CH 17 · notes
How it works
The EMA guideline on health-based exposure limits (HBELs) uses the permitted daily exposure (PDE, mg/day) of the previous product with the maximum daily dose (mg/day) of the next product to derive a toxicological maximum allowable carryover (MACO), scaled by minimum batch size. EMA Q&A expects HBELs for all products; the 1/1000 dose and 10 ppm approaches are not in the finalised Q&As and are shown here only as historical alert-limit comparisons for existing products.
Reported limits use the HBEL / PDE MACO only. Where a historical comparator is tighter, EMA Q&A 6 allows retaining that limit as an alert limit that must not be relaxed. Surface (µg/cm²), swab, and rinse limits use total shared contact area and total rinse volume wetting that area. Swab recovery applies to measured results (limit × R), not by dividing the limit. Last checked 2026-10-22.
Sources
- EMA HBEL / PDE guideline (Nov 2014) — PDE derivation; HBEL for shared-facility risk identification
- EMA HBEL implementation Q&A (19 Apr 2018) — HBEL for all products; Q&A 6 alert limits; legacy dose/ppm not in final Q&As
- PIC/S PI 006-4 Qualification and Validation — cleaning validation (in force 1 Oct 2026); supersedes PI 006-3
- PIC/S PI 053-1 HBEL Q&A — PIC/S transposition of EMA HBEL implementation Q&A
- PIC/S PI 052-1 HBEL inspection aide-memoire — inspector expectations for HBEL documentation in shared facilities
- ISPE Risk-MaPP (reference; not used for numbers) — risk-based shared-facility context only
- APIC cleaning validation guide (reference; not used for numbers) — industry practice context; formulas follow EMA/PIC/S
FAQ
Which MACO value should I use?
Use the HBEL / PDE MACO as the toxicological basis (optionally divided by a safety factor ≥ 1). Legacy 1/1000 minimum therapeutic dose and 10 ppm values are historical alert-limit comparisons only; they do not replace HBELs. If a historical limit is tighter, EMA Q&A 6 permits retaining it as an alert limit that must not be relaxed.
How is the surface limit derived?
HBEL MACO (mg) is converted to micrograms and divided by the total shared product-contact surface area (cm²) to obtain µg/cm². Swab limits multiply that surface limit by the swab area (cm²). Optional swab recovery multiplies the limit (limit × R) when comparing to raw measured results (measured ÷ R); do not divide the limit by R.
Does this replace quality risk management?
No. Confirm limits with the current EMA HBEL guideline, Q&A, and PIC/S texts. Values were last checked 2026-10-22. Calculations stay in the browser.