Problem definition: Biopharmaceuticals are drugs derived from biological sources and produced large- scale using a two-stage biomanufacturing process. In the upstream process, cultivated cells produce the active pharmaceutical ingredient in a non-linear process with random yield. In the downstream process, chromatography resins are used to purify the target protein. Resins suffer from non-linear, random capacity decay. Both stages are often treated as two independent entities operated with fixed operations strategies, neglecting the inherent trade-offs and the regulatory leeway to make condition-based decisions dependent on the current system state. Methodology/results: We develop a stochastic optimization model that uses today's process monitoring data to integrate decision-making on upstream bioreactor harvesting, downstream chromatography purification, and resin exchange. We present a discrete-time, infinite-horizon Markov decision model maximizing profitability. Exploiting the sigmoidal process kinetics of the production formation, we analytically derive the control limit structure for up- and downstream processes and lower and upper bounds for the upstream harvest decision. We compare our methodology to approaches maximizing profitability or batch yield of both stages separately and to stationary operating rules common in the industry. For a typical large-scale biopharmaceutical production process, the profit-maximizing approach achieves 13% higher prof- its than the model maximizing batch yield. Compared to the stationary operating rules, we observe 6% higher profits and 50% fewer resin exchanges. Managerial implications: The derived optimal policy with its two-dimensional control limit structure can easily be implemented in practice. Our condition-based operations policy achieves higher profit and product output, lower cost, and better resin utilization. The results also highlight the importance of maximizing profitability of the entire system instead of maximizing upstream batch yield often proposed in literature. Further, we show that integrated decision-making gains relevance for important industry trends like declining product prices, rising material costs, and increasing upstream product concentrations.     «

Problem definition: Biopharmaceuticals are drugs derived from biological sources and produced large- scale using a two-stage biomanufacturing process. In the upstream process, cultivated cells produce the active pharmaceutical ingredient in a non-linear process with random yield. In the downstream process, chromatography resins are used to purify the target protein. Resins suffer from non-linear, random capacity decay. Both stages are often treated as two independent entities operated with fixed...     »