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The industry considers applying automation and digitalization lessons learned during the COVID-19 pandemic to enhance workflows.
The COVID-19 pandemic has made the complex processes of cell and gene therapy (CGT) development more challenging with severe shortages of raw materials, a decline in R&D activities, and a reduction in manufacturing capacity, which have exacerbated pre-existing challenges. Fortunately, biotherapeutics manufacturers have learned from the pandemic, with many companies turning toward automation technologies and digital connectivity to reduce human touchpoints and mitigate the impact of future pandemics. Advancements in automation and digitalization technologies will change the cultural tide of data recording and management as well as ease regulatory burdens throughout the manufacturing process.
Good manufacturing practice (GMP) protocols require a large team to manage, manufacture, and oversee a given manufacturing campaign. Thus, staff will always be needed. However, minimizing the number of people in a GMP facility at any given time through automation and digital connectivity allows operators and quality personnel to be “virtually present,” without physical proximity.
Biopharmaceutical manufacturing facilities already use a wide range of automation solutions to optimize their workflows, increase throughput, and reduce human error. Robotic instrumentation such as automated liquid handling systems ensure precision and repeatability by accurately performing routine pipetting and mixing procedures (1). Robotic platforms can consistently perform cell culture processes including media exchange, feeding, and passaging, with reduced variability and increased reliability. However, the applicability of these platforms to cell and gene therapies is still being established (2). Inconsistency in production processes, most notably in manual handling tasks, is a major source of human error where automation can potentially help, but the inherent variability arising from multiple donors or patients, which results in cell heterogeneity, continues to be a challenge (3). New technologies are therefore needed to address this and other issues, such as inefficient scalability for allogeneic therapies, poor transferability of CGT workflows to stirred tank bioreactors, batch-to-batch discrepancies, open workflows and multiple human interventions, as theyincrease the risk of contamination and can lead to failures, product loss, and increased costs (2).
Other sectors have demonstrated that reducing hands-on time through automation offers a way to reduce human error, obtain more reproducible results, achieve standardization, and improve the critical quality attributes of the final product. These benefits could be achieved through the automation of a single step, multiple automated steps integrated together in a workflow, or through completely automated workflows (2). Ideally, fully automated platforms would offer an end-to-end solution from donor to product with continuous validation and monitoring for ongoing process optimization activities (2). These systems could be fully closed, eliminating user contact to reduce the chance of contamination and human error (2). Unfortunately, automation platforms designed for biologics and monoclonal antibodies lack the versatility and flexibility required for CGT applications (2). Cell therapies that are living pharmaceuticals require altered, fit-for-purpose manufacturing solutions.
Efforts to enhance these technologies are ongoing, and the industry is now beginning to see the emergence of platforms that incorporate bioreactor and scaffold technologies to provide complete automation for both adherent and suspension cell cultures (2). The next step for system developers is to identify the many factors that contribute to enhancing a bioprocessing strategy and to implement these into their workflows (4). For CGT, the differences between autologous and allogeneic therapies must also be considered. Autologous therapies can benefit from a decentralized approach or a hybrid approach, while allogeneic therapies are more compatible to centralized manufacturing, which is easier to scale up and will make the initial investment in automation solutions more cost effective (5).
Digital connectivity for manufacturing workflows offers opportunities to reduce the number of human touch points, minimize deviations, and improve patient outcomes. Remote process monitoring and optimization are becoming increasingly common in biopharmaceuticals and could easily be translated into CGT development (6). Real-time monitoring and continuous feedback can not only speed up workflows, but could also greatly improve standardization, quality, and reproducibility. With the large degrees of variability existing in CGT development, in-line sensors and analytics could enable live monitoring of processes and potentially lead to better methods for increased accuracy (6).
Digitalization can also streamline the GMP record-keeping process and quality oversight functions. It can reduce the significant amount of paperwork by automating a workflow and digitalizing documentation and data management. This digitalization will provide superior traceability of all manufacturing steps, improve deviation management, and de-risk the process (3). In addition, digitalization can speed up time to market and regulatory procedures through virtual audits. The potential of this approach has been especially highlighted during the current pandemic, where site inspections have been necessarily limited (7). Lastly, digital platforms and data integration tools that monitor chain of custody and chain of identity by creating a “digital twin” of the physical flow of raw materials and products as they circulate around the patient can play a significant role in the success of a complex supply chain process (8).
Digitalization and automation promise to generate large amounts of information and data, which will simplify identification of errors in a workflow and can be used to improve bioprocesses, leading to higher quality products at an accelerated pace (6). More importantly, with the implementation of cloud-based platforms, data could easily be accessed and shared, internally within a company, or between international collaborators (6). Sharing clinical and pre-clinical data globally, especially in CGT research and development into rare diseases that currently lack treatments, could also help to improve efficiency and reduce duplication of efforts (7).
The need for automation and reduction of human touch points in CGT development has been at the forefront of the collective industry mind for some time, and the CGT sector has witnessed the benefits that other biopharmaceutical sectors are enjoying from automating their workflows and modernizing into the digital era. Now CGT development must follow the same path. The COVID-19 pandemic may have highlighted the pitfalls of current practices, but it has also shown how quickly the industry can adapt to continue vital research and manufacturing.
1. M.N. Doulgkeroglou, et al., Front Bioeng Biotechnol. 8, 811 (2020).
2. P. Moutsatsou, et al., Biotechnol Lett. 41, 1245–1253 (2019).
3. J. Ochs and N. Konig, Cell Gene Therapy Insights 2 (4) 499–506 (2016).
4. O. Ball, et al., Cytotherapy 20 (4) 592–599 (2018).
5. A. Stone, “Automation is Key in Cell and Gene Therapy Manufacturing,” www.reutersevents.com, Oct. 30, 2020.
6. U. Saplakoglu, et al., Cell and Gene Therapy Insights 7 (4) 503–518 (2021).
7. T. Qiu, et al., Drug Discov Today S1359–6446 (21) 00207–5 (2021).
8. C. Reed, “The Need For Digital Networks To Support Cell And Gene Therapies,” www.cellandgene.com, Dec. 30, 2019.
Nirupama (Rupa) Pike, PhD, is director of Enterprise Science and Innovation Partnerships at Thermo Fisher Scientific.
Vol. 34, No. 9
When referring to this article, please cite it as N. Pike, “Reevaluating Cell and Gene Therapy Development,” BioPharm International 34 (9) 18–20 (2021).