Beneficial Attributes of Flow Chemistry & Continuous Manufacturing
Although Flow Chemistry and Continuous Manufacturing is nothing new in the chemical industry, where the concept has been used for years to reduce operating costs and gain advantages in throughput and control, its adoption and application within the Pharmaceutical industry has been extremely slow.
In order to leverage this underutilized technology for increased supply chain efficiency, CordenPharma created The Centre of Excellence for Flow Chemistry at CordenPharma Chenôve in France. We believe this cutting-edge capability offers many beneficial attributes for our customers.
BENEFITS OF FLOW CHEMISTRY
Enhanced Safety Profile
A primary driver and benefit of Flow Chemistry is that the overall safety profile is greatly enhanced. The reduced “in process” scale concept means an avoidance of gigantic vessels packed full of highly volatile solvents and reactive reagents. Instead, these are reduced to the types of volumes found in a typical R&D facility, which greatly controls the safety profile of the facility as a result.
Although classic batch processing used for years by the Pharmaceutical industry is considered the normal mode of operation, it requires fixed assets that dictate limited batch sizes. But this means manufacturing more batches creates clear disadvantages in that larger quantities of material are needed, or the size of the equipment needs to be increased. This all then requires further investment, which is a very limiting approach. Flow chemistry overcomes these challenges because it is run continuously with scaled down equipment. The batch size becomes a unit of time and not restricted by equipment volumes. Need more product? We will run the equipment longer.
Reduced Capital Expenditure
Although CAPEX is clearly required for Flow Chemistry solutions, the overall total project lifetime investment in infrastructure is greatly reduced as the footprint of a flow manufacturing facility is greatly reduced, when compared to a general-purpose Batch manufacturing facility.
Batch processes require very specialized equipment trains designed and optimized for only one efficient chemistry process at a time. Yet Flow Chemistry incorporates multipurpose components (e.g. pumps, monitors, etc.), where only the reactors need a specific design for a particular process, and even this can be re-purposed. In short, Flow Chemistry results in a very modular manufacturing set up with more of a plug-and-play concept, leading to greater flexibility, and ultimately, reduced CAPEX costs.
Environmental Profile & Green Chemistry
A general consequence of implementing Flow Chemistry is the improved environmental profile obtained for any process as a result of reduced solvent processes, increased energy efficiency, and overall higher process selectivity obtained by reducing general waste from unnecessary processing.
Overall Project Timeline
When manufacturing in batch mode, each scale-up often requires going back to the development lab to tweak the chemistry or isolations to adjust for the available equipment. In Flow Chemistry, the process is developed up front, where scale becomes a function of time, thus removing each development cycle from the timeline and producing an overall shorter timeline.
WHAT IS FLOW CHEMISTRY & HOW DOES IT WORK?
In its simplest form, Flow Chemistry is the process of pumping two reactive components together at a junction so they can react downstream in a temperature-controlled tube continuously. Fundamentally, this differs from batch chemistry where the two reactants are fed into a reactor at the start of the reaction, with the product extracted once the entire reaction is complete.
A second, alternative approach to Flow Chemistry is the use of Continuous Stirred Tank Reactors or CSTRs. In this example, the two reactive components are pumped into a batch style reactor, with the product being constantly removed as an overflow.
The major advantage of Flow Chemistry in a tubular reactor is the vastly improved heat transfer and mixing that is achieved, leading to overall better control. Due to the small volume of the tubular reactor compared to that of a standard batch reactor, the surface-to-volume ratio of the flow reactor is significantly higher, which results in the better heat transfer. Thanks to this improved heat transfer and the reduced volume in a Flow Reactor, exothermic chemistry that would never be considered safe in a batch reactor is now considered safe.
Furthermore, chemistries that have never proven successful in batch mode may become applicable in Flow Chemistry, such as electrochemistry or photochemistry. Both of these areas are environmentally-friendly synthetic approaches allowing the removal of hazardous reagents that are often present in stoichiometric quantities. In flow mode, both arenas are easily accessible, resulting in extremely elegant transformations that would be difficult at best in batch mode.
OUR APPROACH TO A FLOW CHEMISTRY PROJECT
Why should you consider Flow Chemistry? It is often the case that our customers are not aware of the potential that Flow Chemistry could bring to their projects, so wherever possible, we present it as an effective option for consideration.
Whenever a new project is presented to CordenPharma, we analyze whether Flow Chemistry may bring an innovative solution to the table, and if there is a benefit to highlight it in our proposal.
In general terms, a Flow Chemistry & Continuous Manufacturing project is broken down into these stages:
- >> Firstly, we convert the chemistry from batch mode into flow mode as a proof-of-concept phase, where we demonstrate that the chemistry can be performed, and by using very basic set-ups, start a quick optimization of the chemistry.
- >> As we delve deeper into the chemistry, we consider how the process will come together, including work-up and telescoping of processing steps to improve efficiency.
- >> Next, the process is fine-tuned to create the optimized residence time, mixing dynamics, concentration, temperature and pressure, as well as identifying an appropriate control strategy utilizing PAT methodology. Where possible, we take advantage of off-the-shelf units to perform the chemistry, or work with our engineering team to create, design and build a custom solution. We allow the process to guide our path towards a natural solution, as opposed to constraining the development into a particular equipment configuration. Here we can consider the development phase complete, resulting in a research scale model that can be tested for robustness and consistency.
- >> The next stage of the journey is to design a pilot-scale model in our GMP pilot scale facility. Employing our modular design strategy, we create a mini equipment train that is customized to your process, including full PAT control strategy. Using the equipment, we run the developed process to produce multi kilo quantities of the product and establish the potential future output at full-scale production.
- >> The final stage of the journey is the design and construction of the full production phase equipment. Designed with your future needs in mind, this unit is custom built and operated with a focus on control and efficiency. Whether you need 100s of kilos or multi metric tonne quantities, we can help you navigate the challenges, including regulatory filings and contingency planning.