The bottleneck that keeps patients waiting for access to affordable advanced therapies

The bioprocessing industry’s manufacturing capacity crunch

Behind every vaccine is a manufacturing process (Photo by National Cancer Institute on Unsplash)

Imagine a world where chronic diseases such as heart diseases, cancers, or diabetes that are currently responsible for 41 million deaths every year, are completely cured through targeted therapy (1). A world where type 1 diabetes patients have newly functioning cells that produce insulin (2). A world where vision loss is completely regained through CRISPR-Cas9 gene editing therapies and regrowing cells in the inner ear restores hearing in patients with hearing loss (3,4). A world where there is hope for the 400 million people globally affected by rare diseases previously deemed incurable (5).

These realities could all be made possible through advanced cell and gene therapies (CGT) which involve transferring healthy cells to patients with diseases caused by damaged cells (e.g. stem-cell therapy), or replacing or correcting genetic mutations causing diseases using CRISPR-Cas9 (6). These innovations have major potential to transform patient’s lives by offering curative, targeted treatment lasting the lifetime of a patient. Advanced therapies remove the need for often invasive and costly long-term treatment that can have a large burden that compromises their chance to actively participate in day-to-day activities (6). Cell and gene therapies also have the potential to cure diseases that as of right now have no or only limited effective treatment. If we collaboratively make these life-changing therapies more accessible and affordable, we can revolutionize disease treatment and global health, addressing the growing burden of chronic and rare diseases across the world to ensure good health and well-being for all (Sustainable Development Goal 3) (7).

Bringing novel therapies to market and providing access to these therapies to patients is dependent on numerous factors such as availability of reagents, consumables, equipment, both at the research and development stage and during manufacturing. However, the current CGT manufacturing landscape and the bioprocessing industry is under a “Manufacturing Capacity Crunch” and will continue to struggle to meet the demand of the growing development of therapies. The tension between the growing sector and the capacity crunch risks slowing production of therapies, increasing their costs and therefore limits accessibility and affordability of life-changing treatment. This capacity crunch presents a bottleneck towards delivering biomedical innovations including CGTs, biopharmaceuticals, and biotechnology solutions to patients. It is important to note that as well as manufacturing, factors such as Intellectual Property licenses for therapies, organisational and funding structure, pricing of, and general regulations surrounding steps before therapy approval play major roles - while this article focuses on the manufacturing landscape, an in-depth analysis of these important factors can be seen in the Innovative Genomics Institute's Making Genetic Therapies Affordable and Accessible 2023 Report.

BioPlan Associates annually publish their "Report and Survey of Biopharmaceutical Manufacturing Capacity and Production", reporting on survey responses from over 100 biotherapeutic developers and contract manufacturing organisations and 100 industry vendors about the current manufacturing landscape. These reports provide valuable insight that can be used to understand the CGT manufacturing landscape and how to address the bottleneck.

The challenges behind the accessibility and affordability of therapies

The growing life sciences sector

Accelerating growth and advancement of the life sciences sector continues to place immense pressure on therapy manufacturing facilities with limited production capacity, therefore reducing the accessibility and affordability of life-changing therapies to patients. Technologies such as new stem cell research, iPSCs, increasing accessibility of CRISPR-Cas9, and improvements in DNA sequencing and synthesis techniques have opened a world of opportunity for advanced therapies, evident in the recent growth of the industry (8,9). The Alliance for Regenerative Medicine noted that companies developing CGTs raised over 23.1 billion USD global investments in 2021, a 16% increase since 2020 (9). In 2022, the gene therapy pipeline increased 16% since Q1 2021, and the forecasted 102% increase in clinical trials between 2021 and 2026 will require large manufacturing efforts to carry out these trials (10,11). There are currently 30 FDA approved gene therapies, with an anticipated 7 more approvals in 2023 (12, 13). The FDA has also recently pushed for Accelerated Approval of gene therapies, particularly therapies addressing rare disease patients who currently have limited effective treatment and have poor morbidity (14). The global pharmaceutical manufacturing market size is also expected to grow at a combined annual growth rate (CAGR) of 15.9% from 2022 to 2030 (8).

Gene therapy pipeline growth by number of therapies in clinical trial phase, adapted from LEK Insights (25) and increase in Cell and Gene therapy launch, adapted from McKinsey & Company (26)

Development of novel, innovative therapies are only meaningful when the treatments are manufactured efficiently and brought to patients.

The current capacity and capability of CGT manufacturing facilities and the bioprocessing industry is struggling and will continue to struggle to meet this growing demand for therapy manufacturing. The demand of the CGT market outpaces the limited production capacity of the manufacturing industry, resulting in decreased accessibility and affordability of therapies.

Why can’t manufacturing facilities meet the increasing demand for therapy production?

Between 2020-2022, 15.6% of respondents in the 19th annual BioPlan report (2022) reported that their facility will experience production capacity constraints in five years (15). The capacity crunch is exacerbated by several factors, including the intricate workflow that requires highly skilled workers to fill bioprocessing positions, challenges within the supply chain which raise the cost of therapies, and the dwindling availability of space for expanding manufacturing operations.

1/3 of respondents to BioPlan’s 2020 annual survey noted a significant problem in hiring cellular and or gene therapy staff, and a similar trend is present in biopharmaceutical manufacturing, where in 2022, over 50% of the industry noted a difficulty in finding qualified employees (15, 16). The skills shortage and challenge to hire and retain experienced staff limits the production workforce and therefore slows the process of bringing therapies to patients. This challenge may also reflect the complex nature of handling of the production equipment, and the intricate processes needed for manufacturing, which presents as a factor constraining the capacity to efficiently manufacture therapies.

Complex logistics and supply chain issues were cited by over 50% of respondents in BioPlan’s 2021 report, further slowing production of therapies (17). The inability to access necessary supplies for production slows the manufacturing time and cost, which further reduces accessibility and affordability of therapies.

Limited availability of space in facilities for manufacturing further reduces the capacity to manufacture the increasing number of therapies being approved for patients. This has been cited in the form of assessing manufacturing capacity (the GMP facilities available for producing therapies). According to BioPlan Associate’s 2020 estimates, globally, five-times the current capacity would likely be used for manufacturing if available, suggesting therapies could be manufactured more (16). This may also reflect a greater problem regarding the effective use of space in manufacturing facilities, where the equipment takes up a large cleanroom footprint, yet with limited ability to produce therapies at a large scale.

BioPlan 2020-2022 survey responses to the question "I believe our facility will experience production capacity constraints in five years", adapted from the BioPlan 2022 report (15)

The skills shortage, logistics and supply chain issues and limited space all contribute towards an industry with limited capacity to meet the growing demand for manufacturing, extending manufacturing time and costs, therefore causing a major bottleneck in delivering affordable and accessible life-changing therapies to patients.

The three factors that are putting pressure on the CGT manufacturing landscape

The attempt to de-crunch the crunch: a UK case study

Across the UK in 2020, GMP manufacturing facilities across all CGT manufacturing sites were nearly at full manufacturing capacity (86%), showing limited ability to take on more therapy manufacturing (18). In response, UK facilities have increased the number of full-time employees, seen in the 25% increase in number of highly skilled staff at cell therapy facilities between 2021-2022, and the gradual increase in full-time workers across CGT facilities (19, 20). Furthermore, the recent partnership between Catapult Cell and Gene Therapy UK and the Medicine Manufacturing Industry has prompted the launch of the first Advanced Therapy Medicinal Products Community (ATAC) apprenticeship program (21). The program aims to address the skills shortage and meet workforce demands for production of therapies by training and upskilling high school graduates in developing, manufacturing and delivering therapies at scale through partnerships with organizations such as Oxford Biomedica, GSK and NHS Blood and Transplant (21).

