kg BW) and 1021.8 g/d

(114.8 g/kg/BW/d; 8.9 kg BW) for heavy users (90th percentile) as calculated using data from U.S. NHANES 2007-2008 survey and cited in

GRN 669, Pages 57-58.

3. Toddlers aged between 13 to 35 months old consumed an average of 621.5 g of formula per day (62.4 g/kg/BW/day; 10 kg BW) and 915.0 g/d

(100.6 g/kg/BW/d; 9.1 kg BW) for heavy users (90th percentile) as calculated using data from U.S. NHANES 2007-2008 survey and cited in

GRN 669, Pages 57-58. However, for these numbers (13-36 months), intake estimates may not be statistically reliable, as the sample size

was very low.

4. The concentration of bLf used in these calculations is 1 g/L in reconstituted infant or toddler formula

18
• The intended use of bLf in infant formula is driven by the intent to 

closely align the protein composition of the formulas to that of human 

milk.

– The amount of protein in infant formula is strictly regulated by the Infant Formula Act in 

the U.S. and is codified at 21 CFR 107.100. 

– Global recommended CODEX standards also restrict the level of protein in infant 

formula. 

– The amino acid profile of bLf is lower in histidine, isoleucine, methionine, phenylalanine, 

tryptophan and tyrosine to meet the protein quality requirements for infant formula and 

must be supplemented with other proteins.

• The total maximum protein level permitted and the protein quality as 

determined by the amino acid profile, are self-limiting factors for the 

potential maximum level of use of bLf in formula.

Self-limiting Levels of Use 

19
Global Regulatory Assessments

GOVERNMENTAL AUTHORITY YEAR LEVEL /CONDITIONS OF APPROVAL

Standardization Administration of China -

Guobiao (SAC) 2017 100 mg/100g in infant formula

Singapore 2015 1 g/L ready to feed infant formula

Food Safety Authority of Ireland (FSAI) 2013 Determined that Bioferrin® was substantially equivalent to 

Morinaga’s bLf at this level

EU 2012 1 g/L ready to feed infant formula

Japan 1986 No limit

Taiwan 2000 As practically needed in infant formula

South Korea Food additive for infant and follow on formula

20
Comparison of Bovine Lactoferrin

Regulatory & Company Specifications

PARAMETER Glanbia

European 

Union 

(European

Commission, 

2012a, 2012b)

Peoples Republic 

of China Synlait Milk Ltd.

Morinaga

(GRN 465, 2014,

pp. 28-29 (pdf))

Friesland Campina 

(EFSA Panel on Dietetic 

Products Nutrition and 

Allergies (NDA), 2012, p. 

8)

PHYSICAL AND CHEMICAL PARAMETERS

DESCRIPTION

Virtually

odorless, light 

pinkish 

powder

Pale pink to reddish 

brown powder Pink to tan powder

Pink, 

odorless 

powder

PROTEIN

OF WHICH 

BOVINE LACTOFERRIN 

OTHER PROTEINS

> 93.0%

> 95.0%

< 5.0%

93.0%

90.0%

95.0%

95.0%

94.5%

96.0%

93.0%

95.0%

MOISTURE (LOSS ON 

DRYING) <4.5% <4.5% < 4.5% <4.2% < 4.5%

ASH < 1.5% < l.5% < 1.3% < 1.3% < 1.0%

ARSENIC <2 mg/kg < 1 mg/kg < 0.02 mg/kg <1 mg/kg <1 mg/kg (total heavy

metals)

IRON < 350 mg/kg < 350 mg/kg < 200 mg/kg < 350 mg/kg 100 - 160 mg/kg

IRON SATURATION < 25% < 25% < 20% < 25% < 11%

pH (2% SOLUTION, 20°C) 5.2 to 7.2 5.2 to 7.2 5.2 to 7.2 5.2 to 7.2 5.5 - 6.5

SOLUBILITY 

(2% SOLUTION, 20°C) Complete Complete, 

transparent

Complete, 

transparent

80% transmission, 

Complete

80 - 100% transmission, 

Complete

21

(b) (4)
22

PARAMETER Glanbia

European Union 

(European 

Commission,

2012a, 2012b)

Peoples Republic 

of China Synlait Milk Ltd.

