PMDA ORANGE LETTER_2025.08

♦ It is stipulated in GMP Ministerial Order Article 13 that validation should be performed in the following cases: ① the case where commencing manufacture of a new pharmaceutical for the manufacturing site, ② the case where introducing any change to the manufacturing procedures, etc. that critically impact on the product quality; or ③ other cases that it is deemed to be necessary to perform validation in order to implement production control and quality control suitably for the products; (e.g., periodic validation of critical processes related to sterility assurance).

♦ The manufacturer adopted the "BI/Bioburden Combination Method" described in the ‘Guidance on the Manufacture of Sterile Pharmaceutical Products Produced by Terminal Sterilization’ for the terminal sterilization validation of a pre-filled syringe product. The manufacturer also prepared BIs using the product as a carrier and commercial spore suspension.

♦ The manufacturer documented in the Sterilization Validation Protocol that product sterility would be assured by the results of the BI Challenge Test, among other data.

♦ BI challenge test was conducted in the initial sterilization validation over 10 years ago, but the rationale for selecting the BI strain used at that time was not documented and no one knows it. Furthermore, information such as the D-value of the BI which use product as carrier was also not clear.

♦ The most recent periodic revalidation did not include a BI challenge test. It was unclear when, or for what reason, the test was deemed unnecessary, and the justification for this was not documented.

♦ In BI/Bioburden combination method, a BI strain which is more heat-resistant than the most heat-resistant microorganism found in the product to be sterilized or the sterilization environment should be employed. However, since the basis for selecting the BI strain and the D-value information remains unclear, it is not assured that the required Sterility Assurance Level (SAL) of 10-6 can be met.

♦ In addition, it is ensured that the conditions from the initial validation is being appropriately maintained, and the knowledge management and review throughout the product lifecycle are inadequate.

■ Whether the BI strain used in sterilization validation is appropriate, and is it adequately managed, including the measurement of D-values, etc.?

■ Whether the bioburden and environmental microflora are monitored routinely to confirm that there is no impact on sterility assurance?

■ Whether all the documented validation data appropriately maintained, and whether all these data are accessible?