Advanced therapies present unique challenges from both a regulatory and a chemistry, manufacturing, and controls (CMC) standpoint, particularly in the early stages of development. These CMC and regulatory issues can be mitigated through early engagement with a CMC partner, who can help biomanufacturers develop an understanding of their product and their process, as well as adherence to a Quality by Design (QbD) mindset.
In a recent webinar, experts from Landmark Bio discussed how to work with a knowledgeable CDMO partner to create a viable CMC strategy, proactively identifying gaps in process, analytics, and compliance, to prevent costly delays. Following the webinar, Landmark Bio Chief Technology, Gregg Nyberg, and Chief Quality & Regulatory Officer, Michael Covington, answered questions about creating a CMC strategy, recognizing warning signs before they become problems, and how to foster fruitful interactions with regulators.
Q: We know that CGT is unlike traditional drug review (which focuses most on clinical efficacy) because there's a much higher focus on product manufacturing and quality. The webinar noted that a significant portion of delays in clinical development stem from CMC issues. Can you provide some examples?
Covington: There are a number of examples of CMC issues that could cause delay. For one, your master cell bank (or any working cell bank derived from it) is not appropriately characterized. Or you might lack sufficient data to support your manufacturing process. For example, you have made several changes to your manufacturing process and you have not completed a robust comparability study. Another common issue is problems with your analytics. For example, you lack a potency assay or your potency assay is inadequate.
All these issues can cause organic and regulator-imposed delays, particularly if the problems may affect product safety.
Q: The number of CDMOs supporting CGT has increased sixfold since 2020. How can drug developers differentiate themselves among competitors, especially with expertise in this area being limited when compared to existing expertise with other modalities?
Nyberg: It is critical to choose a CDMO partner that has applicable experience in bringing your type of therapy to market. Additionally, the CGT space has experienced a lot of consolidation over the last year-plus, so the outsourcing landscape continues to evolve. However, it is difficult to operate effectively via a transactional kind of relationship with a CDMO for advanced therapies.
The more precisely defined the product you are making, the more transactional that experience can be. But the advanced therapy space demands collaborative partnership. Will the potential partner work with you — your product, your planned pathway, your vision — or will they try to make you adapt their platform and/or their processes?
Q: You talk about how a phase-appropriate strategy is important for CMC success but what happens at each step isn't always intuitive without experience. For example, Landmark Bio’s timeline shows production of commercial launch quantities before Biologics License Application (BLA) filing. If the approval cycle takes an extended period, will those batches expire and be wasted?
Nyberg: When performing process performance qualification and process validation, commercially sellable material is often manufactured before the BLA is filed, running the risk that those lots may not be commercially releasable. If you have established sufficient stability, or you have the potential to develop data concurrent with the review period, you may be able to work with the FDA to extend the expiries and to use that material commercially. This would require combining stability data available upon filing with additional data, filed as it becomes available. In any such scenario, reaching out to the FDA in advance for feedback about your strategy is recommended.
Q: There are also many practical limitations. How does an organization set comparability acceptance criteria for product quality attributes when minimal pre- and post-change lots exist to evaluate? Does this hinder the use of statistical analyses?
Nyberg: This scenario is not unusual in the advanced therapy space, especially among gene therapy products, but some creative approaches can be applied. Ultimately, the drug developer will be expected to clearly explain how statistical comparisons were executed. For example, researchers may be able to pull data from GMP lots and process development studies to create a higher n — a higher overall number of lots — to help develop an expectation around process variability. But, again, feedback from the FDA is a must before going down that path.
Q: Speaking of FDA feedback, you discuss how regular interactions with regulators should be a staple of CMC development and product lifecycle. Even meetings requests require some experience since clear meeting objectives enable meaningful feedback — plus they might reject your meeting request if the objective is unclear. Which pre-IND meetings with the FDA do you consider most relevant?
Covington: Truly, it depends upon the complexity of your product. If the modality is new to the industry (or relatively new) in the sense the FDA does not have a lot of experience with it, an INTERACT meeting prior to your pre-IND meeting is recommended. Conversely, an INTERACT meeting is unlikely to be needed for a standard platform like CAR-T. You can just go straight to a pre-IND meeting.
