The objective of this study was to detect differences in the microstructure (thermo-mechanical transitions of capsule shells and moisture-induced alternation on the physico-mechanical behavior) of three different HMPC hard capsule shells from different suppliers using mechanical, spectroscopic and microscopic and tomographic approaches. Dynamic mechanical (thermal) analysis (DMTA), thermogravimetric analysis (TGA), vibrational spectroscopic, X-Ray scattering techniques as well as environmental scanning electron microscopy (ESEM) and optical coherence tomography (OCT) were used. Two HPMC capsules manufactured via chemical gelling (using a gelling agent) and one capsule shell manufactured via thermal gelling were included. Characteristic micro-structural alterations regarding (thermo) mechanical and physical properties relevant to capsule performance and processability that are originating from diverse manufacturing routes and suppliers were thoroughly elucidated with the integration of data obtained from multi-methodological investigation. The physicochemical and physico-mechanical data obtained from a gamut of techniques overall implied that thermally gelled HPMC hard capsule shells could offer an advantage in terms of machinability during Dry powder inhaler (DPI) capsule filling owing to their superior micro- and macroscopic as well as specifically the mechanical stability under dry as well as humid conditions. Thermally gelled capsules seemed to be stiffer than chemically gelled counterparts and exhibit higher glass transition (Tg) values, lower moisture content and highest thermo-mechanical stability.