Uncertainty of Size-Exclusion Chromatography Method in Quality Control of Bevacizumab Batches

Abstract

In addition to the analytical challenges related to the size and complexity of biopharmaceutical drugs, the inherent variability that arises due to their manufacturing process requires monitoring throughout the production process to ensure the safety and efficacy of the finished product. In this step, validation data should demonstrate that the process is controlled and reproducible, whereas the manufacturing process must ensure the quality and consistency of the product. For this, the manufacturer sets specification limits according with regulatory guidance. In such a situation, the comparison of different batches is required in order to describe and analyze the variability between them. However, it is unclear how great the variability of the analytical method would be or that in producing the batches. The estimation of the β-expectation tolerance intervals based on the variance components to account for both between-batch and within-batch variability was proposed as a specification limit to control the heterogeneity between batches at the time of manufacture and to verify whether batches meet specification limits. At this point, the variance components were computed by the maximum likelihood method using a linear random model. For this, the protein content, expressed as a percentage of the actual concentration relative to the claim value, and the dimer content (expressed as percentage) were used as critical quality attributes (CQAs) in the monitoring and control process. We used real data from six bevacizumab commercial batches.

Keywords

• size-exclusion chromatography
• bevacizumab
• quality control
• between- and within-batch variability
• tolerance intervals
• assay validation