Three C’s To Enable Continuous Development And Manufacturing For Small Molecule Active Pharmaceutical Ingredient
Nick Thomson joined Pfizer in 1997 as a process chemist in Sandwich, UK. Nick spent his early Pfizer career in the evolving process chemistry departments in Sandwich (UK), Sittingbourne (UK) and Holland, Michigan (USA). From 2005 to 2010, Nick led the Sandwich Research Active Pharmaceutical Ingredient (API) department, with accountability for delivery of API technology from lead development to proof of concept. In 2011, Nick joined the Pfizer Chemical Research and Development department in Groton, Connecticut (USA), with accountability for the Quality by Design development and submission of late stage candidates. In 2014, Nick became head of the Technology API line for Pfizer Chemical Research and Development, and has held accountability for Technology Strategy, High Throughput Screening, Biocatalysis, Pressure Labs, Computational Chemistry, and Flexible API Supply Technologies. Nick has been active in cross pharmaceutical precompetitive collaboration, as Chair of the IQ API Leadership Team and a board member of the Enabling Technologies Consortium.
At Pfizer we are excited to demonstrate our new modular framework for small molecule continuous development and manufacturing. We call it Flexible API Supply Technologies (FAST). We just received our first prototype modules at the Groton site, on a cold February day. The modules are designed to be reconfigurable across a range of products and will be standardized across our clinical and commercial manufacturing facilities through what we describe as module design replication. Over the coming months we will be qualifying our equipment and applying it to GMP clinical manufacture with integrated unit operations. One project will demonstrate our ability to open up new chemical space and deliver through the most efficient route. A second project will demonstrate the ability to reduce manufacturing cycle time through integration of unit operations, with grand challenge of achieving a 50 percent reduction through the product lifecycle.
As we reflect back on our progress and the hard work over the past eighteen months to design and build our prototype technologies, three key challenges had to be overcome. There’s, namely capital, culture and complexity. We had to strive to enable all three to align the organization across research and development and commercial manufacturing. Collaboration and alignment has been critical. As a member of our research and development group, I am extremely happy to see the partnership with our commercial colleagues from individual scientists through to senior leaders. We are better together.
Capital was the first hurdle to align on. Moving to a new paradigm of continuous development and manufacturing requires investment. Key to our success was the alignment on the need for future capacity expansion. If batch capacity is plentiful there is little appetite for investment in new facilities that carry significant depreciation. However, if you are to build new capability, the low footprint of continuous operations will win out in a financial assessment. They aren’t cheap. You still require significant floor space for feed tanks, continuous unit operations and integrated batch hybrid capability. However, the business case is compelling for a dramatic reduction in cycle time, leading Pizer to determine that ‘the time is right’ for investment.
Culture was a second area to tackle. In a community where batch development and manufacturing has prevailed for decades, the new technology is disruptive. Historically, chemists have owned many of the early decisions on route and process design. A great starting place is to utilize continuous to open up new chemical space. This is obvious to the chemist and welcome as a means of broadening the toolkit. The idea of integrating unit operations to reduce manufacturing cycle time requires more scholarship. It is the chemical engineer that naturally considers such matters. Bringing the chemists and chemical engineers together for early decision making has been critical as we evolve our culture. We see this alliance as essential for batch operations, but the level of integration and education of the chemistry community in chemical engineering principles is more pressing for continuous. Of course, the analyst must also be brought in early to ensure that integrated process analytics can be harnessed for real time control of quality.
A great starting place is to utilize continuous to open up new chemical space
The third c is complexity. The delivery of our new paradigm requires significant innovation in equipment design and automation to ensure it works seamlessly and is reconfigurable across multiple projects. In a batch domain the automation is typically light during clinical stages of development and can be cemented during commercial manufacturing. Continuous requires an automation architecture that is installed earlier in the development cycle. This combined with new data required for understanding Quality by Design creates a more complex workflow for research and development. This has to be understood and applied at the right milestones to ensure the reward in reduced manufacturing cycle times remains positive for a new product portfolio that can be susceptible to attrition without warning. Again, alignment between research and development and commercial manufacturing is essential.
With capital, culture and complexity discussed, debated and agreed upon we are looking forward to bringing significant evolution to our small molecule API development and manufacturing paradigm. Over the coming months we hope to demonstrate our new technology and realize the business benefits that the industry has been pondering for a long time;
• An improvement in cycle time as we move from iterative batch unit operations and lengthy cleaning to integrated continuous unit operations with offline cleaning
• An increase in quality by lowering standard deviation through real time control and adjustment of parameters
• Enhanced demand flexibility as we move from taking several months to re-load a batch campaign to running longer or shorter in continuous
• Enhanced environmental sustainability and reduced capital footprint
• Ease of technical transfer and greater flexibility across the API network through use of the same equipment at different stages of development and manufacture
• The ability to manage enhanced chemical complexity through design of specific continuous reactors to fit process requirements and open-up new chemical space
We look forward to sharing our learning and developing a more industry standardized approach that links directly to our Pfizer purpose; breakthroughs that change patients’ lives.