Pyanodon changes factorio so much. The byproducts are a big issue, and you need to get in the mentality that often it's fine to burn up items just to avoid the logistical nightmare. The biggest change for me is how expensive infrastructure is. You often need buildings that eat up 10 minutes of production just in materials. Scaling up is a challenge also because of how huge he buildings are (both a blessing and a curse) and how expensive everything is. Even conveyor belts are expensive at the beginning.

I played py hard mode until py science 1, then later on I started what was supposed to be an easier playthrough in pyblock, but i still stopped with a few parts missing for logistical science.

I still consider it one of the best mods out there (it's really well balanced), but you should start playing it only with a "I will not finish it" mentality, since it's thousands of hours long.