Has to be the inventory system and the shotgunjumping, the former misplaces items (also combines items for you, not optimal), the latter being inconsistent.
There's also a lot of issues in balancing, saws are good but drones aren't, ammo upgrades seem to last even after the item is removed, bubbles are useless, and meat upgrades aren't that useful.
In general, the shop is also weak, since you seem to get all that you'd need naturally, if you're not too bad, you'll stock up on everything you need without needing the shop.