Why Green Chemistry Is Good Chemistry

INTRODUCTION

Dear Community,

This month, I want to highlight a collaboration between Snapdragon Chemistry, a Cambrex company, and NewAmsterdam Pharma that won an American Chemical Society 2026 Green Chemistry Challenge Award.

At Cambrex, we are all very proud to be recognized for a project that reflects our dedication to long-term, sustainable manufacturing solutions, of course; however, rather than hog the spotlight, we were keen to find out what it meant to our partners at NewAmsterdam Pharma. In THE LEAD REACTION, we chat with Sheng Cui, their Chief Manufacturing Officer, who shares his passion for green chemistry, describes the work behind the award and explores what that ultimately means for patients.

As ever, if you’ve been working on optimizing a process with sustainability as a central focus, we’d be interested in hearing all about it – and perhaps sharing it with Synthesis readers.

Until next time,

Matt Bio

THE LEAD REACTION

Why Green Chemistry Is Good Chemistry

Hot on the heels of NewAmsterdam and Snapdragon Chemistry’s joint American Chemical Society 2026 Green Chemistry Challenge Award, Synthesis sits down with Sheng Cui, NewAmsterdam’s Chief Manufacturing Officer.

How did you find your way to NewAmsterdam Pharma?

After training as a synthetic organic chemist, I held increasingly broad development and manufacturing roles. At Amgen, I led the drug-substance project recognized with the 2017 US EPA Green Chemistry Challenge Award. At Boston Pharmaceuticals, I learned to evaluate development decisions through both return on investment and risk mitigation. In 2021, I joined NewAmsterdam because it offered the opportunity to help build the technology, supply and product strategy around an important potential medicine within a focused, entrepreneurial company.

How would you describe NewAmsterdam Pharma?

NewAmsterdam is a physician-founded, science-based biopharmaceutical company with a challenger mindset. Our motto – “Built to go beyond” – describes the culture well. We do not accept “good enough” when patients need better options. We combine deep expertise in lipid biology and late-stage development with the speed and accountability of a focused biotech.

From my perspective, another important distinguishing feature is that we connect decisions across the product lifecycle. Clinical strategy, CMC, intellectual property, manufacturing, supply and commercial value are all considered together from the beginning. This integrated approach helps us move quickly while maintaining the rigor needed to translate scientific promise into a potential medicine for patients.

Where does your interest in green chemistry stem from?

I began my career nearly 30 years ago in China, working in the realm of large-scale chemical manufacturing. It was an exciting period of industrial growth, but I also saw how poorly designed processes could negatively affect the environment. I became convinced that pollution should not be treated as an unavoidable cost of industrial progress. The better answer is to prevent waste through intentional process design.

Over time, I also saw that greenness and economics are not competing goals. When science and technology allow us to design more elegant processes, improve yield, remove steps, reduce solvent and water use and simplify isolation, we usually lower cost and improve reliability at the same time. To me, the best green process is not only more environmentally friendly; it is also safer, simpler, more robust and commercially stronger.

Congratulations on receiving the ACS 2026 Green Chemistry Challenge Award for the Greener Synthetic Pathway in the Synthesis of Pharmaceuticals. What does this award mean to you personally and to NewAmsterdam Pharma?

It is a real honor. The recognition is personally meaningful, but it also reflects something much broader: the strength of the science, leadership and teamwork at NewAmsterdam.

I am especially proud to share the award with our collaborators at Snapdragon Chemistry, a Cambrex company. Together, we demonstrated that a focused biotech and an expert CDMO partner can do great science and drive meaningful innovation at large scale. The award also showcases NewAmsterdam as a science-based organization that applies the same ambition to manufacturing technology and sustainability as it brings to developing potential medicines.

Could you please share details of the work behind the 2026 award?

The award recognizes an organocatalytic asymmetric process for a key chiral intermediate used in the synthesis of obicetrapib. The earlier route produced a racemic mixture and then separated and discarded the undesired enantiomer. Rather than scaling that inefficiency, the teams redesigned the chemistry to directly access the required stereochemistry with an exceptionally low catalyst loading.

The new process uses two manufacturing stages instead of four, improves overall yield from about 14 percent to about 80 percent and reduces process mass intensity by 81 percent. The process also reduced manufacturing time by 70 percent and production cost by 51 percent. The key achievement was translating elegant organocatalysis into a robust, practical and substantially more sustainable large-scale process.

