This is how I setup my files.
Special Effects layer - I fill with black, set layer to screen mode.
Line-Art layer - Only black exist on this layer, no white and DO NOT SET IT TO MULTIPLY!!
HOLDS layer - Any holds I need, I CUT from the Line-Art layer and paste into a new layer. Lock Transparent Pixels, then color the line-art on that layer.
Background Layer - This is where I keep my flats. This layer must remain as the Background layer in Photoshop, DO NOT EVER DELETE THIS LAYER.
When I render I duplicate my flats, and when I need to color a certain section, (Like skin or hair) I use the wand set to 0 tolerance, anti-alias unchecked, and select the skin or hair. Paste into a new layer (ctrl shift v), Lock the transparent pixels and render it. Then when done, I merge it down into the rest of the render.