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June 2008
Additional copies are available from:
Office of Food Additive Safety
Division of Petition Review HFS-265
Food and Drug Administration
5100 Paint Branch Parkway
College Park, MD 20740
(Tel) 301-436-1226
http://www.cfsan.fda.gov/guidance.html
You may submit written or electronic comments regarding this guidance at any time. Submit written comments on the guidance to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.regulations.gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Food Safety and Applied Nutrition
June 2008
TABLE OF CONTENTS
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate telephone number listed on the title page of this guidance.
The Food and Drug Administration (FDA) is responsible for prescribing the conditions of safe use of food additives under section 409 of the Federal Food, Drug, and Cosmetic Act (the Act). To evaluate the safety of food additives and determine their conditions of safe use, the agency uses the food additive petition (FAP) process and the food contact notification (FCN) process. In addition, FDA may, upon request, exempt from regulation as a food additive those substances used in food-contact articles (also known as food contact substances) that migrate into food at levels that are below the threshold of regulation (TOR). This guidance is directed at questions regarding microbiological data requirements for FAPs, FCNs, and TOR requests that are unique to the use of antimicrobial food additives and food contact substances. This guidance will assist petitioners and notifiers in designing studies to determine whether an antimicrobial food additive achieves its intended technical effect. Also, this guidance discusses microbiological data that may be necessary to demonstrate that an antimicrobial agent will be safe for the intended use.
This guidance applies to all FAPs, FCNs and TOR requests where the food additive is intended to control microbes in or on food. This includes sources of radiation for treating food. However, it is important to note that the U.S. Department of Agriculture (USDA) Food Safety and Inspection Service (FSIS) is responsible for determining the suitability of food additives in meat and poultry products; according to FSIS, “suitability relates to the effectiveness of the substance in performing the intended technical purpose of use, at the lowest level necessary, and the assurance that the conditions of use will not result in an adulterated product or one that misleads consumers.”[2] FSIS derives its authority to regulate the suitability of food additives in meat and poultry from the Federal Meat Inspection Act (FMIA) and the Poultry Products Inspection Act (PPIA), respectively. FDA and FSIS currently have a Memorandum of Understanding (MOU) regarding each agency's responsibilities in the evaluation and approval of food ingredients and sources of radiation used in the production of meat and poultry products. In accordance with this MOU, FDA will collaborate with FSIS on any antimicrobial food additive submission to FDA involving meat or poultry.
Given the complexity and variety of antimicrobial products and the diverse conditions of use, no single document can anticipate and address all microbiological issues. Therefore, this guidance is intended to answer common questions associated with microbiological data requirements for FAPs, FCNs, or TOR requests for antimicrobial food additives so that meaningful and sufficient data are provided with each submission. It is intended to assist developers of antimicrobial agents for use in or on food in providing evidence to support their intended uses. FDA recommends that petitioners and notifiers discuss with the agency any proposed studies prior to their initiation to ensure that these studies will address FDA’s safety concerns. In addition, FDA recommends that submitters meet with the agency prior to the submission of a petition or notification to prevent an expenditure of resources on activities that may not provide adequate data.
FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
The term “food additive” is defined in section 201(s) of the Act. The first part of that section states that a food additive is any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of any food including any substance intended for use in packing, packaging, producing, manufacturing, processing, preparing, treating, transporting, or holding food; and including any source of radiation intended for any such use. Section 201(s) goes on to expressly exempt from the definition of food additive certain categories of substances, including substances that are "generally recognized as safe" or "GRAS" for the intended use. A partial list of substances recognized by FDA as GRAS may be found in 21 CFR Part 182, and a list of substances affirmed by FDA as GRAS appears in 21 CFR Part 184. These lists may include substances which are GRAS for use as antimicrobial agents.
"Pesticide chemicals," as defined at section 201(q) of the Act, are exempt from the definition of a food additive. Pesticide chemicals and pesticide chemical residues in or on food must conform to a tolerance, or an exemption from tolerance, established by the Environmental Protection Agency (EPA) under section 408 of the Act.
For the complete definition of a food additive and the exemptions, see section 201(s) of the Act.
The term “antimicrobial food additive,” as used in this guidance, refers to a substance or a source of radiation that meets the food additive definition and is used to control microorganisms such as bacteria, viruses, fungi, protozoa, or other microorganisms in or on food or food contact articles.
