Developing a Methodology for Process Selection in Pharmaceutical Industry Based on Inherent Safety Considerations: A Case Study on Batch Vs Continuous Process

Compared to the petro-chemical and bulk chemical industry, where continuous processes are widely applied, the pharmaceutical industry still primarily relies on traditional batch processes, due to complex substances, multi-step operation, low-volume production, and unstable product involved in pharmaceutical manufacturing. Driven by the contrasting factors of increasing demand for drugs and a less efficient production mode, nowadays, pharmaceutical industry is trying to transform from a traditional batch process to a novel continuous one. Some trials that aimed at this transition have proven the practicability of continuous processing. These trials ranged from lab-scale experiments to pilot factory manufacturing. However, to make a selection among processes, comprehensive analysis and evaluation are necessary. While economic advantages of continuous manufacturing have been demonstrated, and comparisons in sustainability benefits between batch and continuous process have been done by many studies, comprehensive safety considerations still remain quite challenging.

This research identifies the main factors that affect safety in a continuous pharmaceutical process, provides a reliable and integrated comparison for batch vs continuous process, and further improves existing methodology for process selection and screening in pharmaceutical industry. In order to assess risk quantitatively for batch vs continuous process, several inherent safety indices are compared, advanced and integrated for safety evaluation. The Inherent Safety Key Indicators (IS-KPIs) methodology is applied to improve existing methods by providing consequence-based analysis. PHAST, a quantitative process hazard analysis tool, is also applied in this study. Based on these assessments, a comprehensive and practicable process screening and selection procedure with strengthened assessment capability of safety is built. Three commercial-scale batch processes and their alternative continuous processes are compared in this study to demonstrate the methodology. Furthermore, based on hazard and key parameter identified in pharmaceutical industry in this study, more targeted optimization of batch process as well as development of continuous process can be generated.