Pharma Sets a Foundation for Greener API Manufacturing

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In the latest Intergovernmental Panel on Climate Change report issued in August 2021, the organization stressed that while some impacts of climate change cannot be reversed, such as continued sea level rise, “strong and sustained reductions in emissions of carbon dioxide (CO₂) and other greenhouse gases (GHGs) would limit climate change” going forward (1).

The pharmaceutical industry, like other manufacturing sectors, contributes to CO₂ and GHG emissions and is aware of the need to increase the sustainability of its operations. The IQ Consortium’s Green Chemistry Working Group first met with FDA in 2012 to identify opportunities for promoting green chemistry (2).

The IQ Green Chemistry Working Group also adopted the Green Aspirational Level (GAL)—originally developed by Boerhinger Ingelheim (3,4)—as a standardized green efficiency goal for API manufacturing processes that factors in the complexity of the synthetic route; the consortium also developed a Green Scorecard to show the value-added impact of green chemistry and other improvements, including process simplification (5). Individual manufacturers are tackling the issue in many different ways.

Going beyond continuous improvement

Small-molecule API manufacturing, according to Scott Martin, general manager of W. R. Grace & Co.’s Fine Chemical Manufacturing Services (FCMS), is driven by continuous improvement. “Most companies have pursued continuous improvement programs for many years, and many like Grace FCMS have embedded sustainability into those programs,” he says. “The expectation of sustainable manufacturing and the sustainable use of resources is top of mind for everyone in the industry,” he adds.

More specifically, Martin notes that both increasing yields and increasing throughput by definition result in a reduced environmental footprint. In addition to these types of efforts, improvements are also being made with respect to sources of energy, with drug manufacturers pushing utilities to produce more renewable energy, he continues. “As we see it, being more sustainable and pursuing continuous improvement are not two separate issues,” he concludes

Many technologies for ensuring cleaner energy consumption, abating emissions, and improving waste management have already been developed and, thus, are easier to implement and have more acceptable payback periods, adds Brian Peutherer, health, safety, and environment director at Sterling Pharma Solutions. “For contract development and manufacturing organizations (CDMOs), these solutions are the easiest way to make a significant impact on the sustainability of products without actually impacting API design,” he notes.

Sterling, for instance, has invested in a bio plant to treat wastewater, an anaerobic digestion plant to generate energy from waste, and a combined heat and power plant that generates approximately 98% of the energy used at its headquarters in Northumberland, United Kingdom.

Green chemistry and beyond

The concepts of green chemistry and sustainability, according to Jeff Song, vice president of chemical development in the United States for Boehringer Ingelheim (BI) Pharmaceuticals, have been broadly accepted in the pharma industry for the past 15 years. At BI, he says, these concepts are incorporated into daily work, leading to the routine development of greener API processes for all projects through innovative chemical research as well as new technologies.

To achieve true sustainability, though, Song emphasizes that other approaches than green chemistry principles should be considered, such as developing an effective waste management protocol at the end of the process. “Some modifications should be also made to the supply chain by replacing existing methods with greener chemicals and materials and by reducing chemical steps to convert commodity chemicals into value-added building blocks for API synthesis. While efforts have already begun within the industry to track the greenness of chemical processes at building-block suppliers, more work is needed,” he observes.

BI, adds Frederic Buono, the company’s senior associate director of chemical development in the US, looks to design the most direct synthetic approach with the least number of chemical steps using commodity chemicals as early as possible in the API development cycle. The commodity chemicals should have minimal cost, short methods of preparation, and wide availability. There is also a focus on process optimization to reduce waste generation and energy consumption by minimizing reaction concentration and avoiding extreme reactions condition (e.g., cryogenic temperatures).

As a member of the ACS Green Chemistry Institute Pharmaceutical Roundtable, BI researchers have also helped to develop tools to measure process performance with respect to sustainability and greenness, including the innovation Green Aspiration Level (iGAL) (6).

