Extractables and Leachables (E&L) in Emerging Biologics and Advanced Therapies
INTRODUCTION
The rise of biologics and advanced therapies—including monoclonal antibodies, gene therapies, and cell-based products—has revolutionized modern medicine. However, these complex formulations are often highly sensitive to chemical impurities introduced through packaging, storage, or manufacturing systems. Ensuring the purity and stability of these therapies demands a comprehensive approach: Extractables and Leachables Testing for NDA/ANDA.
Extractables and Leachables Testing for NDA/ANDA evaluates potential chemical interactions between the product and the materials it contacts. These tests identify and quantify substances that could migrate from containers, tubing, or process components into the biologic drug, ensuring safety, efficacy, and compliance with regulatory standards.
At ResolveMass Laboratories Inc., we specialize in E&L testing designed to meet the unique challenges of biologics and advanced therapies. Our analytical expertise and regulatory experience help manufacturers navigate FDA and global requirements confidently while safeguarding patient health.
SUMMARY (KEY TAKEAWAYS)
- Extractables and Leachables Testing for NDA/ANDA ensures biologic drugs remain safe and free from harmful chemical contaminants.
- E&L risks are higher in biologics and gene therapies due to their complex formulations and sensitivity to impurities.
- ResolveMass Laboratories Inc. provides end-to-end E&L testing—from material assessment to toxicological evaluation.
- Common analytical techniques include GC-MS, LC-HRMS, and ICP-MS for comprehensive impurity profiling.
- Regulatory agencies such as the FDA and EMA require robust E&L data for NDA/ANDA submissions.
- Early-stage testing minimizes development delays and supports successful regulatory approval.
- Tailored study designs and validated methods ensure accurate, reproducible results.
- Continuous E&L monitoring supports product lifecycle management post-approval.
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UNDERSTANDING EXTRACTABLES AND LEACHABLES IN BIOLOGICS
Extractables are compounds that can be pulled from packaging or process materials under exaggerated laboratory conditions (e.g., heat or solvents).
Leachables, on the other hand, are compounds that migrate into the biologic product during real storage or use conditions.
These impurities can include:
- Plasticizers, antioxidants, and stabilizers
- Process residues, adhesives, or pigments
- Inorganic elements and metal ions
In Extractables and Leachables Testing for NDA/ANDA, understanding these compounds’ presence and behavior is vital to ensure the biologic’s safety, potency, and stability.
IMPORTANCE OF E&L TESTING IN EMERGING THERAPIES
Biologics, gene therapies, and cell-based products are highly susceptible to trace contaminants. Even a minute amount of leachable can alter protein structure, trigger immune reactions, or reduce therapeutic activity.
Extractables and Leachables Testing for NDA/ANDA protects against these risks by:
- Identifying chemical compounds that can migrate into the drug
- Evaluating their toxicological significance
- Ensuring compliance with regulatory requirements like USP <1663>, USP <1664>, and ISO 10993-18
At ResolveMass Laboratories Inc., our E&L studies are tailored to biologic drug properties—ensuring robust data for regulatory review and patient safety.
TYPICAL SOURCES OF EXTRACTABLES AND LEACHABLES
| Material Type | Example | E&L Risk Level |
|---|---|---|
| Primary Packaging | Vials, prefilled syringes, stoppers | High |
| Secondary Packaging | Labels, seals, caps | Medium |
| Manufacturing Systems | Tubing, filters, connectors | High |
| Storage Components | Bags, containers | Variable |
A thorough Extractables and Leachables Testing for NDA/ANDA study maps all contact materials to predict and control contamination sources.
ANALYTICAL TECHNIQUES USED IN E&L TESTING
To achieve comprehensive detection of organic and inorganic impurities, ResolveMass Laboratories Inc. employs advanced analytical technologies:
- GC-MS (Gas Chromatography–Mass Spectrometry) for volatile and semi-volatile compounds.
- LC-HRMS (Liquid Chromatography–High-Resolution Mass Spectrometry) for non-volatile or polar compounds.
- ICP-MS (Inductively Coupled Plasma–Mass Spectrometry) for elemental and metal impurities.
- FTIR and UV-Vis for compound identification and confirmation.
These techniques ensure that Extractables and Leachables Testing for NDA/ANDA meets global regulatory and toxicological standards.
REGULATORY EXPECTATIONS FOR BIOLOGICS AND ADVANCED THERAPIES
Both FDA and EMA require comprehensive E&L data for NDA/ANDA and biologic license applications (BLAs).
Key expectations include:
- Complete risk assessment of all contact materials.
- Defined Analytical Evaluation Threshold (AET) and toxicological evaluation.
- Validated analytical methods for accurate quantitation.
- Scientific justification for test design, extraction solvents, and conditions.
