Antibody-drug conjugates (ADCs) are generating serious buzz in biotech corridors, offering a precision-guided missile against cancer while minimizing collateral damage. But the path from concept to clinic is far from straightforward—especially when the molecule itself bends the rules of traditional bioprocessing.

In this episode from the Smart Biotech Scientist Podcast, David Brühlmann welcomes Amanda Hoertz, Vice President of the Analytical and Formulation Sciences department for the Mammalian network at KBI Biopharma. With oversight of 300 scientists and deep expertise in taking the world's most complicated biologics to market, Amanda has spent her career at the intersection of scientific rigor and patient impact. Her approach goes far beyond cookie-cutter platforms, focusing instead on ground-up problem solving for complex modalities—including some of the trickiest ADCs in the pipeline.

Key Topics Discussed

• How a personal connection to type 1 diabetes and early academic influences shaped Amanda Hoertz’s path into biotechnology.
• The pivotal role of analytical and formulation sciences in enabling next-generation biologics and improving patient outcomes.
• The power and precision of antibody drug conjugates (ADCs) as targeted cancer therapies, and how they differ from traditional chemotherapy.
• Unique challenges in ADC development—from cytotoxic payload handling to ensuring analytical accuracy and employee safety.
• Building robust analytical strategies and bespoke testing methods to ensure ADC stability, efficacy, and manufacturability.
• How close collaboration with clients and a tailored service model distinguish KBI BioPharma from larger, standardized CDMOs.
• Formulation science and safe handling practices that support ADC drug product stability, logistics, and long-term clinical use.
• The value of early-stage analytical insights—such as conjugation site mapping and degradation profiling—in simplifying downstream development.

Episode Highlights

• Why a “one-size-fits-all” platform doesn’t work for all biologics and the role of empirical data in development [00:02:51]
• The unique therapeutic potential of ADCs—and why their potency is both a benefit and a challenge [00:06:49]
• Safety and process risks associated with handling cytotoxic payloads in ADC production [00:07:54]
• The typical workflow and analytical considerations for ADC production: antibodies, linkers, and payloads [00:09:19]
• What drug developers need to consider before investing heavily in a candidate—efficacy, manufacturability, and stability [00:11:09]
• What makes KBI’s approach to client services different, and key factors for choosing a CDMO partner [00:12:23]
• Critical analytical methods for ADC characterization—including challenges in charge heterogeneity and method development [00:14:46]
• Upfront strategic decisions in ADC process design that can save time and reduce complexity [00:15:59]
• How linker selection, conjugation methods, and formulation requirements impact ADC success [00:17:20]
• Practical formulation strategies for handling and shipping ADC intermediates and drug products [00:21:32]

In Their Words

A lot of clients, whether it's ADC or not, they're in the FIH stage. They need to understand whether or not they have a product where they're going to invest tens of millions of dollars into it. So they need to know: is it efficacious, is it manufacturable, is it stable, what can we do with it? And that way they can get through their tox studies and their phase one and then understand if they have the money to invest to go further.

So, information that can be calculated theoretically  - pI, molecular weight - those can be done just based on the sequence. But any hands-on data you have - because as you know, proteins fold differently - a theoretical pI and an observed pI can be different.

Episode Transcript: Mastering ADC Development: CDMO Strategies for Analytics and Scale-Up - Part 1

David Brühlmann [00:00:40]:
Welcome to The Smart Biotech Scientist. I'm David Brühlmann, your host, and today we're diving deep into the fascinating world of antibody-drug conjugates with Amanda Hoertz, who's a Vice President of Analytical and Formulation Sciences at KBI Biopharma. Amanda leads 300 analytical scientists across KBI's mammalian network, tackling some of the most complex challenges in biologics development.

We'll explore her journey from chemistry PhD to industry leader and discover what makes ADCs both incredibly powerful and uniquely challenging to develop. Let's dive in.

David Brühlmann [00:02:35]:
Welcome, Amanda, to The Smart Biotech Scientist. It’s good to have you on today.

Amanda Hoertz [00:02:38]:
Hi David. Thank you for having me. I appreciate it.

David Brühlmann [00:02:43]:
It's a pleasure, Amanda. Share something that you believe about bioprocess development that most people disagree with.

