The present application discloses methods, systems and devices for using charged particle beam tools to pattern and inspect a substrate. The inventors have discovered that it is highly advantageous to use patterns generated using the Hadamard transform as alignment and registration marks (Hadamard targets) for multiple-column charged particle beam substrate processing and inspection tools. Hadamard targets can be written to a substrate using charged particle beams performing, for example, resist-based lithography or resist-less direct processing. High-order Hadamard targets can also be patterned and imaged to obtain superior column performance metrics for applications such as super-rapid beam calibration DOE, column matching, and column performance tracking. Hadamard target blocks can be written highly locally to electrically functional pattern portions, or integrated into said pattern portions, thereby enabling re-registration local and contemporaneous to writing and improving beam targeting accuracy following re-registration. Superior alignment and registration, and column parameter optimization, allow significant yield gains.