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You can swap between as many handgun as you want. I always kept the punisher on the side for shielded enemies.
Some things to note about the run. You can check if you violated the run at any point by scrolling into challenges and seeing the "Minimalist progress: 0". If the number is higher than 0 the run is invalid. You can load older saves of the run and the progress is remembered on that save.
Throwing eggs, grenades, or shooting illegal guns increases the count. Scoping with the gun (like the bio sensor) does not invalidate the run. Using the mounted cannon, mounted machine gun, or rocket launcher special (against Saddler) does not invalidate the run.
The tricky thing was more so niche enemies. Regenerators being problematic, and shielded enemies/spider las plagas being a problem as well. The Punisher does well a better job against all those enemy types. Piercing helps against parasites in a regen body, wooden shields, and spider plagas resting on the back of their controlled foes. But even then the issue is the low damage on the Punisher means it doesn't help by as much as you'd want.