Preserving Tacit Knowledge In ADC Tech Transfers
By Tyler Menichiello, Chief Editor, Bioprocess Online
I’m fascinated by ADCs. Something about combining the targeting power of antibodies with the potency and MOA of small molecules — from conceptualization to construction — really embodies the ethos of “next-generation biologics” in my mind. The idea that you can take established technology like mAbs or traditional pharmaceuticals and make them even more effective by combining them really represents the kind of outside-the-box thinking that pushes medicine forward.
(To be clear, ADCs aren’t new: The first one was approved back in 2000 (Mylotarg). But innovations in linker-payload design have led to an increase of ADCs in development.)
While the idea of an ADC is straightforward enough, anyone who’s been involved in their development or manufacturing knows there is nothing straightforward about ADC production.
It draws on expertise in mAb bioprocessing and pharmaceutical manufacturing alike, and conjugating these disparate components together is a process in and of itself. As such, ADC development and manufacturing often results in a cobbled patchwork of CDMO partners and supply chains.
When you consider the complexity of this development paradigm coupled with that of the molecule itself, it’s easy to imagine how difficult technology transfers can be in ADC development. That’s why we hosted a Bioprocess Online Live event on how to mitigate failure and knowledge loss in ADC tech transfers.
My key takeaways from this event are as follows:
- The loss of tacit knowledge is one of the biggest risks in ADC tech transfers
- Conjugation processes are the most difficult aspect of an ADC to transfer
- The importance of analytical methods and functional assays cannot be underestimated during tech transfers
![]()
Will Olughu
Conjugation Processes Are High Stakes
The conjugation process is what makes an ADC, and according to our panelists, it’s also where teams need to take the most care during a transfer.
Any drift in the conjugation process can yield different outcomes and affect product CQAs, warned Olughu. Such deviations can result in incorrect drug-antibody ratios (DAR) or payload distribution, which can impact the molecule’s potency, stability, and safety.
It doesn’t help that conjugation is one of the most difficult parts of ADC manufacturing to begin with. It’s extremely complicated, said Olughu, because you’re essentially fusing two molecules that don’t necessarily want to be together. “One’s very hydrophilic, the other one is hydrophobic, and you’re trying to force them to engage,” he explained.
Every element of the process, from pH to reaction time, molar concentration, and solvent use is critical for proper conjugation. These conjugation processes also require specific facility conditions that need to be accounted for.
“Those of us that have designed facilities know that in biologics facilities where you have active processing going on, those rooms we call our bubbles,” Kundu explained. “They’re at a higher pressure so that nothing gets into our product.”
“For an ADC facility, where you’re doing the conjugation, the pressure is actually lower than the surrounding pressure in the room so that nothing gets out from the room into the adjoining areas,” he continued. “These are distinct differences that one has to deal with when doing a tech transfer.”
When vetting a CDMO, sponsors should be sure to discuss these facility-fit considerations with potential partners.
Protect Tacit Knowledge
The more complex or proprietary an ADC is, the greater the risk of losing intimate process knowledge in a transfer.
Our panelists and audience members agreed on this, with 58% of our audience identifying in-house process knowledge as the most difficult type to communicate effectively during a tech transfer (compared to process rationale and development history, CPPs, and analytical methods or assay expectations).
This tacit knowledge is something people tend to overlook, said Olughu. These are parts of a molecule or process that aren’t captured in the batch manufacturing record (BMR) or other technical documents: things like what an intermediate looks like after a reaction or how long a sample can sit before being analyzed.
This kind of knowledge needs to be preserved during a transfer, as it informs what Olughu described as “borderline decisions” that need to be made by scientists, like interpreting ambiguous peaks or shoulders in a chromatographic trace.
The importance of preserving tacit knowledge during a transfer is especially true of assets built on platform technologies, where any number of factors around a process or molecule require product- and process-specific knowledge that can be lost in the shuffle — e.g., the rationale behind a particularly difficult reagent.
During a tech transfer, you’re not just transferring the process, said Olughu, you’re also transferring the context behind the process. He implored teams to capture this context in detailed development reports.
The Importance Of Analytics Transfer In ADC Development
Both panelists agreed: the matrix of assorted analytical methods and assays are critical in ADC development, but their sheer volume adds complexity to tech transfers.
“With an ADC, you’re basically dealing with the mAb intermediate, the linker-payload, and the ADC drug product,” explained Kundu. “It’s essentially three products or programs that you’re handling almost at the same time. So, obviously, because of the three different products, you have to deal with three sets of specifications.”
“I would prioritize the functional assays over anything else,” Kundu told the audience.
Olughu agreed.
“You need your functional assay very early, because that takes longer than you would imagine,” Olughu said. Cell-based assays are crucial for demonstrating potency and MOA, but “it takes time and is expensive,” he added.
Regardless of what assay or process is being transferred, governance structure that defines specific roles in collaboration is important during a tech transfer, Olughu told the audience.
For more specific insights into the nuance of tech transfers in ADC development, from plotting timelines to measuring success, watch the full event recording here.
Subscribe to be notified about upcoming Live events, which we host every month on the most pressing challenges and opportunities in biologics development and manufacturing!