ICH Q8(R2) established general guidelines around the Relationship of a Design Space to Scale and Equipment (Section 2.4.4); however, the guideline is not intended to provide guidance on scientific strategy for the application and implementation. It is widely recognized that drug product processes are typically scale and equipment sensitive; however, the same expectation should not be applied broadly to drug substance processes due to fundamental difference between the disciplines. This paper proposes a scientific perspective and strategy of how to develop design spaces that include scale and equipment knowledge for drug substance processes, and how to use that knowledge to mitigate the risk when changing from laboratory thorough commercial facilities.