Yes they do remain set after reconverting to ISO, & yes it can take a bit of time to figure out the right combination of flags to set doing it that way but there are guides you can find online which list the optimal settings so you should only need to set them once & for some games it's the only way to get them working. Yes there are quite a few that require you to use the various options for full compatibility otherwise they can be glitchy (black screens, in-game freezes, gamedata fails to install, can't save properly etc). You can set gamedata to install on an external drive instead of the internal in WebMAN Mod but it doesn't have the other options. ManaGunZ & MultiMan both allow these options to be set but I've never used Irisman so I'm unsure about that one.