(656f) Rapid Development of Nirmatrelvir Tablets Using Digital Design and Predictive Science

Nirmatrelvir is the SARS-CoV-2 Mpro inhibitor component of Paxlovid^TM. Scale-up from the first lab-scale synthesis of the drug substance to the production of hundreds of millions of tablets was achieved in a mere 18 months, roughly 8-fold faster than a typical development timeline. Application of digital design and computational models were key to enable this accelerated ‘lightspeed’ manufacturing process development and will be the focus of this presentation.

Nirmatrelvir film-coated tablets were manufactured using a conventional dry granulation batch process comprised of several key unit manufacturing operations (blending, dry granulation followed by milling, extra-granular blending, and lubrication, followed by tablet compression and film-coating) to produce the drug product. Given the lightspeed development timeline, scale-up of the process from development scale to commercial scale in a short period of time with limited supply of drug substance was extremely challenging. Timelines did not permit running the process at multiple scales to collect data and identify appropriate operational space for manufacturing of drug product with appropriate quality attributes. Instead, state-of-the-art predictive computational and machine learning models were relied on to gain process understanding, which helped to de-risk process development and scale-up to multiple commercial manufacturing sites. A schematic showing computational models representing unit operations of blending, roller compaction, tableting and coating are presented in Figure 1. This end-to-end digital workflow provides a template for rapid process development and scaleup for future small molecule drug products.