Manufacturing facilities of the pharmaceuticals must meet certain level of the cleanness required so that foreign substances such as dust, moisture, heat, microorganism, or virus do not contaminate the product. In case of radiopharmaceuticals for medical treatment and diagnosis, not only should the operators and environment be protected from radiation but also need to be isolated from the foreign contaminant. Therefore, manufacturing facilities for radiopharmaceuticals must satisfy the design standards of both hot cell and clean room which are specified by GNP. However, standards of maintaining negative pressure for preventing spread of radioactive contaminant in isolated facilities conflict with the standards of maintaining positive pressure for keeping cleanness. To solve this problem, are pressure of hot cell was designed lower than in the adjacent area to meet standards of the radiation safety. To keep higher cleanness in certain part of the hot cell for filling, minimal relative positive pressure allows. In order to effectively maintain the cleanness that is required for production of Tc-99m generator, which takes 70% of whole demand of radiopharmaceuticals, the rooms placed in each side of production room are used as a buffer area and three lead hot cells are installed in production room. In this research, we established the appropriate engineered design concept for Tc-99m generator manufacturing facility, which satisfies both GMP cleanness standard for preventing particles, bacteria, other contaminants and the regulations of radiation safety for supervising and controlling the amount of radiation exposure and exhausted radioactivity. And the concept of multi-buffer zones is introduced to apply negative air pressure for hot cell with first priority and to continue relative positive air pressure for clean room.