The Patchwork Of Outsourced ADC Manufacturing
By Tyler Menichiello, contributing editor
Earlier this month, Bioprocess Online’s chief editor, Matt Pillar, hosted a live event centered around navigating the complexity of antibody-drug conjugate (ADC) manufacturing. Matt was joined by DeciBio project leader, Joe Daccache, Ph.D., VP of medical affairs at Vincerx, Amy Johnson, Ph.D., and Mythic Therapeutics’ COO, Sandra Poole.
The hour-long conversation covered a lot of ground, yet it only scratched the surface of the ADC manufacturing landscape. It could have easily gone on for another couple hours, with twice as many expert panelists, and there would still be questions left unanswered. That’s just how complicated the ADC manufacturing space is right now.
A big part of this complexity is due, in large part, to the construct of ADCs. A perfectly crafted ADC is a trinity of the perfect antibody, the perfect linker, and the perfect payload. Each piece of the ADC is critical, and every piece requires very different expertise to get it right. Very rarely can one team do it all. “You need experts in a lot of different areas,” Johnson says. “No one’s doing this on their own. We’re all relying on outsourcing.”
This demand for such diverse areas of expertise has resulted in what Matt describes as a “fragmented outsourcing environment” for ADCs. When it comes to developing unique ADC designs with innovative components (whether it be the linker, the payload, or the antibody), “You need CDMOs that have expertise in each,” Johnson says. However, finding such diverse expertise under one roof is rare.
“You may end up working with multiple companies. For us, someone’s building the antibody, somebody’s building the linker, and somebody’s building the payload,” she continues. “And then, you may even need a fourth company to put them all together.”
Of course, working with multiple CDMO partners can make supply chains “incredibly complex,” says Poole. “The ability to manage these complex CDMO supply chains, for a small company — especially early stage — is incredibly challenging and often underappreciated.”
A Web Of Connected Systems
There are five core elements that need to be considered in such complex manufacturing operations, according to Poole: the equipment and facilities, the process and analytical technologies, the technical operating systems (e.g., a quality management system), the management structures, and the people in the middle holding it all together.
“You’re talking about multiple systems all coming together to form a larger, complex system that you need to keep your eye on and think about as you’re setting your specifications,” Poole explains. “If you set a specification for a manufacturing system that the equipment hasn’t been designed to reliably maintain, it’s going to be a problem. If you’re designing a quality management system that’s not really well-suited for a large system of multiple CDMOs, it can also not serve you well.” It’s important to think about these systems as a whole very early on when writing specifications and procedures.
Moreover, it’s important to have internal CMC experts who can review data relating to analytical methods, release testing, and stability testing. “Having someone on your team who is an expert in doing those reviews, someone who’s done a lot of them and knows what to look for, is vital to have on your team,” Johnson says.
Having this internal expertise is critical for owning the data, according to Poole. “You want your core data and process knowledge to be internalized. You don’t want to be in a position where you’re relying on your CDMO or your vendor for interpretation of the data.”
Engaging With Your CDMO Partners Early
All three panelists agree that it’s never too early to start planning your manufacturing strategy and engaging with your CDMO partners. Failure to engage with your CDMO early on is akin to shooting yourself in the foot, says Daccache. “Even if you’re trying to do things in-house at the preclinical and discovery stage, you’re going to face big struggles and hurdles if you don’t engage with CDMOs and have very early conversations about, ‘Okay, what are your capabilities, and how can we work together to set ourselves up for success in a couple years?’” he explains.
“You don’t want the first time your CEO is talking to the CDMO’s CEO to be when you’re in the midst of a crisis,” Poole says. It’s important to build this relationship with your CDMO partners early on and to view them as an extension of your company. After all, the CDMOs are your manufacturing operation, and it’s on the sponsor to provide regulatory oversight of that operation. This means developing or defining specifications on how equipment will be controlled.
One example Poole uses is the master batch record. “The sponsor should be involved in finalizing that batch record for their process,” she says. “Particularly when you start thinking about the critical process parameters, the sponsors should be the ones approving those. I think the sponsor is very much hands-on and plays an important role in defining the process.”
On The Horizon
ADCs are a rapidly growing modality with a promising future, and it doesn’t seem like the momentum is slowing anytime soon. If you’d like to dive deeper into the panelists’ conversation around ADC advancements, operational costs, and much more in regard to manufacturing, I implore you to watch the full event recording, which is available for FREE thanks to the event’s sponsor, Cytiva.
Also, be sure to check out next month’s live event on August 8 at 11 AM ET, where Matt will be discussing early process development and manufacturing considerations for novel protein therapeutics (specifically, ADCs and fusion proteins) with SOTIO Head of CMC Meinhard Hasslacher, Ph.D. and Vera Therapeutics SVP of Product Development & Manufacturing, Nareej Pakala, Ph.D. You can register to attend this event here for FREE thanks to the event sponsor, Thermo Fisher Scientific.