Leachables risk assessment | Materials Metric | Chem Lab

Leachables risk assessment is the structured process of identifying, quantifying, and evaluating the toxicological significance of chemical compounds that migrate from packaging, container-closure systems, or device materials into a drug product, biologic, or medical device during its intended use. Conducting a thorough leachables risk assessment helps manufacturers demonstrate product safety, satisfy regulatory requirements, and protect patients from unintended chemical exposure. At Materials Metric, we support this process with validated analytical and toxicological testing services tailored to each product type.

Regulatory agencies worldwide — including the FDA, EMA, and ISO technical committees — now expect manufacturers to submit documented leachables data as part of product approval packages. Consequently, the scope and rigor of leachables studies have grown substantially over the past decade. Furthermore, guidance documents such as ISO 10993-18 Chemical Characterization and the USP General Chapter <232> Elemental Impurities have formalized expectations across both drug and device sectors.

Understanding where leachables originate, how to detect them, and what thresholds trigger safety concern is essential for any organization developing regulated products. In addition, a well-executed leachables risk assessment reduces late-stage development failures and costly post-market recalls. This guide walks through the key concepts, regulatory frameworks, testing strategies, and analytical tools that underpin a defensible leachables program.

Key Takeaways

• A leachables risk assessment evaluates chemical compounds that migrate from materials into a product during normal use.
• Regulatory frameworks such as ISO 10993-18, USP <232>, and ICH Q3D set the global standard for leachables evaluation.
• Risk assessment combines analytical detection with toxicological thresholds such as the Analytical Evaluation Threshold (AET) and Tolerable Intake (TI).
• Extractables data from worst-case solvent studies informs — but does not replace — real-world leachables testing.
• Validated analytical methods, including GC-MS Analysis and HPLC Analysis, are essential for credible leachables data.
• Early engagement with a qualified laboratory reduces regulatory risk and accelerates product timelines.

Leachables Risk Assessment: A systematic, science-based evaluation that identifies chemical substances migrating from product-contact materials under normal conditions of use, quantifies their levels, and determines whether those levels pose an unacceptable toxicological risk to patients or users.

Key fact: Leachables from container-closure systems and device materials are a leading cause of drug product impurity findings during FDA pre-approval inspections and NDA/BLA review cycles.

What Is a Leachables Risk Assessment and Why Does It Matter?

A leachables risk assessment is a formal evaluation of chemicals that move from materials — such as rubber stoppers, plastic tubing, adhesives, or coatings — into a finished product during manufacture, storage, or use. These migrating substances can be present at trace levels, yet some carry significant toxicological concern even at very low concentrations. Therefore, accurate identification and quantification are non-negotiable steps in any robust safety program.

Manufacturers often underestimate the complexity of leachables evaluation. For example, a single elastomeric closure can contain dozens of processing aids, accelerators, and antioxidants that may migrate under physiological conditions. Moreover, the migration profile changes with temperature, pH, contact time, and formulation composition. Consequently, a one-size-fits-all approach rarely satisfies modern regulatory expectations.

How Leachables Differ from Extractables

Many teams confuse leachables with extractables. Extractables are compounds released from a material under aggressive, worst-case laboratory conditions — typically using organic solvents at elevated temperatures. By contrast, leachables are the subset of extractables that actually migrate into the product under real-world conditions of use. For a deeper comparison, see our dedicated article on Extractables vs Leachables.

Importantly, not every extractable becomes a leachable. The relationship depends on solubility, partition coefficients, contact time, and the physical properties of both the material and the product formulation. However, extractables studies still serve as a critical risk-screening step. They reveal the chemical universe from which leachables can emerge, guiding the design of targeted leachables monitoring programs.

Who Needs a Leachables Risk Assessment?

Any organization developing or manufacturing a regulated product that contacts a material component must consider leachables. This includes pharmaceutical companies, biologic manufacturers, medical device makers, and combination product developers. Furthermore, contract manufacturers, packaging suppliers, and raw-material vendors increasingly face demands for leachables data from their customers.

Regulatory agencies do not limit leachables expectations to injectables or inhalation products. Topical drug products, implantable devices, and even some oral solid dosage forms with novel packaging now fall under leachables scrutiny. Specifically, products with high patient exposure or vulnerable patient populations — such as pediatric or oncology drugs — receive heightened regulatory attention. For device-specific contexts, our article on Medical Device Extractables and Leachables provides additional detail.

What Are the Key Regulatory Frameworks Governing Leachables Risk Assessment?

