Continuous Flow Chemistry And The Manufacture Of Active Pharmaceutical Ingredients - Part One: Introduction

Continuous Flow Chemistry
And
The Manufacture Of Active Pharmaceutical Ingredients
A Series Of Informative Disquisitions About Continuous Flow Chemistry
This Installment:
Part One:
• Introduction
• Batch vs. Continuous Flow
• Advantages & Disadvantages

Introduction
& API Manufacturing
• In flow chemistry, a chemical reaction is run in a
continuously flowing stream rather than in batch production
• Pumps move fluid into a tube, and where tubes join one
another, the fluids contact one another
• If these fluids are reactive, a reaction takes place
• Flow chemistry is a well-established technique for use at a
large scale when manufacturing large quantities of a given
material
Hessel, V., et al., Novel Process Windows for Enabling, Accelerating, and Uplifting Flow Chemistry.
Chemsuschem, 2013. 6(5): p. 746-789.

• The implementation of continuous flow processing as a key
enabling technology has transformed the way chemistry is
conducted and has expanded synthetic capabilities
• As a result many new preparative routes have been designed
towards commercially relevant drug compounds achieving more
efficient and reproducible manufacture.
Introduction
& API Manufacturing
Hessel, V., et al., Novel Process Windows for Enabling, Accelerating, and Uplifting Flow Chemistry.
Chemsuschem, 2013. 6(5): p. 746-789.

Introduction
& API Manufacturing
• The last 20 years have witnessed a true renaissance in the way
synthetic chemistry is performed due to the implementation of
various enabling technologies allowing the modern synthesis
chemist to select from a range of tools and equipment to best
perform a given transformation
• The trend to question the suitability of classical laboratory
glassware and to utilize more ‘fit for purpose’ synthesis
equipment not only allows the individual chemists to conduct
their research in a more modern fashion, but also adjusts their
mind-set towards the full practical breadth of synthesis
planningWebb, D. and T.F. Jamison, Continuous flow multi-step organic synthesis. Chemical Science, 2010. 1(6): p.
675-680

Introduction
& API Manufacturing
• In this way chemists are more aware of the entire processing
sequence, considering quenching, work-up, extraction and
purification as part of the holistic design of the preparative
route
• The introduction of such thinking earlier in a compound’s
development pipeline significantly simplifies the scaling
transitions required to meet the increasing quantities of
material needed for the different stages of biological and
regulatory testing and then on into the building of the
manufacturing route
Webb, D. and T.F. Jamison, Continuous flow multi-step organic synthesis. Chemical Science, 2010. 1(6): p.
675-680

Introduction
& API Manufacturing
• Arguably one of the most widely amenable of the enabling
technologies is flow chemistry, which accommodates small
foot-print reactors in which streams of substrates and reagents
can be united to react in a highly controlled and reproducible
environment
• Importantly, regulation of many parameters such as heat and
mass transfer, mixing and residence times are much improved
over related batch processes
• Advantageously the flow reactor configuration can also be
readily customized to meet the specific demands of the
reaction and the continuous processing requirementsHessel, V., et al., Novel Process Windows for Enabling, Accelerating, and Uplifting Flow Chemistry.
Chemsuschem, 2013. 6(5): p. 746-789.

Introduction
& API Manufacturing
• The construction of the reactor is often modular being
assembled from several specialized yet easily integrated
components such as heating and cooling zones, micro-mixers,
residence tubing coils, separators, and diagnostic/analysis
units
• This workflow not only allows for facile automation and
continuous operation of such processes, but also enables the
chemist to perform more potentially hazardous and otherwise
forbidden transformations in a safer and more reliable
Baxendale, I.R., The integration of flow reactors into synthetic organic chemistry. Journal of Chemical
Technology and Biotechnology, 2013. 88(4): p. 519-552

Introduction
& API Manufacturing
• The main advantages cited for improved operational safety are
principally the reduced inventories of reactive chemicals, the
small contained reactor units and the ability to install real time
monitoring of the system leading to rapid identification of
problems and the instigation of automated safe shutdown
protocols
• The use of direct in-line purification and analysis techniques
can be implemented thus generating a more streamlined and
information enriched reaction sequence

