Structural approaches to critical quality attributes assessment
Cristina Sensi, Carlo Pergola
A critical quality attribute (CQA) is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. Potential CQAs (pCQA) identification is a key initial step in the development of biopharmaceuticals, that depends on linking the expected quality profile to attributes potentially impacting Bioactivity, PK, Immunogenicity, and Safety.
In fact, the identification of pCQAs allows to focus analytical, pharmaceutical, and process development efforts on those attributes where detailed understanding or better control is needed.
Here we propose the use of structural in silico approaches to improve pCQAs identification in early development phases. In particular, an integrated use of structural tools, such as protein and antibody Homology Modeling, Molecular Docking, and Molecular Dynamics Simulations, can be used to increase knowledge on Biopharmaceutical candidates. For instance, this computational approach can allow the evaluation of the steric hindrance for different kind of glycosylation (fucosylation, sialylation, high mannose forms), of the impact of potential misincorporations on the structure, and can simulate different experimental conditions helping initial classification of aggregation potential (i.e., by increasing temperature).
In turn, the information obtained by the in silico work, together with data collected from analytical and bioanalytical laboratories, supports the understanding of biopharmaceutical entities under development, thus advancing knowledge on molecule and on molecule behaviour.