Process Design, Simulation, and Techno-Economic Evaluation of Recombinant Human Lactoferrin Production via Precision Fermentation in Pichia pastoris with Chromatography-Free Downstream Processing

Lactoferrin is a high-value multifunctional glycoprotein with growing applications in infant nutrition and functional foods. Conventional production relies on extraction from bovine milk, a process limited by low yield and costly chromatographic purification. This study presents a comprehensive techno-economic analysis of an industrial-scale precision fermentation process for recombinant human lactoferrin production. The process employs Pichia pastoris as the expression host and features a chromatography-free downstream purification strategy based on centrifugation and membrane filtration. The entire manufacturing train was modeled using SuperPro Designer ^{textregistered} , simulating fed-batch fermentation in six staggered 100 m ³ bioreactors with extracellular protein secretion. The downstream process integrates sequential centrifugation, crossflow microfiltration, ultrafiltration/diafiltration, and spray drying. This configuration yields an annual production of 251.3 metric tons (251,304 kg) of lactoferrin powder (90% purity), with a batch output of 766.17 kg. The total capital investment is estimated at \$122.5 million, with an annual operating cost of \$66.0 million, resulting in a unit production cost of \$262.60 per kg. At a conservative selling price of \$600 per kg, the process demonstrates strong economic viability with a gross margin of 56.2%, a return on investment of 50.0%, and a payback period of 2.0 years. These results establish that simplified, membrane-based downstream processing enables economically competitive, large-scale production of recombinant lactoferrin for food and nutraceutical markets, offering a sustainable alternative to bovine-derived sources.