What roles did Snapdragon Chemistry/Cambrex and the NewAmsterdam teams play?

I have always viewed CDMOs as partners, not remote suppliers. That is especially important in today’s biotech ecosystem, where focused companies rely on networks of specialized capabilities.

NewAmsterdam defined the product, supply, sustainability and business objectives and kept the work integrated with the broader development program. Snapdragon/Cambrex brought outstanding expertise in process chemistry, organocatalysis, crystallization, reaction engineering and scale-up. We worked as one team, sharing data, challenging assumptions and making decisions together. The success came from combining NewAmsterdam’s asset-level perspective with Snapdragon/Cambrex’s deep technical execution. This kind of partnership is essential to what a small biotech can accomplish.

Why are greener and more sustainable processes important for NewAmsterdam Pharma?

Greener processes matter because responsibility and performance reinforce each other. At the scale potentially required for a widely used chronic therapy, small inefficiencies become significant over time. Better process design reduces waste while strengthening capacity, cost and supply resilience.

For NewAmsterdam, sustainability is therefore part of the science-to-commercialization model, not a side initiative. It helps us prepare for potential global supply with the same rigor and purpose with which the therapy was developed.

How does this work ultimately connect back to patients?

Patients rarely see the manufacturing process, but they experience its consequences through quality, supply reliability, capacity and access. In the US alone, approximately 30 million treated patients remain above their LDL-C goals.

If obicetrapib is approved, we must be prepared to supply it consistently and at a meaningful scale – and that’s why yield, cycle time, capacity and cost matter. A simpler, more efficient process can produce more medicine with fewer resources and a more resilient cost base. Manufacturing cost does not determine access on its own, but it helps lay the foundation for broad, sustainable access for eligible patients who may benefit.

THE METHOD

The Crystal Maze 

Peptide drugs are booming, but how do we optimize stability and purity with process development and scale-up in mind?

Reconfiguring the naturally amorphous arrangement of peptide molecules into an organized crystalline structure makes them easier to process and improves purity at a lower cost than chromatography. But crystallizing peptides can be a labyrinthine undertaking. Their large size and flexibility mean they have a penchant for aggregating into gels, gums or fibers – a dead end for process development. To avoid a sticky situation and reap the benefits of an ordered crystalline structure, experience and expertise are required.

In a recent webinar, Cambrex Edinburgh’s Crystallization Team Leader, Hannah McLachlan, explains how her team uses a well-established process to help drug developers crystallize their vision of a pure and stable formulation.

Each unique peptide enters the maze in the same way. Following preliminary characterization and solubility checks, the team proposes an initial lineup of screening techniques, including high-throughput options that can test up to 96 solvent systems simultaneously.

Once polarized light microscopy (PLM) confirms crystallization, the team completes further experiments to confirm that the material can survive the rigors of drug processing, including:

• Scale-up trials
• Slurry trials at different temperatures and concentrations
• XRPD, HPLC, NMR and thermal analyses to check composition of solids, ensure purity and identify improvements from original materials
• Developability and stability assessment

With a suitable crystalline version of the peptide or peptide fragment in hand, the team is happy to begin refining crystallization, isolation and drying.

To explore how the process works in practice, Hannah shares real-life examples of how the team navigated a variety of twists and turns, blind corners and cul-de-sacs to safely shepherd new peptide drugs through the crystal maze.

Case study 1: Identifying an alternative salt for successful crystallization of a complex peptide.

The molecule: amorphous acetate peptide salt; 34-amino-acid dimer with cyclic branches.

Challenges: relatively large, structurally complex peptide with limited material availability.

Trial 1. A single sample was used for solubility, buffer capacity and 168 research plate (sitting drop) trials. Several conditions generated crystalline material.

Trial 2. Small-scale trials tested stability and generated materials for further trials. Crystalline material was recovered but was unstable under storage.

Trial 3. Another sample was received and salt swap trials were conducted. HCl salt was successfully produced and used for another round of screening. This time, stable crystalline material resulted in a purity uplift compared with the amorphous form. A monomer fragment of the molecule was also tested with similar results.

Case study 2: Methodical screening finds a route forward for a tricky peptide salt.

The molecule: a large, linear peptide (46-mer) isolated as a TFA salt through lyophilization.

Challenges: crystallization screening produced crystalline materials after reverse anti-solvent addition in a dilute system; however, yields were very low.

