Alain Pralong1,3
Renaud Jacquemart2,3
Katrina Cordovado2,3
- Pharma Consulting ENABLE GmbH,
- Omnium Global Consulting Inc,
- ENABLE Biotech AG
Introduction
In the expansive landscape of cell and gene therapy (CGT) development and manufacturing, the industry is experiencing unprecedented growth, with >90 clinical trials initiated in 2023 and almost 4,000 therapies currently in development1. The majority of these innovations are being pursued by biotech start-ups and university spin-off, and almost 75% of CGT start-ups are expected to engage a Contract Development & Manufacturing Organization (CDMO) due to the high investment required to build an in-house manufacturing facility2. However, compared to big pharma companies, these smaller biotechs have unique needs at early clinical development stages that are not always met by existing players in the CDMO space for CGT, ranging from Chemistry, Manufacturing, and Controls (CMC) and Quality Assurance (QA) expertise to finding phase-appropriate pricing and operating models. As consultants specializing in product development, we see firsthand the challenges posed to these smaller biotechs.
Therefore, a next-generation CDMO, meeting start-up needs through their operating model and specialized expertise, is needed to address the distinctive challenges faced by early-stage biotechs in the dynamic landscape of CGT process and early-stage clinical development stages.
Challenges Faced by CGT Start-ups
Finding the right partner for First-in-Human (FIH) clinical production is often the biggest challenge biotech start-ups may face. With over 300 different CDMOs in the world supporting drug developers, many are agnostic to the stage of development or technology type that they work with3. This lack of specialized focus in the industry may pose some challenges for start-ups and spin-off companies who are seeking to manufacture advanced therapies for their pre-clinical or Phase I/IIa studies (common FIH trial design used with CGT). These early-stage companies often cite dissatisfaction with CDMO partners due to pricing, flexibility of scheduling, geographic proximity, production timelines, and available capacity4. One prominent hurdle lies in capacity constraints due to the overwhelming demand for manufacturing services in the CGT sector, providing new clients with current waitlists of over two years from large CDMOs5. With only a few players focusing exclusively on CGT manufacturing, there can sometimes be a trade-off between manufacturing other, more established therapeutics such as large molecule biologics and vaccines. Compounded by their financial constraints, start-ups may feel overshadowed by larger accounts, perceiving that CDMOs prioritize collaborations with more established entities. Start-ups may also be more likely to lack the luxury of an extensive runway to wait for manufacturing processes to unfold, since funding is often dependent on reaching certain milestones. Start-ups and early-stage biotechs in the CGT space often face hurdles in securing adequate funding for research, clinical trials, regulatory approvals, manufacturing and scaling up production. Sometimes the costs of manufacturing with a CDMO can seem prohibitively high. They may also sometimes need to operate with agile project timelines and move fast to respond to changing market demands. Typical CDMOs may not have the capacity for agility, flexibility, and close collaboration with each sponsor, and tech transfer processes can sometimes be complex. Sponsors also often seek the opportunity to be able to watch work happening in the facility, which is usually not possible in the current environment. If they have limited expertise in manufacturing scale-up, spin-off founders may seek additional support from their CDMO for process development and CMC, beyond normal routine offerings.
Sometimes it makes more sense to turn to those manufacturers that are specifically focused on the niche of cell & gene therapy. In response to capacity constraints, several universities and research groups have launched associated manufacturing facilities focused on cell & gene therapies. However, spin-offs collaborating with university GMP labs encounter a series of challenges stemming from the inherent differences between research-focused environments and the manufacturing-scale requirements essential for the development of CGTs. Particularly challenging for start-ups is the initial transition to manufacturing processes as they may lack the foresight to plan for future scale-up. Resource limitations and scalability issues further compound the dilemma, as smaller university labs can adequately support up to Phase I/IIa trials, prompting a potential need for transition to larger facilities as projects progress. This transition, however, introduces complexities, given potential regulatory concerns and tech transfer, especially if scalability and transferability has not been addressed early on. Additionally, when they begin their manufacturing journey, start-ups may lack the background knowledge to effectively vet GMP labs for their regulatory compliance, sometimes requiring trial repeats.
Furthermore, start-ups still may not find the CMC expertise they require in university GMP labs, and sometimes documentation and evaluation processes that should be followed can fall through the cracks for founders who are not familiar with these requirements for ensuring the quality and consistency of their therapeutic products. Often, with a limited knowledge of the expertise they need in preparing for therapeutic manufacturing, start-ups just may not know where to look, and may end up relying too heavily on one partner that does not have the capacity to provide everything they need. This presents the need for a next-generation CDMO, and one offering sponsors CMC expertise especially.
Next Generation CDMO
We propose that a next generation CDMO focused on the cell & gene therapy space should offer four key features to serve the needs of early-stage developers. A unique partnership model would be focused on delivering flexibility, CMC expertise, speed to Phase I/IIa trials, and affordability. Niche CDMOs specifically dedicated to working with early-stage companies in the advanced therapy space are critical in accelerating their journeys to clinics, ensuring that the cost of manufacturing or limited access to specialized expertise does not become a limiting factor for these innovative therapies.
