Strengthening Drug Safety with Proactive Risk Management
On August 4, 2023, the U.S. Food and Drug Administration (FDA) issued new, immediately effective guidance titled “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)”. This critical regulatory update provides pharmaceutical manufacturers with a structured framework to assess, detect, and control the presence of nitrosamine impurities in both approved and investigational drug products.
The guidance marks the latest development in the FDA’s ongoing efforts to enhance the safety and quality of the U.S. drug supply, especially in light of recent recalls involving nitrosamine contamination in common medications like ranitidine, metformin, and angiotensin II receptor blockers (ARBs).
What Are Nitrosamines and Why Are They Concerning?
Nitrosamines are chemical compounds that can form during the manufacturing, storage, or degradation of certain drug substances. Some nitrosamines, including N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), are classified as probable human carcinogens based on laboratory animal studies. Although low levels of nitrosamines can be found in the environment, food, and water, long-term exposure to high levels in medications can pose serious health risks.
The concern over nitrosamines in pharmaceuticals first came to public attention in 2018, leading to global recalls, regulatory action, and intensified scrutiny of pharmaceutical manufacturing processes.
Key Elements of the FDA’s New Guidance
The August 2023 guidance outlines acceptable intake limits for specific NDSRIs and provides a risk assessment framework for manufacturers. Key components include:
1. Acceptable Daily Intake (ADI) Thresholds
- The FDA has established toxicologically derived intake limits for various nitrosamines, which are measured in nanograms per day (ng/day).
- These limits are based on cancer risk assessment models, aiming to protect patients even during chronic use of affected medications.
2. Manufacturer Responsibilities
- Companies must conduct a comprehensive risk evaluation of drug substances and finished products to identify conditions that might lead to nitrosamine formation.
- For identified risks, manufacturers must develop and implement control strategies, such as modifying synthetic routes, optimizing storage conditions, or reformulating the product.
- The guidance applies to both approved products and investigational new drug (IND) applications, ensuring consistent safety standards.
3. Recommended Timeline for Action
- The FDA urges manufacturers to prioritize high-risk products and submit risk assessments and mitigation plans in a timely manner.
- Companies are also encouraged to collaborate with global regulators to maintain consistency and avoid unnecessary supply disruptions.
Public Health and Industry Implications
The FDA emphasized that this guidance reflects the agency’s science-based, proactive approach to safeguarding public health. By clearly defining acceptable impurity levels and encouraging robust risk management, the agency aims to prevent future recalls, restore public confidence, and maintain drug availability.
Pharmaceutical industry leaders welcomed the clarity offered by the guidance, though they acknowledged the technical and logistical challenges of implementing nitrosamine controls across complex supply chains. In response, the FDA has committed to ongoing dialogue with stakeholders and may issue further updates as new data becomes available.
For patients, the FDA reaffirmed that the benefits of taking prescribed medications generally outweigh the potential risks from low levels of nitrosamine exposure, particularly when treatment involves chronic conditions such as hypertension, diabetes, or cancer.
Looking Ahead
The release of this guidance underscores the FDA’s commitment to continual improvement of pharmaceutical safety standards. Manufacturers are now expected to integrate nitrosamine risk mitigation into their quality assurance systems, ensuring that drug products remain safe, effective, and free from harmful contaminants.
As the pharmaceutical industry adapts to these requirements, regulators worldwide—including those in the EU, Canada, and Japan—are also updating their own nitrosamine policies, contributing to a more globally harmonized approach to pharmaceutical quality.
