Critical Quality Attributes and Manufacturing Process Control Strategies of Antibody–Drug Conjugates: A QbD /Risk Assessment Perspective

Abstract

Antibody–drug conjugates (ADCs) have emerged as an important class of targeted cancer therapeutics by combining the specificity of monoclonal antibodies with the potency of cytotoxic payloads. Their complex molecular structure and multi-step manufacturing process, however, there are significant challenges for product consistency, characterization and quality control. The key critical quality attributes (CQAs) of ADCs are discussed in this essay, such as drug-to-antibody ratio, conjugation heterogeneity, aggregation, fragmentation, charge variants, linker stability, and residual free payload, as well as biological activity. It also examines the impact of these attributes upon the quality of the antibody, the properties of the linker–payload, the conditions of the conjugation procedure, and others. Special emphasis is placed on the use of Quality by Design and risk assessment in the connection of the QTPP with the CQAs, critical material attributes and critical process parameters. The analysis suggests that only an integrated, science based control strategy over the entire product lifecycle can ensure the quality of ADC, not just end product testing. However, the complexity and products' specificity of the ADCs might reduce the ability to apply a universal control framework directly. Therefore, process understanding and the development of more sensitive analytical technologies, as well as product-specific risk assessment approaches should be emphasized in the future to facilitate safer, more consistent and more robust ADC manufacture.