Extractables & LeachablesE&L

Extractables are organic and inorganic chemicals released from a material when exposed to a controlled, exaggerated solvent/temperature/time challenge (typically water, 50/50 ethanol/water, hexane or product-specific solvents at temperatures above use). They define what the material could give up. Leachables are the subset of compounds that actually migrate into the drug product under recommended storage and use conditions — they define what the patient is actually exposed to. Leachables are always a subset of extractables, but not all extractables become leachables.

• Parenteral and ophthalmic drug products — required in all major markets (FDA, EMA, PMDA).
• Inhalation and nasal drug products — required; particularly stringent because of lung dosimetry.
• Oral solutions and topicals in plastic containers — required where the container is not previously qualified for the route.
• Solid oral dosage forms in plastic containers — typically lower priority but expected for novel container/closures.
• Single-use bioprocess systems (filters, bags, tubing) used in biologic manufacturing — BPOG/BPSA protocols apply; the leachable assessment is against the API or downstream biologic, not the patient directly.

1. Define the container/closure system — every contact material (vial glass, stopper elastomer, seal, label adhesive, secondary packaging that may migrate through primary).
2. Choose solvents bracketing product polarity — typically aqueous, semi-polar (50/50 ethanol/water) and non-polar (hexane or IPA).
3. Set extraction conditions — temperature 40 °C to 70 °C, time 24 h to 72 h or longer for diffusion-limited systems, with optional sonication or reflux for exaggerated conditions.
4. Apply orthogonal analytical techniques — GC-MS (volatile/semi-volatile organics), LC-MS or LC-UV-MS (non-volatile organics), ICP-MS or ICP-OES (elementals).
5. Quantify above the AET (Analytical Evaluation Threshold) — typically derived from the TTC of 1.5 µg/day (ICH M7) and the patient daily dose; below AET, structures are not required to be identified.
6. Identify and toxicologically assess each extractable above AET — assign each a safety classification (no concern / further data needed / not acceptable).

The leachables study runs the actual drug product in the actual container/closure under ICH stability conditions (long-term + accelerated) and measures the leachable profile at multiple time points across the proposed shelf life. The leachable list should be a subset of (or fully explained by) the extractables list — any leachable not anticipated by the extractables study triggers an investigation into the worst-case adequacy of the extractables protocol. Leachable kinetics often follow Arrhenius-style temperature dependence; accelerated data inform but do not replace long-term confirmation.

The toxicological assessment uses PDE/AI calculations consistent with ICH M7 for mutagenic impurities and route-of-administration-appropriate TTCs for non-cohort impurities. Where a leachable is also an ICH Q3D element, the Q3D PDE applies — never let the E&L PDE and the Q3D PDE for the same element disagree in the filing.

Single-use systems (SUS) — disposable bags, filters, tubing, connectors — present a different problem from primary packaging. The contact times can be short (hours, not years) but the surface-to-volume ratio is much higher, and the manufacturer often qualifies the system once and uses it across many products. BPOG (Bio-Process Systems Alliance) and BPSA published a standardised extractables protocol in 2014 (updated since) that lets system manufacturers publish a common extractables dataset that end-users then apply via process-specific risk assessment. End-users still need to demonstrate that their specific drug product, in their specific process conditions, doesn't generate process-specific leachables of concern.

1. Extractables study performed once during initial qualification and never refreshed when the container/closure supplier changes elastomer formulation.
2. Leachables study truncated to one or two time-points instead of the full ICH stability profile.
3. AET derived without reference to the actual daily dose — typically defaulting to a single conservative value that masks real leachable concentrations.
4. GC-MS or LC-MS used in isolation — semi-volatile species missed by GC and non-volatile species missed by LC-UV.
5. Toxicology assessment done by the vendor's data sheet — no PDE/AI derivation specific to the product, the patient population or the route.
6. Single-use system swapped supplier mid-campaign without revisiting the extractables qualification.
7. Q3D elemental leachables and the Q3D risk assessment held in different files with inconsistent numbers.

• Container/closure (and SUS) register holds the qualified materials, the responsible supplier, the linked extractables/leachables study, the AET and the per-compound PDE/AI assessment.
• Change control auto-routes any container/closure or SUS supplier change to the E&L owner — the study is re-opened, not silently invalidated.
• Stability study integrates with the leachables time-points so the long-term leachable kinetics live alongside the CQA stability data, on the same protocol.
• Q3D elemental conclusions and E&L elemental conclusions reconcile in one register — discrepancies are flagged.
• BMR shows the qualified container/closure batch + supplier on every batch — recall scope on a leachable finding is immediate, not a multi-day reconciliation.