Green Chemistry Institute Pharmaceutical Roundtable Research Articles

Process Mass Intensity (PMI): A Holistic Analysis of Current Peptide Manufacturing Processes Informs Sustainability in Peptide Synthesis.

Small molecule therapeutics represent the majority of the FDA-approved drugs. Yet, many attractive targets are poorly tractable by small molecules, generating a need for new therapeutic modalities. Due to their biocompatibility profile and structural versatility, peptide-based therapeutics are a possible solution. Additionally, in the past two decades, advances in peptide design, delivery, formulation, and devices have occurred, making therapeutic peptides an attractive modality. However, peptide manufacturing is often limited to solid-phase peptide synthesis (SPPS), liquid phase peptide synthesis (LPPS), and to a lesser extent hybrid SPPS/LPPS, with SPPS emerging as a predominant platform technology for peptide synthesis. SPPS involves the use of excess solvents and reagents which negatively impact the environment, thus highlighting the need for newer technologies to reduce the environmental footprint. Herein, fourteen American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable (ACS GCIPR) member companies with peptide-based therapeutics in their portfolio have compiled Process Mass Intensity (PMI) metrics to help inform the sustainability efforts in peptide synthesis. This includes PMI assessment on 40 synthetic peptide processes at various development stages in pharma, classified according to the development phase. This is the most comprehensive assessment of synthetic peptide environmental metrics to date. The synthetic peptide manufacturing process was divided into stages (synthesis, purification, isolation) to determine their respective PMI. On average, solid-phase peptide synthesis (SPPS) (PMI ≈ 13,000) does not compare favorably with other modalities such as small molecules (PMI median 168-308) and biopharmaceuticals (PMI ≈ 8300). Thus, the high PMI for peptide synthesis warrants more environmentally friendly processes in peptide manufacturing.

Streamlined life cycle assessment of single use technologies in biopharmaceutical manufacture

The rapid growth of biologics as the preferred modality in several therapeutic areas has led to changes in the environmental profile of pharmaceutical manufacturing for some companies. The increased use of single use technologies (SUT) in biologics manufacturing has been accompanied by a greater public awareness of plastics waste, but the full life cycle environmental impacts of SUT have had limited study. Therefore, a segment of American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable member companies undertook a streamlined cradle-to-gate life cycle assessment on a biological bulk drug substance (BDS) manufacturing process utilizing SUT at the 2000 L scale. The goal of this study was to highlight where pharmaceutical companies, and biologics producers in particular, can reduce the environmental impact of their drug substance manufacturing. The results have shown that the largest contribution to the life cycle environmental impact for SUT was found to be the electricity used to operate the plant. Interestingly, across all impact categories, the contribution to the environmental footprint from end-of-life due to the use of plastic SUT was extremely small. Although not quantified in this study, these findings and others suggest operational changes that increase process efficiency and decrease time in plant are among the best strategies for reducing the life cycle environmental impact of biologics manufacturing.

Green and sustainable metrics: Charting the course for green-by-design small molecule API synthesis

Sustainable small molecule Active Pharmaceutical Ingredient (API) manufacturing starts at the onset of route development by employing a Green-by-Design strategy. Reliable metrics are imperative for setting targets and measuring process improvements throughout the development cycle. This article reviews some of the many tools and methods established to analyze and assess the greenness and sustainability of a process, each of which highlights different aspects of process efficiency, waste formation or overall environmental impact reduction. Most calculations, such as process mass intensity (PMI), are mass-based and do not consider the types of raw materials used. In contrast, a full life cycle assessment (LCA) offers detailed information about the “cradle to grave” environmental impact of a manufacturing route and its specific resources, but the high data requirements and long timelines are not conducive for multiple processes or repeated assessments during process optimization. To address these challenges, we introduce a Streamlined PMI-LCA Tool, developed in collaboration with the ACS Green Chemistry Institute Pharmaceutical Roundtable (ACS GCIPR), that combines PMI with a “cradle to gate” approach to include the environmental footprint of the synthesis’ raw materials. The frequent re-evaluation of a process continuously highlights areas for improvement and guides the prioritization of process development activities to effectively and rapidly achieve a Green-by-Design commercial synthetic route. The utility of this approach to Green-by-Design is demonstrated with the reduction of PMI for MK-7264 from 366 to 88 over the course of process development.

