Well, above all it needs to be funny. The finale was too serious, so all these things are going to need to be defused or resolved in the opener in some lighthearted way.
First, they have let Amy get too needy. When they first wrote her in, she was asexual and a Sheldon clone. They have allowed her to be influenced by Penny and she is now needing more. But how do you make it funny? I see several weeks of Amy cutting loose while the rest are settling down before she moves back toward Sheldon.
Same with Stewart. I don't see Howard and Bernadette throwing him out. I see something happening where Stewart leaves on his own. Success or total failure in the comic shop, a girlfriend, etc.
I think we may never see Raj' girlfriend again, or he will embrace her quirkiness. Raj has always been a bit of a chameleon. I think he will go with the flow.
To me, the key is Sheldon. The writers have painted themselves very far into a corner there. Leonard and Penny can't start their own household. The Amy thing is unresolvable as it stands. The job is unsatisfying now. Sheldon is going to have to change radically, and that may be the shark jumping moment.