A greener pharmaceutical industry

Process design

Process engineering in the pharmaceutical industry is essential for transforming research breakthroughs into viable products that meet health and safety standards. This discipline focuses on the design, operation, control, and optimisation of chemical, physical, and biological processes, playing a pivotal role in ensuring the sustainable production of pharmaceuticals. Sustainability in process engineering addresses the environmental, economic, and social impacts of production processes, aiming to minimise resource consumption, reduce waste and emissions, and enhance social welfare while maintaining economic viability. 

In the context of sustainability, several key factors must be considered: 

Resource efficiency: Optimising the use of raw materials and energy throughout the manufacturing process to minimize waste and reduce costs (Espro et al., 2021). 

Waste minimisation: Implementing strategies to reduce, reuse, and recycle waste materials, thereby mitigating environmental impacts (Kar et al., 2021). 

Green chemistry: Employing principles of Green Chemistry to develop safer, non-hazardous, and more environmentally benign synthesis routes.

Energy conservation: Designing processes that utilise renewable energy sources and improve energy efficiency to reduce the carbon footprint (Zimmerman et al., 2020). 

Process intensification: Streamlining processes to achieve more efficient reactions and separations, leading to smaller equipment sizes and lower environmental impact (Weaver et al., 2022). 

By focusing on these parameters, pharmaceutical process engineering can drive significant reductions in the environmental footprint of drug manufacturing. For example, adopting 3D printing or microfluidics technologies can lead to more sustainable production methods by reducing material usage and enhancing energy efficiency (Weaver et al., 2022). 

Incorporating sustainability into process engineering practices within the pharmaceutical industry is not only a moral imperative but also a strategic necessity. As regulatory pressures and consumer awareness regarding environmental issues increase, companies that proactively adopt sustainable practices will likely gain a competitive edge. Ultimately, the goal is to ensure that the production of pharmaceuticals contributes positively to societal health without compromising the ability of future generations to meet their own needs. 

The story of nirmatrelvir

Process engineering is essential for industrial expansion but presents several challenges. It involves moving from laboratory-scale to full-scale production, requiring careful planning to maintain product quality, ensure process safety (no risk of chemical accidents), control costs, and comply with very strict regulations. Since pharmaceutical products are intended to be bioactive, their manufacturing process quality demands are exceptionally high and strictly regulated, ensuring safety and efficacy.  

In 2019, the global pharmaceutical sector was confronted with significant obstacles as it strived to address the challenges posed by the SARS-CoV-2 pandemic. Over this crisis, a breakthrough was reported by researchers from Pfizer (Allais et al., 2023). They announced the identification of nirmatrelvir, a highly effective, selective, and orally available compound designed to inhibit the main protease enzyme of the SARS-CoV-2 virus. The urgent need to assess the safety and efficacy of nirmatrelvir prompted swift movement through toxicological evaluations and clinical trials, adopting a highly accelerated development approach known as 'lightspeed'. This necessitated the rapid production of the compound in large quantities, unprecedented in the industry’s history. 

A landmark achievement was reached with the development and upscaling of a cost-effective chemical process for synthesising nirmatrelvir. This pivotal advancement facilitated the expedited progress of Paxlovid, a combination treatment of nirmatrelvir and ritonavir, from its initial synthesis in July 2020 to receiving emergency use authorisation from the FDA in December 2021, within a mere 17-month span (compared to the typical 10 year period).

The project underscored the vital role of pre-existing research and the foundation it provides for future innovations, demonstrating that efforts from prior projects, whether successful in the market or not, are crucial for enabling significant commercial breakthroughs. The urgency to meet a critical healthcare need allowed for the reallocation of research and development (R&D) resources, accelerating the project without the need to weigh it against other potential investments. This scenario suggests that rapid development and deployment of pharmaceutical products are possible when driven by immediate public health demands, highlighting a shift towards more agile and responsive R&D strategies. The strategy also included plans for expanding the supplier network post-launch to meet anticipated commercial demand, illustrating a proactive approach to supply chain management in response to the pandemic. 

The scaling-up process usually requires between 2 to 4 years; in this particular case, 13 weeks were enough to scale-up the production of nirmatrelvir as follows:  

• 2-5 g Laboratory demonstration;

• 20-50 g  Engineering and safety assessments;

• 2-5 kg  Kilo lab campaign;

• 20-50 kg Pilot plant campaign;

• 200-1000 kg Transfer to commercial launch facility.

The authors emphasise the need for efficient development routes for nirmatrelvir's fundamental building blocks, highlighting the importance of a robust supply chain, rapid scalability, and sufficient funding to facilitate commercial production. Involving green methodologies, chemists were able to telescope the reaction (decreasing the number of steps in the synthesis) and the overall yield of the product from the discovery route to the commercial route improved by 30%. The green metrics from the process shows that the Process Mass Intensity (PMI) is 108 for the commercial route in contrast with 472 in the discovery route.

Later on, Algera et al. (2023) discussed the challenges encountered during the scaling up process, primarily related to impurities. At the same time, the chemists developed a telescoped amidation-hydration sequence. This was a significant achievement, eliminating the need to isolate intermediate compounds and thereby reducing steps and potential waste. Solvent and reagent selection was optimised to balance yield, cost, environmental impact, and safety. Additionally, they highlighted process intensification efforts, which included reducing solvent volumes, adjusting reagent equivalents, and optimising reaction conditions (e.g., temperature adjustments) to further improve yields and reduce waste.