The protein drugs should remain stable for several years even under unfavorable conditions during transport or storage. There are several methods for the production of the protein drugs, including freeze drying and spray drying. Spray drying is a method with a high potential and attractive alternative in preparation of solid pharmaceutical drugs by freeze drying. Spray drying is often regarded as a ‘harsh’ drying method due to the surface induced denaturation of bio-molecules during processing, since atomization and subsequent drying could potentially be detrimental to heat sensitive biological materials such as enzyme. Therefore, it is important to develop new formulation concept for encapsulation and stabilization of proteins during spray drying. This article reviewed several factors which result in the substantial inactivation of enzyme protein during spray drying, including the operational conditions of spray drying, the formulation of the feed enzyme solution and additives.