Amanda Hoertz [00:02:51]:
This question makes me nervous, but I'll shoot for it because I don’t pretend to know what everyone else thinks. I think one thing that a lot of people believe is that you can adapt almost any biologic to a single platform. And I think the different classes of molecules and formats need to be considered and need special considerations.

I think we can benefit from a lot of the historical data and the potential power of machine learning to reduce de novo data generation. But a lot of these determinations are empirical and have to be done for that specific molecule.

David Brühlmann [00:03:21]:
That's an excellent point. There's definitely a lot of specificity for each molecule. Before we talk about ADCs, Amanda, let's talk about yourself because you've built an impressive career leading 300 scientists across KBI's network. So tell us how you got started in chemistry, in the pharmaceutical/biotech industry, and what were some interesting pit stops along the way.

Amanda Hoertz [00:03:48]:
Sure. I love science. I love the logical portion of it and how you can understand something and do an investigation and rule out factors. And, funnily enough for my poor family, it’s become part of my actual personal life. I think about things in a very analytical way, similar to an investigation we do at work.

My initial love of chemistry actually came from when I was in high school. My chemistry teacher was a PhD from Berkeley, which was obviously atypical for a high school chemistry teacher. And she had very, very high standards. She’d put us all at the board and we’d be so afraid of being wrong in front of the whole class that it was my major focus to make sure I understood those concepts the best - because that was my nightmare.

In seventh grade, I also became a type 1 diabetic. And it was so impressive to me that this little bottle of clear liquid - when you had such a small injection of insulin - could make you feel dramatically better or worse. So those things together really pushed me in the science direction.

When I was in undergraduate and graduate school, I worked on antibiotic resistance and understanding how we could modify those genes to try to make novel analogs of currently approved drugs and counteract antibiotic resistance, and to make those in a scalable, economic way. That pushed me towards industry.

What I loved about industry was that the work I did in academia was very conceptual and I didn’t really see it being applied in the short term, whereas the work I do at KBI is going into clinics, it’s being used now. Some of them fail, but I see it being realized. I see people getting the benefit, especially as KBI has matured. We’ve had a number of products that started out preclinical and now are commercial. We see the benefits, we see people taking these drugs. And it’s not just a concept that maybe 20–30 years from now it might happen — it’s actually happening. We know people are getting benefits. It’s a great feeling.

David Brühlmann [00:05:47]:
Now, specifically, you're now working in Analytical and Formulation Sciences. What excites you most about working in this very part of biotech today?

Amanda Hoertz [00:06:00]:
There are just so many different options coming forward for patients. We're on the cutting edge. We get to see all the different treatments, and as I said before, some of them fail. And that's a natural part of the industry. But we see how people are innovating their thought process, what different drugs can possibly be offered to patients.

And as we see them getting more and more specific, especially with something like ADCs, we see less side effects, we see patients getting improved options. And it's very exciting to be part of that and to see it being realized.

David Brühlmann [00:06:32]:
I'm very excited to talk about ADCs, because it's a huge trend in our industry - no doubt about that. A lot of people are developing ADCs, but tell us why they are such powerful therapies before we dive into the nitty-gritty of ADC development.

Amanda Hoertz [00:06:49]:
Sure. I mean, there is a payload attached to the antibody, and that can be either non-cytotoxic or cytotoxic. Obviously, the more potent ones are harder to handle. But they are allowing us to take cytotoxic drugs that in general couldn't be administered to a patient, and target them specifically for the tumor.

So by using this basically directing antibody, you're able to get those cytotoxic drugs directly to the tumor. And because we have less of the bystander effect - which is where cells that are nearby are also impacted in the cell death - it's more targeted.

General chemotherapy that started out a long time ago would only target rapidly dividing cells. So that would target other things that aren't part of the target and would result in things like hair loss and nerve damage. By being able to target these with ADCs, we're able to really just target the tumor and we're able to have these ADCs and immunotherapies really be a very specific treatment for the cancer drug.

David Brühlmann [00:07:46]:
And what makes ADC development very challenging compared to traditional monoclonals?

Amanda Hoertz [00:07:54]:
The same thing that’s a benefit is the same thing that makes it very challenging. So, at KBI we’ve worked on and manufactured many non-cytotoxic ADCs. Where it becomes really challenging is when you start working with the cytotoxic payloads.

Those, in very small amounts, are designed to kill cells. Therefore, there's a safety risk for the employees handling them for testing, and handling them for manufacturing. The biggest risk is obviously with the free payload.

