There is a saying in Washington D.C. that, when faced with a crisis, leaders take action so that the American public sees the seriousness of their intent to deal with the issue at hand.

In this case, the crisis involved infant formula—and a truly horrific crisis it was. Beginning in late 2021, several infants who consumed infant formula from powder became ill and, in some cases, tragically died. When traced to an alleged contamination issue, a voluntary recall and a shutdown of major infant formula manufacturing facilities resulted in a shortage of infant formula. The shortage started to subside in June 2022, and supply is now back to normal.

Nonetheless, some six months later, following the release of an internal review by the U.S. Food and Drug Administration (FDA) of its response to the infant formula crisis and shortage¹ and a December 2022 report by the Reagan-Udall Foundation² that was critical of the Agency's oversight of the U.S. food industry, FDA Commissioner Dr. Robert Califf proposed the creation of a unified Human Foods Program. The unified Program would replace the 40-year-old Center for Food Safety and Applied Nutrition (CFSAN) and create an Office of Food Policy and Response (OFPR), incorporating certain functions of the Office of Regulatory Affairs (ORA). James “Jim” Jones, one of the authors of the Reagan-Udall Foundation report and a former U.S. Environmental Protection Agency (EPA) administrator, was named as the first Deputy Commissioner for Human Foods. The Deputy Commissioner will report directly to the FDA Commissioner and oversee the reorganized Human Foods Program. Nothing like a good reorganization to resolve perceived institutional failure!

The Beginning of FDA's Oversight of Infant Formula

In fact, although the infant formula crisis may have heightened present-day attention to the need for a more secure and safe supply of infant formula, the advent of this crisis was not the beginning of FDA's focus on the safety and security of infant food. The U.S. Congress and the Agency began to focus on the unique requirements needed to ensure the safety of infant formula with the passage of the Infant Formula Act of 1980. The Act established minimum nutrient requirements, defined adulteration, provided for establishing nutrient and quality control procedures, prescribed recall procedures, and specified inspection requirements.³

Following implementation of this Act, setting the baseline for FDA's oversight of the infant formula industry to help assure the nutrient content and microbiological purity of the products, FDA took the next step in assuring the safety of infant formula with respect to the articles in which the product is packaged. In March 2010, FDA's Division of Food Contact Notifications (DFCN) formed a working group to consider potential exposure and safety issues related to chemical migration from packaging into infant foods (collectively, infant formula and human breast milk). The formation of the group was motivated by then-recent progress in the fields of infant biology and developmental toxicology and in juvenile toxicity testing paradigms, in addition to enhanced public awareness regarding the possible exposure to infants of chemicals used in food packaging.⁴

In 2014, the DFCN working group published, "Infant Toxicology: State of the Science and Considerations in Evaluation of Safety."⁵ In the article, the working group points out that the exposure pattern to food contact materials for this population is different than that which is used for the adult population. In particular, the authors stressed that since a single type of infant formula and/or breast milk can be (and often is) the sole source of nutrition for the first six months after birth, and since infants consume almost three times as much food per kilogram of bodyweight per day as compared to adults, there exists a potential for elevated exposure to food packaging migrants for infants during this period. Additionally, developing organ systems and the different physiological make-up of infants as compared to adults may alter (enhance or decrease) an infant's susceptibility to toxicants.

FDA Assessments of Packaging for Infant Formula

To account for differing exposure and potential for different toxicology data requirements, FDA began in 2009 to include restrictions in some new food contact notifications (FCNs) on the use of food contact substances (FCSs) in can coatings for infant applications and, by the fall of 2013, FDA expanded infant use restrictions to most, if not all, new FCNs. This included specifically mentioning infant formula under the "Limitations/Specifications" sections of new FCN listings.

Examples of language FDA included in the "Limitations/Specifications" section included:

• "The FCS is not intended for use in coatings in contact with infant formula."
• "Not for use in articles intended for contact with infant food (food for infants 0–6 months of age)."
• "The FCS may be used in repeated use articles intended for the feeding of infants (e.g., baby bottles and sippy cups). Not for use in infant formula packaging."

