If not for the achievement to kill 5,000 enemies it could definitely be done on one play through! But 100%ing Mass Effect 2 & 3 is some of the most fun I've had playing video games :D
You could still theoretically get all the achievements and only play through it once. You can do one I sanity play through and get the rest of the 5000 kills in multiplayer.
I can now add Halo Anniversary and Kingdoms of Amalur to my list, bring it up to 10 completed. All I can say is damn those Library achievements in Halo.
Should have done it the easy way then, make a checklist and then create multiple offline profiles, play a few missions with them and then have your main character join as player 2 and then just go round the weapon shops looking for new weapons, then cycle through new accounts until you get all of them.
I had 1000 in Fallout 3, Fight Night Round 3 and CSI Hard Evidence before I started a new account, they are all easy to 1000 point but Fallout 3 will take a while :)
I thought Fallout 3 was the most enjoyable to 100% I did all the DLC achievement as well and I was upset when I got them all, I couldn't get any more then. lol.