Morinaga 

(GRN 465, 2014, 

pp. 28-29 (pet))

Friesland Campina 

(EFSA Panel on 

Dietetic Products 

Nutrition and 

Allergies (NDA), 

2012, p. 8)

MICROBIOLOGICAL

TOTAL STANDARD 

PLATE COUNT <1000 cfu/g < 1000 cfu/g < 1000 cfu/g < 1000 cfu/g

YEASTS & MOLDS <10 cfu/g < 10 cfu/g < 10 cfu/g < 10 cfu/g < 10 cfu/g

COLIFORMS <10 cfu/g < 3 MPN/g ND / g Negative / 0.1 g ND

SALMONELLA ND / 25 g ND / 250 g Negative / 25 g Negative in 10 g

STAPHYLOCOCCUS 

AUREUS

(COAGULASE 

POSITIVE)

Neg in 1 g ND / 25 g ND / g Negative / g Negative in 1 g

cfu = colony forming unit; MPN = mean probable number; ND= Not Detected

Comparison of Bovine Lactoferrin

Regulatory & Company Specifications

(b) (4)
Current Uses and Levels (EU)

FOOD CATEGORY MAXIMUM USE LEVELS OF bLf

INFANT FORMULAE AND FOLLOW ON FORMULAE (READY TO DRINK) 1 g/ L

FOODS ON DAIRY BASIS INTENDED FOR YOUNG CHILDREN (READY TO 

EAT/DRINK) 200 mg/100 g

PROCESSED CEREAL FOOD (SOLID) 670 mg/100 g

FOODS FOR SPECIAL MEDICAL PURPOSES Depending on individual needs - up to 3 g/day

BEVERAGES BASED ON MILK 200 mg/100 g

POWDERED DRINK MIXES BASED ON MILK (READY TO DRINK) 330 mg/100 g

BEVERAGES BASED ON FERMENTED MILK (INCLUDING 

YOGHURT DRINKS) 50 mg/100 g

NON-ALCOHOLIC DRINKS 120 mg/100 g

PRODUCTS BASED ON YOGHURT 80 mg/100 g

PRODUCTS BASED ON CHEESE 2000 mg/100 g

ICE CREAM 130 mg/100 g

CAKES AND PASTRIES 1000 mg/100 g

CANDIES 750 mg/100 g

CHEWING GUM 3000 mg/100 g

23
• Both acute and sub-chronic (4-week and 13-week) oral 

toxicological studies in rats indicate that bLf is safe for 

consumption, with a no observed adverse effects level 

(NOAEL) of 2000 mg/kg and does not result in treatmentrelated adverse effects or significant changes in clinical 

measures. 

• Chronic oral toxicity was evaluated in 40 and 65-week feeding 

studies containing bLf at 0.2% of diet and up to 5% of the diet 

respectively. No significant treatment related effects were 

reported in either study, however the studies could not be 

used to establish a NOAEL.

• No potential mutagenicity of bLf was determined based on 

the Ames test. 

Toxicological Studies

24
• Cow’s milk allergy (CMA) is a hypersensitivity reaction 

initiated by immunologic mechanisms in response to 

bovine proteins. In most children it is IgE-mediated. 

• Currently there is no evidence to support a role for 

lactoferrin as a causative agent in CMA. 

• The intended uses of bLf are in milk-based formula 

which by law require labeling for the major allergen, 

milk protein of which bLf is a minor fraction.

Allergenicity

25
• A significant body of evidence supports the safety of bLf for infants. 

• In the 36 clinical trials identified in infants (from preterm and term at birth – 12 months) and in 

children (>12 months) and involving approximately 4000 participants, no adverse events related to 

the administration of bLf have been reported. 

• Studies consistently report that the use of bLf is well tolerated. These studies include a wide range 

of exposure to bLf levels from 9.75 mg/kg BW/day (Kawaguchi et al., 1986) to 200 mg/kg BW/day 

(Ochoa et al., 2015) in preterm and VLBW infants; 36 mg/day (Chen et al., 2016) to 2300 mg/day 

(Balmer et al., 1989) in term infants; and 100 mg/day (Egashira et al., 2007) to 3000 mg/day (Zuccotti 

et al., 2009) in children. 

• The range in amounts of bLf safely consumed and tolerated in these studies is higher that the 

maximum predicted EDI’s of bLf subject to this notification (mean 1023 mg/day or 179 mg/kg 

BW/day, 90th percentile 1484 mg/day or 269 mg/kg/BW /day, Table III-4) in term infants aged 0 - 6 

months 

• Most of the studies in preterm and/ or VLBW infants are typically targeted toward the reduction in 

incidence or duration of LOS, NEC or other infective conditions to which this highly vulnerable 

population is especially prone. The studies confirm the safe consumption and tolerance of bLf in 

these infants, and suggest that bLf affords a degree of protection from infection but not necessarily 

colonization by pathogenic species (Manzoni, 2016). 

Bovine Lactoferrin Human Studies 

involving Infants & Toddlers

26
• The safety and tolerance of bLf for term infants has recently been specifically addressed in the 

study by Johnston et al. (2015) who investigated the use of bLf in term formulas at levels of 0.6 g/L 

and 1.0 g/L, the later is equal to the level of bLf added to term formula that is the intended use of this 

notification. The study concluded that bLf, together with other functional ingredients, added to 

formula was safe, well tolerated and associated with normal infant growth. This is supported by a 

number of other studies, that have also looked at potential benefits of bLf added to term formula. 

