Continuous API Manufacturing – It’s time pharma went with the
flow
Dr. Minzhang Chen, CEO at STA Pharmaceutical, a WuXi
AppTec Company Dr. Sam Tadayon, Executive Director at STA Pharmaceutical, a
WuXi AppTec Company
Introduction
There has been a recent surge in interest for
continuous processes in the pharma industry as the benefits have become more
widely known. This is due to the availability of more expertise in the area of
flow chemistry over the last decade, in combination with the need for the
industry to develop safer, faster and more sustainable processes, with higher
quality and less expensive products. But the first thing we need to do is
define what we mean by continuous processing and flow chemistry. The industry
is running two broad types of continuous processing, in finished dosage form
and API manufacturing – often commentary in the media has made little effort to
separate these, and they invariably get confused. Whilst continuous processing
in finished formulations with the potential of on demand dosing is extremely
exciting, for the purpose of this article we are instead going to specifically
look at the improvements flow chemistry can bring to process development and
manufacturing for API’s.
It is time the wider pharma community set aside the
decade-old views of continuous manufacturing as a ‘luxury but impractical tool’
and looked at the technology as a practical and valuable approach that can
resolve our every day chemical processing issues. Flow chemistry offers a more
streamlined and continuous synthesis process as well as a variety of advantages
compared to a batch operation. Incorporating a flow operation results in
increased production with decreased capital. In terms of safety, flow reactors
for pharmaceutical reactions are normally run in much smaller volumes than
those of batch reactions, therefore lowering the risk of hazardous reactions.
Dealing with toxic chemicals is also safer – cytotoxic APIs can be produced in
inexpensive, dedicated, and disposable equipment sets for production of low
volumes of these compounds in the laboratory fume hood.
Not only is flow chemistry safer than batch, it is also
more efficient – better heat and mass transfer alongside less back mixing
contribute to enhancing the purity profile and product recovery. The small size
of the microreactors, either PFR or CSTR, allows for much higher reaction
temperatures and pressures as compared to batch reactors, allowing for safe
reactions that were previously unstable in batch. Reactions can also undergo
superheating, enabling them to be heated above their boiling point, further
resulting in faster reaction rates. The flow operation reduces the break time
between consecutive steps and can significantly reduce the manufacturing time.
An important advantage of flow chemistry is the ability
to fully control many of the parameters, such as mixing, temperature, and
reaction time. By having the capability to add or remove heat almost
instantaneously, one could remove the heat generated from a reaction; for
exothermic reactions or a reaction requiring hazardous materials, this is an
especially important benefit. Flow reactors also allow control over residence
time, which is the time that the reaction is exposed to a set temperature,
allowing for far more precise reaction times. This is immensely beneficial,
particularly if a reaction creates more than one product. There is also
continuous monitoring of the quality – such as purity – by online or offline
sensors, so parameters can still be fine-tuned during the operation in order to
obtain the best product quality. During a batch process, you would need to wait
until reaction is completed, by which point it may be too late to make any
adjustment.
The intense mixing in flow chemistry is provided by microreactors,
which enables scientists to use multiple phase systems, fewer solvents, and
produce purer material – reducing unit operation and work up steps. The
hightemperature, high-pressure flow reactors reduce reaction time and provide
better conversion whilst using starting material more efficiently. This
requires tightly controlled Process Analytical Technologies (PAT), and
resolution of any Quality Assurance issues related to acceptability of the
intermediates. Microreactors can be designed to fit the requirements needed for
the reaction, therefore providing customisation opportunities. In addition,
microreactors have low maintenance and operational costs without abandoning
productivity and efficiency, which provides an economic incentive. These technological
advancements are valuable and vital assets in flow chemistry and have expanded
the versatility in its use.
Although the advantages are clear, before a flow
process can be developed a working small-scale batch process should still exist
since, in general, developing a flow step may take much longer than its batch
equivalent. However, once a flow step has been developed, its scale up is far
easier and encounters fewer issues than in batch. The reason for this is that
the sizes of the reactors in the scale up version are normally less than 20
times the size of the lab version. For example, the diameter of lab scale PFR
tubing is normally around 1/16”- 1/4”, and its pilot plant version is around
3/8” - 1/2” – these are not very different in size. The scale up in the batch
process could be 100 to 1000 times bigger than the original lab scale process –
this is impractical as mixing and other engineering aspects can complicate such
large scale up operations.
The total cost of producing a final product depends on
the cost of the process R&D, starting materials and the operational costs –
of these, the latter two have the greatest impact on the overall cost. Using
the flow operation, cost incentives include the reduction of energy costs and
reduction of impurities and waste products. Awareness by chemists of the
capabilities of flow chemistry as an enabling technology gives them the power
to design shorter synthetic routes, and therefore also reduce the cost once
operational. Of course, reducing waste promotes efficiency, enhances purity,
and is beneficial to the environment. Companies may realize too late that their
drug has an excessive, multi-step process that could have been shortened and
since their cost would be unnecessarily high due to a longer synthetic route,
this could result in losing substantial amounts of profit.
