Leveraging high‐throughput technology to accelerate the time to clinic: A case study of a mAb

Abstract

Acceleration of development timelines to support material production for early‐phase clinical trials has been a continuous goal within the life sciences industry, driven largely by the need to advance an ever increasing number of novel therapeutics into the clinic. This has challenged cell culture and purification development groups to become more efficient, realized in part by leveraging a platform process in the case of mAbs, adopting high‐throughput (HT) technologies, and scaling‐up directly from the HT formats to pilot and clinical scales for toxicology and clinical production. The work presented herein focuses on a case study where a mammalian cell culture process producing mAb A was developed almost exclusively utilizing HT technology. The study describes how HT systems such as microbioreactors for cell culture development and minicolumns driven by robotics for purification development were integrated to rapidly develop a robust production process that was then directly scaled‐up nearly 17 000‐fold for cell culture and 5200‐fold for purification steps to generate material for investigational new drug‐enabling toxicology studies at the 250 L bioreactor scale, followed by another rapid scale‐up to 1000 L for clinical production. Performance comparability across scales demonstrates the effectiveness of HT process development for accelerating the time to clinic.

In situ base release for pH maintenance can allow shake flasks to better mimic bioreactor performance for CHO cell culture

“…Since cell growth, metabolism and protein expression is widely known to be affected by pH, lack of pH control can contribute to such observed differences between culture performance in shake flasks and bioreactors. Various miniature bioreactor systems able to control pH at small scale have been commercialized at different ranges of working volume: SimCell™ (NJ, USA) – 600–700 μL, Micro24™ (CA, USA) – 3–7 mL, ambr™ system (Göttingen, Germany) – variants of 10–15 or 100–250 mL . They have been shown to effectively emulate bioreactor culture performance and product titers .…”

“…Various miniature bioreactor systems able to control pH at small scale have been commercialized at different ranges of working volume: SimCell™ (NJ, USA) – 600–700 μL, Micro24™ (CA, USA) – 3–7 mL, ambr™ system (Göttingen, Germany) – variants of 10–15 or 100–250 mL . They have been shown to effectively emulate bioreactor culture performance and product titers . Studies comparing protein titers in microbioreactors with lab‐scale bioreactors show high correlation coefficients of 0.97 suggesting greater control of process parameters during screening may indeed increase predictive potential of the clone screening assay .…”

Advanced multivariate data analysis to determine the root cause of trisulfide bond formation in a novel antibody–peptide fusion

“…In cell culture modeling there are numerous MVDA techniques available. Multiple linear regression (MLR) models and principal component analysis (PCA) studies are highly suited for media optimization (Beg et al, ; Liu et al, ), scale‐up comparisons (Tsang et al, ), and process optimization and development studies involving DoE experimentation (Holmes et al, ; Siva et al, ). Partial least squares (PLS) modeling is highly suited to process analytic technology (PAT) applications with numerous studies highlighted in the following reviews: Rathore et al (), Glassey et al (), Read et al () and Simon et al ().…”

Scale-down of CHO cell fed-batch cultures

“…These studies show that the result of screening experiments as well as determined process parameters ranges are transferable from ambr to bench-scale systems. In contrast, Siva et al 175 showed that for a fed-batch process using a CHO DHFR-cell line the ambr gave different results compared to 5-L and 250-L STRs. Lower cell density and final titer together with an earlier decrease of cell viability were observed in the ambr system.…”

“…Bench-scale bioreactors (1-10 L) have been used as the main platform for process development and they were traditionally considered as the smallest scale that is still representative for the bioreactors at production scale. However, in order to obtain an accurate definition of the process design space, high throughput experimentation (n>100) is needed 175,189 . Using bench-scale bioreactors for high throughput experimentation is not practical due to the substantial cost associated with materials, space, time, and labor.…”