Extractables vs leachables | Materials Metric

What Are Extractables vs Leachables — and Why Do They Matter?

Moreover,

Extractables vs leachables describes two distinct but closely related categories of chemical compounds that can migrate from materials — such as packaging, medical devices, or drug container systems — into a product or biological environment. Understanding this difference is fundamental for any engineer, scientist, or quality professional working in pharmaceuticals, medical devices, or food contact materials at Materials Metric.

In addition,

Extractables are compounds forced out of a material under aggressive laboratory conditions. Leachables, by contrast, are the subset of those compounds that actually migrate into a product during normal use or storage. Therefore, extractables testing defines the chemical universe of potential migrants, while leachables testing confirms what patients or consumers actually encounter.

However,

Regulatory agencies — including the FDA and ISO — require both types of studies for many product categories. Consequently, a well-designed extractables and leachables (E&L) program protects patient safety, supports regulatory submissions, and reduces the risk of costly product recalls.

Key Takeaways

Extractables are chemicals removed from a material under harsh, exaggerated laboratory conditions.

Leachables are chemicals that migrate into a product during real-world use or storage.

Leachables are generally a subset of extractables — not all extractables become leachables.

Both studies are required by FDA, ISO 10993, and ICH Q3E guidelines for many regulated products.

A structured E&L program protects patient safety and supports regulatory filings.

Analytical techniques such as GC-MS Analysis, HPLC Analysis, and NMR Spectroscopy are central to E&L programs.

Risk-based toxicological thresholds guide decisions about analytical reporting and patient safety.

Extractables vs Leachables: Extractables are chemical compounds isolated from a material under worst-case, exaggerated laboratory extraction conditions, while leachables are the specific compounds that migrate from that same material into a drug, device, or food product under actual conditions of use or storage — making leachables a patient-relevant subset of the broader extractable profile.

Key fact: Leachable compounds from drug container closure systems are a recognized contributor to drug product safety failures — making E&L testing one of the highest-priority analytical activities in pharmaceutical development and medical device qualification.

What Are Extractables? A Closer Look at the Definition

Therefore,

Extractables are chemical substances that migrate out of a material when exposed to solvents, elevated temperatures, or other aggressive extraction conditions in a laboratory setting. Importantly, these conditions exceed anything the material would experience during normal product use. The goal is to create a comprehensive chemical inventory of every compound the material could potentially release.

Furthermore, extractables studies are deliberately conservative. By using exaggerated conditions, analysts ensure they capture even low-abundance compounds that might otherwise go undetected. This broad-spectrum approach forms the foundation of any robust E&L program.

How Extractables Testing Works in Practice

Consequently,

In a typical extractables study, a material sample contacts one or more extraction solvents — often chosen to mimic the polarity of the actual product. As a result, common solvents include water, ethanol, isopropanol, and simulated body fluids. Analysts then apply heat, extended contact time, or other stress conditions to maximize compound recovery.

Consequently, the resulting extract undergoes analysis using multiple complementary techniques. Specifically, GC-MS Analysis excels at identifying volatile and semi-volatile organics. Meanwhile, HPLC Analysis targets polar and non-volatile compounds. Together, these methods generate a detailed extractables profile.

Materials Commonly Evaluated for Extractables

A wide range of materials undergoes extractables assessment. These include polymer tubing, rubber stoppers, adhesives, coatings, medical device components, and pharmaceutical packaging. In addition, single-use bioprocessing equipment — such as bags, filters, and connectors — now receives significant attention due to its direct product contact.

Notably, the chemical complexity of modern polymers means extractables profiles can contain dozens to hundreds of individual compounds. Therefore, thorough analytical coverage is essential. Materials Metric’s Chemical Purity & Contaminant Screening service addresses this complexity directly.

What Are Leachables? Understanding Real-World Migration

Leachables are the compounds that actually transfer from a material into a product under normal or intended conditions of manufacture, storage, or use. By contrast to extractables, leachables reflect real patient or consumer exposure. Therefore, they carry direct safety and regulatory significance.

In pharmaceutical products, leachables appear in the drug formulation itself. For medical devices, they migrate into body fluids or tissues. Consequently, leachables data directly informs toxicological risk assessments and regulatory safety thresholds.