FDA is the primary Federal agency responsible for ensuring the safety of food additives. Under section 409 of the Act, all food additives are subject to review and approval by FDA before they can be marketed in the United States. This guidance applies to FAP, FCN, and TOR submissions. Food additives that are intended to have a technical effect in food are authorized through the petition process prescribed in section 409 of the Act. The standard that FDA applies to determine whether the intended use of a food additive is safe is reasonable certainty of no harm (see 21 CFR 170.3(i)). For food additives demonstrated to FDA to be safe under the intended conditions of use, FDA will issue a regulation that specifies the conditions of safe use. The food additive regulations are codified in 21 CFR parts 172-180 and may be obtained from the Internet by searching the current edition of the CFR. Part 172 lists food additives for direct addition to food, part 173 lists food additives used during food processing, and parts 174-178 list food additives used in food packaging and other food contact articles. Approved sources of radiation for inspecting and treating food are listed in 21 CFR part 179. Food additives permitted in food or in contact with food on an interim basis pending additional study are listed in 21 CFR part 180.
Food additives that are intended for use as a component of materials used in manufacturing, packing, packaging, transporting, or holding food, if such uses are not intended to have any technical effect in food, are considered food contact substances (see section 409(h)(6) of the Act). As a result of the FDA Modernization Act of 1997, the primary method for authorizing new uses of food contact substances is the FCN process (see section 409(h) of the Act). In the case of a food contact substance, FDA will allow a notification for the subject food contact substance to become effective prescribing the conditions under which a food additive may be safely used. The standard used to establish the safety of a food contact substance is the same as that for any other food additive (i.e., reasonable certainty of no harm). More information on this process is available from the Food Contact Substance Program website.
A current Inventory of Effective Food Contact Substance Notifications is found on the CFSAN Internet.
In addition, under 21 CFR 170.39, FDA may, upon request, exempt from regulation as a food additive food contact substances that become a component of food at levels below the threshold of regulation. Such a request is commonly referred to as a threshold of regulation (TOR) submission. More information on the TOR submission process is available in Guidance for Industry: Submitting Requests Under 21 CFR 170.39 Threshold of Regulation For Substances Used in Food-Contact Articles. A current inventory of Threshold of Regulation Exemptions issued by FDA is available on the CFSAN Internet. The data requirements for a TOR submission are the same as those for a FAP or FCN and the safety standard that FDA applies is the same.
For a detailed discussion of FDA’s regulatory authority over antimicrobial food additives, see FDA’s Guidance to Industry entitled, Antimicrobial Food Additives – Guidance. It is important to note that, depending on the proposed use, an antimicrobial food additive may also be a pesticide under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). As such, it may be subject to registration as a pesticide by the EPA as well as regulation as a food additive.
Microbiological data may need to address certain issues raised by the findings that FDA makes under section 409 of the Act. Several are described below.
Antimicrobial food additives are regulated through the FAP process, the FCN process, or the TOR exemption process. Section 409(b) of the Act sets forth the statutory requirements for data in an FAP to establish the safety of a food additive; section 409(h) sets forth the requirements for notification of a food contact substance; and 21 CFR 170.39 sets forth the requirements for a TOR submission. A more detailed description of the information to be submitted in an FAP and the proper format are specified in 21 CFR 171.1; information requirements for a food contact notification are found in 21 CFR170.101. Guidance documents from the FDA detailing the procedures for preparing and submitting an FAP, FCN, or TOR submission can be found on the CFSAN Internet.
It is important to note that there are some antimicrobial additives for which the proposed use makes them both a food additive and drug (e.g., a no-rinse hand sanitizer used by food handlers). In this case, the product will have to comply with the requirements of the Act applicable to both food additives and drug products.
Section 409(b)(2)(C) of the Act requires that a petition for a food additive contain all relevant data bearing on the physical or other technical effect such additive is intended to produce, and the quantity of such additive required to produce such effect. Therefore, data on the intended effect are required in a petition for an antimicrobial food additive. Furthermore, if FDA determines that a tolerance is needed to ensure that the petitioned use of an antimicrobial food additive will be safe, intended effect data will be used to ensure that the tolerance is set at a level no higher than what is reasonably required to achieve the intended physical or other technical effect. In addition, if a tolerance is necessary and data do not establish that the petitioned use will accomplish the intended physical or other technical effect, FDA is not authorized to establish a regulation for that use (section 409(c)(4) of the Act).
For antimicrobial food additives used on meat or poultry, FDA and FSIS have separate regulatory responsibilities which must be satisfied before the additive may be legally marketed. For these cases, intended effect data will be needed to satisfy the requirements of both FDA and FSIS. Under the Federal Meat Inspection Act (FMIA) and the Poultry Products Inspection Act (PPIA), FSIS has authority over suitability of food ingredients and sources of radiation used in meat and poultry processing plants.
