⏱ Extractables & Leachables from Packaging

Packaging Material Selection — Every Component Is Also a Formulation

Primary packaging is not chemically inert. A rubber stopper, a plastic vial, a blister foil laminate — each is manufactured from a base polymer or elastomer blended with functional additives: plasticizers that keep it flexible, antioxidants that prevent oxidative degradation on the shelf, vulcanization accelerators that cure rubber into a usable stopper. Every one of these additives is a potential extractable, and selecting a container-closure system means implicitly selecting its full chemical inventory.

• 8–15: Typical additives per elastomer (plasticizers, curatives, fillers)
• Bromobutyl / chlorobutyl: Common stopper base (rubber, low permeability)
• Inhalation, injectable, ophthalmic: High-risk routes (direct systemic or local exposure)
• ICH Q3D / USP <1663-1665>: Regulatory framework (plus PQRI E&L guidance)

What is inside a "simple" rubber stopper or plastic vial

A container-closure component is a compounded material, not a pure substance:

• Base polymer/elastomer: butyl rubber, cyclic olefin copolymer (COC), polypropylene, PET, or aluminum/polymer laminate foil • Plasticizers: added to polymers (e.g., PVC tubing, adhesives) to improve flexibility — phthalates and adipates are classic examples • Antioxidants: hindered phenols (BHT, Irganox 1010) and phosphites (Irgafos 168) protect the polymer from oxidative chain scission during processing and shelf life • Vulcanization agents and accelerators: sulfur-based curing systems, thiazoles (MBT), and dithiocarbamates crosslink rubber into a functional elastomer, and can leave residual accelerator and nitrosamine byproducts • Processing aids: slip agents (erucamide), lubricants, mold-release agents, and residual monomers or oligomers from incomplete polymerization • Colorants, fillers, and elemental catalysts: titanium dioxide, silica, and organotin or antimony-based catalysts used in polymerization

None of these are impurities in the sense of manufacturing error — they are deliberately formulated into the material to give it the mechanical, barrier, and processing properties a container-closure system needs. But every one of them sits adjacent to the drug product and is a candidate for migration.

Selecting a packaging system is a chemistry decision as much as an engineering one. A material change late in development — switching stopper formulation or foil laminate — can reopen the entire extractables and leachables assessment.

Why route of administration drives the level of scrutiny

Not all dosage forms carry equal E&L risk. Regulatory expectation scales with how directly and how much of the packaging-contacting material reaches systemic circulation or a sensitive tissue:

• Highest risk: orally inhaled and nasal drug products (OINDP), injectables (especially long-term infusion or high-volume parenteral), and ophthalmic products — direct, often prolonged contact with minimal barriers • Moderate risk: transdermal, and injectable products with short dwell time or small volume • Lower risk: oral solid dosage forms (tablets, capsules) with dry, brief packaging contact, though blister foil and desiccant chemistry still warrant characterization

This risk gradient is precisely why the PQRI (Product Quality Research Institute) OINDP and parenteral/ophthalmic E&L guidances set analytical evaluation thresholds an order of magnitude lower than those typically used for oral solids — the tolerance for uncertainty shrinks as the exposure route becomes more direct.

Extractables Study — Mapping Everything That COULD Migrate

Before anyone asks what actually ends up in the drug product, the extractables study asks a deliberately broader question: under exaggerated, worst-case conditions, what is the complete universe of chemicals this packaging material is even capable of releasing? Components are extracted with aggressive solvents spanning a range of polarities, at elevated temperature and extended time, far beyond anything the real product will experience — establishing the outer boundary of chemical risk.

• 3–5: Typical extraction solvents (polar, non-polar, aqueous, pH extremes)
• 40–121°C, days–weeks: Extraction conditions (far exceeds real storage stress)
• 18: Extractables found (max severity) (in this simulated material set)
• Define the risk ceiling: Purpose (not a prediction of actual exposure)

Designing a controlled extraction study

A controlled extraction study (CES) systematically pushes each packaging component past any condition the real product will see:

• Solvent selection: a polarity range covering aqueous (mimics water-based formulations), semi-polar (isopropanol, ethanol/water blends), and non-polar (hexane) solvents, plus pH extremes (0.1N HCl, 0.1N NaOH) to probe hydrolytically-labile extractables • Extraction ratio: surface-area-to-volume or mass-to-volume ratios far higher than clinical contact ratios, so trace extractables concentrate above the analytical detection limit • Time and temperature: reflux or elevated-temperature extraction (40–121°C) for days to weeks — accelerating a diffusion process that in the real product would take months to years • Exhaustive extraction: repeated extraction cycles until no further compound is released, confirming the full extractable inventory has been captured

The result is intentionally an overestimate. Nearly everything chemically extractable from the material — plasticizer, antioxidant, vulcanization byproduct, residual monomer — shows up somewhere in this dataset.

