The other big issue is under Misc in the game planning screen at the bottom. If you pull your starters after the 1st, 2nd, or 3rd quarters in the preseason, then the backups are the starters in those quarters. When they get tired, your starter is out for the game because you benched them, so someone else on the depth chart will fill in for backups. I had WRs and linemen running the ball as my RB in the 3rd and 4th quarters because I benched my starters after the 1st half.
That is usually the biggest issue causing out of position players in the preseason. So check your settings for pulling starters and just set it to 'never' and start your backups if you want them to get the experience and conditioning.