If we assume that flow facilities provide major
benefits at larger scales, we could see that later phase and commercial
products are more amenable to continuous processing and will see the greatest
benefits. Big pharma such as Lilly, GSK, and Novartis are already preparing for
launch of their pilot or commercial plant facilities and, at this time, these
plants are built within their own companies. However, over time these companies
may decide to outsource such operations to CMOs or CDMOs – we have one such
flow chemistry partnership with big pharma, but we’re very much in the
minority. Our belief is that it’s only a matter of time until much more flow
work is outsourced, and we are building up capacity in anticipation of this.
During development, flow steps seem to be more
appropriate for early steps of the synthetic route where less expensive raw
material are available for process development and the volume of the material
to be processed is larger. Perhaps the majority of the API’s currently produced
at a commercial stage have the required volume to be turned into flow. However,
due to regulatory issues, limited changes can be applied to the existing
commercial processes but it can still potentially be achieved with some
investment and time.
The transition from batch to flow operation is
generally thought of as both costly and inconvenient, but implementing this
change in early development is simple and beneficial. Comparing Phase I and Phase
III, it is much easier to manage changes in development and regulation if
switched at Phase I, but to switch at Phase III could result in a delay in
market release and a loss in both time and money. Yet, the number of flow steps
during development currently remains below 5%. The message here is clear: for
flow chemistry to deliver on its huge promise, pharma and CDMOs need to build
the platform into the phase I process R&D of innovative API programmes.
This requires commitment from the beginning of a project, and a wider
commitment to running in flow whenever possible. Flow chemistry has suffered
slow implementation into the industry – especially as compared to some other
industries such as oil and gas – even though more are beginning to recognize
its benefits. This is largely due to the increase in demand for flow chemists
while there remains a lack of experience and education in the field. With an
entirely new manufacturing process people may be reluctant to adopt it as they
think it may slow down the manufacturing process. The safety, efficiency, and
flexibility of flow chemistry are what drives its high interest and is why it
should become an essential component in research, development, and for the
future of the industry
Q&A
on the future of flow chemistry
and its industry adoption
Q) What are the major drivers for the recent surge in
efforts within the pharma industry in choosing to use flow processes and
investing in greener chemistries?
The need of the industry to develop safer, faster, and
more sustainable processes with higher quality and less expensive products,
combined with the availability of more expertise in the area of flow chemistry
built up in the last decade are behind the recent increase in the industry
using more continuous flow processes. Parallel to major pharma companies, we
actively initiated our activities in the area of continuous processing and in
the last two years we have had around 40 steps processed in flow in our Jinshan
plant (in Shanghai).
Q) What uptake do we predict over the next 5 years –
how and why?
Currently, many pharmaceutical companies believe that
there should be a reaction specific driver to using flow technologies in plant
operations, although this might not be the case in the future. At STA, for
example, we have great batch plant facilities in Shanghai and Changzhou in
addition to many experienced batch scientists to support the PRD and plant
operations. It is more economical and meaningful to utilize the existing
knowledge and investments in batch operations, and do the chemical steps in
flow when there is a driver. In the next 5 years however, more advanced flow
technologies will be developed and more dedicated flow companies will be
developing continuous processes, while the existing scientists will build up
more experience in this area. As a result we should expect a wider range of
reactions to be processed through flow, and a lower bar to be established for
selecting a process to be operated in flow. During this time, we expect to see
more multistep flow processes performed.
For companies with a strong flow team, we should also
see more work--up operations steps coupled with the reaction steps in flow. We
expect them to move from the currently 1-2 steps to 5-6 chemical steps in flow.
This should be coupled with 1-2 unit operation steps per a chemical step
including solvent switch, phase separation, extraction, crystallization,
filtration, and dissolution bringing the flow steps to 10-15 steps (including
unit operations). This brings the system closer to full flow operations, but it
is unlikely that within the next 5 years all of the chemical steps on a project
will be carried out using flow technologies.
Q)
As a company you not only utilize more efficient processes, but you are
currently looking to reduce your PMI (Process Mass Intensity), do you think
this is something that will set a trend and we will see more companies moving
to flow chemistry in the future with waste management and safety regulations
getting tighter?
Yes,
environmental regulations including control of PMI are one the industry’s big
concerns. The smart design of a flow step process could end up using less
solvent mass compared to the batch systems. Flow chemistry can not only be
applied to chemical steps, but can also be utilized for unit work-up operation
steps. In fact, it makes sense to do the work-ups between two consecutive
chemical flow steps to be done in continuous mode.