Extractables are a ceiling, not a forecast

It is tempting to treat a long extractables list as alarming, but the entire point of the worst-case design is that most of these compounds will never appear in the finished product at clinically relevant levels. Real storage never reaches reflux temperature, never uses hexane as a diluent, and never continues for weeks of continuous solvent contact.

The extractables list instead functions as a targeted analyte list: an analytical roadmap telling the leachables study exactly which compounds to look for, at what approximate mass and retention time, when the real drug product is analyzed under real conditions. Skipping the extractables study would mean searching for leachables blind, without knowing which of thousands of possible packaging-derived chemicals are even plausible candidates.

Increase the Extraction/Storage Severity slider and watch the extractables count grow — each additional compound represents a material component with a higher activation energy for release, only detected once conditions get aggressive enough to liberate it.

Leachables Study — What Actually Migrates Into the Real Product

The leachables study is the reality check. The actual finished drug product, packaged in its actual container-closure system, is placed on real-time and accelerated stability storage and analyzed at defined intervals. Only compounds that genuinely diffuse through the material, partition into the formulation, and remain detectable in the drug product are leachables — and this list is always a subset of, never larger than, the extractables list.

• always ≤: Leachables = subset of extractables (never a superset)
• 30–60%: Typical leachables found (of the extractables list, in practice)
• Real-time + accelerated: Storage conditions used (e.g. 25°C/60%RH, 40°C/75%RH)
• Diffusion + partition coefficient: Migration driver (polymer → formulation gradient)

Why leachables are always fewer than extractables

Three factors shrink the extractables list down to the true leachables list:

• Kinetics: migration is a diffusion-limited process. A compound with a high activation energy for release from the polymer matrix may need years at real storage temperature to reach a detectable concentration — time the extractables study compressed into days at high heat • Solubility and partitioning: a compound that dissolves readily in hexane may have negligible solubility in an aqueous or lipidic drug formulation; if it cannot partition into the product matrix, it never becomes a leachable regardless of how easily it extracts • Formulation interaction: the drug product's own excipients, pH, and ionic strength can suppress or enhance migration relative to a pure solvent system, and some extractables react or degrade before ever reaching quantifiable levels in the product

This is why leachables studies are run directly on the market formulation, in the market package, under real or ICH-accelerated stability conditions — extrapolating from the extractables study alone would systematically overstate patient exposure.

Time-course sampling and the role of accelerated stability

Because migration is time-dependent, leachables are tracked longitudinally across the stability program:

• Baseline (T0): confirms no leachables present at manufacture • Interim pulls (3, 6, 9, 12 months, etc.): quantify emerging leachables against the extractables target list using validated trace analytical methods • Accelerated conditions (e.g., 40°C/75%RH): used to project long-term leachable accumulation faster than real-time storage, with real-time data confirming the accelerated prediction as the product matures • End-of-shelf-life: the leachables profile at proposed expiry is what ultimately supports the toxicological risk assessment and product labeling

Move the Storage Time Simulated slider forward and the leachables set grows monotonically — reflecting that longer contact time between packaging and formulation allows slower-migrating extractables to finally cross the detection threshold and accumulate toward their asymptotic level.

A compound can be a legitimate, well-characterized extractable and still never appear as a leachable across an entire shelf life — its migration rate under real conditions may simply be too slow to matter within the product's approved dating period.

Analytical Screening & Identification — Finding Trace Compounds Reliably

Detecting leachables at the parts-per-billion to low parts-per-million level, in a complex drug formulation matrix, is an analytical chemistry challenge in its own right. A suite of orthogonal techniques — headspace and liquid-injection GC-MS for volatile and semi-volatile organics, LC-MS/MS for larger or non-volatile compounds, and ICP-MS for elemental impurities — is combined to cover the full chemical space defined by the extractables target list.

• Volatile / semi-volatile organics: GC-MS scope (antioxidants, plasticizers, VOCs)
• Non-volatile, polar, high-MW: LC-MS/MS scope (oligomers, degradants)
• Elemental impurities: ICP-MS scope (per ICH Q3D classes 1-3)
• Low ppb range: Typical LOQ target (set by the analytical evaluation threshold)

The analytical toolkit and the Analytical Evaluation Threshold

Method selection is matched to compound chemistry:

• GC-MS (headspace and direct injection): ideal for volatile and semi-volatile organics — residual solvents, low-molecular-weight degradation products (formaldehyde, acetaldehyde), and many antioxidants and plasticizers • LC-MS/MS (and LC-UV/CAD for compounds without a chromophore or ionizable group): captures larger, non-volatile, or thermally labile species — oligomers, higher-molecular-weight antioxidant degradants, and polar additives • ICP-MS: dedicated to elemental impurities that may leach from metal components, catalysts, or fillers — aluminum, tin, and other ICH Q3D-listed elements are quantified against class-specific limits • Non-targeted screening plus targeted confirmation: an initial non-targeted scan searches broadly using the extractables list as a roadmap, followed by targeted quantitation with validated, compound-specific methods

The Analytical Evaluation Threshold (AET) is the calculated concentration below which a leachable is toxicologically insignificant and does not need individual identification — it keeps the identification burden proportionate to actual patient risk rather than to instrument sensitivity limits.

