Handling of Microbiological Deviations and Sterility Testing - FDA publishes Warning Letter

A few years ago, after the serious incidents with almost 800 meningitis cases and the associated inspection at the New England Compounding Center, the FDA had massively increased the control for such facilities. This led to a large number of Warning Letters, especially in 2012 and 2013.

Now the FDA has issued a Warning Letter to a compounding facility. During its inspections at Central Admixture Pharmacy Services, the FDA found serious deficiencies that jeopardize patient safety, in particular problems in sterile manufacturing. The inspection took place from February 27 to March 30, 2023 and as a result, the FDA issued a 483, which was also responded to and a voluntary recall of sterile drug products was also issued. However, in its subsequent Warning Letter, the FDA states that the manufacturing practice still does not comply with the FDCA or GMP requirements.

The background to this is that the current FDCA regulations allow companies registered as "outcourcing facilities" to be exempted from certain requirements such as the approval requirement (Section 505) and the labeling requirement (Section 502(f)(1)). However, the manufacture must still comply with the current GMP (Good Manufacturing Practice) regulations set forth in 21 CFR Sections 210 and 211.

Violations of the FDCA

The inspection revealed that the drugs were manufactured under unhygienic conditions, which can lead to contamination risks. It was also found that the company concerned had not carried out an appropriate assessment and corrective action following microbial contamination in the ISO 5 aseptic manufacturing zone. The FDA lists the following additional violations:

1. failure to thoroughly investigate unexplained deviations or failure to meet specifications (per 21 CFR 211.192).
2. lack of laboratory standards to ensure the quality of components and finished products (2according to1 CFR 211.160(b)).

Corrective actions requested

Despite the responses from the submitted Form FDA 483 and the recall action, the FDA assessed some of the corrective actions as inadequate. It cited the following deficiencies:

1. Their SOP (Standard Operating Procedure) does not ensure that every microbiological contamination is adequately investigated and corrected. In addition, current results of environmental and personnel inspections in classified areas are missing.
2. No data has been provided to demonstrate that your rapid sterility testing method is appropriate. This ensures that your method provides valid results prior to the release of each batch.

Additional points

The FDA also points out that even when using external facilities and service providers, the company itself remains responsible for ensuring that its processes and raw materials meet the quality requirements, i.e. GMP compliance.

Repeated violations at multiple sites

In addition, the FDA states that it has identified similar deficiencies at other company sites, indicating inadequate management controls. Accordingly, the authority emphasizes the responsibility of company management to correct all deficiencies and ensure CGMP compliance, and the FDA recommends a comprehensive assessment of global manufacturing processes.

For more information, please refer directly to the FDA's Warning Letter.