Also, FDA began using adjusted bodyweights and food consumption values when determining infant exposure to food contact materials. (This actually started as far back as 2010.) Speaking at Keller and Heckman's Annual Food Packaging Seminar on September 18, 2013, Dennis M. Keefe, Ph.D., then Director of FDA's Office of Food Additive

Safety (OFAS), stated that FDA was using a 6.3 kg bodyweight and a food intake level of 900 grams per day to calculate infant exposures.⁶

In June 2014, FDA issued a final rule on Current Good Manufacturing Practices, Quality Control Procedures, Quality Factors, Notification Requirements, and Records and Reports, for Infant Formula. This final rule affirmed certain changes made to FDA's regulations by the interim final rule of the same name published February 20, 2014 in the Federal Register.7 Among other things, the interim final rule added section 106.40 to Title 21 of the Code of Federal Regulations (CFR) to prevent adulteration of infant formula that could result from ingredients, containers, and closures. Specifically, 21 CFR Section 106.40(d) requires infant food manufacturers to develop written specifications for ingredients, containers, and closures and procedures to determine if the specifications are met.

FDA Formalizes Changes

In 2016, FDA issued a draft guidance regarding the preparation of FCNs for FCSs that are intended to contact infant food. This formally outlined the data and other scientific information that FDA recommended notifiers provide to support a determination that a substance intended for use in contact with infant food is safe. The draft guidance was finalized in 2019.⁸ In addition to materials used in packaging for infant food, the guidance applies to materials used to manufacture baby bottles, bottle inserts, and nipples. It contains detailed chemistry, toxicology, and administrative recommendations for preparing and submitting FCNs for these substances.

As I have discussed in previous articles, any substance used in food packaging materials that can be reasonably expected to become a component of food as a result of its intended use requires regulatory clearance by FDA through a food additive regulation or an FCN, unless it is the subject of an exemption. The safety standard for food additives, whether based on clearance through an FCN or a food additive regulation, is "reasonable certainty of no harm" or, as more precisely provided in FDA's regulations, "a reasonable certainty in the minds of competent scientists that the substance is not harmful under the intended conditions of use."⁹

FDA recently held two webinars on infant formula food ingredients and packaging requirements as part of its efforts to help improve the safety and resiliency of the U.S. infant formula supply in the aftermath of the aforementioned crisis. The second one, titled, "U.S. Regulation of Food Contact Substances and Considerations for

Infant Formula Packaging," featured a presentation by Jessica H. Urbelis, Ph.D., a Regulatory Review Scientist in DFCS. Dr. Urbelis explained that FDA's safety evaluation is based on evaluating consumer dietary exposure to an FCS and ensuring that dietary exposures are supported by the available toxicological information. She further explained that the acceptable daily intake (ADI) is equal to the estimated amount of a substance that may be consumed daily over a lifetime with a reasonable certainty of no harm. The estimated daily intake (EDI) is an estimate of the amount of an FCS that may be consumed daily by an individual from the intended uses.

The migration levels of the FCS into the food, along with information on how much of each food type will contact the food contact article, is used to determine consumer exposure. Since formula may be the sole source of nutrition for infants, FDA assumes that the food contact substance being assessed is contacting 100 percent of the diet for infants from birth to six months of age. This results in an infant exposure 70 times greater than an adult exposure for the same FCS during a similar period of time. Accordingly, the 2019 Guidance recommends using default values of 6.3 kg-bw/infant for infant bodyweight and 900 g formula/infant/day for infant food consumption when estimating exposure of FCSs that are intended to contact infant food; the same standard suggested by Dr. Keefe some six years earlier. To determine migration into powdered formula, the Guidance also recommends that testing be conducted with 50 percent ethanol, or a dry food simulant such as Tenax [Poly(2,6- diphenylphenylene oxide)], or other appropriate medium.¹⁰

Concerning baby bottles, the Guidance recommends that the estimate for the mass of food contacting a known surface area should take into account that baby bottles may be used multiple times a day and over a period of several months. Therefore, FDA determined that a food mass-to-surface area ratio of 1,400 g/in² is adequate to represent the mass of food that would contact a feeding bottle over its service life.

