API Continuous Flow Improves Safety, Selectivity

Edition 5 / September 2019
Small Molecules Platform > The Continuous Flow Chemistry Revolution – Are You Ready?

Edition 5 / September 2019

CordenPharma’s Dr. Stephen Houldsworth, Director, Global Small Molecules & Antibiotics Platforms headshot

Author
Dr. Stephen Houldsworth

VP, Global Head of Platform Management & Marketing
CordenPharma International


The Continuous Flow Chemistry Revolution – Are You Ready?

CordenPharma provides a schematic of flow chemistry in blue and grey

CordenPharma offers continuous / flow chemistry in CordenPharma Chenôve (FR).

Among a number of innovative technologies under development within our five strategic technology platforms, the Small Molecules Platform in particular has one major area of focus, which is Continuous / Flow Chemistry at our CordenPharma Chenôve site in France.

There is a lot of buzz in this area in the industry today, where the predictions for Continuous Manufacturing are often presented as a panacea for all challenges that face the industry. CordenPharma takes a more pragmatic approach, as seen for example in this C&EN article Out of the Sea and Into the Factory for Acasti’s Heart Drug Ingredient,1 one in which flow chemistry has particular strengths, but only when applied in certain situations.

First, for those of you who have recently awoken from the hibernation of traditional API pharma manufacturing technologies, what is Continuous / Flow Chemistry? According to the FDA’s first draft guidance “Quality Considerations for Continuous Manufacturing,” Continuous Manufacturing is defined as “a process in which the input material(s) are continuously fed into and transformed within the process, and the processed output materials are continuously removed from the system.” 2

More specifically for CordenPharma, Flow Chemistry is the process of performing chemical reactions where the reactive components are pumped together at a mixing junction, and then made to flow down a temperature-controlled pipe or tube. This concept can be applied to basically any chemical reaction or process, including work-ups and purifications, and can even be applied to heterogeneous chemistry. At CordenPharma Chenôve, we feel the following are the key advantages in the areas of Continuous / Flow Chemistry where we look to apply the technology:

Process Safety

Since smaller volumes of potentially dangerous reactants or intermediates are in contact, the overall safety profile of a particular step of chemistry can be vastly improved over the equivalent batch process. As a result of the greater surface area of solutions in general, the heat exchange potential is greatly enhanced, enabling the manufacturing team to consider reactions and chemistry that would be otherwise ruled out in a classic batch process due to large exotherms.

Risk Mitigation for High Value Products

We often work with your extremely valuable intermediates or products that may have taken months to prepare. When you consider the financial value that may be in a batch reactor at scale, along with the fact that often at early clinical stages the chemistry is not fully mapped out and understood – how do you manage this risk? Using flow chemistry and appropriately developed PAT technologies, you can minimize this financial risk significantly by having much smaller volumes (and as a result smaller $$$) exposed at any one time.

Cleaner Reactions

Flow reactors enable excellent reaction selectivity. The rapid diffusion mixing avoids the issues found often in batch reactors, thus reducing potential side reactions from products being in prolonged contact with reagents. The high surface area to volume ratio (1000x greater than a batch reactor) enables almost instantaneous heating or cooling, and therefore ultimate temperature control.

Slow Reactions

Flow reactors can be easily pressurized, thus allowing reaction mixtures to be heated 100-150ºC above their normal boiling point, creating reaction rates that are 1000s of times faster. Here we can “turbo-charge” a slow reaction rate to get the chemistry completed in a reasonable reaction time, thus reducing effective time-in-plant issues. Concerned about the thermal stability of your product? You needn’t be, as the reaction is only exposed to these extreme temperatures for a short period of time – it is afterwards instantly returned back to “normal” temperatures by the highly effective temperature exchange resulting from the high surface area-to-volume ratio already discussed above.

So what? If your current chemistry does not struggle with any of the above challenges, perhaps we can appeal to your pocket book and budget…….

Long Term Cost Savings

Although initially Continuous / Flow Chemistry may be a slightly more expensive option, we believe there are long-term time and cost savings which will significantly accelerate your programs. For example, as each phase of the clinical program is completed, more and more material is required for the next phase. Often this constant need for increasing scale leads to phases of development work that need to be completed, as the challenges experienced at the smaller scales need to be addressed prior to advancement. With Continuous / Flow Chemistry, this scale challenge is simply addressed via a couple of options:

  1. By running the flow reactors for a longer duration of time you can simply generate the larger quantities needed.
  2. Running the reactions at higher flow rates or with increased diameter of the tube / pipe both take advantage of the high mixing dynamics and excellent heat exchange of the technology.

These two strategies enable larger volumes of products to be managed without huge infrastructure investments, reducing scale-up transitions and site transfers often enforced via classical batch processing. The result is a drastically simplified regulatory pathway, where your process is “locked in” at the outset, reducing the constant process changes, scale-ups or site / technology transfers which usually need to be addressed and justified in clinical filings, without even mentioning the potential quality impacts of impurity profile changes and method redevelopment. These benefits seem to be further enhanced by the recent FDA announcements and the issuance of their first draft guidance “Quality Considerations for Continuous Manufacturing.”

The advantages of Flow Chemistry over classic batch processing is clear, and has been used widely in the area of fine chemicals and petrochemicals for years. We look forward to discussing how we may be able to apply some of the above concepts, or others not even discussed here, to advance your program’s objectives.

1 Chemical & Engineering News, June 25, 2018, Volume 96, Issue 26
2 Quality Considerations for Continuous Manufacturing Guidance for Industry, US FDA, Feb 2019.


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