Honestly, you'd be fine going for this on your first playthrough, just there are some bugs that will probably force you to have to start a second game. You wouldn't have to play the whole thing just a fraction, depending on if you get soft locked out of a Strike Point, or if you got all your kill counts with different weapons, side jobs, etc.
I missed a lot of those on my first playthrough and doing them on Hard wasn't difficult or much of a chore, you can get a lot done in the first few areas then sprint through the rest of the missions.
If you decide to do everything in one go, I recommend spending cash on weapons AFTER you receive a job asking for kills with that specific weapon. I also never really bought Health, I mostly just got Molly's, Bombs, and then Hacks. As long as you keep fully stocked there are more than enough opportunities to rack up your kills.
Random events happen every 15 minutes so if you're short just keep a timer.
After guns and consumables, the first thing I bought was the Vest. I didn't really need anything else but I got them anyways.
There is a point of no return, the game does save right before it, but if everything is Blue then there won't be any more enemies. Be sure to follow individual guides for tips on how the checkpoint/reload save system works if you want to farm.