A container-closure system may appear chemically compatible with a drug product at the beginning of shelf life. That does not necessarily mean the leachables profile will remain unchanged months or years later. Leachables can migrate from packaging, delivery systems, manufacturing-contact materials, or other product-contact components into a pharmaceutical product over time. Their formation and accumulation may be influenced by:

• contact duration;
• storage temperature;
• drug-product composition;
• pH;
• solvents and surfactants;
• container-closure materials;
• surface-area-to-volume ratio;
• storage orientation;
• packaging configuration;
• and material aging.

For this reason, a leachables assessment may need to extend beyond an initial packaging qualification or extractables study and continue through appropriate pharmaceutical stability studies. This principle is reflected in the emerging ICH Q3E framework for extractables and leachables. Draft ICH Q3E states that adequate leachables data should address safety and quality concerns throughout the drug product’s shelf life. Importantly, ICH Q3E remains draft guidance as of October 2026 and should not be described as a finalized harmonized requirement. The scientific rationale, however, is straightforward: Extractables tell us what could potentially migrate. Leachables studies determine what actually migrates into the drug product under relevant conditions. Stability-linked leachables assessment helps determine how that exposure changes over time. Published literature similarly defines leachables as compounds that migrate into a drug product over the course of storage or shelf life. At topiox research, connecting leachables assessment with pharmaceutical stability can therefore help answer a more meaningful question than simply whether packaging contains extractable chemicals: What could the patient actually be exposed to throughout the proposed shelf life of the finished product?  

Why Are Leachables Relevant to Pharmaceutical Stability Studies?

Leachables assessment during stability studies evaluates whether compounds migrate from product-contact materials into the drug product over time and whether their identity, concentration, or impact changes during storage. The underlying process can be represented as: Container-closure / delivery system ↓ Chemical constituents within the material ↓ Drug-product contact ↓ Migration over time ↓ Leachable accumulation in the formulation ↓ Analytical detection and quantitation ↓ Patient exposure assessment ↓ Toxicological and product-quality evaluation This makes time an important variable. A compound absent or present at a very low concentration initially may become measurable later in shelf life. Conversely, a compound detected at an early time point may:

• remain stable;
• increase;
• decrease;
• react with the formulation;
• transform into another compound;
• or become analytically difficult to recover.

Therefore, a single initial measurement may not always characterize the complete leachables profile.  

Extractables and Leachables Are Not the Same

Understanding this distinction is essential.

Extractables

Extractables are compounds that can be released from materials under defined extraction conditions. Extractables studies may use conditions intentionally designed to increase chemical extraction, including:

• elevated temperature;
• selected solvents;
• extended extraction time;
• altered pH;
• or increased material-to-solvent exposure.

Their purpose is often to characterize the chemical substances that could potentially migrate from a material or component.

Leachables

Leachables are compounds that actually migrate into the drug product under manufacturing, storage, or use conditions. Therefore: Extractables = potential Leachables = actual drug-product exposure An extractables study can inform a leachables strategy, but it does not necessarily replace a product-specific leachables assessment. Published analytical literature has long emphasized this distinction.  

Why Can Leachable Levels Change Over Time?

Migration is a dynamic process. A chemical constituent within a polymer, elastomer, adhesive, coating, ink, or other contact material may gradually move toward the material surface and then partition into the pharmaceutical formulation. Conceptually: Material reservoir → diffusion through material → material/product interface → partition into drug product → accumulation or transformation The rate and extent of this process can depend on:

• chemical structure;
• molecular size;
• diffusion coefficient;
• material composition;
• drug-product affinity;
• temperature;
• contact area;
• and duration.

This means that leachable concentration at: T = 0 may differ substantially from: T = 6 months or: T = 24 months or: end of shelf life. That is why leachables and stability can become closely connected.  

Factor 1: Contact Time

Time is one of the most intuitive drivers of leachable migration. Longer contact between the drug product and its packaging can provide more opportunity for compounds to migrate. However, the relationship is not necessarily linear. A leachable might:

• increase continuously;
• approach equilibrium;
• reach a plateau;
• decrease after reaching a maximum;
• degrade;
• react with the API;
• or form secondary products.

