E-factor analysis of a pilot plant for end-to-end integrated continuous manufacturing (ICM) of pharmaceuticals

For the past two decades, the pharmaceutical sector has been under increasing pressure to reduce development costs, and improve efficiency and quality.1 Currently, pharmaceutical manufacturing operates at approximately two to three Sigma quality, which translates to ∼ 6.7–30.9% defects.2 Thus, there is still much work and progress required for the industry to achieve six Sigma quality (i.e., ∼0.0003% defects). Critical factors that could support this objective include economic drivers, performance-based regulation, pharmaceutical quality by design, continuous improvement and operational excellence, and emerging manufacturing technologies. Continuous manufacturing is an emerging technology that can lead to six Sigma quality. Product quality is ensured by the process system integration, process control system, and Process Analytical Technologies (PATs),3–13 which allow for real-time monitoring and control of the process. For example, PATs provide the necessary information to the process control system to activate feed-forward and feedback control actions. As early as 2007, continuous manufacturing was recommended by the Pharmaceutical Roundtable (founded by the American Chemical Society (ACS), Green Chemistry Institute (GCI), and several global pharmaceutical companies) as a number one key green engineering research area. In addition, green chemistry and green engineering have attracted more attention in the past decade, from both academia and the pharmaceutical industry. There are twelve principles of green chemistry – “PRODUCTIVELY”. However, these twelve principles do not include several important concepts from an engineering perspective. For this reason, twelve principles of green engineering – “IMPROVEMENTS” were proposed by Anastas and Zimmerman. In the path to achieve the continuous manufacturing of pharmaceuticals, it should be understood that the synergy of both green chemistry and green engineering paves the way toward a more sustainable future. To estimate how “green” a process is, there have been a number of publications to propose or use metrics to drive towards more sustainable practices. The commonly used metrics include E(environmental)-factor, atom economy, process mass intensity (PMI), and carbon efficiency. E-factor is defined as the ratio of the mass of total waste generated to the mass of desired product formed. For comparison, E-factor = PMI − 1. The ACS GCI Pharmaceutical Roundtable adopted PMI; however, the E-factor also has its advantages. For example, when evaluating a multi-step process, the E-factors of separate steps are additive, but PMI is not. Thus, E-factor could provide more information on the waste generation in each step. The proposed use of E-factor has challenged the pharmaceutical and fine chemical industries to make the paradigm shift from process efficiency (i.e., yields) to waste elimination and resource efficiency optimization. In short, E-factor and other metrics have played a pivotal role in driving environmental responsibility by the pharmaceutical industry in the manufacture of APIs and drug products. In our previous work, we reported the first fully automated end-to-end integrated continuous manufacturing (ICM) pilot plant for small molecule pharmaceuticals. In the current work, some key results of the ICM process are discussed. In particular, the E-factors of the ICM process are analyzed and compared with the corresponding batch process.