Experts in identifying unknown compounds

Increased demand for biopharmaceutical medicines has brought with it a greater need for extractables and leachables (E&L) testing to mitigate cross-contamination risks, prevent product adulteration, ensure patient safety, and comply with regulations.

Quantifying, identifying, and evaluating the potential migration of toxic chemicals and impurities from container closure systems, manufacturing components, or delivery devices into pharmaceuticals and biologics has become a critical quality requirement.

The Eurofins BioPharma Product Testing (BPT) network of laboratories offers the highest standards on extractables studies on primary packaging, biologics, single-use systems (SUS) and other consumables used in the pharmaceutical manufacturing chain, as well as leachables testing in the final product.

With more than 100 dedicated E&L scientists, we possess a deep understanding of evolving regulatory expectations.

Our expert toxicologists and consultants (which include European Registered Toxicologist [ERT] and HAS consultant) perform risk assessment of product configuration or manufacturing chain elements, design studies that provide meaningful extractables data, recommend testing options,

and carry out toxicological evaluation to determine potential impacts on patient safety. When required, we can also develop and validate fully GMP-compliant methods to monitor leachables in drug products or intermediates.

With 20 years of experience, and hundreds of controlled extraction studies carried out every year, we offer a diverse range of controlled extraction techniques to generate extractable profiles.

Our proprietary spectral database (EEI: Eurofins Extractables Index) contains reference spectra for over 1,500 non-volatile compounds (including common plasticisers, anti-oxidants, stabilisers, elastomers, lubricants and accelerants) used to identify extractable compounds detected by LC/MS. Using EEI, QSAR methods, and state-of-the-art analytical equipment, we can precisely match extractable profiles to the intended use of the components under evaluation, and conduct simulated and real-time leachables studies to assess the presence of leachable compounds in drug products. Utilising top-of-the-line instrumentation, our experienced analysts are capable of identifying almost all unknown compounds, and will perform additional investigative testing to recognise even those not in the EEI.

Full-service E&L testing and evaluation

Our approach to E&L testing

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Extractables studies can be designed per guidance protocols such as USP <665>, <1663> and <1664>, as well as ISO 10993, PQRI, BPSA and BPOG documents. Studies are individually developed to meet the expectations of the FDA’s CDER/ CBER/CDRH, EMEA, and other regulatory bodies.

Extraction test techniques

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  • Reflux
  • Soxhlet
  • Sonication
  • Microwave
  • Incubation in controlled temperature conditions (with agitation or recirculation if needed)

Analysis techniques

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Semi-quantitative screening methodologies have been established to analyse extraction solutions by LC/MS, GC/MS, LC/UV, ICP/MS and ICP-OES. Where required, quantitative methods can be developed for specific compounds. These ensure accurate results and meet regulatory expectations.

  • For volatile and semi-volatile organic compounds
    • GC/MS with direct injection sample introduction and electron impact ionisation
    • GC/MS with headspace sample introduction and electron impact ionisation
    • Up-to-date Wiley/NIST databases to assist in identification
  • For non-volatile organic compounds
    • LC/MS TOF (in positive and negative mode using electrospray and atmospheric pressure chemical ionisation), Orbitrap and LC/UV.
    • EEI (containing over 1,500 compounds) to assist in identification.
  • Semi-quantitative analysis for metals
    • Evaluation of samples for 42 metals, including all those listed in USP <232> and ICH Q3D using ICP-OES or ICP/MS
  • Gravimetric determination of extractables
  • TOC
  • FTIR
  • pH

Toxicological evaluation

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  • E&L validation plan: Implementation of the optimal regulatory strategy based upon the specific drug product and drug substance
  • Data gap analysis and quality review: Evaluation of already generated extractable and leachables data and their application to a specific drug product and drug manufacturing process
  • Change assessment for the evaluation of E&L-related  impact within the manufacturing process and primary packaging
  • Risk assessment for a risk-based approach to E&L testing strategy: Risk-level definition for each process component and primary packaging, as well as an appropriate risk mitigation strategy
  • Toxicological risk assessment on the compound of potential concern identified in the E&L studies: Performed by expert toxicologist (including ERT)
  • Permitted daily exposure to evaluate toxicological profile of compounds: Includes expert review-relevant data and scientific literature, use of in silico methods, QSAR, and read-across
  • Evaluation of process-related impurities and special impurities such as nitrosamines
  • Technical support of our consultant in the interaction with regulatory agencies and to reply to deficiencies  
  • Extended experience in project management to help clients navigate into the complexity of an E&L study

Instrumentation

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  • Agilent LC/MS TOF and QTOF
  • Agilent LC/MS Triple Quad
  • AB SCIEX UPLC/MS 4000 Q-TRAP
  • AB SCIEX UPLC/MS 3500
  • Agilent/Waters HPLC/UHPLC - including UV/Vis, RI, Fluorescence, ELSD, CAD and Conductivity detectors
    Agilent GC/MS - with headspace, direct injection, and thermal desorption sample introduction
  • Agilent GC/FID/TCD - both headspace and direct injection sample introduction
  • Agilent ICP/MS
  • Agilent ICP-OES
  • Thermo Scientific iCAP ICP-OES
  • Thermo Scientific ICP-MS
  • Thermo Scientific GC-MS with headspace and direct injection
  • Thermo Scientific LC/MS/MS
  • Thermo Scientific LC/MS Orbitrap
  • Perkin Elmer ICP-OES
  • Dionex ion chromatography system