• Formula supplemented with bLf may decrease the burden of respiratory (King et al., 2007) and 

gastrointestinal (Chen et al., 2016; Ochoa et al., 2013) morbidity in term infants (Manzoni, 2016). A 

number of studies have considered the role of bLf as an iron source, however there is little evidence 

to suggest it provides a more bioavailable source than that of elemental iron sources (Lönnerdal 

and Hernell, 1994), although there is some evidence to suggest bLf is involved in iron transport 

(Chierici et al., 1992).Other studies suggest bLf may modulate fecal flora (Liu etal., 2016; Roberts et 

al., 1992), and thereby provide indirectly a range of other developmental and health benefits to 

infants. 

• The potential of bLf to prevent or mitigate the severity of infections in toddlers and children has 

been investigated in a number of studies all of which have not reported any adverse treatment 

related effects. 

• In especially vulnerable immunocompromised children, high daily doses of bLf were well tolerated 

and no adverse treatment related effects were reported. 

• In conclusion, there are a substantial number of studies in infants and toddlers that provide 

convincing and consistent evidence for the safe consumption and tolerance of bLf for the intended 

use in infants and toddlers. 

Bovine Lactoferrin Human Studies 

Involving Infants & Toddlers

27
• Mead Johnson markets an IF product in the U.S. (ENSPIRE) that contains 

0.6 g/L (600 mg/L as fed); this level is higher than those noted for infant 

formula in GRN 465 and 669). 

• This infant formula has been commercialized in the U.S. since 2016 

without incident - see levels in 

https://www.meadjohnson.com/pediatrics/us-en/products/about-enfamilenspire.

• A Mead Johnson-sponsored large scale pediatric growth monitoring 

clinical study designed to evaluate growth and tolerance in healthy 

infants when fed study formulas with bLf within the range of mature 

human milk at 0.6 and 1 g/L demonstrated normal growth in healthy term 

infants through 365 days of age (Johnston et al., 2015).

• Additionally, in a double-blind placebo-controlled study of bLF in bottlefed infants, King et al. (2007) fed term infants an infant formula containing 

850 mg/L bLf for one year with “beneficial outcomes.” 

28

Bovine Lactoferrin Human Studies 

Involving Infants & Toddlers
Conclusions

• A significant body of evidence, including both animal and human exposure and safety data, 

supports the safe consumption of bLf.

– Both acute and sub-chronic (4-week and 13-week) oral toxicological studies in rats 

indicate that bLf is safe for consumption, with a no observed adverse effects level 

(NOAEL) of 2000 mg/kg and does not result in treatment-related adverse effects or 

significant changes in clinical measures. 

– In the 36 clinical trials identified in infants (from preterm and term at birth – 12 months) 

and in children (>12 months) and involving approximately 4000 participants, no 

adverse events related to the administration of bLf have been reported. 

• Infants are currently exposed to bLf with the consumption of cow's milk-based infant 

formulas. 

• When consuming cow's milk-based infant formulas as the sole source of nutrition the 

average daily exposure of infants 0 to 6 and 7 to 12 month old, and toddlers 13 to 36 months 

old is approximately 137, 120, and 104 mg/day, respectively. 

• With the consumption of bLf from the intended uses their average daily exposure will 

increase to mean daily intakes of 1023, 963, 770 mg/day (1484, 1420, and 1373 mg/day at 

90% percentile), respectively. 

• The proposed bLf use levels are equal to the levels approved for use in Europe 

and lower than the levels of lactoferrin in breast milk.

29
• Lactoferrin is present at levels ranging from 1-3 g/L in human breast milk to 6-7

g/L in colostrum (Montagne et al., 2001).

• bLf is approved in the EU at maximum use level in infant formula at 1000 mg/L 

(Annex II of 2012/725/EU) after EFSA safety assessment (17 July 2012).

• Per the Food Safety Authority of Ireland, Glanbia’s Bioferrin® is substantially 

equivalent to bLf authorized to Morinaga (2012/725/EU), the latter of which is 

GRAS in US (GRN 465) .

• Currently in US, bLf is GRAS at less than the approved EU level (GRAS Notices 

GRN 465 [Morinaga 2014]) - at 130 mg/L); and GRN 669 (Synlait 2017) - at 130-

140 mg/L infant formula.

• There is history of use of lactoferrin in US infant formula at levels exceeding the 

current US GRAS levels e.g., Mead Johnson’s ENSPIRE infant formula in US has 

lactoferrin at 600 mg/L.

• This GRAS notice is for Glanbia’s bLf at intended use levels up to 1 g/L (1000 

mg/L) in infant or toddler formula. 

• This GRAS notice gives examples of growth and safety and other clinical data in 

infants up to 1g/L in infant formula.

Conclusions (continued)

30
Overall Conclusion

The proposed use of bovine lactoferrrin (Bioferrin) as 

a food ingredient in term infant formula and toddler 

food, at a level of up to 1 g/L in reconstituted infant 

formula (equivalent to 770 mg/100 g formula solids 

when reconstituted at 130 g powder per liter) is safe 

and GRAS based on scientific procedures.

31
Questions?

32

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12

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