Making Sustainability Assessment Accessible: Tools Developed by the ACS Green Chemistry Institute Pharmaceutical Roundtable

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTMaking Sustainability Assessment Accessible: Tools Developed by the ACS Green Chemistry Institute Pharmaceutical RoundtableLouis J. DiorazioLouis J. DiorazioMore by Louis J. Diorazio, Paul RichardsonPaul RichardsonMore by Paul Richardsonhttps://orcid.org/0000-0002-3700-8749, Helen F. SneddonHelen F. SneddonMore by Helen F. Sneddon, Audrey MooresAudrey MooresMore by Audrey Mooreshttps://orcid.org/0000-0003-1259-913X, Christiana BriddellChristiana BriddellMore by Christiana Briddell, and Isamir MartinezIsamir MartinezMore by Isamir MartinezCite this: ACS Sustainable Chem. Eng. 2021, 9, 50, 16862–16864Publication Date (Web):December 20, 2021Publication History Received11 November 2021Published online20 December 2021Published inissue 20 December 2021https://doi.org/10.1021/acssuschemeng.1c07651Copyright © Published 2021 by American Chemical SocietyRIGHTS & PERMISSIONSArticle Views997Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (570 KB) Get e-AlertsSUBJECTS:Reagents,Green chemistry,Chemical engineering and industrial chemistry,Solvents,Pharmaceuticals Get e-Alerts

Novel versatile synthesis method for amides, carbamates and ureas employing a Grignard base, an amine and an ester

Methods for the synthesis of amides are extremely important given huge prevalence of this functional group in biological systems, as well as in the pharmaceutical industry. The ACS Green Chemistry Institute Pharmaceutical Roundtable have identified the amide bond formation as one of the most important reactions used in industry for which better reagents are required. We have developed a mild method using simple esters and amines with a Grignard reagent to synthesise, amides, carbamates and ureas (symmetrical and unsymmetrical). The method is significant in its simplicity, wide scope and the molecules that can be accessed.

Merck team wins 2021 Peter J. Dunn Award

The American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable has presented the 2021 Peter J. Dunn Award for Green Chemistry and Engineering Impact in the Pharmaceutical Industry to the Merck & Co. team of Stephen Dalby, François Lévesque, Cecilia Bottecchia, and Jonathan McMullen for developing a greener manufacturing process for belzutifan using a photo-flow bromination. Belzutifan is used in the treatment of cancer and other diseases. The team developed a more direct route from commodity chemical to active pharmaceutical ingredient, employed new reaction conditions, and incorporated a new photo-flow technology. According to L.-C. Campeau, executive director and head of process chemistry and discovery process chemistry at Merck, this is the “first example of a photo-flow reaction run on manufacturing scale at Merck and represents the linchpin of the synthesis.” The improved process for belzutifan, which is expected to launch this year, will reduce the waste associated with its manufacture and

Submissions open for green chemistry research grants

The American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable seeks proposals for research grants to advance green chemistry in the pharmaceutical industry. Grant topics include...

Sustainability Challenges and Opportunities in Oligonucleotide Manufacturing.

With a renewed and growing interest in therapeutic oligonucleotides across the pharmaceutical industry, pressure is increasing on drug developers to take more seriously the sustainability ramifications of this modality. With 12 oligonucleotide drugs reaching the market to date and hundreds more in clinical trials and preclinical development, the current state of the art in oligonucleotide production poses a waste and cost burden to manufacturers. Legacy technologies make use of large volumes of hazardous reagents and solvents, as well as energy-intensive processes in synthesis, purification, and isolation. In 2016, the American Chemical Society (ACS) Green Chemistry Institute Pharmaceutical Roundtable (GCIPR) identified the development of greener processes for oligonucleotide Active Pharmaceutical Ingredients (APIs) as a critical unmet need. As a result, the Roundtable formed a focus team with the remit of identifying green chemistry and engineering improvements that would make oligonucleotide production more sustainable. In this Perspective, we summarize the present challenges in oligonucleotide synthesis, purification, and isolation; highlight potential solutions; and encourage synergies between academia; contract research, development and manufacturing organizations; and the pharmaceutical industry. A critical part of our assessment includes Process Mass Intensity (PMI) data from multiple companies to provide preliminary baseline metrics for current oligonucleotide manufacturing processes.

