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By Paul Richardson, Director, Oncology Chemistry, Pfizer and Juan Colberg, Senior Director within CRD, Pfizer
The ACS GCI Pharmaceutical Roundtable convened on October 9-10, 2018 at the Pfizer site in Groton, Connecticut for their fall meeting. With the vast majority of the 22 member companies represented in person, the meeting provided an opportunity for the various project teams to present updates on the numerous current initiatives on-going throughout the Roundtable ranging from the various grant programs, global outreach, green chemistry enabling tools as well as opportunities arising from engagement in new emerging pharma modalities.
The meeting’s opening remarks were delivered by Pfizer's Steve Brooks, Senior Vice President of EH&S, who has been the senior sponsor for the Pfizer Green Chemistry program for over 10 years. Steve spoke regarding the importance of linking product sustainability to green chemistry and how the program as a whole is embedded within the company’s business imperatives and cultural initiatives. From the Roundtable's perspective, the potential impacts to be realized from the relatively recent ignition grants were highlighted by a presentation within the meeting from Professor Jeff Byers, Boston College, who spoke on the emergence of iron as a viable alternative to the precious metal palladium in mediating carbon-carbon bond formations, which are prevalent throughout the industry. In addition, Greg Whiteker, Fellow at Dow AgroSciences, provided an overview of the chemistry within their crop protection portfolio highlighting the synergy between agrochemicals and pharma in the application of green chemistry principles in process development. Finally, the emergence of continuous manufacturing within the pharmaceutical industry and the paradigm shift this represents in terms of strategy and logistics was stressed by Lynne Handanyan, Vice President of Medicinal Sciences at Pfizer, who presented on the rapidly progressing initiatives on-going within Pfizer to address this challenge.
Coupled to the meeting on October 11, 2018 the ACS GCI Pharmaceutical Roundtable Flow Chemistry Team organized a standalone symposium focused on “Recent Innovations in Flow Chemistry and Continuous Manufacturing.” Despite both the specialty chemical and pharmaceutical industry’s traditional reliance on batch processes, there is a growing realization that continuous processes provide advantages from both a logistical and sustainability perspective. This meeting sought to bring together leading practitioners in flow chemistry from both academia and industry to speak on the latest emerging developments aimed at overcoming the technical hurdles involved in translating a process from batch to a continuous mode.
Scientists from both industry and local academic institutes filled the Pfizer lecture hall, and after a brief welcome from Juan Colberg and Paul Richardson from the Pfizer organizing committee, Lynne Handanyan gave the introductory remarks, stressing both the importance of realization that the implementation of flow-based processes can have significant advantages, as well as reiterating Pfizer’s commitment to this synthesis technology throughout chemical development.
These remarks lead into the first talk from Professor Richard Bourne, University of Leeds, UK, on the use of “Self-Optimizing Reactors for Rapid Sustainable Process Development,” which emphasized the need for an interdisciplinary approach at the interface between chemistry and chemical engineering in order to develop automated flow systems combining online analysis, feedback control as well as evolutionary algorithms to provide both process and understanding and enable optimization. Drawing on a series of examples including the optimization of the final step of the EGFR inhibitor, AZD9291, Richard was able to demonstrate how a flow system was able to automatically work through a series of experiments in a manner resembling a DoE to reach the optimal process conditions whilst evading the pitfall of identifying local maxima.
The second speaker was Kevin Cole, Principal Research Scientist at Lilly, who presented on the “Environmental Aspects of Lilly’s Small Volume Continuous Manufacturing Platform,” highlighting two compounds—prexasertib and merestinib—from the company’s oncology portfolio. In the two cases studies, Kevin emphasized the advantages of employing a continuous-based approach specifically in terms of running hazardous chemistries, minimizing worker exposure to high potency compounds, energy savings and a reduced operating footprint. He also stressed the further challenges that need to be addressed such as avoiding the use of strong solvents (e.g., DMSO, etc.) as well as driving towards a reduced Process Mass Intensity (PMI).
