Beyond "The Building Phase": Evolving The Cell & Gene Outsourcing Paradigm

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

This article is part two of a three-part series examining how advanced therapy scientific and quality expectations are impacting outsourcing business practices/models today and, hopefully, creating a foundation for greater risk-sharing in the future. Read Part 1 here: “Science Over Steel:” Exploring The Foundations Of A Hybrid CGT Outsourcing Strategy.

Just as ATMP biotech innovators are challenged to determine the best, most cost-effective manufacturing/outsourcing model for their products, the CDMO industry doesn’t have it any easier. In addition to facing the same supply-chain and talent shortages as innovators, they’re in the difficult position of figuring out how to sustainably address multiple clients’ manufacturing needs across the entire ATMP spectrum.

As we all know well by now, the broader ATMP divisions of cell, gene, and RNA therapeutics are riddled with eccentricities. There is no such thing as a straightforward AAV gene therapy when there are eleven different AAV serotypes to choose from. The same can be said for a cell therapy when it comes to the auto or allogeneic model, thanks to the variety of different cell types with which to play. Even the RNA industry post-COVID is looking increasingly kaleidoscopic with mRNA, saRNA (both self-amplifying and short activating…), tRNA, miRNA, siRNA, and circular RNA. As you can imagine, all this diversity adds additional complexity to a CDMO’s business and manufacturing systems/facility strategy.

There is a seemingly endless supply of content on how to choose the best CDMO. There is also a lot of discussion in the ATMP space around the current limitations of the CDMO space, whether it be capacity, analytical shortcomings, talent/turnover, or a dearth of suitable platforms. If I were to summarize all this discussion/content, there are four big expectations/characteristics the ATMP industry demands of a manufacturing partner. CDMOs must:

1. Be nimble enough to pivot quickly in the face of the many scientific, supply chain, process development, and logistics nuances/constraints facing each unique technology/modality. In some cases, this nimbleness may be defined as the CDMO having expertise in-house on a specific cell type. We could also define nimbleness as the CDMO’s ability to identify/implement the analytical methods that are agnostic to ATMPs’ inherent process nuances.
2. Run a facility which not only has the technical capabilities, capacity, and expertise to accommodate ATMP’s unstandardized procedures, but which also closes current (or historical) gaps in CDMO analytical and QC capabilities. In addition to analytical quality control, the current dependence on manual processes in the ATMP industry demands greater attention be paid to contamination mitigation, automation, and (long-term) platform development.
3. Expand their supply networks to incorporate the extensive amount of new(-ish) GMP-grade drug-substance and drug-product-related material needed for ATMPs (i.e., gRNA, enzymes, viral vectors, plasmids, LNPs etc.). Equally important is that a CDMO remains diligent about managing the relationships/supply-chain/quality standards for traditional raw materials and supplies that can so often be taken for granted (i.e., vials, saline, disposables, etc.) In turn, the hope is that innovators will not need to be constantly flipping through a rolodex to find and manage multiple suppliers on their own.
4. Possess a flexible vision of an ATMP facility. For ATMPs in particular, this requires thinking as far as a decade out to plan for the inevitable efficiencies and standardizations/platforms taking shape in the longer-term. (If you want to read more on just how many ways we can define the term flexible in manufacturing, I really liked this piece.) In addition to the day-to-day/week-to-week agility required to be “in the moment,” CDMOs need to “always be chiseling” (Glengarry Glen Ross style) an understanding around which modality-agnostic process commonalities exist and which technical evolutions/standardizations in the space will make a future platform or platforms possible. 

You may have finished reading that list and thought that these demands resemble those of any new therapeutic class. For the particularly cynical among us, it may be that such a CDMO exists only in the realms of a Disney film, not the real biotech industry. But based on this recent panel discussion, it’s clear these needs are top of mind for CDMOs looking to incrementally grow their ATMP businesses. (Incremental being a key word here.) Whether a biotech realizes it or not, every process has room to grow and improve — and the same came be said for any outsourcing partnership.

I particularly appreciated this quote from one of the panel participants sharing the difficult questions CDMOs (and their ATMP clients) are facing today about what it means to be a good partner.

“What does it mean to be strategic? What does it mean to share each other’s risk? Will the CDMO pick up the product development risk, and will the product innovator pick up the manufacturer’s risk? The most successful relationships are those where we’re assuming each other’s risk. But I’m not sure we’re at the point yet in this industry where we understand the business model clearly enough to fully answer these questions; we’re still in the building phase.”  