Daniel Bailey wins Peter J. Dunn Award

Daniel Bailey of Takeda Pharmaceuticals is the recipient of the Peter J. Dunn Award for Green Chemistry and Engineering Impact in the Pharmaceutical Industry. The award, established by the ACS Green Chemistry Institute Pharmaceutical Roundtable, recognizes excellence in the research, development, and execution of new green chemistry technologies in the pharmaceutical industry. Bailey developed a technology for greener reaction conditions that reduces a six-step synthesis to four. In addition to shortening the synthetic route, Bailey and his team were able to reduce the amount of raw materials needed to make a final product. Bailey will present his technology during the 24th Green Chemistry & Engineering Conference, which will take place virtually June 15–19. Please send announcements of awards to l_wang@acs.org.

Green chemistry research grants available

The American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable invites proposals for its 2020 research grants. The grant topics are increasing the utility of surfactant-based che...

Peter Dunn Award to Frank Gupton; call for 2020 nominations

B. Frank Gupton, the Floyd D. Gottwald Jr. Chair in Pharmaceutical Engineering at Virginia Commonwealth University, is the recipient of the 2019 Peter J. Dunn Award for Green Chemistry and Engineering Impact in the Pharmaceutical Industry. The award, presented by the American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable, recognizes excellence in the research, development, and execution of pharmaceutical green chemistry technologies. Nominations are being accepted for the 2020 Peter J. Dunn Award. Submissions should highlight impact relative to the principles of green chemistry. The award will be presented at the 24th Annual Green Chemistry and Engineering Conference in Seattle, June 16–18, where the recipient will give an oral presentation. The deadline for nominations is 5 p.m. (EST) on Jan. 31. For details, visit bit.ly/36ReQAe.

Pharmaceutical Roundtable awards grants

The American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable has awarded nearly $200,000 in grants to advance green chemistry research in the pharmaceutical sciences. The roundtable brings together global industry leaders to catalyze the beneficial implementation of green chemistry and engineering. Fernando Albericio and Beatriz G. de la Torre of the University of KwaZulu-Natal were awarded $25,000 for their proposal, “Baroc, a Green α-Amino Protecting Group for Solid-Phase Peptide Synthesis.” Mark Mason of the University of Toledo was awarded $25,000 for his proposal, “Iron-Catalyzed Cross-Coupling of Heterocycles.” Aaron Vannucci of the University of South Carolina was awarded $25,000 for his proposal, “A New Approach to Catalyst Immobilization Research: Designing Molecular Catalysts for Heterogeneous Catalysis.” Arnaud Voituriez of the Institut de Chimie des Substances Naturelles was awarded $25,000 for his proposal, “Towards an Electro-Catalytic Wittig Reaction.” Susan Olesik of t...

ChemPager: Now Expanded for Evev Greener Chemistry.

ChemPager is a freely available data analysis tool for analyzing, comparing and improving synthetic routes. Here, we present an expansion of this application that makes use of the functionality of the PMI Predictor, which the ACS Green Chemistry Institute Pharmaceutical Roundtable has recently published as a web application. This addition enables ChemPager to predict the cumulative process mass intensity of chemical routes, irrespective of their development status, by comparison with a set of reactions executed on large scale. The prediction of this core green chemistry metric aims to improve existing routes and help the decision-making process among route alternatives without the need for experimental data.

Sustainability Challenges in Peptide Synthesis and Purification: From R&D to Production.

In recent years, there has been a growing interest in therapeutic peptides within the pharmaceutical industry with more than 50 peptide drugs on the market, approximately 170 in clinical trials, and >200 in preclinical development. However, the current state of the art in peptide synthesis involves primarily legacy technologies with use of large amounts of highly hazardous reagents and solvents and little focus on green chemistry and engineering. In 2016, the ACS Green Chemistry Institute Pharmaceutical Roundtable identified development of greener processes for peptide API as a critical unmet need, and as a result, a new Roundtable team formed to address this important area. The initial focus of this new team is to highlight best practices in peptide synthesis and encourage much needed innovations. In this Perspective, we aim to summarize the current challenges of peptide synthesis and purification in terms of sustainability, highlight possible solutions, and encourage synergies between academia, the pharmaceutical industry, and contract research organizations/contract manufacturing organizations.

