Implementation of QbD strategies in the inoculum expansion of a mAb production process

Abstract

The quality by design approach was introduced to the biopharmaceutical industry over 15 years ago. This principle is widely implemented in the characterization of monoclonal antibody production processes. Anyway, the early process phase, namely the inoculum expansion, was not yet investigated and characterized for most processes. In order to increase the understanding of early process parameter interactions and their influence on the later production process, a risk assessment followed by a design of experiments approach was conducted. The DoE included the critical parameters methotrexate (MTX) concentration, initial passage viable cell density and passage duration. Multivariate data analysis led to mathematical regression models and the establishment of a designated design space for the studied parameters. It was found that the passage duration as well as the initial viable cell density for each passage during the inoculum expansion have severe effects on the growth rate and viability of the early process phase. Furthermore, the variations during the inoculum expansion directly influenced the production process responses. This carry‐over of factor effects highlights the crucial impact of early process failures and the importance of process analysis and control during the first part of mAb production processes.

Emerging Challenges and Opportunities in Pharmaceutical Manufacturing and Distribution

“…Such models and platforms, also known as digital twins, find applications across a variety of activities in pharmaceutical manufacturing. Computerbased modelling in product development and manufacturing has demonstrated significant potential, offering low-cost experimentation platforms to assess CQA-CPP interplay under a vast spectrum of conditions [71][72][73]. In a similar fashion, PSE researchers are also looking to quantify parameter uncertainty and its impact on product and process performance [74,75].…”

Considerations of the Impacts of Cell-Specific Growth and Production Rate on Clone Selection—A Simulation Study

“…It should be noted that the presented model-based method can be further extended to fed-batch processes which are most frequently applied in industrial large scale manufacturing or to perfusion mode. However, the batch process has been considered in this study because the focus was not to find an optimal operating mode for the production bioreactor, but rather to consider how phenotypic differences effect cell growth in the inoculum train, which contributes significantly to the manufacturing time and overall process productivity, yet is rarely considered in literature [26].…”

Upstream cell culture process characterization and in-process control strategy development at pandemic speed

“…Pharmaceutical QbD is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. 25–28 …”