PMDA ORANGE LETTER_2024.9

ORANGE LETTER

Author:
PMDA Observed Regulatory Attention/Notification of GMP Elements LETTER

Issue: September 2024
Title:  Observations recently found in generic drug manufacturing sites
Source: https://www.pmda.go.jp/files/000270602.pdf
Related GMP Ministerial Ordinance Clause: Please refer to each case. 

1. Case

<Case 1: Out-of-specification handling, product release> (GMP Ministerial Ordinance, Article 11 (1)(viii)，Article 12(1) and (4))
(Japan/ non-sterile preparation manufacturing site)
⚫ An OOS (Out of Specification) result happened in the assay of tablets. The manufacturer determined that it was caused by a wrong sampling, so they carried out resampling and retesting. As the retest results were within the specifications, the manufacturer determined that the lot conformed and shipped it.
⚫ However, there was no rational basis for resampling. In addition, the product is likely to have content variation during the compression process because of its characteristics. But the impact of such characteristics was not investigated in the investigation into the cause of OOS.
⚫ We instructed the manufacturer to investigate the cause of the OOS again and take necessary corrective and preventive measures. 

<Case 2: Product release > (GMP Ministerial Ordinance, Article 12(1) and (4))
(Japan/API manufacturing site)
⚫ Regarding the release management of reprocessed API, it is stipulated in the manufacturing site's procedure manual that the results of stability tests (at 3 months under accelerated test conditions) should be confirmed to be equivalent to those of regular products before releasing.
⚫ However, we confirmed that the reprocessed lot of API that contained metal foreign matters was released before results of accelerated stability tests have been obtained.
⚫ It was confirmed that the release did not conform with the product releasing procedure, and we instructed the manufacturing site to take measures to prevent the recurrence of such activities. 

<Case 3: Stability monitoring, product release > (GMP Ministerial Ordinance, Article 11-2 and Article 12, (1) and (4))
(Japan/ sterile preparation manufacturing site)
⚫ An unknown peak was detected in the purity test (HPLC) for stability monitoring of the injection product. Because no laboratory error was found in the cause investigation, and the manufacturer requested an investigation into the upstream manufacturing site which carried out the production.
⚫ However, the manufacturer released the lot before receiving a response from the upstream manufacturing site. Furthermore, even though the cause of the unknown peak was unclear, "No special notes." was stated in the releasing report. Furthermore, identification of the substance causing the unknown peak had not been completed, and the impact on previously released lots was unknown.
⚫ We instructed the manufacturer to promptly investigate the cause and assess impact on other lots.
 

2. Catchword