Advanced therapy medicinal products (ATMPs) are revolutionizing personalized medicine, offering targeted treatments with long-lasting effects. Traditionally produced at centralized facilities, ATMPs often lose potency due to freezing and transportation delays.
Point-of-care (POC) manufacturing is transforming the field by enabling hospitals to produce ATMPs onsite, ensuring immediate delivery and preserving therapeutic efficacy. As adoption grows, key advancements are shaping the future of POC ATMP production.
This listicle highlights the latest trends in POC manufacturing, from automation to material innovations, and explores how these breakthroughs are enhancing scalability, quality and clinical integration.
Download this listicle to explore:
- The role of automation and digital tools in streamlining ATMP production
- Key challenges in infrastructure, staffing and logistics for POC manufacturing
- Innovations in hydrogels and their impact on advanced therapies
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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.
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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.
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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.
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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.
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