In June 2015, the FDA’s Center for Food Safety and Applied Nutrition (CFSAN) issued a guidance document which describes data requirements for petitions and notifications seeking exemption from labeling for the major food allergens (FDA, 2015a). The purpose of this article is to inform readers about the main points covered in the guidance document, to help them submit the correct document with the necessary steps completed. Although FDA guidance documents “do not establish legally enforceable responsibilities”, the FDA expects recommendations in these documents to be followed, as the FDA often refers to guidance documents when disallowing claims or issuing warning letters.
The guidance begins by providing the statutory definition of a major food allergen as “milk, egg, fish (e.g. bass, flounder or cod), Crustacean shellfish (e.g. crab, lobster or shrimp), tree nuts (e.g. almonds, pecans or walnuts), wheat, peanuts and soybeans” or a food ingredient that contains protein derived from these foods. The definition excludes any refined oil derived from a major food allergen and any ingredient derived from such highly refined oil. The FDA provides two mechanisms by which ingredients derived from major food allergens can be exempted from allergen labeling. If the producer provides evidence that an ingredient derived from a major food allergen is altered to the extent that it does not contain allergenic protein, the ingredient may become exempt from allergen labeling through submission and approval of a notification. If the producer cannot show that the allergenic protein is removed, but can show that the level of allergenic protein in the finished food does not cause an allergic response that poses a risk to human health, submission and approval of a petition for an exemption from allergen labeling is recommended unless there has been a previous determination through a premarket approval process that the ingredient does not cause an allergic response that poses a risk to human health.
Rather than focusing on the differences between notifications and petitions, the guidance stresses requirements that are germane to both documents. Either type of submission should provide a complete description of the ingredient including the common and scientific name, major food allergen source, chemical and biological properties, existing food standards (e.g. FDA, Food Chemicals Codex, Codex Alimentarius), composition (including methods of analysis, particularly for the proteins or peptides in the ingredient), the amount and molecular characteristics of allergenic protein or peptides, and batch to batch variation. For ingredients that are or contain peptide fragments, information about the distribution of peptide fragment sizes (and whether they are large enough to be immunologically relevant) should be provided. If the ingredient contains more than one component, all components (including non-allergens, carriers or diluents and the relative proportion of each in the ingredient) should be described. The method of manufacture should be described “completely”. At a minimum, the FDA would like the description to include information about physical, temperature and/or chemical treatments, growth conditions (if relevant), bioengineering (if relevant), conditions used at each step of manufacture (including time, temperature, pH, pressure, volume and acceptable ranges for each), monitoring and process controls, quality assurance and validation tests and statistics on batch-to-batch variations in protein content, identity and structure. Additional requirements for both notifications and petitions include a description of intended uses, including variations in the usage level that may result from manufacture, limitations due to technical effects, and methods of incorporation and detection in food. All applications require the preparation of an environmental assessment or a claim of categorical exclusion.
For notifications, additional information required includes a complete characterization of the protein (or proteins) and peptides that are present in the ingredient and evidence that the protein(s) or peptides present are not allergenic. If the original major food allergen is known to have only one or a few well characterized allergenic proteins, this step can be accomplished by demonstrating that the protein or peptides in the ingredient are different from known allergenic proteins. However, because each allergic individual may be sensitive to different proteins in a food, the FDA recommends submitters of notifications to perform an in vivo or in vitro clinical test(s) to demonstrate that the ingredient does not contain allergenic protein. If data from animal tests, clinical case reports or in vitro studies are included in the notification, a complete description of study methods (including those used for data analysis) and controls should be provided.
For petitions, the submitter must demonstrate that the ingredient does not cause an allergic response that poses a risk to human health, when manufactured and used as described. The FDA recognizes that “the factors that are relevant for evaluating petitions are the amount of allergenic protein present in a food and the amount of food consumed in a single eating occasion.” Thus, an exposure assessment is an essential part of a petition. For the assessment, the FDA recommends including consumption information for a single eating occasion at the 50th, 90th and 95th percentile levels. Different consumption patterns by age, gender or ethnicity should be considered. Another essential segment of a petition is a proof that the ingredient does not cause an allergic response in humans, via satisfactory results from clinical studies (oral provocation, skin prick or in vitro testing), risk assessment or safety assessment. The double-blind, placebo-controlled food challenge is the best design for an oral challenge, but a single blind or open challenge “may be appropriate depending on the nature of the product and the food allergic individuals involved.” At the time of testing, all subjects should be allergic to the major food allergen that was the source of the ingredient and exhibit the range of sensitivities present in the entire allergic population. A number of other requirements of clinical studies are mentioned in the guidance, including conformance with FDA Human Subject Protection Regulations or Good Clinical Practice in the country where the studies were conducted. Requirements for skin prick testing include use of a validated method, a statistically significant number of well- characterized, food-allergic individuals, appropriate withdrawal periods for interfering medications, and positive and negative controls. If direct clinical or challenge data are unavailable, the submitter may perform a risk or safety assessment, incorporating points mentioned in the guidance document. For either of these approaches, pre-submission consultation with the FDA is advised.
While the guidance document stresses the importance of accurate, sensitive, scientifically appropriate and validated analytical methods for ingredient characterization (including protein or peptide analyses), it is noticeably vague about the methods that should be used. The document does, however, mention that given the limitations of enzyme-linked immunosorbent assay (ELISA)-based methods, additional methods of allergen detection should be used, namely polymerase chain reaction (PCR) or mass spectrometry. Additional guidance about appropriate methods for allergen detection can be found in a report issued by FDA in 2006 about thresholds for major allergens (FDA, 2006), as well as the Food Allergy Research and Resource Program website (University of Nebraska-Lincoln, 2014). Notifications and petitions for exemptions from food allergen labeling that have been submitted to the FDA are publicly available (FDA 2015b,c) and contain a wealth of information about successful and unsuccessful strategies for ingredient characterization, allergen detection and other types of testing.
In conclusion, regardless of whether you are considering filing a petition or notification for an exemption from allergen labeling , the data requirements are largely the same, and particularly onerous. The guidance stresses the requirement for detailed ingredient, manufacturing, methodological, exposure, allergen testing and environmental impact information. A notifier must prove that the allergen is removed, and a petitioner must prove that the level of allergenic protein in the finished food does not cause an allergic response that poses a risk to human health. For more information on how to accomplish this task, consult the references provided below or contact Burdock Group.
FDA (2006). Approaches to Establish Thresholds for Major Food Allergens and for Gluten in Food; available at http://www.fda.gov/downloads/Food/IngredientsPackagingLabeling/UCM192048.pdf.
FDA (2015a). Food Allergen Labeling Exemption Petitions and Notifications: Guidance for Industry; available at http://www.fda.gov/downloads/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/UCM395660.pdf.
FDA (2015b). Inventory of Notifications Received under 21 USC 343 (w)(7) for Exemptions from Food Allergen Labeling; available at http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/Allergens/ucm076656.htm.
FDA (2015c). Inventory of Petitions Received under 21 USC 343 (w)(6) for Exemptions from Food Allergen Labeling; available at http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/Allergens/ucm076631.htm.
University of Nebraska-Lincoln (2014). Evaluation and Improvement of Analytical Methods for the Detection of Allergenic Food Residues; available at https://farrp.unl.edu/research/article-2.