In recent years high throughput technology has become a valuable tool for process development, but challenges with scale-up and predicting performance at larger scale still remain. The work presented herein focuses on a case study where a mammalian cell culture process producing a monoclonal antibody was developed predominately utilizing high throughput technology in order to accelerate and improve process development efficiency ahead of clinical production. This study describes how high throughput systems such as micro bioreactors for upstream development and mini-columns driven by robotics for downstream development were utilized to rapidly develop a robust manufacturing process, which was then scaled-up successfully for tox and clinical lot production. 15 mL micro-bioreactors were employed to screen and select a high-producing clone from a pool of 24 potential candidates in 8 weeks. Downstream development utilized mini-columns to rapidly develop a challenging monomer-aggregate separation that included resin screening (mixed mode and HIC) and detailed process characterization using a response surface design of experiments (DoE) to aid in the selection of optimal processing conditions. Development efficiency improved 3-fold for cell line selection and 18-fold for the aggregate removal step when compared to traditional process development approaches. The process as developed in high throughput format was scaled-up directly to nearly 17000-fold for cell culture and 5200-fold for the aggregate purification step for tox production, followed by another 4-fold scale-up for cGMP lot manufacturing. The results from this study compare the benefits and challenges of employing high throughput technology for early stage process development where speed to clinic is paramount.

Direct scale-up of a mAb production process developed in high throughput format

249th National Meeting (2015)

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