Therefore, the objective of stability-linked monitoring is not simply to prove that: “more time equals more leachable.” The objective is to understand the actual concentration-versus-time behavior relevant to the product.  

Factor 2: Storage Temperature

Temperature can influence:

• molecular diffusion;
• polymer mobility;
• partitioning;
• degradation;
• reaction kinetics;
• and material aging.

Higher temperatures may accelerate migration in some material/product systems. This is one reason accelerated or elevated-temperature studies can be scientifically useful. But an important distinction must be maintained: Accelerated conditions can help characterize risk, but they do not automatically reproduce every chemical process that occurs under long-term storage conditions. A compound may behave differently at high temperature because:

• the packaging material changes;
• the drug product changes;
• reaction pathways change;
• solubility changes;
• or degradation accelerates disproportionately.

Consequently, long-term product-contact data remain valuable for understanding real shelf-life behavior. Studies of formulation contact with stainless steel, for example, have shown that temperature can interact with pH and formulation composition to influence metal leaching.  

Factor 3: Drug-Product Composition

The drug product itself can influence what migrates from the packaging. Relevant formulation characteristics may include:

• pH;
• polarity;
• ionic strength;
• surfactants;
• cosolvents;
• alcohols;
• lipids;
• chelators;
• preservatives;
• buffers;
• and other excipients.

A formulation with strong affinity for a packaging additive may extract that compound more efficiently than a simple aqueous solution. Recent research using HDPE packaging demonstrated that formulation excipients influenced extraction behavior, with benzalkonium chloride showing greater extraction potential for several packaging-related compounds than the other evaluated formulation components. Therefore: The same container may not generate the same leachables profile with every drug product.  

Factor 4: pH

pH can influence both packaging materials and migrating compounds. Depending on the system, pH may affect:

• material compatibility;
• metal corrosion;
• hydrolysis;
• leachable stability;
• ionization;
• partitioning;
• and chemical reactions with formulation components.

In biologics-contact studies, pH has been shown to influence metal leaching from stainless steel, with effects that also depended on temperature. The practical implication is that leachables assessment should evaluate the actual formulation-contact environment, not simply the packaging material in isolation.  

Factor 5: Surface-Area-to-Volume Ratio

The amount of packaging surface contacting a given volume of product can influence potential leachable exposure. A smaller fill volume in a container may produce a higher: contact surface area ÷ product volume than a larger fill volume. This can affect the concentration of material-derived substances in the product. Experimental work involving stainless-steel contact demonstrated that metal leachable concentrations changed with the volume-to-contact-area relationship. This becomes particularly important when a product is marketed in:

• multiple fill volumes;
• multiple container sizes;
• different presentations;
• or configurations with different contact surfaces.

Worst-case selection should therefore be scientifically justified rather than based solely on the largest container.  

Factor 6: Storage Orientation

Storage orientation can change which packaging components contact the formulation. For example, depending on the container: upright storage may primarily expose the formulation to the container body, while: inverted or horizontal storage may increase contact with:

• closures;
• stoppers;
• liners;
• seals;
• plungers;
• adhesives;
• or other components.

This can change the potential leachables profile. Storage orientation should therefore be considered when it meaningfully changes product-contact conditions. The appropriate configuration depends on:

• intended storage;
• shipping;
• product use;
• container design;
• and the risk assessment.

 

Factor 7: Packaging Configuration

A pharmaceutical package is rarely composed of one material. Potential sources can include:

• plastic bottles;
• elastomeric stoppers;
• plungers;
• syringe barrels;
• tip caps;
• needle shields;
• seals;
• adhesives;
• labels;
• inks;
• coatings;
• laminates;
• tubing;
• and secondary packaging where migration through semipermeable primary packaging is plausible.

A long-term ophthalmic study, for example, identified diethyl phthalate in the drug product and traced it to an adhesive associated with a tamper-evident packaging component. The lesson is important: A leachable source may not always be the most obvious product-contact component.  

Factor 8: Material Aging

Packaging materials themselves can change during storage. Potential changes include:

• polymer oxidation;
• additive depletion;
• hydrolysis;
• coating changes;
• elastomer aging;
• radiation-related changes;
• sterilization effects;
• and degradation of material constituents.

These changes can alter:

• migration rate;
• identity of migrating compounds;
• and total leachable burden.

