IBI - Cell & Gene Therapy

Subsection:

Cell and Gene Therapy

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Application Talking PointNote

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Particulates in Cell and Gene Therapies

Over the past few months, I’ve had numerous conversations at work and conferences about particulates in cell and gene therapies. These discussions have highlighted to me two things. Firstly, the importance of identifying both inorganic and organic particulates in cell-based therapies. Secondly, many in the field may not be fully aware of the existing options for this identification, which has significant implications for the quality and safety of these advanced therapies.

Challenges in Cell-based Therapeutic Products Building on these insights, it’s clear that manufacturing finished products for cell-based therapies presents unique challenges.

These therapies often involve living cells, introducing complexities not found in traditional pharmaceuticals. The additional complexity arises from the presence of living cells and their surrounding secretome. For some therapeutics, this secretome is essential for their function and naturally contains organic particulates. Despite these complexities, ensuring the purity and integrity of these products is crucial, as any contaminants, including particulates, can significantly impact their efficacy and safety.

Another challenge caused by the presence of living cells and their surrounding secretome is that it is often not possible to test finished product for sub-visible particles. Therefore, it is essential that a baseline for sub-visible and visible particulate levels is established. To create a baseline, a comprehensive suite of testing of all materials and processes involved in the manufacture of finished product is typically performed. To ensure that the whole manufacturing process is tested, a mock run where the entire manufacturing process without growing cells allows the flushed fluid to be tested for particulates. At this stage, sub-visible, visible and even endotoxin testing may be performed. The data from this mock run helps in understanding the typical levels of particulates present, assessing the risk each component poses and implementing strategies to control this risk. It will also give the reassurance and confidence that baseline particulate levels are acceptable before the actual product is processed.

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While the complexity of a cell-based therapeutic poses challenges when assessing particulates in the final product, in addition to establishing a baseline level generated by the manufacturing process, incoming raw materials should still be assessed for particulates. The materials used to produce the therapeutic will vary but often include common reagents such as DMSO, DPBS, and EDTA. These reagents should be assessed for particulates upon arrival and by screening the reagents before they are used in the manufacturing process means that additional particulates are not being introduce into the process.

When the likely particulate level produced during a manufacturing run has been determined, incoming raw materials analysed, and the risk is at a low and acceptable level. The finished product would still need to be assess for the presence of any visible foreign bodies. During this analysis, any extrinsic object in the samples should be investigated.

Often these bodies are a fibrous material and could contain protein, silicone and non-silicone based plastics or a range of all three. Identifying these foreign bodies are crucial as they may be indicative of a fault or contamination occurring during the manufacturing process.

With foreign body analysis, the presence of living cells and their secretome, again adds complexity. Typically, analysis would involve running the sample through the particle counter and isolation of the foreign body would require passing the sample through various filters. In the case of cell-based samples, both the particle counter and filters with small pore sizes would clog. In addition, if the cell-based sample is run through a filter with a bigger pore size to avoid clogging, there would be an inherent risk that some particles are lost.

Once the foreign body has been isolated, work on identifying it can proceed. A plethora of analytical techniques can be implemented to determine the chemical or elemental composition of the extrinsic material. For elemental analysis, SEM and X-ray microanalysis are typically performed. For chemical composition, two complementary methods Fourier-transform infrared (FTIR) or RAMAN spectroscopy can be used. When single use plastic manufacturing consumables are used, identification

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Talking Point can be further enhanced by collecting and keeping a library of all components used in the manufacturing process. Once a foreign body has been isolated, both the foreign body and library database can then be spectroscopically analysed. If an exact match is generated, then this can help determine where the source of the particulate has come from.

Techniques and Approaches After addressing the challenges, it is crucial to understand the advanced techniques and approaches used to identify particulates: •

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Fourier-transform Infrared (FTIR) Spectroscopy: FTIR spectroscopy is a powerful analytical technique used to obtain the infrared spectrum of absorption or emission of a solid, liquid, or gas. It measures the intensity of infrared light absorbed by a sample at different wavelengths. This method is particularly effective for identifying inorganic particulates, as it can detect specific vibrational modes of chemical bonds. Each inorganic particulate has a unique spectral fingerprint, allowing for precise identification.

By creating a library of all inorganic compounds found in the manufacturing process, the source of particulate contamination can be identified quickly and efficiently.

Raman Spectroscopy: Complementary to FTIR, Raman spectroscopy is especially useful for materials rich in water, which can be challenging to analyse using FTIR. Raman spectroscopy provides detailed information about molecular vibrations, making it effective for identifying both organic and inorganic particulates.

Scanning Electron Microscopy (SEM): SEM examines the surface morphology and ultrastructure. It provides high-resolution images and, when combined with energydispersive X-ray spectroscopy (EDS), determines the elemental composition of the particulates.

