Transitioning from early R&D into clinical trials is a common bottleneck in our industry. How can this be streamlined and improved upon?
Transitioning or translating a cell and gene therapy process and product from development to clinical manufacturing is certainly a major milestone, but not without its challenges, as we all know. Reducing potential bottlenecks to support a more efficient transition is important to the overall success. So, from a research and process development standpoint, while they're typically performed at a much smaller scale with fewer quality control steps, as has been well documented, it's critical to address the quality and scalability of the process. Therefore, one of the most effective tasks that can be performed is a risk-based assessment of the product and the process early in development, as this will help to determine manufacturing gaps to assess scalability and, importantly, identify the critical raw materials. For any cell and gene therapy, the starting or source material is the most critical raw material. The best method to streamline or remove some of the bottlenecks is to limit or reduce source material variability by establishing a robust supply chain early and eliminating overarching quality concerns such as access to GMP-compliant materials. Developing strong collaborations and communicating early with critical raw material suppliers will help to limit process changes and ensure a more seamless transition for long-term clinical and commercial success.
Ensuring consistency of raw materials for allogeneic therapies is becoming an increasing challenge. How can companies plan effectively to ensure consistency and what role do healthcare professionals play in this?
With any CGT product, raw materials play an integral role in the development and long-term success. Given their impact, consistency and reliability of raw materials are perhaps the most essential variables to consider. For allogeneic therapies, one of the most critical and most variable materials is the donor starting material. You want to minimize the potential need for any changes to the raw materials once a process and product transition from development to the clinic. As we know, having to make a significant process change will require some level of comparability studies, which can result in lengthy delays and increased cost.
Eliminating lot-to-lot variability of raw material by establishing the appropriate quality controls is a prime example of ensuring process and product consistency. Given the inherent intrinsic and extrinsic donor characteristics, there is added complexity when defining something like control of lot-to-lot variability for the therapeutic starting material. People and, therefore, donors are variable so for the CGT industry, minimizing variability of starting material is critical to long-term consistency.
To that end, there are several points that should be considered when developing an allogeneic therapeutic reliant on a donor-derived starting material. First, as a manufacturer, it’s important not to begin with highly restrictive donor criteria early in development. Having restrictive donor criteria in place can severely limit donor accessibility. This may not seem like an issue during product development, but much like other critical raw materials, you must think long-term and consider scalability. It's important to engage early with your source material provider to understand the challenges and potential donor pool limitations. Even though you should begin with flexible donor criteria, the criteria will tighten as the process develops to reduce variability. Ideally, you want to work with a provider that has established a large, diverse, well-managed donor pool. Donor access is of course needed, but in order to substantially aid in increased process consistency, having access to a robust recallable and reliable donor pool is key. In other words, the ability to go back to the same donor or same set of donors during the therapeutic lifecycle can reduce the lot-to-lot and collection-to-collection variability and help to ensure long-term availability.
Beyond the donor pool and recalling donors, there are of course other areas, particularly how the products are collected, that will affect the consistency of the product. Certainly, the robustness of the quality systems that are in place, not only for the collection but also for the downstream processes that occur post-collection, will certainly provide favourable impact to process consistency.
What's the key to donor accessibility throughout the development lifecycle from R&D to commercial supply?
Donor accessibility is certainly a very important question for anyone pursuing allogeneic therapies. Referring to the previous question, donor availability starts by ensuring access to a well-established, diverse and extensive donor pool that is both reliable and recallable. Without access to the source material, there is no product. With that in mind, you still want to try and maintain as much flexibility in development as possible with respect to the donor requirements. This might include aspects like age, BMI or ethnicity for example. Over time, you might consider establishing a customized or reserved donor pool to support the product lifecycle. For development and clinical manufacturing alone, this could require multiple years so extended access doesn’t just require available donors but also expertise in active donor management.
To ensure donors, especially reserved or dedicated donors, remain available, active management is necessary to keep them engaged.
