In the competitive world of biotherapeutics, making the right choices in early CMC development can mean the difference between regulatory approval and costly setbacks. The industry has seen increasing regulatory expectations, and what worked a decade ago just won’t cut it today.

In this episode of Smart Biotech Scientist Podcast, David Brühlmann and Henri Kornmann, Head of Biologics Innovation Centre at Ferring Pharmaceuticals,  explore the critical foundations of CMC  development— likening it to building a house where mistakes made early on can have lasting, irreparable consequences.

Key Topics Discussed

• Weak Early CMC Foundations as a Leading Cause of Late-Stage Biologics Failure
• Regulatory Consequences and FDA Scrutiny from Poor CMC Decisions
• Henri Kornmann’s Career Path Across Merck, Biogen, Medtronic, and Ferring
• Ferring’s Gene Therapy Approval Journey: Azteladrin for Bladder Cancer
• Building a Robust CMC Foundation: Cell Line, Cell Bank, and Raw Material Strategy
• Managing the Transition from Phase 1 to Phase 2 Without Process Risk
• Applying Quality by Design (QbD): Defining and Linking CQAs and CPPs Early
• Common CQA/CPP Pitfalls and Long-Term Lifecycle Management Strategies

Episode Highlights

• Evolution of cell bank technology and regulatory expectations [00:33]
• The impact of weak CMC foundations on late-stage failure [00:51]
• Lessons learned from Ferring’s gene therapy approval and CMC gap analysis [06:51]
• FDA statistics on CMC issues in INDs and response letters [08:07]
• Critical early decisions: cell bank clonality and proper storage practices [10:22]
• The importance of comprehensive raw material documentation [12:29]
• Early analytical characterization and discovering molecular “funkiness” before phase trials [13:41]
• Supply strategy for phase 2—why stability and batch knowledge matter [14:49]
• Introduction to critical quality attributes (CQA), process parameters, and quality-by-design principles [15:52]
• Common pitfalls in CQA identification and continued process verification [17:01]

In Their Words

The first step when you build the house is having very solid foundation. And to me, the foundation of the house is the supply of your clinical Phase I. You have to see that as the foundation of the house. Here you cannot make mistakes. And there are mistakes I have seen during my career. When they are done at that stage, they cannot be repaired. A typical example of this type of mistake could be the clonality of your cell banks. Developing cell banks has been a topic for years, but also the technology and the expectations from regulators have also evolved. So you cannot develop a cell bank today as you were doing it 10 years ago.

From IND to BLA: The Biologics CMC Decisions That Determine Regulatory Success - Part 1

David Brühlmann [00:00:51]:
Many biologics that fail in late-stage development share one fatal flaw: a weak CMC foundation laid years earlier. Henri Kornmann has spent two decades developing biologics the right way. From Merck to Biogen to leading Ferring Pharmaceuticals's first gene therapy approval for bladder cancer. Today he reveals why your clonal cell line selection, analytical methods, and early characterization decisions determine whether your therapy reaches patients or collapses under regulatory scrutiny. If you're developing biotherapeutics, the choices you make today will haunt or save you at commercial scale. Let's dive in!

Welcome, Henri. It's good to have you on today.

Henri Kornmann [00:02:51]:
Hello, David. It's good to be with you and with the listeners to your podcast today.

David Brühlmann [00:02:56]:
Henri, share something that you believe about bioprocess development that most people disagree with.

Henri Kornmann [00:03:03]:
That's a difficult question. I think there is something very important for people to understand in drug development in general, but this is even more valid for all the CMC aspect of the drug is that a CMC program is like building a house. You need to start at the beginning of your program at preclinical stage and at, let's say, clinical Phase I, you need to start with very, very solid foundation. And from those foundation, as you progress with the clinical Phase II and Phase III and then request for approval, this is like adding floors and rooms in the house. And I have been in this industry for 20 years, mainly in big and mid-pharma, never working for startup, but I have performed a lot of due diligence. And when I have to due diligence a program, I often realize that colleagues in startups have difficult to understand that. And of course, they have limited financing and they need to go fast, but in that environment, they often forget about some of the fundamentals of CMC that are critical.

David Brühlmann [00:04:21]:
Yeah, I share your observation, Henri. As a consultant, I speak to a lot of startup founders, and that's exactly what I noticed, that a lot of startup founders have next to nothing, or in some cases, little knowledge about what CMC entails. And also, I like your way of looking at it, building a house and you need to lay a solid foundation. And that's also the reason I'm very excited about today's podcast, because we're gonna look at how are we gonna build that house that is gonna endure and not gonna fall eventually. But before we do that, Henri, take us back to the beginning and tell us what sparked your passion for biotech and what were some interesting pit stops along the way?