Light Obscuration and Flow Imaging: These techniques count and size subvisible particulates in a sample. They are particularly useful for monitoring the presence of particulates in therapeutic proteins and other biopharmaceuticals.

Confocal Microscopy: Confocal microscopy allows for high-resolution imaging of particulates and their distribution within a sample. It is often used in conjunction with fluorescent stains to differentiate between different types of particulates.

HIAC Particle Counting: For therapeutic proteins, smaller volumes can be tested using HIAC particle counters to measure protein aggregation and particulate formation.

Practical Considerations Implementing these techniques requires careful planning and execution. Here are some practical considerations to ensure effective particulate identification: •

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Sample Collection and Preparation: Samples must be collected and prepared in a way that prevents additional contamination. This includes using clean containers and avoiding procedures that might introduce particulates.

Method Validation and Standardisation: Ensuring that the methods used for particulate analysis are validated and standardised is crucial. This ensures consistency and reliability in the results.

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•

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Comparing to Controls: Comparing particulate samples to controls is important to determine they are intrinsic to the product or extrinsic contaminants.

Rapid Identification and Response: Once particulates are identified, it’s important to respond quickly to address the source of contamination. This might involve adjusting manufacturing processes or sourcing materials from different suppliers.

Future Directions Looking ahead, the field of particulate identification in cell and gene therapies is continuously evolving. Advances in technology and methodologies are improving the accuracy and efficiency of particulate analysis. Some future directions include: •

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Automation and High-throughput Analysis: Developing automation and high-throughput analysis techniques can speed up the process of particulate identification and characterisation, allowing for faster and more efficient quality control.

Advanced Imaging Techniques: Emerging imaging techniques, such as super-resolution microscopy, provide even greater detail and accuracy in particulate analysis.

Integration with Other Analytical Methods: Integrating particulate identification with other analytical methods, such as proteomics and genomics, offers a more comprehensive understanding of the sources and impacts of particulates in cell and gene therapies.

Conclusion In summary, identifying particulates in cell and gene therapies is a critical aspect of ensuring the quality, safety, and efficacy of these advanced treatments. By combining advanced analytical techniques and practical approaches, manufacturers can effectively identify and address particulate contamination. This ultimately leads to delivering safer and more effective therapies to patients. Establishing a baseline through thorough testing of all materials and processes involved in production is essential.

This proactive approach helps maintain the integrity of the final product and adhere to stringent regulatory standards.

Acknowledgements I would like to thank my RSSL colleague who specialises in particulate analysis, Yohanes Tamene, for his valuable insights and contribution to this work.

Alistair Michel Alistair Michel is an immunologist with a BSc (Hons) from the University of Edinburgh and an MSc from Imperial College London.

He is a member of the British Society of Immunologists and the Royal Society of Biology. With over 20 years of experience as a bioanalytical scientist, he specialises in developing, validating, and optimising methods in GxP-compliant laboratories, focusing on ELISA and immunoassays. At Reading Scientific Services Ltd, Alistair serves as the technical lead for complex bioanalytical projects, delivering tailored solutions to address unique client challenges.

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Application Cell and Therapy Note

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Exploring Cell & Gene Therapies Through the Ages: How

Past Cell and Gene Advancements are Shaping Tomorrow’s Medicines Cell and gene therapies (C&GTs) are revolutionising medicine, offering the tantalising prospect of cures for diseases once considered incurable. This remarkable field has experienced rapid expansion, evolving from tentative experimental trials to groundbreaking U.S. Food and Drug Administration (FDA) approvals that have captured the world’s attention. But this journey hasn’t been without challenges. It’s a story of bold innovation and the unwavering determination to overcome significant hurdles.

In this article, Bill Vincent, a seasoned C&GT biotech founder and CEO, explores the key milestones that have shaped this dynamic field. He delves into the pivotal breakthroughs and setbacks fuelled by the relentless pursuit of scientific progress and the unyielding hope for a healthier tomorrow and examines the promising future that lies ahead.

Reimagining Modern Medicine with C&GTs The C&GTs space is experiencing a surge of innovation and growth, poised to redefine the landscape of modern medicine.

In 2023, C&GTs accounted for a remarkable 10% of all novel drug approvals by the FDA, up from 7% and 6% in 2022 and 2021, respectively.1 This trend underscores the accelerating pace of discovery and development in this field, with a robust approval pipeline promising even more transformative therapies in the years ahead.