A stability-linked assessment therefore has the potential to detect compounds that were not prominent during initial material characterization.  

Factor 9: Interaction Between Leachables and the Drug Product

A leachable does not necessarily remain chemically unchanged after entering a formulation. It may:

• degrade;
• oxidize;
• hydrolyze;
• react with excipients;
• react with the API;
• bind to a biologic;
• promote aggregation;
• or generate secondary impurities.

This creates a particularly important analytical problem: The compound that migrated from the packaging may not be the compound ultimately detected in the aged drug product. For biologics, packaging-derived or process-derived leachables may interact with proteins and potentially affect stability, efficacy, aggregation, or immunogenicity. A broader review similarly concludes that leachables can potentially affect drug-product stability, efficacy, physical acceptability, and patient safety. This is why leachables assessment should not always be treated as separate from conventional stability evaluation.  

Why Extractables Studies Cannot Always Predict Every Leachable

Extractables studies are extremely valuable for identifying potential leachables. But they are not perfect predictors. An actual leachable profile may differ because:

• extraction solvents do not perfectly reproduce the drug product;
• long-term reactions occur;
• packaging ages;
• the drug product chemically transforms the leachable;
• secondary packaging contributes compounds;
• manufacturing introduces additional materials;
• or a compound observed during stability originates from product degradation rather than packaging.

Recent research illustrates this last challenge particularly well. Five compounds observed after long-term storage initially appeared to be potential leachables but were later shown, through targeted experiments and isotopically labelled materials, to originate primarily from formulation ingredients rather than the container system. Therefore: New peak during stability ≠ automatically a packaging leachable Root-cause investigation may be required.  

Targeted vs Non-Targeted Leachables Analysis

A robust stability-linked strategy may use both approaches.

Targeted Analysis

Targets known compounds such as:

• predicted leachables;
• high-risk extractables;
• compounds identified during packaging characterization;
• or substances requiring specific monitoring.

Advantages include:

• strong sensitivity;
• authentic reference standards;
• accurate quantitation;
• and high identification confidence.

Non-Targeted Screening

Looks more broadly for:

• unexpected leachables;
• transformation products;
• previously unidentified compounds;
• or changes in the overall impurity profile.

Techniques can include:

• GC-MS;
• LC-HRMS;
• headspace GC-MS;
• and other complementary analytical platforms.

Broad screening can be important because unexpected compounds may emerge during long-term contact. The balance between targeted and non-targeted analysis should follow the product-specific risk assessment.  

Where Does the Analytical Evaluation Threshold Fit?

The Analytical Evaluation Threshold (AET) helps determine which detected compounds warrant further analytical evaluation under the applicable E&L framework. Conceptually: Safety-based exposure threshold ↓ Product-specific exposure assumptions ↓ AET ↓ Analytical screening ↓ Peaks at or above the relevant threshold ↓ Identification / quantitation / safety assessment For stability-linked leachables studies, the AET provides an important connection between: measured concentration and potential patient exposure. A peak above the AET does not automatically mean that a drug product is unsafe. It means the compound generally requires further evaluation within the applicable framework. For a detailed explanation, internally link here to the topiox research article on Analytical Evaluation Thresholds in Extractables and Leachables Studies.  

Why End-of-Shelf-Life Data Can Be Particularly Important

From a patient-exposure perspective, one of the most relevant questions is: What is the leachables profile when the product is approaching the end of its approved shelf life? That does not mean end-of-shelf-life testing alone is always sufficient. Intermediate time points can help establish:

• migration trends;
• unexpected increases;
• plateau behavior;
• chemical transformation;
• and whether a late-stage result is consistent with earlier observations.

The emerging regulatory direction is particularly clear here. Draft ICH Q3E states that adequate leachables data should address safety and quality concerns throughout the drug product’s shelf life and recognizes that leachables data submitted initially may be aligned with the stability data available at that time. Because ICH Q3E remains draft guidance, the exact study design should remain product- and region-specific.  

Does Every Stability Time Point Need Full Leachables Screening?

Not necessarily. This is an important regulatory and scientific distinction. A risk-based program may not require identical broad-scope E&L analysis at every conventional stability pull. The appropriate schedule depends on:

• dosage form;
• packaging risk;
• product composition;
• route of administration;
• duration of treatment;
• extractables profile;
• available leachables data;
• analytical findings;
• product-contact configuration;
• and applicable regulatory expectations.