Looking to synthetic biology

The petrochemical industry is vital to the pharmaceutical industry today as a supplier of key raw materials used for the production of most synthetic-chemistry-based pharmaceuticals. It also, however, accounts for a large percentage of the world’s energy consumption. According to Jing-Ke Weng, cofounder of Double Rainbow Biosciences, a professor of biology at the Massachusetts Institute of Technology, and a member of the Whitehead Institute, current small-molecule intermediate/API manufacturing almost entirely relies on unsustainable precursors.

“The growing need to quickly move away from fossil fuel amid the threat of climate change creates urgent demand for novel sustainable approaches to replace the current supply chain for small-molecule drug production. Other than sporadic uses of biocatalysts in specific steps of some pharmaceutical syntheses, truly sustainably produced synthetic small-molecule pharmaceuticals are very rare,” Weng asserts.

Synthetic biology that integrates metabolic engineering of various biological hosts (e.g., bacteria, fungi, and plant cells) and enzyme engineering, Weng believes, will be a major solution that will lead to the next green revolution in the way future small-molecule pharmaceuticals will be produced. “Several proof-of-principle studies have shown the feasibility of employing biochemistry instead of synthetic chemistry to produce complex drug-like molecules sustainably; however, we are still far from widely adopting this new approach as a new industry standard,” he comments.

The first step, Weng predicts, will be the gradual replacement of synthetic chemistry production processes for small-molecule intermediates/APIs with enzyme-catalyzed reactions, which he notes are usually efficient, highly selective, and occur under mild conditions.

Begin at the beginning

To contribute to the reduction of CO₂ and GHG emissions, all drug developers and manufacturers need to seriously consider measures to improve sustainability throughout each phase of their industrial processes, according to Weng. “The pharmaceutical industry is due for a major overhaul in all aspects of its unit operations. Essentially, the pharmaceutical industry should be evaluating sustainable alternatives for all current exercises that rely on fossil fuel inputs,” he sates.

“The optimal time to consider sustainability is before the construction of a manufacturing plant, and at the design phase of the synthetic route, as these are the stages at which the most efficient technologies and techniques can be incorporated,” Peuthererasserts. “Considering sustainability from the outset allows the opportunity to integrate sustainability into every stage of a molecule’s lifecycle,” he continues.

Buono agrees that sustainability should be considered throughout the API R&D process starting from medicinal chemistry all the way to commercialization, but with different emphasis for each. “In our opinion, one should strive to implement new synthetic routes (hence those with a much higher level of sustainability) starting with the first clinical batch or shortly thereafter to achieve a balance between the overall speed, sustainability, and attrition rate.”

From the point of view of CDMOs, the greater focus on sustainability in the pharmaceutical industry requires greater collaboration with customers at an earlier stage of project planning and development to incorporate sustainable manufacturing techniques into the API process design, according to Peutherer. “Relationships with supply chains are critical when considering the impact of manufacturing on the environment to ensure expectations are clear, and standards are maintained throughout the supply chain process. This safeguards against companies passing on their environmental burden to others,” he says.

The best time to consider optimal, sustainable production solutions is during the design of the synthetic route to an intermediate/API, notes Martin, because once these processes are validated, it is very challenging to introduce any changes, even if they offer significant improvements in productivity and sustainability.

In addition to identifying transformations that require minimal energy inputs, Martin also remarks that it is beneficial to choose solvents and other reagents that if not consumed in the process can be recycled or at least reused or repurposed in some way.

Companies should become more comfortable with using non-virgin, reclaimed solvents, Peutherer agrees. “Solvents often make up the bulk of materials used in API manufacturing and reducing their use can play a huge part in lowering a process’s costs, carbon footprint, and waste management requirements,” he observes. It is also important to consider other alternative raw materials used in production that have a lower environmental impact.

