Pharmaceuticals are life-saving industrial products. Conventionally, the mainstream medications consisted of small molecules made by chemical synthesis, but in recent years the market share of biopharmaceuticals such as monoclonal antibodies has expanded at a rapid pace. Recent new developments include gene therapy and its commercialization, as well as clinical trials of induced pluripotent stem cells (iPSCs). New methodologies that can support advanced pharmaceutical manufacturing are needed.
We are conducting research on pharmaceutical PSE (Pharma PSE). This is a new field that deals with modeling, simulation, and optimization, to support decision-making in drug manufacturing. We aim at multiscale research that cannot be achieved solely by a monoscale study, by being aware of the connections among molecules and cells, processes, and the healthcare society. We are working on the following topics using both simulation and experimental approaches.
Research theme and approach
Small molecules are the most popular drugs made by chemical synthesis and are usually provided in solid dosage forms, e.g., tablets and capsules. In this field, flow chemistry and continuous manufacturing are actively studied, and new approaches to process design are needed to determine the choice of batch or continuous manufacturing. For solid drug manufacturing, we have been developing a method that enables comprehensive generation of process alternatives and their economic assessment. The research outcome is being implemented by the software package called “SoliDecision”, and a prototype version is available. Regarding granulation processes, key parameters related to product quality were successfully determined through experimental investigations. We are also conducting research on drug substance synthesis and injectable drug manufacturing from the perspective of continuous and batch processes.
Key recent publications Yamada et al., "Economic Model for Lot-Size Determination in Pharmaceutical Injectable Manufacturing", J Pharm Innov, 16, 38–52 (2021) Matsunami et al., "Superstructure-based process synthesis and economic assessment under uncertainty for solid drug product manufacturing", BMC Chem Eng, 2, 6 (2020) Matsunami et al., "Determining key parameters of continuous wet granulation for tablet quality and productivity: A case in ethenzamide", Int J Pharm, 579, 119160 (2020) Matsunami et al., "A large-scale experimental comparison of batch and continuous technologies in pharmaceutical tablet manufacturing using ethenzamide", Int J Pharm, 559, 210–219 (2019) Matsunami et al.,"Decision support method for the choice between batch and continuous technologies in solid drug product manufacturing", Ind Eng Chem Res, 57(30), 9798–9809 (2018)
|Kensaku Matsunami||Junu Kim||Masahiro Yamada||Shungo Matsueda|
Biopharmaceuticals are a new type of drug that contains, among other ingredients, cell-produced antibodies. The global market is rapidly expanding, and the trend is now for small-scale production of various products. Increasing efficiency of manufacturing processes, including changeover operations is becoming critical. With a focus on the manufacturing of injectables, we work on single-use equipment using disposable resins, and cleaning, sterilization, and decontamination of manufacturing equipment, and have developed design methods for efficient processes. We proposed a multi-objective evaluation method that considers economic performance, product quality, supply stability, and environment impacts. A prototype version of TECHoice, a tool for selecting equipment technology, is now available. We are also working on process design for the continuous production of antibodies, including new technologies such as perfusion cultivation and continuous chromatography purification.
Key recent publications Yabuta et al., "Impact of H2O2 sorption by polymers on the duration of aeration in pharmaceutical decontamination", J Pharm Sci, 109, 2767–2773 (2020) Badr and Sugiyama, "A PSE perspective for the efficient production of monoclonal antibodies: Integration of process, cell, and product design aspects", Curr Opin Chem Eng, 27, 121–128 (2020) Zeberli et al., "Approach for multicriteria equipment redesign in sterile manufacturing of biopharmaceuticals", J Pharm Innov, 15, 15–25 (2020) Shirahata et al., "Dynamic modelling, simulation and economic evaluation of two CHO cell-based production modes towards developing biopharmaceutical manufacturing processes", Chem Eng Res Des, 150, 218–233 (2019) Shirahata et al., "Multiobjective decision-support tools for the choice between single-use and multi-use technologies in sterile filling of biopharmaceuticals", Comput Chem Eng, 122, 114–128 (2019)
|Sara Badr||Kozue Okamura|
Regenerative medicine is a future treatment technology using stem cells such as iPSCs. As many clinical trials are in progress, establishing the actual processes has become urgent. We design the blueprint of the processes by making full use of simulation technologies. More specifically, we investigate the process design of aseptic filling and slow freezing for iPSCs. For aseptic filling, we proposed an approach of determining lot sizes by describing the temporal change of cell quality using probability distributions. For slow freezing, we managed to develop a design guidance by simulating the relationship between the cooling rate, the degree of dehydration, and ice crystal formation. We are involved in multiscale research that deals with cells, processes, and supply chains in one framework.
