Introducing Flexible API Supply Technologies (FAST)
The pharmaceutical industry has utilized batch capability as the primary means of manufacturing small molecule active pharmaceutical ingredients (API) for decades. Batch reactors are incredibly versatile, allowing for a broad range of unit operations from reaction to work-up to crystallization. As pharmaceutical companies have had significant batch capacity there has been a strong drive to utilize available capacity and minimize cost of new capital requirements. However, batch manufacturing is inherently slow and iterative. It typically takes multiple days to charge, run a reaction, sample and test, work-up, crystallize, isolate and dry. Often multiple batches of the same step need to be run. The proceeding step cannot be started until the former is complete. A significant amount of time is consumed in cleaning and changeover between steps. This typically results in an overall supply chain of up to a year for an average API. With continued pressure on the industry to reduce cycle times and respond to changes in demand in an agile manner, investment in new advanced manufacturing technologies is critical.
Continuous technologies promise to offer a faster and more agile approach to API development and manufacture. Pfizer are joining companies such as GSK, Lilly, Novartis and Asymchem in proving the benefits and business case for continuous. Within Pfizer we refer to our evolving continuous capability for API development and manufacture as Flexible API Supply Technologies (FAST). Pfizer has a history of utilizing continuous unit operations in the manufacture of APIs, including Lyrica, and we have experience of a broad range of continuous transformations applied to the early development portfolio. We are now focused on a broader strategy of introducing continuous unit operations to our new product portfolio over the next several years. This requires a significant investment in our facilities, technology, workforce, workflows and pharmaceutical quality system.
The Business Case for FAST
Ahead of any major investment, a well-crafted business case is essential.
The business case for FAST was built around the following hypotheses:
- 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.
A full Net Present Value analysis was run, leading to a significant return on investment based on both incremental revenues for our commercial organization and significant cost savings through development and manufacturing. An essential element of our FAST strategy has been the alignment, sponsorship and support between our Worldwide Research & Development and our Pfizer Global Supply (commercial manufacturing) functions. This allowed for a rapid agreement that ‘the time is right’ for investment in continuous technologies. While we had attempted to pursue this path in the past, the timing was not right at that time due to many factors including availability of existing batch capacity and state of continuous technology readiness. Our organization now feels confident in the need and business impact on building a more substantial continuous capability.
The FAST Infrastructure
In order to ensure the full benefits of FAST are obtained, an aligned investment across our facilities, technology, workforce, workflows and pharmaceutical quality system is required (Figure 1). We recently opened up a new FAST laboratory in the US, equipped with a range of continuous laboratory technologies and enabled with a control system equivalent to our plant environment. The laboratory has large walk-in hoods, allowing us to prototype and test manufacturing equipment and lay the foundations for automation and control. This ability to use the same equipment design across all stages of development is a key element of the FAST business case. Our Kilo Laboratory, used for early clinical manufacturing, Pilot Plant, used for late stage clinical manufacturing, and our commercial launch site, will all have the capability to replicate the same equipment design through the project lifecycle. Central to the design is the use of a fume hood environment where continuous unit operations are run, with centralized feed tanks located in an appropriately electrically classified area. This design is similar in nature to the Lilly Small Volume Continuous facility in Kinsale, Ireland.1 The Pfizer commercial manufacturing facility will have the capability of supporting products up to several metric tons per annum, while retaining a strong linkage to the rapid design of new capability in the laboratory and Kilo Laboratory.
From an equipment perspective, Pfizer are developing our continuous platforms using a modularity approach. Platforms are being built up from small boxes, or modules, that are reconfigurable, reproducible and standardized. A plug-and-play design will allow us to reconfigure a small number of modules to fit the needs of the broader portfolio, ensuring we don’t need a large warehouse full of unused equipment on standby. The concept of ‘module design replication’ will allow us to reproduce the same equipment across our network of facilities. Standardization supports both these drivers, where only the reactor modules will be specifically tailored to a product.
An exciting part of the FAST strategy has been the workforce investments to grow and develop new skill sets and new ways of working. Building a centralized technology group has allowed us to advance core skills and capabilities while ensuring we develop broad departmental capability through close collaboration with core process chemistry, engineering and analytical functions.
