Release time: May 19, 2021, Gail Dutton (Gail Dutton)

Although the entire scientific community recognizes the need for sustainable development, green chemistry is still more of a wish than an achievement. However, recent work by the Swiss Contract Manufacturing Organization (CMO) PolyPeptide Group shows that green chemistry is not only feasible, but also economically reasonable.

PolyPeptide Group global development scientist Dr. Jan Pawlas said: “Chemistry must be transformed into a reused science and industry... But finding solutions that do not involve a significant green premium has always been challenging.”

In a speech at TIDES Digital Week in mid-May, he showed how reusable raw materials can replace traditional raw materials to reduce costs and environmental impact.

He pointed out that through coordinated greening efforts, PolyPeptide Group will reduce DMF consumption by 250 cubic meters in 2020 and plans to reduce it by 30% in 2022. In addition, its Ambernath plant in India has become a "zero liquid discharge facility, and its Limhamn plant in Sweden uses all green electricity."

For green peptide synthesis, Pawless recommends, “Evaluate the opportunities for greening the process at every step in the laboratory and GMP manufacturing facilities.” Taking the Fmoc/t-Bu solid-phase peptide synthesis process as an example, the greening opportunities in the peptide production process include:

PolyPeptide Group is committed to developing a green Fmoc/-Bu solid-phase peptide synthesis process, evaluating the physical and chemical and environmental health properties of the starting materials, their kinetics and chemical selectivity, commodity costs, waste management, energy consumption and processing and waste treatment processes Hazards in.

"Adjust the chemical reaction by controlling the temperature, solvent ratio, and choice of reagents and protocols," Pawlas said. "Temperature control is a key aspect. It minimizes the consumption of raw materials, improves solubility and (resin) swelling, and enables more time-saving development and manufacturing."

The company also selected materials that have the awareness of recycling and the ability to use the same solvent throughout the process.  

After optimizing the solid-phase peptide synthesis process to recycle and use more environmentally friendly solvents and minimal amino acids and processing aids, a process for the waste stream was developed, in which “waste is pooled from all processes and treated in the same way ".

Recover 86% of ethyl acetate for reuse, discard 4-methylpiperidine and other volatiles, recover 70% of dimethyl sulfoxide (DMSO) and 38% of oxyma for reuse.

"This is the only example of green solid-phase peptide synthesis, while reducing costs and environmental impact," Pawlas told a digital audience.

Compared with DMF, environmental factors have been reduced by four times, and solvent costs have been reduced by two times.

Therefore, he concluded that recycling of ethyl acetate, DMSO and oxyma is feasible and "is the only wise choice, because ethyl acetate constitutes most of the waste, and recycling of DMSO and oxyma is energy-intensive."

In terms of quality, the analysis shows that the crude protein produced by the green method is equivalent to the crude protein produced by traditional methods.

In contrast, "the current (traditional solid-phase peptide synthesis) method can produce any peptide on a large scale, but it has a great impact on the environment," he pointed out. For example, "Producing one kilogram of the GLP-1 agonist Exenatide will generate up to 34 tons of waste and 118 tons of carbon dioxide."

In view of the current synthetic procedures, green improvements are particularly needed in the field of catalysis or sustainable amide bond formation (ABF) and the replacement of dangerous dipolar aprotic solvents (such as DMF) in Fmoc/t-Bu solid-phase peptide synthesis. However, he emphasized that greening must not be at the expense of quality, cost or time, which makes it difficult to determine viable green solutions.

The PolyPeptide Group is not the only one seeking more sustainable peptide synthesis. The industry has identified several alternative research and manufacturing platforms, but they are often proprietary technologies, leading to increased costs and limited adoption.

In order to overcome these limitations, there must be tangible benefits, "such as lower costs, higher quality, higher yields or shorter production times," Pawlas said. He suggested that other strategies might include government taxation of green practices. Credits, and a better understanding of cost and scale dynamics and the factors driving the adoption of new methods.

As the company transitions to green synthesis, "developing adoption strategies and patent strategies to promote adoption (of green methods)," he urged. In addition to replacing the solvent, there are more green environmental protection.

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