Rethinking traditional manufacturing processes to identify green opportunities

Some call it magic we call it science, says Geert Schelkens, R&D manager, at Ajinomoto Sustainable Solutions

Developing competitive, more sustainable processes across the fine chemicals industry is critical and must be top of mind for developers and manufacturers alike. The complexities of high-value batch chemistry processes produce a significant amount of waste by way of consumption, work-up and crystallisation. As a result, the carbon footprint and waste-to-product ratio in the fine chemical industry is very high.

To combat this, developers will need to enlist a broad array of renewable, raw material sources, green chemistry strategies and innovative technologies. The key is identifying how best to break bad manufacturing habits, developing strategies for sustainable chemical production, and designing approaches to reach sustainability targets.

Approach sustainable manufacturing strategically

Beyond responsibility to the community and our environment, sustainability is a strategic choice and differentiator in the fine chemicals field. In our work at Ajinomoto Sustainable Solutions, we’re striving to build a vision for sustainable growth that prioritises and strengthens our core capabilities. Our team developed the ‘Net Zero Strategy’, which emphasises the following targets:

• Manufacturing to ensure carbon-neutral production via the electrification of our processes, i.e., replacing fossil fuels used for heating reactors with electric heating
• Purchasing from a green supply chain
• Leveraging a low footprint portfolio during R&D
• Maintaining and managing an overarching green strategy

If we translate this goals into figures, in combination with a portfolio growth, the footprint of our commercial processes should reduce 40% by 2030. Furthermore, in 2030, new processes ought to have a footprint that is 80% lower compared to 2019. 

Energy represents only 9% of our footprint. Even by electrifying and making our energy supply green, we are still a long way from our goals. Solvent and waste represent 33% of our footprint, which calls for the use of green solvents, solvent recycling, and the reduction of waste. 

The advanced and typically complex chemicals that are used as the basis for our processes are often known as building blocks and purchased from external suppliers. These building blocks account for 46% of our footprint. To change this, our team will need to reach agreements with our customers, and switch to suppliers with smaller footprints.

Ajinomoto Sustainable Solutions shaped its R&D targets around the 12 principles proposed by Paul Anastas in the book, Green Chemistry: Theory and Practice, published in 1998, most of which are highly important, including atom economy and the reduction of derivatives.

If fewer chemical conversions are possible by working without protecting groups or by using enzymes, a drastic reduction of the footprint of a process can be achieved. Other Anastas principles, including waste prevention, design for energy efficiency, use of renewable feedstock and catalysis, remain very relevant.

After translating this initiative into key performance indicators (KPIs), Ajinomoto Sustainable Solutions developed the ‘ECOpass’, a calculation that combines process mass intensity (PMI) and other key aspects of our footprint. PMI represents the kilograms of raw material needed to make one kilogram of the final compound. This is combined with emission factors for materials, solvents, and building blocks. 

We translate all the materials that are needed into kilograms of CO2. If you are generating a lot of waste, it’s important to discern how best to handle it. For example are you burning aqueous phases or are you able to discard the active phase into your treatment plant? Do you have to burn your chemical solvent waste, or is it recyclable? 

In two instances, our experts disagreed with Anastas’ theories: 'Less hazardous chemical syntheses' and 'Safer chemistry for accident prevention'. Some hazardous chemical reagents are quite useful, including azides, cyanides and oxygen. 

Azides and cyanides are chemicals that, when introduced in a molecule, serve as the simplest but most effective protecting groups for amines and amides. Oxygen has an explosion danger because we typically work in solvents. However, the use of oxygen as an oxidant in combination with a catalyst results in the greenest possible oxidation.

Shift your mindset around standard process development

Standard process development needs to drive sustainability forward. 75% of the CO2 footprint within a process, excluding building blocks, is generated by the work-up. In a classical process, you carry out reactions, add solvent, do extractions, change the solvent and conduct crystallisation, which generates a lot of waste. 

Reducing solvent use or extractions slightly will not enact meaningful change. Therefore, the industry needs to revolutionise its approach to R&D. One option is striving for zero extractions and distillations, i.e. no work-up at all. In the past, this has been done effectively by telescoping stages in which a second chemical conversion is done directly without any intermediate work-up.

Another simple but underdeveloped methodology is doing slurry-to-slurry transformations, in which the final product crystallises at the end of reaction is to collect the product by filtration and recover the solvent. Overall, solvent usage must be readdressed. 

