The promises of biotech often hinge not on bold science alone, but on rigorous CMC decisions. Skipping steps or cutting corners early can sabotage even the most innovative programs down the line, derailing therapies before they reach patients.

In this episode of Smart Biotech Scientist Podcast, David Brühlmann welcomes Henri Kornmann, Head of Biologics Innovation Centre at Ferring Pharmaceuticals, whose experience stretches across multiple commercial launches and clinical lifecycles. Henri’s “house building” approach demystifies CMC’s complexity, showing why early diligence—paired with regulatory fluency and scientific insight—pays dividends for years.

Key Topics Discussed

• Early CMC decisions that define program success: cell line, analytics, and specifications
• Building a strong CMC foundation and the risks of inadequate groundwork
• Scaling from phase 1 to commercial manufacturing: robustness, extensibility, and dual sourcing
• Process validation vs. characterization: understanding the three-stage regulatory model
• Designing stage 1 control strategies and executing stage 2 process performance qualification
• Stage 3 continued process verification and managing lifecycle variability
• Control strategy management and navigating post-approval changes
• Leadership in CMC: project management, scientific expertise, and regulatory mastery

Episode Highlights

• Building a strong CMC foundation in early phases and why later fixes can be costly or impossible [02:45]
• Scaling up: supplying Phase 3 with the final commercial process, including robustness and supply chain strategies such as dual sourcing critical raw materials [03:23]
• Process validation explained: FDA’s three stages, from control strategy justification to continued verification [05:15]
• Process Performance Qualification (PPQ): what it is, how many batches are needed, and optimizing timing [07:43]
• Handling lifecycle changes: maintaining process control, adapting to deviations, and improving systems after regulatory approval [09:34]
• Managing teams, stakeholders, and cross-functional collaboration in CMC programs [11:49]
• Importance of good project management, access to scientific expertise, and interpreting guidelines for your specific program [12:27]
• The “half scientist, half lawyer” analogy for mastering both technical and regulatory aspects [15:08]

In Their Words

You need to understand the regulation. As a CMC biotech scientist, you serve two customers. You serve the patients that are in the clinic. You want them to receive a safe and efficacious product, but you serve also health authorities. This is your client. You need a clear understanding of what they need. And it's there, it's accessible, you have guidelines, but you need to access them, and you need to understand them, and you need to apply them.

From IND to BLA: The Biologics CMC Decisions That Determine Regulatory Success - Part 2

David Brühlmann [00:00:28]:
Welcome back. In part one, Henri Kornmann explained how early CMC decisions, including your cell line, your analytical panel, your specifications, create the foundation that determines success or failure of your CMC program. But a solid foundation isn't enough. Now we tackle the structures you build on top. How do you scale from lab to commercial manufacturing without cracks appearing? How do you control raw materials, manage impurities, and handle stability through lifecycle changes? And critically, how do you maintain process consistency post-approval while still improving? Let's find out.

What are now the next logical steps? Because you mentioned process validation, you mentioned we are in Phase II, eventually we go into Phase III and we have higher volumes, more clinical demand. So what are the next things, let's say, a startup founder should think about, or even somebody who is a CMC leader in a larger company?

Henri Kornmann [00:02:45]:
So I will go back to my house analogy. Phase I is the foundation message again, don't mess up with the foundation, there are things if they are not well done, you will really pay later during the program. Phase II, my approach is we don't change a lot. So you are still on that foundation. From a CMC point of view, or at least that's how I see things, I don't see big difference between supply for Phase I and supply for Phase II, except that suddenly you produce more batches and you create clinical exposure to your CQA.

Then you arrive to supply clinical Phase III. And here the recommendation is to supply clinical Phase III with your final process, with the process that will be used for commercial. So most of the time you need to scale up. So going back to the house analogy, when you think about scale-up is I start to build the structure of my house. Can this structure stand and be extended? Can I put a second floor and a third floor and maybe a garage next to it, making sure that the house stands? So this is the scale-up for commercial, and you need to deliver a commercial process which is robust, which has a good capability, which has limited environmental footprint, where you have secured the supply of your raw materials, where you have maybe for your critical raw materials, dual sourcing.

I have seen some companies, for instance, that have two sources of Protein A resin. They have the main source, but they have also qualified an alternative source from another supplier. So this is what you need to develop. It's a heavy CMC package, scale-up for commercial, but it's fundamental that at the end of this work package you have something that is robust, that you can operate long term because your process will stay for 10 to 15 years. This is usually the lifecycle of a drug. It can stay long term. Going back to the analogy, this is really building the structure, the height of the house.

David Brühlmann [00:04:59]:
And at that stage, typically process validation and process characterization is done. For certain people, it's sometimes difficult to understand what the difference is. Can you just give us a 2-minute version of what do you do and what is the purpose of those activities?

