Occasions may arise in which it is not analytically feasible (due to challenging thresholds, for example) to successfully discover and identify all actual leachables in a drug product leachables study. This circumstance can be managed if the activities of discovery and identification of probable leachables are accomplished in an extraction study, where samples and analyte concentrations are more easily manipulated to achieve the necessary analytical performance. In such a circumstance, the actual drug product leachables assessment is simplified to a high-sensitivity quantitation of targeted leachables that have been discovered and identified as part of this extraction study.

In order to facilitate the discovery and identification of probable leachables, the extraction study must be similar in design to a drug product leachables study. Such an extraction study seeks to simulate the circumstances experienced by the drug product but should produce a test sample that is easier to characterize than the drug product itself. For such a study to be relevant in establishing appropriate target leachables, the solvent(s) used to generate the test sample must have nearly the identical propensity to leach as the drug product formulation. Such a study should be accelerated versus the leachables study so that the extractables, reflecting potential target leachables, can be discovered and identified in a timely fashion.

It is possible that in cases of very low thresholds (e.g., AETs), quantitation of drug product leachables might still not be analytically feasible, even with high sensitivity target compound analytical methods. In such cases, the results of the simulation study (probable leachables identities and concentrations) may be sufficient to establish patient safety and the quality impact of the actual drug product leachables. To the extent that the simulation study mimics the drug product leachables study, the potential safety or quality impact of a compound as an extractable is an estimate of the potential safety or quality impact of the compound as an actual leachable.

If it can be established that a compound quantitated as an extractable under these conditions has an acceptably small impact on safety and quality, then it follows that the same compound as a leachable in the drug product formulation may be assumed to have a similarly low impact on safety and quality as a leachable in the drug product formulation. The acceptability of this approach for any particular drug product needs to be scientifically justified by the drug product applicant.

If a compound is measured as an extractable in a simulation study and targeted as a leachable in a drug product leachables study, the extractables and leachables data for that compound become the basis upon which a leachables–extractables correlation can be made. For such a correlation to be considered to be valid, it is necessary that each leachable concentration in the drug product be less than or equal to the corresponding extractable concentration in the simulated extract, accounting for the uncertainty in the analytical measurements and any justifiable “exaggeration factors” that may have been utilized in the simulation study. Note that in certain justifiable circumstances drug product placebo batches may be used as test articles in drug product leachables studies (stability studies). However, there are also circumstances when placebo batches are not acceptable, such as when there is significant reason to believe that leachables might have an adverse effect on an active pharmaceutical ingredient (e.g., therapeutic proteins).

Inorganic (Elemental) Leachables