Multiple Sustainability Drivers
The global manufacturing community is experiencing a regulatory shift that has significant implications for operations and compliance. Driven by climate concerns and depletion of resources, regulatory bodies around the world and across industries are issuing new guidance to drive better tracking, reporting, and control of consumption and emissions.
It is estimated that pharmaceutical manufacturing contributes approximately a quarter of all greenhouse gas emissions in the United States, making it the third largest contributor. In spite of the fact that pharmaceutical manufacturing is a relatively minor component of the overall industrial sector, it is often regarded as one of the more inefficient and polluting sectors.2,3. Link to Full Article
Green Chemistry and Pharmaceutical Manufacturing
Within the broader pharmaceutical manufacturing spectrum, the sustainability of operations surrounding API manufacturing is often framed by the term “green chemistry.” There are 12 Principles of Green Chemistry that focus on safety, efficiency, and reduction of consumption: prevention, atom economy, less hazardous chemical synthesis, designing safer chemicals, safer solvents and auxiliaries, design for energy efficiency, use of renewable feedstocks, reduce derivatives, catalysis, design for degradation, real-time analysis for pollution prevention, and inherently safer chemistry for accident prevention.9
Improving Sustainability with Flow Chemistry
Continuous flow was identified years ago by regulators as an emerging, potentially transformational technology with respect to both supply chain security and sustainability. The biggest benefit of this technology is the reduction of energy consumption, as heat and mass transfer are much more efficient. There is also a reduction in footprint in manufacturing and chemistry benefits as well. Operating in flow mode allows for the control of highly reactive chemistries that cannot be safely conducted in batch mode, thus allowing access to novel structures and motifs. Due to the removal of heat and flux limitations, photochemistry and electrochemistry, which use greener energy sources, are much more practical as continuous processes. The final benefit of flow chemistry comes from an engineering perspective, where it allows for efficient recycling of solvents and enables simpler workups that use less water and solvent, and therefore produce fewer wastes.
It is important to note, that flow mode is not always applicable. API manufacturing is highly complex, and often reactions do not involve homogeneous solutions. Heterogeneous mixtures are not always amenable to flow processes. Long reaction times are common and are difficult to accommodate in flow. Purification and isolation steps can be highly involved and often generate the greatest amount of waste but are not always easy to implement continuously.
Greening Pharma Manufacturing with Biocatalysis
Biocatalysis is also highly transformational with respect to improving the sustainability of API manufacturing. Perhaps most importantly, with biocatalysis it is possible to effect certain chemistries using biocatalysis that would otherwise require the use of hazardous, toxic, or otherwise harmful reagents and solvents. For instance, using traditional chemistry, a transamination reaction would require some sort of highly reactive hydride reductant that generates a metal-based waste product that must be actively remediated. A biocatalytic approach, however, generates benign, aqueous waste that is easily remediated by the environment.
Need to Go Beyond Reduce and Replace to Include Recycle and Rethink
Continuous flow manufacturing and biocatalysis promote the concepts of “reduce” and “replace.” The pharmaceutical industry has been pretty good about reducing energy and resource consumption. API manufacturers are also effective at replacing toxic/hazardous reagents with more benign alternatives through process design. Recycling, however, is virtually ignored during product development.
Considering Sustainability through the Development Cycle and Across the Supply Chain
In addition to incorporating sustainability considerations at the earliest possible development stage, it is equally important to continue to consider sustainability across the entire development life cycle as other aspects are treated. Quality, for instance, is considered to differing degrees depending on the development phase — coarse or rough early on during preclinical studies and increasingly refined as a pipeline candidate moves to phase I safety studies and ultimately to commercial launch.
Sustainability without Compromising Quality
Sustainability efforts, of course, must be pursued without any compromise on quality. Patient safety is paramount. A holistic assessment of patient safety, however, should consider not only clinical factors but the effect that the drug product has on the environment.
Treating Sustainability in a Holistic Fashion
When treated holistically, sustainability considers business sustainability. In fact, sustainability must have a business case. Governments may try to skew the scales by imposing fines or requirements and offering carbon credits and thus in some ways artificially manipulate the business case. Such efforts reflect the recognition that increasing sustainability cannot simply be an expense; sustainability initiatives in some manner must enable profitability in order to be sustainable themselves.
Asymchem’s Sustainability Solutions
Despite the challenges, it is clear today that sustainability is increasingly essential to remaining competitive. Regulatory and consumer pressures will only increase further. On the regulatory side, the cost of waste disposal is rising. Energy costs are also climbing. Access to water in some areas of the world is increasingly restricted. Reducing consumption and waste and emissions generation positively impact the bottom line as well.
Asymchem has enjoyed significant successes in the areas of flow chemistry and biocatalysis. In collaboration with AbbVie, we recently implemented a photoredox trifluoromethylation in continuous flow at large scale that leverages a more sustainable trifluoromethylating reagent, very low catalyst demand, and a favorable energy source (light) to drive the reaction.15 In collaboration with Amgen, another photochemical continuous flow process was developed16 for which we were presented the CMO Excellence in Green Chemistry Award from the ACS GCI in recognition of our efforts to promote the development and implementation of pharmaceutical green chemistry technologies.17 Likewise, we have reported on biocatalysis advances that have enabled the avoidance of more toxic catalysts/reagents and the potential reduction of organic solvent usage.18,19 We have also combined biocatalysis with continuous flow to compound the advantages that each technology contributes to more sustainable processes.20
In general, flow chemistry is used if it is a good fit. That determination is made using a multifactor analysis that takes into consideration sustainability, cost, quality, and patient safety. Asymchem has an interim goal of transitioning at least one third of processes to flow. The issue cannot be forced, however. If batch mode offers the best solution, then a batch process will be implemented. Asymchem is working to develop continuous flow technologies — and particularly specially designed equipment — for post-reaction processing/purification, which is an area that has not received significant attention to date.
Biocatalysis has afforded Asymchem with measurable upsides. One key benefit has been elimination of a portion of the supply chain. That was achieved by investing in capabilities for enzyme development and production, not just performing biocatalytic reactions. In this manner, we have also achieved greater efficiency and sustainability and reduced costs, because there is often no need to isolate the enzymes; the resultant broth from the enzyme production step can be directly used in the biocatalytic process.
In addition, Asymchem works to develop new mutant strains that are more robust and efficient and continuously evaluate enzyme types that mediate transformations not prevalent in the biocatalysis space, such as oxidases, in order to broaden the scope of chemistries that can be realized using biocatalysis.
Asymchem also pursues recycling of solvents wherever possible. Most notably, we consider recycling opportunities early on in process development and build this information into our product development plants. We also seek to reduce water consumption and appropriately treat the waste that we do generate.
Link to References and Full Article
Featured Contributor:
Mark McLaws, Ph.D. – Vice President CMC & Development, Asymchem.
Dr. McLaws obtained his Ph.D. from the University of Utah and has over 19 years of process chemistry experience in the pharmaceutical manufacturing industry. During his career, he has supported process development and manufacturing of clinical-phase and commercial small molecule APIs in a variety of therapeutic areas. At Asymchem, Dr. McLaws leads a team of technical experts to support CMC activities, with a particular focus on late-stage development, validation, and commercialization.