From a chromatographic peak to a confirmed structure

Identification proceeds through library matching, accurate mass, and fragmentation analysis:

• Spectral library search: GC-MS electron-impact spectra are matched against NIST/Wiley libraries; LC-MS accurate mass and MS/MS fragmentation are matched against in-house or public spectral databases • Confirmation with reference standards: once a tentative identity is proposed, an authentic reference standard is injected under identical conditions — matching retention time and full mass spectrum confirms the identification • Quantitation: a calibration curve using the confirmed reference standard converts peak area into an actual concentration in the drug product (µg/g, µg/mL, or µg/day of intended dose) • Unidentified peaks: peaks above the AET that resist identification are still quantified and carried into the risk assessment as "unknowns," triggering additional structural elucidation (NMR, high-resolution MS/MS) if their estimated exposure is toxicologically significant

Toxicological Risk Assessment — Comparing Exposure Against the Safety Threshold

Identifying and quantifying a leachable is only half the assessment. Each confirmed leachable's estimated daily patient exposure is compared against a toxicologically derived safety limit — a Permitted Daily Exposure (PDE) or Safety Concern Threshold (SCT) — to determine whether the packaging system, as characterized, is safe for its intended clinical use across the full shelf life.

• ~1.5 µg/day: PQRI SCT (parenteral/ophthalmic) (default safety concern threshold)
• ~0.15 µg/day: PQRI SCT (OINDP) (stricter, inhalation route)
• NOAEL / uncertainty factors: PDE derivation basis (per ICH M7 / Q3D-style methodology)
• Further toxicology or redesign: Outcome if exceeded (compound-specific PDE or material change)

Permitted Daily Exposure and the Safety Concern Threshold

Two related but distinct thresholds anchor the risk assessment:

• Safety Concern Threshold (SCT): a generic, conservative default exposure level below which any leachable — even an unidentified one — is considered toxicologically insignificant without compound-specific data. The PQRI frameworks set the SCT lower for higher-risk routes (inhalation, injectable, ophthalmic) than for oral solids, reflecting the reduced margin of safety when packaging-derived chemicals reach systemic circulation or sensitive tissue directly • Permitted Daily Exposure (PDE): a compound-specific limit derived from that chemical's own toxicological database — typically a No-Observed-Adverse-Effect-Level (NOAEL) from animal studies, divided by a series of uncertainty (safety) factors accounting for interspecies extrapolation, individual variability, study duration, and severity of the endpoint, then adjusted to a human-equivalent daily dose

When a leachable's estimated daily patient exposure sits below its PDE (or below the generic SCT, if no compound-specific PDE exists), it is qualified as safe at that level. When exposure exceeds the threshold, the compound requires additional toxicological evaluation, a formal risk-benefit justification, or a change to the packaging material or manufacturing process to reduce migration.

The Toxicological Risk Assessment closes the loop between chemistry and patient safety: it converts an analytical concentration into a clinical judgment, and it is this judgment — not the raw extractables or leachables count — that ultimately determines whether a container-closure system is approvable.

How E&L results feed back into packaging selection and lifecycle management

Extractables and leachables data are not collected once and filed away — they actively shape packaging decisions across the product lifecycle:

• Primary packaging selection: during development, E&L screening of candidate materials (comparing, for example, two stopper formulations or two foil laminates) can eliminate high-risk options before a single stability batch is manufactured • Formulation-packaging compatibility: if a leachable exceeds its threshold, options include reformulating to reduce solubility/partitioning of that leachable, switching to a lower-extractable material grade, adding a barrier coating or film, or accepting the exposure with a documented, toxicologically justified risk-benefit rationale • Post-approval change control: a change in stopper supplier, rubber formulation, or foil laminate after approval typically requires a bridging E&L assessment to confirm the new material does not introduce new leachables or increase existing ones beyond qualified levels • Ongoing stability monitoring: leachables trending data across real-time stability continues to confirm that the qualified safety margin holds all the way to the approved expiry date

In this way, the tiered E&L program — material characterization, extractables study, leachables study, toxicological risk assessment — functions as a continuous feedback loop between packaging engineering and patient safety, not a single gate passed once at filing.