Generic Drug Shortage in Japan: GMP Noncompliance and Associated Quality Issues.

Government campaigns to replace off-patent brand pharmaceuticals with low cost generic products in national health insurance systems have apparently increased their production in the last two decades in Japan. The contamination of a batch of generic itraconazole tablets with the sleep inducer rilmazafone caused significant adverse events and related accidents in 2020, amidst increasing use of the generic products in healthcare. Investigations revealed many Good Manufacturing Practice (GMP) violations and other evidence of poor quality management in the manufacturing/marketing authorization holder (MAH). Urgent inspection of other MAHs found multiple cases of GMP noncompliance that resulted in temporary administrative suspension. Various quality issues, including nonconformity in stability monitoring, in these generic MAHs resulted in prolonged suspension of product shipments and shortages in medical institutions. These problems highlighted long-standing issues in quality management by MAHs and inspections by authorities, which had been neglected during rapid production expansion. This review introduces these manufacturing control and management problems and their countermeasures, and discusses the impact of habitual inadequate development processes that disregard the quality-by-design (QbD) perspective as the root cause of the issues.