It is possible. The newest version of npi-config has option "Boot device". I did not try to boot from already attached SSD HDD but this option offers such opportunity.
In my solution, SD card is practically read-only. All changing files (including whole Domoticz) are located on SSD HDD. Boot partition i changed to read-only in fstab.
Additionally I place all temporary files in RAM-disk, including SQLite files from Domoticz, NTP drift files, PID files etc.