Since the Eudralex Vol 4 came into operation, verification of cleaning of non-product contact surfaces and monitoring of air within the manufacturing area became part of the Quality Risk Management system. The risk assessment should consider operational controls to minimize and mitigate the risk to product quality, as well as risks related to the environment, health, and safety (EH&S). These key aspects are especially of interest in the manufacturing of highly potent APIs (HPAPIs), where high levels of cleanliness must be achieved. In this lecture, various scenarios in which a highly potent/toxic substance can spread within the isolator are presented. Additionally, a new innovative cleaning tool is introduced to help establish suitable contamination control strategies.