Outsourced Complex Protein Development Demands Special Considerations
By Matthew Pillar, Editor, Bioprocess Online
Handing any therapeutic molecular discovery off to a CDMO is rarely an emotionless business transaction. You and your team, and likely, teams before them, have spent countless hours of hard research, discovery, and design work on the project. That work’s value was priceless before the dealmakers even attempted to ascribe hard dollar value to a potential medicinal product and went about their ways negotiating rights and licenses and milestones.
When said molecule is complex—a novel fusion protein or ADC, for instance—the stakes and anxiety around a handoff and all the tech transfer, scale-up, and validation work that goes into it are orders of magnitude higher. There’s a reason so many upstart cell therapy companies, with their complex supply chain, engineering, and manufacturing processes, choose to bite the financial bullet and bear the fundraising strain of internal development. Complex, novel proteins are often similarly intricate and demanding in terms of development and production, but in most cases require larger, more expensive, and certainly more distributed manufacturing infrastructure. For all but the 1%, that’s a non-starter to putting shovels in the ground and internalizing manufacturing, and it’s why ADC innovators, for instance, are often orchestrating the work of three, four, or more outsourced manufacturing partners at once. API, antibody, linker technologies and conjugation steps are rarely all baked from scratch under one roof.
CDMO Track Record, Audit History Among Top Considerations
During last month’s Bioprocess Online Live event, Early Process Considerations For Novel Protein Therapeutics, SOTIO Head of CMC Meinhard Hasslacher, Ph.D. shared some of his fundamental considerations for choosing outsourced development and manufacturing partners. He’s well-qualified on the topic, as SOTIO, where he’s worked for the past six years, outsources all elements of development for all five of its pre-clinical and phase 1/2 ADC candidates.
“We’ve collected some experience here,” Hasslacher quips, before stressing the importance of bolting down raw materials supply. “When you work with a CDMO, you have to assure that the raw materials being used can be sourced globally.” This is critically important, he says, in anticipation of tech transfers to support the transition from development to commercial supply. “It's always a pain if critical raw materials are not available or easily sourced globally for production the U.S., Europe, and Asia.
As it relates to the CDMO’s capability and capacity, Hasslacher advises using its history as your guide. “I think it's important to check the track record of a CDMO, and more specifically, how many projects it’s running per year and how many different modalities it was able to have success with,” he says. He also suggest close scrutiny of the potential partner’s audit history, examining not just how many audits the facility has been subject to, but the outcome of those audits.
Hasslacher also suggests that it’s worth the time to hunt for a CDMO that’s as close to a one-stop-shop as possible, though he admits that’s akin to hunting for a unicorn. “A one-stop-shop [or something close] is important to SOTIO because we are set up quite lean,” he says. With only a few people managing CDMO relationships, and with ADC production being as complex as it is, a partner that can manufacture linkers, payloads, cell lines, mAbs, the enzymes required for conjugation, and one that can conduct the conjugation step is his ideal. SOTIO’s current challenge is finding a CDMO with the qualifications and capacity to bring that all together at the fill/finish level, where the toxicity challenge of ADCs comes to a head. “We had some issues with drug product fillers that were concerned about these highly-potent molecules, particularly around cleaning validation and changeover procedures,” says Hasslacher. “They were even asking us for molecule inactivation kinetics or inactivation data that they could use to conduct changeovers on their side.” He says only a few CDMOs in the world can really fulfill this in the ADC world, and that because many are currently trying to fill the gaps, the fine print of ADC contract manufacturing agreements should be deeply scrutinized. “Most of them can do part of it, but they have to fill the gaps here and there, so it requires a detailed look from the contract perspective,” he says. “You should take your time when negotiating terms, master service agreements, and quality agreements, so that the whole relationship is based on good fundamentals and understanding of the different responsibilities of the CDMO and the sponsor.”
Fusion Proteins Offer More Outsourcing Flexibility
Where ADC complexity creates a distributed contract development and manufacturing challenge, Neeraj Pakala, Ph.D., who serves as SVP of Product Development and Manufacturing at fusion protein developer Vera Therapeutics, fully embraces a multi-point outsourcing environment. While they don’t generally present the toxicity and high potency considerations ADCs do, Pakala says fusion proteins are considerably more complex than mAbs, for instance, and as such, selectivity in outsourced manufacturing environments is important. That selectivity, he says, lends itself to choosing “best-of-breed development partners for specific steps. “In early-stage cell line development, for instance, we’re not looking for a one-size-fits-all partner,” he says. “We look at each specific project, and in very early-stage cell line development, for example, there are a lot of good labs with a lot of good expertise that we don't have, so while there is some level of tech transfer involved, we don't have to stick to the same CDMO for manufacturing that we’re using for cell line development.”
Pakala calls this a divide-and-conquer approach, which allows Vera to match its projects with a selection of CDMOs’ technical capabilities. “Some of the drug product manufacturers are fantastic at manufacturing, but just don’t have the business model set up for development work, for instance,” he says. “We really need to understand those business models carefully and be very selective.” While the outsourcing options in such a scenario are a bit broader, he doesn’t take the agreements forged with those specialty shops lightly. “We take our IP very seriously, so we think carefully about how we set up our master service agreements,” he says, adding that it’s incumbent on the sponsor to closely evaluate associated fees.
The CDMO’s Perspective On Complex Molecule Development
Recognizing that a conversation about CDMO selection with two sponsor company SME’s is incomplete, we invited Lena Tholen, Ph.D. to the table. She’s Director of Cell Line and Bioprocess Development at FyoniBio, a German CDMO with deep expertise in early-stage protein therapeutic development. Tholen gave us some perspective on sponsor and outsourced development partner priorities. While everyone’s ultimately focused on the molecule being developed, she says, sponsors and outsourced development partners must reconcile the inherent friction in their relationships. “The sponsor’s pressing goal is to have their molecule brought to the clinic. As a CDMO, we want to help them by producing the molecule in the best possible way, from a scientific perspective,” she says. That “hurry up” versus “do it right” conflict demands clear and communication and expectations from the start. The relationship, she says, “starts with companies sending out RFPs with a lot of molecule-specific questions and requests. Even at that early level, it's so important to exchange information on the sponsor’s requirements and the CDMO’s capabilities and business models.”
By way of example, and leaning into Pakala’s point about assuring not just the technical capability fit, but the business model fit, Tholen says there are many CDMOs that take a platform process approach, which often indicates a poor fit for companies developing complex, novel proteins. “The CDMO should be very clear about its capabilities from the start,” she says. “That’s the collaborative foundation of the relationship between the sponsor and the CDMO.” Setting that foundation on level ground is prerequisite to a longstanding and expensive commitment, the success of which is predicated on ongoing data exchange.
These insights on outsourced development and manufacturing relationships were just a fraction of this lively discussion. Check it out in its entirety – and access dozens more expert-led panels on bioprocessing, under the Listen & Watch tab at www.bioprocessonline.com.