In accordance with the procedures described in the MOU between FDA and FSIS, requests for approval to use food ingredients and sources of radiation in the production of meat and poultry products are evaluated simultaneously for safety by FDA and for suitability by FSIS. Prior to submission, petitioners and notifiers may wish to consult with FSIS independently; however, FDA believes joint consultations with FDA and FSIS facilitate the petition and notification processes.
To demonstrate that an antimicrobial agent achieves its intended technical effect and that the proposed use level is the minimum level necessary to accomplish the intended technical effect, the following information is recommended at a minimum:
FDA recommends that any study carried out to support the intended technical effect of an antimicrobial food additive should be designed to generate data that directly supports any particular effect(s) specified. For example, if the intended technical effect is extending shelf life, the study should generate data which measure shelf life; or if the intended technical effect is the control of specific organisms, the study should generate data which directly enumerate those organisms. FDA recommends that any of the subject studies reflect the following characteristics, to the extent practical:
A petition or notification will not be treated differently simply because an alternative approach was chosen. FDA invites submitters to consult with the agency in designing experimental protocols and recommends that submitters provide their experimental protocol to the agency for comment prior to the initiation of any study. It is the agency’s experience that these consultations lead to consensus between the agency and the submitter prior to experimentation being conducted. FDA believes these consultations result in studies that are more likely to address the agency’s concerns which leads to a more efficient regulatory process and a faster time to market for the proposed food additive.
There are a number of unique circumstances that might be considered when designing a study to show an antimicrobial food additive's effect. Several are described below.
FDA recognizes it is impractical to design a standard experimental protocol that addresses all relevant safety issues for every antimicrobial agent. However, there are a number of resources specific to microbiological methods that the agency recommends. FDA publishes an online version of its Bacteriological Analytical Manual which presents useful laboratory procedures for microbiological analyses of foods and cosmetics. Furthermore, FDA maintains a website with numerous links to related resources on Microbiological Methods. Also, FSIS maintains a Microbiology Laboratory Guidebook of current protocols for analytical tests required by FSIS in its regulatory activities on meat, poultry and egg products; these test procedures may be useful in the experimental design of technical effect studies. However, a petition or notification will not be treated differently simply because an alternative study design was chosen.
A performance standard defines the minimal level of reduction of microorganisms from the use of the antimicrobial food additive (e.g., a 5-log reduction in the number of microbe(s) targeted). Given the variability in the intended technical effect of antimicrobial food additives and types of food treated, FDA does not have a single performance standard for antimicrobial food additives. However, to prove that an additive achieves its intended technical effect as an antimicrobial agent, data from an efficacy study should demonstrate that, at a minimum, there is a measurable difference between the treated samples and a negative control (e.g., the treatment absent the active agent). Such a demonstration may be achieved through statistical analysis, graphical comparison, or another equivalent method. In those particular cases where the intended technical effect specifies the use of the additive as part of a process where a performance standard has been established by regulation (e.g., Juice HAACP (21 CFR 120.24)) or regulatory guidance (e.g., FSIS guidance on control of Listeria monocytogenes), FDA may consider that performance standard when regulating the additive.
A source of radiation used to treat food is included in the food additive definition (section 201(s) of the Act). Furthermore, section 402(a)(7) of the Act states that a food is adulterated if it has been subjected to radiation, unless the use of the radiation was in conformity with a regulation or exemption under section 409 of the Act. Because a source of radiation used to treat food does not meet the definition of a food contact substance in that it has a technical effect in the food, it is regulated through the FAP process under section 409 rather than the FCN process or the TOR exemption process. In addition to information typically submitted in an FAP, a petition for the use of a source of radiation as an antimicrobial treatment for food should include information related to technical effect, such as:
If an antimicrobial food additive is derived from a microorganism, FDA recommends that the following additional information be provided, at a minimum:
FDA understands that there may be newly developed antimicrobial products for which some of these recommendations may not be valid. A petition or notification will not be treated differently simply because safety information other than that recommended here was provided. We will consider the sufficiency of the safety information provided with antimicrobial product petitions on a case-by-case basis.
[1] This guidance has been prepared by the Office of Food Additive Safety in the Center for Food Safety and Applied Nutrition at the U.S. Food and Drug Administration.
[2] Guidance on the Procedures for Joint Food Safety and Inspection Service (FSIS) and Food and Drug Administration (FDA), Approval of Ingredients and Sources of Radiation Used in the Production of Meat and Poultry Products, U.S. Department of Agriculture, Docket No. 00-022N, E. coli O157:H7 Contamination of Beef Products.
The document above supercedes the previous version issued in September 2007.