Henri Kornmann [00:05:08]:
My career is rather simple. If you draw a line between CMC development and GMP manufacturing, during my career I constantly jump from one side to the other. For instance, I started my career at Merck as junior CMC development scientist being specialized in downstream processing. But then I jump and I became Lean Six Sigma Black Belt, improving GMP manufacturing process. And then ultimately progressing into being responsible for the GMP manufacturing in a multi-product facility based in Switzerland. And then I moved back to CMC development, developing biosimilars. Then I made a 3-year excursion out of biotech working for medical devices, working for an American company called Medtronic. But of course I miss biotech. So after 3 years, I jumped back into TechOps working for Biogen, being part of this fantastic facility that they have in the middle of Switzerland, close to Solothurn. And then ultimately, and this is where I am today, I was called to join Ferring Pharmaceuticals. Ferring is mid-pharma company and I joined Ferring to develop the CMC development side for biologics.

David Brühlmann [00:06:34]:
Tell us about this last part because you were involved in the approval of Ferring's first gene therapy. Tell us more about that and then also tell us how that experience reinforced the importance of getting your CMC foundation right.

Henri Kornmann [00:06:51]:
This program is a gene therapy helping patient fighting with bladder cancer. This therapy has been now approved by FDA. Ferring gets involved in that product at the very end of clinical Phase III, and then the mandate was to take it from there and to bring it to BLA. And it's a very good program. It has been developed by one of our sister companies based in Finland called FinVector. This gene therapy program is called Adstiladrin®. It's gene therapy helping patients fighting for bladder cancer. And of course, one of the first thing you do is review the program and you assess the various CMC work package to see if they are complete or if there are some gaps, because of course when you go into registration, you submit your dossier and you get questions. I think every development program has CMC challenge and that one was not different than others. So we started to close some of those gaps, but it was interesting because there were some gaps that were difficult to close because we were late in the program. And actually, I was saying before that all programs have challenges.

There has been this review from FDA mid of last year, I think in July, where they published the list of the complete response letter starting from 2020. So all the complete response letters are starting— most of the complete CRL, the complete response letters are starting from 2020. And people started to analyze the cause and why the program were not approved first time. And actually 70% of the CRL were having a CMC challenge. So I think this indicates to colleagues working in CMC that this is extremely important because you don't want to arrive there and having your program reject out of CMC topic. There has been another FDA analysis. I think it's an older one from 2020 that was not on the CRL but more on the IND. And that study showed also that a significant amount of those IND, around 10%, they were not allowed to proceed to clinical Phase I, also because of CMC issues. So at the end of the development and at the beginning of the development, CMC can cause delay, increase cost and delay in program if it's not properly done.

David Brühlmann [00:09:29]:
You're making an excellent point. And I just want to reiterate that because this is such an important statement. And also I want to raise awareness because as I'm having conversations with people who want to go into an IND filing, it's so key to understand that you need to get these things right early on. And as you said, Henri, if you make wrong choices or you have some gaps, these can become very costly, especially at the later stage of your program as you're getting closer to your BLA. And that's the very topic of today, to help biotech scientists understand this is important but also have a strategy and have tactics to make better choices. So let's go into your analogy of building this house. Tell us, where do you start? What is the foundation? What do we have to look at? And then we'll go step by step.

Henri Kornmann [00:10:22]:
I like this analogy very much. I'm using all the time when I mentor the next generation of CMC scientists and the next generation of CMC leaders, because I think it's quite self-explaining. So maybe the first step when you build the house is having very solid foundation. And to me, the foundation of the house is the supply of your clinical Phase I. You have to see that as the foundation of the house. Here you cannot make mistakes. And there are mistakes I have seen during my career. When they are done at that stage, they cannot be repaired.

A typical example of this type of mistake could be the clonality of your cell banks. Developing cell banks has been a topic for years, but also the technology and the expectations from regulators have also evolved. So you cannot develop a cell bank today as you were doing it 10 years ago. I have faced, for instance, during due diligence programs where you could not demonstrate the clonality of the cell bank. So what do you do? What do you recommend to your business development department when you realize that it has not been properly done? And that's the analogy with the foundation.

Another example of one of those basic things linked to the cell bank, but also linked to the material you will produce for Phase I is how do you store it? I mean, it has to be stored according to the Good Distribution Practice (GDP). And I have seen examples where people have developed properly a cell bank and then they place it in a cryoconservator that is not according to the GDP rules. And so what do you do again when you observe that and you have to make a recommendation? Do we buy or not this program when you're part of a due diligence? What do you do? It's a challenge, right?

David Brühlmann [00:12:23]:
What about raw materials when you're creating your cell bank? I think that's another critical aspect, right?

Henri Kornmann [00:12:29]:
You are totally right. This is a key aspect where you need to make sure you have collected all the proper documents about your raw material. Something as basic as a TSE/BSE statement for one of the materials you used to create your cell bank can become important. Ten years down the road, when you are at filing, you may receive questions about it, and it can become a major challenge — even though you may not know it at the time, it can still be questioned. So people have to remember that.

The message is that, in a CMC program, there are many things that can be fixed later, but there are a few critical elements — the foundation — that you cannot get wrong. I gave some examples. The idea is not to create an exhaustive list, but to emphasize that foundations are very important.
You also mentioned that you speak with CMC colleagues in startups. They need to be aware of this because if they miss some of these critical elements that cannot be corrected later, it can destroy part of the value of their program.