Several overlapping regulatory frameworks govern leachables risk assessment globally. Understanding which standards apply to a given product type — and how they interact — is essential for designing a compliant study program. Overall, the landscape spans guidance from ISO, USP, ICH, and regional regulatory agencies such as the FDA and EMA.

ISO 10993-18 and the Biological Evaluation Plan

For medical devices, ISO 10993-18 Chemical Characterization defines the framework for chemical characterization and risk assessment. It establishes the concept of the Threshold of Toxicological Concern (TTC) and requires a systematic approach to identifying, quantifying, and evaluating all chemical substances associated with a device. Furthermore, ISO 10993-18 integrates directly with biological evaluation plans under the broader ISO 10993-1 standard.

The standard requires manufacturers to consider both intentional and unintentional substances in a device’s materials. Consequently, residual monomers, processing aids, colorants, and degradation products all enter scope. Additionally, ISO 10993-18 mandates that chemical characterization precede biological testing where possible, reducing unnecessary animal studies. Our Biocompatibility & Toxicity Testing services align directly with this framework.

USP Chapters and ICH Guidelines for Pharmaceutical Products

For pharmaceuticals, the primary standards include USP <1663> (Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems) and USP <1664> (Assessment of Drug Product Leachables). Meanwhile, elemental impurities from container-closure systems fall under USP General Chapter <232> Elemental Impurities and ICH Q3D. These chapters set Permitted Daily Exposure (PDE) limits for 24 elemental impurities across multiple routes of administration.

ICH Q3D classifies elemental impurities into three groups. Class 1 elements — arsenic, cadmium, lead, and mercury — pose the highest human risk. Meanwhile, the Class 2 group includes elements with route-dependent PDEs, such as cobalt, nickel, and vanadium. By contrast, Class 3 elements carry lower toxicological concern under most routes of administration. Each classification directly influences the stringency of leachables risk assessment for elemental species in pharmaceutical products.

FDA Guidance and Industry Standards

The FDA has published multiple guidance documents addressing container-closure systems, metered-dose inhalers, and combination products. For example, the 1999 FDA Guidance for Industry on Container Closure Systems for Packaging Human Drugs and Biologics established the foundational expectation that manufacturers characterize the safety of all product-contact materials. More recent FDA draft guidances have updated safety thresholds and analytical expectations in line with current science.

Industry organizations such as the Product Quality Research Institute (PQRI) have also published widely cited recommendations for inhalation and injectable drug products. Notably, PQRI introduced the Safety Concern Threshold (SCT) and Qualification Threshold (QT) concepts that many regulatory agencies now reference. In addition, the Alliance for the Advancement of Biosafety & Drug Product Safety (ABS) continues to publish best-practice recommendations. Reviewing PubMed Central – Trace Metals Review provides access to peer-reviewed literature supporting these thresholds.

How Is a Leachables Risk Assessment Structured?

A well-structured leachables risk assessment follows a defined, stepwise process. Each phase builds on the previous one, creating a defensible data package that regulators can review with confidence. Furthermore, the process integrates analytical chemistry, toxicology, and regulatory strategy into a unified program.

Step 1: Material Inventory and Risk Ranking

Every leachables program begins with a complete inventory of all product-contact materials. This includes primary packaging components, device materials, adhesives, lubricants, filters, and any material that contacts the product during manufacture. Consequently, supply chain transparency is a prerequisite — manufacturers must obtain full material disclosures from their suppliers. Our article on Supplier Change Risk Assessment explores how material changes trigger re-evaluation requirements.

After building the inventory, teams assign a risk rank to each material based on contact type, duration, temperature, and the product’s route of administration. For example, a rubber stopper contacting an injectable product for two years at room temperature receives a higher risk rank than a polyethylene cap contacting an oral tablet bottle briefly during filling. This ranking guides resource allocation for subsequent testing phases.

Step 2: Extractables Screening Study Design

Extractables screening studies use aggressive solvents to reveal the full chemical profile of a material. Typical solvents include water, acidic aqueous solutions, basic aqueous solutions, and organic solvents such as isopropanol or ethanol. Moreover, elevated temperatures accelerate extraction kinetics, simulating long-term contact in an abbreviated timeframe. Teams then analyze extracts using a battery of orthogonal techniques.

Commonly used analytical tools for extractables screening include GC-MS Analysis for volatile and semi-volatile organics, HPLC Analysis for polar and UV-active compounds, and NMR Spectroscopy for structural confirmation. For elemental impurities, Chemical & Elemental Characterization services using ICP-MS or ICP-OES provide the sensitivity required to meet PDE-based action levels. The goal is to produce a comprehensive chemical inventory — not to prove safety at this stage.

