Considerable progress has been made in the development of cell and gene therapies (CGTs) over recent years. Many new CGT products have already been approved by regulators in the US, EU, and other parts of the world, and many more are in development. The most exciting part is the improvements in patient outcomes that CGTs can potentially achieve. This applies to a range of conditions, including rare and difficult-to-treat conditions such as cancer.
Furthermore, there is an expectation for many CGTs in development that they will be curative, so will replace the lifelong treatment of chronic diseases. In some cases, there is the possibility to achieve this with a single treatment.
While the potential of CGTs is game-changing, there are significant challenges and barriers to overcome – challenges and barriers that are limiting the development and widespread use of CGTs. Examples of those challenges include:
- Clinical trial challenges, including finding enough trial participants, particularly when therapies are being developed for rare conditions.
- Complex regulatory processes that are still evolving.
- Commercialisation, value realisation, and profitability challenges.
Manufacturing is another major challenge limiting the deployment of CGT therapies. It is those manufacturing challenges that we will explore in this blog.
The Challenges of Manufacturing CGTs
Manufacturing CGTs is considerably more complex than manufacturing most other pharmaceutical products.
Specialist facilities are needed, and they are in short supply.
Specialist skills are also needed, and they are in even shorter supply.
While all CGTs present complex manufacturing challenges, including allogeneic (i.e., off-the-shelf) therapies, autologous cell therapies are among the most complex.
With autologous (personalised) therapies, cells are taken from a patient, often in a hospital setting. They are then sent to specialist manufacturing facilities where the therapy is manufactured and sent back to the hospital to be administered to the patient. The challenges of this process are numerous, but the main issues include:
- Time – many autologous cell therapies are highly time-sensitive, i.e., the therapy needs to be administered to the patient as soon as possible after the cells are extracted. This can be for many reasons, including the fact that some patients are in the late stages of disease, so simply won’t survive to receive the treatment if the manufacturing process takes too long.
- Distance – the specialist facilities needed to manufacture CGTs can be located far away from the patient’s clinical setting. This is already a problem in places like the US and Europe, but it is even more of a challenge when other regions of the world are considered.
- Raw materials – many of the raw materials required to produce CGTs are non-conventional, including cells taken directly from patients. This presents supply challenges.
- Quality control – strict quality control procedures need to be followed throughout to prevent contamination, for example, or to maintain the right temperature and environmental conditions at all stages of the process.
- Logistics – even the smallest logistical hiccup can have serious consequences. In fact, the logistical precision required to produce autologous cell therapies is practically impossible to achieve consistently and at scale using traditional manufacturing approaches. Chain of identity and chain of custody processes are also complex to create and manage.
The CAR T Example
CAR T is a cell therapy where chimeric antigen receptors (CAR) enable T cells to identify and kill target cells in the body. There are multiple CAR T products currently approved for use in the US and other jurisdictions. There is also increasing evidence of the effectiveness of CAR T therapies in inducing remission in patients with cancer and autoimmune diseases.
Despite its effectiveness and potential, the rollout of CAR T therapies has been severely limited. There are a number of reasons for this limited rollout, including the challenges faced by other CGT products. There are also CAR T-specific challenges, such as patients developing toxicities and minimal clinical response rates against solid tumours.
As with other CGTs, another major challenge to achieving widespread rollout of CAR T is the complexity and cost of manufacturing.
CAR T therapies are autologous therapies. As they are unique to each patient, they need to be manufactured in what is essentially a batch size of one. Time is also a critical factor with CAR T therapies, as CAR T therapies are most effective when administered as soon as possible after the T cells are harvested from the patient. Ideally, this should be days at most.
Personalised cell therapies currently take about 2-3 weeks to produce, but that is a best-case scenario. The reality is that even a 2-3-week production timescale is rare because of the availability of suitable manufacturing capacity and resources, and the complex logistics that are involved.
That is before you even factor in financial and scalability considerations, both of which are essential to make CAR T therapies widely available and affordable for hospitals and patients, as well as profitable for pharmaceutical companies.
Overcoming the Manufacturing Challenges of CGTs
Allogeneic therapies are more compatible with traditional centralised manufacturing approaches. However, innovative solutions will need to be developed to overcome the challenges of manufacturing autologous therapies. Many allogenic therapies will also benefit from these new manufacturing solutions.
There are six main areas that need to be addressed to overcome the manufacturing challenges of CGTs.
Product Development Cycle
It is essential that manufacturing is considered early in a CGT product’s development cycle.
Additional CGT manufacturing capacity is required, although how that is developed and structured is likely to require a novel approach – see the last point below.
Increasing Skills Availability
The industry needs to increase the availability of skills to ensure manufacturers can recruit and retain the people they need. The fact there is a skills shortage at the moment is understandable as CGTs are an emerging part of the life sciences sector. However, CGTs are expected to continue growing rapidly, so it makes sense to address the skills shortage urgently.
Automate Manufacturing Processes
Automation will play a crucial role in making CGT manufacturing viable both from a practical and financial perspective.
Supply Chain Optimisation
CGT manufacturing supply chains need to be optimised to ensure a consistent supply of materials, including materials such as viral vectors and plasmids.
Bring Manufacturing Closer to the Point of Care
This solution to CGT manufacturing challenges will be the most disruptive, but it also has the potential to be the most transformative. By bringing manufacturing closer to the point of care through innovations like mobile manufacturing facilities or manufacturing-in-a-box concepts, the production of CGTs becomes much more viable:
- The time it takes to manufacture CGTs will be considerably reduced.
- The number of steps will be minimised.
- Human involvement in the manufacturing process will be minimised, particularly when combined with automation technologies.
- The logistical challenges that currently exist can be minimised and potentially eliminated.
The Starbucks Model
There will need to be detailed collaboration between hospitals and manufacturers, but taking a Starbucks approach is likely to be the best route to ensuring the widespread adoption of CGTs, particularly autologous therapies.
The highly skilled team at Starbucks’ Seattle headquarters can probably make a delicious cup of coffee. However, that is no good if you are in Boston, Dublin, Rio de Janeiro, Nairobi, Hanoi, or Auckland. By the time it reaches you, what’s left in the cup will be cold and horrible. What you need is a Starbucks close to the point of need with well-trained baristas using specialist equipment and carefully sourced ingredients.
As mentioned previously, the Starbucks approach is a disruptive model for an industry that has achieved significant success using high-speed, high-volume manufacturing. However, to keep up with the scientific advances being made in CGT development, manufacturers need to embrace this new level of innovation and disruption.