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This article addresses a multi-stage flow shop scheduling problem with unrelated parallel machines. Some practical processing restrictions such as independent setup and dependent removal times are taken into account as well. The objective is to minimize total flow time in the system. A simulated annealing (SA)-based heuristic is proposed to solve the addressed problem in a reasonable running time. The heuristic begins on a well-designed initial solution generator; then a simulated annealing procedure is applied for further improvement of the solution. To assure the quality and efficiency of the solution for the proposed SA-based heuristic, certain mechanisms are developed and introduced into the heuristic. The computational experimental results show that the proposed SA-based heuristic performs well with respect to accuracy and efficiency of solution.