As global supply chains continue to restabilise, innovator companies must carefully manage resources to reach key milestones. Traditional CDMO models with booking, reservation, and other fees devour critical development runway. The new generation of CDMO offers flexible terms, transparent access, and collaboration to ensure success without compromising timelines or budgets.
Approximately 400 million people worldwide are living with a rare disease, and about half of those affected by rare diseases are children. Cell and gene therapies have the potential to revolutionise the treatment of many diseases, including rare genetic disorders and cancer.
In July of last year, PTC Therapeutics achieved a significant milestone when the European Commission (EC) granted authorisation for Upstaza. This treatment marks the first-ever approved therapy for aromatic L-amino acid decarboxylase (AADC) deficiency, a rare genetic disorder affecting the nervous system. Following this, BioMarin received marketing authorisation from the EC in August for Roctavian, the world's first gene therapy developed to treat Hemophilia A, a hereditary bleeding disorder. In the same month, the FDA approved betibeglogene autotemcel (beti-cel; Zynteglo) by bluebird bio for the treatment of beta thalassemia in both adults and children. This therapy had previously obtained approval in the EU back in 2019. Another notable approval came in September when the FDA granted its authorisation for elivaldogene autotemcel (eli-cel; Lenti-D), also developed by bluebird bio. This therapy offers a solution for early and active cerebral adrenoleukodystrophy (CALD) patients without an HLA-matched donor. Lastly, in November, the FDA approved a Hemophilia B treatment developed through the collaboration of uniQure and CSL Behring.
In the realm of chimeric antigen receptor (CAR) T-cell therapies, two notable approvals took place in 2022. In February, Carvykti (ciltacabtagene autoleucel) by Legend Biotech and Janssen received approval from the FDA, marking a significant milestone in CAR-T therapies. In April, Breyanzi (lisocabtagene maraleucel) by Juno Therapeutics, Inc., a Bristol-Myers Squibb Company, obtained approval in the EU. Novartis's Kymriah and Breyanzi also achieved approvals for additional indications, further expanding the reach and potential of these therapies.
Despite the clinical promise, getting these treatments to patients quickly and efficiently is a significant challenge. Bringing cell and gene therapies to market is a complex process that requires a significant investment of time and resources from both a developmental and manufacturing perspective.
The clinical development process for these treatments involves several phases of testing, including preclinical studies, phase 1 safety studies, and larger phase 2 and phase 3 studies to evaluate efficacy and safety in larger patient populations. The process of clinical development can take many years and require significant investment. For diseases with small patient populations with no other treatment options (requiring production of small batches), incentives are often not aligned for large pharmaceutical companies and medium-sized biotech companies to invest in.
Developing cell and gene therapies also requires manufacturing processes that can be scaled up to meet the needs of patients. This can be a challenge, particularly for therapies that involve complex manufacturing processes or require specialised facilities. Additionally, the global supply chain for cell and gene therapies can be complex, as starting materials and other components may need to be sourced from multiple locations around the world. While bottlenecks from pandemic lockdowns have improved since 2021, certain equipment and consumables used in cell and gene therapies continue to have long lead times and unreliable availability.
Contract development and manufacturing organisations (CDMOs) play a crucial role in accelerating the availability of cell and gene therapies to patients by absorbing and mitigating risk, simplifying supply chains with starting material on-hand, and accelerating development with processes and platforms.
However, traditional CDMO models charge fees that can consume critical development runway and negatively impact the financial resources of innovator companies. While fees for traditional CDMO services can vary widely, they can be a significant financial burden for innovator companies. Common charges have included suite reservations and holding, booking, project initiation, tech transfer, onsite accommodation, and programme management. These fees can consume critical development runway and negatively impact the financial resources of innovator companies, which can delay the development of cell and gene therapies.
Another common occurrence as the cell and gene industry evolved was the need to work with multiple providers of steps within the process. For example, an innovator company may need to work with one CDMO for plasmid manufacturing, another for vector manufacturing, and yet another for release testing and analytics. This has led to common challenges in:
Coordination and communication: One of the main challenges of working with multiple CDMOs is coordinating and communicating effectively between the different organisations, in addition to overall vendor management. It can be challenging to ensure that each CDMO is aware of the project’s overall goals and timelines, and that all parties are working together to achieve these goals. This can be particularly challenging when multiple CDMOs are located in different countries or time zones, making it difficult to coordinate schedules and communication.
Quality control: Another challenge with using multiple CDMOs is ensuring consistent quality control across all aspects of the development and manufacturing process. Different CDMOs may have different quality control standards and procedures, making it challenging to maintain consistent quality throughout the process. This can be particularly problematic when there are handoffs between different CDMOs during the manufacturing process.
Intellectual property & licensing: Another challenge with using multiple CDMOs is protecting intellectual property. Developing cell and gene therapies often involves proprietary technology and processes, and it can be challenging to protect this information when working with multiple CDMOs. There may be concerns around confidentiality and the risk of intellectual property theft, which can hamper coordinating work with multiple CDMOs. Furthermore, development using standard materials e.g., (off-the-shelf plasmid or gene editing nuclease) may surprise an innovator company when the CDMO provider is litigated in court.
