Lyophilization biologicals products. Equipment. Technology. Validation.

Abstract

Тhe aseptic process of industrial production of sterile lyophilized biological products is completed by one of the critical stages of the technological process, the freeze-drying. GOST R ISO 13408-3-2011 defines the term lyophilization as a synonym for the sublimation. Sublimation - the physical process on which the freeze-drying method is based. This paper discusses the issues of freeze drying that engineers and biologists, production technologist, designers of dry preparations, and quality specialists face with. Freeze-drying consists of three stages: freezing, freeze-drying and drying. Each stage has its own critical points, input and output parameters. The task of the developer of freeze-drying technology is to determine the need for each parameter and the sufficiency of their quantity. Equipment, technology and regulatory documents are considered as interdependent elements that make up freeze drying as a system. An integrated approach to the freeze-drying process includes the development of modes, equipment control, and internal documentation. The key parameters of the process are the qualitative and quantitative characteristics (reference values, measurement procedures, acceptable range of values) of the semi-finished liquid product and the finished freeze-dried product. Characteristics of the semi-finished liquid product are the temperature of complete crystallization; upper and lower eutectic temperatures; maximum permissible heating temperature (thermo-lability); density; specific (biological) activity. Freeze-drying process characteristics are: at the freezing stage - reaching the temperature of complete crystallization in the entire volume of the material received for drying; at the sublimation stage - maintaining the temperature in the dried material in the range between the lower and upper eutectic temperatures (without going beyond the upper); at the drying stage - reaching the maximum temperature in the material. The duration of each stage depends on the vial in which the dried material is packed, the volume of packaging, and the features of heat, mass, and energy exchange in the sublimation plant. Standard operating procedures (SOPs) should be designed with these features in mind. For example, for different packages (2ml or 10ml) in vials of the same volume, or for the same packaging in vials of different volumes, for example, 2ml in vial of 10-ml or 20-ml, separate SOPs are required in each case. In the current practice of industrial production, the quality of the lyophilized product is evaluated by humidity (GOST 24061-2012). In our work, to assess the quality of the process, we measured the decrease in the mass of liquid material during drying. We recommend measure both indicators, since they complement each other.