Stability-Related Supply Disruption of Generic Pharmaceuticals in Japan

Abstract

Non-conformance with product specifications in stability monitoring, mainly for generic pharmaceuticals, has led to frequent voluntary recalls, suspension of supply, and discontinuation of sales, resulting in large-scale drug shortages in Japan since 2020. We studied the causes and countermeasures of stability-related recalls listed by the Pharmaceuticals and Medical Devices Agency web site and considered these as major risks factors to quality assurance and stable supply. The cases leading to supply suspensions or product discontinuation occurred predominantly among the products of marketing and manufacturing license holders that were subject to administrative action due to Good Manufacturing Practice non-compliance in 2020 and 2021. Many of these products have difficulty ensuring stability even with improved process compliance, strongly suggesting inappropriate formulation and process design that disregards quality by design (QbD) concepts. In addition to improving product development and manufacturing control, revising regulations regarding stability testing conducted during development should reduce stability-associated difficulties. Recalls related to stability monitoring of brand and long-listed formulations occurred mainly for products developed before the 1990s. It should be also necessary to reduce impact of sporadic non-compliance with specifications in the stability monitoring of appropriately developed products on their supply.