Well, Loup-Garou is -21 refresh. Even if a hundred low-refresh characters blasted it, unless they had inherited silver it would do nothing to it.
As for making a "tough" BBEG, here are a few ideas;
Mythic Toughness + Hulking Size + Nimble (negates bonus to hit stunt) + fantastic athletics;
For 6-8 refresh (depending on catch), the character has stress track of OOOOOO(OOOOOO) and they defend at +6 and they have armor 3. Half the attacks are going to miss at least. of those that hit, reduce stress by 3. This means that a group of 4 at 10 refresh will need at least 7 exchanges to win vs the beastie.
Mythic Speed + Fantastic athletics + acrobat;
For 7 refresh, the character defends at olympic (+9) vs melee attacks and at ridiculous (+10) vs ranged attacks. Most attacks will miss. As in, nine out of ten vs a submerged group.
Physical Immunity with Catch: all attacks deal stress but only half stress
That's the quick-and-dirty way to scale a BBEG. For 4 refresh, you effectively double its resilience.
Now, if you want something damn hard to kill but technically killable, give it ALL of the above for -17 refresh. I reserve this for really big nasties like medium dragons, big demons, incarnate Fallen, very powerful sidhe and elementals and lesser outsiders. These are in the lowest end of the supernatural heavyweights.