The Relationship Between Extractables and Leachables

Leachables are not an independent group — they come from the pool of extractables already identified. However, not every extractable becomes a leachable. Many compounds present under harsh extraction conditions never migrate at meaningful levels during real product use. Specifically, factors such as solubility, molecular weight, diffusion rate, and product contact time all control whether an extractable becomes a leachable.

Moreover, the extractables profile acts as a predictive tool. Regulators and scientists use it to anticipate which leachables are most likely to appear and at what levels. This relationship is central to understanding the difference between chemical characterization and biocompatibility in a broader regulatory context.

Leachables Testing Methods and Analytical Approaches

Leachables testing typically involves placing the final product — or a representative system — under actual use conditions for defined time periods. Analysts then examine the product itself, or simulated use extracts, for migrating compounds. Because concentrations are often very low, high-sensitivity analytical methods are essential.

For instance, FTIR Analysis supports compound identification when combined with chromatographic data. Similarly, NMR Spectroscopy confirms structural identity for unknown migrants at trace levels. Furthermore, Chemical & Elemental Characterization covers inorganic leachables, including metals from device components or process equipment.

Extractables vs Leachables: Key Differences Side by Side

Many professionals — especially those new to regulated industries — find the distinction between extractables and leachables confusing. However, the differences are clear once you examine them directly. The table below summarizes the most important distinctions.

Characteristic	Extractables	Leachables
Definition	Compounds removed under exaggerated lab conditions	Compounds that migrate under real-use conditions
Testing conditions	Aggressive solvents, elevated temperature, extended time	Actual product formulation, normal storage and use
Timing in development	Early — material selection and development phase	Later — product development and stability studies
Regulatory purpose	Identifies the full chemical universe of potential migrants	Confirms actual patient or consumer exposure
Relationship	Broader set — includes all potential migrants	Subset — only compounds confirmed under use conditions
Primary concern	Comprehensive chemical identification	Patient safety and toxicological risk
Key analytical tools	GC-MS, HPLC, ICP-MS, headspace GC	GC-MS, HPLC, LC-MS/MS, ICP-MS

Why Both Studies Are Necessary

Some teams ask whether extractables data alone is sufficient for regulatory submission. In most cases, the answer is no. Extractables establish the worst-case chemical inventory, but regulators require leachables data to confirm actual patient exposure levels. Therefore, both studies serve distinct and complementary roles.

For example, ISO 10993-18 Chemical Characterization explicitly requires a structured approach that includes both extractables and leachables assessment for medical devices. Similarly, the FDA’s guidance on container closure systems for pharmaceutical products mandates leachables data as part of drug product submissions.

Connecting E&L Data to Toxicological Risk

Identifying a compound is only the first step. Analysts must then determine whether the detected level poses a safety concern. This process — known as toxicological risk assessment — uses established thresholds such as the Analytical Evaluation Threshold (AET), the Safety Concern Threshold (SCT), and the Qualification Threshold (QT).

Furthermore, toxicological risk assessment links the chemical data from E&L studies to patient safety decisions. Importantly, this step requires both solid analytical data and expert toxicological interpretation. Materials Metric’s Biocompatibility & Toxicity Testing service integrates both capabilities for a seamless workflow.

Quick note: The Analytical Evaluation Threshold (AET) is not a safety threshold — it is a sensitivity target for analytical methods. Compounds detected above the AET require further toxicological evaluation, not automatic rejection. Understanding this distinction prevents unnecessary material rejections and costly program delays.

Regulatory Framework Governing Extractables vs Leachables

Multiple regulatory bodies and standards organizations govern E&L testing. Navigating this landscape requires a clear understanding of which guidelines apply to your specific product type. Moreover, requirements continue to evolve as agencies update their expectations.

The most commonly cited frameworks include FDA guidance documents, the ISO 10993-18 Chemical Characterization standard for medical devices, ICH Q3E (under development for drug products), and the PQRI (Product Quality Research Institute) guidelines for orally inhaled and nasal drug products. In addition, the USP General Chapter <232> Elemental Impurities addresses inorganic leachables in pharmaceutical products.

FDA Requirements for Container Closure Systems

The FDA’s 1999 guidance on container closure systems for packaging human drugs and biologics remains a cornerstone document. It requires manufacturers to demonstrate that packaging materials are safe and compatible with the drug product. Consequently, both extractables and leachables data appear in most drug applications for parenteral, ophthalmic, and inhalation products.

