If your library is properly self-contained then app updates should be saved in the iTunes Media folder. See Make a split library portable for details.
The other main issue will be device backups which are stored on whichever drive is hosting your profile, normally C:
Relocate MobileSync Backup folder
You can redirect <Profile>\<AppData>\Apple Computer\MobileSync\Backup to a folder on another drive using NTFSLink (shell ext., might only work on XP) or Junction (cmd line tool).
In essence you move the existing folder to a new location, create an empty folder where the old one used to be, then get the operating system to link the two together and silently redirect any file operation on the old location through to the new one.
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