Extractables & Leachables (E&L)
Extractables and leachables (E&L) is the discipline of understanding what chemical species a packaging or manufacturing material can transfer into a drug product, and whether those species pose a safety risk to the patient. It matters because the container, the closure, and increasingly the single-use manufacturing components are in intimate, prolonged contact with the product, and materials are not chemically inert — they can release compounds that end up in what the patient receives. The two terms name two different things, and keeping them straight is the whole basis of a rational E&L program. This page covers the distinction and the study logic; the physical integrity of the container is the [container closure integrity](/topics/container-closure-integrity) explainer. USP <1663> and <1664> frame the assessments.
What an explainer is not
A topic explainer is SPEQ’s synthesis of what a practice involves, cited to the standards that govern it. It does not reproduce their text, and it does not determine which of them apply to your product or process.
[ POSITION IN THE FRAMEWORK ]
7 DIMENSIONS · 22 LINKSExtractables map what a material could release; leachables are what actually migrates into the product — an E&L program is a risk-based, lifecycle judgment that a quiet component change can silently invalidate.
06 · QUALITY MATURITY — EXTRACTABLES & LEACHABLES (E&L), REACTIVE TO ADAPTIVE
E&L is a one-time registration study filed and forgotten; a resin or component change never triggers reassessment.
An E&L SOP and extractables/leachables protocols exist, but studies run to a generic checklist regardless of route or contact.
Study depth scales with route, dose, and contact; leachables track alongside stability and feed a toxicological safety judgment.
Leachables are trended over shelf life; material and supplier changes are screened for E&L impact before they reach the product.
Material selection is E&L-informed by design; single-use and packaging choices are evaluated for leachable risk before qualification.
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07 · REGULATORY & EVIDENCE
GOVERNING STANDARDS · 2
Derived from the 2 standards SPEQ maps to this subject, across 2 regulatory bodies: FDA, EMA.
RECORDS & OBJECTIVE EVIDENCE
- Extractables study reports characterising the material under exaggerated conditions (USP <1663>)
- Leachables studies on the finished product across its real shelf life (USP <1664>)
- Toxicological assessments of identified leachables against patient-exposure limits
- A risk assessment linking route of administration and contact to E&L study depth
- Change-control records evaluating material, supplier, or component changes against the E&L conclusion
COMMON INSPECTION FINDINGS
- E&L treated as a one-time filing, never revisited after a component change
- Leachables assessed only against a target list, unable to detect unknown compounds
- Single-use system leachables from the manufacturing process never characterised
- No toxicological justification for observed leachable levels
- Analytical methods lacking the sensitivity to detect trace leachables in the matrix
Extractables vs leachables — potential vs actual
**Extractables** are the chemical species that can be pulled out of a material under **exaggerated laboratory conditions** — aggressive solvents, elevated temperature, extended time — designed to reveal everything the material *could* release. They represent the potential: the universe of compounds that might migrate, discovered by deliberately stressing the material beyond real-world conditions. USP <1663> frames this assessment of extractables from a pharmaceutical packaging or delivery system.
**Leachables** are the species that **actually migrate** into the drug product under **normal conditions of storage and use**, over its real shelf life. They are the reality: a subset of the extractables (usually), present in the actual product a patient receives, at the concentrations that real contact and time produce. USP <1664> frames the assessment of leachables. The relationship is the key to the whole discipline — extractables studies (the stress test) inform what to look for in leachables studies (the real test), so that the leachables program is targeted rather than blind. Treating the two as the same thing is what makes E&L programs either over-test (chasing every extractable as if it were a real risk) or under-test (assuming an extractable list covers the actual leachables without confirmation in the real product).
Why the risk scales with the product
E&L risk is not uniform — it scales with how the product contacts the material and how the patient receives it. The FDA and USP framing is that risk rises with the **route of administration** and the **duration and intimacy of contact**: an inhalation or injectable product in prolonged contact with a plastic component carries far higher E&L risk than a tablet in a blister, because the dosage form is a better solvent, the contact is closer, and the route delivers any leachable more directly and dangerously. This risk-based scaling is why a solid oral drug and a large-volume parenteral demand very different E&L rigour.