Henri Kornmann [00:05:15]:
I will go back to my house analogy. So the foundation, then I have the house, and then you move— so you have developed a process for commercial, the house is almost ready, and then you enter the house and you check, can I live in that house? Are lights working? Can I heat my house? This type of thing. And this is what we call process validation. This is another big work package that is happening after scale-up and development for commercial. Process validation according to FDA, and here I'm using the FDA terminology, they divide it into 3 stages: process validation Stage 1, Stage 2, and Stage 3.

Process validation Stage 1, this is all the studies that are needed just to design and justify your process control strategy. Just to give an example, I'm operating my bioreactor between 36 degrees and 37.5 degrees. That's my range. This is what I will put in my dossier. I need to justify those two numbers. So I justify it either because I control it very tightly or I need to test it. So this is process validation Stage 1. At the end of it, you have what we call the process control strategy, which is how do I control my process? How many samples do I take? How many cycles can I do on my chromatographic resin? How long is my hold time in my process? If I have a hold time, can it be overnight? Is it 3 days? Is it 1 weekend? So this is all process validation Stage 1.

So maybe one message, because sometimes this process validation Stage 1 is difficult to sell to management because it's requiring a lot of resources. So when you look at benchmarks, process validation Stage 1 is typically 12 to 18 months for a team of 10 to 15 FTEs. So it's massive. But again, it's a requirement because you need to justify all your limits and how you control your process.
Then you move into process validation Stage 2. And here, this is what we call PPQ batches. So you run your process full scale.

David Brühlmann [00:07:40]:
What does PPQ mean? Can you explain that for us, please?

Henri Kornmann [00:07:43]:
PPQ means Process Performance Qualification. And this is your process at final scale, essentially commercial scale, with the process control strategy in place, that you operate a certain number of times. And this is actually to prove that you can run this process and that it's delivering a drug substance and a drug product that are within the specifications that you have set.

There are two tricky elements to consider, at least to me. One is the number of PPQ batches that you will produce. Twenty years ago, this number was 3 and everybody was happy about it— if you have 3 consecutive successful PPQ runs, that's okay, your process is good and validated. Nowadays, you need to justify the number of PPQ batches. So you have a lot of literature and publications and discussions about this number of PPQ batches. But this number is one tricky element of process validation Stage 2.

The other tricky element is the timing of it. Because obviously there is a lot of value in this material. I mean, this is material you can sell and distribute. They are GMP batches. So you want to run those PPQ batches not too early because then you will have shelf life issues. If you run them too early, then you need to go into BLA, the dossier is reviewed until you get your approval. And not too late because they have to be part of your dossier. So the timing has to be thought through. So this is process validation Stage 2.

And then building on the house analogy, you move into process validation Stage 3, which is continued process verification. And this is usually happening after BLA approval. And here in the house analogy, this is, can I maintain my house? Can I improve my house? And this is typically process validation Stage 3.

And this is also a very important CMC package because I said before that your process will be there for 10 to 15 years, maybe 20 years, and it will deviate. People say that in the lifecycle of a process, the process will deviate by one sigma, by one standard deviation. Of course, some processes never deviate, other processes deviate much more, but your process will deviate because some raw materials will change, because one vendor will stop supplying that filter and you will have to use another filter, because you will be interested to optimize your process and maybe increase the productivity, so you will fine-tune your process parameters and so on and so forth. So this is why process validation is important, to make sure that once the process has been registered, because it will by definition deviate, it is still in a state of control.

David Brühlmann [00:10:47]:
This is a very important point because the house building is extremely important, but then you want to live in the house for a long time. So you have to also make sure that you can tweak certain things. And I think that's also where good control strategy comes into play and that you still can post-approval change a bit or also react to certain raw material changes between lots and so on, that you have some levers.

Henri Kornmann [00:11:13]:
Exactly. And I think the main message I wanted to convey to the CMC colleagues and the scientists that are listening to this podcast is CMC is obviously important. There are mistakes that you could do that can never be fixed down the road, hence having a huge impact on the value of your program. And I think this message is supported by those two FDA analyses about how much CMC impacts the complete response letters from FDA and refusals to file an IND.

David Brühlmann [00:11:49]:
I would also like to touch upon the human aspects because you worked in different companies, you have seen a lot of different scenarios, different ways of working. I'd just be curious—because you have a lot of things to orchestrate, you have people from engineering, process development, manufacturing, and oftentimes even external stakeholders, especially when you're in a smaller company working with a CDMO or a CRO—what are some pieces of advice you can give to the people listening to manage the leadership part or the management part of this whole CMC program?

