Leachables can be regarded as subsets of extractables (11). These impurities are released from container, closure, and packaging
components into the drug product (See Figure 1). Leachables can be found in a variety of drug products, including orally inhaled
and nasal drug products (OINDPs), injectables, solid-dosage forms, etc., and they include both organic and inorganic chemical
entities. Organic leachables can be monomers or oligomers of the polymeric material, or additives, cross-linking or curing
agents, antioxidants, plasticizers, pigments, lubricants, and mold release agents, etc., that are used in the manufacture
of the container, closure, and packaging materials. Labels, inks, and adhesives can also leach impurities into the drug product
(19, 29). Leachables include both soluble and insoluble chemical entities.
Figure 1. Examples of leachables derived from packaging components
Identification of leachables can be a significant analytical challenge for some dosage forms. For example, in an MDI, the
rubber and plastic components of the metering valve are in direct, constant contact with the formulation, which is primarily
a propellant, such as a chlorofluorocarbon (CFC) or more ozone-friendly hydrofluoroalkane (HFA), which are both good organic
solvents. It is anticipated that these plastic and rubber valve components in the MDI will leach various agents, and ultraviolet
stabilizing agents are being incorporated in plastics to obtain container-closure systems of desired characteristics. However,
presence of large numbers of ingredients in the plastic container-closure systems pose a serious problem with regard to leaching
Because both the drug product and plastic container happen to be formulations, therefore, contact between these two formulations
can naturally lead to leaching, sorption and chemical interaction. Problems arise with increasing number of components. This
necessitates thorough study of the stability and compatibility of the primary plastic container with the drug product for
which it is to be used. A major disadvantage of plastic containers when compared to the glass is the problem of permeability,
which may result in loss of component(s) of drug product by volatilization or sublimation, or may facilitate degradation of
drug product by allowing contact with atmospheric oxygen or moisture. Materials leached from the primary plastic container
or closure into a liquid preparation leads to contamination. Similarly, any component(s) from the drug product can be adsorbed
onto or absorbed into primary plastic container or closure system with a possibility of a chemical or physical reaction. The
extent of permeation, leaching, sorption, diffusion, and chemical reactivity naturally varies considerably from one plastic
composition to another (1, 2, 30, 31).
With few exceptions, compendial standardization of plastics for parenteral product packages does not exist. Therefore, each
potential vendor's plastic components must be demonstrated to be compatible with drug product through extensive stability
Apart from glass and plastic, certain metals are also being used as primary containers or closures for drug products. Numerous
semisolid products such as paste, gel, cream, or ointment can be conveniently packaged into metallic collapsible tubes. Metallic
containers and cans are also being used for aerosols and other liquid products. Metals commonly used are tin, plastic-coated
tin, tin-coated lead, aluminum, coated aluminum for collapsible tubes, and aluminum- and tin-plated steel for cans/aerosol
containers. Single material tubes/cans can be readily tested for stability with drug products. The steel container is not
chemically inert and, therefore, can react with environment and its contents. Steel's major ingredient, iron, is a chemically
active metal which readily takes part in reactions involving water, oxygen, acids, and other reactive elements or compounds.
Though the application of tin to the surface of steel significantly improves its resistance, the potential for corrosion or
chemical attack still persists. However, coated tubes/containers present additional problems because any absence of continuity,
as well as inertness of the coatings, may lead to chemical interaction or leaching. Moreover, coating should exhibit resistance
towards cracking and solvent(s) (1, 2, 32).
Natural and synthetic rubbers of varying compositions are being widely used in pharmaceuticals and allied products as stoppers,
cap liners, and parts of dropper assemblies.