PMDA ORANGE LETTER_2026.01

♦It is stipulated in The GMP Ministerial Order that Manufacturers should select among specifications of the pharmaceuticals the items which are vulnerable during storage or are deemed to have impact on efficacy and safety of such pharmaceuticals when out of specifications thereof occur, to conduct testing in the stability monitoring at suitable intervals. In addition, in the case where any actual or potential out of specifications has been identified upon outcome of the assessment of impact on the quality, necessary actions should be taken, such as prompt notifications to concerned marketing license holders of the pharmaceutical.

♦In the stability monitoring of final products, unfavorable trends were observed in multiple products and multiple test items. However, because no actions—such as evaluating the possibility of exceeding specifications within the expiry date, increasing test frequency, or investigating root causes—had been taken, this was listed as a deficiency during the GMP inspection.

♦As a response to the deficiency, the manufacturing site calculated predicted values through trend analysis and identified products with a possibility of exceeding specifications within their expiry date. For the identified products, additional testing was conducted at the midpoint before the next scheduled testing time point.
As a result of the additional tests, several results deviated significantly from the previous trends. However, this was not evaluated.

♦An additional root cause investigation was conducted, and it is concluded that there is no intentional change from approvals and the production remained stable based on the correlation between the yield trend, process parameters and the test results.  

♦However, the additional stability test results revealed that the range of variation (precision) established in analytical method validation has been exceeded. The reason for this trend is presumed to be the variation in sample preparation operations among different analysists, and this variation was not considered in the initial analytical method validation. Since necessary variables were not fully covered in the analytical method validation, analytical method validation including sample preparation was planned to be re-conducted.

♦Rather than one test point, whether trend over time is evaluated in stability monitoring? And whether the trend is evaluated even if all the results are in the acceptable range?

♦Whether all the necessary variables based on the actual operation are covered in the analytical method validation? In addition, in case that operations which may affect the test results are identified through verification, detailed procedures are established to ensure consistent operation no matter who conducts the test.

♦It is easy to pay attention to stability monitoring results when they are out of specification or approaching the upper/lower limits. However, in the case that the results are within specification, even if they significantly deviate from the previous trend, there is a tendency to judge that there is no quality issue with the lot. It is crucial to assess quality over time.

♦Analytical method validation is the foundation of the reliability of test results and is extremely important. Please re-verify whether the scope of validation is appropriate.