Q: What are some of the topics you can cover in an INTERACT meeting?
Covington: INTERACT meetings that occur prior to the pre-IND meeting usually cover high-level topics — perhaps CMC or tox discussions — but even preclinical and clinical topics can be on the table if they are high-level, such as discussions about intended patient population. In terms of CMC, you can use the meeting to set a preliminary quality target product profile (QTPP) and some preliminary critical quality attributes (CQAs) alongside your product definition.
Q: A common misconception about cell and gene therapy development is that Quality by Design (QbD) is difficult to apply, or should not be applied, because the product definition contains so many unknowns. Is it feasible to apply QbD methodologies to complex modalities where CQAs are poorly understood?
Nyberg: While this can be a challenge, it illustrates the importance of applying QbD methodology and thought processes. Going through that process helps researchers think through product definition, as well as knowns and unknowns: Where do gaps exist in our understanding, and what can we do to close some of those gaps?
Having process and product definition intertwined, particularly with poorly understood CQAs, can lead to gaps in your understanding that you're unable to close easily. That may limit the kinds of changes you're willing to make at an acceptable risk profile downstream in development.
Q: Are any QbD tools standardized by the industry available for public use, or are they mostly bespoke for each company/CDMO?
Nyberg: Some published tools are publicly available. One example is a tool initially developed for application to recombinant protein production that also is extensible to other modalities. Other examples include literature documenting the framework some people have used to apply PQAA and PQRA tools, as well as the tools used by Genentech.
Project A-Cell and Project A-Gene are among the few initiatives or publications that describe how QbD tools have been applied in the advanced therapy space. The details of how each assessment were performed and the scoring matrices used are helpful starting points, even if they require some customization to be adapted to the advanced therapy space.
Q: We all understand we're at a unique moment in the industry but also that innovation is increasingly driven by academia and small biotechs. Reaching a value inflection point is often an existential issue for a startup company. How can these milestones be achieved with constrained funding and without accruing excess “tech debt”?
Nyberg: It is true that sponsors should plan programs with the end in mind, attempting to perform as much important work and gain as much knowledge upfront as possible. But the reality is misusing your limited resources early can impact the company’s ability to take an asset forward later. The question becomes: how do you reach those value inflection drivers in a way that helps de-risk your program? To this end, there is a lot of value in engaging a CMC partner early.
For some of its clients, Landmark Bio has partnered to execute early tech transfer to make material for, say, an important animal trial. Preclinical models can be value inflection drivers for a company, but the act of transferring the process to a CDMO teaches all parties more about the process and its reproducibility. It also provides the CMC partner an opportunity to give feedback about what could potentially be addressed as the program moves further along the development life cycle.
One way to handle this challenge, minimizing your future risk, is to be thoughtful about when you make engagements to help achieve your value inflection points. At the same time, start moving the project toward your long-term goals, getting feedback along the way regarding what may need done differently if the product advances to human trials.
Q: Executing early tech transfer makes a lot of sense in theory but how adaptable is that for unique processes? Does Landmark Bio utilize a proprietary production platform (for example, for viral vector production) or do clients need to tech transfer their process?
Nyberg: Landmark Bio is unusually flexible as far as that goes. We do offer our own Platform Optimized for Scale-up and Transfer (POSTmark) platform processes for LVV and AAV production, as well as CAR-T therapies, to be leveraged for client programs. However, we also are willing to transfer in client processes or co-develop platforms together. Some of our partners have done more in-house development, creating a stronger platform starting point, while others engage us earlier in their product life cycle. We are able to help regardless of the entry point.
About the Contributors
Dr. Nyberg holds a Ph.D. in chemical engineering from the Massachusetts Institute of Technology and a B.S. in chemical engineering and petroleum refining from the Colorado School of Mines.
Most recently, Mr. Covington served as the Vice President of Regulatory Chemistry, Manufacturing, and Controls (CMC) at Novartis Gene Therapies. Before that, he was Vice President of Regulatory CMC at Orchard Therapeutics and held leadership roles at Juno Therapeutics, Dendreon, and Amgen. He holds a B.A. in biology, with a focus on cellular and molecular biology, from the University of Missouri-Columbia.