From a solid bench with sand bags or similar.
Absolutely work up a tight grouping load before worrying about sighting in, except to make sure it's close at 25 so you'll be on paper at 50. If groups are at least 2" or less at 25 and patches look good, then I move straight to 50. Stay at 25 and play with patch size and lube amount until patches look good and groups are decent as needed. I start with a lower end powder charge so that poor patches aren't the result of too high of a charge, just eliminates one thing to consider right off the bat.
Once patches look good and I'm hitting center at 25 with at least 2" or less groups, then I move to 50. At the lower end of the powder charge spectrum for whatever caliber rifle it is, shoot 3 shots, up the charge 5 grains, shoot another 3, etc. etc. until finding the point of the groups shrinking and then starting to open back up. The last charge used before the group size started to increase again is what you're looking for. Be aware that there are sometimes lower charges and upper charges that a rifle may like, aka "target" charges and "hunting" charges. My main goal is hunting, so I start at the lower end of a "hunting" charge. (I realize that can be a highly debated thing all on its own)
After optimum powder charge is found I like to play with patch thickness and lube quantities to see if I can shrink groups down more.
I swab every shot when doing the above. Once I'm happy with group size at 50 and the sights are dialed in, then sight in at whatever zero you want. After that I like to shoot at my zero sight in distance without swabbing. I just swab every shot all of the time, but it's nice to know if groups size stays consistent and loading effort is acceptable in case I find myself in a hunting situation where I want the time benefit of skipping swabbing if necessary. My Renegade for whatever reason, and with a very tight fitting PRB combo, absolutely goes haywire in where it puts them after three shots if I don't swab.