I've done some testing on this and I know the circumstances under which it happens, but not how to permanently cure the problem.
1. Our server is set with a max limit of 2gb upload for large courses etc.
2. If you don't change the settings for the course - (site upload limit) the upload of files seems to fail, but if you change it to something else, it then works fine (even if you change it back to site upload limit).
Any ideas on the actual source of the problem?