For orally inhaled products, the PQRI’s leachables guidance provides specific thresholds and study designs. Furthermore, the FDA increasingly expects E&L programs for topical products and other dose forms where direct material contact is significant. The Chemical & Analytical Testing services at Materials Metric support all of these submission types.

ISO 10993 and Medical Device Requirements

Medical device manufacturers must comply with the ISO 10993 series, specifically ISO 10993-18, which governs chemical characterization of device materials. This standard provides a risk-based framework for E&L studies. Notably, it aligns closely with FDA’s expectations for 510(k) submissions and pre-market approval (PMA) applications.

Under ISO 10993-18, manufacturers select extraction conditions based on device contact type — surface contact, external communicating, or implant — and contact duration. By contrast, pharmaceutical E&L programs focus more on the drug product formulation as the extraction medium. Understanding these differences is essential when designing a compliant study. The FDA chemical characterization review process provides additional context for device submissions specifically.

Elemental Impurities and Inorganic Leachables

Inorganic leachables — particularly heavy metals — receive specific regulatory attention. The USP General Chapter <232> Elemental Impurities sets permitted daily exposure (PDE) limits for 24 elemental impurities in drug products. Similarly, ICH Q3D provides the same framework at an international level.

Analytical techniques such as XRF Analysis and XPS Analysis support elemental screening of materials. Furthermore, inductively coupled plasma mass spectrometry (ICP-MS) provides the high-sensitivity quantitation needed for PDE-level compliance in final drug products. Materials Metric’s Chemical & Elemental Characterization service covers both screening and quantitative elemental analysis.

Advanced Analytical Techniques for Extractables vs Leachables Studies

Choosing the right analytical methods is critical to any successful E&L program. Furthermore, no single technique captures the full chemical diversity of modern materials. Therefore, most programs combine multiple orthogonal methods to maximize coverage and confidence.

Published research in ScienceDirect consistently highlights the value of multi-technique approaches in trace-level contaminant studies. Moreover, regulatory agencies expect analytical strategies that account for both organic and inorganic migrants across a wide concentration range.

Chromatographic Methods: GC-MS, HPLC, and LC-MS/MS

Gas chromatography-mass spectrometry remains the workhorse for volatile and semi-volatile organic extractables. It delivers excellent sensitivity, broad spectral library matching, and reliable quantitation. GC-MS Analysis is therefore standard in nearly every E&L program.

For polar and non-volatile compounds, HPLC Analysis provides complementary coverage. Coupled with mass spectrometry (LC-MS/MS), it achieves sub-parts-per-billion detection limits for targeted leachables monitoring. Consequently, this combination supports even the most demanding pharmaceutical and biologics submissions.

Elemental Analysis: ICP-MS, ICP-OES, and AAS

Inductively coupled plasma mass spectrometry (ICP-MS) is the gold standard for quantifying elemental impurities at trace and ultra-trace levels. It covers the full periodic table and meets the sensitivity requirements of USP Elemental Impurities guidance and ICH Q3D.

ICP optical emission spectrometry (ICP-OES) offers a cost-effective alternative for elements present at higher concentrations. Meanwhile, atomic absorption spectrometry (AAS) provides targeted single-element quantitation when screening for specific metals. Materials Metric’s Chemical & Elemental Characterization service deploys all three techniques based on project requirements.

Spectroscopic and Structural Identification Tools

Structural confirmation of unknown migrants requires spectroscopic tools beyond chromatography. FTIR Analysis rapidly identifies functional groups and polymer fragments in extracts. Additionally, Raman Spectroscopy provides complementary structural data — particularly for inorganic and carbon-based compounds.

For unambiguous structural elucidation, NMR Spectroscopy remains the definitive tool. It identifies molecular connectivity and confirms compound identity independently of spectral libraries. Furthermore, surface-sensitive techniques such as XPS Analysis characterize elemental states and surface chemistry — especially useful for metal device components.

Method Development and Validation for E&L Programs

Analytical methods used in regulated E&L studies must meet defined performance criteria. Specifically, methods require validation for specificity, linearity, accuracy, precision, and detection limits. This ensures results are defensible during regulatory review.

