Key Takeaways
- “Low extractables” is not a label. It’s a risk decision tied to solvent, temperature, time, sterilization, and analytical sensitivity.
- USP <665> is the modern reference point for plastic manufacturing components—and it’s explicitly informational unless regulators make it applicable. (USP-NF)
- USP <1663> / <1664> are still the backbone frameworks for thinking clearly about extractables vs leachables. (USP-NF)
- ICH Q3E is active and risk-management-driven (aligned with ICH Q9 principles); it’s the direction the industry is converging toward. (European Medicines Agency (EMA))
- If your “low extractables” program ignores gaskets, inks, adhesives, tubing additives, you’re basically leaving the back door unlocked.
Direct answer (first 100 words)
To achieve low extractables in pharma and lab systems, pick materials that remain chemically stable under your worst-case conditions (solvent strength, temperature, contact time, sterilization, and cleaning chemistry), then demand credible extractables data and a defensible E&L strategy. Use standardized frameworks—USP <665> for plastic manufacturing components and systems, USP <1663>/<1664> for extractables/leachables thinking, and the evolving ICH Q3E risk-based approach—to align testing solvents and conditions with your process, set reporting thresholds, and avoid “mystery peaks” that trigger revalidation loops. (USP-NF)
If you’ve ever watched a team argue about one unexpected LC-MS peak like it’s a courtroom drama, you already know this truth:
Extractables aren’t a technical detail. They’re a project schedule.
And the way this goes wrong is almost always the same. Someone picks a material because it’s “chemically resistant,” slaps on “low extractables” like a motivational sticker, and calls it done. Then real life shows up—gamma, steam, caustic CIP, surfactants, long holds, elevated temperature—and suddenly your polymer assembly becomes a tiny chemistry factory.
So let’s do the adult version. Not “which polymer is best,” but:
- What’s the worst-case contact scenario?
- What do you need to prove (and to whom)?
- Where do extractables actually come from—the whole assembly, not just the headline material?
The outline (what we’ll actually solve)
- What “extractables” and “leachables” mean (and why mixing them up wastes months)
- The standards map you should keep on your desk: USP <665>, USP <1663>/<1664>, ICH Q3E, BioPhorum
- How chemical resistance and extractables risk are welded together
- Practical selection tactics that reduce surprises
- FAQ written for how people search now (AEO-friendly)
Extractables testing is intentionally aggressive—strong solvents, elevated temperatures, long durations—because it’s building an inventory of what might migrate under harsh conditions. USP <1663> frames this as a design and execution framework for extractables assessments. (USP-NF)
H3: Leachables = “what actually shows up in the real product”
Leachables are measured in the real drug product (or representative process fluid) under actual use conditions. USP <1664> frames a design and implementation framework for that leachables assessment. (USP-NF)
Here’s the mental model I use: Extractables is your “suspect list.” Leachables is your “case file.” Confuse the two and you either test forever or you test the wrong things with great confidence.
H2: The standards map (aka: how to stop reinventing the wheel badly)
USP’s own text is blunt: USP <665> is informational and not compendially applicable unless regulators specify otherwise. (USP-NF)
USP also published a notice about official dates and stakeholder engagement—relevant if you’re tracking timelines and expectations in 2026. (uspnf.com)
Why you should care: single-use systems (bags, tubing, connectors, filters) live here. If your components touch product streams during manufacturing, <665> helps you build a defensible, structured story.
H3: USP <1663> / <1664> — still the cleanest mental framework
Even outside “packaging-only” conversations, <1663>/<1664> remain the clearest way to explain your logic to QA, auditors, and your future self. They explicitly present frameworks for extractables and leachables assessments. (USP-NF)
H3: ICH Q3E — the direction of travel (risk-based, global)
Regulators are converging on risk management language. EMA’s ICH Q3E page emphasizes risk management principles (aligned with ICH Q9) and patient safety/product quality focus. (European Medicines Agency (EMA)) FDA also has a page discussing Q3E draft guidance and its holistic E&L framework. (U.S. Food and Drug Administration)
Translation: if you align your internal playbook to Q3E thinking now, you’ll spend less time translating your rationale later.
BioPhorum’s extractables protocol exists to standardize extractables testing for polymeric single-use components in biopharmaceutical manufacturing. (BioPhorum)
This matters because “supplier data” is only useful when it’s comparable across suppliers—and when it matches your process reality.
H2: Chemical resistance and low extractables aren’t separate topics. They’re roommates.
A chemically “compatible” material can still generate extractables. And a material that’s poor in a solvent often becomes an extractables fountain.
Three knobs crank extractables upward fast:
H3: Solvent strength
A 50:50 ethanol-water mix, strong surfactants, aggressive organics—these don’t just “contact” polymers; they interrogate them.
