Page 177 - CW E-Magazine (18-2-2025)

Continuous Manufacturing Continuous Manufacturing

API production. These benefi ts include made continuously by directly reduc- They can, thus, tremendously shorten have to supply 10K of additional heat to 2. Novartis continuous manufacturing with Green
reducing the consumption of raw mate- ing CO to hydrocarbons in an aque- the workfl ow of bringing technologies get to reaction temperatures. The utility Novartis has been a pioneer in Chemistry, particularly in producing
2
rials, energy, and water and minimiz- ous medium. This, too, could be done from the laboratory to commercial pro- consumption has, therefore, dropped implementing continuous manufacturing APIs for respiratory drugs. GSK has
ing emissions and waste. Continuous near ambient pressure and temperature duction. by a factor of 22! For industries wor- to produce APIs. One notable example is developed continuous fl ow processes for
Green Manufacturing (CGM) is there- conditions. Further, sourcing electricity ried about decarbonization and cooling their continuous production process for several APIs, reducing the need for large
fore well able to meet increasingly from renewable sources makes it possi- Even with the promise, these tech- water conservation, here is the ultimate a cardiovascular drug. solvent volumes and lowering energy
stringent regulatory standards for qua- ble to have a genuinely carbon-neutral nologies have yet to see industrial-level low-hanging, high-impact fruit! But this consumption. These processes have also
lity and environmental impact, making process. deployments. Part of the reason is that is only possible with the fl ow. Novartis developed a fully integrated allowed for the use of less hazardous
it an attractive option for pharmaceuti- some technologies are new (like deploy- continuous manufacturing process that reagents, reducing the environmental
cal companies seeking to future-proof Another technology that is worth able LLMs). But another part of the Technologies are being developed includes the API’s synthesis, crystal- impact of production.
their operations. watching is focused energy addition. reason is that even well-studied techno- for continuous hydrogenation and other lization, fi ltration, and drying. This
It works with Microwave irradiation. logies (microwave, electrocatalysts) have heterogeneously catalyzed reactions, approach has reduced the time required To produce the respiratory drug fl uti-
Emerging Technologies to Keep in Microwaves are selectively absorbed not found investors who would take the with catalyst recovery and recycling in to produce the API from several weeks casone propionate, GSK implemented
Mind by materials with a signifi cant dipolar risk to develop the ancillary technologies fl ow. Even continuous crystallizations to just a few days. By adopting a continu- a continuous manufacturing process
The use of microorganisms and moment and metals. Hence, non-polar to translate them into commercially are nearing piloting. In India, a number ous process, Novartis could signifi cantly that signifi cantly reduced waste and
enzymes to effect chemical transformation solvents with non-polar reactants can deployable products – something we of these innovations are being done in reduce solvent use, waste generation, improved process effi ciency. The continu-
is probably older than written history selectively activate a metallic catalyst, will touch upon in greater detail below. the Amar Flow Laboratory LLP. and energy consumption. The method ous process allowed better control over
(think wine, yogurt, cheese, and leave- providing activation energy precisely uses less raw material, creating a more reaction conditions, producing a more
ned bread). However, a major, Nobel- at the site required for maximum effec- Deployable Continuous Green Manu- The transition to continuous green sustainable production process. Novartis consistent and high-quality product.
Prize-winning breakthrough was made tiveness. The microwaves are not just facturing manufacturing in the pharmaceutical received approval from the U.S. Food GSK has reported that their continuous
by discovering the directed evolution glorifi ed heaters: there are poorly under- Several technologies are low-hang- industry is gaining momentum, with and Drug Administration (FDA) for the manufacturing processes have reduced
of enzymes(2). With the ability to syn- stood phenomena by which microwaves ing fruit for continuous green manufac- several companies leading the way. fi rst drug produced using a continuous greenhouse gas emissions and a lower
thesize practically any protein imagin- interact with substrates to yield effi cient turing. For instance, nitration in fl ow can Here are some notable examples of how manufacturing process, setting a prece- overall environmental footprint for their
able and select the most optimum for transformations(4). be executed without mixed acids – only industry leaders implement continuous dent for the industry(8). API production.
a given application, tailoring enzymes commercial nitric acid [5] at slight molar green manufacturing processes for API
for selected catalytic transformations is While digital technologies have long excess and super-ambient temperatures. production. 3. Pfi zer 5. Vertex Pharmaceuticals
now possible. The ability of enzymes to been an essential part of chemical manu- The tremendous benefi ts in safety and Pfi zer has also embraced continu- Vertex Pharmaceuticals has adopted