For some programs, strategically selected time points may provide sufficient information. For others, more extensive monitoring may be scientifically justified. The study should answer: Can the available data characterize patient exposure and product-quality risk throughout shelf life? rather than: Did we test every time point using every analytical method?  

Leachables and Conventional Stability-Indicating Tests

Traditional stability programs commonly monitor attributes such as:

• assay;
• degradation products;
• pH;
• appearance;
• dissolution;
• particulate matter;
• preservative content;
• moisture;
• sterility;
• or other dosage-form-specific characteristics.

These tests may not necessarily detect or identify packaging-derived leachables. For example, a routine HPLC assay may not detect:

• volatile packaging compounds;
• trace antioxidants;
• plasticizers;
• oligomers;
• elemental leachables;
• or compounds outside the method’s analytical window.

Research on biopharmaceutical systems has specifically noted that leachables or leachable-derived product modifications may not always be detected by routine stability-indicating assays. Therefore: A stability-indicating method is not automatically a comprehensive leachables method.  

High-Risk Product and Packaging Scenarios

The appropriate level of E&L investigation is product-specific, but certain configurations can justify particularly careful evaluation. Examples may include:

• parenteral products;
• ophthalmic products;
• inhalation products;
• biologics;
• prefilled syringes;
• large-volume parenterals;
• semipermeable packaging;
• long shelf lives;
• high daily exposure;
• complex delivery systems;
• and formulations containing strong solvents, surfactants, or chelators.

Prefilled syringes illustrate the issue well because the drug product may contact:

• barrel material;
• plunger;
• stopper;
• lubricant;
• adhesive;
• needle components;
• and other device materials.

Published reviews emphasize that syringe-derived leachables can potentially influence safety, efficacy, stability, aggregation, and other product characteristics.  

A Practical Stability-Linked Leachables Strategy

A scientifically structured program may follow:

1. Characterize product-contact materials ↓ 2. Conduct appropriate extractables studies ↓ 3. Identify potential leachables ↓ 4. Establish an applicable AET or other evaluation threshold ↓ 5. Develop targeted and/or non-targeted analytical methods ↓ 6. Integrate leachables samples with the stability program ↓ 7. Evaluate relevant storage conditions and time points ↓ 8. Monitor known and unexpected compounds ↓ 9. Investigate trends and new peaks ↓ 10. Quantify relevant leachables ↓ 11. Estimate patient exposure ↓ 12. Conduct toxicological and product-quality assessment ↓ 13. Establish appropriate lifecycle controls

The exact program should be adapted to the drug product rather than applied as a universal checklist.  

Common Mistakes in Stability-Linked Leachables Studies

Testing Only at Initial Release

This can miss compounds that migrate or accumulate during storage.

Assuming Extractables Equal Leachables

Extractables identify potential migrants; actual drug-product exposure must be evaluated appropriately.

Testing Only the Packaging Material

The formulation itself can strongly influence migration.

Ignoring Storage Orientation

Different orientations can expose the product to different packaging components.

Assuming Accelerated Conditions Perfectly Predict Long-Term Results

Accelerated studies can be informative but may not reproduce every long-term migration or reaction pathway.

Monitoring Only Known Extractables

Unexpected compounds can emerge during storage.

Calling Every New Stability Peak a Leachable

Some new peaks may originate from API or excipient degradation rather than packaging.

Ignoring Leachable–Product Reactions

A migrated compound can transform after entering the formulation.

Assuming Routine Stability Methods Cover E&L Risk

Routine QC methods may not provide adequate chemical coverage.

Treating Detection as Proof of Safety Risk

Detection should be connected to concentration, patient exposure, and toxicological significance.  

Best Practices for Leachables Assessment During Stability

Begin With a Risk Assessment

Consider product, route, packaging, formulation, daily exposure, and shelf life.

Understand the Extractables Profile

Use material characterization to identify plausible leachables.

Link Sampling to the Stability Program

Where scientifically appropriate, coordinate leachables testing with relevant stability conditions and time points.

Include Long-Term Data

Do not rely exclusively on accelerated extraction or accelerated stability data when long-term exposure is relevant.

