This manuscript presents the remote monitoring of the main parameters in the 18O isotope separation technological process. It proposes to monitor the operation of the five cracking reactors in the isotope production system, respectively, the temperature in the preheating furnaces, the converter reactors and the cracking reactors. In addition, it performs the monitoring of the two separation columns from the separation cascade structure, respectively, the concentrations of the produced 18O isotope and the input nitric oxides flows. Even if the production process is continuously monitored by teams of operators, the professionals who designed the technical process and those who can monitor it remotely have the possibility to intervene with the view of making the necessary adjustments. Based on the processing of experimental data, which was gathered from the actual plant, the proposed original model of the separation cascade functioning was developed. The process computer from the monitoring system structure runs the proposed mathematical model in parallel with the real plant and estimates several signal values, which are essential to be known by the operators in order to make the appropriate decisions regarding the plant operation. The separation process associated with the final separation column from the separation cascade structure is modeled as a fractional-order process with variable and adjustable differentiation order, which represents another original aspect. Neural networks have been employed in order to implement the proposed mathematical model. The accuracy, validity and efficiency in the operation of the proposed mathematical model is demonstrated through the simulation results presented in the final part of the manuscript.