What Is CMC in Cell and Gene Therapy? Why Companies Fail on It
CMC stands for chemistry, manufacturing and controls: the work of showing that a therapy can be made consistently, at scale, to a defined quality standard. In cell and gene therapy it is often where companies fail. David Crean, an investment banker and founder of Cardiff Advisory, told Lori Ellis on Open Door Salon that he has watched many companies fail on CMC. A founder who treats it as an afterthought, he said, presents an incomplete story to investors. Phil Vanek, chief commercialization officer of the International Society for Cell & Gene Therapy (ISCT), called manufacturing and control of the supply chain the backbone of a successful product.
Why do cell and gene therapy companies fail on CMC?
Because manufacturing is treated as a late-stage problem when it decides whether the product is real. Crean described the pattern he sees in meetings and in boardrooms, where CMC gets the last five minutes of the agenda:
In this area cell and gene therapy, I think it actually needs to be higher up in that agenda. It's such a huge point because I've seen so many cell and gene therapy companies fail on the CMC aspect. And so it cannot be a part of the appendix. It needs to be brought up.
For a cell or gene therapy, the manufacturing process is closely tied to the product itself. Crean put it the way he was taught, that the product is a process and the process is the product.
What do investors need to see on CMC?
Evidence of consistency, scalability and a believable cost. Crean set the bar plainly:
If you cannot demonstrate consistency, scalability, and credible cost structure on this CMC, I frankly feel that the clinical story is really incomplete.
That is why, in his view, the asset an investor wants is one with the biology shown to work and proof that the product can be manufactured reproducibly. The FDA's own expectations for gene therapy programs entering the clinic are set out in its guidance on CMC information for human gene therapy INDs.
How does ISCT look at manufacturing?
As one perspective among several that a product has to satisfy. Vanek described the society's membership as spanning the asset, manufacturing, and life sciences tools and technologies, and said that mix shapes how ISCT approaches CMC:
Manufacturing and more broadly CMC, kind of having control over supply chain all the way through manufacturing as well as optimization of processes, is kind of the backbone of a successful product.
He linked that to commercialization: a therapy has to be one the market needs, and it has to be one the company can actually make and supply. Both questions arrive early for an investor reviewing a cell or gene therapy program. On the deal side, Crean explains in how long biotech M&A deals take why an acquisition announced at the J.P. Morgan Healthcare Conference usually began months earlier.
How does CMC connect to the target product profile?
The profile defines what the product must be; CMC shows it can be made that way. Vanek came at the CMC question through the target product profile, the document we covered in what a target product profile is and why to write it first:
I do agree with David that ultimately the CMC, if you can't make it, you can't manage a supply chain, then it's going to be dead in the water anyway.
How should a company harden its manufacturing supply chain?
By checking every component, supplier and contract against the scale the product will need. Vanek described what he evaluates:
Do you have redundancy where needed? If it is a sole source product, is the supplier up to the quality standard? Is the supplier also able to provide to whatever your TPP scale will demand?
He added that companies may need longer-term supply contracts to secure the components their process depends on. A sole-source input that cannot scale with the product is a CMC risk even when the science is strong.
What about the distribution side of the supply chain?
It needs the same testing as production. Vanek separated the two supply chains: manufacturing, and delivery into the market. Distribution, he said, means deciding whether a therapy goes through specialized clinical centers or regional medical centers. It also means confirming that cold chain, chain of custody and patient identity management are in place and tested. His summary:
So security of supply, but then also a very hardened and robust ... distribution network is going to be absolutely critical for success.
Is manufacturing cost the biggest risk?
Not in Crean's ranking. He puts capital first, reimbursement second and manufacturing cost third, and explained why cost comes last even though it is a major problem:
The engineers and certainly the industry that are affiliated with like cell and gene therapy, they have the greatest ability to engineer against through like process improvement, scaling, automation, better manufacturing technology.
In Crean's framing, cost is the constraint engineers can work down over time, while consistency and scale are what an investor needs to see demonstrated. The cost side of the field is examined in why cell and gene therapy is so expensive. Why reimbursement ranks ahead of cost, and why Crean and Vanek say payer planning starts early in development, is covered in when a biotech should plan for reimbursement.
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This post is drawn from the recorded, on-the-record conversation between Lori Ellis, Phil Vanek and David Crean on Open Door Salon; quotes are lightly edited for clarity, and the full episode is the record.