Analytically, we handle that very carefully. We only need that for really one assay - the free drug - where we have to run a standard curve of the free drug and then run the actual sample to see how much has been released. But handling that free drug to be able to run that standard curve is the risk to our employees, and to any employee that would then service that instrument.

Conversely, in the process development and manufacturing space, they would need to handle an even larger amount of that payload to be able to conjugate it to the actual product. And so those are the highest risks. Making sure that we have the right safety protocols so that we are not exposing our employees to any of these deleterious effects - which are by design for the cancer cells, but not by design for the general population - is critical.

David Brühlmann [00:09:03]:
Can you give us just a high-level view of how ADCs are actually produced? I mean, you have quite a puzzle: you have the antibody, you have the linker, you have the payload. What’s the general sequence, especially for people who might not be familiar with ADC development?

Amanda Hoertz [00:09:19]:
Many ADCs are developed before they come to KBI, but for some we’re involved from the beginning. There’s an antibody - typically one that’s already well understood - and companies will modify the amino acid sequence to target the specific locations where the linkers can bind to then get that payload attached.

By modifying how the molecule is formed, you're able to target specific numbers of attachment sites and specific amounts of that cytotoxic payload. It is very important that we have the analytical tools to look at both the antibody, the free linker, and the free payload. The more stable that is, the better.

Obviously, we want it to conjugate, and then we want none of the free linker to be showing up. The free linker tends not to be a problem - it's just a sign that we're actually losing some of the payload. The payload obviously is a problem if we have high amounts of free payload.

So we develop analytical tools to monitor that over the course of stability under many stresses, and understand whether or not agitation stress, freeze–thaw stress, temperature stress, duration of stress, or chemical stresses - including acidic, basic, and oxidative - are influential in either damaging the linker or releasing that payload.

That’s the function of our stability studies: to quantify the amount of free payload that gets released. It's also impactful if we don't have payload attached, because then the drug is not efficacious.

So usually it’s the free payload that ends up being the problem, because in small amounts it's impactful. But we also want to make sure that the drug we're delivering still has that payload attached.

David Brühlmann [00:10:53]:
Let's make this practical. Let's assume I'm a CEO of a biotech company and we are developing an ADC and we're coming to you, to KBI. What are the first critical questions your team would ask my company to set up our analytical strategy for success?

Amanda Hoertz [00:11:09]:
One of the things that's great about KBI is that we're bespoke services: we offer what you need. A lot of companies have a platform approach: you give them this amount of material, or they produce this amount of material, and then they do these fixed experiments.

What we do is take in the information you have. So if you were coming to me with an ADC that you want to develop, I would want to understand what information you already have. What do you understand about the molecule? What can we leverage from historical data? And then we would set up, based on your timeline and your budget, what we can further investigate to get you to the next stage.

A lot of clients, whether it's ADC or not, are in the FIH stage. They need to understand whether or not they have a product where they're going to invest tens of millions of dollars into it. So they need to know: is it efficacious, is it manufacturable, is it stable, what can we do with it?

And that way they can get through their tox studies and their phase one, and then understand if they have the money to invest to go further.

Information that can be calculated theoretically - pI, molecular weight - those can be done just based on the sequence. But any hands-on data you have, because as you know, proteins fold differently, a theoretical pI and an observed pI can be different. That data helps us maximize your timeline and your budget.

David Brühlmann [00:12:23]:
You said that one thing that sets you apart is offering bespoke services. Because choosing a development partner or a CDMO can be quite overwhelming. So why should I, as this fictional CEO, choose KBI? Or why should I go to another CDMO? What are some decision parameters I should consider?

Amanda Hoertz [00:12:45]:
If you're looking for an IgG1 - a very “vanilla” antibody - you probably don't need the services of KBI.

KBI has a very high advanced-degree rate. We are very good at complex molecules. Our experience includes bispecifics, conjugated molecules - the list goes on. But we are going to be more expensive than the Lonzases or Thermos of the world.

So if you just need an antibody produced, that’s going to be your better path. But if you need something that has nuance, that requires more thought and more experimentation - that’s where KBI fits into that niche market with bespoke services.

We’re not going to compete with the huge WuXis of the world. But what we do bring is the experience you need to make your complicated molecule successful.