Market projections are equally optimistic. The global C&GT market, valued at an impressive $18.13 billion in 2023, is expected to reach an estimated $97.33 billion by 2033.2 This represents a remarkable compound annual growth rate (CAGR) of 18.3% from 2024 to 2033, signaling a burgeoning industry brimming with potential.3 Groundbreaking advancements are driving this growth, offering the opportunity to transform the treatment landscape for previously intractable diseases. In recent years, we have witnessed the emergence of novel therapies offering newfound hope for patients battling conditions like spinal muscular atrophy (SMA), hemophilia and sickle cell disease.4–6 As researchers and clinicians continue to push the boundaries of scientific understanding, we can anticipate a future where these therapies play an increasingly pivotal role in transforming patient care and offering a brighter outlook to countless individuals worldwide.

Building on a Foundation of Innovation The rapidly growing C&GT space is built upon decades of pioneering research and bold experimentation. Even before the full complexities of DNA were understood, scientists were exploring the therapeutic potential of cell-based interventions.

Landmark events such as the first attempt to treat aplastic anemia 60 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

with bone marrow injections in 1939, laid the groundwork for the field’s evolution.7 In 1957, researchers attempted the first bone marrow stem cell transplant from a donor to a patient. Although there were complications due to immune system responses, this pioneering treatment highlighted the critical importance of ensuring compatibility between donor and recipient tissues.

This spurred further research into the complex interactions between the immune systems of donors and recipients.8 However, progress in this field has not been without its challenges, particularly surrounding immunogenicity. The unfortunate 1999 death of Jesse Gelsinger, who experienced a severe immune reaction to the vector used in a gene therapy trial, served as a grave reminder of the potential risks associated with these treatments and emphasised the critical need for strict safety measures.9 Additionally, the unexpected development of leukemia in some patients taking part in several gene therapy trials in the early 2000s underscored the importance of refining gene delivery methods to minimise the risk of unintended genetic changes.10 These setbacks, while undeniably difficult to overcome, have driven crucial advancements in patient safety and the effectiveness of treatments.

Recent Advances Expanding the C&GT Space Recent advancements have propelled the C&GT field into an era of unprecedented promise. Building upon the foundation laid by pioneering researchers, scientists and clinicians are leveraging cutting-edge technologies to address the limitations of traditional approaches and expand the therapeutic potential of C&GTs. From enhancing safety and efficacy to improving accessibility and affordability, these advancements are paving the way for a future where C&GTs are a cornerstone of modern medicine.

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Safer Gene Delivery A pivotal step toward safer gene delivery was marked by the introduction of self-inactivating lentiviral vectors (LVVs) in 2010.11 These innovative vectors, designed to minimise the risk of unintended genetic changes, have significantly enhanced the safety profile of gene therapies.

The field’s unwavering commitment to progress is evident in the ongoing research focused on refining viral vector designs, optimising immune modulation strategies and developing even more precise gene editing tools. For example, researchers are utilising in silico approaches to predict novel capsid designs with properties that could lead to better targeting of specific tissues, improved transduction efficiency and reduced off-target effects.12,13 The development of refined separation methods is also enabling more efficient isolation of full capsids, minimising Winter 2024 Volume 7 Issue 4

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Application Cell and Therapy Note the risk of adverse reactions associated with empty capsids.

Concurrently, the engineering of specialised cell lines designed to package full capsids more effectively is further enhancing the quality, yield and potency of viral vectors.

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Enhancing Specificity The pursuit of enhanced specificity in C&GT therapies is driving a wave of innovation across multiple fronts. Novel adeno-associated virus (AAV) serotypes and engineered capsids are being developed to improve targeting and efficiency, enabling more precise delivery of therapeutic payloads to specific tissues and cell types.14 The emergence of lipid nanoparticles (LNPs) as an alternative to viral vectors offers the potential for tissue-specific and targeted delivery while reducing the risk of adverse immune responses. For specialised applications like retinal gene therapy, alternative delivery methods are also being explored to overcome anatomical barriers and achieve targeted transduction.15 Delivering ”Off-the-shelf” Potential Allogeneic therapies, often referred to as “off-the-shelf” treatments, are set to transform the C&GT landscape.

By utilising cells from healthy donors, these therapies offer the promise of broader patient access and reduced costs compared to personalised autologous approaches.

The ability to manufacture and store allogeneic cell products in advance eliminates the need for lengthy and expensive patient-specific cell processing, making these life-saving treatments more readily available to a wider population.

However, allogeneic therapies present unique challenges, including the risk of graft-versus-host disease (GvHD) and

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ensuring consistent cell quality across different batches. To address these hurdles, researchers are exploring innovative strategies such as developing universal donor cell lines engineered to circumvent GvHD, refining manufacturing processes to enhance scalability and implementing rigorous quality control measures to ensure product consistency.16–18 •

Embracing the Power of Gene Editing Over the past decade, the C&GT field has experienced a remarkable acceleration in innovation, with groundbreaking discoveries and technological advancements swiftly leading to approved therapies. A pivotal moment in this journey was the development of CRISPR/Cas9 in 2012, a revolutionary gene editing technology that has redefined genetic manipulation.19 With its ability to precisely target and modify genetic material, CRISPR/Cas9 holds immense promise for correcting disease-causing mutations and enhancing therapeutic outcomes. The transformative potential of CRISPR is exemplified by its rapid translation from the lab to the clinic. In just 11 years, the first FDA-approved therapy utilising CRISPR/Cas9 (marketed as CTX001™ and now Lovo-cel™), was approved for treating sickle cell disease.5 This remarkable achievement underscores the game-changing impact of CRISPR and its potential to reshape the future of medicine.