Step 3: Establishing the Analytical Evaluation Threshold

The Analytical Evaluation Threshold (AET) is a critical concept in pharmaceutical leachables risk assessment. It represents the lowest concentration at which a leachable must be reported and evaluated for safety concern. Regulatory guidance calculates the AET from the SCT (typically 1.5 µg/day for inhalation products and 5 µg/day for injectable products) and the maximum daily dose of the product. Therefore, the AET varies for each product and delivery system combination.

Laboratories must develop and validate analytical methods capable of detecting compounds at or below the AET. This demands highly sensitive instrumentation and rigorous method performance criteria. Specifically, our Method Development & Validation team designs fit-for-purpose methods that meet regulatory expectations for specificity, sensitivity, linearity, and accuracy. Pairing robust method validation with sound study design is what separates a defensible leachables program from an incomplete one.

Furthermore, establishing the AET early in the program prevents both over-testing and under-testing. Over-testing wastes resources by chasing compounds with no safety relevance. By contrast, under-testing creates regulatory gaps that reviewers will flag during submission. A correctly calculated AET focuses analytical effort where it matters most — on compounds present above the threshold of toxicological concern.

Analytical Techniques That Support Leachables Risk Assessment

No single analytical technique detects all classes of leachable compounds. Therefore, effective leachables risk assessment relies on a complementary suite of methods. The selection of techniques depends on the compound classes expected from a given material and the sensitivity required to meet the AET.

Spectroscopic methods add structural insight beyond chromatographic identification. For example, FTIR Analysis identifies polymer degradation products and additive classes. Similarly, Raman Spectroscopy provides complementary molecular fingerprinting, particularly for inorganic compounds and surface residues. For particle and surface characterization of leachable deposits, SEM Analysis combined with energy-dispersive X-ray spectroscopy (EDX) reveals morphology and elemental composition simultaneously.

Elemental leachables require dedicated inorganic methods. XRF Analysis provides rapid, non-destructive elemental screening of solid materials, while XPS Analysis characterizes surface elemental states at the sub-nanometer depth. In addition, our Chemical Purity & Contaminant Screening services integrate multiple detection platforms to ensure complete coverage of both organic and inorganic leachable species. For an overview of our full analytical portfolio, explore our Chemical & Analytical Testing capabilities.

How Do Toxicological Risk Assessments Support Leachables Evaluation?

Detecting and quantifying leachables is only half the work. The other half involves determining whether detected compounds pose an unacceptable risk to patients. Therefore, toxicological risk assessment sits at the heart of every credible leachables program. Our dedicated guide on Toxicological Risk Assessment explains the broader methodology in detail.

Toxicologists evaluate each identified leachable against established safety thresholds. Specifically, they consider the compound’s route of exposure, daily patient dose, and duration of use. Furthermore, structural alerts — chemical features associated with mutagenicity or carcinogenicity — trigger more rigorous evaluation pathways, such as ICH M7 genotoxic impurity assessment.

Threshold of Toxicological Concern (TTC)

The Threshold of Toxicological Concern (TTC) provides a pragmatic risk-screening tool. It sets a generic, compound-class-based daily exposure level below which toxicological risk is considered negligible — without requiring compound-specific animal data. For most organic leachables, the TTC is 1.5 µg/day for compounds with structural alerts and 120 µg/day for non-alerting compounds.

Regulators widely accept TTC-based arguments for compounds lacking adequate toxicological databases. However, the TTC does not apply to highly potent compound classes such as aflatoxins, dioxins, or inorganic metals. In those cases, compound-specific Tolerable Intakes (TIs) derived from published toxicological literature must support the leachables risk assessment.

Permitted Daily Exposure and Safety Margins

For elemental leachables, the Permitted Daily Exposure (PDE) value defines the maximum acceptable daily patient dose for each element. Consequently, the leachables risk assessment compares measured elemental concentrations — after dose-normalization — against the element’s PDE. A safety margin greater than one confirms acceptable exposure. By contrast, a margin below one triggers either reformulation, material substitution, or additional risk justification.

Our Biocompatibility & Toxicity Testing team applies both TTC and PDE frameworks depending on the product type and applicable regulatory guidance. Moreover, we integrate toxicological assessments with analytical data to produce complete risk summary reports. These reports directly support regulatory submissions and biological evaluation plans.

Industry-Specific Applications of Leachables Risk Assessment

Leachables risk assessment is not a single, uniform exercise. Different industries apply the same core principles through distinct regulatory lenses and product-specific considerations. Understanding these differences helps teams design appropriate, targeted studies from the outset.