H3: Temperature
Heat accelerates diffusion and can promote degradation pathways. Your “room temperature data” may become a fairy tale at 60°C.
H3: Time
Minutes vs days matters. Holds, soak steps, and long residence times aren’t a rounding error—they’re the plot.
H2: The part nobody wants to hear: “low extractables” usually dies in the small stuff
You can pick the world’s most chemically resistant film… and still get wrecked by:
H3: Elastomers and gaskets
O-rings and seals are frequent offenders because they contain additives, cure residues, and sometimes a more complex chemistry story than the plastic itself.
H3: Adhesives, potting compounds, end-cap bonds
If there’s a bonding step, you have a potential chemical signature. Period.
H3: Printing inks, labels, and “harmless” markings
The tiny black print you never cared about? That can become your chromatogram’s starring role.
My opinion: if a supplier can’t describe the full bill of materials (BOM) in a way your quality team can live with, you don’t have a “low extractables component.” You have a future deviation report.
H2: Practical material selection tips (that feel boring now and brilliant later)
H3: 1) Define your worst case like you mean it
Write it down:
- fluid composition (including surfactants)
- max temperature and hold time
- sterilization method (gamma, steam, autoclave)
- cleaning chemistry (NaOH, acids, peracetic acid, etc.)
- surface area-to-volume exposure reality
This one step eliminates 80% of bad conversations.
H3: 2) Ask for data that matches your process, not someone else’s brochure
A generic extractables summary is better than nothing… and still not enough.
Demand clarity on:
- extraction solvents used
- time/temperature conditions
- analytical methods (LC-MS/GC-MS/ICP-MS/TOC/NVR)
- reporting thresholds and detection limits
- sterilization status of the test articles
If the supplier can’t answer, the safest assumption is: the data won’t survive QA review.
H3: 3) Anchor your strategy to recognized frameworks
- Use USP <665> as the reference language for manufacturing components (and remember its informational status). (USP-NF)
- Use USP <1663>/<1664> for the cleanest explanation of extractables→leachables logic. (USP-NF)
- Track ICH Q3E thinking for global alignment and risk-based justification. (European Medicines Agency (EMA))
- Use BioPhorum protocol-based packages for comparability in single-use systems. (BioPhorum)
H3: 4) Decide early how you’ll use the results (tox and thresholds)
Extractables data doesn’t “approve” anything by itself. It feeds risk assessment. If you don’t think about toxicological evaluation early, you’ll re-run studies later with different reporting thresholds—because someone finally asked, “Is this peak relevant?”
H2: A simple, repeatable framework you can steal
H3: Step 1 — Categorize the component by risk
Ask:
- Is it product-contact?
- What’s the contact time and temperature?
- Is it single-use with sterilization?
- What’s the patient exposure pathway?
H3: Step 2 — Pick candidates based on stability under worst-case chemistry
Then add the “hidden” materials: seals, adhesives, inks.
H3: Step 3 — Require credible documentation + change control
Because the world’s best extractables report is useless if the supplier changes formulation quietly.
FAQ (People Also Ask)
What’s the difference between extractables and leachables?
Extractables are compounds that could migrate under aggressive lab conditions; leachables are compounds that actually migrate into the real drug product under real use conditions. USP <1663> and USP <1664> present frameworks for each assessment. (USP-NF)
How does USP <665> relate to single-use systems in biopharma manufacturing?
USP <665> addresses plastic components and systems used to manufacture pharmaceutical drug products and biopharmaceutical drug substances/products and explicitly states it is informational unless regulators make it applicable. (USP-NF)
Is ICH Q3E final?
ICH Q3E is still evolving; regulators (EMA/FDA) describe it as a risk-based framework focused on patient safety and product quality, and it’s being rolled out through the ICH process. (European Medicines Agency (EMA))
Because compatibility doesn’t mean zero migration. Additives, processing aids, residuals, and degradation products can still be present—especially under heat, long contact time, and strong solvents.
What supplier documents should I request to reduce E&L headaches?
Ask for: extraction conditions, solvents, time/temperature, analytical methods, reporting thresholds, sterilization status, full BOM transparency (including seals/adhesives/inks), and change control commitments aligned to recognized frameworks (USP/BioPhorum/ICH). (USP-NF)
If you want fewer surprises, don’t treat E&L like a late-stage checkbox.
Treat it like engineering:
- define worst case
- pick stable materials (whole assembly)
- demand credible data
- tie results to a risk and tox strategy
- lock down change control
Because the chromatogram doesn’t care what your supplier meant. It only reports what your system did.
If you share your actual use case (fluid, max temp, contact time, sterilization, cleaning chemistry), I can tighten this into a decision table—“best pick / safe runner-up / avoid”—written the way a QA reviewer thinks.