Infant Formula Notifications: Packaging Review

Dr. Urbelis also discussed the written specifications that are required for containers of infant food when submitting an Infant Formula Notification (INF). These include:

1. Summary of the packaging information or other food contact article, to include a list of components of the packaging or article
2. Identity and regulatory status information, to include certification that each component (e.g., can, can ends, liners, adhesives, lids, etc.) is authorized for that use; a declaration of compliance from manufacturers/suppliers; and a summary of any changes made from previously reviewed packaging, including information to support the change.

The packaging manufacturer's declaration may be submitted by the infant formula manufacturer or confidentially from packaging manufacturers, she explained.

An IFN is not an appropriate avenue to obtain an authorization for the use of an FCS, Dr. Urbelis cautioned. However, she further explained that an IFN submission may include packaging changes that do not involve a duplicative review of every material used in the packaging. These can include a change in an article used, such as a lid or can, and changes in components of an article, such as a resin or colorant. Supporting information for these types of changes should be in the form of:

• Declarations of compliance from manufacturers
• New identity information and regulatory status
• Scientific rationale for the change where applicable.

References to previous IFNs can be made for the other components, Dr. Urbelis added.

Conclusion

It is not yet clear where FDA's Division of Food Additive Safety will reside in the new Human Foods Program. Right now, it seems likely that it would fall under the Office of Food Chemical Safety, Dietary Supplements, and Innovation. Wherever it may reside, one can expect that the staff of this division will carry forward in the same rigorous manner of assuring the safety of infant formula and the materials used to package such products through the IFN process, as well as through the FCN and other premarket review programs. Sometimes, it is not the organizational structure that dictates success, but rather the availability of sufficient resources to allow FDA personnel to carry out their jobs.

References

1. U.S. Food and Drug Administration (FDA). "FDA Evaluation of Infant Formula Response, September 2022." https://www.fda.gov/media/161689/download
2. Reagan-Udall Foundation. "Operational Evaluation of the FDA Human Foods Program," December 2022. https://reaganudall.org/sites/default/files/2022-12/Human%20Foods%20Program%20Independent%20Expert%20Panel%20Final%20Report%20120622.pdf
3. Newberry, Raymond E. "Infant Formula Act of 1980." Journal of Association of Official Analytical Chemists 65, no. 6 (November 1982): 1472–1473.
4. "FDA Toxicologist Discusses Food-Contact Materials for Infants at Keller and Heckman Seminar." PackagingLaw.com. Keller and Heckman Annual Food Packaging Seminar, 2015.
5. Neal-Kluever, April, Jason Aungst, Yan Gu, et al. "Infant toxicology: State of the science and considerations in evaluation of safety." Food and Chemical Toxicology 70 (2014): 68–83. https://pubmed.ncbi.nlm.nih.gov/24824476/
6. "Submitters of Active FCNs Will Receive Objection Letters if the Government Shuts Down, FDA's Keefe Says at Keller and Heckman Conference." PackagingLaw.com. Keller and Heckman LLP.
7. FDA. Current Good Manufacturing Practices, Quality Control Procedures, Quality Factors, Notification Requirements, and Records and Reports, for Infant Formula. June 10, 2014. Federal Register. https://www.federalregister.gov/documents/2014/06/10/2014-13384/current-good-manufacturing-practices-quality-control-procedures-quality-factors-notification
8. FDA. Guidance for Industry: Preparation of Food Contact Notifications for Food Contact Substances in Contact with Infant Formula and/or Human Milk. May 2019. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-preparation-food-contact-notifications-food-contact-substances-contact-infant.
9. Code of Federal Regulations. 21 C.F.R. §170.3. "Definitions."
10. FDA. Guidance for Industry: Preparation of Premarket Submissions for Food Contact Substances (Chemistry Recommendations). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-preparation-premarket-submissions-food-contact-substances-chemistry#iid1c.Note: This Guidance continues to recommend the use of 10 percent ethanol as the simulant for oil-in-water dairy products (i.e., milk).

George G. Misko, Esq., is a Partner in the Washington, D.C., office of Keller and Heckman LLP.