Alleviating CGT bottlenecks: Standards needed to ensure volumes, quality of starting material

Adding capacity, building efficiencies, and alleviating bottlenecks within the cell harvest infrastructure is essential to ensuring high-quality starting material will be available, said the company, which provides cell sourcing services for allogeneic cell or gene therapies, as part of its raft of services.

Any misstep in this area can mean significant, costly setbacks and delays.

Optimizing the identification, sourcing, collection and delivery of allogeneic donor starting material is therefore key, said Chris McClain, senior vice president, sales and business development, BTMB.

“Right now it is not clear to anyone who exactly or what consortium of suppliers may be able to supply the prospective commercial volumes and then an additional challenge will be ensuring those volumes in a consistent and quality manner. ​

“We, as suppliers, are working on this issue but we also need industry to participate,”​ he told BioPharma-Reporter.

He is calling on cell and gene therapy (CGT) developers to step up in terms of engagement with BTMB and other vendors to develop standards as part of the effort to ensure a reliable supply chain for starting materials.

Customization challenge

“Currently there is a lot of customization, a lot of custom build in terms of the requests for allogeneic donor starting material and I think it is unsustainable, and I would bet a lot of it is unnecessary. ​

“Let’s weed out what is essential and what is it non-essential for the betterment of the industry.”​

There is a variety of different starting materials that CGT developers might want to manufacture with: from whole blood to stimulated apheresis to bone marrow to core blood units.

“These might all be excellent vehicles for manufacturing but, within each category, what we, and I believe other vendors, are observing is that the companies are experimenting with the specific criteria they would like met in each donor category, some want donors that fit a certain demographic, often resulting in the use of more sophistical screening panels, such as genetic ones. ​

“And while we have to constantly remember that the field is pioneering, that it is breaking new ground every quarter, and that there aren’t really tried and true methods for doing a lot of this, the question, from a supply side, is how much of these [multiple and varied demands] can we bear? ​

“For example, if we have 15 clients that all want non-mobilized apheresis product – a leukopack – but each of them want something slightly different in that leukopack, while it can be done, it is going to take a long time and it will be expensive. ​

“And if that is the model for the future, you could then have a potential scenario where each of those 15 companies go on to have an approved product, and they all increase their demands for their particular type of donor by 10-fold or even 15-fold. I just don’t see such a model working,”​ stressed McClain.

Companies might also request that harvesting occurs on a specific machine, using specific tubing and bags. “We all understand that: manufacturing of these drugs is highly regulated and you don’t want to change the process. But does it actually make a difference if the specific machine, bag and tube are used? Probably not. So we, as an industry, could look to standardize those aspects, going forward.”​

And the industry might look to standardize in terms of donor characteristics as well, added McClain.

Standards development projects 

Prior to the pandemic, BTMB hosted the AcCELLerate Summit,​ where it convened industry stakeholders to progress standardization efforts in the CGT space, said McClain, with the executive acknowledging that there are a number of standards building initiatives now in play.

Some of the more prominent, ongoing projects include the initiative led by the FDA-funded body, the Standards Coordinating Body for Regenerative Medicine (SCB); it is looking to identify and understand the areas with the greatest need for standardization to help the industry advance as quickly, for the benefit of patients. 

ASTCT has recently launched a standards building initiative, and management consultancies, Accenture and Deloitte, both have similar efforts underway, with additional work in the space being done by smaller groups throughout the EU and the US, said the BTMB executive.

Such work though, stressed McClain, requires a lot resources, and it is challenging to get consensus on a lot of the issues from the multiple actors involved in the field.  “BTMB is ​in the midst of it, we are leading in some cases, we are participating in others.”​

Building donor pipelines

Another constraint he highlighted is the fact that many organizations do not have decades of experience building pipelines comprising thousands of donors.

The strength of BTMB is that it is business unit of Be the Match, a group critical to the global bone marrow and hematopoietic stem cell transplant ecosystem, and one that relies extensively on allogenic donors, he said.

“In the case of Be the Match, that involves over 6,000 donors a year; we need to secure those for the benefit of leukemia and lymphoma patients. So, as an organization, we are very good at this. We have built a pipeline through which we can acquire thousands of donors every year for the special purpose of bone marrow and hematopoietic stem cell transplants. We are unique in that way; the rest of the cell therapy industry has not been in a position where organizations have had to acquire that number of donors a year for any therapies as they are all still in clinical trials. The number of patients that might be prospectively treated in a clinical trial for a cell therapy could be 100 individuals over two years, and that requires a very different set of processes from what is needed to acquire 6,000+ donors per year. ​

“So we have experience doing this and BTMB is the avenue through which the emerging cell and gene therapy industry would tap into that infrastructure.”​

But, regardless, a bottleneck remains: the lack of vendors that could supply thousands of donors to support a commercially approved cell and gene therapy, he added.

“Fundamentally, the supply does not exist. We will be one of the biggest players [in the CGT space] but this is a new endeavor for us as well.”​

Apheresis capacity 

On top of those challenges is the issue of apheresis capacity.

The US national apheresis capacity was never built with approved cell therapies for prevalent solid tumor cancers - lung or breast - in mind, where you might have hundreds of thousands of patients being treated annually, he remarked.

“There is not enough capacity in the US network, not even close, to harvest that many donors, whether they are autologous or they are​ allogeneic. There are not enough machines or beds, and there is not enough personnel. ​I think the industry needs to be prepared to make an investment in that infrastructure to secure that critical capacity because, right now, it is just riding on top of the existing infrastructure,"​ commented McClain.

By way of comparison, he noted how, in relation to the CGT manufacturing bottleneck, with restricted contract manufacturing capacity, and production processes that are cumbersome, and labor and people intensive, the industry has not been long in finding solutions. 

“What has been the reaction of the industry to the manufacturing bottleneck? It is developers raising hundreds of millions of dollars and building their own manufacturing facilities. This is happening all over the industry. So maybe companies can raise hundreds of millions and dollars and invest in their own apheresis centers as well. It goes hand in glove with manufacturing.”​

In the allogeneic cell therapy arena, there is still the hope, though, that the requirement for a massive amount of donor material could be reduced dramatically if the final product created from a single donor can be expanded, stored and used to treat multiple patients, commented McClain.

“Maybe from just a handful of a few donors you could manufacture thousands of therapies. If that is the case, if that is the future, of course the simple math is that apheresis capacity is much less of an issue. ​

“On the other end of the spectrum, though, there are allogeneic cell therapies that rely on the building of banked inventoried cells and those will continue to need increasingly large volumes of donors just to sustain the banking of the cells. So it depends on which model wins out.”​ ​