ORANGE LETTER
Author:
Observed Regulatory Attention/Notification of GMP Elements LETTER
Issue: May 2025
Title: Problems Behind Discrepancies with product authorization requirements
Source: https://www.pmda.go.jp/files/000275662.pdf
Related GMP Ministerial Ordinance Clause: Article 3-2, Article 5(1)(iii), Article 7(i)
1．Observations and Causes
a. In-process control tests described in the Drug Master File (MF) were not performed. Furthermore, the site was unaware of the content of the marketing approval, and some of the identification tests for raw materials described in the approval files were not conducted.
（Only parts of API production process and formulation production processes were conducted ）
【Cause】Although the manufacturing site was aware of the discrepancy between the MF and actual production, the person in charge of discrepancy checks had left the company, and the follow-up was not properly handed over and was left unaddressed. Additionally, no agreement regarding the content of the marketing approval was concluded between the Marketing Authorization Holder (MAH) and the in-country caretaker of the MF, so matters that the manufacturing site should be aware of were not shared.
（Only parts of API production process and formulation production processes were conducted ）
【Cause】Although the manufacturing site was aware of the discrepancy between the MF and actual production, the person in charge of discrepancy checks had left the company, and the follow-up was not properly handed over and was left unaddressed. Additionally, no agreement regarding the content of the marketing approval was concluded between the Marketing Authorization Holder (MAH) and the in-country caretaker of the MF, so matters that the manufacturing site should be aware of were not shared.
b. Reference standards used for product testing were not prepared under the conditions described in the marketing approval. Moreover, the reference standards actually used were not tested according to the specifications and test methods described in the approval, and its suitability was not evaluated.
【Cause】The MAH did not provide approved information regarding the reference standards to the manufacturing site, and the site was unable to grasp the information. Therefore, the discrepancy could not be identified during routine checks for differences between the marketing approval and actual practice.
【Cause】The MAH did not provide approved information regarding the reference standards to the manufacturing site, and the site was unable to grasp the information. Therefore, the discrepancy could not be identified during routine checks for differences between the marketing approval and actual practice.
c. Some product tests were not performed. Additionally, for tests that were performed, it was found that the amounts of sample and reagent used are different from those described in the MF.
【Cause】The manufacturing site regularly checked for discrepancies between the MF and actual practice and was aware of the differences. However, they judged that there was no impact on product quality and did not report it to the in-country caretaker of the MF or others.
【Cause】The manufacturing site regularly checked for discrepancies between the MF and actual practice and was aware of the differences. However, they judged that there was no impact on product quality and did not report it to the in-country caretaker of the MF or others.
2．Root Causes Suggested by These Discrepancies
●The Marketing Authorization Holder is not proactively and actively involved.
●The manufacturer does not understand the product authorization requirements or the regulations.
●There is a lack of communication between companies, leading to an inability to notice differences in perception and values.
3．Catchword
Have you identified and resolved the "true root cause" of the discrepancies?
✓ Although clauses aimed at preventing discrepancies between product authorization requirements and manufacturing practices have been incorporated into the GMP Ordinance, considering that such discrepancies are still frequently observed as in the cases above, isn't it necessary to seek a fundamental cure rather than just symptomatic treatment?
✓ Recent GMP inspections have revealed cases where the manufacturing site is not aware of the product authorization requirements, the manufacturing site does not accurately understand Japanese regulations, or the manufacturing site does not evaluate the necessity of regulatory procedures for changes in manufacturing processes. We are concerned about the proactiveness of the MAH and communication between companies, including the in-country caretaker of the MF.
✓ PMDA provides English translations of the GMP Ordinance and other regulations on its website for overseas companies and continuously urges compliance with the product authorization requirements. We ask all companies not to stop at superficial checks but to pursue the true root cause—including whether the responsibilities of the manufacturing manager are being fulfilled (Article 5(1)(iii)) and whether necessary items are described in the Pharmaceutical Product Specification File (Article 7(1)(i))—and strive to prevent recurrence.
About Author
Career The profile is the information as of the time of writing.
Related Articles
Search by Keywords
Comment
/
/
/
Comment