We’ve had a number of clients that request RFPs from KBI and then come back to us saying our proposals are more expensive. They go to a cheaper CDMO, and then later we get them back. By then they’ve sacrificed part of their budget and had a failure at a more platform-based CDMO. They’ve also sacrificed six or seven months of their timeline to figure that out.

So, for that theoretical CEO, the key is knowing how complicated your molecule is and whether you need the nuance we offer.

Our batch success rate for fiscal year 2024 was 93%, and we don’t do engineering runs. We put in place upfront the cell line, the analytical, and the process development engine, so that by the time we’re making it at the scale of 2,000 liters, you actually get a product successfully.

David Brühlmann [00:14:21]:
Let’s talk about the analytical puzzle. Because there’s a lot going on: we’ve got the antibody, the linker, the payload. We need all kinds of different analytical methods. So tell us your approach - how do you develop methods to characterize each component? Because at the end of the day, you need a sophisticated process control to ensure you’re actually getting the very ADC you want to develop.

Amanda Hoertz [00:14:46]:
Yes, there are a number of compendial methods that are standard for any antibody. We also have product quality methods — your classic SEC, where we need to understand the HMW. You want to keep aggregates low. That’s not specific to ADCs versus non-ADCs.

Where it gets specific for ADCs is in the characterization of the free payload, the free linker, and the charge heterogeneity. That’s usually where we see the most nuance required, both with cytotoxic and non-cytotoxic ADCs.

There seems to be more of a development challenge for the iCE or IEX methods we run. We see shifting profiles, we see inconsistency in achieving good separation. For example, in iCIEF, having the right blend of pharmalytes and the right handling conditions is critical to get us from the development stage, to the qualification stage where we’re generating GMP data, and then to the validation stage where we can execute this across multiple sites and multiple analysts. It has to be robust.

That’s the biggest challenge I’ve seen. The free payload tends to be a pretty straightforward reverse-phase method where we’re just titrating against a standard curve.

It’s the charge heterogeneity that keeps me up at night.

David Brühlmann [00:15:59]:
And what are the things you can do even upfront, before we would even come to KBI or another development partner? Are there some strategic choices companies should make to avoid, for instance, these headaches? I mean, I know there's a lot of complexity, but are there maybe some early decisions that simplify or reduce the complexity?

Amanda Hoertz [00:16:21]:
I think a lot of it is understanding your linker attachment sites. The most successful conjugated materials we’ve made are those where both the conjugation sites and the post-translational modifications that may influence them are very well understood.

We have a dedicated mass spec team. For example, we can produce forcibly degraded material so they can understand how it’s going to degrade, and at the molecular level identify which sites are prone to modification. Then we can actually monitor that.

For example, oxidation or other modifications can be identified through detailed peptide mapping. That allows us to pinpoint individual peaks, and when we see a peak grow, we understand what’s happening.

Peptide mapping requires some upfront development - for instance, recognizing that when this site gets oxidized, a shoulder or a peak appears. But once we’ve identified what each peak represents, we can monitor them in a much more streamlined and cost-effective way over the product’s lifetime.

David Brühlmann [00:17:20]:
You mentioned that the linker is very important, and I also imagine the conjugation method. So can you tell us what is the state of the art today? Because I mean, a lot has happened in the last few decades in ADC.

Amanda Hoertz [00:17:35]:
There are a number of ways to conjugate. Most commonly, thioethers, disulfide bonds, and peptides are used and they’ve been very successful.

Having specific attachment sites, like I said before, is also critical. You don’t want random attachment. That was the approach for the early ADCs, where we were hoping for the best and aiming for a certain amount of payload attached.

The actual conjugation decision-making is a little bit out of my expertise. I usually deal with the molecule after the payload is attached, and how we can understand its properties. But of course, how those decisions are made also has a direct impact on efficacy. You want to make sure none of the sites critical for binding are blocked.

We continue to refine as we learn. The ADC market is going exponential. There are 12 approved ADCs, but we’re aware - and the market is aware - of hundreds more in development. A lot of those won’t make it, but once a platform is successful, it can often be applied multiple times. So when a client has one success, that client usually has a higher rate of success in follow-on programs.

David Brühlmann [00:18:39]:
Now let’s talk about formulation, because that’s also quite a challenge. An antibody by itself is quite well managed, but probably more complex modalities pose extra issues. How does that play out for an ADC? What are the challenges, and what approaches have you developed as a team to tackle formulation challenges?

