Optimization of biopharmaceutical manufacturing with scheduling tools - Experiences from the real world

Abstract

This paper presents industrial experience with a resource-constrained batch process scheduling program. The batch process representation is loosely based on the ISA S88 batch process standard. This representation allows the import of batch process information from other software, e.g. batch process simulators. The scheduling algorithm is a non-optimization approach that proceeds in two steps. First a bottleneck analysis is done to determine a lower bound on the process cycle time, and all the batches are scheduled accordingly. Second, if conflicts remain, they are resolved by applying progressively aggressive modifications to the schedule.

This approach to scheduling was tested on several biotech processes. These processes consist of a sequence of batch steps performed with dedicated equipment. The scheduling challenges in biotech processes lie in the ancillary operations: media and buffer preparation, vessel and line cleaning, and chromatography column preparation. Such operations may use shared resources and may serve to couple process suites with otherwise dedicated equipment. These considerations are further complicated by variability in process durations.

Three case studies, which are based on a process for the manufacture of monoclonal antibodies (MABs), illustrate the value of a constrained-resource scheduling tool for biotech processes. In the first case study, the scheduling tool shows that auxiliary cleaning equipment can limit batch production. A second case study shows how scheduling tools can calculate the size of a purified water system. A third case study illustrates how to use scheduling tools to mitigate the effects of process variability.