**2. Review**

The review by Marianthi Ierapetritou et al. [19] informs the reader of the latest development and application of emerging technologies of Industry 4.0, enabling the realization of digital twins (D.T.). D.T.s is a crucial development of the close integration of manufacturing information and physical resources that raise much attention across industries. The critical parts of a fully developed D.T. include the physical and virtual components and the interlinked data communication channels. Following the development of Internet of Things (IoT) technologies, there are many applications of D.T. in various industries, but the progress is lagging for pharmaceutical and biopharmaceutical manufacturing. This review paper summarizes the current state of D.T. in the two application scenarios, providing insights to stakeholders and highlighting possible challenges and solutions to implementing a fully integrated D.T. In pharmaceutical manufacturing, building blocks of a D.T., including process analytical technology (PAT) methods, data managemen<sup>t</sup> systems, unit operations, flowsheet models, system analyses methods, and integration approaches, have all been developed in the last few years, but gaps in PAT accuracy, real-time model computation, model maintenance capabilities, real-time data communication, as well as concerns in data security and confidentiality, are preventing the full integration of all the components. Several insights seem appropriate to solve these challenges. First, developing new tools such as near-infrared spectroscopy (NIRS) and in-line U.V. spectroscopy, iterative optimization technologies, and different online adaptive methodologies can help resolve the existing issues in PAT methods. Second, efficient algorithms and reduced-order modeling approaches need further study for process models to reduce simulation time to achieve real-time computation. Third, adaptive modeling methods with online streaming data will be under further investigation in model maintenance. Third, to have a fully integrated and automated D.T., the information flow from the virtual component to the physical plant also must be established. Moreover, the virtual plant should be able to change system settings and control the physical plant to help achieve an optimized process within the design space. Ideally, all these components require appropriate physical and virtual security protocols.
