Medical devices and pharmaceutical products are only as safe as the data that supports them. Before a device reaches a patient or drug advances through development, manufacturers must demonstrate that materials, impurities, and potential leachables do not present unacceptable toxicological risk. Toxicology screening is central to that effort, providing the chemical insight necessary to identify potential hazards, characterize exposure, and support defensible safety assessments. From extractables and leachables studies to impurity profiling and degradant identification, toxicology screening generates complex chemical data sets that can be technically precise yet challenging to interpret in a meaningful toxicological context. Recognizing where toxicology screening commonly falters, and how to address those weaknesses, is crucial for generating reliable, defensible results that accurately characterize potential hazards and inform appropriate risk controls.
Toxicology Screening Pitfall 1: False Positives and False Negatives
What goes wrong
In medical device and pharmaceutical toxicology, screening methods such as non-targeted Gas Chromatography-Mass Spectrometry (GC-MS) or Liquid Chromatography-Mass Spectrometry (LC-MS) analysis are often used to identify extractables, leachables, impurities, or degradation products. While these approaches are highly sensitive, they can generate both false positives and false negatives. False positives may arise from laboratory contaminants, instrument background, column bleed, or misidentified spectral library matches. Conversely, false negatives may occur when analytes fall below detection thresholds, co-elute with dominant compounds, degrade during sample preparation, or fall outside the analytical scope of the selected method. When toxicology screening is confined to a single analytical platform, the resulting data set may present only a partial view of chemical composition, thereby distorting the overall toxicological risk profile of the material or formulation.
How to avoid it
- Use orthogonal analytical techniques (for instance, Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)) to confirm compound identity.
- Apply high-resolution mass spectrometry if detailed structural characterization is required.
- Incorporate appropriate blanks, controls, and system suitability checks to identify laboratory artifacts.
- Conduct confirmatory analysis before incorporating findings into toxicological risk assessments.
Toxicology Screening Pitfall 2: Limited Analytical Scope in Extractables and Impurities Profiling
What goes wrong
Standard toxicology screening workflows often focus on predefined compound classes or target lists. In medical device testing, this may include volatile organic compounds, semi-volatiles, or specific additive chemistries. However, materials, particularly polymers, coatings, adhesives, and inks, can generate unexpected degradation products or reaction byproducts that fall outside of routine screening parameters. Targeted toxicology screening approaches, such as GC-MS or LC-MS analyses constrained to predefined compound lists, may fail to detect unanticipated degradation products or structurally novel leachables. Under these conditions, a “no significant findings” outcome may indicate insufficient analytical breadth instead of genuine chemical absence.
How to avoid it
- Use non-targeted screening methods during early-stage characterization like full-scan GC-MS and high-resolution LC-MS, to capture a broader range of potential extractables and degradation products.
- Periodically review analytical scope against current material formulations and manufacturing changes.
- Expand detection libraries and update spectral databases to improve identification accuracy and capture emerging or structurally novel compounds.
- Apply toxicological risk assessment (TRA) frameworks to contextualize tentatively identified compounds, unidentified peaks, or substances lacking established toxicological data.
Toxicology Screening Pitfall 3: Sample Preparation and Stability Artifacts
What goes wrong
The integrity of toxicology screening data begins well before instrumental analysis, shaped by extraction design, solvent compatibility, and storage conditions. During extractables and leachables studies, aggressive solvents, elevated temperatures, or extended extraction durations can induce degradation pathways that would not occur under normal clinical use, artificially increasing the apparent toxicological burden. Storage variables introduce additional complexity. Exposure to heat, light, or oxygen may promote hydrolysis or oxidation, while adsorption to container surfaces can reduce measurable concentrations of trace-level leachables, particularly in low-dose pharmaceutical formulations. Without carefully controlled preparation and handling protocols, analytical results may reflect laboratory-induced artifacts rather than compounds relevant to real-world patient exposure.
How to avoid it
- Design extraction conditions in accordance with ISO 10993-18 and relevant regulatory guidance to ensure clinical relevance and appropriate chemical coverage.
- Assess extract and test material stability under anticipated storage and handling conditions before proceeding with definitive analysis.
- Select inert containers and validated storage parameters to minimize degradation, oxidation, or adsorption losses
- Maintain detailed documentation of preparation parameters to support data integrity, traceability, and regulatory defensibility.
Toxicology Screening Pitfall 4: Misinterpretation of Screening Results
What goes wrong
Toxicology screening in medical devices and pharmaceutical programs often reveals chemical entities but fails to immediately clarify their safety relevance. Analytical detection alone does not equate to patient risk; each identified compound must be interpreted in the context of exposure estimates, route of contact, duration of use, and established safety thresholds. A trace-level leachable, for example, may fall well below the threshold of toxicological concern (TTC), indicating minimal safety risk despite being detectable. Conversely, structurally similar substances can differ substantially in biological activity, making superficial comparisons unreliable. With no structured risk assessment to contextualize these findings, toxicology screening data may either exaggerate potential harm or overlook clinically meaningful exposure.
How to avoid it
- Integrate analytical findings into a formal toxicological risk assessment in accordance with ISO 10993-17 to translate detected compounds into exposure-based safety evaluations.
- Evaluate each identified substance against route of exposure, duration of contact, and intended patient population to ensure clinically relevant risk characterization.
- Apply structural-activity relationship (SAR) analysis and consult authoritative toxicological databases to assess compounds with limited experimental data.
- Clearly document the level of identification certainty, exposure assumptions, and safety justification within regulatory submissions to support defensible conclusions.
Toxicology Screening Pitfall 5: Over-Reliance on Preliminary Screening Without Confirmitory Characterization
What goes wrong
Early-phase toxicology screening offers valuable preliminary insight into material composition and potential safety concerns. But screening-level identification is inherently provisional; spectral matches alone do not constitute definitive structural confirmation. Regulatory evaluation of medical devices and pharmaceuticals requires compound identification supported by accurate mass measurements, fragmentation patterns, and, where appropriate, comparison to authentic reference standards. Should preliminary detection not be followed by confirmatory characterization, analytical findings may fall short of regulatory expectations, potentially delaying submissions or prompting additional scrutiny.
How to avoid it
- Confirm critical toxicology screening findings using validated, targeted methods such as LC-MS/MS or GC-MS operated in quantitative mode to ensure accurate compound identification and exposure estimation.
- Incorporate authentic reference standards, when available, to verify retention times, fragmentation, patterns, and analytical specificity.
- Clearly define and document levels of identification certainty, such as tentative, probable, or confirmed, to support transparent interpretation.
- Match the depth of analytical characterization to the expectations of the intended regulatory submission to avoid unnecessary delays or follow-up inquiries.
Building a More Reliable Toxicology Screening Workflow
Precise toxicology screening depends on rigorous methods, meticulous sample handling, and careful interpretation. At Jordi Labs, we provide analytical expertise that can support this level of precision. Our chemists support medical device manufacturers and pharmaceutical developers through extractables and leachables studies, impurity profiling, degradant characterization, and toxicological risk assessments. We develop custom analytical methodologies, apply advanced mass spectrometric techniques, and generate defensible data packages suitable for regulatory submission. By integrating analytical chemistry with toxicological interpretation, we help clients to strengthen their safety evaluations and reduce regulatory uncertainty. Contact us to discuss our toxicology services today.
