Extractables and Leachables: An Overview of Emerging Challenges - Pharmaceutical Technology

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Extractables and Leachables: An Overview of Emerging Challenges
Extractables and leachables are a growing concern for pharmaceutical manufacturers and regulatory bodies.


Pharmaceutical Technology
Volume 32, Issue 8


Figure 1. Examples of leachables derived from packaging components
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.

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 and sorption.

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 studies (22).

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.


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