They can also use reduced factorial design. It is even possible to buy kits based on reduced factorial design. It can be possible to find ideas about optimising the crystallisation procedure from database. You can also use seeding techniques. The most frequent problem is that no crystal forms, but, as you can see from the list, there are many other potential problems as well.
Crystallographers spend a lot of time trying to produce good crystals.
When researchers get no crystals , they try to do more experiments based on physical properties of the protein. The problem of micro-crystals is considered solvable. This list shows the crystallisation strategies used by many labs. Most labs have their own de novo methods. There is a special plate for building crystals.