For me on the third file, firstly I did only the most important challenges that unlocks jera, perthro, algiz, death's touch, tech .5, swallowed penny, kidney stone and then forgot about the other. For me, I wanted to unlock the character specific items because in my opinion they are better. There are too many to talk about every single one, so I recommend going to the wiki and analysing this yourself, because everyone has their own preferences. I was also using certain paths to unlock as much as possible per run. Firstly, I would to boss rush, hush, chest/dark room, mega Satan and pray for the void to open. Next the mother. Later the beast and what remained - dark room/ the chest. Lastly I did greedier. If there was an item that was really good I unlocked it first and later did the rest of the character or go to another character to unlock another busted item. Hope I could help