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Abstract: During the excavation process of tunnel boring machines (TBMs), the precision of manufacture and accuracy of assembly components comprising the main drive seal lubrication structure, and operational conditions, directly impact the overall sealing performance. This, in turn, affects the lifespan of the main bearings and the entire TBM. Simulating the process of injecting grease into the internal structure of the main drive seal lubrication chamber under different working conditions is crucial. Analyzing the distribution of grease within the chamber and the pressure distribution within the system enhances the ability of the main drive seal structure to prevent external contaminants from infiltrating, ultimately extending the lifespan of the main drive structure. This study integrated VOF multiphase flow simulations and experimental investigations to systematically analyze the effects of different eccentricities, the number of grease injection ports, and inner wall rotation speed on EP2 grease distribution. When the eccentricity between the inner and outer seal axes was within 0.75 mm, the number of external grease injection ports was increased and the inner wall rotation speed decreased, the grease was evenly distributed in the flow channels. An injection optimization strategy based on pressure monitoring was proposed. In the design of the main drive sealing structure, controlling the eccentricity below 0.75 mm, arranging 12 injection ports along a single chamber while setting the inner wall rotation speed as 5 r/min can effectively improve the sealing performance of the main drive system.