Warning Letter for US Pharmaceutical Manufacturer: Container/Closure Issues and Other Deficiencies

Recommendation

17-19 September 2024

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GMP Compliance and Technology for the Manufacture of Oral Solid Dosage Forms

The US FDA has recently published a Warning Letter describing the deficiencies observed during an inspection performed in September 2018 at a US pharmaceutical manufacturer. One serious deficiency concerns leaking product containers. Furthermore, defects in the stability programme, in the CAPA system and in data integrity have also been reported.

The client of the pharmaceutical manufacturer had noticed a product leakage in three units of the validation batches. The batches were later rejected. The pharmaceutical manufacturer then changed its container/closure system. During the inspection, it became apparent that the stability samples' containers of the new validation batches were also leaking. In addition, the pharmaceutical manufacturer received four complaints due to leakage in the product containers. These were classified as "unconfirmed" by the pharmaceutical manufacturer. The manufacturer's suggestion to label the product cartons with the words "keep product upright" and "upwards arrows" is not sufficient for the FDA. The FDA also doubts the manufacturer's statement that these leaks do not negatively affect quality. Specifically, the FDA sees the risks of content or quantity changes, degradation due to oxygen exposure or microbial contamination.
The FDA expects a comprehensive CAPA review with the clarification of the cause for the leakage, a revision of the risk analysis and an independent evaluation of the deviation/CAPA system.

The CAPA system is also criticized in the Warning Letter. The pharmaceutical manufacturer is accused of lacking quality oversight. The FDA reports 40 open deviations during the inspection, one of which has already been in progress for more than one year. Among other things, not only the leakage issues already described were among these deviations, but also deviations with regard to quality-critical production parameters and OOS results in the final product. In addition, the company did not follow its own procedure for out-of-limit measurements in environmental monitoring.

The stability programme was also a cause for concern. According to the FDA, many samples were not tested in the laboratory within the specified time after removal from the stability chambers. In one case, a sample had already been in the laboratory for 254 days without having been tested.

At another facility of the company, QC measurement worksheets were found in the recycling bin. The documents showed OOS results of testing product containers and caps. The regularly filled test reports showed compliance with the specifications, without mentioning OOS results. In response, the pharmaceutical manufacturer stated that the employee responsible for the process no longer worked for the company.

Because of the company's inspection history with repeated deficiencies, the FDA doubts that the quality department can fulfil its tasks and responsibilities. The company should provide a sufficiently authorized quality function with the necessary resources. In addition, the involvement of a GMP consultant is recommended.

Please also see the complete Warning Letter for Pharmasol Corporation.