Why FDA Complete Response Letters Involve Manufacturing Issues – and What Must Change in Cell Therapy
In the race to bring transformative cell and gene therapies to patients, speed often dominates early decision-making but industry data reveals a significant trend: between 2020 and 2024 a significant portion of FDA Complete Response Letters (CRLs) issued by the U.S. Food and Drug Administration involve manufacturing and quality issues.1 This industry trend is also reflected specifically in cell and gene therapy, where complex processes and novel modalities amplify the risk. These setbacks are rarely caused by last-minute missteps. More often, they trace back to decisions made years earlier during preclinical and Phase 1 testing when programs are under pressure to move fast and reduce costs.
A Predictable Pattern of Late-Stage Setbacks
Across the industry, the same challenges continue to emerge late in development. These findings don’t arise overnight – they expose gaps that were embedded in development programs years earlier.
The consequences surface at the worst possible moment: when a company is advancing toward approval, investor expectations are highest, and five or more years of development – and significant capital – have already been invested. The results are major approval delays, immense unplanned costs, and challenges that can fundamentally alter a company’s trajectory.
Cell Therapy Intensifies the Challenge
While these statistics highlight industry-wide trends, cell therapy adds unique challenges that magnify these risks. In this space, early decisions carry disproportionate weight: deficiencies in process design or scale-up can ripple through development and delay approval, even years later.
These risks tend to play out in consistent ways across programs, pointing to key areas that must be managed carefully to ensure successful development.
Critical issues to avoid:
Unresolved CMC and facility readiness issues, with critical details missing from Chemistry, Manufacturing, and Controls (CMC) packages, and manufacturing sites not fully prepared for FDA inspection
Assays not built for late-stage demand, often revealing limitations because they were designed for early research rather than commercial scale, robustness, and regulatory expectations
Product quality and manufacturing success-rate challenges, where teams struggle to consistently produce product that meets specifications, particularly around viability, stability, and other critical quality attributes
Difficulty scaling manufacturing, where processes that work at early stage can fail under commercial demand, making it hard to demonstrate comparability, reproducibility, or consistent performance
Building Success from the Start: ElevateBio Addresses the Root Causes
At ElevateBio, we’re focused on advancing the field of cell and gene therapy by combining genetic medicine technologies with manufacturing scale and expertise. So, we understand that manufacturing cell therapy is inherently complex, requiring robust processes, careful planning, and rigorous quality systems from the very start. This requires the right processes, the right people, and a quality-first mindset embedded from day one, so we can help our partners avoid the costly mistakes that set their programs back.
ElevateBio BaseCamp® is dedicated to the development and manufacturing of genetic medicines to address these challenges. Designed to be an integrated part of our partners’ development and approval journey, BaseCamp provides the foundation needed to withstand late-stage scrutiny and accelerate time to patients.
What sets ElevateBio BaseCamp apart:
- A world-class team with proven experience manufacturing and releasing complex cell and gene therapy products
- Expanding commercial manufacturing infrastructure engineered for reliability, scale, and regulatory readiness
- Deep product understanding, supported by regulatory expertise and advanced analytical capabilities
- A culture of quality and collaboration that prioritizes speed with accuracy, transparency, and true partnership
This combination matters because ElevateBio has already solved the problems others are discovering too late. Our partners benefit from established systems, extensive experience, and an operational model designed to anticipate regulatory and manufacturing challenges.
Manufacturing Setbacks are Not Inevitable
Many issues stem from rushing early development, choosing the wrong partners, or re-learning lessons the industry already knows.
The promise of genetic medicines is real. These therapies are transforming care for diseases once considered untreatable. But realizing that promise requires treating manufacturing as a strategic driver, not a downstream function. In cell and gene therapy, regulatory success is shaped years before submission and depends on partners with the right processes and quality systems in place from the start. That is what ElevateBio provides: the experience, infrastructure, and commitment to quality needed to turn scientific breakthroughs into approved therapies – and ultimately deliver them to patients who are waiting.
Learn more about ElevateBio BaseCamp's approach
References:
- Slabodkin, Greg. “FDA’s CRLs Reveal 74% of Applications Rejected for Quality, Manufacturing Issues.” Pharma Manufacturing, 14 July 2025, www.pharmamanufacturing.com/all-articles/article/55302937/fdas-crls-reveal-74-of-applications-rejected-for-quality-manufacturing-issues.
Cindy Riggins, Ph.D., Vice President, CMC Regulatory Affairs
Cindy Riggins, Ph.D. is Vice President, CMC Regulatory Affairs at ElevateBio. Cindy started her career in cell and gene therapies in 2001 at FDA/CBER as a post-doctoral fellow studying xenotransplantation and later transitioning to product reviewer for various cell therapy products. After leaving FDA in 2008, she has been involved in development of monoclonal, cell, and gene therapies through CMC Regulatory Affairs roles at AstraZeneca, Novartis, Autolus and ElevateBio. She was part of the regulatory team at Novartis responsible for submission and approval of Kymriah®, the first gene therapy product approved in the USA.
