1Introduction and Background

United States

Food products that are designed and marketed for infants are regulated under the Federal Food, Drug and Cosmetic (FD&C) Act of 1938 (21 U.S.C. §301) (Vanderveen, 1991). FDA, an agency in the U.S. Department of Health and Human Services (HHS), regulates infant formulas and evaluates the safety of food and color additives.

Two sections of the FD&C Act, 409 and 412, are the primary laws that relate to infant formulas. Section 409 gives authority to HHS to ensure the safety of new food ingredients (e.g., food additives and Generally Recognized as Safe [GRAS] substances) “under the conditions of its intended use” (e.g., in infant formulas). Manufacturers may propose the addition of new ingredients to infant formulas in the United States by either filing a Food Additive Petition with FDA to request a formal premarket review, or making a GRAS determination. It is important to point out that it is the use of the substance, rather than the substance itself, that is eligible for the GRAS determination (see Chapter 4).

Under Section 412 of the FD&C Act, regulations have been promulgated and ultimately implemented that are intended to ensure proper formulation for infants to thrive. They include:

• Infant Formula Quality Control Procedures (21 C.F.R. §106),
• Records and Reports Regulations (21 C.F.R. §106.100),
• Infant Formula Labeling Requirements (21 C.F.R. §107.10–107.30),
• Exempt Infant Formulas (21 C.F.R. §107.50),
• Nutrient Requirements for Infant Formulas (21 C.F.R. §107.100), and
• Infant Formula Recall Requirements (21 C.F.R. §107.200–107.280).

FDA (1996) has proposed to revise these regulations to establish quality factors, current good manufacturing practices, and revised quality control procedures. Table 1-1 lists some of the U.S., Canadian, and European Union laws and regulations related to adding new ingredients to infant formulas.

TABLE 1-1

Selected Laws and Regulations Related to New Ingredients Added to Infant Formulas.

Other Countries

European Union

The European Union also has regulations in place for food additives, novel foods, and genetically modified organisms. However the European regulations are not specific for adding new ingredients to infant formulas.

In June 2002 representatives of academia, the infant food industry, the European Commission, food regulatory bodies of some European Union member states, and consumer organizations met to discuss opportunities to evaluate the safety of ingredients new to infant formulas (Koletzko et al., 2002). Topics included consumer expectations, preclinical and clinical evaluations, investigations of infant growth and nutrient bioavailability, and in-market surveillance. The participants also discussed a position paper written by members of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition's Committee on Nutrition (Aggett et al., 2001). The paper provided 13 points for consideration for the evaluation of infant formulas; these points are presented in Box 1-1.

BOX 1-1

Key Points of the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition's Committee on Nutrition Commentary on the Nutritional and Safety Assessment of Breast Milk Substitutes and Other Dairy Products for Infants. Although human (more...)

Types of Ingredients

The committee focused on new potential ingredients and existing ingredient ratios that could be added to infant formulas to:

• impart potential health benefits within the first year of life, later in childhood, and perhaps even during adult life; and
• change color, extend shelf life, or modify marketing or manufacturing processes because they could potentially be associated with harmful short- or long-term effects.

Several compounds have been seriously considered for addition to formulas, but no final decision has been made about their addition for a variety of reasons. For example, cholesterol is present in human milk at levels higher than is present in cow's milk. A recent article reported that breastfed infants had lower total cholesterol and low-density lipoprotein cholesterol in adulthood and suggested that infant formulas should have added cholesterol to more closely match that of human milk (Owen et al., 2002). On the other hand, animal studies of formulas with added cholesterol found no evidence of any beneficial short- or long-term effects (LSRO, 1998). In addition, lysozyme and lactoferrin are also present in human milk at levels higher than in cow's milk. These factors may be important in growth or host defense and have been considered for addition to formulas (Lo and Kleinman, 1996). Many substances found in human milk have not been added to infant formulas, perhaps due to the lack of information on their function in human milk or their effect on the infant.

The committee proposes a functional classification of potential target areas of ingredients new to infant formulas, as summarized in Table 1-2, according to potential targeted endpoints. The committee also considered the types of molecules or ingredients that could be considered as new additives, including:

TABLE 1-2

Functional Classification of Potential Target Areas of New Ingredients.

• new sources of existing ingredients;
• prebiotics and probiotics;
• lipids;
• nitrogen-containing ingredients (e.g., recombinant proteins; single amino acids, such as glutamine, and immunoglobulins; and bioactive peptides/polyamines/proteins, such as lactoferrin, enzymes, and hormones);
• oligosaccharides;
• vitamins, minerals, and flavonoids;
• flavoring and coloring agents; and
• nonprotein recombinant-derived products.

However the committee did not simply consider molecules or new ingredients as isolated substances, it also considered three important characteristics: (1) the compound itself (the molecule), (2) the matrix in which it is delivered, and (3) its amount and ratio relative to other constituents in the infant formula. The committee also realized that certain potential new additions to infant formulas might be in the form of complex ingredients or biologicals (e.g., probiotics). Some of the recommended chemical, physical, and in vitro characterization steps might not apply to complex ingredients (see Chapter 5).

The committee also reviewed whether ingredients derived from genetically engineered techniques should have the same safety recommendations for use in infant formulas as compared with other classes of new ingredients. Even though compounds derived from genetic engineering techniques would have properties similar to those of natural compounds, they would still have to be tested. Similar to other ingredients, the short- and long-term unintended compositional changes that result directly or indirectly as a result of genetic engineering would need to be considered. In addition, the unintended functional consequences of a successful, specific intentional alteration would need to be considered and monitored over long time periods. Thus the committee recommends that standards for safety should be the same for ingredients derived from genetically engineered techniques as they are for other classes of ingredients. Guidelines should maintain emphasis on a “reasonable certainty of no harm” for all ingredients.