As the C&GT space rapidly evolves on the back of technical and scientific advancements, a collaborative approach will be paramount to realising the full potential of these therapies.

Open dialogue and knowledge sharing between researchers, clinicians, manufacturers and regulators are essential to

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Cell and Gene Therapy navigate the complexities and address the formidable challenges in their production, including scalability, variability and regulatory compliance. By fostering collaboration and transparency, stakeholders across the C&GT ecosystem can leverage advancements, streamline development processes and ensure the safe and effective delivery of these transformative therapies to patients worldwide.

Ongoing Evolution and Unforeseen Possibilities The current C&GT landscape is nothing short of remarkable, with over 30 gene therapies and more than 65 non-genetically modified cell therapies already approved globally.20 The field shows no signs of slowing down; new technologies and therapies are emerging at a breathtaking pace. Just this year, a novel gene editing technique derived from bacterial “jumping genes” has captured the imagination of researchers, offering the potential to overcome some of the limitations of CRISPR.21 The future of medicine is being rewritten with the advent of increasingly powerful C&GTs, but the road to widespread adoption will be paved with challenges. To navigate complexities surrounding scalability, variability and regulatory compliance, the C&GT industry must embrace collaboration, sharing insights and knowledge to help accelerate and broaden access to life-changing C&GTs. REFERENCES 1.

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6.

7.

8.

9.

10.

11.

12.

13.

14.

https://www.cellandgene.com/doc/2024-market-outlook-for-cellgene-therapies-0001 https://www.novaoneadvisor.com/report/cell-and-gene-therapymarket https://www.precedenceresearch.com/cell-and-gene-therapymarket https://www.fda.gov/vaccines-blood-biologics/zolgensma https://www.fda.gov/vaccines-blood-biologics/vaccines/hemgenix https://www.fda.gov/vaccines-blood-biologics/casgevy George W. Santos, History of bone marrow transplantation, Clinics in Haematology, Volume 12, Issue 3, 1983, Pages 611-639, ISSN 0308-2261. https://doi.org/10.1016/S0308-2261(83)80003-4. https://ascopost.com/issues/july-10-2016/the-age-of-the-atomichematologistsoncologists/ Sibbald B. Death but one unintended consequence of gene-therapy trial. CMAJ. 2001 May 29;164(11):1612. PMID: 11402803; PMCID: PMC81135.

Maetzig T, Galla M, Baum C, Schambach A. Gammaretroviral vectors: biology, technology and application. Viruses. 2011 Jun;3(6):677713. doi: 10.3390/v3060677. Epub 2011 Jun 3. PMID: 21994751; PMCID: PMC3185771.

Cavazzana-Calvo M, et al. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature.

2010 Sep 16;467(7313):318-22. doi: 10.1038/nature09328. PMID: 20844535; PMCID: PMC3355472.

Wang D, Tai PWL, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov. 2019 May;18(5):358378. doi: 10.1038/s41573-019-0012-9. PMID: 30710128; PMCID: PMC6927556.

Zinn E, Pacouret S, Khaychuk V, Turunen HT, Carvalho LS, Andres-Mateos E, Shah S, Shelke R, Maurer AC, Plovie E, Xiao R, Vandenberghe LH. In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector. Cell Rep. 2015 Aug 11;12(6):1056-68. doi: 10.1016/j.celrep.2015.07.019. Epub 2015 Jul 30. PMID: 26235624; PMCID: PMC4536165.

Issa SS, Shaimardanova AA, Solovyeva VV, Rizvanov AA. Various AAV Serotypes and Their Applications in Gene Therapy: An Overview.

Cells. 2023 Mar 1;12(5):785. doi: 10.3390/cells12050785. PMID: 36899921; PMCID: PMC10000783.

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15. Peters CW, Maguire CA, Hanlon KS. Delivering AAV to the Central Nervous and Sensory Systems. Trends Pharmacol Sci. 2021 Jun;42(6):461-474. doi: 10.1016/j.tips.2021.03.004. Epub 2021 Apr 13. PMID: 33863599; PMCID: PMC9302199.