Henri Kornmann [00:12:27]:
You just said: a CMC program is multiple elements connected together. We discussed about the cell bank that needs to feed process development to to different supply, drug substance, drug product, then distribution to the clinical site. So to me, the efficacy of CMC program strongly relate with good project management skill. I think one piece of advice is make sure you have a very solid project management in place that will be able to build the plan, connect all the work package together, and most importantly, adapt the plan on the go because by definition your plan is not correct and you need to redesign constantly that plan and realign all those work packages. This is one element.

And the other element of solid CMC package is obviously solid scientific background. Of course it makes a lot of difference when you have access to expertise of people that can advise because it's a multiple choice things every day, every week. When you are part of those those CMC drug product development, you take decision and direction, and you need guidance. Sometimes you need guidance. So I would really also making sure that in one way or another, I could access this expertise.

And finally, and that will be my third point, is you need to understand the regulation. As a CMC biotech scientist, you serve two customers. You serve the patients that are in the clinic. You want them to receive a safe and efficacious product, but serve also health authorities. This is your clients. You need a clear understanding of what they need. And it's there, it's accessible. You have guidelines, but you need to access and you need to understand them and you need to apply them.

David Brühlmann [00:14:23]:
Yes, most of these guidelines are public now, so you should be able to access them. But as you said, you also need the scientific and technical background to make meaningful conclusions from them.

Henri Kornmann [00:14:37]:
You are right. The guidelines are guidelines, so by definition, they are generic. And this is how do you translate those guidelines to your program that is key. But yes, they are by definition, they are accessible and public. They are issued by public institutions. So they are accessible.

So that's the three elements

• super strong project management,
• access to scientific expertise,
• and a very good understanding of the guideline.

There is another analogy I like to use when I mentor CMC scientists. I say to them, you know, you are half of a scientist and half of a lawyer. I mean, you need to understand the regulation because you need to navigate that regulation. If you are only a good scientist, it's not helping. Of course, if you have a perfect top-notch on regulation, it's not helping too. You need to master the two aspects.

David Brühlmann [00:15:25]:
Before we wrap up, Henri, what burning question haven’t I asked that you are eager to share with our biotech community?

Henri Kornmann [00:15:33]:
I think you did a pretty good job asking the right questions. Again, the main message I would like to convey is: a CMC program is like building a house. If you approach it that way, you will be successful.

David Brühlmann [00:15:49]:
Great. That’s awesome. So what is the most important takeaway from our conversation?

Henri Kornmann [00:15:54]:
Never underestimate CMC. If you do, you will pay for it later.

David Brühlmann [00:16:06]:
Never underestimate CMC. That’s a great way to conclude our conversation, Henri. It has been fantastic. Thank you for the memorable analogy and for helping us understand the critical importance of CMC—and how to approach it practically. Where can people connect with you?

Henri Kornmann [00:16:28]:
The easiest way is probably on LinkedIn.

David Brühlmann [00:16:33]:
Fantastic. I’ll leave the link in the show notes. Henri, thank you again for being on the show today.

Henri Kornmann [00:16:40]:
Thanks for the invitation, David. It has been a pleasure. Bye everyone.

David Brühlmann [00:16:45]:
Henri’s house-building analogy reveals a profound truth: biologics development isn’t about heroic late-stage rescues. It’s about disciplined foundational work at the beginning of CMC development. Solid ground, Quality by Design, risk-based structure, strong project management systems will get you there.

Get these right early—and your therapy reaches patients.
Get them wrong—and no amount of late effort can fully save you.

If this conversation changed how you think about CMC development, leave us a review on Apple Podcasts or your favorite platform. Thank you for tuning in, and I’ll see you next time.

Alright, Smart Scientists—that’s it for today on the Smart Biotech Scientist Podcast. Thanks for joining us on your journey to bioprocess mastery. If you enjoyed this episode, please leave a review and help us empower more scientists like you. For additional bioprocessing tips, visit smartbiotechscientist.com. Stay tuned for more 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, brings over 20 years of leadership experience in CMC development and GMP manufacturing within the biotechnology and medical device sectors. At Ferring Pharmaceuticals, he led the development of the biologics pipeline and was instrumental in advancing Adstiladrin to approval, marking the company’s first gene therapy and expanding treatment options for patients with bladder cancer. His work reflects a strong focus on translating scientific innovation into compliant, scalable manufacturing solutions.

Throughout his career, including senior roles at Biogen, Merck, and Medtronic, Henri has guided complex programs from early development through regulatory approval and lifecycle management. He is widely regarded for his strategic approach to CMC, regulatory readiness, and building high-performing technical teams.

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.  

Hear It From The Horse’s Mouth

Want to listen to the full interview? Go to Smart Biotech Scientist Podcast. 

Want to hear more? Do visit the podcast page and check out other episodes. 
Do you wish to simplify your biologics drug development project? Contact Us