The path from preclinical research to API drug commercialization is fraught with risk and complexity, with thousands of compounds narrowing down to a single drug suitable for patient use. The intense scrutiny in this process often puts sustainability on the back seat, especially during early phases. But this is exactly when sustainability should come to the forefront. By embedding green chemistry principles from the outset, pharmaceutical developers have the opportunity to reduce their environmental impact and design processes that are scalable, cost-effective, and compliant with evolving regulatory expectations.
We spoke with Axel Zimmermann, Director, Process Development Services, Pharma Services, and Peter McDonald, Director, Process Development Services, Pharma Services, both at Thermo Fisher Scientific, to find out more about greener API manufacturing.
Why is early-stage API development ideal for embedding sustainability principles?
API supply for early phase clinical trials and underlying tox batches typically relies on synthetic approaches, which are designed for the divergent synthesis of compound libraries, tolerating a broad substrate scope. Green chemistry aspects, waste reduction by process intensification, solvent recovery, water conservation, or the use of starting materials from renewable sources, play a subordinate role.
Generally, companies begin to consider the switch to a commercially viable and sustainable synthetic route towards the end of phase II. By this stage, the medchem route is often no longer scalable, or is becoming too expensive to supply sufficient material for later stage trials. At the same time, efficacy and safety have been established sufficiently to justify the investment in developing a scalable and cost-effective manufacturing process.
Switching the synthetic route at this point still allows sufficient time to develop, optimize, and validate a sustainable and commercially viable process before large-scale production for phase III trials and regulatory approval.
Implementing green chemistry and scalability aspects at later stages of the clinical development program can lead to significant costs and delays during product commercialization. For example, new impurities that may arise from the commercial manufacturing route will potentially require extensive bridging studies to validate the new route, and ensure it meets safety and efficacy standards.
Scale-up, as well as thermal process risks, are becoming prominent if detected late in the process development. Scaling from lab to commercial production may reveal inefficiencies and inconsistencies, leading to production delays, increased costs, and logistic supply during the transport and storage of hazardous reagents. Ultimately, speed to market can be delayed as the transition requires time for scale-up and validation, potentially leading to missed market opportunities.
How can green chemistry approaches be integrated without compromising yield, scalability, or time-to-market?
In general, green chemistry principles are not contradictory to the development of viable commercial synthetic processes; they are foundational to it. A well-designed, scalable, and intensified commercial manufacturing process that starts with raw materials originating from renewable feedstocks is intrinsically green. It prevents waste rather than treating or cleaning up waste, uses non-hazardous raw materials and reagents at low consumption levels, and operates at high space-time yields, thereby minimizing energy consumption.
Additionally, processes designed with green chemistry principles in mind are often more scalable and require less adaptation towards regulatory approval, ensuring significant time and cost savings on the path to product commercialization. For example, technologies such as continuous flow chemistry enhance reaction control, reduce scale-up issues, and improve safety, leading to faster development times and more efficient processes. Optimizing reactions to minimize by-products and waste, along with in-line monitoring, maintains high yields and reduces the need for extensive purification.
Furthermore, aligning green chemistry principles with regulatory requirements and engaging with regulatory bodies early helps integrate these practices without causing delays.
What role do solvents play in the overall environmental footprint of API production?
The demand for drugs, with improved target specificity, results in APIs with increasing molecular complexity. Consequently, these molecules require additional synthetic steps, specialized reagents and reaction conditions, and extensive purification. All of these factors lead to increased solvent consumption and complex solvent systems that are difficult to purify for later reuse or external recycling.
Beyond environmental and cost considerations, the handling of solvents and resulting waste streams can pose significant logistical disposal issues if not adequately addressed. With Process mass intensity values ranging from 150 to 1,000, this is particularly critical for pharmaceutical manufacturing processes.
To minimize the use of solvents in pharmaceutical manufacturing, a “refuse, reduce, reuse, recycle” strategy can be applied. This involves designing efficient synthetic routes with fewer steps and simpler solvent systems. By doing so, not only are the volumes of solvents reduced, but the recovery and reuse of recycled solvents in the manufacturing process are facilitated. Such a proactive design strategy ensures that solvent use is minimized from the outset, making the entire process more sustainable.
When changes to the manufacturing process are no longer feasible at a late stage of clinical development, the focus shifts to “reduce.” Underlying manufacturing processes can be optimized in terms of space-time yield to enhance throughput while simultaneously reducing waste and energy costs.
