During monoclonal antibody process and product development, critical quality attributes need to be well characterized and controlled to ensure process consistency throughout life cycle management. Due to the complexity and heterogeneity of biologic products, a wide variety of product related substances need to be monitored and characterized throughout process development and process characterization phases in order to develop a risk balanced control strategy and fully understand the root cause of these attributes. Process Development Analytics (PDA), a group within BMS Late-State Biologics Process Development, currently leverages a variety of methods for characterization of product substances during commercial process development. Due to the evolving nature of process development, the current PDA strategy requires high-throughput (HTP) functionality to provide rapid, relevant, and robust data. Discussed will be case studies involving specific HTP analytical characterization methods including: aggregate analysis by SEC-MALS1, fragmentation analysis by CE-SDS2, and charge variant analysis by iCIEF3. SEC-MALS and CE-SDS deliver robust analytical results by characterizing product impurities with a molar mass. However, while charge variants are routinely analyzed by iCIEF providing qualitative insights into general distribution of acidic and basic groups, characterization of the specific variant species at molecular level poses a larger challenge. To overcome this challenge, an automated enrichment method by continuous chromatography was developed and implemented which allowed for collection of individual charge variant species. The enriched samples that result from this method can achieve &gt; 90% purity, and be characterized by enzyme digestion and mass spectrometry. By achieving this level of characterization, fluctuating process parameters can be precisely correlated to known product substances in a HTP environment during commercial process development, leading to a more robust manufacturing process and ultimately a higher quality final drug product.

Characterization of product related substances in high-throughput analytical environment during late-stage biologics commercial process development

2019 Spring National Meeting

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