Pharmaceutical and Biologic Drug Products

Pharmaceuticals and biologics represent the most heavily regulated segment for leachables. Inhalation products face the strictest thresholds because inhaled compounds bypass first-pass metabolism and deposit directly in sensitive lung tissue. Similarly, injectable products require low SCTs due to direct systemic exposure. Oral products generally receive less stringent thresholds, reflecting gastrointestinal metabolism and lower bioavailability of many leachables.

Biologics present additional complexity. Protein-based drugs are highly sensitive to trace metals, oxidizing agents, and surfactant leachables that can destabilize or aggregate the active molecule. Therefore, leachables risk assessment for biologics must consider not only patient safety but also product quality impacts. Our Chemical & Analytical Testing services cover both safety and product quality dimensions of leachables evaluation.

Medical Devices and Implantable Components

Medical devices span an enormous range of materials — from silicone and polyurethane to titanium alloys and ceramic composites. Each material class carries a distinct leachables profile. Furthermore, the ISO 10993-18 framework requires chemical characterization of all device materials, not just the primary patient-contact layer.

Implantable devices require especially rigorous leachables programs because leachables exposure is continuous and often lifelong. Consequently, even sub-microgram-per-day exposures to certain metals or degradation products can accumulate to toxicologically significant levels over years of implantation. Our Chemical & Elemental Characterization services provide the high-sensitivity elemental data that device manufacturers need for these long-term risk evaluations.

Combination Products and Drug-Device Interfaces

Combination products — such as prefilled syringes, autoinjectors, and drug-eluting stents — present the most complex leachables scenarios. Both the drug product and the device component contribute to the total leachables profile. Moreover, interactions between the formulation and device materials can generate novel leachable species not present in either component alone.

Regulatory agencies expect sponsors to evaluate leachables from both the drug and device perspectives. In practice, this means applying both pharmaceutical USP <1664> expectations and ISO 10993-18 device frameworks simultaneously. Our Scientific & Technical Consulting team helps clients navigate this dual-framework challenge and design unified study protocols. Research published in ScienceDirect continues to advance the analytical methods available for these complex systems.

Quality Assurance and Best Practices in Leachables Programs

A technically sound leachables risk assessment can still fail regulatory review if quality assurance practices are inadequate. Regulators scrutinize study documentation, method validation records, instrument qualification data, and the traceability of all reported results. Consequently, quality systems must be embedded throughout the leachables program — not applied as an afterthought.

Method Validation and GMP Compliance

Analytical methods used in leachables studies must meet GMP or GLP standards, depending on the product type and stage of development. Specifically, methods must demonstrate specificity, linearity, accuracy, precision, limit of detection (LOD), and limit of quantitation (LOQ) at concentrations relevant to the AET. Our Method Development & Validation team builds validation packages that satisfy both FDA and EMA submission requirements.

Importantly, method validation for leachables differs from routine pharmaceutical method validation. Matrix effects from the drug formulation, low analyte concentrations near the LOQ, and the chemical diversity of potential leachables all complicate validation. Furthermore, the validation must cover the full analytical workflow — from sample preparation through detection — not just the instrument performance. Rigorous validation protects the integrity of all downstream risk conclusions.

Documentation and Data Integrity

Comprehensive, audit-ready documentation is non-negotiable in any regulated leachables program. Every analytical result, instrument run, calibration record, and deviation must be captured in a traceable data package. Moreover, data integrity requirements under 21 CFR Part 11 and EU Annex 11 apply to electronic records generated during leachables testing.

Study reports must clearly describe the rationale for material selection, the study design, the analytical methods, the identified compounds, and the toxicological risk conclusions. Additionally, reports should explicitly state the AET used, the basis for its calculation, and any compounds identified above or below that threshold. Clear, transparent reporting accelerates regulatory review and reduces the likelihood of information requests that delay submissions.

Comparison of Key Leachables Evaluation Thresholds

The table below compares the primary safety thresholds used across different product categories and regulatory frameworks. Understanding these thresholds helps teams set appropriate AETs and design studies with the correct sensitivity targets.

Quick note: Applying the wrong threshold to a product type is one of the most common regulatory deficiencies in leachables submissions. Always confirm which framework — and which specific threshold value — applies before calculating your AET or interpreting risk conclusions. Our Scientific & Technical Consulting team can help you make the right determination.

Continuous Monitoring and Change Control

A leachables risk assessment completed at product launch is not a permanent certificate of safety. Material changes, supplier switches, manufacturing process modifications, and storage condition shifts can all alter the leachables profile of a product. Therefore, robust change control procedures must trigger leachables re-evaluation whenever a relevant change occurs.