Intensify operations

There are many opportunities to improve operations no matter what type of chemistry or chemical products are involved, according to Martin. He points to crystallization as one area that could use some attention. “Many small-molecule intermediates and APIs are solids and automatically purified via crystallization, which requires the use of solvents and often low temperatures. Under certain circumstances, distillation can be a more effective approach,” he explains.

There are, in fact, many opportunities to increase process greenness and sustainability by intensifying unit operations, Buono observes. For example, solvent volumes can be limited using a continuous extraction process, and aqueous/organic separation during work-up can be maximized using some separative commercial membrane units.

Keep things flowing

Flow chemistry is one of the technologies being employed to some extent in API manufacturing to increase sustainability, because, according to Song, the principles of green chemistry and green engineering are both leveraged in this manufacturing approach.

The versatility of the batch reactor has, until recently, meant any gains from continuous processing were previously unjustifiable, notes Peutherer. “With improving technology and techniques, however,” he notes, “continuous processing, especially in tandem with process intensification, can majorly impact on the inherent safety of a process and lower utility demands, as well as improving process specificity and reducing waste.”

Continuous flow technology, says Buono, can enhance heat and mass transfer by shortening process times with precise residence time control, which can lead to increased safety and reproducibility and thus afford product quality, all combined with easy scalability. “For these reasons, flow chemistry may offer a more sustainable technology for chemical synthesis compared to traditional batch chemistry,” he says.

In one example, BI developed a convergent, robust, and concise synthetic route which reduced the overall complexity (by eliminating a deprotection step) for an API that leverages a continuous flow-based Curtius rearrangement (the thermal decomposition of an acyl azide to an isocyanate with loss of nitrogen gas) (7). The overall process is 160% greener than the industrial average and 58% more efficient than the original batch process, according to Buono.

It is important to remember, though, notes Martin, that flow chemistry, while useful in some cases, is not applicable to all. Drugs produced in only small volumes, such as orphan cancer drugs, will likely not benefit from a continuous process because only limited quantities are required. In addition to lengthening development timelines for drugs where speed to market is essential, the upfront investment in the design of processes and equipment may not be easily recovered.

Role for digital technology

Digital technologies will play a crucial role in enabling greater sustainability of small-molecule API development and manufacturing. “We need to embrace digital technology to revolutionize the drug discovery process, and to adopt artificial intelligence and machine learning into our processes,” Song asserts. Doing so, he adds, is in concordance with Chemistry 4.0, which calls for the implementation of more digitalization and lab automation.

“To achieve these goals, collaboration across the industry is crucial,” says Song. “Pulling together expertise and insights from chemists, process engineers, theoretical chemists, IT specialists, and computer scientists will allow us to efficiently develop the digitalization solutions of the future for application to process development,” he concludes.

Regulatory cooperation needed

Ideally improvement of the sustainability of all drug manufacturing processes should be achieved; however, the pharma industry needs to establish a mechanism for addressing the shortcomings of older, existing processes for previously approved drugs.

“Altering existing processes is always challenging, but the urgency of available climate projections suggests the effort will be well worth it in the long run,” asserts Weng. “The near-term investment in sustainable solutions will push the industry towards more efficient API production processes while leaving a greatly reduced carbon footprint,” he adds.

In addition, Weng suggests that given the threat of global climate change, a failure to proactively embrace sustainable solutions may result in environmental regulatory agencies mandating sustainability targets for pharmaceutical manufacturers and other chemical industries.

Currently, it is extremely time-consuming and costly to implement changes due to the complex regulatory process that is involved. One possible solution, notes Martin, is to offer simpler regulatory pathways for certain types of changes related to sustainability improvements that do not affect the intermediate or API itself.

In cases where alterations to processes are a challenge, Peutherer says the best way to achieve a more sustainable outcome is through gains in ancillary aspects: cleaner energy generation, improved waste treatment options, pollution incident prevention, and carbon offsetting. This lowers the overall carbon footprint of the manufacturing.