Evaluate Worst-Case Configurations Scientifically

Consider fill volume, contact area, orientation, material composition, and packaging presentation.

Use Targeted and Non-Targeted Methods Appropriately

Monitor expected compounds while maintaining the ability to detect unexpected ones when warranted.

Use the AET Correctly

Apply a product-appropriate threshold to prioritize further evaluation.

Trend Concentrations Over Time

A concentration-versus-time profile may provide more information than a single endpoint.

Investigate Unexpected Peaks

Determine whether they originate from packaging, formulation degradation, manufacturing, or analytical artifacts.

Connect Chemistry With Toxicology

Translate measured concentration into patient exposure before interpreting safety.

Reassess After Significant Changes

Packaging, supplier, formulation, process, sterilization, or shelf-life changes may alter the E&L risk profile.  

Regulatory Context: ICH Q3E and Stability

As of October 2026, ICH Q3E remains a draft guideline and is not final guidance for implementation. The draft nevertheless provides important insight into the emerging harmonized regulatory direction for pharmaceutical E&L programs. It describes a holistic, risk-based framework covering:

• extractables;
• leachables;
• analytical evaluation;
• AET;
• safety assessment;
• quality impact;
• risk control;
• and regulatory documentation.

Most relevant to stability programs, the draft states that adequate leachables data should address safety and quality concerns throughout the drug product’s shelf life. It also recognizes that initial submission data may be aligned with the stability information available at filing, with additional data potentially supplied later subject to the relevant regulatory framework. This supports an important development principle: Leachables assessment should be designed around the product lifecycle rather than viewed solely as a one-time packaging test.  

Current FDA Container-Closure Context

FDA also issued a new draft guidance on Container Closure Systems for Human Drugs and Biological Products in August 2026. That document provides updated principles for evaluating the quality and suitability of container-closure systems, including systems used with drugs, biologics, and certain combination products. Because it is currently draft guidance, its recommendations should not be presented as final requirements. For development teams, however, the direction reinforces the importance of treating the container-closure system as an integral part of pharmaceutical product quality rather than as a passive storage vessel.  

Leachables Stability Assessment at topiox research

A stability-linked leachables program can require expertise across:

• pharmaceutical packaging;
• material characterization;
• extractables;
• targeted leachables analysis;
• non-targeted screening;
• GC-MS;
• LC-MS/LC-HRMS;
• ICP-MS where relevant;
• analytical evaluation thresholds;
• stability study design;
• impurity identification;
• toxicological assessment;
• and root-cause investigation.

At topiox research, integrating E&L assessment with pharmaceutical stability studies can help development teams determine:

• which compounds could migrate;
• which compounds actually appear in the drug product;
• how concentrations change over time;
• whether new compounds emerge during storage;
• whether packaging-derived compounds affect product quality;
• and whether patient exposure remains adequately controlled throughout shelf life.

The goal is not simply to produce an extractables report. It is to understand the real chemical relationship between the drug product and its packaging over time.

Conclusion

Leachables assessment may need to continue through pharmaceutical stability studies because drug-product exposure to packaging-derived compounds can change over time. Important drivers include:

1. Contact time
2. Storage temperature
3. Drug-product composition
4. pH
5. Surface-area-to-volume ratio
6. Storage orientation
7. Packaging configuration
8. Material aging
9. Leachable–product interactions
10. Shelf-life duration

The central scientific principle is: A packaging material’s extractables profile describes what could migrate; stability-linked leachables data help determine what the drug product and ultimately the patient may actually encounter over time. Published studies demonstrate that formulation composition, temperature, pH, contact configuration, packaging materials, and storage duration can influence leachable behavior. The emerging draft ICH Q3E framework further reinforces the importance of generating adequate leachables information to address product safety and quality throughout shelf life. At topiox research, connecting E&L science with stability study design, trace analysis, impurity identification, and toxicological interpretation can help create a more complete understanding of packaging–product compatibility throughout the pharmaceutical lifecycle. Developing a stability-linked leachables strategy for a pharmaceutical product? Connect with topiox research for extractables and leachables study design, stability-linked leachables monitoring, AET strategy, GC-MS and LC-MS screening, compound identification, and integrated impurity assessment.