How can pharmaceutical manufacturing become greener?
As the human impact on our environment continues to increase, all industries will need to act to reduce their environmental footprint, improve sustainability and live within the boundaries of our planet. This is no exception for the chemical and pharmaceutical industries.
In this interview, we talk to Dr Jochen Becker, Global Project Manager RD&I at Evonik, to learn about opportunities and find out how challenges may be overcome.
How is greening the pharmaceutical industry different to other industries?
All industries can and should contribute to make manufacturing processes greener. The pharmaceutical industry is no exception. However, there are some industry-specific factors to consider in the approach to obtain improved sustainability. If we look at waste produced during manufacturing, the bulk chemical industry, for example, generates a very high volume of products with a relatively low amount of waste produced per kilogram. This is the opposite for the pharmaceutical industry which generates comparatively low volumes of product but high amounts of chemical waste per kilogram.
The current focus, therefore, of the bulk chemical industry is to work on reduction of energy consumption, circular economy and more sustainable or biodegradable products to reduce the impact on the environment. By contrast, the framework for product design in the pharmaceutical industry is to design drug products for a specific pharmacological action while reducing unwanted toxicological effects for the patient.
Does this mean that green chemistry is incompatible with pharmaceutical manufacturing?
Quite the contrary! Green chemistry and sustainability aspects are highly important, and with time, becoming essential in the field of pharmaceutical process development and manufacturing. The 12 principles of green chemistry as expressed by Anastas and Warner in 1998 provide a common, general framework to guide current pharmaceutical process development.. These principles are still highly relevant and will be increasingly so in the coming decades. By building in these principles in chemical route selection and process design, it is possible to reduce both manufacturing hazards and the amounts of hazardous waste generated per kilogram of pharmaceutical product.
The focus has often been on economic cost reduction of manufacturing processes while meeting stringent quality regulations of pharmaceuticals. An increased emphasis needs to be put on sustainability aspects when designing pharmaceutical processes. We need to intensify the implementation of green chemistry principles, while continuing to invent and use new tools.
What is driving pharmaceutical manufacturing to become greener?
In order to assure accessibility of medicines for a growing world population we need to change and continuously improve the sustainability of manufacturing processes. Otherwise, the footprint of growing manufacturing volumes will impact our planet and bring considerable additional risk to human health. Ideally, the goal would be to assure access to high-quality medicines for all humans while having zero emissions and waste generated. This is more a vision than reality at the moment, but we can work towards this direction. Anastas and Warner nicely described the shift of the role of chemists in their 1998 book on green chemistry. Historically, the challenge was to design processes which provide the product in the best yield at lowest financial costs. This has changed in the 90s towards inclusion of environmental costs, as well as the associated environmental risks in the process design. We need to continue on this path and increasingly implement sustainability aspects and new tools in pharmaceutical manufacturing.
On a very basic level, I am always impressed when I visit our drug manufacturing sites in Hanau, Germany or Tippecanoe in the U.S. Both are surrounded by forest and nature. The Tippecanoe plant is actually located next to a very diverse wildlife habitat at the Wabash River. This motivates us on a day-to-day basis to take care of our ecosystems on a local and global scale.
We, as one of the global key suppliers for pharmaceutically active ingredients and excipients, have to take responsibility not only for the quality of the manufactured pharmaceuticals but also for the footprint of our manufacturing processes on this planet.
Of course, among the key drivers towards improving the sustainability of pharmaceutical manufacturing are regulatory measures. The regulations of the US EPA and the state are very stringent and in the past, Tippecanoe laboratories have received the US EPA Green Chemistry Award and US EPA Clean Air Excellence Award. The site is continuing to operate at a high level of focus on environmental protection when we introduce new processes.
At a European level the EU Reach regulations also have stringent requirements for the European chemical industry. The Reach databases and toxicological information are also extremely helpful for finding data for assessments to protect the environment and the operators, as well as guaranteeing the safety of products. The chemicals strategy of the EU Green Deal is also investing in the green transition of EU industries, including the pharmaceutical industry.