Increase in full-time workers and cleanroom footprint across cell and gene and multifunctional facilities in the UK over time, data extracted from Catapult UK Cell and Gene Therapy's Manufacturing Reports 2019-2022

Furthermore, to increase production capacity, UK facilities have increased the number of cleanrooms, seen in the 111% increase in cleanroom footprint since 2018, and 16% growth in the number of clean rooms between 2021-2022 (19, 20). In the 2022 Catapult Cell and Gene Therapy survey, 68% of respondents agreed they use third-party logistic services to support supply chain/logistic needs to address the supply chain challenges (20). As a result of these changes, the UK’s manufacturing capacity has slightly increased, decreasing their national booked capacity to 67%, which, despite still being high, is an improvement compared to the extremely limited capacity in 2020 (18, 20).

Despite this promising improvement, these attempts to address the capacity crunch are not long-term, sustainable solutions that address the problem at hand. Building more facilities and hiring more staff provides a temporary fix to the crunch, however, this solution doesn’t address the complexity of the workflow which demands highly skilled, full-time workers, nor does it alleviate the supply chain challenges, and the solutions do little to increase the affordability of therapies. Rather than implementing short-term solutions, manufacturing facilities need to reconsider their production process, mainly the production efficiency, rather than continuing with site and staff expansion to address the capacity crunch. This is a key distinction between scaling-up and scaling-out manufacturing: while scaling out transfers existing bottlenecks across multiple facilities, introducing novel solutions for scaling-up manufacturing in a more effective way will improve the efficiency and therefore affordability and accessibility of advanced therapies. With the rise of personalised cell and gene therapies, the manufacturing industry needs to find solutions to manufacture smaller batch sizes on a large scale to tackle mass customisation.

Production efficiency over facility expansion

While expanding facilities may provide a short-term solution, changing the workflow can often be more effective both from a productivity and cost point of view, enabling innovative therapies and curative treatments to reach patients at a lower cost and within in a shorter time period. Improving efficiency and re-thinking processes in the CGT manufacturing industry can be made in several ways:

Matthew Durdy, CEO of Cell and Gene Therapy Catapult, envisions a “future requiring less physical space” where companies improve productivity by implementing processes that use less footprint to produce the same amount of product, improving efficiency (22). Introducing scalable, easy-to-adopt manufacturing systems will also improve efficiency by removing the need to optimize protocols at different levels of manufacturing and lowering labor intensity and complexity of use. This reduces the pressure to hire highly skilled workers for manufacturing, strengthening the production workforce. Furthermore, digitization and automation could expand the innovative possibilities of therapy manufacturing. Advanced production technologies, digital twins (virtual versions of physical equipment or processes), paper-free factory operations and remote performance monitoring have the potential to increasing plant capacity by 25%-40% by (23). By improving labor productivity, reducing product transfer times and stricter control to ensure manufacturing of high-quality products, digitization and automation can increase the affordability and accessibility of the manufactured products. Furthermore, standardising the manufacturing process across all facilities and adopting a point-of-care manufacturing model (rather than centralised model) using automated, closed systems will greatly reduce logistical burdens of transport and storage, decrease labour costs and increase manufacturing capacity (24)

Green Elephant Biotech GmBH aims to solve the bottleneck in the biopharmaceutical production sector to increase patient accessibility and affordability of life-changing, novel therapies by producing innovative labware from plant-based plastic. Our first product, the CellScrew®, is an easily scalable adherent cell expansion system that is easy to handle and requires little to no additional equipment for use and has the potential for automation, contributing to the workflow efficiency. Implementing solutions like the CellScrew® within upstream bioprocessing immensely contributes to an increase in production efficiency, and the delivery of therapies to patients.

Revolutionary technological advancements in the life sciences sector have enabled the development of innovative CGTs that have the potential to reduce the growing burden of chronic diseases affecting millions of lives today. Manufacturing capacities need to prioritize workflow efficiency over staff and site expansion to increase the affordability and accessibility of life-changing therapies for all.

References

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(2) Garvan Institute of Medical Research (2022). World-first gene therapy clinical trial for type 1 diabetes to proceed. [Internet]. Available from: https://www.garvan.org.au/news-events/news/world-first-gene-therapy-clinical-trial-for-type-1-diabetes

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