Assessing the Completeness of an Extractables Assessment

The completeness of an extractables assessment can only be judged against the overall goals of the assessment. For example, an extractables assessment accomplished solely for materials characterization might include one extracting solvent, one extraction technique, and one set of extraction conditions; along with a materials-based threshold (e.g., 10 ppm w/w). 

Such an extractables assessment might be considered complete if all extractables above the defined threshold were identified to the confident level (defined above) and quantitated. For an extractables assessment designed to establish a rigorous leachables–extractables correlation for a high risk drug product, where a challenging safety threshold might apply (e.g., 0.15 µg/day; see reference 5), good scientific practice and due diligence requires the following:

  • Generation of extracts should be accomplished with
    1. Multiple solvents or extracting media with varying extracting power based on the known extracting power of the drug product vehicle;
    2. Multiple and complementary extraction techniques, including those with the capability for volatiles analysis;
    3. Extraction conditions that allow equilibrium to be achieved.

  • Characterization of extracts should use
    1. Multiple and complementary analytical techniques;
    2. Careful sample preparation, keeping the analytical technique(s) in mind;
    3. A systematic process for identification and quantitation of extractables.

In this case, the extractables assessment might be considered complete if all extractables above the defined threshold were identified to at least the confident level, quantitated, and correlated both qualitatively and quantitatively with drug product leachables data (if available) and the known ingredients in the packaging system, packaging component(s), or material(s) of construction.It should be noted that limited extractables assessments with relatively narrow goals can be accomplished to required completeness with a relatively focused effort. For example, extraction studies designed to quantitate the levels of specific chemical additives in specific packaging components/materials can be done with specified extraction parameters and analytical methods (see Containers—Plastics <661>).

The reader is also referred to various sources which describe extractables assessments and extraction studies for pharmaceutical applications (2, 5, 6), as well as other general sources which refer to extractables assessments for medical devices (9) and food contact (11).Reference is also made to compendial chapters in this Pharmacopeia which include extraction studies with specific goals and purposes:

  1. Biological Reactivity Tests, In Vitro <87>
  2. Biological Reactivity Tests, In Vivo <88>
  3. Elastomeric Closures for Injection <381>
  4. Containers—Plastics <661>