This is also why E&L has become far more prominent with the rise of **single-use systems** in biomanufacturing — bags, tubing, filters, and connectors made of polymers that contact the product (or process intermediates) during manufacturing. These introduce leachables from the *process*, not just the final package, and one class in particular has driven regulatory attention: compounds that are not just a toxicological concern but can actively degrade the product, such as certain antioxidants from plastics that can affect protein biologics. E&L is therefore both a patient-safety question (is the leachable toxic at its level of exposure?) and, increasingly, a product-quality question (does the leachable harm the drug itself?).
From study to safety judgement
An E&L program moves from chemistry to a toxicological safety conclusion. Extractables studies characterise and identify the compounds a material can release; leachables studies — run on the actual product, often alongside stability so leachables are tracked over the real shelf life — quantify what actually migrates. Identified leachables are then assessed toxicologically against the patient’s exposure, using concepts such as safety thresholds and permitted daily exposure to decide whether a given leachable at its observed concentration is acceptable, requires control, or demands a material change.
The analytical challenge is real: leachables are typically present at trace levels in a complex product matrix, which is why the analytical methods must be sensitive and, crucially, capable of detecting *unknown* compounds, not just a target list — a leachable no one predicted is exactly the one a target-only method will miss. This connects E&L to the analytical-method lifecycle and to stability, and it is why a credible E&L program is designed around the material, the dosage form, the route, and the shelf life together, rather than run as a generic checklist. (ICH has been developing a dedicated guideline, Q3E, on extractables and leachables, which is worth watching as the harmonised reference matures.)
E&L in the quality system
E&L sits at the intersection of packaging development, CMC, and quality risk management, and its conclusions have long reach. The material and packaging choices an E&L assessment validates become part of the product’s established conditions, so a change to a resin, a supplier, a single-use component, or a sterilisation method for the packaging can invalidate the E&L conclusion and must run through change control against the question "does the existing E&L assessment still hold?" A quietly substituted component with a different additive package is a classic way a previously-clean product acquires a new leachable.
The through-line to the rest of the quality system is that E&L is a risk-based judgement maintained across the lifecycle, not a one-time registration study. It is driven by quality risk management (the risk scales with route and contact), it is tracked over the real shelf life alongside stability, and it is protected by change control on the materials and processes it depends on. An operation that treats its E&L assessment as permanently settled, rather than as a conclusion contingent on unchanged materials and contact conditions, has a gap that a component change can silently open.
FREQUENTLY ASKED
What is the difference between extractables and leachables?
Extractables are the chemical species that can be pulled out of a material under exaggerated laboratory conditions (aggressive solvents, heat, time) — the potential universe of compounds it could release, assessed under USP <1663>. Leachables are the species that actually migrate into the product under normal storage and use over its real shelf life — the reality, usually a subset of extractables, assessed under USP <1664>. Extractables studies inform what to look for in leachables studies.
Why does E&L risk depend on the type of product?
Because risk scales with the route of administration and the duration and intimacy of contact. An inhalation or injectable product in prolonged contact with a plastic component carries far higher E&L risk than a tablet in a blister — the dosage form is a better solvent, the contact is closer, and the route delivers any leachable more directly. A solid oral drug and a large-volume parenteral therefore need very different E&L rigour.
Why has E&L become more important with single-use systems?
Single-use systems in biomanufacturing — bags, tubing, filters, connectors made of polymers — contact the product or process intermediates during manufacturing, introducing leachables from the process, not just the final package. Some, such as certain plastic antioxidants, are not only a toxicological concern but can actively degrade protein biologics, making E&L both a patient-safety and a product-quality question.
What makes E&L analytically difficult?
Leachables are typically present at trace levels in a complex product matrix, and the methods must be able to detect unknown compounds, not just a target list — an unpredicted leachable is exactly the one a target-only method misses. Identified leachables are then assessed toxicologically against patient exposure using safety thresholds and permitted daily exposure. A material or supplier change can invalidate the E&L conclusion, so it runs through change control.