In the long run, the best way to farm ISO is to farm champions, generally in the arena. Duplicating champions generates ISO. I can't remember the last time I ran out of ISO: I'm usually selling tens of thousands to hundreds of thousands of points of ISO a week on average. In fact selling ISO is my largest source of gold, because I'm constantly selling ISO.
Story mode act 4 is best bet for that route, otherwise hit most if not all of the arena milestones. Gives PHC shards and opening characters you have already gives you colored crystals based on that duped characters class. Bigger bonus if sig is maxed out, gives a lot more colored ISO.
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Oh yeah and also gold...
Oh yeah and also units...
You should play more arena.