Extractables and Leachables Assessment in Biopharmaceuticals

Extractables and leachables assessment is a critical facet of biopharmaceutical development and quality control, ensuring that medicines remain safe, effective and uncontaminated by substances migrating from packaging, processing or delivery systems. Extractables are compounds that can be forcibly removed from materials under aggressive laboratory conditions, whereas leachables are those compounds that migrate into a drug formulation under normal storage or use. A comprehensive risk‐based assessment comprises material characterisation, identification of potential extractables under various solvents and temperatures, analytical method development to detect leachables at trace levels, and toxicological evaluation against established safety thresholds. Regulatory guidelines require establishment of analytical evaluation thresholds and permitted daily exposures to ensure patient safety. Advances in single‐use technologies and novel container‐closure systems have accelerated biologics manufacturing but have also heightened the need for robust extractables and leachables strategies. Integrated workflows now combine wide‐scope screening by high-resolution mass spectrometry, semi-quantitative risk ranking and predictive modelling of migration behaviour. Collaboration between material suppliers, manufacturers and toxicologists underpins control strategies that range from selection of low-risk polymers and additives through to in-process monitoring, final product testing and post-marketing surveillance.

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Extractables and Leachables Assessment in Biopharmaceuticals publication trend

The graph below shows the total number of articles in extractables and leachables assessment in biopharmaceuticals across all publications each year (not limited to Nature Index journals).

Technical terms

Extractables: Compounds that can be removed from packaging or processing materials under laboratory conditions, representing the maximum potential contaminants.

Leachables: Substances that migrate into a biopharmaceutical formulation under normal storage or use, requiring detection at trace levels.

Analytical Evaluation Threshold (AET): The lowest concentration at which a contaminant must be reported and evaluated during extractables and leachables testing.

Permitted Daily Exposure (PDE): A toxicologically derived limit on the daily intake of a leachable contaminant deemed safe for patients.

Postcolumn Infusion: An analytical technique in which a reference compound is continuously introduced into the mass spectrometer to monitor and adjust for signal variability during chromatographic runs.

High-Resolution Mass Spectrometry (HRMS): A detector capable of precise mass measurement, facilitating the identification of unknown extractables and leachables in complex matrices.

References

1. Determination of Response Factors for Analytes Detected during Migration Studies, Strategy and Internal Standard Selection for Risk Minimization. Molecules (2023).
2. Development of a generic approach for monitoring leachable compounds in hospital pharmacy-prepared prefilled plastic packaging by ultrahigh-performance liquid chromatography coupled to high-resolution mass spectrometry with postcolumn infusion. Journal of Pharmaceutical and Biomedical Analysis (2023).
3. Study of leachable compounds in hospital pharmacy-compounded prefilled syringes, infusion bags and vials. Journal of Pharmaceutical Sciences (2024).
4. Approaches to Quality Risk Management When Using Single-Use Systems in the Manufacture of Biologics. AAPS PharmSciTech (2015).