What does cleaning validation have to demonstrate?

Why

EU Annex 15 covers cleaning validation in detail. Residue limits should be based on a toxicological evaluation, referring to the EMA guideline on health based exposure limits, and documented in a risk assessment. Limits are also needed for cleaning agents, and the cumulative effect across the equipment train should be considered.

A visual check is an important criterion but not acceptable on its own, and repeated cleaning until results pass is not acceptable either. Validation should use worst cases for factors that affect cleaning, such as operators and rinse times, and for campaign length. It should define dirty and clean hold times and pick a worst-case product, using solubility, cleanability, toxicity and potency, with a written rationale.

Sampling by swab or rinse must not influence the result, and recovery must be shown from every product contact material. Microbial and endotoxin risk must be considered. Biologics are a special case.

Annex 15 notes that therapeutic proteins and peptides degrade under pH extremes and heat, so a toxicological limit for the active may not apply, and nonspecific measures such as total organic carbon can be used. For example, a shared granulator might be validated with the hardest-to-clean, most potent product, swabbed at the impeller shaft seal where residue collects, against a limit derived from that product's permitted daily exposure.