16. Lv, Z., Luo, F., & Chu, Y. (2023). Strategies for overcoming bottlenecks in allogeneic CAR-T cell therapy. Frontiers in Immunology. https:// doi.org/10.3389/fimmu.2023.1199145 17. Lonez C, Breman E. Allogeneic CAR-T Therapy Technologies: Has the Promise Been Met? Cells. 2024 Jan 12;13(2):146. doi: 10.3390/ cells13020146. PMID: 38247837; PMCID: PMC10814647.

18. Jo, S., Das, S., Williams, A. et al. Endowing universal CAR T-cell with immune-evasive properties using TALEN-gene editing. Nat Commun 13, 3453 (2022).

19. https://www.fiercepharma.com/pharma/atara-makes-history-worldfirst-nod-allogeneic-t-cell-therapy-ebvallo 20. American Society for Gene + Cell Therapy. Q2 2024 Landscape Report. Accessed at: https://www.asgct.org/publications/landscapereport 21. https://www.fiercebiotech.com/research/no-crispr-no-problemjumping-gene-system-could-be-bridge-complex-gene-editing

Bill Vincent Bill Vincent has over 35 years of experience working in the pharma and biotech sector.

He is the board chair of Genezen, a biotech contract manufacturer of viral vectors, cell manufacturing, and testing services. He founded the company fourteen years ago and grew it from his one-person operation to its current 60 employees with an outside investment of $45 million. Bill has since become a consultant for early-stage biotech and medical device companies coming into the market from an academic background.

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Cell and Gene Therapy

Delivering the Future:

Overcoming Shipping Challenges in Cell and Gene Therapy The rise of cell and gene therapy (CGT) is revolutionising how we treat complex diseases, offering life-changing treatments for patients in need. However, with these innovations come significant logistical challenges.

Ensuring these highly specialised therapies reach patients on time, without damage, is crucial. As the CGT market expands, logistics must keep pace to protect the integrity of these groundbreaking treatments.

High-Stakes Medicine Meets Outdated Logistics The CGT industry is growing rapidly, but the logistics supporting it have struggled to keep pace. CGT treatments are personalised, highly sensitive, and time-critical, making their durability and availability incredibly limited. Simply put, these treatments are some of the most expensive and delicate shipments moving around the world right now – and that means the standard supply chain playbook no longer applies.

Reaching upwards of $4 million per dose, CGT offers life-altering potential at an incredibly high cost. Once manufactured, these therapies must be administered to patients within hours, and they often require ultra-low temperatures during transport. Should any of these treatments be lost, damaged, or delayed in transit, the manufacturing process would

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have to start over. For patients waiting to receive these therapies, that’s time that they may not survive.

It’s no wonder the logistics behind this process are daunting. Not only do logistics teams face the possibility of losing millions of dollars in product, but they are responsible for delivering potentially life-saving treatments. The specific needs of these fragile therapies create a new set of issues that many companies don’t fully understand, and therefore, aren’t ready to support.

The CGT Cold Chain Challenge One of the key issues in CGT shipping is outdated cold chain infrastructure. Traditional shipment tracking methods, such as barcode scanning, provide only a snapshot of the shipment’s location, leaving teams in the dark about the cargo's real-time condition. Considering how incredibly time-sensitive CGT shipments are, this lack of visibility can be catastrophic.

Additionally, the extreme temperature requirements of CGT products – often needing cryogenic conditions of -150°C or lower – further complicate shipments. If temperature control fails at any point, the entire shipment could be lost. Adding to the strain are stringent regulatory demands. CGT is still a relatively new area of medicine, and additional transport requirements like packaging, surcharges, and restrictions are constantly evolving. This web of intricate cold chain conditions,

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Cell and Gene Therapy

regulatory compliance, and constant monitoring needs creates a perfect storm of risk.

The stakes are incredibly high. A single misstep could delay or prevent a patient from receiving treatment, underscoring the dire need for improving the CGT logistics market. As the industry expands, these challenges will only intensify unless there is a significant transformation in how CGT therapies are transported.

Innovative Solutions Transforming CGT Shipments Fortunately, the logistics industry has begun to develop solutions tailored to the unique needs of CGT. New technologies and approaches are transforming how companies ship these sensitive therapies, providing the precision and reliability that the market demands.

The development of advanced cold chain technology is a critical innovation given the ultra-low temperatures CGT products require. To help maintain treatment integrity, many companies are now leveraging advanced cryogenic packaging that can maintain consistent temperatures over extended periods. When combined with real-time temperature monitoring, these containers can ensure a shipment's condition from origin to destination.

To that end, real-time visibility into shipment location and condition has become essential. GPS-enabled tracking devices offer a live feed of the shipment’s status, including temperature, humidity, and even shock events that might compromise the therapy. These devices enable real-time data collection and monitoring, so teams can not only react quickly if something goes wrong but pull from collected data to demonstrate compliance if need be. This visibility not only reduces risk for companies but also provides peace of mind to healthcare providers and patients.