carry out their activities at near ambient facturing (think process control), the environmental footprint to the pharma- 1. Eli Lilly and Company ous manufacturing, particularly in pro- continuous manufacturing to produce
conditions of temperature and pressure advent of deployable artifi cial intelli- ceutical, dye, and explosives industries Eli Lilly has been at the forefront of ducing APIs for small-molecule drugs. the API for their cystic fi brosis drug,
makes them especially suitable for gence and machine learning has opened cannot be overstated. adopting continuous manufacturing pro- One of their notable projects involved Orkambi. The continuous manufactur-
future green-chemistry transforma- up tremendous possibilities for green cesses. One of their key achievements is the continuous synthesis of an onco- ing process at Vertex integrates several
tions. Continuous green production of continuous manufacturing. The most Similarly, technology from the IMM the continuous API production for their logy drug. The continuous manufactur- unit operations, including reaction, crysta-
various APIs under near ambient conditions critical technology to remember is using Fraunhofer Institute in Germany has diabetes drug, insulin Lispro. Eli Lilly ing process developed by Pfi zer allowed llization, fi ltration, and drying, into a
becomes feasible by designing fl ow industry-specifi c large language models demonstrated continuous production of signifi cantly improved effi ciency and for a more streamlined and effi cient API single continuous fl ow. This integration
reactors with in-built enzyme recovery (LLMs) to trawl through literature Grignard reagent from Mg metal on a sustainability by shifting from a tradi- production, with real-time monitoring has streamlined production and reduced
units. rapidly, emerge with relevant literature pilot scale [6]. This technology is at the tional batch to a continuous process(7). and control of reaction parameters. This the time required to produce the API.
data on any problem of interest, and threshold of realizing the potential of has led to higher yields and reduced The continuous process has enabled
It is also possible to do chemical present that data lucidly. The ability to making industrial-scale Grignard syn- The continuous process utilized in waste. Pfi zer’s continuous process mini- Vertex to reduce solvent usage, energy
transformations with electrons from a ask questions in natural languages to thesis safe and green. insulin production incorporates Green mizes hazardous reagents and solvents, consumption, and waste generation.
voltage source with an electrocatalyst to further drill down on the data means that Chemistry principles, including using aligning with Green Chemistry princi- The process also offers improved scala-
direct the electrons to/from the desired any young technologist has the same In several cases, utility savings alone aqueous solvents and minimizing hazar- ples. The method also operates at ambi- bility and fl exibility, allowing Vertex to
site on the chemical substrates. This access to knowledge that it would have can pay for the entire fl ow reactor sys- dous chemicals. This shift has led to a ent temperature and pressure, reducing respond to changes in demand quickly.
approach can be particularly advanta- taken a person several decades to imbibe. tem. Consider a batch reactor raising the reduction in solvent waste and energy energy requirements. The continuous Vertex’s continuous manufacturing pro-
geous for redox reactions common in AI engines like Elicit: The AI Research temperature of a process from 30°C to consumption, enhancing the environ- manufacturing approach improved the cess for Orkambi received regulatory
API production. As with traditional Assistant essentially reproduce the feel 250°C, carrying out a reaction, and then mental profi le of the production process. production process’s sustainability and approval, highlighting the growing
catalysts, the advent of high-entropy of having a mentor read the paper with cooling back to 30°C. That is a 220°C The company has reported a signifi cant enhanced API production’s scalability acceptance of continuous manufacturing
materials has substantially increased you. LLMs can suggest ways to ana- temperature swing, and all that heat is decrease in waste generation and a lower and reliability, contributing to the boom- in the pharmaceutical industry.
the scope of electrocatalysis(3). With lyze data, write software for the same, wasted. If, instead, the hot effl uent of the carbon footprint for the production of ing drug commercialization(9).
electrocatalysis coupled to fl ow pro- analyze the results, and even produce reactor could be cross-exchanged with insulin lispro. Additionally, the continuous Challenges to Continuous Green
cessing, it is feasible to consider a pro- reports and presentations, all driven by a the cold feed with a temperature driv- process has enabled a more consistent 4. GSK (GlaxoSmithKline) Manufacturing
cess where organic chemicals could be few lines of natural language “prompts.” ing force of 10K, the utility would only and higher-quality product. GSK has led the integration of The adoption of continuous green

176 Chemical Weekly February 18, 2025 Chemical Weekly February 18, 2025 177

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