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

Extractables and leachables in container-closure systems

Table II: Common extractables and leachables
All primary package components contain constituents such as ingredients, impurities, contaminants, and degradants that have the potential to accumulate in the product. These constituents are typically referred to as extractables or leachables. They may also include compounds present on the surface of the packaging that simply solubilize in the product. In pharmaceutical products, the extractables from the container-closure system and the components of the container-closure system that can leach into the product formulation are important to understand (23). See Table II for a list of common extractables and leachables.
"Extractables are compounds which can be extracted from the container/closure component under extreme conditions such as the presence of harsh solvents or elevated temperature. These compounds can contaminate the drug product. Leachables are compounds that are released into the drug product from the container/closure component as a result of direct contact with the drug product under normal conditions " (11).

Extractables are chemical species released from a primary container or component material that has the potential to contaminate a pharmaceutical product. Extractables are frequently generated by interaction between products and their packaging over time, depending on solvent and temperature conditions. The organic chemical entities into the drug product. Fortunately, information on potential leachables maybe obtained from the known ingredients of the rubber and plastic materials, as well as the fabrication process of the valve (16). For example, thiurams, dithiocarbamates, and mercaptobenzothiazoles are commonly used sulfur-containing curing agents in rubber manufacturing, hence, they are potential leachables in the drug product where sulfur-cured rubber is used. Polybutylene terephthalate (PBT) is a widely used polyester plastic in medical device and MDI valve components. PBT oligomers and other residuals or degradants can be similarly leached from the valve components fabricated from this material (19).

Sources of extractables and leachables

Sources of these compounds include plastic components, elastomers, coatings, accelerants, antioxidants, inks, colors, and vulcanizing agents. Phthalates are one specific example. These carcinogens are added to plastics to make them more flexible and can be found throughout the manufacturing process and in packaging materials. Other examples are nitrosamines and polynuclear aromatic hydrocarbons (PAHs), which are classes of carcinogenic compounds found in rubber (17). Many drug products are distributed or administered in packages made of plastic and rubber components, and, therefore, phthalates, PAHs, or nitrosamines could potentially come into contact with the drug product and be passed on to the patient. MDIs, DPIs, and nebulizers can be complex because they may be constructed from a myriad of plastic, rubber, and stainless steel components. Nevertheless, these devices have many advantages (e.g., rapid absorption and onset of activity and reduced dosing) for effective drug delivery (18).

Extractables and leachables can have considerable influence on the efficacy and safety of drug products, especially highly active biopharmaceutical drug formulations, which may contain extremely small amounts of the active ingredient. Perhaps more important than the toxicology of such materials is their potential to elicit serious immunologic responses, even at extremely small dosages. Extractables and leachables pose problems at every stage: they may interfere with drug product assays, or medical diagnostic tests; they may increase the impurity level of a drug product to an unacceptable level; and they may react with one or more drug product components (18).


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