The PSE Model-Based Innovation Prize 2020

Winning paper

System model development and computer experiments for continuous API manufacturing by Boung Wook Lee*, Kehua Yin, Yangmu Chloe Liu, Alexander O’Brien of CMC Statistics, Biostatics, GlaxoSmithKline, USA; John J. Peterson, Greg S. Stockdale of Product Development & Supply, GlaxoSmithKline, USA.

Published in Chemical Engineering Research and Design, Elsevier.

Authors

Boung Wook Lee John J. Peterson Kehua Yin
Boung Wook Lee John J. Peterson Frank Yin
Greg S. Stockdale Yangmu Chloe Liu Alexander O’Brien
Greg Stockdale Chloe Liu Alexander O’Brien

Abstract

This work details development of a system/process model and usage of Computer Experiments methodology for continuous manufacturing of Active Pharmaceutical Ingredients (API). The process of interest has three interconnected continuous unit operations, with the first two being reactors and the last being an evaporator. The overall workflow detailed can be summarized as follows: a) develop mechanistic process models, b) verify/validate the model, c) convert model parameters to process parameters d) design computational grid to simulate the model – Latin hypercube design in this case, e) perform simulations, f) fit meta-model (surrogate model) to the output parameter/attribute of interest, g) analyze the meta-model using global sensitivity analysis, and h) slice and dice the model, e.g., study response surfaces of interest, for further analysis. This workflow has several practical advantages in process development, optimization, and troubleshooting, especially when the number of process inputs and/or parameters are large and/or output response surfaces are potentially complex. Phenomenological model development is detailed for biphasic reaction with large solvent volume change.

Biographies

“Tim” Boung Wook Lee*

Tim obtained his B.S. and Ph.D. in Chemical Engineering with research focused on all things multiphase reactors (scale up, mixing, dispersion, etc.). In GSK, he has held roles as System Based Modeler in Modeling & Simulation Group, Principal Statistician in CMC Statistics Group, and Process engineer & modeling scientist in Upstream Process Development Group, where his focus has been on development and implementation of mechanistic and data-driven models.

John J. Peterson

Dr. Peterson received his B.S. degree from the State University of Stony Brook with a double major in Applied Mathematics and Computer Science. He received his Ph.D. in Statistics from the Pennsylvania State University. John is an elected Fellow of the American Statistical Association, an Associate Editor of the Journal of Quality Technology, and recipient of the 2019 national AIChE QbD Drug Product award.

After retiring from GlaxoSmithKline Pharmaceuticals where he was a Senior Director in the CMC Statistics group, John heads up PDQ Research & Consulting, a statistical consulting company.

Frank Yin

Dr. Frank Yin obtained his bachelor’s degree in chemistry at Peking University in 2011 and PhD degree in Chemical Engineering at the University of Virginia in 2016 with focus on heterogeneous catalysis and reaction engineering. He joined GSK in 2016 and has delivered kinetic modeling, system modeling work packages to support the development of continuous and batch drug substance process.

Greg Stockdale

Greg has worked at GlaxoSmithKline in the statistical sciences (CMC) group for the past 16 years. He received a BS in Biology from Syracuse University and his MS in Applied Math and Statistics from Rochester Institute of Technology. Worked at Eastman Kodak where he gained valuable experience in quality and reliability engineering and was a Six-Sigma Blackbelt. He also supported development and manufacturing of optical fiber for Corning, Inc. before joining GSK. As a proven leader in CMC statistics he drives innovative, science and risk-based solutions through collaboration utilizing novel experimental designs, Bayesian methods, and machine learning, and more aimed at modernizing the approaches used in the biopharmaceutical industry.

Chloe Liu

Dr. Chloe Liu is a Senior Engineer II at Alexion Pharmaceuticals, where she uses her training as a chemical engineer to help develop synthetic processes of small molecule drug substances that are used to treat patients with rare and ultra-rare diseases. She started her career in GlaxoSmithKline, where she was fortunate to gain experiences in process modelling applications in late phase pharmaceutical development on the project featured in this work. In her spare time, Chloe enjoys exploring new hobbies such as glass blowing and sewing.

Alexander O’Brien

Alex studied Chemistry at the University of Bristol (MSci 2006) and Organic Synthesis at Imperial College London (PhD 2010). He carried out postdoctoral studies at the Max Planck Institute for Colloids and Interfaces, Berlin and The Scripps Research Institute, La Jolla CA before moving to GlaxoSmithKline, Collegeville PA in 2014 to work as a process chemist on the industrialization of continuous manufacturing technologies. Alex contributed to numerous clinical phase programs while at GSK including the development and filing of the novel therapies DUVROQ and BLENREP. In 2020, Alex moved to Merck, West Point PA as a scientist in the Regulatory CMC Post Approval group.


* Submitting author

More Information
An excellent work illustrating the use of gPROMS FormulatedProducts modelling environment for the simulation, surrogate model development and global sensitivity analysis of an integrated flowsheet for the continuous manufacturing of Active Pharmaceutical Ingredients (API).
JUDGES' COMMENT

2020 Winner Paper