Development of our workflow has also been key to ensure we design through the lens of continuous and translate all the potential business benefits to reality. Examples include the evolution of high throughput screening capability to ensure screening of conditions amenable to flow, design of processes to simplify unit operations and evolution of risk assessment processes to accommodate the variables associated with flow.
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The FAST infrastructure fits well within our Pharmaceutical Quality System (PQS). Key elements that are being further evolved include the ability to clearly define a batch, ensure appropriate tracking of genealogy and support of new ways of working that accelerate delivery while assuring quality, such as alternative methods to equipment qualification.
Application to the Portfolio
The Pfizer strategy for implementing continuous technologies has a strong focus on demonstrating business value through the late stage new products portfolio. We are selecting products where we can utilize continuous to design a platform to meet chemical process requirements (overcome heat or mass transfer issues in batch) or where we can reduce cycle time through integration of unit operations.
A good example of the design of a platform to meet chemical process requirements is a project where a very large exotherm is observed in a key step. Through multi-dose addition in batch experimentation we are able to determine a kinetic model that allows us to predict performance in a one, two or three stage plug flow reactor or continuous stirred tank reactor. The in-silico experimentation can be confirmed by a few targeted experiments, allowing us to rapidly design the preferred configuration for clinical and commercial success.
In order to drive cycle time reduction, we are working towards designing processes with integrated unit operations. Understanding where reactions can be telescoped together versus where critical isolations are required is essential to efficient design while building in quality. Consideration of purification methods beyond crystallization and isolation is also helpful to develop a highly efficient process that can deliver API in an accelerated manner.
Technology Evolution
Initial applications of continuous processes at Pfizer are using well developed technologies, such as plug flow reactors, liquid-liquid extraction and continuous stirred tank reactors. Primary focus of technology development for these ‘tier 1’ technologies is in developing a strong modularization approach and in ensuring bespoke design of specific reactors to meet the reaction requirements in terms of heat transfer, mass transfer and residence time. However, there are other technologies that are less well advanced in the pharmaceutical industry. Continuous crystallization techniques have evolved in recent years but the industrialization of robust processes requires further scientific understanding. Enhanced Process Analytical Technology, modelling, control and nucleation science are all leading towards greater confidence in application of continuous crystalization. Another key platform of interest to Pfizer is a fixed bed catalysis platform for solid-liquid and solid-liquid-gas transformations that can truly intensify processes while minimizing unwanted by-products. We are discovering new science that will help ensure consistent activity in the fixed bed, consistent residence time distribution and effective design of a new wave of fixed bed catalysts. The ability to integrate multiple steps on such a platform shows tremendous promise for the development of highly efficient and elegant syntheses in the future.2
Further Considerations
As we head towards commercial application of FAST, close collaboration and alignment between research and development and manufacturing is critical. An alignment team is responsible for oversight of program management and to ensure foundations are in place for the project teams to execute this new paradigm. In addition to development of the technology and facilities, the alignment team is responsible for coordinating development of the regulatory approach and data systems for process analytical technology, automation and control. One area where significant focus is required is automation. Research and development facilities typically have a light approach to automation in order to keep the flexibility required for fluid clinical supply chain support. For continuous operations, research and development labs and clinical manufacturing facilities need a significant upskilling in automation capability to ensure we can prototype and build automation fundamentals in parallel with equipment prototyping. This has a significant impact on workforce requirements relative to batch.
From a research and development perspective the formation of a centralized continuous technology function has also been important to the execution of a new continuous paradigm. A centralized function creates the infrastructure to align technology development with project application, ensuring creative challenges are addressed and evolved in a resource protected environment. However, it is also essential to ensure that the long-term trajectory is to create meaningful change across the broader development group and avoid a ‘them and us’ environment through close collaboration and learning across the organization. The linkage of technology advancement to a specific project offers a clear path to implementation, although the challenges associated with implementing at speed, on critical path, with an attrition risk, requires thoughtful consideration.
At Pfizer, we hope to deliver on such a challenge over the coming years to prove the business case for continuous and develop a new paradigm for API development and manufacture. 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.
References
- https://ispe.org/pharmaceutical-engineering/ispeak/meet-eli-lilly-and-company-2019-facility-year-process-innovation
- T. Tsubogo, H. Oyamada and S. Kobayashi, Nature, 2015, 520, 329-332.
Author Biography
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.