Nowadays, shorter product life cycles and increased product varieties make it difficult to produce some products on traditional production lines. The best that can be done is to manufacture them in one-piece flow production systems. However, the conventional quantitative and qualitative production system design techniques focus on the part of the complex production system (i.e. machining cell, assembly line) rather than the entire production system. Therefore, they are not the best choice for creating the one-piece flow production system with mixed flows. In this article, a systematic procedure based on the timed process flow diagram (TPFD) for design one-piece flow production system is represented. The main idea of the proposed method involves two steps: one is to design and describe the initial production system based on TPFD, that is, define the production family, construct the manufacturing cell and handle the continuous flow within a cell; another is to improve the initial production system according to the critical path of TPFD and focus on reducing the lead time (LT) of product in the complex production system with mixed flows and synchronising the whole production system in a systematic way. One case in real life was studied to evaluate the workability and efficiency of our proposed method in the complex one-piece flow production system.