Special Focus
Designing for Success: Points to Consider in Developing Migration Studies for Packaging Materials
Mar 2002
Charles V. Breder Ph.D.
Any use of a new food-contact substance first requires that migration studies be conducted, under the intended conditions of use, to determine if and to what extent the substance may become a component of the daily diet. A number of important points must be considered in designing and carrying out migration studies to provide the type and quality of chemistry data that the U.S. Food and Drug Administration needs to establish the safety of the intended use of the new substance and to issue an effective Food Contact Notification (FCN).
The same type and quality of chemistry data will also be needed by Keller and Heckman to issue a legal opinion concerning the suitable FDA status of the substance.
Regulatory Scheme
Food-contact substances that are anticipated, or have been shown, to become components of food when used as intended must be the subject of either: 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, a number of "exemptions" to the Federal Food Drug and Cosmetic Act permit substances not otherwise specifically regulated to be legally used in contact with food.
Clearance of substances under these various regulatory schemes is generally accomplished on the basis of migration studies demonstrating their anticipated concentration in the daily diet when used as intended; the safety of these dietary concentrations is supported by adequate toxicology data. Finally, many currently effective regulations were issued with an "end test" requirement to demonstrate compliance of the regulated substance with the regulation.
A number of important issues must be considered when designing and carrying out migration studies for new food-contact substances. For a broad overview of these issues, see FDA's Guidance for Industry: Preparation of Premarket Submissions for Food Contact Substances: Chemistry Recommendations.
Significant Information Necessary
In designing appropriate migration studies, it is essential that the identity of the food- contact substance be known. The identity includes not only its chemical names, Chemical Abstract Service Registry Number, trade names, molecular and structural formulae, and the identity and quantity of impurities, but also its manufacturing process. This information will dictate, to a great extent, what analytes need to be looked for in the extracts when a migration study is done.
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 level will it be used?
- Will the substance be in direct contact with food, or is it separated from food contact by another material that may serve as a functional barrier to the migration of the substance?
The answers to these and other questions will dictate the type of sample that must be prepared for the migration studies.
For example, if the substance is a polymer article (such as a film, sheet, or container), a sample should be prepared that represents the thickest article anticipated for use commercially. However, it is not necessary to use a sample thickness greater than 20 mils in 2-sided migration studies, because FDA generally assumes that 10 mils is an infinite thickness from a migration standpoint. For additives, samples should be prepared containing the maximum commercially anticipated use levels. There are, of course, other sample preparation considerations such as crystallinity and orientation for testing polymers, and the types of polymers best used for testing additive extraction. Continuing with the intended use of the substance:
- What types of foods will it contact: aqueous, acidic, alcoholic, fatty and/or dry?
- What will be the maximum temperature of food contact: room temperature, hot- fill, cooking, etc.?
- Will the food contact be single use service, such as a food package, or will it be repeated use 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, the food itself is not used in migration studies because food is often compositionally complex, and determining the concentration of trace amounts of the migrating substance into complex matrixes can be extremely difficult. Further, food simulating solvents can be used to represent broad ranges of foods within given food types. For example, all aqueous, acidic, and low- alcohol foods, regardless of their specific makeup and complexity, are represented by one simple, easy-to-analyze food simulating solvent: 10 percent ethanol in water. For fatty foods, several food simulants may be employed. Ideally, an actual food fat or food oil can be used, but, as mentioned above, there may be analytical problems associated with such use. For polyolefins (and for other polymers used in contact with food whose glass transition temperatures are below the food use temperatures), 95 percent ethanol in water can be used. For polymers not suitable for testing with 95 percent ethanol in water, and for paper and paperboard articles, 50 percent ethanol in water can be used. Finally, heptane can be used in some cases.
What about testing temperatures? FDA has developed a range of food-contact use temperatures from retort canning conditions ("Condition of Use A") down to frozen storage ("Condition of Use G"). There is also "Condition of use H" for precooked food intended to be reheated in the container. Special applications include conventional oven cooking in the package, and susceptor microwave cooking (for popcorn and pizza).
Testing times also vary depending on the temperatures of use mentioned above and the polymers used in the testing. For example, any hot fill or retort-type uses require an initial exposure at some elevated temperature (depending on the specific uses), followed by an extended exposure at a somewhat elevated temperature to simulate extended shelf life in the food-contact article at room temperature. In addition, some polymers require only a 10-day extended exposure at the somewhat elevated temperature, while others may require a 30-day 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.
Analysis Varies
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 sensitivity, given the needed detection limit based on what is known about the toxicity of the food-contact substance, and
- it can be validated according to specific procedures recommended by FDA.
With regard to analytical method sensitivity, obviously the more potentially toxic the food-contact substance, the more sensitive the analytical method must be to ensure that the calculated dietary concentration is within the safety parameters for the substance. Finally, the migration study data—and the methods used to generate the data—must be suitably validated, as validation will be required by either FDA or to properly support a conclusion that a substance is not a food additive because it is not reasonably expected to become a component of food.
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