Besides the regulatory framework, pharmaceutical process development generally includes reducing the risks: for the patient by providing pure compounds at affordable costs, for the operators by reducing hazards and exposure, and for the environment by utilizing green chemistry principles and sustainability considerations. The environment impacts us as humans, so a holistic view on health care also provides a driver to take care of the environment and to make the right decisions in the design of pharmaceutical manufacturing processes.
Are there synergies between green chemistry and pharmaceutical manufacturing?
I believe there are. Pharmaceutical drug design seeks to optimize the pharmaceutical effects for a certain target while minimizing toxicological effects of the drug molecule. The goal of pharmaceutical process development is to provide efficient manufacturing conditions that avoid and minimize impurities with toxicological actions. Avoiding the use of toxic solvents and process conditions that form impurities aligns with the green chemistry principle ‘choose synthetic routes using nontoxic compounds’ as well as with regulatory requirements such as those expressed in the ICH guidelines on residual solvents (ICH Q3C) and impurities in drug substances (ICH Q3/B).
The ICH Q3C guideline for residual solvents in pharmaceuticals classifies solvents into three classes from class 1 solvents that are toxic or carcinogenic solvents to be avoided to class 3 solvents with low toxicologic potential. The use and definition of green solvents from a green chemistry viewpoint to protect the environment is in close harmony with the pharmaceutical guidelines which aim to assure the safety of the patient.
Where do you think there might be conflicts?
Regulations are increasing in complexity. There is also more pressure on pharmaceutical development timelines, as well as cost constraints. The stringent requirements for the purity and quality of raw materials often limit the opportunities to re-use or recycle those materials.
For pharmaceuticals there is no compromise in regard to patient safety which is highly regulated and controlled prior to a patient receiving the medicine in clinical trials and later on when the pharmaceutical is on the market. In order to meet the specification and assure the supply of the product on time, chemists tend to apply classical, well established reaction conditions. Novel, more sustainable protocols and technologies can add additional risk to timelines, especially if these technologies have never been scaled up.
Another hurdle is registration. For registered, validated pharmaceutical processes, changing to greener reaction conditions can mean a costly re-validation and registration process. This can mean that additional cost and quality improvements might be needed as rationales to justify a switch to greener process conditions.
What can be done to overcome these challenges?
Key in my view is understanding the conflicts, having good tools to solve them, and setting the right focus. The pharmaceutical industry has in the past been among the most innovative industries. The targets, hurdles, and conflicts are often very challenging, but the mindset of our industry is very innovative and creative. And there is a spirit to work very hard on products and changes for the benefit of the health of humans and therefore also our planet. To increase sustainability, a framework needs to be set by authorities and within the companies which ensure that decisions can be made with the right focus.
Balancing quality, environmental, cost and timeline aspects in pharmaceutical development programs is highly complex and it is becoming increasingly complex. The total cost of developing a drug and bringing it to the market is nowadays typically more than two billion euros, including the development failures. Drug discovery and early clinical trials need limited quantities of drug product, and the focus is set on timelines. Towards the later clinical phases and launch, the quantities increase, and a parallel increased focus needs to be set on process efficiency and sustainability.
There are many parties with different viewpoints involved in pharmaceutical manufacturing and we need to understand our common ground, as well as challenge each other through dialog.
The regulatory agencies such as the US EPA and EU Reach regulations often set the framework to foster changes toward more sustainability. To implement changes, novel sustainable reaction conditions from academia and industry innovations are needed. Sharing on-scale applications of green chemistry fosters implementation and reduces the perceived risks of changes.
To give an example, in 2006, the polar aprotic solvents DMF and DMAc were classified as Substances of Very High Concern due to their toxicological properties. DMF is restricted by the Reach regulations: by the end of 2023 it will prohibited from the market and exposure of workers will need to be controlled below the derived no effect level (DNEL). As these solvents were used in many pharmaceutical intermediate processes, a strong motivation was set to switch to alternative solvents or to reduce the use of DMF and DMAc. Sustainable reaction protocols with greener reaction media from academic research provided the initial tools for industrial process development to switch from DMF to greener solvents.
