Extractables & Leachables: Practical Risk Assessment (ICH Q9)

Extractables & Leachables: How to Decide When E&L Studies Are Needed Without Over-Testing

In Extractables & Leachables (E&L) studies, audits and regulatory reviews are won or lost not because “you tested a lot”, but because you can demonstrate that you assessed the risk and applied proportionate measures.

This is the logic that is becoming increasingly central in E&L management: identifying potential hazards, assessing the real patient exposure and building a documented, defensible rationale that is consistent with the risk.

The practical problem is always the same:

• if you test everything, costs, timelines, unknown peaks and analytical deviations increase — and then you need to explain them;
• if you do not test when testing is needed, you risk GMP findings, dossier questions, CAPA and regulatory delays.

What you need is an audit-ready decision-making framework: clear, repeatable and documentable.

Table of Contents

• Operational definitions: Extractables vs Leachables
• The 6 E&L risk drivers
• The golden rule: Risk = Hazard × Exposure
• Ready-to-use E&L risk matrix
• Decision tree: what to do for low, medium and high risk
• When E&L studies effectively become mandatory
• When dedicated studies can be avoided
• Errors that undermine defensibility
• Audit-ready mini-checklist
• Conclusion
• Do you want a complete practical guide on E&L studies?

1. Operational definitions: Extractables vs Leachables

The distinction between extractables and leachables is fundamental. During an audit, however, repeating the theoretical definition is not enough. You must demonstrate that you can connect it to the real risk for the patient, product quality and compliance.

1.1 Extractables

Extractables are chemical compounds that can be extracted from materials, process components, packaging systems or devices under forced laboratory conditions.

They represent the potential.

In practice, an extractables study aims to understand which substances could be released from a material if it is exposed to aggressive conditions, such as solvents, elevated temperatures, prolonged contact times or stress conditions.

1.2 Leachables

Leachables are compounds that actually migrate into the product under real conditions of use, for example during shelf-life, storage, contact with packaging or use of the device.

They represent the real risk.

During an audit, the implicit question is always this:

Is there a risk for the patient or for product quality? And how are you controlling it?

2. The 6 E&L risk drivers

When you build an E&L risk assessment, the risk level does not depend on a single factor. The real score comes from the combination of several elements.

2.1 Route of administration

The route of administration is one of the most important drivers.

Parenteral, inhalation and ophthalmic products have much stricter attention thresholds than oral solid dosage forms because patient exposure is more direct and potentially more critical.

2.2 Dosage form

Liquid dosage forms are generally more extractive than solid forms.

A tablet or capsule tends to have a lower E&L risk than a solution, suspension, injectable formulation or inhalation product.

2.3 Extractive power of the matrix

The composition of the product can increase or reduce the extraction risk.

Particularly relevant factors include:

• organic solvents;
• surfactants;
• extreme pH values;
• propellants;
• complex formulations;
• excipients with high solubilising power.

The more extractive the matrix, the higher the likelihood that chemical compounds will migrate from the material into the product.

2.4 Contact time

Contact time can radically change the assessment.

A few minutes of contact during a manufacturing process does not have the same meaning as months or years of contact during product shelf-life.

2.5 Temperature and stress conditions

Elevated temperatures or stress conditions may increase substance release.

Typical examples:

• sterilisation;
• gamma irradiation;
• freeze-thaw cycles;
• incubations;
• accelerated storage;
• critical transport conditions.

2.6 Material and formulation complexity

Not all materials have the same risk profile.

Materials such as rubber, elastomers, plasticised PVC, adhesives, lubricants and complex plastics require greater attention than more inert materials such as Type I glass or PTFE.

3. The golden rule: Risk = Hazard × Exposure

If you want to use effective language during an audit, the clearest summary is this:

Risk = Hazard × Exposure

3.1 Hazard

Hazard represents the intrinsic dangerousness of potentially leachable substances.

It may include:

• general toxicity;
• genotoxicity;
• presence of metals;
• sensitising substances;
• compounds with very low toxicological limits;
• impurities with a poorly known profile.

