(547a) Quality Risk Assessment to Enable Q13 Compliance for Drug Substance Continuous Manufacturing

The adoption of continuous manufacturing (CM) in pharmaceutical manufacturing offers several advantages, including reduced cycle times, increased process control, and improved product quality. Moreover, CM enables real-time monitoring and control of the process, which facilitates early detection and correction of process deviations, leading to a reduction in waste and reprocessing. However, the implementation of CM also entails several challenges related to process validation, quality control, and supply chain management, which require robust risk assessment and control strategies.

Earlier this year, ICH guidance Q13 Continuous Manufacturing of Drug Substances and Drug Products was adopted by the FDA. This guidance builds clarification on regulatory considerations of CM development, CTD filing and life cycle management. A need for industry is to develop or adopt existing workflows to Q13 in conjunction with other ICH guidelines, i.e., Q8-Q12.

In this work, we developed a two-step quality risk assessment (QRA) framework suited for development of drug substance continuous manufacturing. The first QRA step is conducted after the proof-of-concept of a continuous process in lab scale, where a modified FMEA based tool is used to systematically assess the risks around the unplanned disturbances originating from material attributes and process parameters to inform future development plans, and equipment/system design. The second QRA step is performed in parallel with further development and leverages the FMEA learnings to establish risk-based sampling strategies, process monitoring and control, process models (e.g., RTD, chemometric models, soft sensors) and disturbance management plans. The finished step 2 QRA can be used in multivariate process characterization and process validation planning.

We would like to share our thoughts on risks to consider during development of a continuous manufacturing process and its corresponding control strategy that we developed for an integrated process involving three reactions – transmetalation, coupling and quench, and a phase separation step.