How CDMOs Can Help Partners, Broader ATMP Industry “See It All”

This quote got me thinking about how the CDMO industry — much like the innovator industry with its hybrid in-and outsourcing structures — is working to shape itself into a more meaningful and risk-sharing partner. As one expert explained to me last year in my 2022 CGT Manufacturing outlook article, this demands a shift in the traditional outsourcing partnership structure and business offerings.

“We don’t believe the CDMO partnership of the past is going to be that of the future,” Kiniciti’s Geoff Glass explained to me. “The outsourcing partnership will not be just an exchange of funds for a basic bank of services. There won’t be enough value-add there. CDMOs will have to marry proprietary, high-value, transformative technologies with the ability to deliver GMP solutions at scale. We believe those two offerings must come together for a CDMO to play a meaningful role in the future.”  

One such early example of this model is arguably that of the Lonza/Cocoon technology, the journey toward which my colleague outlined nicely in this article, “Nick And The Cocoons”: Automation for Autologous Therapies.”

Both Glass’ quote and the Lonza/Cocoon example depict the important role CDMOs are challenged to play today and in the future. They are best positioned to identify where the commonalities exist between the many different ATMP manufacturing processes that can pave the way toward greater industry standardization/platform approaches. They may also be in the best position to increase the “democratization” or access to such platforms across the industry outside of their own organization.

But before we can even get as far as that big S-word standardization, CDMOs and innovators are all aligned around the fact that this will not be possible without better analytics/understanding of the processes of today, tomorrow, and next year. As one expert in this panel discussion put it best, “The ATMP contract manufacturing space is different than that of an antibody manufacturing company, where you can produce something that can be well defined on several different platforms. This requires a much more intimate relationship between all the providers.”

As I see it, there are two ways we can unpack this quote. Both underscore innovators’ need for greater transparency in the outsourcing realm.

On the one hand, there’s a need for greater scientific transparency on a molecular and process development level. The demand for a better outsourced analytical/QC regimen is and will continue to be an evergreen request across product classes, not just in the ATMP space. But it is only in improving these offerings that innovators and CDMOs alike can garner better scientific insights into products’ structural and functional profiles. But if we think beyond a molecule’s CQAs, we’re also able to garner a more holistic understanding of how raw materials, drug substances, process steps, process changes, and new technologies leave their unique fingerprint on a product’s quality.

Beyond “seeing it all” analytically, the relationship between a CDMO and innovator must also become better structured digitally to ensure that data is more accessible between partners. The more capable a CDMO is at digitizing all development and manufacturing work from the start, the more accelerated the scientific and process learnings of the whole industry. Piecemeal digitization of data leads to piecemeal understanding of a product and its process controls. This becomes exceptionally problematic in late-stage trials when the FDA needs to see a company’s command over its processes and products.

My colleague hosted a fantastic panel that touched upon many must-haves in ATMP outsourcing partnerships — including the benefits of digitization. As one speaker pointed out during that conversation:

“Your data is the most valuable asset you have coming out of a manufacturing campaign. So, when you’re outsourcing, it is essential to have a plan for how you’re going to get your data and what it is going to look like. We also need to start working toward a digital architecture that not only enables real-time monitoring, machine-based learning, and better automation, but — more simply — shifts us away from the traditional, less efficient means of sharing data, whether that be SharePoint or email.” (If you want to read another perspective on the importance of digitalization — and what this really means/looks like — for CDMOs, check out this worthwhile read.)

So often, trust and communication are singled out as the most foundational elements of an outsourcing partnership. As I explored throughout this article, the arrival of ATMPs has encouraged CDMOs to weigh several complicated technical and even philosophical questions about capabilities, collaboration, and risk. How and when each CDMO answers these questions will be essential to defining what a trusting and communicative ATMP partnership looks like now and in the future.

However, such considerations are in no way limited to outsourcing firms. As I plan to outline in the final installment of this series, there have been several partnership models established that nicely define the shift in how CDMOs and ATMP innovators are approaching each other. As this article and the previous installment in this series explained, they both need to be considering — or reconsidering — how their business and manufacturing systems speak to one another internally. But equally important to consider is how these processes extend beyond their four walls and establish the foundation for a less transactional outsourcing relationship.