Concept Article pubs.acs.org/OPRD
Complexity-Based Metric for Process Mass Intensity in the Pharmaceutical Industry Douglas P. Kjell,* Ian A. Watson, Chad N. Wolfe, and Jeremy T. Spitler Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, 46285, United States S Supporting Information *
ABSTRACT: Process mass intensity (PMI) is a key metric for evaluating the sustainability of a manufacturing process. Within Eli Lilly and Co. (Lilly), a process based on the molecular complexity and the projected market demand has been adopted to set PMI targets for prospective drugs. This strategy is described. PMIs for relevant molecules from publications in this journal were also calculated and compared to the model. These data illustrate the strengths and weaknesses of the model.
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INTRODUCTION Pharmaceutical process development is complex.1 Multiple aspects influence the desirability of a synthesis intended for commercial manufacturing. Purity (assay, related substances, etc.) must be consistently high. Equipment utilization should be maximized. Cost and environmental impact should be minimized. Trade-offs must often be made between these factors. As a simple example, adding a purification step (e.g., a recrystallization) will increase the purity and reliability of the synthesis at the expense of equipment utilization and environmental impact. Thus, is it a good idea? Historically, within Eli Lilly and Co. (Lilly) the decision has been left to the judgment of the lead chemist with retrospective review by management and peers. In recent years Lilly process development has codified criteria, including expectations, to reduce the environmental impact of the process and to help make these decisions more systematic. PMI (process mass intensity) is used as the metric for environmental impact. The American Chemical Society Green Chemistry Institute’s Pharmaceutical Roundtable has adopted PMI as the key metric for evaluating the sustainability of a manufacturing process.2 The importance of green chemistry to process research and development has been reviewed.3 PMI is simply the mass of all materials used divided by the mass of product. The mass of all materials is measured from commodity chemicals already on the market going forward. All solids and liquids used in the synthesis, including water, are included in the calculation. Within process development at Lilly the PMI or the related E-factor2,3 has been used as a metric for over 5 years. Overall, this metric has been an effective tool. A target PMI is set for the process during development with the goal of reaching this target by the product launch. Progress towards this target is periodically reviewed when assessing the development of the synthetic process. Originally, a goal was set to have a PMI of