Weng believes, though, that as sustainable means of small-molecule pharmaceutical development are expanded and tested to validate their performance against conventional synthetic chemistry-based approaches, industry peers and regulatory bodies must work together to embrace these solutions.

Always moving forward

All drug manufacturers are faced with these challenges. Contract manufacturers such as Grace FCMS work with customers to push the adoption of more sustainable solutions as part of continuous improvement efforts. “It is a combined effort that includes increasing yields, using more sustainable raw materials, and more environmentally friendly packaging equipment to recycling and reuse of solvents and shipping containers, all with the goal of reducing the environmental footprint of small-molecule intermediate and API manufacturing,” Martin states.

“Sustainability,” Martin continues, “is now at the forefront. Most public companies have sustainability targets and hold regular discussions with suppliers regarding their sustainability expectations. Grace FCMS is therefore continually looking at ways to help customers reach their sustainability goals while ensuring continued supply of high-quality API product on time and in full.”

New changes will continue to be made and observed due to the enhanced awareness and continued innovation, agrees Song. “The power of machine learning and digitalization will quickly bring the most efficient synthetic pathways to chemists, not only for reaction design but also for process optimization,” he notes.

Improvements to be made across the industry can be implemented in two ways, according to Peutherer. “Firstly, gradual improvements in the processes that companies presently undertake or redesigning of operations (e.g., microwave versus traditional oven drying) will have cumulative impacts. Secondly, on a more process-specific level, implementation of environmental operation studies at the concept stage, and waste audits on longer-running processes, can bring tremendous benefits,” he explains.

In the near term, Peutherer expects the greatest gains to be made in areas not directly associated with processes, including utility consumption and waste prevention/treatment. “For example, at Sterling we treat waste on site and are currently building an ‘energy-from-waste’ plant as part of our strategy to reduce the company’s overall carbon footprint,” he comments. Longer term, Peutherer predicts wider application of the green chemistry principles and improvements in API design and manufacturing processes will have a major impact on the industry.

Progress that has been made to date should be recognized too, Song adds. He points to the growing development and adoption of flow chemistry for API synthesis, and recent advances in catalysis, particularly in biocatalysis and non-precious metal catalysis (copper, nickel and iron), that offer an improved ability to build complex molecules with much higher efficiencies but less waste. Interest is also resurging in the photochemistry and electrochemistry due to the inherently green nature of these technologies, especially when coupled with flow technology.

Double Rainbow, according to Weng, employs twounique sustainable technology platforms to produce sustainable therapeutics: rich glycosylation biochemistry in all domains of life to produce glycosylated drug products that harbor unique pharmacological activities but are too difficult to be made using conventional synthetic chemistry methods and bioengineered microbial systems to recreate valuable medicinal natural products that are traditionally sourced from fragile natural ecosystems.

“In the near term, we anticipate moving several of our promising early-stage sustainable therapeutic candidates to clinical trials. Longer-term, we believe our bioengineered therapeutics will emerge as a new class of therapeutic modalities that play important roles in the future of health care while contributing to the sustainability of our planet,” Weng concludes.

References

1. Intergovernmental Panel on Climate Change, “Climate Change Widespread, Rapid, and Intensifying–IPCC,” Press Release, Aug. 9, 2021.
2. IQ Consortium, “Green Chemistry Working Group,” iqconsortium.org, accessed Aug. 23, 2021.
3. F. Roschangar, et. al., Green Chem. 19, 281–285 (2017)
4. F. Roschangar, R. A. Sheldon, and C. H. Senanayake, Green Chem. 17, 752–768 (2015).
5. IQ Consortium, “Inspiring Sustainable Drug Manufacturing,” iqconsortium.org, accessed Aug. 23, 2021.
6. ACS, iGAL 2.0 Scorecard Calculator, acsgcipr.org, accessed Sept. 19, 2021.
7. M. Marsini, F. Buono et al. Green Chem., 19, 1454–1461 (2017).

About the Author

Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.