Matt Bio, CEO and President of Snapdragon, gave a presentation entitled “One Process from Milligrams to Kilograms: Efficient Drug Substance Development Enabled by Continuous Manufacturing Technology.” A recurring theme throughout Matt’s presentation was the development of a customized reaction engineering approach in order to optimize the chemistry at the development stage, and thus allow seamless and efficient scale-up to be realized using scaled equipment. This was highlighted by solutions presented to chemistries that are often challenging to run in batch, such as photoredox and gas-liquid reactions—specifically here ozonolysis.
Directly prior to the lunch break, Professor Frank Gupton, Virginia Commonwealth University, spoke regarding “Increasing Access to Global Healthcare through Process Intensification: The Medicines for All Initiative.” This initiative takes a multifaceted approach to ensuring global access to life-saving medications considering the complete life cycle through synthetic-route design, environmental impact, as well as implementation of a commercial supply network. Within the synthesis portion, novel manufacturing platforms such as flow play a critical role, and Frank presented case studies including the development of a newer higher-yielding synthesis of the antiviral (HIV) nevirapine, work for which he (and Prof. Tyler McQuade) were recently recognized for with the 2018 Green Chemistry Challenge Academic Award.
Recipient of the 2018 Green Chemistry Challenge Award, Professor Frank Gupton (left),
answering questions after his presentation (with Juan Colberg of Pfizer).
Joel Hawkins, Senior Research Fellow at Pfizer, initiated the afternoon session proceedings with an overview on his teams work on “Flow Chemistry for Greener and More Efficient API Synthesis”. Highlights of the presentation included application of a trickle-bed meso-flow reactor allowing the selective hydrogenation of a series of pyridine-based substrates as well as the application of flow chemistry to the synthesis of a fluorocyclobutane-containing H3 antagonist. Seongho (Ryan) Oh, Vice President of R&D at Biotek, then provided an overview of the continuous processing based technology implemented within SK Biotek. The talk was split into three sections looking at continuous organic synthesis, continuous homogeneous and heterogeneous catalytic reactions and integrated continuous synthesis. As well as several highly impactful examples of running hazardous chemistries in flow, the presentation also demonstrated the advantages of running cryogenic chemistry under this paradigm with several lithiation-based chemistries developed and subsequently executed on metric-ton scale.
University of British Columbia's Professor Jason Hein’s talk, entitled “Continuous Preferential Crystallization as a Simple, Scalable Technique to Access Chiral Targets,” demonstrated how the manipulation of parallel solid-liquid equilibria in continuous flow could be utilized to resolve a mixture of enantiomers. This methodology was successfully applied to pharmaceuticals such as naproxen and omeprazole, and then extended to non-natural amino-acids such as 2-fluorophenylglycine. Jason then described how robotics and a feedback loop had been applied to this technology to ensure a continuous “self-correcting” system, and spoke about his laboratories further endeavors with the implementation of automation.
The final speaker of the day was Richard Robinson, Senior Investigator at Novartis, who spoke regarding “Batch to Flow Transfer via a Self-Optimizing Reaction Platform.” Richard initially described a slug-flow-based approach to reaction screening utilizing an oscillating-reactor, which could be easily adapted to evaluated photoredox-based transformation. Results from the screen could be coupled with a self-optimizing algorithm with the optimization and subsequent scale-up of an Ir/Ni-mediated decarboxylative arylation demonstrated in a commercial Vapourtec flow reactor. Several other examples were presented including a case study involving the successful manipulation of suspensions in flow with future needs in this area identified specifically surrounding the development of more complex algorithms capable of optimizing around non-continuous variables.
The symposium as a whole was a great success and served to highlight rapid advances in flow and continuous manufacturing from across both academia and industry. There is no doubt that this is an exciting time to be involved with the evolution of this technology, and the work presented emphasized that although there are still challenges ahead, these will be met with creative solutions from those involved in this field.