Antibody-drug conjugates (ADCs) are innovative biopharmaceutical products in which a monoclonal antibody is connected to a small molecule drug with a stable linker.
So far, most currently available ADCs have been developed to treat cancer but there is enormous potential to use them to address a variety of other conditions.1,2
To date, 14 ADCs have been approved by the United States Food and Drug Administration (FDA) and more than 90 are under clinical development worldwide.
From an industry perspective, notes Sales Manager Jörg Küpper — and for customers of GEA — ADCs represent a new field in oncology.
Depending on the source, the global ADC market was estimated to be valued at $13.7 billion in 2024 and is expected to reach $51.2 billion by 2033.3
Although that seems quite significant, he notes, the overall oncology market size was destined to reach an overall value of $225.01 billion in 2024 … which is more than 15 times larger.4
It’s a very new kind of application, he continues, and GEA is keen to position itself as a first mover here because working with ADCs basically obligates the manufacturer to lyophilise the product.
They’re sensitive, labile and have an extremely short shelf‑life. Without being stabilised by freeze drying, ADCs may not actually have a shelf-life at all as they’re often unstable in liquid form.
Magic bullets
In terms of how ADCs work, adds GEA Lyophil’s Dr Benjamin Ledermann, regular cancer treatments take a somewhat shotgun approach whereas these new drugs behave more like a sniper rifle.
The application is much more specific; you’re not just targeting cancer, per se, but particular types of the disease because of the antigen specificity of monoclonal antibodies.
Essentially, it’s a new level of cancer treatment. Not only that, he continues, you can also use drugs that are considerably more potent than in general chemotherapy … and this is all because of the antibody.
In basic terms, ADCs consist of two parts. They are complex molecules comprising an antibody linked to a biologically active cytotoxic payload or drug.
Unlike chemotherapy, antibody-drug conjugates target and kill tumour cells without harming healthy cells. As such, it’s a very specific approach in that you only kill the cancer cells or those that surround the tumour.
If you have a lung tumour drug, for example, it shouldn’t have any detrimental effects on your kidneys or other organs.
The toxicity factor
It is this toxicity that presents the current challenges for ADC production. Many traditional approaches to making oncology drugs now need to be combined and/or improved to be able to cope with these highly potent active ingredients.
“We’ve become familiar with the concept of OEB5 level drugs, for instance, which are both toxic and difficult to handle … but now we’re moving into the realms of OEB6,” says Jörg.
Handling these molecules takes considerably more effort; it makes the production of ADC products much more dangerous and what would traditionally be seen as a simple freeze-drying task has, suddenly, become impossible. Operator safety must be our primary concern.
Containment considerations: The first duty of every responsible employer is to prevent the exposure of employees to substances that are hazardous to their health.
The company should implement additional personal protection measures only when this cannot be guaranteed by suitable technical options. In most western countries this is law.
However, as exposure can’t be fully prevented, the company has to ensure — by using suitable equipment — that the operator’s real daily intake (RDI) of a hazardous substance doesn’t exceed the product-specific acceptable daily intake (ADI).
GEA has published extensively about containment and is an established expert in all aspects of aseptic processing.5–8
Risk assessment: When freeze drying ADCs, a number of input parameters must be considered, including
- the OEL of the active pharmaceutical ingredient (API) and its type (in this case a cytotoxic molecule)
- the amount of API per vial
- the nature of the cake (solid, dusty)
- the scale of the operation
- how loading/unloading will be achieved
- the risk of falling/damaged vials (Figure 1).
Figure 1: A risk assessment of the steps involved in manufacturing ADCs
Just thinking about line clearance, notes Jörg, you might look inside the freeze dryer and spot a fallen vial or a rogue cake. This, in the past, might not be a significant issue. Now, with an ADC, it poses a problem.
You need to ensure that there is no powder anywhere. It needs to be bound in a liquid so that it doesn’t get airborne. Because, once it does, that powder or residuals from the cake can be inhaled … and you then have a very serious threat to the machine operators.
Areas of concern
Almost the entire freeze-drying process needs to be re-evaluated, including cleaning. Simple clean-in-place (CIP) may no longer be enough: now you must deal with many different aspects of the entire manufacturing line.