How is sustainability implemented in pharmaceutical manufacturing at Evonik’s sites?
At our main pharmaceutical process research and development site we have implemented green chemistry principles as a checklist into the process development guidance documents. Germany, for example, has water hazard classes for chemicals and the development groups are always looking to substitute reagents and solvents for less toxic, greener alternatives during process development.
The staff at the Tippecanoe, U.S. and Hanau, Germany, sites realize the importance of protecting nature basically every day when passing the woods while going to work. Our technical teams actively work on applying green principles to our manufacturing processes and sustainability aspects to minimize their environmental footprints, such as reducing energy consumption of the utility facilities on site. These efforts are further steered by regulations, Evonik’s sustainability program goals, and process development and engineering programs to reduce waste as per green chemistry principle No. 1.
Outside the site boundaries, our supply chain groups qualify raw material suppliers in regard to quality and sustainability aspects. The waste which is generated by the processes is investigated to reduce impact to the environment by choosing the best forms of waste management. For example, wastewater treatment or solvent recovery are evaluated to reduce the need for thermal incineration of waste streams.
Do you have any specific examples of greening pharmaceutical manufacturing at Evonik?
When it comes to sustainability assessments, we handle customer CDMO projects and Evonik Health Care products in very similar ways. The process development, engineering, and production groups review the processes jointly with the sustainability and life-cycle assessment (LCA)/Environment Health and Safety (EHS) groups. This helps identify weaknesses and alignment on ideas and actions for improvement.
If a customer has an idea about how to improve sustainability, these can be further developed in our labs and scaled up for the first time within Evonik’s assets. This could be, for example, a switch from a batch process to a continuous process in order to improve the safety of highly energetic reactions such as Grignard reactions. In the last 10 years, we have jointly developed and scaled up continuous Grignard reactions, Grignard additions, and Kumada couplings with partners in the pharmaceutical industry. A case study has been published in Chemistry Today in 2019, and a collaboration of Evonik’s process development team with Biogen has been published in OPR&D in 2020.
Further, we are investigating to replace the use organic solvents by greener rection media and novel technologies such as chemistry in water. This is based on the surfactant technology of Professor Bruce Lipshutz at UCSB and includes cross-coupling reactions and peptide chemistry. A scientific article on amide and peptide couplings in aqueous media will be published soon.
To give another example, our process for lactide, which is used in the biodegradable Resomer pharma polymers, only utilizes the green solvents isopropanol and ethyl acetate and the raw material lactic acid produced from renewable feedstock. The result is a fully biodegradable product. Initially toluene was used in the process, but this was switched to ethyl acetate as a greener alternative.
For new processes our goal is always to develop the process in a way that the scale up in the plant proceeds “first time right”. This is important, because every manufacturing batch with a failing out-of- specification (OOS) result generates unnecessary waste, costs, and extends delivery timelines. These issues can be reduced by sufficient process understanding and by applying the green chemistry principle on process monitoring methods and utilization of process analytical tools (PAT).
Any final comments?
Overall, we need defined regulations and metrics to rate the sustainability and “greenness” of products and processes. These help to ask the right questions and identify areas for improvement during the right phase of a new drug product’s lifecycle. Further, we need good and innovative tools for chemical transformations and engineering design. These three items: (1) sustainability regulations and green chemistry metrics, (2) process design tools and (3) engineering design tools, all need to be addressed in an organized development workflow with iterative cycles in order to find good solutions for the right questions.
For more information about green chemistry and pharmaceutical manufacturing see Green chemistry and sustainability metrics in the pharmaceutical manufacturing sector
Thank you for your time today!
For more information about green chemistry and pharmaceutical manufacturing see the review article "Green chemistry and sustainability metrics in the pharmaceutical manufacturing sector" by Jochen Becker, Carolin Manske and Stefan Randl: