In the absence of standards specific for testing the reduction robustness of the levels of harmful and potentially harmful constituents (HPHCs), the aerosol from the THS 2.2, a heated tobacco product, was compared with the mainstream smoke of the 3R4F reference cigarette over a broad range of machine-smoking regimes. The average reduction and the introduced concept of threshold limits of robust reduction were derived from HPHC concentrations, in mass per tobacco-stick normalized per total puff volume, to propose an alternative for the assessment of products where nicotine-adjusted yields would be inappropriate. In addition, this study explores the influence of 3R4F reference cigarette filter ventilation, and discusses the roles of temperature and precursors in the present context of robustness of HPHC reduction. Fifty-four HPHCs were analyzed under multiple regimes in THS 2.2 aerosol and 3R4F cigarette smoke. The average reduction of HPHC concentrations compared across all regimes characterized the robustness. Threshold limits of reduction of individual HPHCs were statistically determined across all regimes. The results observed under Health Canada Intense (HCI) and more intense regimes indicated that on average the reductions in HPHCs levels investigated in THS 2.2 aerosol were more than 90% and that the majority of the 54 HPHCs investigated in THS 2.2 aerosol showed more than 90% reduction. The robustness of THS 2.2 in maintaining the levels of reduction of representative HPHCs, whatever the puffing regime, can be quantified. The mass of HPHC per tobacco-stick normalized per total puff volume is a valuable approach to compare the robustness of the performance of a product over a large range of puffing conditions. Our findings will greatly complement the assessment for robustness of current and future similar products where classical approaches would present limitations.