Materials Metric’s Method Development & Validation service builds and qualifies fit-for-purpose methods for both extractables screening and targeted leachables quantitation. Importantly, a validated method aligned to the AET ensures that no safety-relevant compound falls below the analytical detection limit.

Industry-Specific Applications of Extractables vs Leachables Testing

E&L requirements vary significantly across industries. However, the underlying science remains consistent — identify what migrates, quantify it, and assess the risk. The sections below outline how different sectors apply extractables and leachables principles in practice.

Pharmaceuticals and Biologics

Drug product manufacturers face the most developed regulatory framework for E&L testing. Container closure systems, primary packaging, and drug delivery devices all require assessment. In particular, parenteral, inhalation, and ophthalmic products receive the highest scrutiny because they deliver drugs directly into the body.

Biologics present additional complexity. Protein-based drugs are sensitive to leachables that can cause aggregation, degradation, or immunogenic responses. Therefore, E&L programs for biologics often include functional impact studies alongside chemical identification. The Chemical & Analytical Testing team at Materials Metric supports pharmaceutical clients across all dose form categories.

Medical Devices and Implants

Medical device E&L programs operate under the ISO 10993-18 framework. Device manufacturers must characterize all materials in patient contact and assess migration risk based on contact type and duration. Consequently, implantable devices face the most rigorous requirements.

Additives such as plasticizers, stabilizers, antioxidants, and colorants are common extractables targets in device polymers. Furthermore, metallic implants may release corrosion products or wear debris over time — making long-term leachables monitoring essential. For complex device systems, the reusable medical device testing framework adds another layer of E&L consideration.

Single-Use Bioprocessing Systems

Single-use technology — including bioreactor bags, tubing, and filter assemblies — has transformed biologics manufacturing. However, these polymer-intensive systems introduce significant E&L risk at the drug substance level. Regulators now expect comprehensive extractables profiles for all single-use components in contact with drug intermediates.

Industry consortia such as BPOG (BioPhorum Operations Group) have published standardized extractables testing protocols for single-use systems. Moreover, manufacturers increasingly require supplier-generated extractables data before qualifying new components. Materials Metric supports both supplier-side testing and manufacturer-side qualification programs.

Food Contact Materials and Consumer Products

E&L principles extend beyond regulated pharmaceuticals and devices. Food packaging, beverage containers, and consumer product packaging all face migration testing requirements under regulations such as EU Regulation 10/2011 and FDA’s food contact substance notification program.

In these contexts, leachables testing assesses whether packaging components migrate into food or beverages under storage and heating conditions. Similarly, chemical purity evaluation under Materials Metric’s Chemical Purity & Contaminant Screening service applies directly to food contact compliance studies.

Best Practices for Designing a Robust E&L Program

A well-designed E&L program saves time and cost while satisfying regulators. However, poorly planned studies often generate insufficient data — forcing expensive repeat testing. Therefore, upfront investment in program design is always worthwhile.

Start with a Material Risk Assessment

Begin every E&L program with a systematic material risk assessment. Identify all components in contact with the product, rank them by contact type and duration, and prioritize materials with the highest migration potential. This step aligns with the risk-based approach required by ISO 10993-18 and FDA guidance.

Notably, early engagement with regulatory strategy — through Materials Metric’s Scientific & Technical Consulting service — helps teams avoid common design errors. For instance, selecting inappropriate extraction solvents or insufficient contact times can invalidate an entire study.

Apply a Tiered Analytical Approach

Most successful E&L programs use a tiered strategy. The first tier focuses on broad-spectrum screening to identify all compounds above the AET. The second tier quantifies confirmed extractables using validated methods. The third tier correlates extractables data with leachables observed in product stability studies.

This structure prevents unnecessary analytical work at higher tiers for compounds eliminated at the screening stage. Consequently, costs remain manageable without sacrificing scientific rigor. The following list summarizes the core tiers:

Tier 1 — Screening: Broad-spectrum extraction and identification using GC-MS, HPLC-UV, and ICP-MS.
Tier 2 — Quantitation: Validated targeted methods for confirmed extractables above the AET.
Furthermore, Tier 3 — Leachables correlation: Product-contact leachables studies linked to stability testing programs.

