In the frame of a sustainable development, investigations dealing with massive Hydrogen production by means of nuclear heating are carried out at CEA. For nuclear safety, thermodynamic efficiency and waste minimization purposes, the technological solution privileged is the coupling of a gas cooled Very High Temperature Reactor (VHTR) with a plant producing Hydrogen from an Iodine/Sulfur (I/S) thermochemical cycle. Each of the aforementioned facilities presents different risks resulting from the operation of a nuclear reactor (VHTR) and from a chemical plant, including Hydrogen, other flammable and/or explosible substances as well as toxic ones. Due to these various risks, the safety approach is an important concern. Therefore, this paper deals with the preliminary CEA investigations on the safety issues devoted to the whole plant, focusing on the safety questions related to the coupling between the nuclear reactor and the Hydrogen production facility. Actually, the H2 production process and the energy distribution network between the plants are currently at a preliminary design stage. A general safety approach is proposed, based on a Defence In Depth (DID) principle, permitting to analyze all the system configurations successively in normal, incidental and accidental expected operating conditions. More precisely, the dynamic answer of an installation to a perturbation affecting the other one during the previous conditions, as well as, the potential aggressions of the chemical plant towards the nuclear reactor have to be considered. The methodology presented in this paper is intended to help the designer to take into account the coupling safety constraints and to provide some recommendations on the global architecture of both plants, especially on their coupling system. As a result, the design of a VHTR combined to a H2 production process will require an iterative process between design and safety requirements.