Key recent publications Hayashi et al., "Slow Freezing Process Design for Human Induced Pluripotent Stem Cells by Modeling Intracontainer Variation", Comput Chem Eng, 132, 106597 (2020) Sugiyama et al., "A distribution-based approach for determining lot sizes in the filling of human-induced pluripotent stem cells", Regen Ther, 12, 94–101 (2019)
|Yusuke Hayashi||Benedikt Scholz||Keita Hirono||Akinori Shigeyama|
In pharmaceutical processes that require strict quality control, a large number of measurement sensors are available, and electronic recording systems are in operation. The climate is ready for fully utilizing the large amounts of data obtained. We are developing methods to support process operation and improvement using data science technologies for manufacturing biopharmaceutical injectables. We proposed an approach to yield improvement based on comprehensive statistical data analyses, a cleaning method of raw data using dynamic DNA sequencing and machine learning, and a lead time improvement method using Monte Carlo simulation and global sensitivity analysis. Some of the results were implemented in an actual industrial process that was investigated in our study. We are also addressing the question of how to use “information” obtained from data as “knowledge” using chemical engineering approaches.
Key recent publications Casola et al., "Data mining algorithm for pre-processing biopharmaceutical drug product manufacturing records", Comput Chem Eng, 124, 253–269 (2019) Casola et al., "Uncertainty-conscious methodology for process performance assessment in biopharmaceutical drug product manufacturing", AIChE J, 64(4), 1272–1284 (2018) Eberle et al., "Rigorous approach to scheduling of sterile drug product manufacturing", Comput Chem Eng 94, 221–234 (2016)
|Sara Badr||Anicia Zeberli||Philipp Zuercher|
We are converting academic research into tools for business practice by developing software based on research outcomes. The following prototype versions have been released to date.
- SoliDecision（Click here for details）：This is a tool for comprehensive generation and economic evaluation of process alternatives in solid drug manufacturing. The input parameters can be represented as probability distributions, and thus the tool can assess the uncertainty from clinical development to commercial production.
- TECHoice（Click here for details）：This is a tool for decision support between single-use and multi-use technologies in aseptic filling processes. The tool can perform multi-objective assessments on the economy, environment, quality, and supply.
Development of other software packages is also in progress. We are developing commercial versions in collaboration with Todai TLO (Technology Licensing Organization).
Key recent publications Matsunami et al., "Superstructure-based process synthesis and economic assessment under uncertainty for solid drug product manufacturing", BMC Chem Eng, 2, 6 (2020) Shirahata et al., "Online decision-support tool "TECHoice" for the equipment technology choice in sterile filling processes of biopharmaceuticals", Processes, 7(7), 448 (2019)
Press releases "Superstructure-based process synthesis and economic assessment under uncertainty for solid drug product manufacturing", The University of Tokyo, February 12, 2020 "Online decision-support tool “TECHoice” for the equipment technology choice", The University of Tokyo, July 18, 2019
|Kensaku Matsunami||Yusuke Hayashi||Masahiro Yamada|
In the modern healthcare society, the trend is growing toward drug diversification. With ever more treatment options being available for various diseases, e.g., infectious, lifestyle-related, and cancer, the entire system needs to be sustained. We have initiated an analytical study for advancing and diversifying drugs from a systems perspective, and to design and operate the whole. Our aim is to explore a multiscale systems engineering approach that can address challenges at all levels, encompassing development of cells and complex molecules and their application in healthcare, by treating various processes, such as research and development (R&D), manufacturing, and supply of drugs, as well as diagnosis and treatment of patients, in one framework. The main discussion forum will be in the Systems Med & Pharma Group, Division of Systems, Information, and Simulation Technologies (SIS) in the Society of Chemical Engineers (SCEJ), Japan, which was established in March 2020, and in the Pharma PSE COP of the International Society for Pharmaceutical Engineering (ISPE) Japan.External links Systems Med & Pharma Group in the SIS Division of SCEJ
Pharma PSE COP in ISPE Japan