Hi
According to your description ,I suggest that you can try to do the action below:
1.Collect live log to check why the ISA block your traffic at that moment
You can enable log and export it to a text file because it is intermittent
problem. Please refer to the link below to enable TMG log function.
Configure TMG log
http://technet.microsoft.com/en-us/library/bb794937.aspx
2. Please check your server if has another program using port 25 at that moment.
It is difficult to monitor ports all the time . I suggest you to use remote management when the issue happens.
Please type command netstat -n in command window to check if there is another application using port 25.
3. Please check if you configured Schedule rule