PMDA ORANGE LETTER_2025.12

♦It is stipulated in The GMP Ministerial Order that necessary corrective actions and preventive actions should be taken in the case where any significant deviation has occurred, and necessary measures should be implemented in the case where any rectification is needed based upon outcomes of the internal audits.

♦In this case, a manufacturing site experienced a deviation where a dissolution liquid for granulation was accidentally sprayed onto the previous batch still remaining in the granulator due to human error. The manufacturing process for this product involved performing granulation, drying, and sizing across four batches, which were then blended and tableted to form a lot. At the time, 2 lots production were planned in a day. 

♦Multiple instances of non-compliance with SOPs and inappropriate records were found.

♦During GMP inspection, we observed multiple failures to follow standard operating procedures (SOPs) and inappropriate recording. It was revealed that an overcrowded production schedule had been set despite human resource shortage, which makes timely recording and double-checking impossible. Furthermore, procedures and records for operations, including line clearance during batch changeovers, were insufficient.

♦In a self-audit conducted prior to the occurrence of this deviation, the manufacturing site had already detected and listed deficiencies related to SOP non-compliance, data integrity, and personnel shortages through on-site tours and interviews with operators. However, because the procedures for handling that list were not defined, the necessary measures for improvement were not taken.

♦The personnel shortage in the production department was not included in the management and proper resources were not allocated.

♦Risk of critical quality issues arising will increase if resource shortage is left unaddressed or neglected and the improvement cycle for resolving these problems is unable to function.

♦As an immediate action to prevent recurrence, the manufacturer rectified the production schedule to one lot per day until standard operating procedures are established and the necessary personnel are secured. Furthermore, training on this incident and compliance was conducted.

♦As preventive actions, the manufacturer decided to shift toward a quality-first culture by strengthening management training, establishing a planned production system that is not driven by tight deadlines, optimizing process improvement and personnel allocation, and promoting the reporting of deviations and issues.

♦Whether the root causes are investigated for non-conformance and other undesirable situations detected through self-audit, deviations, OOS, etc.?

♦Whether the most critical issues have been identified through self-audit, and culture and set of values have been instilled to prompt self-improvement with foresight?

♦Whether system to resolve root causes through sharing actual situations, issues with the management functions properly? 

♦Contributing the cause of issues arose merely to human errors and training personnel involved are often observed in manufacturing sites. However, failure to address the root cause of quality issues may lead to a chain of violations across multiple laws and regulations.

♦To resolve root causes, we urge you to conduct continuous improvement from a long-term perspective. Providing information to management is the responsibility of the manufacturing site and investing in improvements is the responsibility of the management.