Abstract.NOs and NOv were determined in the interstitial air of surface snow and in ambient air at Summit,

Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.

[1] Peroxyacetyl nitrate (PAN) was measured in ambient and snowpack interstitial air at Summit, Greenland, in June and July of 1998 and 1999 and at a rural/forest site in the Keewenaw Peninsula of Michigan in January of 1999. At Summit, we found that PAN typically represented between 30 and 60% of NO y . In the summer of 1999, a significant diel variation in both PAN/NO y and NO x /NO y was observed, but this was much less pronounced in 1998. Experiments during SNOW99 near Houghton, Michigan, indicated that PAN undergoes weak uptake onto snow grain surfaces. At Summit, we found that PAN concentrations in the snowpack interstitial air were significantly elevated (by as much as 2 -5 times) relative to ambient levels, implying a flux of PAN out of the snowpack during the study period. We also observed evidence that PAN can be photochemically produced in snow that is exposed to polluted air. These observations indicate that interactions with the snowpack can have a significant impact on PAN concentrations in the boundary layer and point to potential difficulties associated with investigation of long-term changes in PAN uptake into ice cores because of the impact of postdepositional processes.

Development of a small volume continuous process that used a combination of batch and flow unit operations to manufacture the small molecule oncolytic candidate merestinib is described. Continuous processing was enabled following the identification and development of suitable chemical transformations and unit operations. Aspects of the nascent process control strategy were evaluated in the context of a 20 kg laboratory demonstration campaign, executed in walk-in fume hoods at a throughput of 5–10 kg of active pharmaceutical ingredient per day. The process comprised an automated Suzuki–Miyaura cross-coupling reaction, a nitro-group hydrogenolysis, a continuous amide bond formation, and a continuous deprotection. Three of the four steps were purified using mixed-suspension, mixed-product removal crystallizations. Process analytical technology enabled real-time or nearly real-time process diagnostics. Findings from the demonstration campaign informed a second process development cycle as well as decision making for what steps to implement using continuous processing in a proximate manufacturing campaign, which will be described in part 2 of this series.

The design, development, and implementation of a pilot-scale continuous Schotten−Baumann amide bond formation and reactive crystallization to afford LY2886721 is described. The material met all API quality attributes and was comparable to material produced by a defined batch process. The scalability of the reaction and crystallization processes was confirmed during the development process. The pilot-scale equipment set was contained in a walk-in fume hood and operated at a production rate of 3 kg/day in a 72 h continuous run. Significant technical and business drivers for running the process in continuous flow mode were proposed and examined during development. The continuous process provided for lab hood commercialization and provided for minimal material at risk in the process. The demonstration also confirmed the risk inherent to operation of a tubular reactor under supersaturated conditions, and fouling occurred in the plug flow reactor. Fouling also occurred in the crystallizer. Recognizing these deficiencies, the process operated within the footprint of a standard walk-in fume hood, providing a successful demonstration of the opportunities afforded by continuous processing for low volume pharmaceuticals.