The early-stage dilemma
For many early developers, reaching FIH (first in human) quickly is both a scientific milestone and a financing necessity. Clinical data may unlock the next funding round or give a platform the credibility it needs to attract investment. In that context, a CMC (Chemistry, manufacturing and Controls) strategy focused on speed is entirely rational. Small teams, finite cash, and limited in-house manufacturing experience leave little room for overengineering.
The challenge is to move quickly while risk assessing which decisions may become prohibitively expensive or time-consuming to revisit. A process inherited from the research team can rapidly become the clinical process that must be justified to regulators, optimized under pressure, assessed for comparability, and eventually scaled for broader use.
Developers do not need to establish the finalized commercial process before FIH. They do, however, need to make phase-appropriate decisions that support immediate progress while planning for later development.
Why “FIH fast” can become expensive
A CMC strategy built around speed alone may conceal issues that only become apparent once a program gains momentum. Establishing a target cost per dose and demonstrating that a process has the potential to be robust and scalable is much harder if not considered early.
Some choices are reasonable for FIH but become difficult to defend later without a plan for how they will evolve. Manual or open manipulations, operator-dependent steps, a limited understanding of critical process parameters (CPPs) and control strategies based solely on final release testing can all create challenges when a process needs to transfer, scale, or change.
Manufacturing changes made after FIH are likely to trigger comparability expectations, and regulatory guidance for cell and gene therapies (CGTs) now addresses change management and comparability explicitly (1–3). A seemingly straightforward improvement may require additional analytical work, retained samples, bridging datasets, or repeated development studies.
If sample retention was not planned, process understanding was not prioritized, or assay development remains immature, the cost of change can rise quickly. Whilst investors generally accept that an early process will be imperfect, they do however expect to see a strategy for how a robust and commercially viable manufacturing process will be achieved.
Pragmatism requires planning
A phase-appropriate CMC strategy does not attempt to resolve every technical uncertainty before FIH. It distinguishes between decisions that cannot be deferred and those that are acceptable for the current stage, supported by a documented plan for addressing remaining gaps.
The rationale for key decisions, accepted risks, and future development work should be recorded and traceable. This helps internal stakeholders remain aligned as teams change and prevents earlier discussions from being repeated unnecessarily.
Regulators, investors, and future manufacturing partners will also look for evidence that risks were considered consciously and managed in line with relevant guidance.
Develop a staged CMC pathway
A staged CMC development pathway can help early developers connect the current process with the intended FIH process and the likely later-stage or commercial direction. It does not need to be elaborate, but its milestones and stage gates should be explicit. It should also remain a living document that evolves with the program.
An effective pathway identifies known process gaps, planned changes, analytical development needs, and future comparability considerations. It should also account for controlled documentation, appropriate reviews, and approvals.
Material controls should align with the phase of development. GMP-suitable materials should be used where possible, while alternatives should be risk-assessed and justified where not feasible.
The roadmap should give cross-functional teams a shared understanding of next steps, the data that need to be generated, and the points at which change control may become significant.
It should also link technical work to business milestones, including completion of the preclinical package, regulatory submissions, first patient dosing, funding rounds, and later clinical planning. A technically sound development plan can still fail if it does not support the milestones required to keep the company and program moving.
Model cost of goods early
Cost-of-goods (CoGs) modeling is often viewed as a late-stage commercial exercise.However, for early CGT programs operating with limited resources and compressed timelines, it can be a valuable development tool.
The aim is not to predict launch costs precisely. It is to identify which parts of the process are most likely to undermine long-term viability if they remain unchanged.
Important cost drivers include elements such as labour, facility occupancy, vector use, consumables, QCtesting, logistics, and batch success rates amongst others. A process that appears workable for FIH may be viewed differently when these factors are considered holistically.
A process step that requires substantial operator intervention, increases batch-failure risk, or introduces avoidable licensing costs may deserve earlier attention than a technically elegant improvement with little effect on dose cost or operational reliability. Industry analyses continue to show that personnel, space utilization, process design, and transduction-related parameters can materially affect the economics of autologous CAR-T manufacturing (4–6).
Phase-appropriate CoGs modeling provides teams a clear, data-driven basis for prioritizing development spending. It reduces reliance on instinct, habit, or enthusiasm for a particular vendor or technology.
Use sensitivity analysis to set priorities
Once a basic economic model is available, sensitivity analysis will demonstrate how changes in key variables affect cost, feasibility, and scalability. It helps teams decide which improvements are worth pursuing immediately and which can wait.
Developers might compare the effect of improving yield, reducing failure rates, changing culture systems, or introducing greater automation. For a cash-constrained program, this helps direct resources toward changes that offer meaningful value and away from work that is scientifically interesting but commercially marginal at the current stage.