ResolveMass ensures all E&L studies align with USP <1663>/<1664>, ICH Q3D, and ISO 10993-18 standards, providing submission-ready reports.
WHY BIOLOGICS NEED TAILORED E&L STRATEGIES
Biologics differ from small-molecule drugs due to their:
- Larger molecular structures
- Protein sensitivity to pH, temperature, and metal ions
- Higher potential for immunogenic reactions
This makes Extractables and Leachables Testing for NDA/ANDA in biologics more complex. ResolveMass designs custom E&L protocols that mimic real-world conditions to capture the true leachable profile without compromising the biologic’s integrity.
BENEFITS OF PARTNERING WITH RESOLVEMASS LABORATORIES INC.
Choosing ResolveMass Laboratories Inc. for Extractables and Leachables Testing for NDA/ANDA offers several advantages:
- End-to-End Service: From risk assessment to final report generation.
- Advanced Instrumentation: State-of-the-art LC-HRMS, GC-MS, and ICP-MS.
- Regulatory Expertise: Deep understanding of FDA and ICH guidelines.
- Flexible Timelines: Rapid project execution to meet submission deadlines.
- Transparent Reporting: GLP-compliant documentation ready for NDA/ANDA submission.
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10 MOST ASKED QUESTIONS ABOUT E&L TESTING IN BIOLOGICS
Because biologics are sensitive, complex, and often injectable, even trace contaminants can cause immune reactions, protein denaturation, or loss of efficacy.
Extractables and Leachables Testing for NDA/ANDA ensures that no harmful substances migrate from packaging, tubing, or manufacturing materials into the drug.
This testing safeguards drug purity, stability, and patient safety, which are key for regulatory acceptance under NDA or ANDA submissions.
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E&L testing should begin early in formulation or packaging design to identify potential chemical risks before finalizing materials.
Performing extractables studies during early stages helps developers:
-Select safe container closure systems,
-Prevent reactive impurities, and
-Avoid delays during NDA/ANDA approval.
Early integration of Extractables and Leachables Testing for NDA/ANDA is a cost-effective and compliance-focused strategy.
The biggest challenges include:
– Matrix interference: Complex protein solutions can mask low-level leachables.
– Ultra-trace detection: Many impurities exist in parts-per-billion concentrations.
– Protein stability: Aggressive extraction conditions can damage biologic molecules.
To overcome these, specialized labs like ResolveMass Laboratories Inc. use validated gentle extraction methods and high-resolution mass spectrometry for accurate results.
Biologics are large, fragile macromolecules, while small molecules are simpler and more stable.
Thus, Extractables and Leachables Testing for NDA/ANDA in biologics requires:
–Gentler extraction solvents (to avoid protein damage)
–More sensitive detection techniques (e.g., LC-HRMS)
–Stricter contamination control during sampling
This ensures that biologics maintain their structure, potency, and safety profile throughout testing and storage.
Standard analytical platforms include:
–GC-MS (Gas Chromatography–Mass Spectrometry): For volatile organics and plasticizers.
–LC-HRMS (Liquid Chromatography–High-Resolution Mass Spectrometry): For semi-volatile and polar compounds.
–ICP-MS (Inductively Coupled Plasma–Mass Spectrometry): For metal and elemental leachables.
–FTIR (Fourier Transform Infrared Spectroscopy): For compound identification and functional group confirmation.
These techniques provide comprehensive chemical profiles for regulatory submissions.
Regulatory expectations for Extractables and Leachables Testing for NDA/ANDA are defined by:
USP – Assessment of extractables from packaging/delivery systems
USP – Evaluation of leachables in drug products
ISO 10993-18 – Chemical characterization for medical and biologic interfaces
FDA Container Closure Guidance – Defines E&L study requirements for biologic and parenteral products
Following these ensures global compliance with FDA, EMA, and Health Canada requirements.
CONCLUSION
In the era of complex biologics and gene therapies, Extractables and Leachables Testing for NDA/ANDA is not just a regulatory formality—it’s a scientific necessity. It ensures that every therapeutic product reaching patients is safe, pure, and stable.
With its advanced analytical platforms and regulatory insight, ResolveMass Laboratories Inc. empowers pharmaceutical developers to achieve compliant, data-driven submissions that accelerate approval and protect patient health.
Reference
Jenke, D. R. (2013). Extractables and leachables considerations for pre-filled syringes and injection devices. PDA Journal of Pharmaceutical Science and Technology, 67(5), 430–445. https://doi.org/10.5731/pdajpst.2013.00905
Norwood, D. L., & Stults, C. L. M. (2015). A practical approach to extractables and leachables in pharmaceutical packaging and drug delivery systems. Journal of Pharmaceutical Sciences, 104(2), 388–396. https://doi.org/10.1002/jps.24224
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