From laboratory to production: a journey of GMP implementation for controlled ice nucleation in Amgen’s manufacturing network

Abstract Controlled ice nucleation (CIN) offers a transformational approach to pharmaceutical lyophilization by inducing simultaneous nucleation at a predetermined temperature, thereby reducing cake resistance (Rp) and intra-batch variability. In this work, Amgen’s network-wide implementation of ice-fog CIN across production freeze dryers (shelf area 10–42 m²) is described, encompassing engineering retrofits, control system integration, and commissioning/qualification strategies. Comparative analyses of laboratory-scale (shelf area 0.74 m²) and production-scale runs demonstrated consistent post-nucleation cooling rates (≤ 1 °C/hr difference) and Rp ratios (laboratory/production) of 1.2–1.6 for the tested formulations and vials size, indicating lower Rp at production-scale. In-silico heat and mass transfer modeling, parameterized with laboratory data, accurately predicted primary drying temperatures within 1.5 °C of measurements. Production-scale CIN cycles exhibited higher Pirani slopes (≈ 1.62 µbar/hr vs. ≈0.62 µbar/hr in non-CIN), reflecting faster and more uniform sublimation. In CIN cycles, primary and secondary drying phases were of similar duration, emphasizing the need to optimize secondary drying conditions. Finally, Automated visual inspection (AVI) recipes were refined for CIN lyophilized drug product using an offline AVI station, enabling rapid baseline recipe development. Overall, this represents the largest GMP deployment of CIN to date, demonstrating enhanced process robustness, cycle efficiency, scalability, and providing a practical framework for wider adoption. Graphical Abstract