Well, if calibre is busy moving files around, the backup might catch the library halfway through, and have some files in the wrong place.
It depends on what sync application you use.
FreeFileSync (Windows) in Admin mode can use Volume Shadow Copy I believe to get a view of the filesystem at a single moment in time, then make a copy of that.
On linux, you can use an LVM snapshot to do much the same thing.
calibre performs all file writes in an atomic fashion, so you shouldn't get corrupted files.
I still wouldn't risk it, either way. I prefer scripting the backup to happen automatically after calibre closes, and locking calibre from opening while it is running.