What resolution are you doing this in? 300 pixels/inch or what? If you are going for super high resolution it's going to make a big file really fast.

I usually end up creating a stripped down file myself because after a while you just have too many layers going on and if you don't need to revisit them you may as well create a new flattened base and work from there. It also provides you with a series of backup files you can go back to in case you have a catastrophe.