There are many rules, but balance is the key. It all depends on your processes, type of equipment you plan to run the panel through, as well as the type of components going onto the board. If your single up circuit has 6 thru-hole caps, 5 connectors, and 8 wires coming out of it, you probably don�t want to make this a 20-up panel. Especially if you only have 3 hand insertion stations before wave and have to hand load your wave. In this case a 2-up or 3-up panel would work better. But then this might whip your surface mount line that can place all the SMT components on a single board in 5 seconds, so a 3-up is only 15 seconds where the 20-up might be preferred. On the other hand a 3-up is also the wrong way to go if you have work orders of 50 or 100 pieces each time. Scrapping a perfectly good board or two each work order is waste. X-outs are another variable tossed into the mix too.
Breakaways are another science on their own. Score lines can sag if not properly cross supported during oven or wave processes. Mouse bites or drilled tabs support well but some board houses use 0.093� routes or 0.100� routes. You should specify your board dimension and also your panel dimensions. Actual detail of your drilled tabs is critical too. Each board house will do as they feel if you do not detail this. Breakaways can also mess with SMEMA sensors or other board available sensors if placed in the wrong spot. Knowing your equipment and it�s sensors is the key to this.
So, as you can see form these examples, penalization can be a juggling game.