Sequential Multivariate Cell Culture Modeling at Multiple Scales Supports Systematic Shaping of a Monoclonal Antibody Toward a Quality Target

Biotechnol J. 2018 Apr;13(4):e1700461. doi: 10.1002/biot.201700461. Epub 2018 Jan 30.


The development of cell culture processes is highly complex and requires a large number of experiments on various scales to define the design space of the final process and fulfil the regulatory requirements. This work follows an almost complete process development cycle for a biosimilar monoclonal antibody, from high throughput screening and optimization to scale-up and process validation. The key goal of this analysis is to apply tailored multivariate tools to support decision-making at every stage of process development. A toolset mainly based on Principal Component Analysis, Decision Trees, and Partial Least Square Regression combined with a Genetic Algorithm is presented. It enables to visualize the sequential improvement of the high-dimensional quality profile towards the target, provides a solid basis for the selection of effective process variables and allows to dynamically predict the complete set of product quality attributes. Additionally, this work shows the deep level of process knowledge which can be deduced from small scale experiments through such multivariate tools. The presented methodologies are generally applicable across various processes and substantially reduce the complexity, experimental effort as well as the costs and time of process development.

Keywords: Bioprocess Scale-Up; Cell cultures; Critical Quality Attributes; High throughput; Multivariate analysis.

MeSH terms

  • Algorithms
  • Animals
  • Antibodies, Monoclonal / analysis*
  • Batch Cell Culture Techniques / methods*
  • CHO Cells
  • Cricetulus
  • Decision Trees
  • Least-Squares Analysis
  • Models, Biological


  • Antibodies, Monoclonal