Cell and gene therapies promise transformative outcomes but they also carry elevated risk and regulatory scrutiny. As the CGT sector matures, the FDA has sharpened its focus on manufacturing, control systems, and end-to-end quality culture.
Below are five key observation areas CGT firms must take seriously:
1. Weak Quality Systems & CAPA Implementation
What is happening: Across CGT inspections, the FDA frequently observes deficiencies in foundational quality systems, particularly deviation management, CAPA implementation, root-cause analysis, documentation and training.
Why it matters for CGT: With complex starting materials, manipulations, and patient-specific products, CGT manufacturing leaves little margin for error. A weak CAPA system suggests reactive culture rather than proactive prevention.
Typical observations:
- Deviations not appropriately triggered or documented
- CAPAs with no follow-through or effectiveness check
- Training records missing or outdated relative to process complexity
Action point:
Build a QMS road-map specific to CGT risks. Ensure root cause analysis goes beyond the batch to systemic vulnerabilities. Demonstrate trending, metrics, and management review.
2. Facilities, Equipment & Environmental Monitoring Gaps
What is happening: FDA inspectors identify issues in cleanroom classification, sample placement for viable and non-viable monitoring, equipment cleaning/qualification, and ingress controls.
CGT specifics:
- Many CGT products are exposed during manipulations, so first-air, airflow visualization, and effective monitoring are critical.
- Equipment may be established or modified for autologous manufacture, which increases qualification risk.
Typical observations:
- Particle or viable monitors placed in corners rather than representative critical points
- Cleaning validations either absent or insufficient for cell therapy environments
- Equipment not adequately qualified for intended CGT operations
Action point:
Review EM programs in ISO 5/7 zones with CGT-specific risk in mind. Ensure equipment qualification addresses the “patient batch” mindset; not just generic concepts.
3. Aseptic Process Validation & Product Handling Risks
What is happening: Aseptic process simulations (APS)/media fill, batch record completeness, hold-times, and process deviations remain high-risk areas for CGTs.
What makes CGT different:
- Many CGT products are non-fill/finish in traditional format which means Aseptic Assurance is critical, often in novel formats (bags, infusion sets, cell concentrates).
- Delay or deviation means the patient may already be waiting or product already used.
Typical observations:
- APS not representative of commercial operations (e.g., missing actual manipulations)
- Hold‐time definitions not justified or extrapolated for CGT specific units
- Batch records lacking completeness for each significant step of a unique patient lot
Action point: Design APS protocols that reflect your CGT workflow. Ensure all significant steps are captured. Capture manipulations and reflect them in the APS. Maintain detailed batch documentation as if every lot is unique.
4. Raw Material, Import, Donor-Material & Supplier Control
What is happening: For CGTs, starting materials, donor-derived material, complex consumables and reagents increase supply-chain risk. Observations include insufficient material controls, inadequate supplier qualification, missing testing or certificates of analysis.
CGT specifics:
- Autologous and allogeneic therapies rely on human/tissue/viral vectors. These materials require rigorous oversight.
- Third‐party suppliers are often small and specialized; oversight must be proportionate.
Typical observations:
- Materials used without full specification review
- Incoming testing incomplete for high-risk materials
- Traceability gaps for donor-derived or viral vector components
Action point:
Map all unique material paths for your CGT product. Perform risk‐ranking. Build supplier qualification programs specific to vector, donor and novel consumables.
5. Post-Approval & Long-Term Follow-Up Challenges
What is happening: With increasing approvals in the CGT space, the FDA is pushing for robust post-approval data collection, real-world evidence (RWE) and long-term monitoring.
Why it matters:
CGT products often have limited clinical trial populations and novel risk profiles, so oversight doesn’t end at launch.
Typical observations:
- Plans for long-term follow-up insufficient or not integrated with quality systems
- Registries or real-world data collection weak or not validated
- Post-approval manufacturing changes not tied back to surveillance data
Action point:
Establish a lifecycle compliance model for your CGT product. Ensure post-approval monitoring is integrated with QMS, CAPA, change control and communication plans.
Closing Thoughts
2025 marks a moment of increased regulatory intensity for cell and gene therapy firms. The FDA is no longer just watching innovation; it is evaluating how well organizations build systems to manufacture, assure, and sustain these complex therapies at scale.
At heart, the message is clear: Innovation must be matched with manufacturing and quality rigor.
Challenge for you
Use the five observation areas above as a self-assessment. Identify your weakest area. If you could pick one gap to address this quarter, what would it be and how will you execute?