Introduction: The Whys and Wherefores of Sustainability Efforts in Peptide Synthesis

Although established over a quarter-century ago, the concept of green chemistry has only recently advanced to become a genuine movement¹ It is now prominently embraced by organizations striving to address known challenges within peptide chemistry. While the “how-to” for greening historically hazardous and wasteful synthesis processes continue to evolve, the direction is clear. Efforts are underway worldwide to create synthetic methods with greener solutions that improve outcomes for both industry and individuals.

Propelled by innovative chemistry and technology advances, large scale peptide manufacturing, founded by research that occured predominately in the mid-to-late 20^th century, has become increasingly receptive to considering alternative, greener synthetic methods. An obvious question that begs examination is “why is interest increasing now?” Several motivating factors account for the growing interest in redesigning chemical processes to reduce impacts on human health and the environment. Below is a very brief overview.

Moving toward Sustainability in Peptide Synthesis

Over the past decade, a focus on environmental, social, and governance issues (ES&G) across all industries has grown. Globally consumers and governments are increasingly exerting pressure on corporations to demonstrate their commitment to sustainable business practices. Fine and specialty chemicals, such as those involved in the production of peptides, have paid particular attention. A range of incentives has driven this scrutiny, including but not limited to growing regulatory challenges, stakeholder demands, and global competition.

Regulations

There have been numerous laws enacted prompting improvements in sustainability and green chemistry. One of the most notable is The European Union’s Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) regulation which went into effect on June 1, 2007. REACH regulations require that “If the risks cannot be managed, authorities can restrict the use of substances in different ways [including imposing stiff fines]. In the long run, the most hazardous substances should be substituted with less dangerous ones.”²

Shortly after the original REACH regulation was enacted, California, the world’s fifth-largest economy, passed two laws beginning their movement towards green chemistry.³ Similarly, Article 15 of the European Union’s Cosmetics Regulation 1223/2009 addresses carcinogenic, mutagenic, or toxic substances for reproduction (CMR substances) in cosmetic products. In general, using CMR substances in cosmetic peptides is prohibited.⁴

Subsequently, the European Union, architect “of one of the most comprehensive and protective regulatory frameworks for chemicals,” found cause to revisit the REACH regulations from thirteen years prior. In late 2020, the “Chemicals Strategy for Sustainability Towards a Toxic-Free Environment” was released. It was more comprehensive and ostensibly impactful on the peptide synthesis.⁵

As recently as January 1, 2021, there has been US federal legislation passed that “recognizes that green chemistry discoveries and inventions “are important and essential for the mission of every agency from Energy to Agriculture, from Commerce to Defense, from the National Institutes of Health to the Environmental Protection Agency.””⁶

Stakeholder Demands

Beyond regulatory pressures, pressure from stakeholders, including consumers and investors, is driving change. Consumers today are informed and intentional about the ingredients used in products, and they care about sustainability. Today’s buyers are as interested in processes that make the product as the product itself. In a recent survey conducted by Forrester and reported by Forbes, 32% of US consumers prioritize companies actively reducing their impact on the environment.⁷ Furthermore, they found that “…empowered shoppers” – purchasers with unprecedented access to information – “scout information from company values to manufacturing and supply chain practices in search of sustainable options.” They found that “68% of highly empowered consumers plan to step up their efforts to identify brands that reduce environmental impact, 61% seek out energy-efficient labels when making purchases.”⁷ The inherent reward from satisfied consumers is increased sales and brand enhancement.

Competition

The shortlist of common challenges facing peptide producers is no secret:

1. control the costs to manufacture more and more complex APIs;
2. maintain quality and reliability to avoid risk; and
3. reduce the effects of hazardous chemicals on worker health and the environment.

To address these points, academic and commercial efforts are researching and investing in ways to develop and implement processes that positively impact peptide manufacturing and better position themselves to respond to growing consumer needs.

A glance online at key market leaders’ websites underscores that a greener peptide synthesis is recognized as essential for growth. For example, Bachem researchers recently wrote: “… eco-friendly transformation of the manufacturing processes is not only advantageous for the environment but also makes the overall process more time-efficient and cost-effective.”⁸ Industry leaders are looking internally and externally to bring about these advances.

Bachem is not alone as other collaborative efforts by key players in the Life Sciences industry, focused on innovation, are also eyeing growth opportunities via improvements in sustainability. These efforts primarily focus on redesigning SPPS to address solvent substitution, recycling solvents, and reducing the number of solvents and raw materials used. On a parallel track, there are also newer technologies advancing sustainability in liquid phase peptide synthesis (LPPS).

