Extractables & Leachables: Finding What the Packaging Leaves Behind
Container closure integrity testing proves the seal doesn't leak. Extractables and leachables testing answers a different question entirely: what does the packaging itself quietly give off into the product over its shelf life?
01Why this is a different risk than a leak
A container closure can pass every integrity test in the earlier CCIT post and still introduce risk a completely different way: by chemically shedding trace compounds from its own materials of construction into the product it's holding, over the entire length of the shelf life.
Extractables are compounds that can be pulled out of a packaging, delivery system or manufacturing component under exaggerated, forcing laboratory conditions — a worst-case map of what the material is theoretically capable of releasing. Leachables are the subset of those compounds that actually migrate into the real drug product under real storage conditions, and they're the ones that matter for patient safety.3,5 The whole discipline exists to connect those two studies into a defensible, risk-based safety case.
Because rubber stoppers, plastic components, adhesives and coatings all touch the product throughout its stated shelf life, this risk ties directly back to both the packaging controls and the stability program covered earlier in this series — an E&L program is, in a sense, a chemistry-specific extension of both.
Leachables and Extractables Handbook — Douglas J. Ball (Ed.)
Written with contributors from the PQRI Leachables and Extractables Working Group itself, covering the development and practical application of the safety threshold concepts this post is built around.
Find it on Amazon →02The regulatory foundations
| Framework | Issuing body | Core contribution |
|---|---|---|
| USP <1663> — Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems | United States Pharmacopeia | Framework for designing and executing the controlled extraction study3,4 |
| USP <1664> — Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems | United States Pharmacopeia | Defines the Analytical Evaluation Threshold (AET) and its derivation from the Safety Concern Threshold1,3,4 |
| PQRI Safety Thresholds and Best Practices (2006) | Product Quality Research Institute | Originated the SCT/AET threshold framework later incorporated into USP, initially for orally inhaled and nasal drug products2,4,5 |
| FDA ANDA Submission: Risk-Based Extractable and Leachable Assessment | U.S. FDA (CDER) | Current agency expectations for E&L assessment in generic drug submissions1 |
USP <1663> and <1664> were formally adopted in 2014, codifying what had started as PQRI's 2006 OINDP-specific recommendations into a general compendial framework now applied far beyond inhalers and nasal sprays.5
03The E&L program lifecycle
An extractables and leachables program runs through three connected stages, moving from a worst-case chemical map to routine, ongoing control. Click each to expand it.
Packaging or delivery system components are deliberately extracted under exaggerated conditions (aggressive solvents, elevated temperature, extended time) to generate a worst-case profile of everything that could theoretically migrate.
- Multiple solvents chosen to span a range of polarities, not just one convenient solvent
- Results compared against the Analytical Evaluation Threshold before anything is called "significant"
Guided by the extractables profile, the actual drug product is analyzed under real or accelerated storage conditions to determine which of those compounds genuinely migrate into the product, and at what concentration.5
- Target compounds informed by, but not limited to, the extractables profile
- Timepoints aligned with the stability program covered earlier in this series
Once a reliable correlation between extractables and leachables is established, routine extractables testing can serve as an ongoing surrogate control for incoming packaging components, without repeating a full leachables study every time.
- Correlation justified and documented, not assumed
- Component or supplier changes trigger reassessment per the change control process covered earlier in this series
Extractables and Leachables — Dennis Jenke
A current, comprehensive reference from one of the field's most prolific authors, covering chemical characterization and toxicological risk assessment across drug products, packaging and medical devices.
Find it on Amazon →04SCT, AET and TTC
Three threshold concepts anchor nearly every E&L safety assessment. Switch tabs to compare them.
Safety Concern Threshold (SCT). A daily intake level below which a leachable is considered to present negligible safety risk, regardless of its specific toxicological profile. PQRI's original OINDP recommendation set the SCT at 0.15 µg/day for individual organic leachables; other product categories and more recent frameworks have applied different values, such as 5 µg/day for certain organic compounds.1,4
Analytical Evaluation Threshold (AET). The practical, measurable concentration derived from the SCT and the product's own dosing parameters — the threshold above which a detected leachable must actually be identified and reported for toxicological evaluation. This is the number analytical chemists work to, converted from the toxicologically-derived SCT.1,3
Threshold of Toxicological Concern (TTC). A broader toxicological concept — an exposure level below which a chemical, even without compound-specific safety data, is considered to present negligible risk of carcinogenicity or other serious harm. TTC principles inform SCT-setting for categories where no OINDP-specific or product-specific threshold yet exists.
05AET calculator
The Analytical Evaluation Threshold is derived mathematically from the Safety Concern Threshold using the product's maximum daily dose.1 Enter your values to see an illustrative AET.
AET estimator interactive
AET = SCT ÷ Maximum Daily Dose, where MDD is expressed in the same units as your leachable result (e.g., doses/day, mL/day). This simplified form omits the analytical uncertainty correction (response factor adjustment) a full AET determination applies.
This is a simplified illustrative calculation, not a substitute for a real USP <1664>-compliant AET determination, which also incorporates analytical response-factor and uncertainty corrections. Never rely on this tool alone to set a real reporting threshold.
Pharmaceutical Packaging Technology — D.A. Dean, E.R. Evans & I.H. Hall (Eds.)
Covers the materials science behind the rubber, plastic and elastomer components that are the actual source of extractables and leachables, tying this post back to the packaging controls post earlier in this series.
Find it on Amazon →06E&L program self-check
Readiness checklist
07Where programs fail inspection
- AET set after the data comes in. Establishing the threshold before testing, as USP <1664> expects, keeps the evaluation objective — setting it afterward to match whatever results appeared undermines the whole exercise.1
- Extractables treated as leachables. A worst-case extractables result is not automatically a real-world leachable — conflating the two can both overstate and understate actual patient exposure risk.
- Analytical sensitivity above the AET. If a method can't reliably detect compounds down to the AET, a "clean" result may simply reflect a blind spot in the method, not genuine absence.
- Packaging changes made without E&L reassessment. A new stopper formulation, adhesive, or resin supplier can silently introduce new extractables an old study never characterized.
08Specimen quality forms
An extractables study summary and a leachables/AET qualification record — the two documents that typically anchor an E&L program's documentation.
Form EL-01 — Extractables Study Summary
Specimen only — not a controlled document. Full study report should include complete chromatographic/spectral data as an appendix.
| Compound detected | Concentration | Above AET? | Follow-up action |
|---|---|---|---|
Form EL-02 — Leachables / AET Qualification Record
Specimen only — for recording leachables results against the derived AET and any toxicological qualification performed.
| Leachable identified | Timepoint | Concentration | Toxicological qualification needed? |
|---|---|---|---|
These specimen forms illustrate typical content only. Your quality system's document control procedure — numbering, revision history, approval routing — takes precedence over this format.
09References
- U.S. Food and Drug Administration (CDER). "ANDA Submission: Risk-Based Extractable and Leachable Assessment." fda.gov
- Product Quality Research Institute. "Summary of the PQRI Leachables and Extractables Recommendations." pqri.org
- Nelson Labs (Karen Pieters). "Testing of Packaging Systems for Large Volume Parenterals: Extractables Study Design and Challenges." nelsonlabs.com
- Product Quality Research Institute. "PQRI PODP Research Project Proposal" (history of USP <1663>/<1664> and SCT/AET development). pqri.org
- Chemistry World. "Extractables and Leachables Testing." chemistryworld.com
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