Watching the 737 MAX hearings, and one thing is patently clear:

Any modifications to an airframe or powerplants that require compensatory modifications elsewhere in the aircraft's airframe or powerplants must be considered a new model and undergo type certification.

A supplemental type certificate is acceptable for swapping out engines when there are no changes required to manual user experience and operation, any modifications to airframe upstream of the bolts holding engine mount to pylons, including pylon location, demand new type cert.

If the aerodynamic properties of the aircraft change, a new type certificate should be required.

Changes to center of gravity (onboard equipment, pax and cargo loads) should be addressed but shouldn't necessarily require new type certification absent concomitant airframe mods.

to be clear, same goes for amended type certificates.