Developments in Point-of-Care Manufacture of Advanced Therapies

1 Listicle Advanced therapy medicinal products (ATMPs) represent a frontier in personalized medicine and regenerative healthcare. This innovative medical treatment utilizes gene therapy, somatic-cell therapy or tissue engineering – sometimes designed based on each patient's clinical or even genetic features – aiming for long-lasting or permanent effects to treat disease. Currently, ATMPs are manufactured at a few centralized sites, meaning the starting materials and/or final products are generally frozen for transportation – often resulting in reduced therapy potency. Therefore, the therapy must be delivered to the patient some minutes or seconds after manufacture. Point-of-care (POC) manufacturing aims to overcome this limitation by producing ATMPs in hospitals. This is especially important when it needs to be delivered to the patient without delay and there is no time for storing the medicine. POC manufacturing enables hospitals to be in contact with cutting-edge products, refining the therapeutic skills that they hold and increasing the range of therapies made available to patients. POC ATMPs remain at the cutting edge of medical innovation, with ongoing advancements enhancing the ATMPs and streamlining the administration processes involved in POC manufacturing. In this listicle, we explore some of the latest trends and innovations shaping the field of POC manufacturing for ATMPs. POC manufacturing readiness and decentralization of manufacturing systems In 1974, NASA proposed the idea of technology readiness levels to assess the maturity of certain technologies. 1 Adopted by the US Department of Defense, manufacturing readiness levels were then introduced, with the most mature stage (i.e., highest readiness level) detailing all materials, equipment, facilities and personnel are in place and have met full-rate production requirements.2 Developments in Point-of-Care Manufacture of Advanced Therapies Isabel Ely, PhD Manufacturing readiness levels The manufacturing readiness level serves as a metric to evaluate the maturity of manufacturing processes, analogous to technology readiness levels used to gauge technological development. Manufacturing readiness levels provide quantitative measures to assess the readiness of a technology, component or system specifically from a manufacturing standpoint. DEVELOPMENTS IN POINT-OF-CARE MANUFACTURE OF ADVANCED THERAPIES 2 Listicle Now, manufacturing readiness is being applied to a range of technology fields – with recent applications in the biomedical field and POC manufacturing of ATMPs.3 Over the past few decades, UK hospitals have produced ATMPs in limited quantities. In the future, this production is expected to become more seamlessly integrated into routine clinical practices, with the technical and regulatory expertise hospitals have gained forming the basis for scaling up and increasing production frequency in the coming years – known as POC manufacturing readiness. Achieving POC manufacturing readiness is necessary to produce POC ATMPs, in which several resources, skills and institutional processes must be present for their success. The three main aspects of POC manufacturing readiness include staff and institutional procedures, infrastructure and transportation.3 Staff and institutional procedures The adverse effects of ATMPs can be severe, meaning their quality must be strictly monitored and individuals who conduct ATMP POC manufacturing need to be highly skilled. Often, this central role is played by a “qualified person” (QP) – a professional indicated on the manufacturer’s license as being legally responsible for ensuring that the product has been manufactured in line with quality and efficacy parameters. It is generally believed there is an insufficient number of QPs in the UK, especially in hospitals, with only 21 hospital-based QPs being registered since 2011.3 Hospitals have, therefore, attempted to advance other staffing aspects to improve manufacturing readiness, such as the creation and refinement of ATMP committees.3 These committees play a liaising role in ATMP manufacturing processes due to the various departments and facilities involved (i.e., testing laboratories, pharmacies and clinical wards). When ATMP POC manufacture becomes more frequent, these ATMP committees will play a decisive role, either by having their responsibilities expanded or by serving as a model for the creation of even more specialized committees in hospitals. Infrastructure Manufacturing cell and gene therapies undoubtedly incur high costs for infrastructure changes, which could be even more apparent for hospitals, as they were not originally designed to host ATMP manufacturing activities. Therefore, today’s hospital staff need to find ways of accommodating POC manufacturing activities in a clinical setting. Hospital laboratories will also play a key role in ATMP POC manufacture, as they may need to be mobilized for performing tests on tissues and cells as part of the quality control associated with therapy manufacture. There is also the obvious need for equipment. ATMPs ideally need to be produced in a closed system where starting materials and reagents are processed within machines, with little human manipulation, so the risk of contamination and human errors is reduced.4 Further, it is sometimes possible to freeze starting materials and final products, which requires equipment for accurate temperature control so that living structures are not damaged.5 Transportation The production of ATMPs in hospitals entails procuring a quite long list of products, be it for collection of starting materials, quality control or manufacture itself – meaning hospitals need to engage in a series of external relations. DEVELOPMENTS IN POINT-OF-CARE MANUFACTURE OF ADVANCED THERAPIES 3 Listicle Starting materials and final products cannot be transported easily due to the presence of fragile living structures such as cells, meaning factors such as temperature and vibration need to be controlled if it is necessary to transport cells and tissues. Currently, hospitals procuring or shipping biological materials use commercial courier services. Evolving airline service strategies and security policies have complicated the model of product transport, so