What 200+ FDA CRLs Reveal — and 10 Lessons for Life Sciences Facilities

Between 2020 and 2024, the FDA issued over 200 Complete Response Letters (CRLs) — formal notices explaining why a drug or biologic application could not be approved in its current form.

Recently, the FDA published those, giving manufacturers greater insight into their decision-making process and the common deficiencies cited that must be addressed before their application is approved.

The warning letters (CRLs) often highlighted issues related to facility standards, process design, and compliance protocols, rather than simply clinical problems directly associated with patient treatment. that some companies may not have prioritized these areas during their early-phase activities, even though they are essential for obtaining regulatory approval. The shortcomings in clinical and regulatory compliance often pertain to aspects such as facility readiness, equipment validation, and record-keeping. Many applications are rejected due to water quality, HVAC controls, or other engineering challenges. As a result, remediation steps are frequently required. Forward-thinking companies take heed. Proactive steps in the early planning stages can help you avoid significant setbacks.

Below are the top 10 challenges and implications:

1. Inadequate Facility Segregation and Flow

Issue: CRLs frequently cite poor segregation of materials, personnel, and product streams — especially in facilities handling biologics, gene therapies, or high-potency APIs.

Example: A 2023 CRL for a gene therapy facility noted that “viral vector production areas lacked physical and procedural separation,” raising cross-contamination concerns.

Implication: Facilities must be designed with unidirectional flow, proper airlocks, and containment strategies tailored to the product risk profile.

2. Missing or Incomplete Commissioning & Qualification (C&Q)

Issue: Several CRLs flagged the absence of documented performance qualification (PQ) for critical systems like HVAC, WFI, and clean steam.

Example: A 2021 CRL for a sterile injectable cited “lack of PQ documentation for HVAC and water systems,” undermining sterility assurance.

Implication: C&Q must be planned early and executed thoroughly, with traceable documentation for all critical systems.

3. Fire Protection and Hazardous Material Handling Deficiencies

Issue: Facilities using flammable solvents or reactive chemicals were cited for inadequate fire suppression, ventilation, or explosion protection.

Example: A 2022 CRL noted that “Class I flammable liquids were stored without compliant fire-rated enclosures or suppression systems.”

Implication: Fire protection and life safety systems must be integrated into facility design and meet NFPA and local code requirements.

4. Critical Utility System Failures

Issue: CRLs often cite inconsistent or unreliable utility systems — particularly WFI, compressed air, and clean steam — as risks to product quality.

Example: A 2020 CRL flagged “microbial excursions in WFI loop due to dead legs and inadequate sanitization procedures.”

Implication: Utility systems must be designed for reliability, maintainability, and compliance with USP and EU Pharmacopeia standards.

5. Environmental Monitoring System (EMS) Gaps

Issue: Several CRLs highlighted EMS systems that lacked real-time alerts, audit trails, or integration with building automation.

Example: A 2024 CRL for a biologics facility noted that “environmental data was recorded manually and lacked 21 CFR Part 11 compliance.”

Implication: EMS must be automated, validated, and integrated with facility controls to ensure data integrity and timely response.

6. Container Closure and Packaging Validation Issues

Issue: CRLs frequently cite missing extractables/leachables data, container closure integrity testing, or packaging validation.

Example: A 2022 CRL for a prefilled syringe product required “full revalidation of container closure integrity due to missing worst-case scenario testing.”

Implication: Packaging systems must be validated in the context of the product and process, with supporting data for regulatory review.

7. Inadequate Cleanroom Classification and Control

Issue: Some CRLs noted that cleanrooms were not properly classified or monitored, especially in aseptic processing areas.

Example: A 2021 CRL cited “Grade B cleanroom with particle counts exceeding ISO 7 limits during dynamic operations.”

Implication: Cleanroom design must align with ISO 14644 and EU Annex 1, with robust monitoring and control strategies.

8. Lack of Preventive Maintenance and Asset Management

Issue: Several CRLs flagged missing calibration records, unclear maintenance responsibilities, or lack of equipment readiness documentation.

Example: A 2023 CRL noted that “critical equipment lacked documented preventive maintenance schedules and calibration logs.”

Implication: Asset management systems must be in place to track equipment lifecycle, maintenance, and readiness for GMP operations.

9. Inadequate Documentation and Change Control

Issue: CRLs often cite poor documentation practices, including missing SOPs, uncontrolled forms, or undocumented changes to systems.

Example: A 2020 CRL stated that “HVAC setpoint changes were implemented without change control or impact assessment.”

Implication: Documentation systems must be validated, version-controlled, and integrated with quality systems.

10. Sustainability and Environmental Controls Overlooked

Issue: While not always a direct cause of CRLs, several FDA inspections noted poor environmental controls (e.g., temperature, humidity) that impacted product stability.

Example: A 2022 CRL noted that “ambient storage areas exceeded temperature limits during summer months, compromising stability data.”

Implication: Environmental control strategies must be integrated into facility design — not just for compliance, but for product integrity and sustainability.

How Genesis AEC Helps

The CRLs reveal a consistent theme: facility readiness and compliance are critical to regulatory success. Many of the issues cited could have been prevented with better planning, design, and execution.

Genesis AEC supports life sciences clients across the full facility lifecycle:

• Facility Planning & cGMP Design: From concept to construction, we design compliant, efficient, and scalable spaces.
• Engineering & Critical Utilities: Our engineers design robust systems for back-up power, central chiller and boiler plants, WFI, clean steam, and more. 
• Commissioning, Qualification & Validation (CQV): We ensure your systems are tested, documented, and ready for inspection.
• Asset Management: We help you track, maintain, and document equipment readiness.
• Sustainability & Environmental Controls: We integrate energy efficiency and environmental stability into every project.

By learning from the past — and building with the future in mind — we help clients avoid costly delays and accelerate their path to approval.