This translates into of a variety of technical solutions that manufacturers will require. In terms of cleanability, for example, the internal design of the chamber and the condenser must ensure reliable access with the minimum number of built-in parts, moving parts and dirt corners as possible.
The ideal scenario would be plant with an easy-to-validate cleaning procedure that consumes as little water as possible to minimise the amount of contaminated wastewater. Another example is the simple vacuum pump.
With an ADC application, these must be protected from contamination. So, you need to install a filter … but how do you maintain that filter and how do you accommodate the fact that this is now a part of the same machine and subject to potential contamination?
Of course, the filter must be cleaned … but how … and how do you treat the water/steam that was used to bind or remove the unwanted particles? An obvious solution, perhaps, would be a toxic drain that goes into a kill tank with an additional non-toxic drain.
Likewise, it might be necessary to redesign the loading/unloading system or implement a more reliable cleaning regime. A falling vial on a conveyor belt would contaminate all the small crevices.
And with air pulling through the system, any splashed liquid would dry and, once again, you have the threat of airborne particles. Similarly, cleaning the bellows is a much more serious consideration with ADCs.
Up until recently, for instance, users have only needed a specific set of “status codes” for their plant to know when it was “sterile,” etc. Now we also need to be able to show when the freeze dryer is contaminated … and poses a threat.
Pressure equalisation: to open a maintenance door between the chamber and a technical room can be difficult if there is a pressure discrepancy (it either slaps you in the face or you cannot open it at all depending on where the over pressure is).
As such, you need a bypass valve; but if the environment in the freeze dryer is highly toxic, you can’t just open a valve to equalise the pressure!
Conclusion
Our role as a technology supplier is to develop comprehensive technical solutions to overcome the hurdles that manufacturers are facing, notes Benjamin.
We’ve been involved in many projects comprising toxic products in recent years and had to deal with, maybe, one or two of these challenges somewhere in the machine.
But now, with ADCs, we need to combine all these solutions into one complete offering that showcases our expertise. It’s important to remember, regarding the production process, that when you formulate an ADC and it’s in liquid form (in a solvent), it’s not overly dangerous.
The problem arises when it becomes a powder and has the potential to create an aerosol. So, from a GEA point of view, ADCs suddenly become very hazardous when you start drying them (or they dry out in an unplanned situation).
During loading, for instance, with the ADC in liquid form, it’s not a particularly nasty threat. As soon as you spill it, however, and evaporation begins, you have a problem.
Even if a tiny amount of powder becomes airborne in an uncontrolled drying environment (such as a laboratory), you potentially run the risk of having a completely contaminated isolator.
Essentially, prior to the lyophilisation step, the ADC presents a low risk. But, as soon as the freeze-drying process starts, the threat level rises considerably.
Yet, ADC products must be lyophilised because they are unstable. However, until packed and sealed, they’re extremely dangerous.
To ensure that you have a stable sterile product that’s ready for parenteral administration, a key consideration is to prevent the degradation of the linker structure between the antibody and the drug.
If the active payload becomes detached from the antibody — and you inject it into the patient — you could potentially poison them. As such, it’s important that the antibody-drug conjugate retains its original structure.
To summarise, says Benjamin, this is an emerging market opportunity; we want to be first movers and we want to be seen as a company that understands the complexities of planning and executing ADC production.
We know exactly what each customer needs and have the expertise to be able to guide them through the process. We understand the product, we design and build the plant, and we have a wealth of experience to draw on.
Contact us today for advice, guidance and the technology you need to safely bring your next ADC project to a successful conclusion.
References
- https://pmc.ncbi.nlm.nih.gov/articles/PMC8628511/.
- www.manufacturingchemist.com/the-abcs-of-adcs-manufacturing-ultra-high-potent.
- www.globenewswire.com/news-release/2024/09/05/2941601/0/en/Antibody-Drug-Conjugates-Market-Is-Expected-To-Reach-Revenue-Of-USD-51-2-Bn-By-2033-at-15-8-CAGR-Dimension-Market-Research.html#.
- www.precedenceresearch.com/oncology-market#.
- www.gea.com/en/customer-cases/containment-fundamentals/.
- www.manufacturingchemist.com/potent-oral-solid-dosage-apis-containment-fundamentals-123055.
- www.gea.com/en/assets/142439/.
- www.gmp-journal.com/current-articles/details/safe-handling-of-highly-potent-substances.html.