Evaluating the Impact of a Decade of Funding from the Green Chemistry Institute Pharmaceutical Roundtable

Starting in 2007, the ACS Green Chemistry Institute Pharmaceutical Roundtable (GCIPR) has invested in sustainable chemical reactions and technologies in order to positively impact the pharmaceutical manufacturing routes and processes of the future. It has done so by committing over $2 million to support a grant program focused on spurring innovative and sustainable solutions to industrially relevant problems with significant unmet need. This has resulted in the funding of 28 research programs from academic groups across the globe, spanning a wide range of greener chemical technologies such as C–H activation, flow chemistry, biocatalysis, novel catalytic transformations, base metal catalysis, and solvent substitution. The application of this work has encompassed a range of therapeutic modalities, from traditional small molecules to peptides and biologics. This manuscript reviews the impact of the GCIPR funding program in its first decade by drawing together in one place the outputs of each project funded, ...

Introduction of a process mass intensity metric for biologics

Biopharmaceuticals (or biologics), large molecule therapeutics typically produced using biotechnology, are a rapidly growing segment of the pharmaceutical market. As such, the environmental footprint of the production of these molecules is coming under scrutiny from various stakeholders such as healthcare providers, investors, and even employees. Process mass intensity (PMI), originally adopted for small molecules by the Green Chemistry Institute Pharmaceutical Roundtable, is a simple metric that can also be applied to evaluate the process efficiency of biopharmaceutical production. PMI for biologics is defined as the total mass input in kg of water, raw materials and consumables, required to make 1 kg of active pharmaceutical ingredient. Six large pharmaceutical companies participated in a benchmarking exercise to calculate the PMI for monoclonal antibody (mAb) production. On average, 7700 kg of input is required to produce 1 kg of mAb. Over 90% of the mass is due to water use, highlighting the water-intensive nature of biologics production.

Benzene alkylation using acidic ionic liquids

Methods for the synthesis of amides are extremely important given huge prevalence of this functional group in biological systems, as well as in the pharmaceutical industry. The ACS Green Chemistry Institute Pharmaceutical Roundtable have identified the amide bond formation as one of the most important reactions used in industry for which better reagents are required. We have developed a mild method using simple esters and amines with a Grignard reagent to synthesise, amides, carbamates and ureas (symmetrical and unsymmetrical). The method is significant in its simplicity, wide scope and the molecules that can be accessed.

Progress towards a more sustainable synthetic pathway to ibuprofen through the use of solar heating

The ACS Green Chemistry Institute Pharmaceutical Roundtable was formed in 2005 to encourage the incorporation of green chemistry techniques into the synthetic pathways of pharmaceuticals. Through this initiative, synthetic pathways of several pharmaceuticals have been altered to adapt more environmentally friendly procedures. The amount of electricity required to complete chemical reactions have become an environmental concern due to depleting fossil fuels. A technique was recently developed in which satellite dishes were repurposed as solar reflectors capable of providing a heat source through solar irradiation. The ability to use the solar reflector as the sole heat source for synthetic reactions has been analyzed for the commercially important pharmaceutical, ibuprofen. Ibuprofen synthesis also incorporates chemicals that are not particularly friendly to the environment. The exchange of these chemicals with more environmentally friendly substitutes has been analyzed. The goal of this study is to incorporate a solar energy heat source to develop an alternative energy, more environmentally friendly pathway to ibuprofen.

ChemInform Abstract: Sustainable Chromatography (an Oxymoron?)

AbstractReview: [54 refs.

Sustainable Practices in Medicinal Chemistry: Current State and Future Directions

The medicinal chemistry subgroup of the American Chemical Society's Green Chemistry Institute Pharmaceutical Roundtable (ACS GCI PR) offers a perspective on the current state of environmentally sustainable practices in medicinal chemistry with the aim of sharing best practices more widely and highlighting some potential future developments.