I don't think the Settlement and Settlement production is a problem in Chapter 21. The Settlement is easy to build and upgrade. The buildings are cheap enough (Settlement roads too), that you can choose your settlement size. The big bottleneck for me is Mana. The chapter requires a huge amount of mana for everything; settlement production, research and upgrades. Unurium and Seeds may be trick, but you probably have a good production from previous chapters.
This is spot on. The overall mana requirements are dependent on your portal production buff, of course (if your portal buff is higher, you're making more stuff for the same amount of mana, so overall lower total mana reqs), but even when very high (180%+) the requirements are huge. You could be looking at between 130m-160m total mana required to complete the chapter (and that actually *doesn't* include upgrading your T1/S1/A1 manufactories, which cost 2.3m/ea).
Seeds and unurium initially don't seem super problematic at the outset of the chapter, but they get to be an issue as you progress -- in particular, once you've got your workshops upgraded. It's not massive in terms of direct expenditure on production (i.e., the seeds/unurium you spend making oblations isn't tough to manage), but the sentient/ascended goods requirements are huge to keep your workshops running, and obviously that requires seeds and unurium.
Example: I've got 12 Diabhals and 12 Vallorians. If I want to keep those running all day (8x/day Diabhals and 4x/day Vallorians), my costs are:
Sentient Tier 1: 384,000
Sentient Tier 2: 288,000
Sentient Tier 3: 208,000
Total Sentient: 880,000
Ascended Tier 1: 289,600
Ascended Tier 2: 179,200
Ascended Tier 3: 118,400
Total Ascended: 587,200
That's right -- to run my settlement workshops all day, I need to be producing 880k Sentient goods and 587.2k Ascended goods. For me, keeping everything running with MM spells is mandatory to come close to this level of production. Even then it becomes pretty tough. There are certainly AWs out there that can make this a whole lot easier, though -- I just don't happen to have any of them!