Coupled with real-time visibility, predictive analytics can help not only prevent issues but improve overall operational efficiency. By analysing historical shipping data, weather patterns, and traffic conditions, companies can predict potential delays and proactively reroute shipments. On top of minimising disruptions, these insights can help guide future shipments, helping companies continually optimise their supply chains. www.international-biopharma.com

Of course, the importance of close collaboration with experienced logistics service providers (LSPs) cannot be overstated. Specialised LSPs that understand the complexities of CGT regulatory compliance, packaging, and temperature needs, are invaluable in navigating the intricacies of CGT logistics. Their expertise helps reduce the margin for error, ensuring that the product arrives intact and ready for patient administration.

Modernising CGT Supply Chains for Lifesaving Impact While the challenges of CGT logistics are significant, they are not insurmountable. By embracing innovative cold chain technology, real-time monitoring, and predictive analytics, companies can navigate the complexity of CGT supply chains.

These advancements are more than just technical upgrades – they’re lifesaving improvements.

The future of cell and gene therapy depends not only on scientific innovation but also on the logistics systems that bring these treatments to life. By adopting an integrated, real-time solutions, approach, companies can protect the integrity of their therapies and ensure they reach the patients who need them most.

Alex Guillen Alex Guillen is an established executive with a proven record in global business and market development, with well-rounded experience in multicultural sales management and brand building. Guillen has extensive experience and expertise in cold chain; as Global SME, Life Science and Pharma at Tive, Guillen leads sales and business development within the company's rapid-growth Life Science division. Previously, Guillen served as a Board Member and leader of Corporate Strategy at SWITRACE S.A, a developer of temperature and humidity data loggers compliant to the Pharma and Biotech industries. Guillen’s extensive experience also includes serving as Global Cold Chain Director of Fisher Clinical Services, CEO of Escort Cold Chain Solutions SA and Director for Commercial Operations for Novartis Vaccines.

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Cell and Gene Therapy

PEER REVIEWED

Overcoming Portal Fatigue in Cell and Gene Therapies: Optimising Orchestration

Frustration, exhaustion, and a sense of being overwhelmed – these are the hallmarks of “portal fatigue”, a growing problem for approved treatment center (ATC) staff in the cell and gene therapy (CGT) field. Juggling a multitude of digital platforms and systems, each with its own unique interface and login credentials is taking a toll on productivity, morale, and potentially, patient care.

This fatigue is particularly acute in CGT due to the intricate nature of the field, characterised by complex supply chain relationships between treatment providers, ATC staff, manufacturers, and other stakeholders. While technology platforms have emerged to streamline and simplify these processes, their rise has inadvertently introduced new challenges, such as communication barriers and process inconsistencies. These issues can lead to confusion, delays, and errors, further contributing to the burden of portal fatigue.

In this article, Dr Akshay Peer, Senior Vice President Product, TrakCel will explore the causes and consequences of portal fatigue in CGT, discuss the need for standardisation and collaboration, and offer solutions and recommendations for mitigating this growing challenge.

The Rise of Technology Platforms in CGT The complexity of supply chains associated with personalised CGTs, combined with requirements such as ensuring the correct treatment reaches each patient, creates a challenging order-totreatment process. This complexity grows as therapies advance from clinical development to commercialisation, and the number of patients and other stakeholders in the supply chain increases. Manual approaches to supply chain co-ordination and management are difficult, if not impossible at scale. This has led to the development of supply chain orchestration software.

Orchestration systems streamline and simplify the CGT process, offering benefits such as: • • • •

Chain of custody and chain of identity: Ensuring the secure tracking of therapies throughout the supply chain.

Improved efficiency: Coordinating and scheduling activities between stakeholders.

Automated processes: Streamlining payer approval verification and order-to-cash processes.

Real-time visibility: Providing updates on the progress of individual therapies.

Almost all commercial personalised CGT therapies are supported by their own custom orchestration platform.

However, as an increasing number of CGTs are commercialised, the abundance of platforms has created new challenges, particularly for ATC staff who must navigate multiple systems, each with its own unique interface, login credentials, and processes.

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The Pitfalls of Custom-built Solutions Developing a custom-built orchestration platform can seem like the ideal solution, promising a perfect fit for the unique needs of cell and gene therapy. However, the allure of customisation often masks significant pitfalls. This approach frequently leads to unforeseen challenges such as spiralling development costs, integration complexities, and the burden of ongoing maintenance, which can strain resources and hinder the efficient delivery of therapies to patients.

One of the most significant pitfalls is the contribution to portal fatigue. Healthcare providers are increasingly burdened with a multitude of digital platforms, each with its own login credentials, user interface, and workflows. Custom-built solutions exacerbate this problem by adding yet another platform for ATC staff to learn and navigate. This lack of standardisation forces users to switch between different systems, leading to frustration, decreased efficiency, and the risk of errors that can compromise patient safety.

