FDA’s Flexible GMP Expectations for Cell and Gene Therapy: Innovation Accelerator or Deferred Risk?

The FDA’s new announcement, Flexible Requirements for Cell and Gene Therapies to Advance Innovation, signals a notable shift in how regulators are thinking about manufacturing controls during early- and mid-stage development of cell and gene therapies (CGTs). The intent is clear: reduce unnecessary friction, lower barriers to clinical entry, and accelerate innovation for therapies often targeting serious or life-threatening diseases. 

At the heart of the guidance are two statements that have drawn particular attention across the industry: 

• Before an investigational product is manufactured for phase 2 or 3 trials, the manufacturer will not be expected to comply with 21 CFR part 211. 

• As final specifications for the drug substance and drug product are not expected until the end of the investigational process (21 CFR 312.23(a)(7)), INDs may provide for permissive product quality release acceptance criteria in investigational studies… CBER will allow minor manufacturing changes supported by data showing comparability… without expecting overly stringent and onerous comparability data. 

  
  

On paper, this approach offers flexibility. In practice, however, sponsors developing CGTs globally may find that the promised efficiencies are more nuanced—and potentially more complicated—than they initially appear. 

What FDA Is Actually Changing (and What It Isn’t) 

Under this draft guidance, CBER is reinforcing a long-standing regulatory principle: investigational products are not held to the same standards as commercial products.

Specifically: 

• Full compliance with 21 CFR Part 211 (cGMP) is not expected prior to Phase 2 or Phase 3 manufacturing. 

• Final drug substance and drug product specifications are not required until later in development, consistent with 21 CFR 312.23(a)(7). 

• Sponsors may use permissive release criteria in investigational studies. 

• Minor manufacturing changes between phases may be supported by streamlined comparability packages rather than exhaustive analytical datasets. 

  
  

From a U.S. regulatory perspective, this is not a radical departure, but the announcement makes the flexibility more explicit, particularly for CGTs where manufacturing processes often evolve alongside scientific understanding. 

The Global Reality: GMP Expectations Don’t Stop at U.S. Borders 

The challenge is that most CGT programs are global by necessity, not choice. 

While FDA may allow relaxed GMP expectations for early-phase manufacturing, many other regions require GMP-compliant material for Phase 1 clinical trials. The EU, UK, Japan, and other jurisdictions often expect manufacturing to occur in GMP-certified facilities from the outset—even for first-in-human studies. 

This creates an immediate tension: 

• Sponsors cannot easily “toggle” between non-GMP and GMP manufacturing models. 

• Global development strategies frequently default to the most stringent common denominator. 

• Manufacturing decisions made early—cell source, vector design, process controls—are difficult and costly to unwind later.

As a result, the theoretical cost and time savings suggested by FDA’s flexibility may be limited for sponsors pursuing multinational development programs. 

Faster Entry vs. Accumulated Change Debt 

One of the most consequential elements of the guidance is FDA’s openness to minor manufacturing changes supported by comparability data without overly onerous requirements as programs progress toward efficacy-establishing trials. 

This is appealing in theory. In practice, it raises important questions: 

• How many “minor” changes can accumulate before comparability becomes contentious? 

• How aligned will global regulators be on what constitutes sufficient comparability? 

• Does early flexibility simply defer complexity to later phases, when timelines are tighter and stakes are higher? 

For CGTs—where even small manufacturing changes can materially affect product attributes—sponsors may find themselves managing a growing ledger of process modifications, regional justifications, and bridging arguments. 

What looks like agility early can become change debt later, requiring additional data generation, expanded regulatory narratives, and prolonged health authority dialogue. 

Risk Is Not Just Clinical—It’s Strategic 

This guidance also introduces a subtler category of risk that sponsors must weigh carefully. 

Beyond patient safety, regulatory alignment risk is increasingly central in CGT development. Sponsors may hesitate to fully leverage FDA’s flexibility if doing so: 

• Increases the likelihood of late-stage disagreements on manufacturing controls 

• Complicates global licensure strategies 

• Creates uncertainty during inspections or marketing application review 

For many companies—particularly smaller or resource-constrained biotechs—predictability can be more valuable than speed. The risk of having to renegotiate manufacturing acceptability late in development may outweigh the benefit of earlier clinical entry. 

Does This Actually Reduce Development Costs? 

The central question remains: does this guidance meaningfully reduce real-world development costs? 

The answer, at least for now, is it depends. 

• For U.S.-only or early proof-of-concept programs, the flexibility may allow faster entry with lower upfront manufacturing investment. 

• For globally positioned CGT programs, the savings may be modest, as sponsors continue to plan for GMP-aligned processes from the beginning. 

• For platform-based developers, the guidance may enable iteration—but only if those iterations remain globally defensible later. 

In other words, the efficiencies are conditional, not universal. 

Final Thoughts: Time Will Tell 

FDA’s draft guidance reflects a thoughtful attempt to balance innovation with oversight in one of the most complex areas of modern drug development. It acknowledges the realities of evolving science and seeks to avoid unnecessary rigidity during early stages. 

Whether it delivers true efficiencies will depend on sponsor risk tolerance, global development strategy, and long-term manufacturing vision. 

Time will tell whether developers fully embrace this flexibility—or continue to default to conservative GMP approaches—and whether early agility ultimately accelerates patient access or simply shifts complexity downstream. 

Ready to Turn Regulatory Flexibility Into Strategic Advantage? 

FDA’s evolving approach to manufacturing flexibility for cell and gene therapies creates opportunity, but only when paired with a globally aligned regulatory strategy that anticipates downstream impact. 

At Synterex, we help sponsors translate regulatory flexibility into coherent, defensible development strategies across regions, phases, and health authorities—so efficiencies gained early don’t become friction later. 

Learn more about our regulatory strategy and CMC support at: https://www.synterex.com/services/cmc-writing-strategy  

Related reading: For a deeper look at how regulatory systems are evolving alongside innovation, see What the FDA’s Innovation Push Reveals About Where Regulatory Systems Are Headed on the Synterex blog.