The Industry Responds to Calls for Sustainability 

In a recently published article, Polypeptide Group – collaborating with Ypso-Facto – noted that “The main challenge of the coming years will be to cope with growing demand for peptide manufacturing in an acceptable way.”⁹ We stated earlier that industry leaders have been redesigning SPPS methods to better align with environmental and regulatory factors.¹⁰ One of the most widely recognized ways to align those efforts with industry challenges is by reducing solvent use since this component of peptide synthesis accounts for the most significant amount of waste and is generally the most hazardous.¹¹ Additionally, minimizing raw materials usage and energy consumption are other recognized targets for fiscal and environmental savings.¹²

Solvent Substitution

DMF is a standard solvent commonly used in SPPS. Alas, DMF is categorized as a substance of very high concern (SVHC) by the European Chemical Agency (ECHA) due to its environmental and health hazards.”¹³ However, finding a suitable alternative had proven to be a somewhat quixotic quest. If found, there is a treasure chest of potential and rewards. Recently partnerships have emerged, sharing the burden of these searches with some success. For example, Novo Nordisk, in collaboration with Bachem, has thoroughly investigated solvent replacements, and their efforts have generated “a toolbox of greener possibilities that may be considered to replace DMF in SPPS in the future.¹⁴

Recycling of Solvents 

At PolyPeptide Group, sustainability efforts resulted in research shared in 2019 in the Journal of Green Chemistry. Jan Pawlas, Ph.D. and ‪Jon Rasmussen, Ph.D., presented “ReGreen SPPS,” which demonstrated a simple process for reagent and solvent recycling of the waste stream from a SPPS process using greener solvents. The new method shows an almost 80% improvement in E-factor¹⁵ (a measure of how green the reaction is). Similarly, at AmbioPharm, peptide chemists have embraced recycling solvents and announced their commitment in 2019 to construct a new facility in Shanghai, including a waste recycling and recovery unit to improve their green footprint.¹⁰

Reduction of Raw Materials

Jan Pawlas, Ph.D., the scientist in global development at PolyPeptide Group, recently shared with a digital audience that focusing on solvents and recycling is only part of the green equation.¹⁵ Solutions that balance the economics of the SPPS process – such as reducing the raw materials used in synthesis – that result in lower production costs must also be considered in alignment with other factors, such as reducing energy consumption and other resources. Pawlas shared only one example that he could cite of green SPPS that resulted in both cost and environmental impact reductions.¹⁶ Similarly, we found one reference to a collaboration between Amgen Inc. and Bachem, which the EPA recognized in 2017 as a successful green process for commercial manufacture.¹⁷ The method was implemented and allowed substantial savings in material, processing, and energy costs.¹⁸

The few published examples of commercially successful green synthesis routes lead us to conclude that there remains an opportunity to fill a proven need. And developing a green peptide synthesis process that performs reliably, economically, and as a readily scalable solution for peptide production is no simple task. Considerable resources have been invested into short-term, greener platforms for SPPS while simultaneously exploring a range of lasting alternatives for sustainability in peptide synthesis. The results may be a bit mixed, but they are generally promising. On a brighter front, GAP Peptides is successfully advancing its sustainability-designed, efficiency optimized, scalable, and innovative platform technology for application to peptides across all industries. For more information about our process, visit our website or contact info@GAPPeptides.com.

References 

1. T. Anastas and J.C. Warner, Green Chemistry: Theory and Practice, Oxford University Press: New York, 1998, p.30. By permission of Oxford University Press.
2. https://echa.europa.eu/regulations/reach/understanding-reach
3. https://dtsc.ca.gov/green-chemistry/
4. https://ec.europa.eu/trade/policy/eu-position-in-world-trade/
5. https://ec.europa.eu/environment/pdf/chemicals/2020/10/Strategy.pdf
6. https://cen.acs.org/environment/green-chemistry/Sustainable-chemistry-legislation-enacted-US/99/web/2021/01
7. https://www.forbes.com/sites/forrester/2021/01/21/empowered-consumers-call-for-sustainability-transformation
8. Chimia 2021, 75, No 6, (2021). doi:10.2533/chimia.2021.476
9. Specialty Chemical Specialty Magazine, p48 9 (2019).
10. RSC Adv., 10, 42457 (2020).
11. Wegner, et al., Green Chemistry Letters and Reviews, 14:1, 153-164,
12. Jad, et al., ACS Sustainable Chem. Eng., 7, 3671 (2019).
13. https://echa.europa.eu/documents/10162/2842450/agreement_n_n-dimethylformamide_14560_en.pdf/1f8a3309-1e9f-81a5-bb7a-681466e4639c
14. Green Chem., 23, 3312 (2021). https://doi.org/10.1039/D1GC00604E
15. Green Chem., 21, 5990 (2019). https://doi.org/10.1039/C9GC02775K
16. PolyPeptide Group Outlines Cost-Effective Green Methods for Peptide Synthesis | BioSpace
17. https://www.epa.gov/greenchemistry/green-chemistry-challenge-2017-greener-reaction-conditions-award
18. National Law Review, Volume VII, (163)