Once donor criteria are determined and a reserved donor pool has been established based on the required CGT therapeutic output, ensuring donors are available for that product over the long-term is very challenging. A CGT manufacturer might need a leukapheresis collection every two months for development purposes, but then the demand changes to a collection once every six months during an early phase clinical trial. Donors are people with everyday lifestyles, stresses and other responsibilities. To ensure donors, especially reserved or dedicated donors, remain available, active management is necessary to keep them engaged. Some examples of individual active engagement might include regular phone calls, testing and collections, whereas active management of a dedicated donor pool could also include screening and testing of new potential donors. Without these necessary management steps and techniques, a manufacturer simply might not have access to the necessary starting material when it’s required. Here again, with any critical raw material, establishing a robust supplier relationship is important. You need to collaborate and partner early in process development to make sure both parties are aligned with immediate and extended goals to increase the chances of long-term success.
The supply chain for advanced therapies is highly complex. How can raw material collection and management be streamlined to help manage complexity and what are the most important factors to ensure viability and quality of starting materials?
Again, for an allogeneic product, everything points back to the starting source material and donor management. The quality of the primary cells required for the actual manufacturing process is reliant on the collection and, in many ways, the health of the donor at the time the collection is performed. Given the inherent variability from donor to donor and even between collections from the same donor, active donor management, as stated earlier, directly impacts starting material quality. It begins with a proper donor health assessment followed by managing the donor ahead of the planned collection which includes ensuring they aren’t sick and they’ve been eating properly and hydrating appropriately. Unlike traditional blood centres, it takes a very experienced apheresis collection centre to understand the intangible components related to managing such a complex donor pool for allogeneic starting material. Any single one of these factors can negatively impact the quality of the collection and the product and this is all prior to the physical collection! For the actual collection process, there are numerous critical factors that can impact the quality of the starting material. Having proper collection devices and qualified, validated procedures are important, but the quality of the apheresis nurses and the number of supporting personnel performing the collections are invaluable to resultant quality and consistency.
Following the physical collection, it's imperative to understand what the downstream aspects are for that product. We must keep in mind that the starting material is composed of a complex mixture of living cells, which have a limited shelf-life from the point of collection. Oftentimes, products are collected and shipped fresh to the processing facility, but stability is limited meaning that cell viability and overall starting material quality is diminishing with time. So, considering options where you might extend that stability to not only improve the quality but the downstream flexibility, is an important aspect to think about early in your process. Fresh is certainly best but receiving the product fresh will not always be possible especially when you consider scale-up beyond early process development. With any critical raw material, delays can occur and for a starting material, which can significantly impact quality. To streamline access and maintain cell viability, options including immediate processing following collection and/or cryopreservation should be considered. Some collection facilities, like HemaCare, are equipped with onsite GMP-compliant cleanrooms to perform cell isolation and cryopreservation within hours of collection. The ability to cryopreserve a product as soon as possible post-collection is a critical aspect to consider in the effort to minimize any loss in product quality. Onsite processing can help streamline downstream processing steps and reduce variability in an effort to support stringent quality requirements when transitioning from development to clinical manufacturing.
What are the answers to shipping these time-and-temperature-sensitive materials globally?
Yes, this is definitely a critical question for cell and gene therapy products. It certainly depends on the product, the downstream processing needs of that product, and lastly the long-term strategy for the therapeutic. As we discussed previously, the stability of the starting material is a limiting factor, especially when you're working with a fresh product, and shipping that product, potentially, long distances either from one side of the country to the other, or even globally. It’s imperative that you fully assess and understand the process and product needs over the entire lifecycle and then manage the stability requirements of the starting material. For example, process development or early phase clinical trials may be local to the collection facility. Receiving the starting material fresh is very convenient but if the later clinical phases require the starting material to be shipped and manufactured globally, fresh will not be nearly as convenient. As mentioned, a potential consideration is to perform immediate processing and to cryopreserve that starting material at the collection site. This will eliminate some of the concerns over the limitations in the shelf-life and the stability of that starting material.