It also provides a clear basis for internal decisions regarding why one process improvement has been prioritized over another.
Consider scalability and closed processing early
Many CAR-T processes work at small scale because the scientists who established them understand the unwritten details that keep them running. That does not guarantee that the process will reproduce reliably, transfer cleanly into GMP manufacturing, or support a sustainable commercial model.
Recent reviews continue to highlight the move from manual, open processing toward closed and more automated systems as a way to improve reproducibility, reduce contamination risk, and support scale-out (7–8).
Early developers do not need to adopt an expensive, end-to-end automated platform before FIH. However, closed processing can reduce operator dependency and make GMP translation easier, and evaluating scalable platforms early may prevent a major redesign later.
The right approach will depend on the product, available budget, clinical plan, and intended manufacturing model. What matters is that the choice is evaluated deliberately and that any planned transition is documented.
Establish a phase-appropriate control strategy
A control strategy is unlikely to be fully mature at FIH, but documentation and tracking of product and process understanding should begin early.
A structured Quality by Design (QbD) approach can help developers build an iterative understanding of the target product profile (TPP), critical quality attributes (CQAs), and an emerging potency assurance strategy as development progresses (9–10).
Considering the control strategy early helps define which process parameters are potentially critical and should be characterized first and what data can be generated later. Evidence that the team is building process knowledge, connecting assays to the mechanism of action and key product attributes, and managing uncertainty is more credible than a strategy based primarily on final-product testing.
What is “good enough” for FIH?
“Good enough” does not mean poorly understood, undocumented, or insufficiently developed, and there should be no compromise on patient safety.
It should mean that the process is appropriate for its stage and aligned with the clinical, regulatory, funding, and manufacturing strategy. A team should be able to explain what has been fixed for FIH, what remains under development, which risks are still open, what data will be generated next, and which future changes may trigger comparability requirements.
”Good enough” means disciplined pragmatism rather than a reduction in quality. The aim is to make data-driven, phase-appropriate decisions with the appropriate planning to prevent the program from repeatedly paying for early shortcuts later in development.
Helping therapies survive the journey
Promising CAR-T therapies need more than encouraging early clinical data. A robust CMC strategy helps developers use limited resources effectively while protecting the path beyond FIH.
The objective is to reach the clinic without creating unnecessary obstacles to later development, technology transfer, or commercial manufacturing. A documented, risk-based plan linked to business milestones can also build confidence among regulators, investors, and future manufacturing partners.
Most importantly, it shows that the team understands the current limitations of the process, the work still required, and how the program will ultimately become a commercially viable therapy that can be manufactured reliably for the patients who need it.
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References
- FDA, “Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products; Draft Guidance for Industry” (2023). Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/manufacturing-changes-and-comparability-human-cellular-and-gene-therapy-products
- FDA, “Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products; Guidance for Industry” (2024). Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-development-chimeric-antigen-receptor-car-t-cell-products
- European Medicines Agency, “Questions and Answers on Comparability Considerations for Advanced Therapy Medicinal Products (ATMP)” (2019). Available at: https://www.ema.europa.eu/en/documents/other/questions-answers-comparability-considerations-advanced-therapy-medicinal-products-atmp_en.pdf
- “Industrializing CAR-T Cell Therapy: Impact of Automation on Cost and Space Efficiency of Manufacturing Facilities,” Frontiers in Bioengineering and Biotechnology (2026).
- L. Abdo, L. Batista-Silva and M. Bonamino, “Cost-Effective Strategies for CAR-T Cell Therapy Manufacturing,” Molecular Therapy Oncology, 33 (2025).
- K. Spink and A. Steinsapir, “The Long Road to Affordability: A Cost of Goods Analysis for an Autologous CAR T Process,” Cell & Gene Therapy Insights, 4, 1105–1116 (2018).
- “Closing the Loop: Closing Cell Therapy Manufacturing Processes,” Pharmaceutical Engineering (May/June 2026).
- “Biomanufacturing in Gene and Cell Therapy,” Molecular Therapy – Methods & Clinical Development, 32, 101261 (2024).
- Alliance for Regenerative Medicine, “A-Cell: A Case Study-Based Approach to Integrating Quality by Design Principles into Cell Therapy CMC Programs” (2022). Available at: https://alliancerm.org/manufacturing/a-cell-2022/
- Parenteral Drug Association, “Technical Report No. 81: Cell-Based Therapy Control Strategy” (2019). Available at: https://www.pda.org/bookstore/product-detail/4880-tr-81-cell-based-therapy-control-strategy
