Specific aspects of the quality control strategy for biomedical cell products containing genetically modified human cells

Abstract

Regulatory authorities around the world have so far endorsed eleven products containing cells with a genome modified by a viral vector (VV) carrying the sequence of the target gene (ex vivo gene therapy cellular products, GTPs). These products (referred to as biomedical cell products, BMCPs, in accordance with Russian legislation) are intended for treatment of haemato-oncological diseases (using the technology of chimeric antigen receptors) and genetic hereditary diseases. Approval of production and marketing for such ex vivo GTPs is based on adequate and comprehensive assessment of their quality, which is challenging due to specific composition of these products that include both viable cells and viral genetic material. The aim of this study was to analyse international experience in quality assurance of ex vivo GTPs in order to identify specific aspects of their quality control strategy during development, production, and expert quality control as a part of the national authorisation procedures. The data presented in public reports of the U.S. Food and Drug Administration (FDA) (Summary basis for regulatory action) and the European Medicines Agency (EMA) (Assessment reports) provided the basis for evaluation of quality control strategies used in the production and release control of approved ex vivo GTPs. The comparative analysis helped to identify specific features of quality control strategies used for these products upon control of raw and initial materials, creation and characterisation of cell banking systems, implementation of in-process and release controls, including development of specifications for active substances and final products, validation of the manufacturing process, stability studies during storage and transportation of active substances and final products. For instance, the use of VVs for transfection requires assessment of such quality attributes as insert integrity, quantitative titer, biological activity, purity and impurities (admixtures), bacterial endotoxins, biological burden, sterility, presence of potentially replication-competent viruses, etc. Transduction of viable cells, in its turn, requires quality control of medicinal products in terms of such quality attributes as viability and proportion of transduced cells (TCs), activity, purity, impurities, safety, and others. Due to specific nature of ex vivo GTP production which is a two-stage process (obtaining the vector at stage 1, and producing TCs and final product at stage 2) characteristic of all the products considered in the study, it seems reasonable to provide separate specifications for the active substance (viral vectors), and a general specification for the active substance (TCs) and the ready-to-use product. Test results for a number of parameters included into the final product specification could not be obtained at the stage of product inspection, but may be derived from earlier stages of production, or even during pre-clinical studies, upon validation of the manufacturing process as well as during the product development.