Assessing the Risk of Leachables from Single-Use Systems - This article is the second in a two-part series on extractables and leachables. - BioPharm International

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Assessing the Risk of Leachables from Single-Use Systems
This article is the second in a two-part series on extractables and leachables.


BioPharm International
Volume 25, Issue 2, pp. 32-40

Another strategy for incorporating QbD is to use materials cleared as food contact substances (FCS) under 21 CFR. There are several ways in which a chemical can obtain clearance as an FCS, such as being a prior sanctioned substance, an indirect food additive, generally recognized as safe (GRAS), obtaining a threshold of regulation (TOR) exemption, or obtaining a food contact notification (FCN).

Prior sanction substances are chemicals for which there was explicit approval by FDA or the United States Department of Agriculture before Sept. 6, 1958. Some of these substances are listed in 21 CFR 181.

Indirect food additives are substances that come into contact with food as a part of packaging, holding, or processing, but are not intended to be added directly to the food. These substances are listed in 21 CFR 175–178 and include adhesives, paper, polymers, and adjuvants.

GRAS substances have been adequately shown to be safe under the conditions of their use. These substances are listed in 21 CFR 182–186. TOR exemptions are substances that have been exempted by FDA from a need to submit an FCN because the substances are expected to result in exposures below 1.5 g/person/day. The specific regulations are listed in 21 CFR 170.39.

Food contact notification (FCN) is the mechanism by which a substance can be cleared as an indirect food additive. The testing requirements in support of the substance clearance will depend on the expected exposure concentration. If the expected concentration is less than 1.5 g/person/day, a TOR exemption should be sought. If the expected concentration is between 1.5–150 g/person/day, only short-term genetic toxicity tests (e.g., Ames test and mouse lymphoma assay) are required. If the expected concentration is between 150–3000 g/person/day, then more in-depth tests are required. If the expected concentration is greater than 3,000 g/person/day, a Food Additive Petition should be sought.

Finally, it should be noted that the 1958 Amendment to the Food Drug and Cosmetic Act includes the Delaney Clause, which states: "no (substance) could be deemed safe or given FDA approval if found to cause cancer in man or experimental animals (4)." Therefore materials cleared as an FCS under 21 CFR will not include any carcinogens.

The third strategy to incorporate QbD into single-use components is through use of materials qualified as US Pharmacopeia (USP) Class VI plastics. The USP sets standards for the quality, purity, strength, and consistency of these products—all critical to the public health (5). One such standard is USP <88> Biological Reactivity Tests, In Vivo. In this standard, extracts of test material are prepared in several solutions, which are then injected into mice and rabbits. The plastic components are classified based on the reaction to a systemic injection test, an intracutaneous test, and an implantation test. Based on the results of the tests, the material is classified as Class I through Class VI, with Class VI being the most stringent.

Another important standard is USP <87> Biological Reactivity Tests, In Vitro. This standard is designed to determine the biological reactivity of mammalian-cell cultures following contact with plastic materials. The tests performed include the agar diffusion test, the direct contact test, and the elution test. In this standard, the material is found to pass if there is no reaction or only a mild reaction.

No matter how well single-use systems are engineered, leachables will still enter the solution because of the gamma irradiation step. While gamma irradiation is used to reduce the bioburden of these components, the same energy used to destroy bacteria also results in some polymer degradation. An additional complication associated with gamma irradiation is that several compounds will be created depending on the strength of the gamma irradiation, the amount of oxygen present, and the length of time since the gamma treatment.


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