Safety Definitions

The committee reviewed other existing reports and guidelines, including those available from FDA and the Life Sciences Research office (LSRO), and it considered current recommendations relating to safety. While the committee recognized that its recommendations had to be targeted with safety as the ultimate objective, additions of ingredients new to infant formulas need to consider potential efficacy (i.e., health benefits) considerations.

The concept of “safety” refers to a reasonable certainty of no harm per the FD&C Act; to safe and adequate levels of nutrients, including essentiality, stability, history of use, and toxicity per LSRO; or, in some circumstances, a reasonable balance between costs (e.g., risks, harm) and benefits. Safety, therefore, is not an inherent biological property, but rather a point on a continuum that is influenced by intellectual concepts and judgment. Generally, a “hazard” refers to a substance or combination of substances that produce undesired outcomes; in the case of infant formulas, the undesired outcome is health related. “Risk” implies that an adverse event will be expressed under specified conditions, and “harm” refers to the nature of an undesired outcome associated with a hazard. Details about the concept of safety and surrounding issues are provided in Chapter 2.

Use of a Hierarchical Approach to Safety Assessment

The committee recognized that its charge was to provide comprehensive guidelines for evaluating the safety of the addition of ingredients new to infant formulas—not to produce a “how to” document. With this in mind, the committee discussed an initial outline and agreed that for each area it would review the existing systems, identify gaps or limitations of the systems, and make recommendations for revised guidelines. The committee also agreed on the concept of a hierarchical approach to determine levels of safety assessment needed for each ingredient.

To evaluate the safety of the addition of new ingredients to infant formulas, the committee proposes the use of a hierarchical approach, which involves matching the level of safety assessment with the degree of concern about the potential harm. Such an approach needs to be considered in terms of a new ingredient's potential: (1) harm (e.g., toxicity), and (2) adverse effects. This hierarchical approach will guide the levels of assessment applied depending on the nature and purpose of the new ingredient.

Considerations about the degree of concern and, therefore, about the level of safety assessment required would include: whether potential harmful effects of a new ingredient would be reversible or irreversible, the severity of the effect, and the consequences. For example, levels of safety assessment might not be as intense for an ingredient with a proven lack of adverse effects (e.g., an ingredient added for formula stability) as compared with a new ingredient added to induce a positive biological effect (e.g., better visual acuity). In its hierarchical approach, the committee includes assessments that consider whether an adverse effect manifests immediately (while the infant is ingesting the formula) or later (even into adulthood and future generations). The committee also recommends assessing the likelihood that a new ingredient could adversely affect a specific system and whether the effect would be common or rare.

To help facilitate the hierarchical approach, the committee recommends the use of algorithms. An algorithm diagrams the process into a step-by-step decision tree. The steps in the algorithm include:

• recommended observations and assessments,
• decisions to be considered, and
• actions to be taken.

Standardized symbols are used in a flowchart to display each step in the algorithm (SMDMC, 1992) (Figure 1-2). Arrows connect the numbered boxes, indicating the order in which the steps should be followed. A letter within a box of an algorithm refers the reader to corresponding text (or sidebar). The sidebar elaborates on the recommendations and statements that are found within each box of the algorithm. Readers should keep in mind that the algorithm depicts the logic of the process, but does not denote a chronology (e.g., a manufacturer may initiate several different studies and procedures at the onset of the process, the results of which are assessed at different steps of the algorithm).

FIGURE 1-2

An example of an algorithm.

The algorithms presented in Chapters 4 through 7 are designed to encompass a broad spectrum of components for evaluating the safety of new components added to infant formulas. The use of algorithms in applying the hierarchical approach provides several advantages. First, the utilization of algorithms should simplify the process of planning the type and depth of safety assessments for each new ingredient. Second, evidence suggests that an algorithm approach improves data collection, problem solving, and decision making. Third, multiple levels of information are incorporated into a single, unified document. Finally, the algorithmic format allows the regulatory agency and the manufacturer to follow a linear approach to critical information needed at the major decision points.

The algorithms in this report are provided as generic guides and as tools for stepwise approaches to be used in assessing the safety of ingredients new to infant formulas. The committee realizes that it cannot provide specific recommendations for each compound and that some variation in these approaches may be needed for specific ingredients. Thus the committee recommends that the manufacturer and an expert review panel establish the relative importance of potential adverse effects for each specific new ingredient and determine the depth of preclinical and clinical studies and in-market surveillance needed to assess safety.

Using this flexible, stepwise approach, each potential new ingredient is considered using evidence-based approaches and high-quality scientific data to assess potential adverse effects on:

• growth and development (including temperament),
• the immune system (including allergic and infectious risks),
• metabolism (e.g., acid-base balance, effects related to lipid and carbohydrate processing), and
• other organ systems (e.g., hematological, gastrointestinal).

For each distinct area of safety assessment (i.e., preclinical, clinical, and in-market monitoring) the committee designed algorithms or stepwise decision trees to be applied to new ingredients for infant formulas. The committee's approach was based on the uniqueness of the infant population. Therefore each step in the process requires empirical evidence from many disciplines and the application of the highest standards, whether using methods of bioassay, nutritional analysis, or basic chemistry. This approach could be applied to new ingredients to be added to infant formula regardless of the regulatory process used.