A Review on the Stability Challenges of Advanced Biologic Therapeutics.

Advanced biotherapeutic systems such as gene therapy, mRNA lipid nanoparticles, antibody-drug conjugates, fusion proteins, and cell therapy have proven to be promising platforms for delivering targeted biologic therapeutics. Preserving the intrinsic stability of these advanced therapeutics is essential to maintain their innate structure, functionality, and shelf life. Nevertheless, various challenges and obstacles arise during formulation development and throughout the storage period due to their complex nature and sensitivity to various stress factors. Key stability concerns include physical degradation and chemical instability due to various factors such as fluctuations in pH and temperature, which results in conformational and colloidal instabilities of the biologics, adversely affecting their quality and therapeutic efficacy. This review emphasizes key stability issues associated with these advanced biotherapeutic systems and approaches to identify and overcome them. In gene therapy, the brittleness of viral vectors and gene encapsulation limits their stability, requiring the use of stabilizers, excipients, and lyophilization. Keeping cells viable throughout the whole cell therapy process, from culture to final formulation, is still a major difficulty. In mRNA therapeutics, stabilization strategies such as the optimization of mRNA nucleotides and lipid compositions are used to address the instability of both the mRNA and lipid nanoparticles. Monoclonal antibodies are colloidally and conformationally unstable. Hence, buffers and stabilizers are useful to maintain stability. Although fusion proteins and monoclonal antibodies share structural similarities, they show a similar pattern of instability. Antibody-drug conjugates possess issues with conjugation and linker stability. This review outlines the stability issues associated with advanced biotherapeutics and provides insights into the approaches to address these challenges.