Additionally, stability programs should incorporate leachables monitoring at defined time points throughout shelf life. Leachables levels can increase over time as materials age, plasticizers migrate, or antioxidants deplete. Consequently, end-of-shelf-life leachables data provides the most conservative — and most regulatorily defensible — safety picture. Partnering with an experienced laboratory early ensures that stability protocols capture leachables data alongside traditional chemical and physical attributes.

Frequently Asked Questions About Leachables Risk Assessment

What is the difference between a leachable and a contaminant?

A leachable originates specifically from a product-contact material — such as packaging or a device component — and migrates into the product under normal conditions of use. By contrast, a contaminant is an unintended substance introduced from the manufacturing environment, raw materials, or process equipment. Both require risk evaluation, but leachables assessment focuses specifically on material-derived migration under defined contact conditions.

When should leachables testing begin in the product development lifecycle?

Leachables risk assessment ideally begins at the material selection stage — well before clinical trials or regulatory submission. Early-stage extractables screening identifies high-risk materials before significant development investment occurs. Consequently, teams can substitute problematic components without costly late-stage redesigns. Regulatory agencies also expect leachables data packages to mature progressively from Phase 1 through NDA or 510(k) submission.

Which analytical methods are most important for leachables risk assessment?

No single method covers all compound classes. Effective programs combine GC-MS Analysis for volatile and semi-volatile organics, HPLC Analysis for polar and non-volatile compounds, and ICP-MS or ICP-OES for elemental impurities. Furthermore, structural confirmation techniques such as NMR Spectroscopy and FTIR Analysis add chemical identity confidence to quantitative data. The specific combination depends on the material type, product contact conditions, and applicable regulatory framework.

How does leachables risk assessment differ for inhalation versus injectable products?

Inhalation products carry the strictest leachables thresholds because inhaled substances bypass hepatic first-pass metabolism and contact sensitive airway tissues directly. The SCT for inhalation products is 1.5 µg/day, compared to 5 µg/day for injectable products. Additionally, inhalation leachables studies must consider aerosol dynamics and the deposition of particulate leachables in the lung. Injectable products require leachables evaluation across the entire container-closure system — vials, stoppers, crimp seals, and any in-line filters used during administration.

Does a leachables risk assessment need to be repeated after a supplier change?

Yes — any change to a product-contact material, including a supplier switch, a reformulation of that material, or a change in manufacturing site, should trigger a leachables re-evaluation. Specifically, the re-evaluation scope depends on the magnitude and nature of the change. Our article on Supplier Change Risk Assessment provides detailed guidance on scoping these re-evaluations appropriately. In addition, regulatory agencies may require a Prior Approval Supplement or equivalent notification if the leachables profile changes significantly.

What documentation does a regulatory agency expect in a leachables submission?

Regulatory submissions should include a complete description of all product-contact materials, the extractables screening data and methods used, the AET calculation and its basis, a list of all identified leachables above the AET, toxicological risk assessments for each identified compound, and a clear overall risk conclusion. Furthermore, method validation reports, instrument qualification records, and representative chromatograms or spectra support the analytical credibility of the package. Consulting authoritative resources such as USP Elemental Impurities and ISO 10993-18 helps teams align their documentation with current regulatory expectations.

Conclusion

A rigorous leachables risk assessment is one of the most critical investments a regulated product developer can make. It protects patients from unintended chemical exposure, satisfies increasingly demanding regulatory expectations, and prevents costly late-stage development failures. Moreover, a well-documented leachables program demonstrates a manufacturer’s commitment to product quality and patient safety — attributes that regulators and customers alike value highly.

Building a credible leachables program requires the right combination of analytical expertise, toxicological knowledge, and regulatory strategy. Specifically, it demands validated methods capable of detecting compounds at or below the AET, an orthogonal suite of analytical techniques, and experienced toxicologists who can translate data into defensible risk conclusions. Furthermore, quality systems must support the program from study design through final report delivery.

At Materials Metric, our integrated team of analytical chemists, toxicologists, and regulatory consultants provides end-to-end support for leachables risk assessment across pharmaceutical, biologic, medical device, and combination product programs. From early-stage extractables screening through final leachables monitoring and stability testing, we deliver the data and documentation you need to move forward with confidence.

If your organization is starting a new leachables program, responding to a regulatory information request, or re-evaluating a product after a material change, we are ready to help. Contact Materials Metric today to discuss your specific leachables risk assessment needs and learn how our team can support your regulatory and safety objectives.

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