Hope in a Dose: CGT Podcast | Ep 11 | CMC Foundations for FIH Success: Getting CGT-Ready from Day Zero

In this episode, we focus on building the right CMC foundation for cell and gene therapy success. From manufacturing variability and potency assays to comparability and cold chain logistics, the CMC story is often the story regulators focus on.

Host: Louise Kearney, Head of Cell and Gene Therapy, Strategy and Delivery at Fortrea

Participant: Sanjay Jain, Executive Director of Global Regulatory Affairs Strategy at Fortrea

Transcript

SPEAKER_01 0:07

Welcome to Hope in a Dose. I'm Louise Kearney, and in this episode of our CGT series, we're focusing on a topic that can make or break first in human progress, building the right CMC foundation for CEN and gene therapy success. From manufacturing variability and potency assays to comparability and cold chain logistics, the CMC story is often the story regulators focus on. And I'm joined today by Sanjay Jane from Fortria, who will share practical insights on common challenges, phase appropriate strategies, and the pitfalls sponsors can avoid as they move from the lab into the clinic. Let's get started. Hi Sanjay, thanks for joining us today. Let's start by thinking about some of the challenges. What CMC challenges can be a sticking point for clients looking to move from the lab into the clinic? And why is this more complex than for other IMPs?

SPEAKER_00 0:59

Thank you, Lewis. This is a great question. I would say that the CMC challenges are more complex for cell engine therapies or CGTs compared to other investigational medicinal products or IMPs. These challenges often lead to significant chemistry manufacturing and controls of CMC-related deficiencies with a large percentage of clinical holds from the agencies for CGTs are caused by manufacturing issues. Unlike a small molecule, which are synthesized with higher precision, CGT starting materials are biological. Living systems with higher donor-to-donor variability making consistent manufacturing difficult. Many CGT processes are manual, open, and high touch, leading to higher risks of human error and contamination compared to the automated closed systems used for traditional pharmaceuticals. Changes to manufacturing processes, example, scaling up, are common, but proving that the new product is comparable to the old one is extremely difficult when the product itself is not uniform. Developing a suitable potency assay that directly relates to the mechanism of action or predict clinical efficacy is challenging. CGTs have shelf life measured in hours or days or require an unbroken minus 150 degrees C cryogenic chain. Therefore, the CMC must prove that product remains viable and sterile throughout extreme logistics. There are few industry-wide standards, regulatory guidelines or public precedents to follow for manufacturing and analyzing these therapies, creating high regulatory uncertainty. Lastly, bridging the gap between the academic research and clinical good manufacturing practice of GMP is a common hurdle as academic laboratories normally focus on innovation and proof of concept, while GMP focuses on reproducibility, safety, and documentation.

SPEAKER_01 3:26

Thanks. And I think we see some of the uh impacts of that as we work through the on the clinical side, on the operation side as well, because we can quite often see difficulties in delays because of manufacturing delays as they try and scale up or limits on slots or amounts of um materials. Are there any strategies that sponsors can do to prepare to ensure they have met all the CMC requirements that regulators will have?

SPEAKER_00 3:54

Yes, uh there are several uh proactive strategic and uh phase-appropriate approaches that a sponsor can implement to ensure their CMC packages for cell and gene therapy meet uh regulatory expectations. I would start by saying that engage regulators for early advice, example, an interact uh meeting with the US FDA on manufacturing and analytical, example, potency assay plants, and participate in programs like the FDA's CMC strategy pilot. In general, the inherent variability of cell engine therapy means that the rigorous documentation of the process is considered evidence of the product safety, meaning processes the product. While phase one does not require full current GMP compliance in the US, start with good scientific and quality control principles. Maintain a document that map all changes and provides in real time the data necessary to demonstrate comparability between the pre- and post-change products. Define a track a quality target product profile or QTPP, including critical quality attributes or CQAs or critical process parameters or CPPs early to establish a robust control strategy. Mitigate key regulatory risk areas, example, develop quantitative potency assets that clearly reflect the mechanism of action. Generate real-time stability data early, perform degradation mapping and set an interim self-life with an extension plan. Ensure stringent qualification of starting materials, example, vector construct cell banks, and implement robust procedures for chain of identity and chain of custody and validate cold chain logistics. Tactical preparation could include leveraging platform data for validation to reduce the burden of proof on individual products, store adequate samples from early clinical trials for side-by-side testing during future comparability studies, and start organizing CMC data in digital format, example structured data to prepare for future electronic submission requirement. Rather, they focus on a risk-based approach tailored to the product. Finally, follow good artificial intelligence practice or principles.

SPEAKER_01 7:10

Thanks. And as we see sort of certain gene therapy studies starting in different places in the world and then quite often moving regions, are there any differences you need to be mindful of in different regions at all?