Typically, chemists follow the literature precedent for solvent usage rather than trying aqueous chemistry. Instead, consider if the chemistry can be done in water. If that’s too difficult, add a small amount of solvent. If that still doesn’t address the issue, add an emulsifier or surfactant to perform micellar chemistry.

Starting a green process development revolution requires a lot of project preparation. The team must be trained, informed about new developments, and aware of green chemistry development principles. Let’s consider a few examples. 

Figure 3 gives an example out of the pharmaceutical business.1 It shows six chemical stages conducted in aqueous medium and only the last stage, from API crude to pure, is still solvent. Work-ups can be simplified and reduced to specific stage work-ups if you have a good grasp on the critical impurities towards the API; you may be able to switch to less than three purifications throughout the synthetic scheme. 

The pathway uses a few different tricks to drive sustainability. The first stage uses water while the second stage uses a tiny amount of THF in water. If one uses 15% volume of THF instead of 5 volumes or 10 volumes, that’s a major improvement.

A coupling reagent that can be used in water, which implies that even dehydration chemistry is possible in water. The only point that might be lacking in the example is an enzymatic conversion or biotransformation that also typically runs in water. 

An Aji Bio-Pharma project where we conducted phosphorylation in water using POCl3. Chemists would never do POCl3 chemistry in water; however, in this case, it worked perfectly fine and 98% phosphorylation is observed versus only 2% free phosphate forming.

Another important tool to drive sustainable innovation is using enzymes from fermentation. For example, a typical chemical process to tweak sugar is to decorate the sugar with protecting groups, remove one protecting group, modify the free alcohol, then do a general deprotection. 

Reducing the number of stages through a biotransformation requires metabolic engineering of enzymes to ensure that the enzyme effectively and selectively does its job and will do it in a highly concentrated medium. This enzyme can be produced through fermentation, a possible pathway offered to our customers. 

Third, we apply enzymatic or whole cell chemistry in practice. Our team has experience with transaminases, esterases, phospholipases, dehydrogenases, laccases, oxidoreductases and more.

If water is an ineffective replacement, green solvents are the next step. There are a number of green solvents, some of which have a high footprint on their own, and they need to be chosen carefully. Consider the following:

Does the green solvent have a large footprint that requires a lot of stages and purification?

Should feedstock still be used to make solvents?

Is it wise to develop processes using a solvent that may not be acceptable ten years from now?

The focus of renewable solvents is solvents from CO or CO2. One is closing the cycle by using CO2 and making formic acid, acetic acids, methanol, ethanol, etc. Besides biorenewable solvents, new technologies are becoming available. You might conduct chemistry above the boiling points of solvents rather than refluxing, which is energy-consuming and demanding.

Leverage innovation strategically

Rather than using precious metals with massive footprints, base metals present a compelling alternative. In terms of innovation, consider continuous flow processing and low footprint manufacturing.

Continuous manufacturing opens up a lot of new processing windows. A few examples include the use of photochemistry reactors to build up molecules rapidly or the use of high pressure, high temperature chemistry, and even supercritical chemistry. Dangerous conversion reactions can be done effectively and safely by continuously limiting the concentration of these dangerous reagents or their intermediates.

Another tool to drive sustainability is performing gas reactions in flow. Hydrogen and oxygen are the simplest and most atom-effective molecules for hydrogen reductions and oxidations. 

Ajinomoto Sustainable Solutions is investigating hydrogenation inflow using static mixers. If that is combined with high pressure, this also opens up opportunities to use base methods. If aiming for solvent free chemistry, then mechanochemistry comes into the picture, which is an early-stage technology. 

To achieve our 2030 goals, though, we are developing a few long shots, including mechanochemistry. In this case, solid-to-solid conversions are targeted by working without solvents or with minimal solvents, which is then classified as paste chemistry.

Collaborate with partners from Day 1

Of late, drug developers are increasingly interested in sustainable process development. Ultimately, the effort needs to be phase-appropriate as the path from Phase I to market is long. Phase II is the critical point at which a sustainable, relatively commercial-ready process should be established. At Phase III, final adjustments are made to optimise loss, i.e., solvent recycling and simplified unit operations.

Rather than a silver bullet, manufacturers need a diverse toolbox to build more sustainable processes. We are striving to think innovatively with a range of strategies, including continuous manufacturing, efficient synthetic routes, and simplified process stages with limited work-up.