Introduction
& API Manufacturing
• Continuous processing for the production of key building blocks
and intermediates for small-molecule APIs is no longer viewed
as a technology of the future
• Most pharmaceutical companies with in-house manufacturing
use flow chemistry to some extent, and smaller companies that
outsource production expect their contract-manufacturing
partners to have continuous-flow systems available
• Advances in microreactor technology for commercial-scale
production and implementation of continuous downstream
processes will ultimately enable the complete continuous
synthesis of complex organic molecules required for small-
molecule API manufacturing

Introduction
& API Manufacturing
• The vision of continuous manufacturing is of an industry with
processes that are integrated, based on a systems approach,
having model-based control, and making use of flow
• Thus, seeing as a continuous manufacturing process is
designed as a whole, the distinction between upstream and
downstream or drug substance and drug product ultimately
disappears
• Given that continuous manufacturing encompasses integration,
a systems approach, flow, and model-based control, future
continuous facilities will be set up quite differently than existing
facilities

Introduction
& API Manufacturing
• There will be fewer partitions and few to no hallways, as
equipment will be placed in larger areas where it can be
engaged on-demand as needed for a particular process
• Existing partitions will be chosen to separate different product
safety classes so proper protective equipment would be used
in a given location
• Perhaps any necessary particulate handling would be done in
separate partitions and the main production floor would
consist of only equipment and piping with pharmaceutical
materials never exposed to the atmosphere
• Even cleaning could be performed without opening the
equipment

Introduction
& API Manufacturing
• Quality control would be performed inline, there would be no
separate quality operations at the facility, although
development work might be performed there
• Processes will be run 24/7 for 50+ weeks a year with a week or
two for annual maintenance
• The facility will be modern, streamlined, with little presence of
personnel on the floor, except for set-up, shut-down,
troubleshooting, and maintenance
675-680

Introduction
& API Manufacturing
• Continuous manufacturing will lead to reduction of process
steps, smaller footprint, smaller equipment, and higher
product quality, all leading to cost savings, reduced risk of
product failure and stock-outs, and in the end, better
pharmaceuticals for patients
• Integration within a systems approach itself leads to reduction
of process steps, as the number of “correction” steps can be
reduced or eliminated
675-680

Batch
vs.

Batch
vs.
Comparing parameters in Batch vs Flow:
Reaction stoichiometry
• In batch production this is defined by the concentration of chemical
reagents and their volumetric ratio
• In Flow this is defined by the concentration of reagents and the ratio of
their flow rate

Batch
vs.
Comparing parameters in Batch vs Flow:
Residence time
• In batch production this is determined by how long a vessel is held at a
given temperature
• In flow the volumetric residence time is used given by the ratio of
volume of the reactor and the overall flow rate, as most often, plug flow
reactors are used

Batch
vs.
Advantages
• Continuous flow synthesis is a great alternative to traditional batch
synthesis/production when it comes to demanding chemistries such as
hazardous reactions or potentially challenging conditions like high
pressure and temperature
• Continuous flow processing provides many technical advantages over
traditional batch methods, including speed of development, process
reliability and product quality, maximization of process safety when
employing hazardous chemistries, and minimization of investment
during product development
• The more consistent quality that is achieved with continuous
manufacturing, particularly for sensitive products, is of significance

Batch
vs.
Advantages
• Some products that cannot be produced
in large batch processes due to the
thermodynamic nature of the reactions
involved
• Under continuous flow conditions,
however, because only small quantities
of reagents and products are present at
any given time, these issues can be
avoided
Mascia, S., et al., End-to-End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final
Dosage Formation. Angewandte Chemie-International Edition, 2013. 52(47): p. 12359-12363

Batch
vs.
• Flow chemistry is often considered as an option when exploring new
chemical routes, increasing yield, lowering the cost of goods, and
generating IP
• One of the main drivers for the implementation of flow chemistry is,
however, to perform a reaction that cannot be done with traditional
batch production, such as those involving azide intermediates or
oxidation using oxygen
• Currently, the drivers for adoption are academia and institutes and
providers of continuous flow equipment who are looking for innovation
and often work together with the pharmaceutical industry to solve
specific problems
Advantages

