Materials in Manufacturing and Packaging Systems as Sources of Elemental Impurities in Packaged Drug Products: An Updated Literature Review

Abstract

Elemental impurities in drug products arise from different sources and via a number of different means, including leaching of elemental entities (including the elements themselves or element-containing compounds) from the drug product's manufacturing or packaging systems. Thus, knowledge about the presence, level, and likelihood of leaching of elements in manufacturing and packaging systems is relevant to understanding how these systems contribute to a drug product's total elemental impurity burden. To that end, this manuscript updates a previous review of available literature on elemental entities in pharmaceutically relevant polymers and the presence of these elemental entities in material extracts and/or drug products. This updated review contains the information that has been published subsequent to the publication of the initial review and considers two questions: (1) What elemental entities are present in the relevant polymers and materials and at what levels are they present? (2) To what extent are these elemental entities leached from these materials under conditions relevant to the manufacturing and storage/distribution of solution drug products? The compiled recent data reaffirms the conclusions drawn from the original review: (1) Elemental entities are present in the materials used to construct packaging and manufacturing systems as these materials either contain these elemental entities as additives or are exposed to the elemental entities during their production. (2) Unless the elemental entities were parts of the materials themselves (e.g., SiO₂ in glass) or intentionally added to the materials (e.g., metal stearates in polymers), their incidental amounts in the materials were generally low. (3) If elemental entities were present in materials and systems, generally only a very small fraction of the total available amount of the entity could be leached under conditions that were relevant to the packaged drug products. Thus, although sources of certain elemental impurities may be ubiquitous in the natural environment, they were not ubiquitous in materials used in pharmaceutical packaging and manufacturing systems and when they were present, they were not extensively leached under relevant conditions of use for those systems. This conclusion, supported by an ever-increasing body of literature, suggests that in general the manufacturing and packaging systems, by themselves, do not contribute sufficiently large quantities of elemental impurities that the impurities pose a meaningful threat to patient safety. Furthermore, this conclusion should be considered when standards are developed for the characterization and qualification of manufacturing systems, packaging systems, and their associated materials and components of construction.