Development of the Commercial Manufacturing Process for Nirmatrelvir in 17 Months

A novel coronavirus was identified in 2019, associated with a pneumonia outbreak in Wuhan, China, in December of that year.1,2 Sequencing studies of the virus (SARS-CoV-2) revealed a close homology with SARS-CoV-1, the virus that caused severe acute respiratory syndrome (SARS) in 2002.3 In March 2020 a special report summarizing publications and patents in the CAS content collection related to the disease was published in this journal.4 In response to these reports, Pfizer initiated a program to identify a small molecule, oral antiviral therapy based on inhibition of the 3CL protease involved in viral replication of SARS-CoV-2. In November of 2021, Pfizer medicinal chemistry colleagues reported the discovery of PF-07321332 (nirmatrelvir), a potent, selective, and orally bioavailable inhibitor of SARSCoV-2 Mpro.5,6 The urgency for evaluating this compound in safety/toxicology studies and clinical trials, together with adoption of an aggressive, "lightspeed" development paradigm,7 led to an unprecedented demand for multikilogram quantities of this material. An overview of the project challenges is shown in Figure 1. The successful development and scale-up of an efficient chemical synthesis of nirmatrelvir allowed for progression of Paxlovid (the cotherapy of nirmatrelvir and ritonavir) from first laboratory synthesis (in July 2020) to FDA emergency use authorization8 (in December 2021), a period of just 17 months. This is a new record for Pfizer and, to our knowledge, the pharmaceutical industry. This paper will provide a high-level overview of the synthetic chemistry, supply chain, and other logistical challenges that had to be addressed to achieve this goal.