Isotopically labelled molecules are vital tools within drug discovery and are used extensively to assess a given candidate's ADMET profile. Related to this, transition metal-catalyzed hydrogen isotope exchange (HIE) has become a prominent technique for the selective late-stage installation of a deuterium or tritium label. Despite having wide applicability, the current state-of-the-art in this specific field is limited when particularly co-ordinating motifs are present within a molecule to be labelled. For example, the exceptional binding strength and sterically unencumbered nature of the nitrile functionality leads to catalyst inhibition and has hindered the development of efficient methods for the HIE of nitrile-containing molecules. Herein, in silico solvent binding energy approaches have facilitated the discovery of uniquely tolerant neutral iridium catalyst species that demonstrate a significantly lower binding strength with nitrile functionality. In turn, we describe the first effective nitrile-tolerant HIE methodology enabled via ortho-directed C(sp2)-H activation using air- and moisture-stable iridium pre-catalysts of the type Ir(COD)(NHC)Cl under a deuterium gas atmosphere. This methodology proceeds under mild and practicable reaction conditions with a range of directing groups, including heterocycles, ketones, and amines, with this class of catalyst also shown to be applicable towards bioactive molecules, resulting in high levels of isotopic labelling.