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Extractables and Leachables in Vial Seals and Closures: A Practical Guide

Extractables and Leachables in Vial Seals and Closures: A Practical Guide

Extractables and leachables (E&L) are chemical compounds that can move out of packaging materials and into a medicine, and they are studied to confirm that a vial’s closure system does not introduce harmful substances into the drug product. Extractables are compounds that can be pulled from a material under deliberately aggressive laboratory conditions; leachables are the subset that actually migrate into the drug product under normal storage and use. For injectable vials, the elastomeric stopper, the aluminium or aluminium-plastic seal, and any coatings or inks are all potential sources, so each is assessed against pharmacopoeial and regulatory expectations.

This guide explains the difference between extractables and leachables, why closure components are studied, how E&L relates to USP <381>, <382>, <661.1>, <661.2>, <1663>, and <1664> and to ICH Q3D, and why material selection and a Drug Master File (DMF) matter when sourcing seals and closures.

Key takeaways

  • Extractables come out under forced lab conditions; leachables are what genuinely migrates into the drug during real storage and use. Leachables are usually a subset of extractables.
  • Every component in direct or indirect contact is in scope: the rubber stopper, the aluminium or aluminium-plastic seal, coatings, and inks.
  • E&L work supports the container closure system safety case alongside USP <381> (elastomeric components), USP <382> (functional suitability), and USP <661.1> / <661.2> (plastic materials of construction and plastic packaging systems).
  • The USP informational chapters specific to this work are USP <1663> (assessment of extractables) and USP <1664> (assessment of leachables), which describe how to design and justify the studies.
  • Elemental impurities from metals and other inorganic sources are assessed against the ICH Q3D guideline.
  • The typical workflow is a controlled (forced) extraction study, then a simulation/migration study, then a toxicological risk assessment of the compounds found.
  • Sound material selection and a supplier DMF reduce E&L risk and give the drug manufacturer documented evidence to reference in a regulatory submission.

What is the difference between extractables and leachables?

Extractables are compounds released from a packaging material under exaggerated laboratory conditions; leachables are the compounds that actually migrate into the drug product under normal conditions of storage and use. The two terms are related but not interchangeable.

A controlled extraction study deliberately stresses the material, using aggressive solvents, elevated temperature, and extended time, to map the worst-case universe of compounds that could come out. That universe is the extractables profile. Leachables are then the compounds (often a smaller set) found in the actual drug product, or in a representative simulating solvent, after realistic contact over the product’s shelf life. Because injectables are sterile, aqueous, and administered directly, even low-level leachables can matter, which is why the assessment is rigorous for vial closures.

The U.S. Pharmacopeia and the FDA’s guidance on container closure systems treat extractables/leachables as a core part of demonstrating that packaging is safe and compatible with the drug it holds.

Why are stoppers, seals, and coatings studied?

Elastomeric stoppers, aluminium-plastic seals, and any coatings or inks are studied because each is a different material chemistry in contact with, or close to, the medicine, and each can contribute its own extractables. A vial closure is not one material; it is an assembly.

Elastomeric stoppers

The rubber stopper is in direct contact with the drug and the headspace, so it is the most scrutinised E&L source on a vial. Elastomers contain curing agents, fillers, antioxidants, and processing aids that can extract. This is why stoppers carry their own pharmacopoeial framework under USP <381> for elastomeric closures.

Aluminium and aluminium-plastic seals

The seal crimps over the stopper and completes the container closure system. An aluminium-plastic seal combines an aluminium shell with a moulded plastic top, so both the metal (and any conversion coating or lacquer on it) and the plastic disc are potential contributors. The plastic component is assessed in the same spirit as USP <661.1> (plastic materials of construction) and USP <661.2> (plastic packaging systems for pharmaceutical use).

Coatings, lacquers, and inks

Lacquers on the aluminium, plus any printing inks or embossing, add further chemistries. Where these surfaces face the stopper or the vial interior, they are included in the E&L assessment rather than assumed inert.

How does E&L relate to USP and ICH standards?

E&L assessment is not a single standalone test; it draws on several pharmacopoeial chapters plus the ICH elemental-impurities guideline, each covering a different material or risk. They work together rather than overlap.

Reference What it governs Relevance to closures
USP <381> Elastomeric components in injectable packaging Physico-chemical and biological framework for the rubber stopper
USP <382> Functional suitability of elastomeric components Function (penetration, self-sealing) of the stopper in use
USP <661.1> Plastic materials of construction The plastic resin used in the plastic part of a combination seal
USP <661.2> Plastic packaging systems for pharmaceutical use The assembled plastic packaging system
USP <1663> Assessment of extractables Informational framework for designing the extractables study
USP <1664> Assessment of leachables Informational framework for the leachables study
ICH Q3D Elemental impurities Limits and risk assessment for metals and other elements
ICH Q3C Residual solvents Solvent classification context (governs drug-substance and drug-product solvents, not packaging E&L)

USP <381> and <382> address the elastomeric stopper, the part in direct contact and the most studied. USP <661.1> and <661.2> cover plastic materials and the assembled plastic system, which is relevant to the plastic disc or button on a combination seal. The informational chapters USP <1663> and <1664> describe how to assess extractables and leachables themselves. ICH Q3D sets the framework for elemental impurities, the route by which metals or inorganic species are evaluated and limited. ICH Q3C governs residual solvents in the drug substance and drug product rather than packaging E&L, though its solvent classification informs how extraction solvents are viewed. The U.S. Pharmacopeia publishes and maintains the USP General Chapters referenced here (usp.org).

