PMDA ORANGE LETTER_2025.03

1．Cases
Insufficient quality impact assessment

2．Background
◆ Though it is specified in the GMP Ministerial Ordinance that items that are deemed to have impact on efficacy and safety when out of specifications thereof occur should be selected as testing items and conduct tests in proper frequency.  Furthermore, impact on the quality of the pharmaceuticals should be assessed based upon the results of the tests.

3．Observations
◆ In the stability monitoring at the 6-month point, potency was found to be under the lower limit of the approved specification (Out of Specification: OOS).
◆ Retests were performed and 3 out of 6 results were OOS. However, considering the variability in test values, it was deemed that there was no change in quality from the 0-month point and it was considered that no special measures were necessary.
◆ At the 12-month point, OOS in potency was also found. In addition, 4 out of 6 re-test results were OOS, but it was concluded the same as the 6-month point, that no special measures were necessary.
◆ No impact on other lots of the same product was concluded.

4．Problems/Risk
◆ In the case that the possibility of OOS or temporal changes cannot be denied with evidence, because the impact on product quality cannot be denied either, this series of judgments is inappropriate.
◆ As a certain degree of variability in the test results is allowed, even if compliant results near the standard value are obtained , there is a risk that pharmaceuticals that do not meet the desired quality may be distributed.

5．Check Point
◆ Whether favorable results being arbitrarily adopted? Are unfavorable results being arbitrarily excluded or ignored?
◆ Whether there exists a system in place to discuss the necessary measures such as increase monitoring points and to promptly contact the MAH If an abnormal trend is detected, 
◆ For other details, please refer to Check Points in ORANGE Letter No. 3 and No. 9.