During the course of manufacturing, packaging, storage, distribution, and administration; dosage forms and their constituents can contact components and materials of construction of manufacturing and packaging equipment, and primary and secondary packaging components and systems. Such contact may result in interactions between the dosage form and these components and materials. 

One such interaction is the migration or leaching of substances from any of these components and materials into the dosage form with subsequent delivery to the patient during drug administration. Patients also can be directly exposed to substances via direct contact with the packaging/delivery system during drug administration. Leachables, which can include both organic and inorganic chemical entities with wide chemical diversity, are of concern due to their potential safety risk to patients and potential compatibility risks for the drug product (e.g., drug substance interaction/degradation, pH change, appearance change, particle formation, protein aggregation/structure change, etc.). 

In order to assess these risks and manage the potential issues posed by leachables, it is necessary to know the identities and the levels to which leachables will accumulate in the finished drug product over its shelf-life. These two pieces of information can be used to establish the magnitude of patient exposure (dose) and therefore the safety risk posed by an individual leachable, as well as the likelihood of any compatibility issues involving the drug product. 

Regulatory guidelines and various best-practice recommendations all state that assessment of the potential impact of contact between a component or material and a final dosage form involves testing the final dosage form for leachables. This assessment therefore includes a migration or leachables study whose purpose is to discover, identify, and quantitate leachables that have migrated from the contacted system, components or materials and accumulated in the dosage form. 

There are many science-based and practical reasons why such a leachables assessment cannot stand alone as the single means of assessment. Since the pharmaceutical packaging/delivery system is the primary source of potential leachables, it is appropriate that any leachables assessment be preceded by an extractables assessment performed on the packaging/delivery system, its primary and certain critical secondary packaging components, and/or packaging and delivery system materials of construction; consistent with regulatory guidelines and best-practice recommendations. Such an extractables assessment can also be performed on particular components and/or materials of construction of manufacturing and packaging equipment, as well as certain tertiary packaging components, that are deemed of high leaching potential or have been implicated in an identified leachables problem with a particular drug product.   Extractables assessments can be used to:

  • Characterize packaging/delivery systems, packaging components, combination product medical device components, manufacturing components, and their various materials of construction 

  • Facilitate the timely development of safe and effective dosage form packaging/delivery systems, manufacturing systems and processes by assisting in the selection of components and materials of construction 

  • Understand the effects of various manufacturing processes (e.g., sterilization) on packaging components and their potential leachables 

  • Establish the worst-case potential leachables profile in a manner which facilitates leachables studies, the development of leachables specifications and acceptance criteria (should these be required), and the safety evaluation/qualification of potential and actual leachables 

  • Establish the worst-case potential leachables profile in a manner which facilitates the safety evaluation/qualification of probable leachables when it is not scientifically possible to determine actual leachables • Facilitate the assessment of patient exposure to chemical entities resulting from direct contact between a patient's body tissue(s) (e.g., mouth, nasal mucosa) and a packaging or combination product medical device component (e.g., a metered dose inhaler's plastic actuator/mouthpiece) 

  • Facilitate the establishment of qualitative and quantitative leachablesextractables correlations 

  • Facilitate the development of extractables specifications and acceptance criteria (if these are required) for packaging components, combination product medical device components, and materials of construction 

  • Facilitate investigations into the origin(s) of identified leachables whose presence causes out-of-specification results for a marketed product

  In these ways, extractables assessments can support Quality by Design principles for the development and manufacture of pharmaceutical packaging/delivery systems and drug products. Note that although characterization of packaging/delivery systems and materials is a goal of many extractables assessments, regulatory guidances and bestpractice recommendations clearly stress that extractables assessments also serve as investigations into potential leachables (1–6).   

As stated previously, it is not a goal of this chapter to identify each case in which an extractables assessment is required for packaging/delivery systems, individual packaging components, or materials of construction for any particular type of dosage form. This is the responsibility of the sponsor, and assumes appropriate consideration of applicable regulatory guidance documents. 

Rather, this chapter addresses the question 

“If an extractables assessment is required, what are the scientific principles and best demonstrated practices under which it should be accomplished?”   

Achieving the objectives of an extractables assessment requires performance of an extraction study in order to create extractables profiles. An extraction study has two critical dimensions: laboratory generation of the extract (extraction) and testing the extract (characterization)