Designing for Success: Points to Consider in Developing Migration Studies for Packaging Materials
Use of a new food-contact substance (FCS) requires an assessment of the substance’s potential to migrate to food, under the intended conditions of use, to determine the extent to which it may become a component of a consumer’s daily diet. In certain cases, these evaluations can take the form of worst-case calculations that assume complete transfer of the substance to food (i.e., assuming 100% migration) or through the use of Fickian diffusion models that approximate the potential for a substance to migrate under specific time and temperature conditions of use. If undertaken correctly, these mathematical approximations may be sufficient to support the submission of a Food Contact Notification (FCN) to the U.S. Food and Drug Administration (FDA). However, if the estimated dietary intake of the substance at issue is determined to be too high to be considered safe by the FDA analytical testing, in the way of migration studies, may be required to develop a more precise estimate of migration that will (hopefully) support the safety of the FCS for the intended use.
If migration studies are needed, several important points should be considered in designing and performing these tests to provide the type and quality of chemistry data that FDA will need to establish the safety of the intended use of the new substance and permit an FCN to become effective.
This same type and quality of chemistry data may also be needed to support the justification that a substance is exempt from the need for FDA pre-market authorization or clearance.
Food-contact substances that are anticipated, or have been shown, to become components of food when used as intended must be the subject of an applicable FDA regulation (found in Title 21 of the Federal Code of Regulations), an FDA Threshold of Regulation (TOR) exemption, or an effective FCN. In addition, various "exemptions" to the Federal Food, Drug, and Cosmetic Act’s definition of “food additive” will permit certain substances to be legally used in contact with food without an explicit FDA listing. (See the packaginglaw.com article, Frequently Asked Questions on Food Contact Notifications, for more information on FDA’s FCN program.)
Obtaining clearances for new food-contact substances under these various regulatory schemes, generally speaking, may require migration studies that quantify the amount of the substance that transfers to food when it is used as intended, along with toxicology data that adequately supports the safety of the corresponding levels of dietary intake. It is important that studies of this nature be designed and executed in a manner that comports with FDA's Guidance for Industry: Preparation of Premarket Submissions for Food Contact Substances: Chemistry Recommendations, 2007.
Information Necessary to Appropriately Design a Migration Study
In designing appropriate migration studies, it is essential that the full chemical identity of the food-contact substance be known. Required identity information includes not only the chemical name, Chemical Abstract Service Registry Number, trade names, and molecular/structural formulae of the intended food-contact substance, but also the identity and quantity of all manufacturing impurities that may remain in the finished product as a result of the production process.
Although many process chemicals are not expected to remain in measurable quantities in the finished food-contact substance, a quantitative evaluation of all reasonably expected impurities is essential for evaluating the safety of a food-contact substance. Thus, manufacturing process details will, to a great extent, dictate what chemical residues need to be included as analytes in the migration studies.
Second, a clear understanding of the intended use of the food-contact substance is required. For example:
- Is the substance the food-contact article, per se—such as a film or a coating—or is it used in the manufacturing process for the food-contact article, such as a catalyst, emulsifier, or chain terminator?
- Is the substance a component of the food-contact article, such as a colorant, stabilizer, or plasticizer, and at what maximum level will it be used?
- Will the substance directly contact food, or is it separated from food contact by another material that may serve as a functional barrier to the migration of the substance and/or its impurities?
The answers to these and other questions will determine the samples that will need to be prepared for the studies.
Continuing with the intended use of the substance:
- What types of foods is the substance intended to contact: aqueous, acidic, alcoholic, fatty and/or dry? Powdered or liquid infant formula? Human milk?
- What will be the maximum temperature at which the food will contact the substance: room temperature, hot-fill, cooking, etc.?
- Is the food-contact substance expected to be used a single time prior to disposal, such as a food package, or will it be used repeatedly, such as in conveyor belts, coatings for food processing machinery, or tubing/piping?