David Brühlmann [00:13:34]:
Besides the cell bank, is there any other aspect that is fundamental in this foundational part?

Henri Kornmann [00:13:41]:
I'm sure that there are more. One I think about is how deep you characterize your substance. My approach or my recommendation is even if you are short in money and you have to make some decision, do not save money on the characterization at the beginning as part of the foundation because you don't want to discover something funky in your molecule at later stage. So full state-of-the-art characterization of your drug substance prior to Phase I will be a recommendation. There has been programs where you realize that you have very high level of misincorporation in your molecule. This you want to discover rapidly.

David Brühlmann [00:14:31]:
Absolutely. So we have now laid a solid foundation. What is the next step, Henri?

Henri Kornmann [00:14:37]:
The next step is— so you have your foundation, you have supply for your clinical Phase I. You move into supplying clinical Phase II. My approach and my recommendation is not to change things between supply of Phase I and Phase II. Some people might want to scale up because they believe it will require less batches and maybe saving money on the supply of clinical Phase II. My approach, it is usually simpler. You stay with your Phase I process. Maybe you produce a little bit more batches to supply your Phase II. This is actually not stupid move because with more batch, you start to build your knowledge about your CQA and you have clinical exposure of your potential CQA.

David Brühlmann [00:15:34]:
Can I ask you something about this? Because you mentioned CQAs. So just explain what that is. And it leads me to a further question. When do you start thinking about the quality by design approach. Just explain also what are these different things we should think about?

Henri Kornmann [00:15:52]:
So the Quality by Design (QbD) approach has to be embedded in your program starting clinical Phase I. You need to think about what could be your potential CQAs - your critical quality attributes -, which means the quality attributes of your molecule that may have an impact on the efficiency and the safety of your product. And you need to think about your potential critical process parameters (CPPs), which are the process parameters that are impacting the potential CQA. So this has to start Phase I and it has to be part of your IND. Of course, at Phase I, you know very little about your process and you know very little about your product, but there is a lot of things that are published. If you work with platform molecules such as antibody, there is a lot of things that are produced, so you can also use that, but it has to be embedded in your IND for Phase I.

David Brühlmann [00:16:53]:
What is a typical mistake or pitfall you see with respect to CQAs or CPPs?

Henri Kornmann [00:17:01]:
I think one of the challenge, QbD, is identifying CQA. There are ones that are very obvious, but there are ones you don't know. And of course in the clinical trial you have are not designed to test your CQA. They are designed to test the safety and the efficacy and the dose of your product. So this is a challenge, and here you need history and literature. And the other challenge is the link between process parameter and CQA, which is usually covered much later in the program during your process validation stage 1. But even there, it's also difficult to cover everything. And this is the reason actually why you have a process validation stage 3, what the regulator called the continued verification. It's because we know this understanding of the process during clinical development is limited. And we will continue to learn down the road when the product is on the market.

David Brühlmann [00:18:09]:
We have explored what makes solid ground for biologics development: a robust clonal cell line, comprehensive analytical panels, justified specifications, and why it's essential to define your critical quality attributes early. In part two, Henri walks us through scale-up challenges, controlling raw materials and impurities, lifecycle management, and building post-approval control strategies that actually work. If these CMC fundamentals resonated, leave a review on Apple Podcasts or your favorite platform to help other scientists like you find this conversation. Thank you so much for tuning in today, and I'll see you next time.

For additional bioprocessing tips, visit us at smartbiotechscientist.com. Stay tuned for more inspiring biotech insights in our next episode. Until then, let's continue to smarten up biotech.

Disclaimer: This transcript was generated with the assistance of artificial intelligence. While efforts have been made to ensure accuracy, it may contain errors, omissions, or misinterpretations. The text has been lightly edited and optimized for readability and flow. Please do not rely on it as a verbatim record.

Next Step

Book a free consultation to help you get started on any questions you may have about bioprocess development: https://bruehlmann-consulting.com/call

About Henri Kornmann

Henri Kornmann, PhD, is an executive leader with more than two decades of experience in pharmaceutical CMC development and GMP manufacturing across biotech and medical devices. At Ferring Pharmaceuticals, he joined in 2019 to build and lead the Biologics Innovation Centre at Biopôle in Lausanne, assembling a multidisciplinary team dedicated to advancing innovative biotechnology-derived medicines from early development through commercialization. He played a key role in strengthening the company’s biologics capabilities and development strategy.

Prior to Ferring, Henri held senior leadership roles at Biogen, Merck, Medtronic, and Nestlé Health Science, consistently bridging breakthrough science with robust, scalable GMP manufacturing and global supply. He earned his PhD in Bioprocess Science from the Swiss Federal Institute of Technology Lausanne and is recognized for building strong CMC foundations that enable long-term program success.

Connect with Henri Kornmann on LinkedIn.

He is also a biotech technology innovation coach, technology transfer leader, and host of the Smart Biotech Scientist podcast—the go-to podcast for biotech scientists who want to master biopharma CMC development and biomanufacturing.  

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