Equipment and Technology Problem Statements
Problem 1
Pharmaceutical and fine chemical scale-up chemical synthesis facilities are dominated by
batch processing. Due to this constraint, processes are often designed to accommodate a
batch scale-up methodology rather than optimizing environmental performance. While
this is done for all unit operations, of particular interest is around chemical
transformations and crystallizations, which often dictate the complexity of subsequent
purification operations and have the greatest impact on mass and energy usage. It is
desired to evaluate the mass efficiency and energy savings possible when flow chemistry
is considered by first intent to be the selected processing method used.
Exemplification of Problem
Mass and energy inefficiencies due to batch scale-up paradigms result from primarily 2
areas
 Extra solvent is added to systems. This can occur both because large batch
vessels require a certain volume to achieve good agitation, or in order to serve as
thermal ballast for highly exothermic reactions in large batch vessels to prevent
temperature excursions
 Chemical transformation ‘workarounds’ are developed to enable batch scale-up,
but at the expense of atom economy and therefore process efficiency.
There have been several publications which have examined the use of flow chemistry to
solve challenging problems, some of which are attached here:
U:\Green Chemistry\ U:\Green Chemistry\ U:\Green Chemistry\ U:\Green Chemistry\ U:\Green Chemistry\
Continuous\op9000516.pdf
Continuous\op8002695.pdf
Continuous\op9000516.pdf
Continuous\jnj continuous.pdf
Continuous\Corning - 13th Green Chemistry and Engineering
U:\Green Chemistry\
Microwave in
Continuous\Watts review - hull.pdf
flow.pdf
The papers above all address instances where a transformation has been used to develop
synthetic reactions, but little focus has been dedicated to the exact benefit gain or as to
how the use of an individual reaction facilitated an entire synthetic scheme to deliver a
route benefit. A common theme is a workaround for safety purposes, but it is unclear
what total benefit this workaround delivers.
Expected outcome of research
We would like to understand the specific mass and energy benefits for continuous
reactions and crystallizations through:
1. The integration of flow chemistry into an entire synthetic design with a clear
comparison of benefits relative to a baseline case. The PIs are encouraged to
select a synthesis or GSK could provide some API structures which could be used
as targets for a synthetic scheme. A base case would be a comparable batch
process which would be otherwise designed. Mass intensity and energy
considerations are outputs of this comparative work, along with details of the flow
chemistry synthetic design.
2. The evaluation of certain reaction classes, such as those indicated in the
aforementioned papers (e.g., nitration, diazotizations, microwave, etc), and direct
mass and energy comparisons of these processes versus those run in batch mode.
3. The description of how a continuous crystallizer would look like to be applicable
to different crystallization methods (e.g. cooling, antisolvent, reactive). Key
criteria for scaling up. Considerations of how to minimise API loss in start-up,
maximise throughput (by shortening residence time), PAT techniques and
strategies to deal with deviations from steady state.
While this is one problem statement, it likely requires shared chemistry and chemical
engineering skill sets to complete.
Problem 2
Continuous Processing offers many potential benefits in the manufacture of Active
Pharmaceutical Ingredients, for example:
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It is inherently safer allowing small working volumes (milliliters instead of liters)
It makes a step change in the containment issues associated with manufacture
It has a lower energy requirement per kg of product
It has smaller equipment
It is easier to recycle
However there is a barrier to adoption of the technology – the Capital Cost and associated
with building new plant and facilities, at a time where there is ample batch processing
capacity.
The problem to solve is to design a facility that leverages the differences in core
processing technology of continuous processing vs batch to reduce Capital Costs and
Operating Costs of the support Facility.
Exemplification of Problem
A Study to put a 100tpa Continuous Processing Facility onto the Jurong Site estimated a
Cost of circa £70M. This facility was designed assuming the Standards and Rules
required to make a Batch Processing Plant with approximately 4000L reactor scale
compliant to Safety and Quality standards. The charts below illustrate how some of the
money is allocated:
Building Costs 100tpa FW Study
Lift
2%
Decontamination
1%
ACMV Service Room
1%
Piles
5%
Access
10%
Plant Room
14%
Office/Admin
16%
Technology
1%
Computing
1%
Library
0%
Air Lock
7%
Power/Rack rooms
6%
Process
26%
Materials Movement
4%
Tankage
4%
Product Offload
2%
Access
Office/Admin
Library
Air Lock
Power/Rack rooms
Materials Movement
Tankage
Product Offload
Process
Computing
Technology
Plant Room
ACMV Service Room
Decontamination
Lift
Piles
100tpa Building Cost by Type
Ltg, S.P & Comms
8%
Fire Protection
4%
Building Structure
41%
ACMV
17%
Building Structure
Internal Finishes
ACMV
Ltg, S.P & Comms
Fire Protection
Internal Finishes
30%
This data prompts some questions:
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If we move away from general purpose reactors, can we reduce the standard of
finishes on parts of the building where raw materials and products are not exposed
to the outside world?
What needs to be inside the building?
Can we reduce the cost of Air Conditioning and Ventilation?
What is the additional cost of combining Offices and Plant – traditional
Continuous Processing Industries would separate the two?
What services can be supplied in a different way if the technology becomes
smaller – for example heating and cooling of process equipment is traditionally
delivered from a central supply, distributed throughout the building to consumers
and circulated locally via a pumped loop to maintain heat transfer coefficients to a
large reactor or dryer. Are there alternatives that would deliver the hot and cold
services (typically -80C to 200C) more effectively reducing the energy footprint
of the facility when the reactors become small plate or micro reactors?
What is the best way to manage inventories of Liquids with respect to the facility?
Expected Output of Research
There are three expected outcomes, comparing a traditional Batch Processing Facility
with a Continuous Processing Facility:
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What would be recommended to reduce the Capital Cost of the Facility but
maintain compliance (Safety and Quality)
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What would be recommended to reduce the environmental impact of the Facility
through smarter use of technology, building materials and of deliver services
efficiently to the process, to provide appropriate ventilation/air conditioning to the
parts of the plant that needs it again whilst maintaining compliance (Safety and
Quality)
What barriers would remain to applying these answers today?
Are there ‘general’ solutions which can be applied across a wide range of
products?