What would be the best approach to align a photomask onto a PCB panel?
It seems like you are trying to align something to an existing PCB/PCA process.

As @Wilhelmsen says, you just need to put down alignment marks.  I'd suggest using the ones used in semiconductor litho systems either the early aligners or the later stepper scanners.
They are designed for a best fit statistically.  Place them in copper not in teh drill holes as drills wander and wear. Fig 4 &amp; 5 here give you an idea

There are targets ones for X, Y , X&amp;Y and rotation.

By using one set of alignment marks for all processes you minimize the overlay error.

In chips we place them in each die corner and also in 6 global locations (which will be harder for you).