Amanda Hoertz [00:18:58]:
Absolutely - that is definitely a component. We need to develop a formulation for the drug substance intermediate (DSI), which is the pre-conjugation material. That formulation can’t inhibit the conjugation reaction. So we need to be careful: no surfactants, no small molecules that could interfere.

Our classic approach at KBI is to design a very simple formulation that is stable to freeze–thaw. Buffers and excipients can shift during freeze–thaw, and we don’t want to damage the biologic during that process. That’s critical for the DSI as it moves into DS production.

Once the product is conjugated, it’s more typical for us to include a small amount of surfactant to reduce stress from agitation and freeze–thaw, and to add excipients that increase stability.

The gold standard for biologics is 24 months of stability at 2–8 °C. So our goal is to design formulations - with appropriate excipients - to achieve that. But at the DSI stage we must be very cautious: no surfactants, minimal excipients, so that nothing interferes with conjugation.

David Brühlmann [00:20:03]:
And for those who are not familiar with ADCs - the DS formulation is important because certain companies are not able to produce the antibody and then do the conjugation at the same site. So there’s some shipment involved, right?

Amanda Hoertz [00:20:19]:
Exactly. For non-cytotoxic drugs, at KBI we are able to produce the DSI and then conjugate it to generate the DS. That is then typically shipped to a fill–finish facility for DP (drug product) manufacturing, which usually involves filtration and filling operations.

For cytotoxic ADCs, KBI currently does not offer the conjugation. So we generate the DSI, then ship it to another site for conjugation, and then onward to a different site for DP production, depending on the vendor.

The less handling required once it’s conjugated, the better. Every operation increases the risk of damaging the payload, damaging the product, and also increasing risk to employees.

So, our approach is to maintain a pH that is acceptable, with minimal excipients and no surfactants at the DSI step, so that stabilizers can be added later once it’s conjugated. Then the DP step is usually just filter, fill, and finish.

David Brühlmann [00:21:20]:
I got you. So you have a formulation for your DSI, you do the conjugation, and then you add whatever is needed to stabilize your molecule, right?

Amanda Hoertz [00:21:30]:
Exactly.

David Brühlmann [00:21:31]:
It makes sense.

Amanda Hoertz [00:21:32]:
The DSI and the DS are typically frozen formulations. That needs to be taken into consideration. The DP is typically stored at 2–8 °C. That’s the most financially successful option for companies when shipping to clinics - everyone has a refrigerator.

Once you start requiring storage at –20, –50, or –75 °C, you face challenges: do clinical sites have those freezers, and do you need to supply them to each site?

David Brühlmann [00:21:59]:
And to what extent are the DS and DP formulations for an ADC different from a standard mAb, or are they quite similar?

Amanda Hoertz [00:22:07]:
They are quite similar. It’s difficult for us to include a surfactant, although as I said, it reduces agitation as well as freeze–thaw impact. Depending on the molecule, we might need to add other stabilizers, like arginine, to reduce aggregation.

The pH is obviously critical. Different buffers can be more or less successful, and that’s generally determined empirically. Of course, we have targets based on the pH values we’re looking at, and that’s largely a function of the molecule’s isoelectric point (pI). So it’s also important to assess whether the linker or the payload impacts the overall pI.

David Brühlmann [00:22:42]:
That wraps up part one of our conversation with Amanda Hoertz. We’ve explored her remarkable journey and the exciting world of ADC development.

Please leave us a review on Apple Podcasts or whatever platform you found us on. It helps other biotech scientists like you discover the show. I thank you so much already - and I love hearing from you. So thank you very much for tuning in today. Stay tuned for part two where we'll dive into the analytical complexities of ADCs.

For additional bioprocessing tips, visit us at Smart Biotech Scientist Podcast - Master Bioprocess Development. 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.

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About Amanda Hoertz 

Amanda Hoertz is the Vice President of the Analytical and Formulation Sciences department for the Mammalian network at KBI Biopharma. She oversees a network of 300 analytical scientists who execute method development, verification, qualification, validation, formulation development, forced degradation, characterization, and stability testing for preclinical to commercial products at the CDMO. 

She has been at KBI for 14.5 years and prior completed her Ph.D. in Chemistry at Duke University. Her undergraduate and other academic experiences include Johns Hopkins University and the University of Pennsylvania.

Connect with Amanda Hoertz 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

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