In the development of soft sensors for industrial processes, the availability of data for data-driven modeling is usually limited, which led to overfitting and lack of interpretability when conventional deep learning models were used. In this study, the proposed soft sensor development methodology combining first-principle simulations and transfer learning was used to address these problems. Source-domain models were obtained using a large amount of data generated by dynamic simulations. They were then fine-tuned by a limited amount of real plant data to improve their prediction accuracies on the target domain and guaranteed the models with correct domain knowledge. An industrial C4 separation column operating at a refining unit was used as an example to illustrate the effectiveness of this approach. Results showed that fine-tuned networks could obtain better accuracy and improved interpretability compared to a simple feedforward network with or without regularization, especially when the amount of actual data available was small. For some secondary effects, such as interaction gain, its interpretability is mainly based on the interpretability of the corresponding source models.