For example, a more effective work-up is provided if a
multi-step counter current extraction system is used to separate the liquid
phases instead of using batch mode phase separation; this means less solvent is
used in the process. In addition a flow chemical step might generate purer
intermediates and less work-up might be needed. Furthermore because the flow
reactors are smaller, less solvent is used to wash these reactors after run
completion. Additionally, the high temperature accessibility provided by flow
may mean less solvent requirements due to the higher solubility for compounds
at high temperatures or even going fully green by performing the reactions at
melt conditions.
Q) Does using continuous flow techniques allow you
produce drugs that you were perhaps unable to make using batch processes?
Experience has shown that the batch chemists can
ultimately find routes to develop the final API. Therefore it may not
necessarily enable us to produce new drugs, but it allows us to use shorter
routes to the final product. The reason for this is that flow chemistry enables
us to adopt a reaction path that might not be possible in batch mode due to the
safety or quality concerns. As an example, performing azide or ozonolysis
reactions usually reduces the length of synthetic steps – these reactions are
much safer in flow than in batch mode. Around 30% of the flow reactions we have
performed at STA are related to the safety; without flow capabilities we may
not have been able to do these steps or may have had to take different and
perhaps longer synthetic routes.
Q) How crucial is support from the authorities in
ensuring flow chemistry secures a place in the future of the pharma industry?
This is very crucial. Fortunately, the FDA is a strong
supporter of converting from batch to continuous. Continuous processing has
less manual operations and logistics and disturbances that caused process
review concerns with the FDA. However, last year the FDA gave the green light
to Johnson & Johnson to produce its HIV drug Prezista in flow mode and then
invited other companies to take the same approach. Johnson & Johnson has
now said that it may want to produce up to 70% of its highest volume drugs
using flow manufacturing. Vertex has also built a continuous manufacturing
plant in Boston for one of its drugs.
Q) Why has pharma and the wider industry been slow to
adopt flow chemistry and continuous processing?
Bulk chemicals industries such as fertilizer, sugar,
and oil are at least 50 years ahead of pharmaceuticals in using flow
technologies. There are at least two reasons for this: the first and most
important reason in this difference is the volume of the commodities they are
dealing with. The other reason is hidden in the structure of pharmaceutical
industry. Prior to the 1990’s, chemists were almost the only lab scientists
developing chemical processes, and management of process R&D centres was
also done by chemists. By end of the same decade, chemical engineers had been
hired as research staff to deal with chemical reaction kinetics and unit
operation steps including crystallization and distillation. The same engineers
later expanded their scope of work into flow chemistry. By around 2004, several
major companies had flow teams. By 2010, almost all major companies and many
intermediate size companies had either expanded into or at least touched the
area.
Q) How much
money across the entire industry do you think could be saved using flow
chemistry and/or how much money do you think will be invested into it over the
next 5 years?
Perhaps it would be difficult to put a number for
saving across the entire industry, but MIT scientists estimate a saving of
15-50% by switching to flow. The wide range of these numbers indicate
uncertainty in the estimation, which perhaps depends on what items are counted
in the estimation.
Q) Do you believe that technological advancements over
the next few years will allow flow chemistry processes to become more
accessible on a global scale?
More technologies will certainly be invented and more
processes will be amenable to flow systems. The MIT flow system sponsored by
Novartis inspired Novartis and other companies to perform multi-steps or full
steps including formulation in flow. We have heard that Novartis renewed the
sponsorship for the second time for another 5 years term of the MIT setup,
which is good news for flow chemistry.
Q) What challenges does the industry as whole face over
the next 5-10 years when it comes to using flow chemistries?
The existence of experienced batch scientists combined
with lack of experts in flow chemistry makes traditional process development
very tempting. In addition, flow chemistry has put forward some new questions
for quality of the products. For example, we can clean and validate a
multi-purpose batch reactor using established methods, but those are not valid
for a plug flow reactors as the access to the internal walls of the tubing is
restricted. These are not very difficult obstacles to overcome, however there
are very limited opportunities for drug development companies to learn from
each other due to the restricted access of information, the reality is that
most companies have to face and resolve these challenges on their own.
Q) What needs to be done to speed up the adoption of
flow chemistry processes?
To move faster in the direction of flow, more
chemical engineers should get involved with the development. The speed of
development is crucial for Pharma and with current infrastructure and
expertise; batch processes still win this competition in most cases. “Think in
flow” is yet not the mentality in pharmaceutical companies’ management The
industry needs to see more successful commercial cases to be convinced that
applying flow offers significant advantages over traditional batch processes.
https://gmpnews.net/wp-content/uploads/2017/10/cphi-pharma-annual-ind-report-2017-part1-v3.pdf
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