Sterility Testing, GPT and More - Warning Letter of the US FDA with various deficiencies

During an inspection by the FDA from November 4 to 15, 2024, in Lenoir, NC, several serious violations of CGMP requirements (according to 21 CFR 210/211) were identified at Exela. Various drugs were classified as “adulterated” within the meaning of 501(a)(2)(B) of the FD&C Act. According to the FDA, the formal FDA 483 letter dated December 9, 2024, was not followed by an adequate response or sufficient measures. This led to the current Warning Letter. This can be summarized as follows:

I. Deficiencies in drug manufacturing

1. Inadequate investigation of deviations (21 CFR 211.192)
a. Failed growth promotion tests (GPT) for sterility test media

• A media batch was used for release testing of many injectables, even though it failed two GPTs and only passed on the third attempt.
• Insufficient causal investigation: “human error” was indicated, but not specifically documented.
• Several other media batches were also affected.
• No comprehensive traceability of the affected drug batches.
• Inadequate CAPA (corrective and preventive actions).

b. Incorrect OOS evaluation in particle testing

• OOS results in particle testing were declared invalid without a thorough root cause analysis.
• No training or procedural adjustments.
• Repeating the test with new vials led to acceptable results – risk of data manipulation cannot be ruled out.

FDA requirements:

• Retrospective review of all OOS results (including GPT).
• Validation of root cause analyses.
• CAPA system for OOS investigation: including QA monitoring, trend analysis, and training.

2. Incomplete/deficient microbiological data records (21 CFR 211.194(a))

• Incorrect counting of colony-forming units during active air monitoring.
• No second check of plate counts.
• Data integrity compromised; quality assurance (QA) not effective.

FDA requirements:

• Comprehensive assessment of laboratory practices.
• Improvement plan: methods, equipment, documentation, training.

II. Deficiencies in production at the outsourcing facility (according to 503B)

Although registration as a 503B facility has currently been revoked, violations remain relevant:
Summary of significant microbiological/sterility-related violations:

1. No sterility testing of each batch (21 CFR 211.167(a))

• Sterility testing not performed for each batch.
• Use of unvalidated media (e.g., media batch despite faulty GPT results (see 1.a.)
• Repeated GPT failures without clear clarification of causes (see 1.a.).

2. Unclear SOPs for GPT and data verification

• SOP revision (SOP-000189) insufficient.
• No clear definition of time windows and procedures for secondary checks.
• Delayed and potentially inaccurate data entry into the software system.

3. Inadequate verification of environmental monitoring results

• Only one person performs plate counting, data entry, and initial evaluation.
• No simultaneous or subsequent visual secondary control.
• FDA found incorrect plate counts during the inspection.

FDA requirements:

• Complete SOP revision with defined responsibilities and time frames.
• Ensuring data integrity in environmental monitoring and GPT.
• Training and system adjustments to improve QC control.

Other relevant deficiencies (briefly summarized)

• Lack of written procedures for process control (21 CFR 211.100).
• Lack of documentation of QC release (signatures) (21 CFR 211.194(a)(8)).
• No stable stability program (21 CFR 211.166).
• Inadequate training of personnel (21 CFR 211.25(a)).
• Incomplete visual inspection programs, lack of defect libraries, inadequate risk assessments.

FDA recommendation

Before resuming the manufacture of sterile products, a comprehensive evaluation of all systems is strongly recommended—in particular, microbiological controls and aseptic procedures. The use of an external consultant with expertise in sterile manufacturing is also recommended.
A detailed description of the deficiencies found and the required measures can be found directly in the FDA Warning  Letter .