CMC for a Cell or Gene Therapy IND

For a cell or gene therapy IND, FDA’s CMC review is primarily a safety review. The agency is not looking for a commercial-ready manufacturing package. It is looking for enough control, testing, and characterization to show that your product can be made consistently and is safe to give to the first patients.

The must-haves cluster in a few places: safety testing (sterility, mycoplasma, endotoxin, adventitious agents, and replication-competent virus where the vector calls for it), a defined release specification (identity, purity, strength or dose, and a measure of potency), adequate characterization, and stability covering the clinical-use period. Full process and assay validation is phase-appropriate and fully matures after IND.

The mistake FDA sees most often is under-testing. Sponsors hear phase-appropriate and take it as permission to go light everywhere, including on the safety testing that is not flexible at all. Validation can mature after IND, but sterility, adventitious agents, and replication-competent virus cannot wait.

This explainer draws the line that matters before you file: which requirements scale with your phase, and which ones are fixed from the very first subject in an IND. It walks the full CMC package, shows how FDA thinks about potency across development, and identifies the gaps that most often cause problems.

01 · WHAT THE REVIEW IS FOR

A safety review, not a commercial readiness review

When a CMC reviewer opens Module 3 of a cell or gene therapy IND, the question they are trying to answer is narrow and specific: can this product be made the same way twice, and is it safe enough to put into a human being right now? They are not grading your process against what it will need to look like at licensure in a BLA. They are checking that you have control over your materials, that your safety testing is in place, that your product is characterized well enough to know what it is, and that it will hold up over the period it will actually be used.

That risk-based framing explains almost everything about where FDA is flexible and where it is not. Anything that is really about long-term manufacturing consistency, tightening specifications, or commercial scale can mature after IND. Anything that protects the first patients in the trial is expected on day one, and needs to be addressed in your IND. The trouble comes from treating those two categories as one.

Phase-appropriate is a real and useful principle, but it applies to the depth of validation, not to whether safety testing exists. You can qualify rather than fully validate an analytical method at IND. You cannot skip sterility because you are early. The distinction between requirements that scale with your phase and the ones that are fixed from the first patient is the single thing worth getting right before you file.

02 · THE MUST-HAVES

The CMC package at a glance

The table below sorts the CMC package into what FDA expects in hand at IND and what is genuinely phase-appropriate. Read the status column as the bar for a first-in-human filing, not for a BLA.

03 · WHAT FDA REQUIRES

What CMC information a CGT IND has to contain

The regulatory anchor is 21 CFR 312.23(a)(7), and the organizing structure is eCTD Module 3. The clearest way to build the section, and the way a reviewer reads it, is to walk from drug substance to drug product and cover each element in turn.

Start with the manufacturing process: a clear, reproducible description of how the drug substance and then the drug product are made, supported by a flow diagram. Then the control of materials: the identity and quality of your critical reagents and components, with particular attention to anything animal- or human-derived. Then banking: your master and working cell banks, and for vectors your seed and master banks, established, characterized, and safety-tested.

From there, the release specification is where the safety and quality tests live: the sterility, mycoplasma, endotoxin, and adventitious agent testing, replication-competent virus testing where the vector class calls for it, and the identity, purity, strength or dose, and potency measures that define the product. Characterization supports the specification by showing you understand what the product is beyond the release panel. Stability shows the product holds up over the clinical-use period, including any in-use and hold times. Container-closure closes the loop on basic suitability.

Written in plain language and kept phase-appropriate, that sequence is the spine of a CGT IND CMC section. The depth of each element scales with your phase, but the elements themselves are all expected to be present.

04 · POTENCY

How FDA thinks about potency at the IND stage

Potency is where cell and gene therapy programs most often misjudge the IND bar, and that misjudgment does the most damage later. The key thing to understand is that FDA’s expectation scales with your phase of development. What is required at first-in-human is not what is required at BLA, and the gap between them is wide.

At Phase 1, first-in-human, you do not need a validated potency assay and you do not need final acceptance criteria. Your analytical methods, potency included, need to be fit for purpose: characterized for accuracy, reproducibility, sensitivity, and specificity, but not locked down. What FDA expects to see beginning at this stage is the development of your potency assay. FDA understands that you may still be identifying potency-related quality attributes at this early stage. Use your early characterization data to identify the critical quality attributes that will eventually define it. This is also a good stage to align with FDA directly, and an INTERACT meeting is a natural venue for that conversation before you have committed to an approach.

By Phase 2 and 3, the expectation tightens: release tests, potency included, must be qualified, with predefined acceptance criteria, under CGMP. By BLA, the potency assay must be fully validated.

The bar itself is straightforward, so why do so many programs get caught out at Phase 2 and beyond? Because potency assays are genuinely difficult to develop for complex biological products, and because full validation is not required early, companies defer the work until it is too late to do it well. A potency assay is not something you can stand up on a short timeline when a reviewer asks for it. The programs that stay ahead of this treat potency as a strategy that matures across development, anchored to the product’s mechanism of action from the start, rather than a box to check before a filing.