Document, Document, Document

Regulatory reviewers scrutinize E&L study documentation carefully. Every extraction condition, analytical method, instrument calibration, and data interpretation decision must be recorded. Furthermore, chain-of-custody records for materials and samples provide essential traceability.

Importantly, studies conducted under good laboratory practice (GLP) or at ISO 17025-accredited laboratories carry greater weight in regulatory submissions. Therefore, selecting a qualified testing partner with documented quality systems matters as much as the analytical techniques themselves.

Integrate Toxicological Evaluation Early

Many teams treat toxicological risk assessment as a final step — conducted only after all analytical data are available. However, integrating a toxicologist early in the program design improves efficiency significantly. Early input defines the AET, shapes extraction strategies, and identifies compounds of concern before costly studies begin.

Materials Metric’s Biocompatibility & Toxicity Testing service pairs analytical chemists with toxicological experts. This integrated model streamlines the path from raw data to a defensible safety conclusion. Additionally, it supports the toxicological risk assessment documentation required for regulatory submissions.

Quick note: Always align your extractables study design with the intended leachables monitoring plan before any laboratory work begins. Mismatched solvent systems or extraction conditions between the two studies are a leading cause of regulatory questions and program delays.

Frequently Asked Questions About Extractables vs Leachables

What is the main difference between extractables and leachables?

Extractables are chemicals removed from a material under exaggerated laboratory conditions. Leachables are the subset of those chemicals that migrate into a product under real use or storage conditions. Therefore, leachables represent actual patient or consumer exposure, while extractables define the worst-case chemical inventory.

Are leachables always a subset of extractables?

In the vast majority of cases, yes. Regulators and industry guidance documents treat leachables as a subset of extractables. However, rare situations exist where a leachable forms through a reaction with the product formulation — making it a degradation product rather than a direct extractable. Consequently, thorough leachables monitoring sometimes reveals unexpected compounds not present in the extractables profile.

Which regulatory guidelines govern E&L testing?

Several frameworks apply depending on product type. For pharmaceutical products, relevant guidelines include FDA container closure guidance, PQRI leachables guidance, and ICH Q3E. For medical devices, ISO 10993-18 is the primary standard. In addition, USP Elemental Impurities guidance applies to inorganic leachables in drug products.

What is the Analytical Evaluation Threshold (AET)?

The AET is a calculated method sensitivity target — not a safety limit. It defines the minimum concentration at which an analytical method must reliably detect and quantify compounds. Specifically, the AET derives from the Safety Concern Threshold (SCT) and accounts for the maximum daily dose of the product. Compounds detected above the AET require further toxicological evaluation.

How long does an E&L study typically take?

Timeline varies based on product type, number of materials, and study design complexity. A focused extractables screening study may complete in four to eight weeks. By contrast, full leachables programs tied to product stability studies can span twelve to twenty-four months. Early planning and well-defined study protocols reduce delays significantly.

Can a material’s extractables profile change over time?

Yes, and this is an important consideration. Manufacturing changes, supplier changes, or material aging can shift a material’s extractables profile. Notably, new additives or processing aids introduced by a supplier may appear without prior notice. Therefore, ongoing extractables monitoring — especially following any material change — is a sound quality practice.

Conclusion

Understanding the distinction between extractables vs leachables is foundational to safe product development across pharmaceuticals, medical devices, and regulated materials. Furthermore, a well-executed E&L program protects patients, satisfies regulators, and builds long-term confidence in your materials and packaging systems.

From broad-spectrum extractables screening to targeted leachables monitoring, the analytical journey requires careful planning, validated methods, and expert toxicological interpretation. Moreover, as regulatory expectations continue to evolve, keeping your E&L program current demands ongoing investment in both science and strategy.

Materials Metric brings together advanced instrumentation, experienced analytical chemists, and regulatory expertise under one roof. Consequently, our team supports E&L programs from initial material risk assessment through final regulatory submission — regardless of product type or regulatory jurisdiction.

Whether you need a rapid extractables screen, a validated leachables monitoring method, or full toxicological risk assessment support, we are ready to help. To discuss your specific project needs and learn how Materials Metric can support your E&L program, please contact Materials Metric today. Our team will respond promptly to scope your requirements and recommend the right analytical approach for your program.