What does an E&L study involve?

A typical E&L program runs in three stages: a controlled extraction study to find what can come out, a simulation study to see what actually migrates, and a toxicological assessment to judge whether those compounds are safe at the levels found. The depth scales with the risk of the dosage form, and injectables sit at the high-risk end.

Controlled (forced) extraction study

The material is exposed to multiple solvents of differing polarity at elevated temperature for a defined time to generate the broadest realistic extractables profile. Analysis uses chromatography and mass spectrometry (for example GC-MS, LC-MS, and ICP-MS for elements) to identify and semi-quantify the compounds.

Simulation and migration (leachables) study

The closure is then evaluated against the actual drug product or a representative simulating solvent, under conditions that mimic real storage and shelf life, to determine which extractables become genuine leachables and at what concentration.

Toxicological risk assessment

Each identified compound is assessed against a safety threshold. Industry practice references the analytical evaluation threshold (AET) concept and toxicological screening described in PDA technical reports on E&L (pda.org), so that compounds above the threshold get a documented toxicological evaluation and those below it can be justified as negligible. Elemental impurities are evaluated against the permitted daily exposure limits in ICH Q3D.

Why do material selection and a DMF matter?

The cleanest way to control E&L is to choose well-characterised materials up front and to document them in a Drug Master File (DMF), so the drug manufacturer can reference the supplier’s data instead of re-deriving it. E&L risk is designed in (or out) at the material-selection stage, long before testing.

Selecting elastomer formulations, aluminium grades, lacquers, and plastics with known, controlled compositions narrows the extractables universe and lowers the chance of an unexpected leachable. A supplier that holds a DMF has filed the confidential material and process details with a regulator, which lets a pharmaceutical customer cite that file to support its own submission. Combined with manufacturing under an ISO 15378 GMP-aligned quality system, consistent material composition and traceability are what keep an extractables profile stable batch to batch, which is exactly what an E&L assessment depends on.

How this works in practice at Autofits

Autofits manufactures aluminium-plastic FlipTop® seals and related vial closures, including tear-off and tear-down aluminium seals and aluminium pilfer-proof caps, all of which form part of a vial’s primary packaging and closure system. Production runs under an ISO 15378:2017 GMP-aligned quality system (alongside ISO 9001:2015 and ISO 14001:2015) with a Drug Master File (DMF) on record, in a 75,000 sq ft Nashik facility that includes an ISO Class 8 cleanroom with high-speed visual inspection. For E&L, the relevant levers are controlled material composition, the lacquers and inks used on the metal and plastic, and full batch traceability, the documentation a pharmaceutical customer draws on when building the closure-system safety case for a submission. The full certification set is listed on the quality page.

Frequently asked questions

What is the difference between extractables and leachables?

Extractables are compounds released from a packaging material under exaggerated laboratory conditions (aggressive solvents, heat, and time) and represent a worst-case profile. Leachables are the compounds that actually migrate into the drug product under normal storage and use, and are usually a subset of the extractables. Extractables studies map what could come out; leachables studies confirm what really does.

Why are vial seals and stoppers tested for E&L?

Because the rubber stopper, the aluminium or aluminium-plastic seal, and any coatings and inks are different material chemistries in contact with, or close to, an injectable drug. Each can contribute compounds that migrate into the product, so each is assessed to confirm the closure does not introduce unsafe substances. Injectables are higher risk because the drug is sterile, often aqueous, and administered directly.

Which standards apply to extractables and leachables for injectable closures?

The elastomeric stopper is governed by USP <381> (elastomeric components) and USP <382> (functional suitability). Plastic components fall under USP <661.1> (plastic materials of construction) and USP <661.2> (plastic packaging systems). The USP informational chapters specific to this work are USP <1663> (assessment of extractables) and USP <1664> (assessment of leachables). Elemental impurities are assessed against ICH Q3D. FDA guidance on container closure systems and PDA technical reports describe how to structure the overall E&L assessment.

What is a controlled extraction study?

A controlled or forced extraction study exposes a packaging material to several solvents of differing polarity, at elevated temperature for a set time, to generate the broadest realistic profile of extractable compounds. The extracts are analysed by techniques such as GC-MS, LC-MS, and ICP-MS to identify and quantify what is present, which then guides the leachables and toxicological work.

Why does a Drug Master File (DMF) matter for E&L?

A DMF lets a packaging manufacturer file confidential material and process details with a regulator. A pharmaceutical customer can then reference that file to support its own drug submission, rather than re-deriving the supplier’s material data. This shortens qualification and gives documented confidence that the closure’s composition, and therefore its extractables profile, is controlled and consistent.

Related reading

Sources

  • U.S. Pharmacopeia (USP-NF), General Chapters including <381>, <382>, <661.1>, <661.2>, <1663>, and <1664> (https://www.usp.org/)
  • U.S. Pharmacopeia, Extractables and Leachables resource page (https://www.usp.org/impurities/extractables-and-leachables)
  • ICH: Quality Guidelines, including Q3D Elemental Impurities and Q3C Residual Solvents (https://www.ich.org/page/quality-guidelines)
  • FDA: Container Closure Systems for Packaging Human Drugs and Biologics, guidance (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/container-closure-systems-packaging-human-drugs-and-biologics)
  • PDA: Parenteral Drug Association technical resources on extractables and leachables (https://www.pda.org/)

*Last updated: 2026-06-10. This article is general regulatory information, not legal or compliance advice; confirm current standard editions and requirements with USP, ICH, and the relevant regulator.*

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