Abstract
Background
Product recalls play a critical role in pharmacovigilance, safeguarding public health under modern regulatory frameworks. Since 2018, the detection of carcinogenic nitrosamine impurities especially those exceeding acceptable intake (AI) limits has become a significant driver of drug recalls. These incidents have raised serious concerns about prolonged patient exposure, revealing systemic weaknesses in current Good Manufacturing Practices (cGMP), such as ineffective impurity control, poor risk assessment, and inadequate supplier oversight. Regulatory authorities now classify these as major cGMP violations, necessitating stronger quality systems and proactive compliance measures.
Methods
A retrospective analysis was conducted on recalls issued by the United States Food and Drug Administration (USFDA) from July 2018 to March 2025. Data were obtained from the USFDA Drug Recall Database, Enforcement Reports, and nitrosamine-specific resources. Recalls linked to nitrosamines and Nitrosamine Drug Substance-Related Impurities (NDSRIs) were identified, categorized, and evaluated using descriptive statistical methods to determine frequency, root causes, and mitigation approaches.
Results
The analysis revealed that Angiotensin II Receptor Blockers (ARBs) and Metformin accounted for the highest number of recalls. Recalls were particularly associated with older drug formulations and structurally complex Active Pharmaceutical Ingredients (APIs). Although risk mitigation strategies such as reformulation, enhanced analytical methods, and real-time monitoring have been introduced, their application remains inconsistent across the industry.
Conclusions
This study highlights the urgent need for enhanced regulatory-industry collaboration, adaptive compliance frameworks, and the adoption of risk-based strategies. Strengthening quality systems and aligning industry practices with regulatory expectations are essential for minimizing future nitrosamine-related recalls and ensuring continuous patient safety.