Case Study: Valsartan Recall (2018)

Background

• Valsartan is an angiotensin II receptor blocker (ARB) widely prescribed for hypertension and heart failure.

• In July 2018, several regulatory agencies, including the USFDA, EMA, and Health Canada, announced recalls of Valsartan-containing products.

Issue Identified

• The recall was triggered when N-Nitrosodimethylamine (NDMA), a probable human carcinogen, was detected in Valsartan API manufactured by Zhejiang Huahai Pharmaceuticals (ZHP), China.

• NDMA contamination occurred due to a change in the manufacturing process introduced in 2012:

  • Use of dimethylformamide (DMF) solvent.

  • Unintended side reaction led to the formation of nitrosamine impurities.

Impact

• Global recalls affected millions of patients.

• EMA and FDA classified NDMA as a genotoxic impurity with lifetime cancer risk concerns.

• Multiple manufacturers using the contaminated API from ZHP were forced to recall their products.

• Supply chain disruption created drug shortages, especially in the US and Europe.

Regulatory Action

• USFDA and EMA issued guidelines on nitrosamine impurities in ARBs and later extended to other classes of medicines.

• Stricter requirements for root cause analysis, risk assessment, and validated control strategies.

• Global Nitrosamine Guidance released (2019–2020) to ensure manufacturers evaluate and mitigate risks.

Lessons Learned

1. Process Changes = Risk → Even minor changes in API synthesis can introduce new impurities.

2. Robust Impurity Profiling is critical to detect genotoxic impurities.

3. Global Supply Chain Vulnerability → A single API supplier can impact worldwide drug availability.

4. Regulatory Vigilance → Strengthened oversight on nitrosamines across all pharmaceuticals.

5. Patient Safety Priority → Rapid recalls and risk communication are crucial.