By, Arthur Tzianabos, CEO of Lifordi, as part of the From The Trenches feature of LifeSciVC
I often hear biotech leaders refer to their company’s technology and approach in terms of the “secret sauce” or “how the sausage gets made.” I have probably used these phrases myself over the years. But here is an interesting question…I wonder how often these words are said with the company’s Chemistry, Manufacturing and Controls (CMC) in mind?
CMC is usually on the critical path and increasingly a major cause of Complete Response Letters (CRLs). Of the >270 CRLs released by the FDA in recent months, more than 50% of the rejections cited CMC issues and resulted in significant delays, as Bruce Booth highlighted in Atlas Venture’s Year in Review 2025. Perhaps this is not surprising given the difficulties in developing and producing some of the more complex medicines we have today. With the regulatory requirements for advancing research grade material to clinical supply and then moving to developing and manufacturing pivotal trial supply, it seems that it’s one gigantic leap after the next.
CMC represents a significant expense and is often the highest risk since a major part of the spend precedes clinical data. So why don’t we talk about CMC more across our companies and in Boardrooms? Why don’t we share what we’re learning along ‘the CMC way’ so that we can help others adopt and cultivate the right mindset at each step, thereby achieving better outcomes for patients?
Here, I will piggyback on the irrepressible Mike Gilman’s most recent blog on LifeSciVC. Mike described a fundamental truth about science: “There are standards – the right way to do science – and they are non-negotiable.” Back in my graduate school days in the Department of Microbiology at the University of New Hampshire, I met a guy early in my first year who was in the Biochemistry Department (one floor below us) named Dave Nichols. We hit it off immediately as we shared a similar view on scientific rigor and the quality of the draft beer at the local bar in downtown Durham where we often went to grab dinner (and a beer) after a long day in the lab and before heading back to finish up with experiments later into the evening. That was 40 years ago…so how does this relate to the topic of CMC you might ask?
Post graduate school, I spent 15 years heading up a lab at Harvard Medical School where it turned out that manufacturing was key to the success and quality of the research we did to establish a new paradigm in immunology: that polysaccharides isolated from the surface of certain bacteria could activate and convert naïve T cells to become T regulatory cells. This concept was considered heresy in immunology circles as textbooks taught us for decades that sugars from bacteria are T cell-independent antigens. The argument from critics and reviewers of our work was that there must be some protein contaminant in our manufacturing preps that was responsible for this finding. Well, it took a while, but we put that argument to rest through rigorous science and strict quality control measures that we employed in our processes. This body of work ended up being published in top-tier journals and the technology was ultimately licensed to pharma.
So, when I joined Shire in 2005, you might say that I had an ‘enhanced’ view of the importance of CMC and manufacturing compared to most academics at the time. The importance of this capability only became more evident when programs I worked on in Discovery reached the development candidate stage and needed to be transferred over to the Process Development (PD) group within the Technical Operations function. And guess who was a key person in that group at the time? My old friend Dave Nichols. This transition from Research to PD had historically been a tough one at the company. But Dave and I worked together to make this process more seamless and efficient over the years.
Later on at Shire when I headed up Program and Alliance Management, I was responsible for leading diligence on potential acquisition targets to bolster our pipeline. Dave was often part of those teams, and we saw many great companies with promising drugs, but we would often pass because companies were just not prepared on the CMC side for moving these drugs into the clinic or progressing them to pivotal trials. It became very clear that smaller companies (and even some large ones) did not realize the many advantages of incorporating early CMC effort into their workstreams. A proactive, integrative mindset for development, quality, process, and product understanding was not a priority.
The critical role that CMC plays was crystallized for all of us in 2008 when the FDA asked Shire to ramp up supply of VPRIV, an enzyme replacement therapy for Type 1 Gaucher disease, to help with a CMC crisis that a major competitor and, by extension, their patients were facing. Shire was able to meet that demand as the leaders in our company always kept CMC front and center. I learned a lot from this experience, and it is why I insist on having a CMC mindset for companies that I run, advise, or evaluate.
In the summer of 2023, I reconnected with Dave over lunch after he had just finished his run at Magenta, an antibody drug conjugate (ADC) company focused on oncology indications. I discussed with him the concept of a new company that I was forming with ARCH Venture Partners, Atlas Venture, and 5AM Ventures as investors. Lifordi Immunotherapeutics (as the company was named) endeavored to take the ADC concept in a different direction. I told him that we were going to lead the way by leveraging the success of ADCs in oncology and bringing them into the immunology and inflammation (I&I) space. Lifordi’s lead program was a novel ADC conjugated to a steroid designed to target immune cells, and I asked for his help. His eyes lit up at the thought of this approach for ADCs. But in Dave-like fashion his first question was, “Have you started the long-lead CMC activities yet? Because if you haven’t, you better move your ass.” That’s when I immediately asked, “Hey, what do you think about getting the band back together for this?” Luckily for Lifordi, Dave agreed to be my first hire, initially as a consultant, and we started to get CMC moving ‘at risk’ since it was ahead of getting Lifordi officially started. Thankfully, my investors saw the wisdom in this approach and funded the work with a note in advance of closing the $70M Series A. And from there, we have not looked back as CMC has never been on the critical path. Lifordi started a Phase 1 clinical trial of our lead ADC program, LFD-200, in Rheumatoid Arthritis in October that is enrolling and dosing healthy participants.