3.2 Exposure

Exposure represents the real exposure of the patient.

It depends on:

• daily dose;
• frequency of administration;
• duration of therapy;
• estimated concentration of the leachable;
• route of administration;
• target population.

E&L are not a “peak hunt”. They are structured risk management for the patient and for product quality.

4. Ready-to-use E&L risk matrix

In practice, a simple matrix based on the following works well:

Probability of leaching × Severity of impact

A Low / Medium / High matrix is often sufficient because it is:

• quick to complete;
• easy to explain;
• defensible if the criteria are justified;
• suitable for integration into SOPs, reports or risk assessments.

The value is not in complex mathematics. The value is in the consistency and traceability of the rules you choose.

4.1 Probability of leaching

High probability

Examples of high-probability conditions:

• liquid products or products containing solvents;
• prolonged contact;
• elevated temperatures or stress;
• elastomers;
• plasticised PVC;
• complex or poorly characterised materials.

Medium probability

Examples of medium-probability conditions:

• aqueous liquids;
• standard polyolefins;
• moderate contact;
• known materials but with data that are not fully representative.

Low probability

Examples of low-probability conditions:

• oral solid dosage forms;
• Type I glass;
• PTFE;
• minimal contact;
• widely used compendial materials.

4.2 Severity of impact

High severity

Examples of high-severity scenarios:

• parenteral products;
• inhalation products;
• ophthalmic products;
• fragile populations;
• high dose;
• chronic use;
• direct exposure to sensitive tissues.

Medium severity

Examples of medium-severity scenarios:

• oral liquids;
• products with repeated exposure;
• formulations with moderate extractive capacity.

Low severity

Examples of low-severity scenarios:

• oral solid dosage forms;
• minimal indirect contact;
• well-known and compendial materials;
• low patient exposure.

5. Decision tree: what to do for low, medium and high risk

A good E&L process must lead to a clear decision.

It is not enough to classify the risk: you must link each risk level to a proportionate action.

5.1 If the risk is low

Typical scenario:

• oral solid dosage forms;
• compendial materials;
• low extractive power;
• limited contact;
• historical data available.

In these cases, the following may often be sufficient:

• compendial compliance;
• supplier declarations;
• historical data or applicable literature;
• written rationale;
• change control on the supplier or material;
• documented assessment of the absence of critical issues.

5.1.1 Practical example

Tablets or capsules in an HDPE bottle.

The risk may be justified as low if:

• the matrix is poorly extractive;
• the route of administration is oral;
• the material is known and widely used;
• applicable compendial data or supplier data are available;
• there are no relevant stress conditions.

In this case, the objective is not to “do nothing”, but to document why dedicated studies are not necessary.

5.2 If the risk is medium

Typical scenario:

• oral liquids;
• new material/product combination;
• partial supplier data;
• moderately extractive matrix;
• significant but not extreme contact.

Effective approach:

• gap assessment of supplier data;
• verification of the representativeness of available data;
• possible targeted extractables screening;
• toxicological assessment based on TTC, PDE or an equivalent approach;
• definition of proportionate controls and monitoring.

Here, you win by avoiding two opposite mistakes:

• inertia: “it is not needed because we have never done it”;
• over-testing: “let’s do full leachables on everything”.

5.3 If the risk is high

Typical scenario:

• injectable products;
• inhalation products;
• ophthalmic products;
• combination devices;
• new materials;
• critical elastomers or adhesives;
• long contact;
• highly extractive formulations.

Realistic expectation:

• structured extractables study;
• real or simulated leachables study;
• involvement of a toxicologist;
• assessment of unknown peaks;
• definition of acceptable limits;
• lifecycle control strategy;
• monitoring and change control.

For high-risk products, the system must demonstrate that packaging, components and product-contact materials protect the product and do not compromise its quality and safety.

6. When E&L studies effectively become mandatory

Without beating around the bush, there are scenarios where not having solid E&L evidence will almost certainly expose you to regulatory questions, additional dossier requests or findings.

