PMDA ORANGE LETTER_2024.6

The department in charge decided by itself that there was no need to implement change control.

◆　GMP Ministerial Ordinance stipulates that upon introducing any change to specifications of the starting materials, packaging/labeling materials or products, or to the manufacturing procedures, etc., such manufacturer, etc. must assess the impact by the change on the product quality and the product authorization requirements.

◆　Changes to test methods are included in the scope of the change control procedure of the manufacturer.

◆　In a purity test of the product using HPLC, an unusual peak appeared immediately after the main peak. It was decided to be caused by a column defect after OOS (Out of Specification) investigation. When a new column from another manufacturer was used, the peak disappeared, so the new column was adopted for the test method instead of the conventional one.

◆　Because the filling materials of the columns before and after the change were both phenyl-based, the QC department determined that there was no need to implement change control because the base material are of the same classification. As a result, impact assessment on product quality and approved items was not carried out.

◆　The filling material of the new column has a different substituent, which differs from the provisions of the approval document.

◆　In the test using the new column, the elution position of related substances changed significantly, but validation of the analytical method was not carried out.

◆　When changes are made to test methods, there is a risk that appropriate test results will not be obtained if analytical performance (specificity, trueness, precision, quantification limit, detection limit, etc.) cannot be assured due to the necessity of analytical method validation has not been discussed.

◆　When changes are made to test methods, there is a risk that appropriate test results will not be obtained if analytical performance (specificity, trueness, precision, quantification limit, detection limit, etc.) cannot be assured due to the necessity of analytical method validation has not been discussed.

◆　Whether the necessity of change control is not decided by the department in charge alone, but consulted with knowledgeable staff, such as change control managers?

◆　Whether the manufacturer is familiar with the approval items and inform the changes to the marketing authorization holder (and the MF in-country caretaker) when implementing changes?

✓　Even if intended result is obtained through a change, there is a possibility that the change may have affected parts other than those intended. When implementing a change, sufficient discussion on the content of the change and the characteristic of the product is required so that all risks are considered and assessed.

✓　It is essential for the manufacturer to understands the contents of the approval document and API registration master register (MF) and understands what changes need to be made! For this purpose, the manufacturing site needs to communicate with the marketing authorization holder and the MF in-country caretaker more frequently than usual.

✓　However, the marketing authorization holder and the MF in-country caretaker are not aware of the changes made at the manufacturing site, and there are sporadic discrepancies between the actual situation at the manufacturing site and the approval document/MF! Proactive communication from the marketing authorization holder and the MF in-country caretaker to the manufacturing site is also necessary.