I think the warning is telling you that when you tweak the System Configuration, you are unable to do a RUN MODE EDIT - i.e. in order to update the System Configuration on the next Write to PLC, Designer will put the PLC in Program mode, then put it back in RUN mode.
When a PLC goes to PROGRAM mode, all Outputs go to OFF/0. For many installations, this is not an issue, especially during development. But some installations, this is CRITICAL, hence the user needs to figure out a good time to update the PLC (i.e. when the machine's outputs can all go OFF).
You can typically do RUN MODE EDITs by tweaking the PROGRAM and/or DOCUMENTATION. However, System Configuration changes cannot be "bumpless".