Manufacturing advanced therapies is a business theme
A recent report by Deloitte on their survey amongst Cell and Gene Therapy (CGT) Executives, reveals careful and widespread (90% of responders) optimism in the sector about the next coming 12-18 months and highlights the factors most impacting confidence.
These advanced therapies have already delivered breakthrough results for the patients. The number of CGTs approved and now available to patients has been increasing over the years, providing new treatment modalities to diseases that have so far represented a high burden for the patient and for the health systems. With more than 1800 clinical trials running worldwide, more approvals are expected in the coming years.
CGT is one of the most exciting and fast-growing sectors of medical innovation. It is also one of the areas where the production of the therapies is very complex and the price of the treatments is so high, that novel payment models had to be developed.
There are many manufacturing challenges for CGTs, given their relative novelty. This also means that there is a lot of opportunity for innovation and for working with regulators on the critical safety aspects of these therapies.
In Biopharma business conferences, manufacturing tends to be a subject less discussed than for example patient populations or a drug target or mechanism of action. We, at chart Biotech have been arguing that developing a fit manufacturing strategy is essential for company success. In this Deloitte CGT survey, the subject of manufacturing appears as one of the top priorities for the ecosystem of executives surveyed. Manufacturing is cited by the respondents to the Deloitte survey as 1.) a critical aspect in itself, 2.) a priority within regulatory and 3.) a critical aspect in commercialization, given the current manufacturing scale-up challenges.
For this report, Deloitte surveyed executives working with CGT innovators (55% of respondents), healthcare providers and CDMOs (Contract Development and Manufacturing Organisations), their roles spanning multiple areas beyond manufacturing alone. CDMOs are essential within the Biopharma ecosystem and they are critical in the establishment of manufacturing innovation and the advancement of innovative biotherapies.
CGTs requires complex manufacturing, often developed patient by patient. Scaling up such therapies poses specific challenges, for which a range of strategies is being deployed. The top three critical obstacles to scaling up CGT manufacturing cited in this report are:
- Limited access to resources (e.g., talent, supplies, raw material)
- Lack of standardized/proven manufacturing technology
- Inflated cost of capital and/or limited access to capital
We want to highlight that access to talent is one of the concerns of these executives, for the short term. Education and training for Biomanufacturing Engineers and Operators is a critical piece of the future success of these therapies and beyond. In the coming months, we will be looking and writing about what is being done to mitigate the current need for trained workers for the biomanufacturing expansion that is anticipated, to meet the needs of the various industries.
“Nearly 40% of respondents lacked confidence in their current manufacturing capabilities to meet demand within the next two to three years. Short-term barriers to scaling up manufacturing included limited access to inputs (e.g., raw material supply), lack of standardized or proven manufacturing technology, and limited access to capital”.
While the “proven manufacturing” status will be reached over time and use of the novel modalities, standardizing raw materials and ancillary materials should be reachable in a shorter timeline, but limitation in access to inputs may remain an aspect that developers need to learn to accept, given that some CGTs are personalized and that the patients’ own cells are sometimes used as starting materials.
These advanced therapies processes may require new ways of defining product standardization, in close dialogue with the regulatory agencies. Access to capital for scaling-up manufacturing likely will remain a challenge, until manufacturing processes become “proven”. Meanwhile, the challenges in scale-up will need to be addressed, with CDMOs playing a significant role in supporting early clinical development.
When asked about the top three forces expected to significantly impact commercialization of CGTs in the next 12–18 months, the Deloitte report respondents highlighted 1.) payer and reimbursement challenges, 2.) ability to raise capital, and 3.) manufacturing capacity and quality consistency constraints.
Commercialization is of course tightly related to the ability to scale-up production within the required quality parameters of the industry, thus it is not surprising to find that challenges related to biomanufacturing processes are being recognized as critical in the path to CGT commercialization.
The biomanufacturing Ecosystem
Biopharma has for more than 20 years adopted a manufacturing subcontracting approach, with CDMOs constituting important players and stakeholders in the industry. Business models for CDMOs are varied, and it remains a challenging business. The big opportunities to make money are well identified, and there is strong competition amongst CDMOs for those.
In the early development stages of a therapeutic (including process development and transfer of technology), the risk is very high all round, both for the sponsors of the novel treatment modalities and for the CDMOs servicing them. This is the case even for very well established technologies such as the production of monoclonal antibodies with mammalian cells, or use of E.coli to produce plasmid, let alone for novel molecules or novel manufacturing systems and technologies. Robustness of process is an important objective in biomanufacturing and the broad experience of CDMOs can be an important contributing success factor.
It is nevertheless important to bear in mind that for successful outcomes, both sponsor and CDMO need to invest in the business interaction. While a CDMO has an interest in supporting their early-stage clients to reach the more profitable later clinical and commercial phases, the sponsor needs to have a keen interest in developing a robust process for its assets. As we all know well, and numerous specialist articles and reviews illustrate, subcontracting has nothing to do with “throwing the parcel” over the wall, and waiting for a result be thrown back.
Once a bioprocess is in control, there is strong predictability of product quality, but the path to a well- controlled process can be long and expensive.
CGTs suffer from all these challenges and more, as some treatments are living cells that will interact with patients, whose health status may be very weak.
For a CDMO contracting any bioproduction early-stage process, there is always a risk that the sponsor may fail in the clinic. This risk impacts the overall portfolio of clients for the CDMO, who needs to account as well for the risk of a sponsor not being able to raise the funds needed for clinical development of new molecules and/or new treatment.
It is also understood that, though there are well established parameters for biomanufacturing of classes of molecules such as mABs, for new classes of molecules – or even for some challenging mABs – the biology of producing the molecule may be less understood and it can feel like the process knowledge accumulated with the CDMO experience needs to constantly be adapted to new processes. A successful CDMO is not only technically excellent, it is also excellent at initiating and keeping long term businesses with its customers.
We mentioned here that manufacturing is not a subject that tends to feature high up in the agenda in business discussions – except as we see in this report, when it becomes clear that manufacturing is impacting the business. In CGT, manufacturing capacity or quality consistency constraints is cited by respondents to the Deloitte survey as one of the “top three forces expected to significantly impact commercialization of CGTs in the next 12 – 18 months”.
For perspective, let’s remember how in the early 2000s, concerns about lack of manufacturing capacity for mAbs were impacting the industry. In 2023, the annual BioPlan industry survey indicates that 29% of respondents indicated that they were doing all of their biomanufacturing for mammalian platforms (the split for mAb and viral vector production is not cited) in-house; this is half the proportion of companies who reported similarly in 2006 (58%), according to Langer, president of BioPlan.