Smart investors and pharma companies make similar decisions when they evaluate biotech assets with a CMC lens. In fact, this is a key reason why Sanofi Ventures just invested in Lifordi as part of our recent financing. They recognized the value of an ADC-based approach for I&I, as well as the potential of LFD-200 based on a strong preclinical and non-clinical data package. Sanofi also agreed that investing in CMC earlier rather than later is prudent, especially when it can shave 12-18 months off the timeline to a potential Phase 2 study. It’s hard to argue that this is not a good use of proceeds.
Under Dave, our CMC team works very closely with multiple CDMOs that they have known and trust to produce each of the three components of our ADCs and another to conjugate them in a final product. Even though ours is a complex process, CMC remains ahead of schedule. Importantly, our research team continues to work hand-in-hand with CMC on building the pipeline and vetting new molecules upfront. If CMC can’t make it, repeat it, and deliver it with an eye toward scaling it, the molecule is put aside and significant savings in time and costs are realized. Developing a cell-based mechanism of action assay and building off an industry-precedent setting subcutaneous formulation for our DAR 8 ADC generated by our Research team in New Hampshire, CMC has established a stable, pure, and scalable ADC in LFD-200 that is critical to our success.
What I have learned is that if you underestimate the time or complexity of CMC, Executive teams can:
- Rely too heavily on CDMOs
Do not assume that the development and manufacturing can run on autopilot. Trusting the CDMO to know what they are doing all the time can lead to performing work that isn’t required, and this can happen at each stage of development. It may also result in cost over-runs that typically go unnoticed when there isn’t enough depth of in-house expertise and experience to know that you are being over-charged. For years CDMOs have thrived outside the U.S. despite the added complexities related to storage, shipping logistics, customs challenges, and time zone snafus. This is fortunately shifting now that pharma companies have committed billions of dollars to training people and building more manufacturing facilities in the U.S.
- Under hire technical expertise or mismanage the timing or number of FTEs
Do not assume that any technical person or any type of technical expert should be able to oversee CMC. That is a big mistake and it’s usually too late when you realize it, e.g., when the FDA expresses concern, trials are delayed, material is lost, and costs escalate. This is when management teams often react by building in-house expertise. Demonstrating safety to the FDA and other regulatory authorities requires careful measures and a deep understanding of the robustness, purity, reproducibility, and quality of your product, among other things. ALL this needs to be clearly presented at the time of the regulatory filing. I remember a regulatory filing where CMC totaled 300 pages out of approximately 900 pages. It took approximately four months to complete the document, which for the most part was written by in-house scientific and technical experts who were intimately involved in the process development and manufacturing of the drug. Just imagine the time and cost that all of that work would have amounted to if it were fully outsourced.
- Fail to question, understand, or devote time to regular CMC updates
CEOs, Board members, or investors rarely, if ever, have a background in CMC or have risen up through the ranks from a development/manufacturing career. As a result, fewer questions are asked or a misconception that CMC isn’t an important part of the business can develop. The impact of CMC-related decisions on time and money may be sorely underestimated. For example, it is not uncommon for CMC updates at Management Team and Board meetings to last as little as 3-5 minutes. Consider then that 25-40% or more of a financing may be devoted to CMC/ manufacturing, and yet <1% of the meeting time might be spent on discussing it at the highest levels of the organization.
It’s never too early to start CMC work and it’s definitely too late if you are just talking about it. CMC needs to be a tie that binds teams and cross-functional efforts by integrating a development and production mindset into early scale development for a much smoother drug development path. While we all understand and appreciate that clinical data moves the investment needle, preclinical and non-clinical data are ways to gaze into the “crystal ball” to gauge potential trial readouts. Importantly, it also supports some ‘at-risk’ investment in CMC. Recognizing the difficulty that comes with committing precious capital to CMC, especially early on and in ‘risk-off’ environments, I always think that the risk in NOT supporting CMC is likely to be far worse.
What I’ve learned about CMC can be summed up nicely:
When you can, build it.
When you can’t, buy it.
In either case, control it.
And in all cases, fund it.
CMC deserves to be on our radar for good reasons. If we wait until bad news focuses our attention on it, it’s too late. Now that CMC/manufacturing is coming back to the U.S., it is a good time to talk about the power of ‘the CMC continuum’ and to bring it to bear throughout all phases of drug development. We should be sharing more about the ‘secret sauce’ that an integrated CMC mindset yields in our companies, where we find that thoughtful CMC planning and practices turn good ideas into leads, development candidates into clinical assets and commercial products into medicines that can improve patient’s lives.