No matter how you prepare your starting material, the valuable material still needs to be shipped to the downstream processing facility. With that in mind, it's essential to develop a robust supply chain early and establish collaborations with the logistics providers that are integral to shipping these products. Having that communication and understanding together will only ensure that if there are potential hold-ups during the transit, as commonly happens, the materials are properly managed and arrive as intended. So again, developing a strong relationship with the logistics providers will reduce some of the risks and ensure the materials arrive as planned.
What impact will commercialization of allogeneic therapies have on starting material accessibility?
That's a very interesting question given the state of development of allogeneic therapies, and the consideration for the donors and the donor starting material. One of the biggest areas that will likely be impacted is donor access and that reflects the earlier questions about the robustness of the available donor pool. If the initial donor pool is limited, then the long-term supply chain may be a crucial factor. Active donor management is another point that will need to be assessed. Currently, aside from a few products, the product lifecycle for allogeneic CGTs have mainly been short-term given most products are entering early clinical phase testing. The requirements of the donor starting material to support commercialization will potentially be far more extensive. It is an emerging industry and we are learning and adapting as we go.
We don’t necessarily know the true impact that commercialization of allogeneic therapies will have on donor starting material access, but we are addressing this collectively. You can include many of the aspects touched upon in the earlier questions as each will be a factor. As a manufacturer, you don’t want to start off with stringent donor requirements as that immediately limits donor and starting material availability. Once the process has been finalized, it will be important to maintain long-term consistency by establishing a dedicated donor pool but commercialization will require active management for greater security of supply. As the old saying goes in this industry, you have to begin with the end in mind.
Having dedicated or reserved donor pools to support a specific allogeneic process and product is certainly ideal with respect to long-term supply continuity, but I also think it’s important to consider the potential long-term impact that this could have for the industry. As we begin to have more and more commercial success with allogeneic products, available donor pools could become limited especially if each respective allogeneic manufacturer opts to have custom, reserved donor pools. With proper donor management and industry collaboration, donor and source material availability will remain strong, but we will need to monitor this key aspect collectively. One final key aspect that I will leave for consideration are the ongoing questions around donor testing and eligibility and how the banked materials intended for clinical and commercial manufacturing are managed over the product lifecycle. As novel infectious diseases arise for consideration, how does this impact banked clinical and commercial starting material or cell banks? A well-designed risk assessment will help to resolve this question along with many of the other factors impacting the importance of the starting material especially if this is performed early.
If my biotech is operating smoothly in the US, what do I need to be aware of when opening clinical trials in Europe?
I would say donor eligibility is perhaps one of the biggest aspects to be aware of when considering the use of the starting material for an allogeneic therapy for global clinical trials. Donor eligibility requirements are variable and are not aligned regionally. We would stress to our clients that they need to take the time to engage early and regularly with the respective regulatory bodies that have oversight of the eventual clinical trials and determine what their regulatory obligations truly are upfront. Often, clients will assume they have the full picture from reviewing available regulatory directives or citations, or worse yet, they decide that taking the most stringent approach is best and then require donor criteria that have no regulatory basis. Once you’ve gone down that path and included such criteria in your regulatory filings, you are stuck with these requirements. This type of approach goes back to our earlier discussion about having highly restrictive donor criteria early in the process as this can severely limit long-term access and availability.
You should also keep in mind that many of the regulatory agencies are still very much in the process of trying to determine what qualities the starting material donor should meet for an allogeneic product. Factors like HHV6 and HHV7 status are currently a prime example of this aspect and clients should need to understand this is a rapidly evolving area. As I mentioned in the prior questions, new issues may be identified in patients in clinical trials requiring donor eligibility criteria to evolve to meet industry needs. Engaging early with dedicated starting material providers, who have extensive knowledge with donor requirements and eligibility, will help ensure long-term clinical and commercial success.