Online and real-time analysis of a chemical process is a major analytical challenge that can drastically change the way the chemical industry or chemical research operates. With in situ analyses, a new and powerful understanding of chemistry can be gained; however, building robust tools for long-term monitoring faces many challenges, including compensating for instrument drift, instrument replacement, and sensor or probe replacement. Accounting for these changes by recollecting calibration data and rebuilding quantification models can be costly and time-consuming. Here, methods to overcome these challenges are demonstrated with an application of Raman spectroscopy to monitoring hydrogen isotopes with varied speciation within dynamic gas streams. Specifically, chemical data science tools such as chemometric modeling are leveraged along with several examples of calibration transfer approaches. Furthermore, the optimization of instrument and sensor cell parameters for targeted gas-phase analyses is discussed. While the particular focus on hydrogen is highly beneficial within the nuclear energy sector, mechanisms built and demonstrated here are widely applicable to optical spectroscopy monitoring in numerous other chemical systems that can be leveraged in other processes.