Custom-built solutions frequently overlook the importance of the user experience. By neglecting to incorporate feedback from ATC staff and other end-users, these systems can miss the mark in addressing their needs and streamlining workflows. This can lead to resistance to adoption and a less efficient process. In contrast, standardised platforms that offer a unified interface, streamlined workflows, and features like single sign-on (SSO) can significantly alleviate portal fatigue and enhance user experience.

Another significant challenge is the potential for scope creep and overcomplexity. As stakeholders identify new requirements or modifications, software can become increasingly complex.

This can lead to delays, cost overruns, and a system that is difficult to use and maintain – such complexity can also hinder integration with other critical systems, creating data silos and workflow inefficiencies.

Maintaining and supporting a custom-built platform also poses its own set of challenges. Companies must invest in dedicated IT resources to manage the system, address bugs, and implement updates. This can divert resources from core competencies, such as research and development or patient care. Moreover, as technology and regulatory frameworks evolve, custom-built solutions can become obsolete, requiring further investment to remain functional and secure.

Furthermore, custom-built platforms may lack access to specialised but essential features readily available in commercial solutions. Features like SSO and advanced scheduling capabilities can significantly enhance security and efficiency but may require extensive development effort in a custom-built system.

The Consequences of Portal Fatigue Portal fatigue, while a growing concern, has far-reaching consequences that extend beyond individual frustration. It Winter 2024 Volume 7 Issue 4

Cell and Gene Therapy

presents a significant challenge to healthcare organisations, impacting not only the well-being of ATC staff but also the efficiency, safety, and financial health of the institutions they serve.

For ATC staff, constantly juggling multiple platforms and logins increases workload and stress. This can lead to reduced efficiency and productivity, as valuable time is lost navigating complex systems and reconciling inconsistent information. The cognitive burden of managing disparate platforms can also increase the potential for medical errors, as attention is diverted from patient care. For example, treatment delays caused by navigating complex platforms with unfamiliar terminology and workflows can compromise the efficacy of time-sensitive CGT products. Similarly, difficulties accessing critical patient information due to a maze of different logins and interfaces can lead to frustration, wasted time, and potential errors in treatment decisions.

Beyond the individual level, portal fatigue places a significant financial and resource burden on healthcare organisations.

The costs associated with training staff on multiple platforms, managing user access and permissions, and addressing IT issues related to system incompatibility with existing IT infrastructure can be substantial. Furthermore, the reduced efficiency and productivity resulting from portal fatigue can lead to increased operational costs and potentially impact the quality of care delivered.

The Need for Standardisation and Collaboration Standardising processes and terminology across different platforms is crucial. This would reduce the cognitive burden on ATCs, who currently have to navigate a maze of different systems with varying requirements. Standardised data formats and workflows would improve efficiency, reduce the risk of errors, and facilitate better communication between stakeholders.

Collaboration between technology providers and ATC staff is equally important. Technology providers need to understand the needs and challenges faced by ATCs in their daily work, while ATCs need to be involved in the design and development of new technologies. This collaborative approach can ensure that platforms are user-friendly, intuitive, and tailored to the specific needs of the CGT workflow.

Several initiatives are underway to address portal fatigue and promote standardisation. For example, the TrakCel-led Industry Advancement Board (IAB) is bringing together ATCs, manufacturers, and technology providers to discuss challenges and develop solutions. Such collaborative efforts are essential for driving progress and creating a more unified and efficient CGT landscape. www.international-biopharma.com

By embracing standardisation and collaboration, the CGT industry can create a more user-friendly and efficient environment for healthcare providers, ultimately leading to better patient outcomes and a more sustainable future for this promising field.

Solutions and Recommendations The consequences of portal fatigue highlight the urgent need for solutions that prioritise standardisation, interoperability, and user-centric design in CGT platforms. By streamlining workflows, reducing the cognitive burden on ATC staff, and improving efficiency, the industry can mitigate the negative impacts of portal fatigue and ensure that technology serves its intended purpose – enhancing patient care and accelerating the delivery of life-saving therapies.

Addressing the pervasive issue of portal fatigue requires a multi-pronged approach, encompassing technological solutions, collaborative initiatives, and a commitment to user-centric design.

1. Technology Solutions Developing user-friendly and intuitive platforms is paramount.

Complex, cumbersome interfaces exacerbate portal fatigue, while streamlined workflows and intuitive navigation can significantly reduce cognitive burden and improve user experience. Implementing SSO solutions can eliminate the need for ATCs to remember multiple login credentials, simplifying access and enhancing security. Additionally, minimising the number of clicks required to complete a task can significantly enhance usability for busy ATC staff.

