Nitrosamines Impurity Challenges

Regulatory agencies such as the United States Food and Drug Administration (FDA) have established limits for the number of certain nitrosamines that are allowed in drug products to protect patients from excessive exposure to these compounds. Drug manufacturers are required to test their products for nitrosamine impurities and take appropriate actions if levels exceed these limits.   

The limits for nitrosamines in drug products vary depending on the specific nitrosamine and the type of drug product. Regulatory agencies such as the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have established specific limits for certain nitrosamines in drug products, and these limits may be updated as new information becomes available.  

As one example, the FDA has set a limit of 96 ng/day for N-nitrosodimethylamine (NDMA) in ranitidine products, and a limit of 0.32 ng/day for NDMA in metformin products. The EMA has set a limit of 26.5 ng/day for NDMA in sartan blood pressure medications, and a limit of 96 ng/day for NDMA in ranitidine products.  Again, this is one example. 

It is important to note that these limits are based on the potential cancer risk from long-term exposure to these compounds. Drug manufacturers are required to test their products for nitrosamine impurities and take appropriate actions if levels exceed these limits. If nitrosamine contamination (above the limits described) is detected in a drug product, the drug manufacturer must notify regulatory authorities and take action to recall or remove the affected products from the market.   

ICH M7 (R2) guideline defines N-nitrosamines as the “cohort of concern” for which limits in medicinal products for which there is Threshold of Toxicological Concern (TTC).  

Regulatory Expectations 

It is the manufacturer’s responsibility to monitor and control all nitrosamine impurities throughout the lifecycle of the drug product.   

This should be done in 5 specific ways:  

  1. Performing a risk assessment per product and its manufacturing process.  Identifying every step where nitrosamines can be formed is essential.  Products cannot be grouped together to perform this assessment – each product, the raw materials used, and the manufacturing process must be looked at individually.
  2. Qualification of raw material suppliers followed by testing the raw materials for nitrosamines used in the manufacturing of drug product and providing alternative sources of materials is necessary when these materials are at risk of reacting to create these impurities.  
  3. Monitoring the manufacturing processes to identify any steps that may give rise to nitrosamine impurities.  And ultimately, modifying the process steps and validating them, as needed, to consistently prevent or reduce the risk of these impurities.
  4. Conducting stability studies with appropriate standards for nitrosamine formation during storage and transport is necessary.  
  5. Conduct regular testing to ensure the drug product when tested falls below the required limits.  This includes having predefined specifications for nitrosamine contamination consistent with regulatory guidance. 

Testing 

There are several test methods that can be used to detect and quantify nitrosamines in drug products. The choice of test method depends on the specific nitrosamine compound being tested for, the type of drug product being tested, and the sensitivity required for the analysis. This assessment of methodology used should be part of the risk assessment performed per product.  

Here are some common methods:  

  1. Gas chromatography (GC): GC is a widely used method for detecting and quantifying nitrosamines. The drug product is first extracted and then the extract is analyzed by GC using a nitrosamine-specific detector, such as a mass spectrometer. 
  2. Liquid chromatography (LC): LC is another common method for nitrosamine analysis. The drug product is extracted and then analyzed by LC using a nitrosamine-specific detector, such as a UV/Vis spectrophotometer or a mass spectrometer. 
  3. High-performance liquid chromatography (HPLC): HPLC is a type of LC that uses high pressure to separate and analyze components in a sample. It can be used to detect and quantify certain nitrosamines in drug products.
  4. Enzyme-linked immunosorbent assay (ELISA): ELISA is a method that uses antibodies to detect and quantify specific nitrosamines in drug products. It is a relatively simple and fast method but may not be as sensitive as chromatographic methods.  Use in conjunction with a sensitive method.
  5. Total organic carbon (TOC) analysis: TOC analysis measures the total amount of organic carbon in a sample, which can include nitrosamines. It is a screening method that can be used to detect the presence of nitrosamines in drug products but cannot quantify the specific type or level of nitrosamine present. Use in conjunction with a quantitative method. 

Overall, a combination of these methods may be used to ensure thorough testing for nitrosamine impurities in drug products. The choice of method should be based on the specific needs and requirements of each product and be validated to ensure consistency of method performance. 

Standards 

Several pharmacopeia and commercial reference standard providers offer nitrosamine standards.  By using nitrosamine reference standards, drug manufacturers can ensure that their testing methods are accurate and reliable, and that their drug products meet regulatory requirements for nitrosamine impurities.   

A good source of information and tools can be found in the United States Pharmacopeia (USP) Nitrosamine Exchange.  This Community of Practice is a collaborative effort among USP, regulatory agencies, and industry stakeholders to address questions related to nitrosamines in drug substance and drug products. The Nitrosamine Exchange provides an open platform for sharing information and best practices related to nitrosamine testing, risk assessment, and control strategies. The Exchange includes a database of analytical methods for detecting nitrosamine impurities in drug products, as well as a forum for discussing regulatory updates and industry trends.    

Additional changes are on the horizon, though, with FDA currently soliciting public comments on the identification, assessment, and control of nitrosamines drug substance-related impurities (NDSRIs). The notice was published in the Federal Register under docket ## FDA-2023-N-1585. The deadline for comments submission July 3rd 2023. 
https://www.federalregister.gov/documents/2023/05/04/2023-09526/identification-assessment-and-control-of-nitrosamine-drug-substance-related-impurities-in-human-drug  


QxP Vice President Christine Feaster is a 20+ year veteran in pharma quality assurance. Prior to joining QxP, Christine was a vice president of U.S. Pharmacopeia.

You may be interested in reading Christine’s blogs on: “Quality is Number One, Even When Trying to Address Supply Chain Issues,” and “Bacterial Endotoxin Testing is on the Move.”

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