GMP Deficiencies in the Sterile Area

Recommendation

17-19 September 2024

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In a Warning Letter addressed to a US-American pharmaceutical manufacturer, the FDA identified various deficiencies in sterile production. Among other things, deficiencies in the design of equipment and rooms, air flow and visual inspection are described.

Aseptic Design

The FDA criticises the inadequate smoke studies in the ISO Class 5 area (corresponds to EU GMP Class A, i.e. the aseptic core area). These were not carried out at all or only superficially as requested in the FDA inspection and were not suitable for demonstrating aseptic conditions during production.

The smoke studies were not carried out under dynamic conditions, i.e. without simulated interventions. In addition, there was also a lack of adequate visualisation of the air flow in the ISO 5 area, including the filling, closing and capping areas. The FDA could not observe "unidirectional airflow and sweeping action away from product".

In addition, the FDA describes other deficiencies in the sterile design of equipment and its environment:

• "The equipment design, layout, and operating practices of the aseptic processing line, its filling cabinet and the cleanroom pose hazards to sterile products you manufacture."
• "The HEPA-filtered airflow is insufficient to ensure robust ISO 5 aseptic conditions throughout the aseptic processing line."
• "The filling machine frequently alarmed during aseptic processing. You explained some of these high priority alarms may be due to air disrupting load balance cells used for weight measurement. You failed to evaluate the impact of the airflow on your aseptic processing line."
• "Inadequate aseptic processing operator gowning (e.g., some components are not sterile) practices also pose a significant contamination hazard in your aseptic processing operation."

The media fills of the pharmaceutical manufacturer also gave reason for complaint. The evaluation of the filled vials, i.e. the examination of incubated media for microbial growth, was not carried out by sufficiently qualified (trained) staff.

Environmental monitoring

The FDA also criticised the company's monitoring of the environment conditions as deficient. For example, no airborne microbial count measurement was carried out during aseptic production. Some of the procedures described for carrying out microbiological and particle measurements are missing: Alarm limits, frequency and duration of sampling, actions when limits are exceeded, and assessment of trends.

According to the FDA, environmental monitoring should be designed to quickly obtain meaningful information about the condition of the aseptic processing environment and associated classified areas. Unfavourable trends and potential pathways of contamination should be identified promptly so that appropriate follow-up action can be taken to prevent contamination of products.

Visual inspection

Another area criticised by the FDA is visual inspection. According to the FDA, the manufacturer only inspects a small portion of the filled units for visual defects. [Note: 100% visual inspection is required here]. Also, the visual inspection of the units was not performed against a white and a black background as required by the pharmacopoeia [for manual inspection]. In addition, procedures were lacking that adequately describe how the visual inspection activities were to be carried out.

The FDA therefore requires a formalised 100% visual inspection programme designed to detect particulate contamination and other visible defects. The inspection process should be described in detail therein, categories of defects and the associated acceptance and rejection limits identified. The training and qualification of visual inspection staff should also be included in it. In addition, there should be a retrospective review of all batches of medicinal products that have been released without being subjected to appropriate visual inspection by qualified staff. Likewise, a visual inspection of retain samples should be carried out for all batches already in distribution.

Investigation of deviations

The adequate investigation of deviations, including a root cause determination and the expansion to all potentially affected batches, was also cause for complaint.

The FDA cites a deviation report: "when transferring from formulation vessel to the ISO 5 filling space… the ink from the tubing started leeching into the solution. [...] It seems the ink, or the process by which the ink is applied to tubing changed."

Although the sub-batch was rejected, the FDA's investigation lacked a root cause determination. The investigation also lacked a review of other batches of other drug products manufactured using the same tubing that may have been adversely affected by this chemical contamination. The investigation also lacked information on the toxicity of this foreign contaminant.

Again, the FDA is requiring a retrospective investigation or assessment of all batches manufactured and distributed using these tubes. In addition, the FDA requires a comprehensive evaluation of the entire system to investigate deviations. The pharmaceutical company should ensure that all phases of a deviation investigation are properly conducted. This should include: ensuring that equipment performance issues are identified immediately, that equipment and facilities are upgraded in a timely manner, that preventive maintenance plans are followed, that repairs are made effectively, and that ongoing management review is established.

The FDA writes that similar GMP deviations had already been found during an inspection in February 2019. The authority further notes that following discussions with the FDA, the manufacturer has initiated a recall of all sterile products that are approaching their expiry date.

The original Warning Letter can be found on the FDA website.