General Concepts for Leachables Assessment

During the course of manufacturing, packaging, storage, distribution, and administration, dosage forms and/or their formulation constituents 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. Leachables, which can include both organic and inorganic (i.e., elemental) 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. In order to assess these risks and manage the potential issues posed by leachables, it is necessary to know their identities and the levels to which they 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 drug product compatibility issues.

Regulatory guidelines, requirements, and various best practice recommendations all state that the definitive assessment of the potential impact of contact between a packaging/delivery system and a final dosage form involves testing the final drug product for leachables. 

In its most essential form, this impact assessment involves performing 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 finished dosage form under the product's actual manufacturing, storage and clinical use conditions. A leachables study is a laboratory investigation into the qualitative and quantitative nature of a particular leachables profile(s) over the proposed shelf-life of a particular drug product. 

The purpose of a leachables study is to systematically and rationally identify and quantify (i.e., characterize) drug product leachables to the extent practicable, and within certain defined analytical threshold parameters. The results of leachables studies are used in the overall leachables assessment to understand the impact of leachables on patient safety and drug product quality and stability.

Leachables studies can be used within the context of an overall leachables assessment to:

  • 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

  • Facilitate the establishment of qualitative and quantitative leachables–extractables correlations in drug products, when coupled with an appropriate extractables assessment(s)

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

  • Identify trends in drug product leachables accumulation levels over the shelf-life of a particular drug product

  • Facilitate change-control processes for drug product packaging/delivery systems (as appropriate), packaging components, materials of construction, formulation constituents, etc.

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

In these ways, leachables studies and assessments can support Quality by Design (QbD) principles for the development and manufacture of pharmaceutical packaging/delivery systems and drug products.

A complete leachables assessment includes understanding the safety impact of individual leachables, safety qualification of individual leachables, and developing an understanding of the impact of individual leachables on drug product stability (i.e., compatibility) and stability. Although safety qualification is presented in general terms, the details of attaining this goal are beyond the scope of this chapter, which is limited to general scientific principles and best practices for the conduct of leachables studies and the other stated uses of the results of leachables studies within an overall leachables assessment. The reader is directed to authoritative manuscripts on this topic (2,8,9).

Note that certain packaging and combination product medical device components are (or can be) in direct contact with a patient's mouth, nasal mucosa, or other body tissue(s) during normal use of the drug product. Such packaging components include metered dose inhaler and dry powder inhaler mouthpieces, transdermal patches, etc. Patients are potentially exposed to chemical entities by direct contact from such components. Assessment of patient exposure in such direct contact scenarios is best accomplished with appropriate extractables assessments and extraction studies, and the reader is referred to 1663.