RATIONALE With the recent introduction of the dynamically harmonized cell, the complexity of tuning has expanded drastically, and fine‐tuning of the DC voltages is required to optimize the ion cloud movement. As this adjustment has typically to be performed manually, more reliable computational methods would be usefil. METHODS Here, we propose a computational method based on a design of experiments (DoE) strategy to overcome the limits of classical manual tuning. This DoE strategy was exemplarily applied on a 12T FTICR equipped with a dynamically harmonized ICR cell. The chemometric approach, based on a composite central face design (CCF), was first applied on a reference material (sodium trifluoroacetate) allowing for the evaluation of the primary cell parameters. Eight factors were identified related to shimming and gating. The summed intensity of the signal corresponding to the even harmonics was defined as one quality criterion. RESULTS The DoE response allowed for rapid and complete mapping of cell parameters resulting in an optimized parameter set. The new set of cell parameters was applied to the study of an ultra‐complex sample: Tholins, an ultra‐complex mixture that mimics the haze present on Titan, was chosen. We observed a substantial improvement in mass spectrometric performance. The sum of signals related to harmonics was decreased by a factor of three (from 4% for conventional tuning to 1.3%). Furthermore, the dynamic range was also increased and this led to an increase of attributed peaks by 13%. CONCLUSIONS This computational procedure based on an experimental design can be applied for any other mass spectrometric parameter optimization problem. This strategy will lead more transparent and data‐driven method development.