The answers to these and other questions will dictate the types of food simulating solvents that should be used in the migration studies, the temperature and duration of the migration studies, and the treatment of the developed migration data.
Food-simulating solvents are used in migration studies instead of the actual foods expected to contact the substance. Generally, food itself is not used in migration studies because actual food products are often compositionally complex, and determining the concentration of trace amounts of a migrating substance into complex matrices can be extremely challenging. Further, food simulating solvents can be used to generally represent broad categories of foods rather than specific products.
For example, in the U.S., all aqueous, acidic, and low-alcohol foods, regardless of their specific makeup and complexity, are represented, in most instances, by one simple, easy-to-analyze food simulating solvent: 10% ethanol in water. However, in certain circumstances, such as when food acidity is expected to result in significantly higher levels of migration than with 10% ethanol, or if the food-contact substance is acid sensitive, separate extractions in water and 3% acetic acid may be required instead of 10% ethanol.
For fatty foods, several food simulants may be employed. Ideally, an actual food fat or food oil can be used but, as mentioned above, analytical complications can be associated with the use of such substances. For polyolefins, 95% ethanol in water can be used as the fatty food simulant. For several other polymers, such as rigid poly(vinyl chloride), polystyrene and rubber-modified polystyrene, and poly(ethylene terephthalate), and for paper and paperboard articles, 50% ethanol in water is typically used to simulate contact with fatty foods.
Furthermore, irrespective of the chemical identity of the food-contact substance, FDA generally recommends the use of 50% ethanol in water to simulate contact with infant formula (liquid or powdered) and/or human milk.
What about testing temperatures? FDA has developed a range of food-contact use temperatures from retort canning conditions ("Condition of Use A") to frozen storage ("Condition of Use G"). There is also "Condition of Use H" for precooked food intended to be reheated in the container. Elevated temperature cooking applications covered by "Condition of Use J" (Cooking at temperatures exceeding 250° F) include conventional oven cooking in the package, and susceptor microwave cooking (for popcorn and pizza). “Condition of Use I” is used for food intended to be irradiated in a package. (For more information on Conditions of Use, see the packaginglaw.com article, FDA’s Multiple “Conditions of Use”.)
Testing times also vary depending on thermal processing required for the food, as mentioned above, and the polymers used in the testing. For example, any hot fill or retort simulations require an initial exposure at an applicable elevated temperature (depending on the specific uses), followed by an extended exposure at a lower temperature (i.e., 40°C) to simulate extended shelf life in the food-contact article at room temperature. In addition, some polymers require only a 10-day extended test exposure at 40°C to simulate long-term shelf storage of packaged food at room temperature, while others may require a 30-day test exposure.
Thus, a clear understanding of the intended conditions of use for a food-contact substance is needed before suitable test samples can be prepared and adequate testing can be performed.
After the migration studies are complete, analyses of the test sample extracts must be conducted to determine if, and to what extent, the substance is anticipated to become a component of food when used as intended. Any analytical method may be used provided:
- It has adequate analytical sensitivity, given the needed detection limit based on the known toxicity profile of the food-contact substance, and
- The analytical results can be validated according to specific procedures recommended by FDA.
With regard to analytical limits of detection needed for such analyses, the more potentially toxic the food-contact substance, the lower the analytical limit of detection must be to ensure that the use of the substance is safe. For example, if the available toxicity data for a substance is adequate to support a safety determination at levels of 0.5 parts per billion (ppb) in the diet, the necessary analytical limit of detection for a migration study must correspond to a migration value that will ensure that the substance does not enter the diet at levels exceeding this safety threshold. Of course, correlating a concentration in a food or food simulating solvent (i.e., the necessary analytical limit of detection) for a particular substance with the corresponding dietary concentration that would result from its use requires a specific understanding of the breadth of applications in which the substance may be used. Finally, the migration study data—and the methods used to generate the data—must be suitably validated; FDA requires validation as a part of its review of an FCN.