other methods, such as overnight shipping services, have been explored to assess their feasibility.6 These courier companies have designed specialized package tracking and monitoring programs developed specifically for healthcare and scientific businesses, which hospitals have also used. Further, hospitals have tried to ensure quality in their relations with companies transporting materials and samples by using ISO certifications. Automation and digital integration Currently, manufacturing processes for ATMPs are largely manual and performed in planar culture systems – processes that are highly laborious and difficult to scale up. Resultingly, such processes are prone to human error and can result in batch-to-batch variability, high manufacturing costs, high risk of contamination and batch loss.7 Manufacturing products following good manufacturing practice (GMP) guidelines will minimize process variability and variation in factors such as cell quality. However, full GMP compliance in the ATMP realm is currently challenging – particularly due to the increased difficulty in sourcing compliant starting material. Automation has been increasingly integrated into biopharmaceutical industries, particularly cell and gene therapies.8 Automation reduces human error, increases scalability and reduces production time. Digital tools such as real-time monitoring and artificial intelligence for process optimization are also increasingly being adopted. POC manufacturing can experience in-process variation from human handling which can subsequently impact product quality. Even when following stringent protocols, variation is observed between different handlers resulting from minor procedure imprecisions, such as variation in pipetting technique or slight deviations in incubation times. Automation can eliminate such in-process variation in multiple ways, such as through robotic arms to repeatedly and consistently perform pipetting or a mixing action. Even cell culture sub-processes (e.g., medium changes) can be automated, allowing for consistent speed, force and accuracy – thus leading to reduced variability and increased process reliability. Integration and automation of process analytics can remove the subjectivity of processing decisions, making more sophisticated processing rules possible. An example of this is the development of pattern recognition and image processing software that can be used to objectively determine confluence.8 Cell culture protocols rely on passaging adherent cells when they reach a confluence level of 80-90%. Confluency is typically estimated through microscopic visualization with the percentage estimation entirely subjective and dependent on the individual. Employing automated image acquisition and processing can allow for adaptive processing based on objective and comprehensible criteria.9 Automation integration in POC manufacturing of ATMPs faces several challenges including the development of technologically advanced interfaces, compliance with good manufacturing practices, the need to extensively validate automated systems and how to limit the effects on ATMP production if there is ever system downtime. Addressing these challenges requires a combination of advanced engineering, robust software solutions, regulatory foresight and interdisciplinary collaboration to realize the full potential of automation in POC ATMP manufacturing. DEVELOPMENTS IN POINT-OF-CARE MANUFACTURE OF ADVANCED THERAPIES 4 Listicle Advancing ATMPs techniques: innovations in hydrogels Innovations of new techniques and products continue to emerge in ATMPs. Hydrogels – which are highly hydrated three-dimensional polymeric matrices – are one of these recent innovations that hold substantial promise in biomedical fields due to their biocompatible, chemically modifiable and physically tunable nature.10 For example, hydrogels have demonstrated the potential to support cell viability and functionalities and facilitate targeted delivery and controlled release of therapeutic agents.11,12,13 Synthesis and modification technologies used today have matured enough to advance hydrogel material significantly, moving away from the simplistic structures exhibited by early-generation hydrogels. Now, hydrogels have been developed to react to specific biological and pathological stimuli such as pH, temperature and reactive oxygen species, allowing the intricate requirements of specific diseases and heightened clinical demands to be met.14,15,16 Furthermore, the stable structure hydrogels experience upon water absorption acts as a delivery platform for bioactive substances and pharmaceuticals. Hydrogels can also mimic the extracellular matrix environment, promoting the growth and survival of encapsulated cells.17 The development of biodegradable variants of hydrogels, either allowing degradation over time or under specific stimuli, enables the release of their contents without eliciting toxic side effects to surrounding tissues.18 Injectable hydrogels further ensure sustained and controlled drug release at the targeted site, significantly reducing the adverse reactions associated with systemic drug exposure.19 Although significant advancements have been made in the use of hydrogels, which contribute to enhancing POC ATMPs, challenges remain. Many studies focused on hydrogel-based cell therapies remain in the nascent stages, with research progression hindered by technical complexities, biological intricacies, safety concerns, funding limitations and challenges of interdisciplinary collaboration.20 Importantly, extrapolation of results from in vitro and animal models to humans is complicated by biological variability, necessitating a comprehensive safety assessment of hydrogels to prevent adverse effects on patients. Injectable hydrogels are viewed as the most promising candidates for clinical translation. However, challenges in understanding biological degradation mechanisms and injection timing require further clarification. The mis-injection of hydrogels into critical areas, such as major blood vessels therefore increasing the risk of embolism, warrants the need for protocols to mitigate such risks and highlights the complexity of clinical complexity. References 1. Sadin SR, Povinelli FP, Rosen R. 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