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  • Identification of Extractables and Leachables Impurities

    Extractables are chemical compounds that migrate from any product contact material when exposed to an appropriate solvent under exaggerated conditions of time and temperature.

    Leachables are chemical compounds that migrate into the drug formulation from any product contact material, including glass, plastic, stainless steel, elastomeric, or coating components as a result of direct contact with the drug formulation under normal process conditions or accelerated storage conditions and are found in the final drug product. They can increase the toxicity and impurity levels of the drug product and react with product components.

    The packaging materials for pharmaceutical products are designed to protect them from environmental contamination. However, the presence of extractable and leachable originating from these packing materials in the pharmaceutical product can lead to a change in its composition that can in turn modify its therapeutic action, its organoleptic properties, or its stability. Following is the Revised table adapted from USP;

    Degree of Concern Associated with Route of AdministrationLikelihood of Packaging Component-Dosage Form Interaction
    HighMediumLow
    HighestInhalation: Aerosols, SpraysInjections and Injectable Suspensions; Inhalation SolutionsPowders: Sterile, Injectable, Inhalation
    HighTransdermal Ointments and PatchesOphthalmic Solutions and Suspensions Nasal Aerosols and Sprays 
    LowTopical: Solutions and Suspensions, Aerosols Oral: Solutions and Suspensions Oral: Tablets, Capsules, Powders Topical: Powders

    Detection of Extractables and Leachables:

    The analytical techniques used for the quantitative and qualitative characterization of impurities such as infra-red (IR), visible ultraviolet spectroscopy, High-performance Liquid Chromatography (HPLC), or gas chromatography (GC), both coupled with mass detectors. ICP-OES & ICP-MS Plasma spectroscopy is also used for the quantification of metals.

    Nature of ImpuritiesAnalysis Performed by the Instruments
    Semi-volatile organic compoundsGC-MS or high-resolution accurate mass (HRAM) GC-MS
    Non-volatile organic compoundsHRAM LC-MS/MS.
    Elemental impurities (metals)ICP-MS

    Regulatory Guidance:

    The FDA Guidance for Industry, Container Closure System for Packaging Human Drugs and Biologics, provides guidance on principles for submitting information on packaging materials used for human drugs and biologics. For solid dosage forms, there is a low risk of contact between packaging material and a solid oral dosage form.

    For medical devices, extractables and leachables testing are required by the Centre for Devices and Radiological Health (CDRH) of the FDA. Also, various ISO guidelines address the issue of impurities. Development, validation, and testing of components must be carried out under the International Conference on Harmonization (ICH) and US Pharmacopeia guidelines. The ICH Tripartite Q6A guideline Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances indicates that an extractable study is only recommended for oral liquid and parenteral drug products, but not for tablets or hard capsules. The guidance references the threshold of toxicological concern (TTC) as 1.5 µg/day.

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