The third pillar is the “recycle” approach, which involves the reuse of purified solvent streams within the same manufacturing process or their external recycling in less regulated processes. Since the reuse of solvents often requires purification, which incurs significant costs for personnel and energy (e.g., through distillation columns), it is crucial to develop processes with simple solvent compositions. Such compositions can significantly ease the purification of solvent streams, making the recycling process more efficient and cost-effective. Focusing on solvent recovery and reuse, the industry can further reduce its environmental impact and resource consumption.
How has Thermo Fisher implemented circular economy principles in API development or manufacturing?
In 2021, Thermo Fisher Scientific was awarded the contract for manufacturing a high-volume API, which was under significant time constraints for its product launch. A critical transformation in the synthetic process involved a complex solvent system for the reaction and subsequent work-up, necessitating the handling of approximately 1,500 metric tons of a waste stream containing a ternary solvent mixture within a two-month production window.
The associated costs and logistical challenges of managing this solvent waste prompted the development of a reuse strategy alongside the regular tech transfer and scale-up activities. This strategy utilized an entrainer to break different azeotropes in the ternary mixture, achieving a recovery rate of over 80 percent for the two key components. The initiative was executed in close collaboration with the client, including the establishment of a control strategy for the recycled solvents. This facilitated the sustainable production of the API without compromising the yield or quality target product profile.
How can pharmaceutical developers evaluate the trade-offs between process efficiency and environmental responsibility?
The sustainable design of a chemical manufacturing process not only addresses economic challenges, but also enhances ecological process characteristics. By integrating sustainability principles into process design, manufacturers can achieve cost savings through increased efficiency, reduced waste, and lower energy consumption.
Simultaneously, these practices contribute to environmental benefits such as decreased pollution, conservation of resources, and reduced carbon footprint. Thus, sustainable process design creates a synergy where economic and ecological advantages reinforce each other, leading to more responsible and effective manufacturing operations.
Are regulatory frameworks evolving to better support or incentivize sustainable practices in API development?
For decades, the pharmaceutical industry has transformed patient lives through the development of medicines. While quality, efficacy, and safety remain paramount, there is now a growing focus on sustainability, driven by initiatives such as net zero emissions, circular economy practices, and green chemistry. However, the implementation of sustainability-driven post-approval changes for launched products faces many challenges from a chemistry, manufacturing, and controls regulatory point of view, making it complex to improve sustainability for commercialized products.
With the ICH Q12 guideline, a globally agreed and harmonized framework for managing post-approval CMC changes is provided. While previous guidelines, such as ICH Q8(R2) and Q11, focus primarily on early-stage product development, registration, and launch, the ICH Q12 guideline offers a predictable and efficient regulatory framework that builds on the process knowledge of critical parameters, critical quality attributes (CQAs) and rationalized specification established during product launch (established conditions), thereby facilitating sustainable post-approval changes and complementing previous quality ICH guidelines.
The definition of established conditions can be challenging, however, as it requires a thorough understanding of what constitutes critical quality attributes and critical process parameters. The definition of established conditions can be critical – especially for older filings applying modern quality by design-based principles. Misinterpretation or misclassification of established conditions can also lead to compliance issues.
What innovations could drive greener API development over the next five to ten years?
The API manufacturing process has the most significant environmental impact within the pharmaceutical product supply chain. The prevention of waste streams by a sustainable design of synthetic routes and development of high yielding, intensified processes can have far more impact and treating waste after it has been produced.
Green chemistry principles using advanced technologies such as (bio)catalysis, synthetic biology, and flow chemistry approaches will play a larger role in enabling more sustainable drug synthesis. Advanced manufacturing technologies in combination with AI tools, such as model predictive control optimizations, can help to speed the optimization of chemical reactions, predict reaction outcomes, and identify greener solvents and catalysts, leading to more efficient and sustainable processes. Once a sustainable process is in place, the emphasis can then move to circular economy approaches, with a focus on “reuse” in the process and the external recycling of process streams.
The modelling of liquid-liquid separations will become crucial for optimizing separation processes, thereby enhancing the solvent quality for reuse in the process. In this context, machine learning, which integrates experimental and simulation data from computational fluid dynamics and thermodynamic modelling will be key to enhance model accuracy and predict distillation behaviour.
Collaborative efforts with manufacturers, suppliers, and academic partners are all crucial to develop sustainability approaches and incorporate them early into the overall improvement process.
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