In practice, a strong potency strategy is rarely a single assay. It may comprise multiple complementary measurements tied to the mechanism of action. For an AAV gene therapy, that often means pairing a measure of how much functional vector is delivered (for example, transduction or transgene expression) with a measure that the expressed transgene product actually does what it is supposed to do. For a CAR-T product, it often means pairing a measure of CAR expression with a functional readout such as target-specific cytokine release or cytotoxicity against antigen-positive cells. The point is not the specific pair. It is that no one measurement captures potency, so you build a set that together reflects the biology as it relates to the intended use of the product.

05 · WHAT CAN WAIT

What is phase-appropriate, and what can wait until after IND

The mirror image of under-testing is over-building. Full process validation, full analytical method validation, complete comparability packages, and final commercial specifications are not required at IND. Sponsors who try to bring all of that to a first-in-human filing spend time and money on work FDA is not asking for yet, and often lock themselves into a process they will need to change anyway as the program matures.

There is a recent development worth reading precisely. In 2026, FDA finalized guidance on CMC flexibilities for cell and gene therapy products. It is important to be exact about its scope: that guidance addresses CMC flexibilities for products developing toward a BLA. It is not a loosening of IND safety requirements. The flexibilities it describes, such as a lifecycle approach to process validation and phase-appropriate release criteria, are about how the CMC package can mature on the way to licensure, not about what you can leave out at first-in-human. These flexibilities always existed but most companies and consultants were not aware of the extent of flexibility, so this guidance communicates FDA’s position more broadly.

For early CMC strategy, flexibilities reward product understanding built early. The programs best positioned to use them later are the ones that invested in characterization and a coherent control strategy from the start. That is fully consistent with the IND bar described here: do the safety testing now, develop your assays and characterization now, and the flexibility framework has something to work with when you reach a BLA.

06 · WHERE PROGRAMS SLIP

The CMC gaps that most often cause problems at IND

The same handful of gaps account for most of the CMC trouble at IND. None of them are exotic. They are the predictable result of treating a fixed safety requirement as if it were phase-appropriate, or of deferring difficult work until it is too late to do well.

• Insufficient safety testing: missing or weak sterility, adventitious agents, or replication-competent virus testing.
• No potency or biological-activity measure, or no coherent potency assurance strategy.
• Inadequate control of critical materials, especially animal- or human-derived materials.
• Characterization too thin to assure identity and purity.
• Stability that does not cover the clinical-use period.
• No comparability when the process changed between the tox lot and the clinical material.

07 · CELL VS GENE

How the CMC differs across cell and gene therapy

The framework is the same across modalities, but the specific tests, the dose metric, and the product-specific safety concerns differ. Genetically modified cell products such as CAR-T sit at the intersection and generally carry expectations from both columns.

08 · FAQ

Frequently asked questions

What CMC information is required for a cell and gene therapy IND? A phase-appropriate Module 3 built on 21 CFR 312.23(a)(7): a manufacturing process description, control of materials, cell and vector banking, a release specification (identity, purity, strength or dose, potency, and the safety tests), characterization, stability, and container-closure.

Is a validated potency assay required at IND? No. A fit-for-purpose measure of biological activity plus a potency assurance strategy is what is expected. Full validation is phase-appropriate: qualified at Phase 2 and 3, fully validated at BLA.

What safety testing does FDA require for a CGT IND? Sterility, mycoplasma, endotoxin, adventitious agents, and replication-competent virus testing for the applicable vector class. Applicable donor eligibility screening and testing are also required for cell-based therapies.

What CMC issues cause clinical holds for cell and gene therapies? Most trace back to insufficient safety testing, a missing potency measure or strategy, inadequate control of critical materials, characterization too thin to assure identity and purity, stability that does not cover the clinical-use period, or missing comparability after a process change.

Do the 2026 FDA CMC flexibilities lower the IND requirements? No. They apply to development toward a BLA, not to IND safety requirements.

How is CMC different for cell therapy versus gene therapy? The framework is shared, but the signature safety tests, the dose metric, and the special considerations differ, and genetically modified cell products such as CAR-T generally carry expectations from both.

FDA sources & references

• 21 CFR 312.23(a)(7) — IND content and format, CMC information. fda.gov ↗
• CMC Information for Human Gene Therapy INDs — FDA guidance for industry on CMC expectations for gene therapy INDs. fda.gov ↗
• Potency Assurance for Cellular and Gene Therapy Products — FDA guidance on a potency assurance strategy across development. fda.gov ↗
• CMC Flexibilities for Human Cellular and Gene Therapy Products for a BLA — FDA (CBER) final guidance, 2026, on CMC flexibilities heading toward a BLA. fda.gov ↗
• 21 CFR Part 1271 — Human cells, tissues, and cellular and tissue-based products, including donor eligibility. fda.gov ↗
• 21 CFR Part 211 (and 21 CFR 210.2(c)) — Current good manufacturing practice, applied phase-appropriately for investigational CGT products. fda.gov ↗

This document is general educational information about CMC expectations for cell and gene therapy INDs. It is not legal or regulatory advice and does not create an attorney–client or consulting relationship, nor does it substitute for FDA’s guidance documents or the applicable regulations. CMC for cell and gene therapy is highly product- and indication-specific, and FDA’s views are informal and non-binding. Confirm current FDA procedures and consider professional review of your specific program before acting.