Why CMC and Manufacturing Decide CGT Success
The Hidden Work That Determines Whether Cell and Gene Therapies Reach Patients
February 3, 2026
The Hidden Work That Determines Whether Cell and Gene Therapies Reach Patients
Cell and gene therapies (CGTs) represent one of the most transformative advances in modern medicine. From CAR-T therapies that reprogram immune cells to AAV-based gene therapies that correct disease at its source, the science is breathtaking. Yet the uncomfortable truth is this: discovery rarely determines success. Execution does.
More than 90% of cell and gene therapy programs fail to commercialize—not because the biology is wrong, but because manufacturing, scale-up, and regulatory readiness fall apart. At the center of this execution gap sits an often-overlooked discipline: Chemistry, Manufacturing, and Controls (CMC).
CMC’s Overlooked Role in Advanced Therapies
Strong preclinical data is no guarantee of clinical or commercial success. Roughly 12% of Phase I cell and gene therapy programs ever reach approval, and a significant share of failures can be traced back to CMC gaps—insufficient GMP readiness, weak IND packages, or poorly justified control strategies.
CMC is often misunderstood as regulatory paperwork. In reality, it is the operating system of translational medicine: the framework that ensures a therapy can be produced consistently, tested reliably, transported safely, and defended scientifically in front of regulators. Without it, even the most elegant biology remains stranded.
Manufacturing Realities: Where Theory Meets the Shop Floor
Unlike small molecules, CMC in CGT is intensely physical and unforgiving. It lives on the shop floor: batch records, deviation investigations, change control, audits, raw-material traceability, and cold-chain logistics.
Vaccines and monoclonal antibodies have shown us that scaled GMP manufacturing is non-negotiable. But cell therapies introduce an added layer of complexity—patient-specific processes, variable starting material, short shelf lives, and fragile living products. When CMC planning is deferred, programs often collapse under real-world pressure. Industry analyses suggest that nearly 40% of clinical halts in CGT can be linked directly to manufacturing and quality failures.
The High-Stakes Choice of CDMOs
For most developers, Contract Development and Manufacturing Organizations (CDMOs) are not optional—they are existential partners. A poor CDMO fit can trigger delays, expensive rework, regulatory holds, and loss of investor confidence, compounding the already staggering $1–2 billion cost of bringing a therapy to market.
The mistake is often philosophical. Developers chase “flexibility” instead of depth. In practice, CGTs demand specialization. A CDMO excellent in CAR-T may be mediocre in AAV, and vice versa. Surveys suggest that more than 60% of CGT program failures involving outsourcing are linked to mismatches between a sponsor’s needs and a CDMO’s true capabilities.
Right-Sizing in an Unpredictable Market
Cell and gene therapies do not behave like traditional pharmaceuticals. Patient populations are small, heterogeneous, and often unpredictable. Overbuilt facilities can consume 30% or more of project budgets without delivering proportional value. Underbuilt systems, meanwhile, create bottlenecks that stall trials and frustrate regulators.
Right-sizing is not about minimalism; it is about alignment. Cross-functional planning—linking clinical strategy, manufacturing design, and regulatory pathways—allows programs to scale responsibly. This is especially critical in emerging markets such as APAC and the GCC, where infrastructure is evolving alongside demand.
Regulation: Preparation Beats Complexity
Contrary to popular fear, regulators do not punish innovation. They reward preparation.
Programs that engage early, articulate clear assay rationales, and align CMC strategy with clinical intent consistently move faster. Accelerated pathways have proven this point. Robust dossiers and scientifically defensible control strategies outperform convoluted ones. Clarity, not complexity, is what regulators look for.
When CMC Fails: Real-World Lessons from the Field
CMC failures are not theoretical—they have halted some of the most promising therapies in recent years. Regulatory data show a sharp rise in clinical holds across CGT programs, with 40–50% tied directly to manufacturing inconsistencies, unvalidated assays, or stability failures.
High-profile examples illustrate the stakes:
- Bluebird bio faced a 2021 clinical hold on its CALD gene therapy due to questions around manufacturing controls and process validation—despite compelling efficacy data.
- Rocket Pharmaceuticals saw its Fanconi anemia program halted after regulators flagged missing potency assays, transport stability data, and comparability studies following manufacturing changes.
- Ultragenyx and Capricor both received complete response letters where CMC deficiencies—not clinical outcomes—were decisive.
- In CAR-T, Allogene encountered a clinical hold linked to chromosomal abnormalities traced back to process gaps, while real-world data from lymphoma patients showed manufacturing failure rates approaching 20% in certain cohorts.
- Beam Therapeutics experienced an IND hold due to insufficient genomic and cytokine control data—before a single patient was dosed.
Across dozens of cases, the pattern is consistent: biology advances, but CMC lags—and programs stall.
The Path to Scalable Cures
The global cell and gene therapy market is projected to exceed $50 billion by 2028. But growth will not be limited by scientific imagination. It will be limited by execution.
CMC is no longer a downstream function to be addressed after proof-of-concept. It is a strategic pillar that defines whether therapies survive scale-up, audits, and time. Programs that right-size CMC from day one—validating assays early, selecting specialized partners, and engaging regulators proactively—turn “promising” science into approved medicine.
If we want more cures to leave the lab and reach patients, we must elevate CMC from an afterthought to a first-order conversation. The future of cell and gene therapy depends on it.
Across dozens of cases, the pattern is consistent: biology advances, but CMC lags—and programs stall.
Key Reference Links
- BioSpace, “90% Failure Rate in CGT,” 2024: BioSpace on Gene Therapy Approvals & Challenges
- ARM, “2023 Cell & Gene Therapy Landscape Report”**: ASGCT/ARM Q4 2023 Landscape Report (PDF)
- FDA, “IND Review Statistics,” 2024, FDA CGT Regulatory Considerations 2024
- ISCT, “Manufacturing Delays Survey,” 2023 ISCT CGT Approvals & Delays 2024
- McKinsey, “Next-Gen Biopharma Operations,” 2023**: McKinsey Insights on Cell & Gene Therapy
- FDA, “Bluebird Bio Hold Letter,” 2022 BioPharma Dive on FDA Bluebird Hold
- Evaluate Pharma, “CGT Cost Analysis,” 2025 Evaluate CGT Landscape
- BioProcess Intl., “CDMO Survey,” 2025 BioProcess Intl. CGT Headwinds
- BCG, “CGT Facility Optimization,” 2024 BCG New Drug Modalities 2024
- PwC, “APAC/GCC Biotech Report,” 2024 Towards Healthcare APAC CGT Market
- FDA, “RMAT Program Update,” 2025 FDA New Drug Therapy Approvals 2024
- Grand View Research, “CGT Market Forecast,” 2025 Precedence Research CGT Market
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