1 – manufacturing bonuses (reductions in material needs and manufacture time) for NS and WH space mean that if you want to profit, you need to move your production to more “dangerous” areas of space. Note that LS also gets a manufacturing bonus, but it is much more at risk of being impounded due to structure bashing stuff.
2 – Manufacturing is a lot more complex now, and it takes a lot of manufacturing slots to do all of the tiers of intermediary components for the larger ships, and items that require MUCH more investment into manufacturing and research skills. If you have the research skills, T2 production is still very much viable, though you will spend about half of your manufacturing slots making intermediary materials (and the other half purchased and hauled from a trade hub).
It takes a fair bit more active management than before, which helps make those activities more profitable overall though the profit compared to effort has gone down a bit.
3 – as others have said, you can make better isk per item sold, though at a lower volume (generally), by leveraging smaller regional trade hubs. Generally the last HS next to a LS faction warfare hotspot, or next to a highsec->Nullsec gate. Alternatively, worm holes are quite lucrative as you will generally have options of both smaller and larger hubs, as RNG and bob’s grace allow, and with more relative safety compared to LS or NS if you are in a smaller corporation.