Developability studies before initiation of process development

Abstract

Monoclonal antibodies constitute a robust class of therapeutic proteins. Their stability, resistance to stress conditions and high solubility have allowed the successful development and commercialization of over 40 antibody-based drugs. Although mAbs enjoy a relatively high probability of success compared with other therapeutic proteins, examples of projects that are suspended due to the instability of the molecule are not uncommon. Developability assessment studies have therefore been devised to identify early during process development problems associated with stability, solubility that is insufficient to meet expected dosing or sensitivity to stress. This set of experiments includes short-term stability studies at 2−8 þC, 25 þC and 40 þC, freeze-thaw studies, limited forced degradation studies and determination of the viscosity of high concentration samples. We present here three case studies reflecting three typical outcomes: (1) no major or unexpected degradation is found and the study results are used to inform early identification of degradation pathways and potential critical quality attributes within the Quality by Design framework defined by US Food and Drug Administration guidance documents; (2) identification of specific degradation pathway(s) that do not affect potency of the molecule, with subsequent definition of proper process control and formulation strategies; and (3) identification of degradation that affects potency, resulting in program termination and reallocation of resources.

Aggregation risk prediction for antibodies and its application to biotherapeutic development

“…Early developability assessment has the potential to reduce drug attrition at later stages of drug development, reduce production costs and increase the probability of success. 9,[30][31][32][33] We presented here an example of a developability assessment performed during antibody engineering. Variants were designed, screened in silico for the risk of aggregation and potential immunogenicity using the Epibase TM T cell epitope profiling platform.…”

Using extensional flow to reveal diverse aggregation landscapes for three IgG1 molecules

“…A caveat of these latter in silico methods is the necessity of high resolution structural data for the molecule under study. These developing in silico approaches complement established accelerated stress studies that are performed in vitro to predict the shelf‐life and stability of biologics (Jain et al, 2017; Yang et al, 2013). Various methods are employed to generate such data including heating (Cheng et al, 2012; Hamrang et al, 2015), stirring (Luo et al, 2011; Sediq, Van Duijvenvoorde, Jiskoot, & Nejadnik, 2016), shaking (Kiese, Papppenberger, Friess, & Mahler, 2008; Rudiuk, Cohen‐Tannoudji, Huille, & Tribet, 2012), and simulation of transportation (Fleischman, Chung, Paul, & Lewus, 2017).…”

High-throughput screening for developability during early-stage antibody discovery using self-interaction nanoparticle spectroscopy

“…1,2 In an effective antibody discovery program, both the biology and developability of the lead candidates must be carefully examined to ensure efficacy while minimizing downstream risks. [3][4][5][6] In the past, the strongest focus has been placed on identifying biologically relevant, high affinity antibodies against selected targets. However, many discovery programs have ultimately failed due to poor antibody expression, low solubility and high viscosity, poor stability or high polyspecificity, the latter of which may lead to shorter serum half-life.…”