Extractables for Parenterals

Testing for extractables and leachables from parenteral packages can be a frustrating endeavor because regulations are inconsistent and the process can become quite burdensome if every potential impurity must be analyzed.

This challenge was the focus of a PDA-sponsored (Bethesda, MD) summit of industry, government, and academia held November 12–13, 2001, in Rockville, MD, and titled "The Extractables Puzzle: Putting the Pieces Together." During the forum, several experts proposed ways to make standards more coherent and the testing process more science-based.

Even though FDA's 1999 guidance on container-closure systems provided more regulatory insight than ever before, governing and pharmacopeial bodies throughout the world continue to disagree, sometimes within the same document, on issues from suitability for intended use of a package to specification limits for extractables tests to acceptance criteria for the qualification of packaging materials, said Maxine M. Gallagher, vice president of global regulatory affairs for West Pharmaceutical Services Inc. (Lionville, PA). Therefore, some in industry argued for standards tied more directly to what actual effects a certain amount of an extractable would have on the health of a patient.

Jeff Fleitman, PhD, director of pharmaceutical analysis at Allergan Inc. (Irvine, CA), noted that reporting thresholds for extractables in drug products tend to be more stringent than for known carcinogens in food packaging and drinking water. That is because standards for the other fields are based on a person's total daily intake of the substance.

In some cases, Fleitman said, extractable levels that require analysis in stability studies are "orders of magnitude below known carcinogens. Therefore, we have to ask if the effort to identify and quantify these things is too much. As our analytical techniques get better and more sensitive, we see more things. But are we chasing a needle in a haystack?"

Instead of the current exhaustive two-stage extractable testing process that must be conducted with every stability study (some before the drug product is even available) and on every finished package, Fleitman said the industry should consider moving to a one-time qualification of a package based on the maximum potential extract from its materials. Therefore, if extractable levels in the second stage of the testing process were found to be lower than those qualified in toxicology studies, finished-package extractable specifications might not be needed and perhaps shouldn't be required for every new drug application that uses the same container-closure system, he said.

The situation is even murkier for inhalation technologies, said Gordon Hansen, an official with the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS; Washington, DC). Recent FDA draft guidances for orally inhaled and nasal drug products place unrealistic expectations on extractable studies, requiring every peak to be analyzed regardless of its potential impact on the health of a patient, he said. IPAC-RS suggests that control extractables studies should only be conducted on the components that contact the formulation or the patient's mouth or nasal passage and that only extractable levels of 100 µg/g or more be identified. Leachables studies, he said, should have a 0.2 µg total daily intake reporting threshold and a 2 µg total daily intake identification threshold. "We should focus on the compounds that the patient is actually exposed to," he said.

But the conference did offer some hope from regulatory officials that changes might be on the way. Ronald Brown, a toxicologist from the Health Sciences Branch of the Office of Science and Technology for FDA's Center for Devices and Radiological Health, noted that his branch has moved to a risk-assessment-based approach for evaluating the toxicity of extractables. This approach compares the dose of an extractable received by a patient to the tolerable intake value, and its principles might work when applied to parenteral containers, he said. James C. Boylan, RPh, PhD, a member of the U.S. Pharmacopeia's Council of Experts, said USP is ready to devote much energy to the issue of extractables from elastomeric closures, especially in terms of harmonizing with the European and Japanese pharmacopeial bodies.

Erik Swain


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