I struggled with this a little bit myself, but then I remembered that 50 Shades of Grey was basically just Twilight fanfiction with a few names changed so it could be published, so I'm probably okay with something taking that route.
With the obvious caveat that editing a pre-existing character design template (like a lot of MLP OCs) would still place it as fanfiction, and that maintaining worldbuilding/story elements, even with new characters, would still place something as fanfiction.
I also feel like I should mention, slightly altering a few characters but maintaining others would still make something fanfiction. Everything fanfiction-y would need to be removed, not just a few things. So it doesn't matter if some fanfiction changes a few characters.