HBEL / PDE vs Dose-based / 10 ppm
Toxicology-based cleaning limits vs the old 1/1000-dose and 10-ppm rules.
What a comparison is not
A comparison is SPEQ’s reading of how two published documents differ. Neither is the right answer, it is not a determination of which applies to you, and neither is summarised in a way that replaces reading it.
Cleaning-validation limits set how much residue may carry over onto the next product. The modern basis is a health-based exposure limit (HBEL), expressed as a Permitted Daily Exposure (PDE) derived toxicologically. The legacy bases were arbitrary rules — 1/1000 of the therapeutic dose, or 10 ppm. Regulators have shifted decisively to HBEL because it is tied to actual patient safety.
| ASPECT | HBEL / PDE | DOSE-BASED / 10 PPM |
|---|---|---|
| Basis | Toxicological (PDE from the safety data) | Arbitrary convention (1/1000 dose, 10 ppm) |
| Tied to patient safety | Yes — derived from a safe daily exposure | No — a rule of thumb, not a safety threshold |
| Regulatory position | Expected (EMA HBEL guidance, PIC/S) | Superseded; may be used only as an additional check |
| Where it drives limits | MACO from PDE, batch size, shared surface area | MACO from dose fraction or ppm |
| Highly potent compounds | Handles them via low PDE | Under-protective for potent compounds |
Use HBEL/PDE as the primary basis for cleaning limits — it is the toxicologically justified, regulator-expected approach and correctly handles highly potent and hazardous compounds.
The dose-based and 10-ppm criteria are legacy rules; they may still be applied as an additional, more-conservative check, but they should not be the sole justification for a cleaning limit today.
HBEL replaced the rules of thumb. The 1/1000-dose and 10-ppm criteria are arbitrary and can be dangerously under-protective for potent compounds, so regulators expect cleaning limits derived from a health-based exposure limit. Best practice sets the maximum safe carryover from the PDE (and may cross-check against the legacy criteria, taking the most conservative), rather than relying on the old rules alone.
HBEL / PDE vs Dose-based / 10 ppm: frequently asked questions
Common questions on how HBEL / PDE and Dose-based / 10 ppm differ and when each applies.
Why did regulators move from dose-based limits to HBEL?
Because the 1/1000-dose and 10-ppm criteria are arbitrary conventions unrelated to actual toxicity, and can be under-protective for highly potent or hazardous compounds. A health-based exposure limit (PDE) is derived from safety data and ties the cleaning limit to a genuinely safe daily exposure.
Can I still use the 10-ppm or 1/1000-dose criteria?
They may be used as an additional, more-conservative check alongside HBEL, but not as the sole scientific justification for a cleaning limit. Current expectations (EMA HBEL guidance, PIC/S) require a health-based limit as the primary basis.
What is MACO?
Maximum Allowable Carryover — the amount of a product residue that may safely carry over into the next product. It is calculated from the health-based exposure limit (PDE), the batch size of the next product, and the shared equipment surface area, and drives the acceptance limit for cleaning validation.