To address these challenges, a new generation of CDMOs has emerged. These CDMOs offer flexible solutions—both in terms of contracting as well as facilities, equipment, and platforms. As early stage clinical and scale-up clients face capital headwinds, models being tried include:
Modular contracting: Allows innovator companies to select specific services from a menu. For example, a CDMO might offer separate modules for process development, analytical development, and manufacturing, and innovator companies can choose some or all of the modules they need based on their in-house talent.
Pay-for-performance: Under this approach, payment is contingent on specific performance metrics, such as meeting project milestones e.g., (vial thaw, successful batch) or achieving specific quality standards such as yield. This approach can help incentivise the CDMO to perform at the highest level possible and can help mitigate risk for the innovator company.
Flexible pricing: Some CDMOs are offering more flexible pricing models to meet the changing needs of innovator companies. For example, a CDMO might offer a fixed-price contract for a specific scope of work, or a cost-plus pricing model where the CDMO is paid for the actual costs incurred plus a percentage markup. Increasingly, as programs are rationalised and at the mercy of clinical data readouts, recent contracts have offered parking lots and offramps for innovators to manage their pipeline.
In terms of facility design, fit-for-purpose cell therapy CDMOs have re-engineered and decoupled unit operations to eliminate process and operator bottlenecks. As an example, early-generation autologous cell therapy suites manufacture a patient dose in a singular Grade B environment with operators responsible for the entire process. This requires both time-intensive gowning for current staff as well as lengthy training and focused retention efforts. These headwinds lead to both lower throughput due to non-process time and space utilisation, as well as risk to output from attrition.
In next-generation suites, process steps with that can be contained (cell selection, activation, transduction, expansion, and harvest) are performed in closed Grade C space while those that require access to the (formulation, filling) are performed in stricter Grade B to enable quick movement of personnel materials across the GMP facility as operators do not have to gown/de-gown as often as in Grade C as they would in a Grade B environment. This enables seamless processing steps to handle higher throughput.
For vector manufacturing, process steps are broken down into seed, upstream processing, and downstream processing. The seed and upstream processing steps are performed in a contained area to ensure high levels of purity, while downstream processing steps that require access to the open environment are performed in a less strict environment. Additionally, this approach enables the manufacturing team to become highly specialised in their respective roles making it more conducive to larger batches and pooling strategies with multiple upstream bulks to one downstream run. Efficiency and batch success metrics are optimised, leading to lower COGS per dose of vector-based therapy.
In light of increasingly complex therapy development, the pace at which cell and gene therapies on accelerated approval pathways speed through clinical trials, and patients with no other choice waiting for therapies, tighter collaboration between innovators and CDMOs is key. A more collaborative relationship enables speed and increases chances of first-time success as sponsor companies share more information and expertise with the CDMO, and the CDMO takes a more active role in risk mitigation and resolution beyond simply executing an initial scope of work.
At the Center for Breakthrough Medicines (CBM), we enable tighter collaboration through programmes such as Partner-in-Plant (PIP) and digitally-enabled suites and infrastructure. Unlike audit-only models, PIP allows a sponsor company access to their product with office space and access to manufacturing suites (with appropriate GMP training) at CBM. Sponsor company scientists can work hand-in-hand in our process development labs to work through parameters that influence batch success.
For partners that are unable or choose not to be onsite, CBM’s digitally native facilities enable access globally 24/7. Live 360-degree cameras are thoughtfully located in suites to capture a complete view of the production environment. The cameras capture video footage of the manufacturing process from all angles, providing a comprehensive view of the production line. This technology can be used for process improvement and employee training. By having a real-time view of the manufacturing process, operators can identify bottlenecks, optimise workflows, and improve production efficiency.
Sensor-enabled equipment can also provide real-time visibility into a manufacturing process. These sensors collect data on temperature, pressure, flow rates, and other critical parameters. The data collected by these sensors can be analysed to predict and mitigate risk and manage deviations, improving overall product quality and reducing waste.
As cell and gene therapies continue to evolve and mature in an uncertain global macroeconomic environment, the new CDMO model of flexible collaboration and access is critical to managing scarce resources and constrained timelines to deliver product globally to the patients that need them.
CBM provides faster turnaround times for client projects by having all development, testing, and manufacturing capabilities connected digitally on shared platforms and physically on one campus, and by having invested working capital in consumable materials and critical supplies for cell and gene therapies. This approach reduces the risk of supply chain disruptions and improves overall supply chain resilience. Our proactive inventory strategy has enabled the company to establish strong relationships with strategic suppliers and secure favourable pricing agreements. By anticipating client needs for consumable materials and supplies and investing our working capital accordingly, the company can quickly respond to client requests thereby accelerating the path to product manufacturing. This approach has helped clients focus their time and energy on value-added activities aimed at delivering advanced therapies to patients rather than being consumed with the complexities associated with building bespoke supply chains in today’s highly complex global sourcing environment.
To discuss how to collaborate with CBM on an ideal outsourcing model or supply chain strategy, reach out to firstname.lastname@example.org