Typical examples:

• sterile injectables;
• inhalation products;
• nasal sprays;
• ophthalmic products;
• prefilled syringes;
• pens and autoinjectors;
• combination devices;
• new materials;
• supplier change for critical components;
• material change in closure systems or product-contact components;
• primary packaging with prolonged contact;
• elastomeric materials or adhesives close to the product.

In these cases, the risk assessment can help define the scope of the studies, but it can hardly justify the complete absence of evidence.

7. When dedicated studies can be avoided

Dedicated studies can only be avoided if the rationale is well written and supported by evidence.

Typical defensible examples:

• oral solid dosage forms with widely established and compendial-compliant materials;
• indirect or secondary contact;
• very short contact;
• applicable historical data;
• same material, same matrix and same conditions of use;
• full compendial compliance in a low-extractivity context;
• no relevant change in material, supplier, process or packaging.

7.1 Phrase to avoid

“It is not needed because it has always been done this way.”

7.2 Correct phrase

“A dedicated study is not needed because data X/Y/Z demonstrate that the risk is low in this specific context of use.”

The difference is huge: the first sentence is habit; the second is risk control.

8. Errors that undermine defensibility

Even if you performed testing, you can still lose defensibility if the rationale is weak.

8.1 Over-testing without rationale

Testing too broadly or under excessively aggressive conditions may generate non-representative peaks, unknowns and results that are difficult to explain.

The issue is not only cost. Every unexpected result must be assessed, justified and managed.

8.2 Using supplier data without gap assessment

Supplier data are useful, but they should not be accepted automatically.

You must verify whether they are representative in relation to:

• the material actually used;
• manufacturing process;
• solvents;
• contact times;
• temperature;
• irradiation;
• sterilisation;
• formulation;
• route of administration.

8.3 Forgotten minor components

Many E&L risks arise from apparently secondary components.

Examples:

• labels;
• adhesives;
• O-rings;
• lubricants;
• gaskets;
• tubing;
• filters;
• single-use components;
• “non-obvious” parts of the system.

During an audit, forgetting a minor component can weigh as much as getting the main study wrong.

8.4 Lack of lifecycle control

E&L risk does not end with the initial study.

It must be kept under control through:

• change control;
• supplier qualification;
• periodic review;
• assessment of new materials;
• risk assessment update;
• deviation and trend management.

9. Audit-ready mini-checklist

Before closing an E&L risk assessment, verify these points.

9.1 Materials and components

• Have I mapped all direct-contact materials?
• Have I assessed indirect-contact or potentially relevant materials?
• Have I considered minor components such as gaskets, adhesives, lubricants, filters and tubing?
• Have I checked for any material or supplier changes?

9.2 Risk classification

• Do I have clear criteria for probability and severity?
• Have I defined what Low, Medium and High mean?
• Have I justified the classification with data or rationale?
• Have I considered route of administration, matrix, contact time and temperature?

9.3 Decision on studies

• Do I have a “what to do” table for Low, Medium and High risk?
• Have I justified the possible absence of dedicated studies?
• Have I assessed whether supplier data are representative?
• Have I defined any gaps to be closed?

9.4 Toxicology and limits

• Have I involved toxicology where required?
• Have I defined thresholds, limits or acceptability criteria?
• Have I assessed unknown peaks or potentially critical substances?
• Have I documented the acceptability rationale?

9.5 Lifecycle and change control

• Have I planned a lifecycle control plan?
• Have I linked the risk assessment to change control?
• Have I defined what happens in case of material, supplier, process or packaging change?
• Have I planned periodic review where applicable?

10. Conclusion

The point is not “doing E&L”.

The point is being able to demonstrate that you are controlling risk with a proportionate, repeatable and defensible approach.

This is what truly holds up in audits, dossiers and regulatory reviews: not the quantity of testing, but the quality of the rationale and the robustness of the decisions.

11. Do you want a complete practical guide on E&L studies?

Do you want the complete ready-to-use version, with matrices, examples, inspection FAQs and documentation templates?

Download the GuideGxP premium guide:

Extractables & Leachables (E&L) – Practical Guide to Risk-Based Compliance