8/9 June 2021
A US-American medical manufacturer has received a Warning Letter from the FDA due to foreign particles in a solution for oral application and especially regarding the handling of this incident. Besides, further deficiencies were observed during the inspection such as errors in the evaluation of HPLC data and data integrity in the laboratory in general.
The manufacturer had noticed foreign particles during the filling process of an oral solution. These were filtered, visually inspected and the batch was subsequently released. The FDA criticizes the insufficient investigation of the type and source of the particles and their effect on product quality. In a deviation investigation, the manufacturer stated wipes during equipment cleaning as the cause. However, the deviation investigation was not completed before the batch was released, nor, according to the FDA, was there any evidence that the wipes were the actual source of the foreign particles. Consequently, the measures taken by the manufacturer to examine the retained samples and not to use these wipes in the future were also insufficient. As a result of the inspection, the manufacturer later recalled the batch concerned.
The FDA had also noticed further significant process deviations that had not been sufficiently documented and investigated by the manufacturer.
The FDA now expects, among other things, a scientific examination of particles that had been found in the products even earlier, including microscopic and chemical analyses. In addition, the FDA expects an independent evaluation of the manufacturing documents of the last four years (!), regardless of whether they contain deviations that did not lead to a CAPA investigation, as well as appropriate measures to be taken.
The FDA also found justified cause for complaint in the laboratory. Indeed, the company was found to have incorrectly performed the evaluation of HPLC chromatography data. Peaks were integrated in such a way that OOS results of impurities with similar retention times could not be detected. The company self-identified this problem in 2016. A training course was then held on how to correctly analyse HPLC data. Nevertheless, the interpretation was performed incorrectly until an affected batch was also detected in the stability testing. The FDA found several other cases where the analysis of HPLC data had been likewise performed incorrectly. The company's response to improve or refine the method as well as the statement that the analysis method had little effect because affected batches had been recalled later was not sufficient for the FDA.
The topic of data integrity led to another inspection finding in the laboratory. According to the FDA, inspection data is not sufficiently protected against manipulation or deletion. For example, quality assurance employees have administrator rights on the HPLC systems. Data can be changed or deleted without an audit trail. This has already been noticed by the FDA in previous inspections.
On the FDA website you can find the detailed Warning Letter to the US-American pharmaceutical manufacturer for more details.