The development of a robust tablet formulation for a high dose active pharmaceutical ingredient (API) by the trial-and-error approach is challenging. To meet the growing needs of bringing drugs to market faster and with reduced costs, more targeted and efficient development practices are in demand. Here we show detailed understanding of mechanical properties of API and excipients are essential in achieving efficient development of a high API loading formulation. The loading of the experimental drug, AMG458, was 50 wt% plus accompanying 1:1 molar ratio organic acid of approximately 19%. We assessed manufacturability of powders based on their flow and compaction properties using a shear cell and a compaction simulator, respectively. We selected granulation process on the basis of poor flow properties of API and its blends with common direct compaction excipients. During the course of formulation development, we could quickly identify manufacturability deficiencies in the lead formulation. With detailed knowledge of the mechanical properties of excipients and formulated powders, we improved the lead formulation by overcoming manufacturability deficiencies using predictive and material sparing (<10 g) approaches. Larger batches were subsequently manufactured to confirm predictions.