Batch
vs.
Advantages
• Reaction temperature can be raised above the solvent's boiling point
as the volume of the laboratory devices is typically small
• Typically, non-compressible fluids are used with no gas volume so that
the expansion factor as a function of pressure is small
• Mixing can be achieved within seconds at the smaller scales used in
flow chemistry
Organic Process Research & Development. 20 (2): 386–394

Batch
vs.
Advantages
• Heat transfer is intensified
• The area to volume ratio is large
• Endothermal and exothermal reaction can be thermostated
• The temperature gradient can be steep, allowing efficient control over
reaction time

Batch
vs.
Advantages
Safety is increased:
• Thermal mass of the system is dominated by the apparatus making
thermal runaways unlikely
• Smaller reaction volume is also considered a safety benefit
• The reactor operates under steady-state conditions

Batch
vs.
Advantages
• Flow reactions can be automated with far less effort than batch
reactions
• This allows for unattended operation and experimental planning
• By coupling the output of the reactor to a detector system, it is possible
to go further and create an automated system which can sequentially
investigate a range of possible reaction parameters (varying
stoichiometry, residence time and temperature) and therefore explore
reaction parameters with little or no intervention
Org. Biomol. Chem. 5: 1562–1568

Batch
vs.
• Typical drivers are higher yields/selectivities, less needed manpower
or a higher safety level
• Multi step reactions can be arranged in a continuous sequence
• This can be especially beneficial if intermediate compounds are
unstable, toxic, or sensitive to air, since they will exist only
momentarily and in very small quantities
Advantages

Batch
vs.
• Position along the flowing stream and reaction time point are
directly related to one another
• It is possible to arrange the system such that further reagents
can be introduced into the flowing reaction stream at precisely
the time point in the reaction that is desired
Advantages
Movsisyan, M.; Delbeke, E. I. P.; Berton, J. K. E. T.; Battilocchio, C.; Ley, S. V.; Stevens, C. V. (2016-09-12). "Taming
hazardous chemistry by continuous flow technology". Chemical Society Reviews. 45 (18).

Batch
vs.
Advantages
• It is possible to arrange a flowing system such that purification is
coupled with the reaction
• There are three primary techniques that are used:
 Solid phase scavenging
 Chromatographic separation
 Liquid/Liquid Extraction

Batch
vs.
Advantages
 Reactions which involve reagents containing dissolved gases are
easily handled, whereas in batch a pressurized "bomb" reactor would
be necessary
 Multi phase liquid reactions (e.g. phase transfer catalysis) can be
performed in a straightforward way, with high reproducibility over a
range of scales and conditions
• Scale up of a proven reaction can be achieved rapidly with little or no
process development work, by either changing the reactor volume or
by running several reactors in parallel, provided that flows are
recalculated to achieve the same residence times

Batch
vs.
Disadvantages
• The main issue is the large existing batch manufacturing
infrastructure
• If a company gets trapped in the question ‘use existing or build
new?’
 it will use the existing equipment in the present business
environment
• Continuous equipment like microreactors are added when needed,
and the existing vessels modified to serve other purposes, such as
hold-up tanks used to define the batch for regulatory purposes

Batch
vs.
Disadvantages
• Dedicated equipment is needed for precise continuous dosing
(e.g. pumps), connections, etc.
• Start up and shut down procedures have to be established
• Scale up of micro effects such as the high area to volume ratio is
not possible and economy of scale may not apply
• Safety issues for the storage of reactive material still apply
Org. Process Res. Dev. 15 (5): 989–996

Batch
vs.
An Example
Org. Process Res. Dev. 15 (5): 989–996

Batch
vs.
An Example

Stuart Silverman
CEO & Founder
RyMat Incorporated
stu@rymatinc.com
RyMat Incorporated

Continuous Flow Chemistry And The Manufacture Of Active Pharmaceutical Ingredients - Part One: Introduction

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