A greener pharmaceutical industry

Nirmatrelvir

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 decreasw 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.