Quality Risk Assessment in Late Phase Drug Substance Process Development

This presentation outlines the process and tools that Bristol-Myers Squibb uses to conduct Quality Risk Assessment (QRA), to achieve consistent drug substance quality and production process performance. The QRA is carried out at multiple stages during the drug substance development lifecycle, with the knowledge requirements and risk mitigation plans increasing with each subsequent iteration. During this process, the quality attribute(s) (QAs) of the drug substance are established, and risk based linkages from the process raw materials and production procedures to these QAs are established. From this analysis, high risk items are identified to focus further development work, improve scientific understanding of the process and/or develop additional process controls. A Failure Modes and Effects Analysis (FMEA) methodology is employed that identifies failure modes (for the QAs) and potential causes (variability in process parameters, chemical equivalents, etc.). The impact of the failure mode (severity) is determined, together with the probability and detection of its occurrence. Understanding failure modes leads to the development of a control strategy designed to ensure the proposed acceptance criteria are consistently met. Ultimately, this risk assessment process establishes a thorough understanding of the process variables and their collective impact to the drug substance QA, thereby effectively managing risk to quality.