Integrating with existing healthcare systems, such as electronic medical records (EMRs), can streamline data exchange and reduce the need for duplicate data entry. This not only saves time but also minimises the risk of errors. Prioritising interoperability between different platforms is also crucial, allowing for seamless data sharing and reducing the need for ATCs to switch between disparate systems.

2. Collaborative Initiatives Collaboration between technology providers and ATC staff is essential. Technology providers need to actively seek feedback from ATCs to understand their needs and challenges, while ATCs need to be involved in the design and development of new technologies. This collaborative approach can ensure that platforms are tailored to the specific needs of the CGT workflow.

Industry-wide initiatives, such as the IAB can play a crucial role in driving standardisation and addressing portal fatigue. By bringing together stakeholders from across the CGT ecosystem, these initiatives can foster collaboration, knowledge sharing, and the development of best practices.

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Cell and Gene Therapy

3. Recommendations •

For Technology Providers: Prioritise user-centric design, interoperability, and integration with existing systems.

Actively seek feedback from ATCs and involve them in the development process to ensure platforms truly meet their needs.

•

For Healthcare Organisations: Invest in comprehensive training and support for ATCs, empowering them to effectively utilise technology platforms. Foster a culture of collaboration and knowledge sharing between departments and stakeholders to maximise efficiency and minimise confusion.

•

For Policymakers: Promote policies that encourage standardisation and interoperability in CGT platforms.

Support initiatives that foster collaboration between technology providers and technology users.

By embracing these solutions and recommendations, the CGT industry can mitigate the negative impacts of portal fatigue, empower ATC staff, and pave the way for a more efficient and patient-centric future.

Looking Ahead: The Future of CGT Platforms Portal fatigue presents a significant challenge in the cell and gene therapy landscape, hindering efficiency, increasing the risk of errors, and potentially compromising patient safety. The consequences of this fatigue can be far-reaching, impacting 68 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

not only the well-being of ATC staff but also the financial and operational health of healthcare organisations.

To address this challenge, the industry must prioritise standardisation and collaboration. By working together, technology providers and platform users can develop solutions that streamline workflows, reduce the cognitive burden on ATCs, and improve the overall efficiency and safety of CGT delivery.

This includes initiatives like the IAB, which brings together stakeholders to identify challenges and develop solutions.

The future of CGT platforms lies in creating user-friendly, interoperable systems that prioritise the needs of the user. Let's move forward with a commitment to developing and adopting standardised practices, fostering open communication, and prioritising the needs of the ATC staff who are at the forefront of delivering these life-changing therapies.

Dr. Akshay Peer Dr. Akshay Peer is the Senior Vice President of Product Development and a Co-founder of TrakCel. He has over 12 years of experience in creating technology-based solutions for cell and gene therapy industry. His long-standing tenure in this field reflects a dedicated commitment to advancing innovation and contributing to the industry's growth.

Winter 2024 Volume 7 Issue 4

QC-Analysis of Inhaled Antisense Oligonuclotides and mRNA Analytical support for ASO and mRNA based therapies from early development to batch release Antisense oligonucleotides (ASOs) and full-length mRNA-based therapeutics promise diseasespecific treatment options. One of the challenges of these therapies is the tissue- or cellspecific delivery. Inhalation has been an effective means to deliver pharmaceutically active substances to the respiratory tract for centuries. Today there is a growing interest in the industry to leverage on the experience with different inhalation technologies to deliver ASO and mRNAbased treatments directly to diseased respiratory tissues.

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C) Celibatarian curves from a parallel detection by UV (above) and MS (below). generic cell-based bioassay, we can help to predict the transfection efficiency of different LNP formulations. A&M STABTEST has also developed a generic LC-MS/MS method to support early ASO development projects, offering data on quantity, purity and impurities in one analytical run.

A&M STABTEST can support your early development and more advanced ASO and mRNALNP projects whether inhaled or not. With our experience spanning well over two decades of providing the pharmaceutical industry with high quality analytical services, we are well suited to find analytical solutions for the industries most innovative drug development programs. &Žƌ ŵŽƌĞ ŝŶĨŽƌŵĂƚŝŽŶ͕ ƉůĞĂƐĞ ĐŽŶƚĂĐƚ ƌ͘ ^ƚĞǀĞŶ ͘ tĂƚƚ ĞŵĂŝů͗ ƐƚĞǀĞŶ͘ǁĂƚƚΛĂŵͲůĂďŽƌ͘ĚĞ ͖ ƉŚŽŶĞ͗ нϰϵ ;ϬͿϮϮϳϭ ϳϱϱϵ ϭϬϬ www.international-biopharma.com

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Winter 2024 Volume 7 Issue 4

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Winter 2024 Volume 7 Issue 4