I don't believe that should be an issue, provided you don't go very extremely high definitions. Regardless if they are sprites or handrawn, they still need to align in the spritesheet.
When set the Sprite for the Player or and Entity for instance, you set the Sprite Dimensions individually, so you could have every Character or NPC in the game to use a different Sprite Dimension. But per sheet they need to fit into that set Dimension.
For instance, Final Boss Blues Time Fantasy Sprites, at 32x32, uses a 26x36 Frame. So each individual Sprite on that Sheet neatly fits into that box.
And the same will apply if you use custom handrawn images.