Trial 1. Longer hold times and immediate isolation of the crystalline material formed an unusable gel.

Trial 2. Alternative method of crystallization, using slow evaporation in water, produced crystalline material but resulted in a drop in purity caused by prolonged time in solution.

Trial 3. Salt swap trials generated a promising new crystalline form but scale-up was unsuccessful.

Trial 4. Undeterred, the team turned to fragments of the peptide. Six fragments were tested, from 4–24 amino acids. Crystalline solids were recovered with high purity from both freebase and TFA salt forms of a 24-amino-acid fragment – giving the developer not one, but two manufacturing pathways to explore.

In the full webinar, you’ll find more detailed case studies drawn from Hannah’s wealth of experience, including:

• Analysis of peptide characteristics following crystallization
• How successful results in peptide fragment crystallization can direct screening of the complete peptide
• How high-throughput screening is being used to save time and guide further development work
• The effects of scale on purity

Watch the full webinar.

THE CATALYST

What we are reading…

It is typical that when we speak about sustainability in pharmaceutical manufacturing the focus is on process mass intensity or the mass of the waste divided by the mass of the final product. But another major contributor to sustainability is the energy requirements of the process in terms of heating or cooling. Solvent exchange and batch concentration unit operations are usually performed using short-path distillation. Distillations, particularly those involving solvent swaps, can require many hours of heating a batch vessel to distil off the unwanted solvent.

During the manufacture of biologics such as monoclonal antibodies, there are also typically steps in the process where there is a requirement to exchange one aqueous buffer for another or to concentrate the biologic from a predominantly aqueous stream. This is typically done by tangential flow filtration (TFF) across a membrane that selectively permeates molecules based on molecular weight. The high molecular weight biologic is retained, and the lower molecular weight water, solvent and buffer is permeated through the membrane. Traditionally the membranes are cellulose based and require large molecular weight differences between the retained biologic and the permeated solvent or buffer. Due to the chemical stability of the cellulosic membranes and the large differential in molecule size required for efficient separation, traditional TFF technology has found little use in synthetic pharmaceutical manufacturing. However, advances in membrane technology have led to the development and commercialization of polymeric and ceramic membranes which are both highly chemical stable and can efficiently separate small molecules with relatively small differences in molecular size.

Two membrane separation technologies are beginning to find use in synthetic pharmaceutical manufacturing – pervaporation and organic solvent nanofiltration¹. Pervaporation is a powerful tool for the dehydration of solvents, able to remove water to below the azeotropic limit of water removal and with significantly lower energy cost. Pervaporation membranes are also finding application in reaction development where the removal of a small molecule as permeate can drive an equilibrium reaction, such as the removal of ethylene from a ring-closing metathesis reaction². Organic solvent nanofiltration (OSN) technology can replace distillation as a means of batch concentration or solvent swap with some reporting >200x lower energy input requirement for membrane vs. distillation. OSN can also be used as a purification technology where in an undesired contaminant, impurity or reaction byproduct can be separated from the target molecule using the selective permeability of the membrane. This has been exploited for solution phase peptide³ and oligonucleotide⁴ synthesis where the growing biopolymer is retained while the byproducts and impurities are removed through the membrane. The application of membrane technologies in these examples results in significantly improved sustainability for peptide and oligo manufacture by obviating the need for solid phase technology and preparative HPLC, technologies which both have poor sustainability metrics associated with them.

The application of membrane separation technology to synthetic pharmaceutical manufacturing can reduce or eliminate the need for energy intensive processes like distillation and may be able to also deliver PMI improvements. Before you start that next distillation, consider using a membrane.

¹ Org. Process Res. Dev. 2024, 28(4), 891-923. https://doi.org/10.1021/acs.oprd.3c00470
² Org. Process Res. Dev. 2020, 24(10), 2298-2303. https://doi.org/10.1021/acs.oprd.0c00061
³ Org. Process Res. Dev. 2021, 25 (7): 1628–1636. https://doi.org/10.1021/acs.oprd.1c00108
⁴ Org. Process Res. Dev. 2025, 29 (6), 1577−1592. https://doi.org/10.1021/acs.oprd.5c00117

THE SIDEBAR

Scaling complex chemistry through smarter, more sustainable processes

When it comes to the future of API manufacturing, I would like to think about the sustainability of our processes. How can we, for example, make molecules that have a high complexity in as few steps as possible?