As outlined in the ICH Q8(R2) guidance, identifying the critical quality attributes (CQA) is a crucial part of dosage form development; however, the number of possible formulation and processing factors that could influence the manufacturing of a pharmaceutical dosage form is enormous obviating formal study of all possible parameters and their interactions. Thus, the objective of this study is to examine how quality risk management can be used to prioritize the number of experiments needed to identify the CQA, while still maintaining an acceptable product risk profile. To conduct the study, immediate-release ciprofloxacin tablets manufactured via roller compaction were used as a prototype system. Granules were manufactured using an Alexanderwerk WP120 roller compactor and tablets were compressed on a Stokes B2 tablet press. In the early stages of development, prior knowledge was systematically incorporated into the risk assessment using failure mode and effect analysis (FMEA). The factors identified using FMEA were then followed by a quantitative assessed using a Plackett–Burman screening design. Results show that by using prior experience, literature data, and preformulation data the number of experiments could be reduced to an acceptable level, and the use of FMEA and screening designs such as the Plackett Burman can rationally guide the process of reducing the number experiments to a manageable level.