Integrated Design of H2O2 Decontamination Processes and Scheduling in Sterile Drug Product Manufacturing

Abstract

We explored the integrated design of H2O2 decontamination processes and scheduling in sterile drug product manufacturing, considering productivity and product quality. Models were developed that (i) deal with the scheduling of filling and the changeover of multiple batches/products and (ii) configure the aqueous H2O2 injection rate into the isolator as a process parameter. The total production time for all planned batches and the sterility assurance level of the products were defined as the objective functions for productivity and product quality, respectively. The models were applied to a multiobjective evaluation of the decontamination and scheduling options in the production of 15 batches (different products and batch sizes). Pareto-optimal solutions were obtained that indicated a trade-off between the two objectives. The inclination of the Pareto frontier increased when the product became more vulnerable to residual H2O2 after aeration and when the batch size became smaller. The quantitative results confirmed an increased impact of the configuration of the decontamination process on both productivity and product quality. The small batch-size production of H2O2-sensitive products is increasingly popular, especially for biopharmaceuticals, and the results of this study encourage the collaborative development of decontamination processes and production schedules in sterile drug product manufacturing.