Innovative Operating Model
The cornerstone of an innovative CDMO operating model would be flexibility and collaboration. By working closely with project sponsors, CDMOs can develop a deep understanding of their goals and challenges. With a mandate to bring clinical products to patients, next-generation CDMOs should begin each project with the final commercial manufacturing process in mind, considering aspects such as scale-up, industrialization, continuous process verification, and purchase price variance early on. Adaptability is also key, ensuring responsiveness to the dynamic landscape of CGT and the unique needs to start-ups, allowing for changes in project timelines or needs when required. With a focus on early-stage support, these next-generation CDMOs would do well to consider implementing processes to prepare sponsors for a smooth tech transfer process to another CDMO that is better adapted once they reach later stage clinical or commercial manufacturing stages. Such a shift would relieve pressure on CDMOs to become full-service partners and allow provision of phase-appropriate support to sponsors. A commitment to transparency can also include offering sponsors the unique opportunity to visit their facility or remotely connect to watch their therapies being produced on a larger scale. This operating model differs from what larger full-service CDMOs often have the capacity to offer, but transparency can be critical for sponsors at the process development and tech transfer stage. Given the critical nature of these early stages in determining whether an asset goes forward to clinical implementation, we propose that the biggest need is for CDMO support and expertise at the early stages, where preliminary efficacy is being studied. A next generation CDMO does not have to replace current players, but instead would service a niche market of early-stage drug developers in one technology focused area while preparing them for the next stages of late-stage clinical and commercial manufacturing.
CMC Expertise
Considering CMC early in development is critical to ensuring the success and integrity of advanced therapies, especially as a start-up or academic spinout. This goes beyond quality controls alone, with a dedicated adherence to phase-appropriate regulatory requirements being critical. A next-generation CDMO would be equipped with a team bringing sponsors the expertise required to assist with preparing CMC sections for regulatory submissions, ensuring compliance with various requirements. Additionally, CMC experts proactively anticipate clinical development needs, making suggestions incorporating what would be required for scaling up manufacturing processes starting in early development stages6.
This expertise is instrumental in the optimization of manufacturing processes, striking a delicate balance that not only enhances efficiency but also ensures cost-effectiveness7. These hands-on teams could thus assist sponsors with the whole product development journey, rather than just manufacturing. By assisting their clients in navigating regulatory pathways, CDMOs would play a critical role in helping optimize products & processes and ensuring successful journeys through clinical trials.
Affordability
A next-generation CDMO could employ several potential avenues to improve cost-effectiveness without compromising quality. Firstly, exploring options to share manufacturing facilities would allow CDMOs to offer more affordable pricing to early-stage clients by reducing overhead and variable costs. This would also introduce the opportunity to share use of equipment, personnel, and quality control systems, taking advantage of expertise while reducing the cost to CDMOs. There is also the option of novel payment models, such as renting manufacturing suite space on a pay-per-day or pay-per-month basis. Secondly, CDMOs can incorporate novel operating models involving streamlining or automating manufacturing processes, significantly reducing both time and resources required for development. Finally, cost efficiency can also be maximized by not solely relying on one equipment provider but equipping a facility with fit for purpose technologies to deliver seamless manufacturing processes at low costs. Manufacturing processes could thus be personalized to each product’s optimal requirements, considering future estimated clinical and commercial demands. Building a platform of devices from different manufacturers can allow CDMOs to flexibly manage costs and meet client needs in the most efficient way possible. With high commercial price tags often being a burden to clinical use of advanced therapies, CDMOs have an opportunity to start thinking about operation and pricing models as a way to support the development of affordable cell & gene therapies being developed by small biotechs and spin-offs.
Speed to Phase I/IIa
For sponsors, finding a CDMO partner with the capacity to help them reach First-in-Human trial stages as quickly as possible is critical. A CDMO that prioritizes adaptability brings the flexibility to align seamlessly with client project timelines. A flexible resource optimization model involving resource spread across multiple projects in parallel can also be considered, thus optimizing efficiency and mitigating potential bottlenecks in the development process. To maximize use of available capacity, projects can also be scheduled systematically based on sponsor milestones. Considering these aspects, a next-generation CDMO could offer start-ups the unique opportunity to partner with a CDMO that prioritizes efficiency and rapid project progression, operating with agility just like them. CDMOs focused on meeting the unique needs of companies at early clinical stages could be the key to helping innovators develop their assets quickly and efficiently to Phase I/IIa while equipping them for future success and industrialization, ensuring these life-safing therapies will reach patients for clinical impact.
Conclusion
A next-generation CDMO that is equipped to partner with start-up and spin-off companies is critical in advancing access to cell and gene therapies. This requires a focus on CMC expertise to ensure the quality and consistency of therapeutic products, equipping start-ups to navigate the complexities of regulatory compliance with ease. A unique operating model ensuring affordability is also key, ensuring sponsors reach First-in-Human quickly and cost-effectively, empowered to move forward. Above all, a next-generation CDMO should aim to create an environment where partnerships flourish, working together with sponsors for mutual success. We envision a future focused on driving innovations that not only meet but exceed the evolving needs of cell and gene therapy developers, translating lab discoveries to clinical practice and ultimately shaping a new era of possibilities in transformative healthcare solutions.
References
- Citeline. (2023). Gene, Cell, + RNA Therapy Landscape Report: Q2 Quarterly Data Report. American Society of Gene + Cell Therapy.
- Business Tech News, (2023, September 11). CGT CDMO market: Growth, size, and share (2023-2030). LinkedIn.
- CDMO market trends and Dynamics. Manufacturing Chemist. (n.d.).
- Garguilo, L. (2024, February 19). Why are cell-therapy outsourcers unhappy? investors know. Ecosystem Investing for Cell-Therapy Outsourcing.
- The CGT CDMO bottleneck isn’t capacity–it’s capability. European Pharmaceutical Review. (2023, June 12).
- Pralong, A., Galliher, P. (2013, April 2). When the process becomes the product: Single-use technology and the next biomanufacturing paradigm. BioPharm International.
- Jacquemart, R., Vandersluis, M., Zhao, M., Sukhija, K., Sidhu N., Stout, J., (2016), A Single-use Strategy to Enable Manufacturing of Affordable Biologics, Computational and Structural Biotechnology Journal
