Don't overthink this.
There's essentially no difference to "setting up" an external USB3 SSD, as there would be to setting up an internal drive.
The Mac almost never cares about which drive is the boot drive.
So long as it finds a bootable drive, it "runs with it".
I'm surprised by how many Mac users don't reailize this.
That said...
There IS a consideration.
That is, will the SSD be 256gb, 512gb, or 1tb?
If you use a smaller-capacity SSD, you will want to keep large libraries of pics, movies, and music on the internal HDD.
There's no reason to "clog up" the SSD with them. They probably aren't accessed often and you want to keep the SSD "lean, clean, and mean".
I would set up the SSD external booter to have:
- the OS (of course)
- your apps
- your accounts (with large libraries left on the hdd)
- keep smaller files that you're working on, on the SSD for speed.
Also -- leave the internal HDD to remain bootable.
You always, ALWAYS, ALWAYS want a "second fully-bootable drive" nearby and quickly available.
And... you might want to consider a SECOND external drive (doesn't have to be an SSD) to serve as a backup to the "external boot" drive.
Personal experience:
I use a 240gb external booter for my late-2012 Mac Mini. I have the SSD partitioned. One partition is my "boot partition". The second serves as my "Main" partition, where all my data files (going back 30+ years!) are stored.
I back both of these up to similar partitions on the Mini's internal 1tb drive.
The Mac Mini has run GREAT for more than four years in this configuration.
TRIM (or the lack of it because of USB3) has NEVER been an issue.