SPEAKER_00 7:23

This is a great uh question. Yes, there are significant differences in CMC requirements for CGTs across various regions, primarily between the US FDA, European Medicines Agencies or EMA, and Japan's Pharmaceuticals and Medical Devices Agency or PMDA. I would say key differences to be mindful of include firstly, CGTs are generally categorized as biologics and are governed by regulations for human gene therapy products, cell therapy products, and human cells, tissues and cellular-based products in the US, while these are regulated as advanced therapy medicinal products or ATMPs, which are subdivided into gene therapy medicinal products or GTMP, somatic cell therapy medicinal products or SCTMP, and tissue engineered medicines or TEM. Secondly, in the US, viral vectors are typically treated as drug substances or DSs, requiring stringent facility licensing and strict quality metrics for purity and potency, whereas these can be sometimes classified as starting material for ATMPs, particularly in XVivo gene therapies, which may have different quality requirements compared to a final DS. Thirdly, the FDA has stricter regulations regarding raw materials, particularly regarding bovine spongiform in cephalopathy and transmissible spongiform in cephalopathy. Risks from animal-derived materials while in the EU. Donor testing requirements for autologous materials can vary by member state, and EMA may require specific testing for viruses like hepatitis E orvovirus B19, not always mandated elsewhere. Fourthly, the FDA often emphasizes the use of historical data for comparability assessments during manufacturing changes, while EMA may not always require this. Furthermore, FDA often calls for a more thorough real-time assessment of stability compared to EMA, particularly for changes made during later stage development. And the EMA may consider replication competent virus or RCV testing unnecessary on the final product or DP if it has been demonstrated to be absent in the vector, while the FDA typically requires testing on the final drug product. Fifthly, the EU has specific GMP guidelines tailored to tailored for ATMPs that offer some flexibility on quality control compared to traditional biologics, while the FDA is adopting a more flexible risk-based approach. Lastly, compared to the US and Europe, some Asian regulatory bodies are relatively new to the complexities of cell and gene therapy manufacturing and may have less standardized requirements. In addition, Japan has uh distinct guidelines focused heavily on the product manufacturing process, quality, and non-clinical tests, which can be stricter for cell therapy for stem cell products.

SPEAKER_01 11:17

So it seems like there's a lot to think about. What are the common pitfalls people make in celly gene therapy CMC pathways?

SPEAKER_00 11:26

I would say the key pitfalls in CGT CMC development can be failure to keep the end goal in mind or define target product profile for scientific, regulatory, and commercial aspects. That is a roadmap for the global development and focus on the regional development. Translation gap meaning relying on manual open handling processes in early development introduces high variability, which becomes a bottleneck during a scale up to commercial production. Furthermore, using non-GMB grade raw materials early on or failing to secure supply chains for critical reagents, example wireless vectors, can cause significant disruptions in production. Making significant process changes, example shifting from adherent to suspension culture, changing raw materials between early and late stage trials without proper validation, leading to failure and demonstrating that product remains consistent. If post-change manufacturing cannot be bridged to early clinical material, the agency may treat the product as a new entity. Weak analytical methods and potency assays is a major recurring reason for failure to define a robust quantitative potency assay that adequately reflects the mechanism of action, in addition to inadequate reference standards and insufficient stability data. Regulatory and documentation deficiencies include delayed investment and CMC, poorly structured IND application submissions, and an inadequate facility readiness, win-to-win failures and logistical failures could compromise the product. Lastly, failure to embrace ever changes regulatory aspectations.

SPEAKER_01 13:37

Okay, so quite a few. And and how can this how can CROs or CGMOs help in this? What are their roles in regulatory CMC strategy?

SPEAKER_00 13:47

Clearly, contract development and manufacturing organizations or C DMOs and contract research organizations or CROs are essential partners in navigating the complex regulatory CMC land scale for CGTs. Therefore, a well-defined CMC strategy supported by expert partners is essential for avoiding costly delays in securing regulatory approval. In a nutshell, their role involves guiding the overall regulatory path, preparing for the meetings with the agencies, example EMA, and ensuring compliance with evolving standards, implementing stringent testing for raw materials, example viral vectors, developing scalable, robust, and reproducible manufacturing processes that are GMP compliant, validating analytical methods to ensure the key pharmaceutical attributes like quality, beauty, identity, potency, which is crucial for regulatory approval, generating technical data for CMC submissions, example INDs, conducting studies to demonstrate that products manufactured in early phases are comparable to those in the latest stage trials, reducing the regulatory burden. Specialized C DMOs and CROs provide crucial expertise, example in vector production, a major bottleneck and gene therapy development, or translational expertise in bridging non-clinical safety data with early clinical CMC information to support first and human trials, designing studies to define the shelf life and storage conditions of sensitive cell and gene therapy products. CDMOs ensure secure tracking for patient-specific autologous therapies. And lastly, there is a growing trend in the use of integrated CDMO CRO partners, which provide a seamless approach from pre-clinical research to commercial production. This model helps to reduce handoffs, uh accelerate timelines and ensure continuity.

SPEAKER_01 16:12

Yeah, and if you look back on other podcasts we've done, we've worked with SCT Bio, who we have a collaboration with, to try and reduce sort of the friction between those things. So Foldrayer can certainly help in the aspect by joining you up with C DMOs and helping you with that strategy.

SPEAKER_00 16:29

Yeah, I agree. Thanks, Savanj, Luis.

SPEAKER_01 16:32

That brings us to the end of today's episode of Hope and a Dose. A big thank you to Sanjay for breaking down what good CMC looks like for CGTs. From defining the target prof product profile and building robust control strategies to planning for comparability, stability, and regional regulatory expectations. If you've found this discussion useful, please subscribe and share the episode with your colleagues who are navigating early development or preparing for first and human milestones. And if you'd like to learn more about how Fortria can support your CGT program, whether through CMC strategy, operational planning, or connecting you with the right partners, we'd love to continue the conversation. Thanks for listening and join us next time for another Dose of Hope.