The FDA has updated its guidelines to assist pharmaceutical manufacturers in addressing the risks associated with nitrosamine impurities.  

In September 2024, the FDA released its updated guidance, replacing the February 2021 version. The new guidelines outline crucial steps for manufacturers to detect, manage, and prevent the presence of nitrosamine impurities in both active pharmaceutical ingredients (APIs) and finished medicinal products. 

Scope of the Guidance 

The updated guidance applies to the following categories: 

• Chemically synthesized APIs 
• Medicines containing chemically synthesized APIs or fragments, including certain biological products 
• Semisynthetic and fermentation-based products that may be at risk due to their chemical structure 
• Medicines at risk of contamination, as detailed in sections III.B, C, and D of the guidance 

Key Elements of the Updated Guidance 

The updated guidance incorporates the latest scientific and technical developments related to nitrosamine impurities. Key aspects include: 

1. Risk Assessments and Sources of Nitrosamines: Manufacturers are required to conduct comprehensive risk assessments to identify potential sources of nitrosamines throughout the drug production process. This involves evaluating the entire supply chain, from raw materials to finished medicines, and identifying contamination sources such as solvents and chemical reactions during synthesis. Early identification enables more targeted preventive measures. 
2. Detection and Testing: The guidance recommends implementing analytical methods to detect nitrosamines at low levels. Testing should be conducted at all stages of production to ensure that nitrosamine impurities are identified early. Robust testing systems are crucial for minimizing contamination and maintaining control throughout the manufacturing process. 
3. Acceptable Intake Limits (AI): The FDA has established AI limits for specific nitrosamines based on their potency, ranging from 26.5 ng/day to 96 ng/day. When multiple nitrosamines are present, stricter limits apply. These thresholds guide manufacturers on when further action is necessary to reduce risk. 
4. Mitigation Strategies: If nitrosamine impurities are detected, the guidance outlines strategies for mitigating the risk. This could involve modifying the manufacturing process or reformulating products to reduce contamination. The guidance also suggests adopting an alternative bioequivalence approach to meet more rigorous safety standards. 

Key Revisions 

The revised guidance introduces nitrosamine drug substance-related impurities (NDSRIs), a unique class of impurities related to specific APIs. NDSRIs share structural similarities with the APIs and pose additional risks.  

The guidance now addresses two primary categories of nitrosamine impurities: 

1. Small-molecule nitrosamine impurities, which are not structurally related to the API and can be present in various medicines. 
2. NDSRIs, which are structurally related to the API and unique to specific drugs. 

Impact on Industry Standards 

The updated FDA guidance reflects advances in the understanding of nitrosamine contamination, and significantly raises the standards for quality control within pharmaceutical manufacturing. Companies are now required to enhance their risk management systems and supply chain oversight, as well as strengthen detection and analytical methods. The inclusion of NDSRIs and their differentiation from small-molecule nitrosamines allow for more precise risk assessment and tailored mitigation strategies.