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What are Nitrosamines in the Pharmaceutical Industry ?

What are nitrosamines?

Nitrosamine impurities in Active Pharmaceutical Ingredients (API) and drug products
Testing of Nitrosamine impurities in Active Pharmaceutical Ingredients (API) and drug products is critical.

Nitrosamines are chemical compounds classified as probable human carcinogens, meaning they can potentially cause cancer. They form through a chemical reaction between nitrites and secondary amines, which are found in various industrial processes, including the manufacturing of pharmaceuticals.

The introduction of nitrosamines into pharmaceutical products can occur at various stages of the drug development and manufacturing process. One primary route is through the synthesis of drug substances. Specific reactions or conditions during the manufacturing process can facilitate the formation of nitrosamines. Additionally, contamination can arise from raw materials, intermediates, or even the final drug product if they come into contact with nitrosating agents. Another potential source is the degradation of certain drug substances over time, leading to the formation of these impurities. Cross contamination during production, storage, or transportation can also contribute to the presence of nitrosamines in drug products.

While there is a very low risk that nitrosamine impurities could cause cancer at the levels found in drug products, individuals may be at increased risk if exposed to nitrosamine impurities at above acceptable levels or over long periods of time. The detection of nitrosamine impurities in several commonly prescribed medications, including antibiotics, antacids, and antidiabetics, rapidly resulted in the recall of these drug products. Consequently, many patients worldwide faced temporary interruptions in their treatments.

Now, mitigating nitrosamine contamination is at the top of global regulatory priorities for the pharmaceutical industry, with the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) making it a legal obligation for drug manufacturers to present their reformulation and risk mitigation plans

What industry should know about nitrosamine impurities?

Manufacturers are responsible for understanding their processes, which includes preventing the presence of unacceptable impurities. Manufacturers are also responsible for developing and using suitable methods to detect and limit unacceptable impurities, including any new impurities that may arise when they make changes to their manufacturing processes.

FDA has published testing methods that can be used by industry to detect nitrosamine impurities.

FDA, in collaboration with regulatory counterparts around the world, has set internationally recognized acceptable daily intake limits for nitrosamines. If drugs contain levels of nitrosamines above the acceptable daily intake limits, FDA recommends these drugs be recalled by the manufacturer as appropriate or not be released for distribution to the market.

The agency is working with industry to determine the source of these impurities, but there are multiple reasons why nitrosamines can be present in medicines.

FDA has provided information to industry on mitigation strategies to reduce the risk of nitrosamine drug substance related impurities (NDSRI) in drug products.

  • Evaluate possibility of nitrosamines being present in every concerned medicine within 6 months
  • Priorities evaluations, starting with medicines more likely to be at risk of containing nitrosamines
  • Notify authorities of outcome of risk evaluations
  • Test products at risk of containing any nitrosamines
  • Immediately report detection of nitrosamines to authorities
  • Apply for necessary changes to marketing authorizations to address nitrosamine risk
  • Complete all steps within 3 years, prioritizing high risk

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Root Causes of Nitrosamine Impurities in APIs and Drug Products

Understanding the Root Causes of Nitrosamine Impurities in APIs and Drug Products.

Nitrosamine impurities in Active Pharmaceutical Ingredients (APIs) and drug products are a significant concern due to their potential carcinogenic effects. The FDA has identified various root causes for these impurities, which can be categorized into process-related factors, supply chain issues, and stability concerns. Below is an elaboration of these factors based on FDA guidelines:

Properties of the Starting Materials, Intermediates, or Drug Substance:

  • Contaminated Raw Materials: Starting materials or intermediates might already be contaminated with nitrosamines, which can carry through the manufacturing process into the final drug product.
  • Inherent Properties: Certain materials inherently possess properties that may lead to nitrosamine formation, especially if they contain secondary or tertiary amines which can react with nitrosating agents.

 

Specific Process Conditions:

  • Reaction Conditions: Specific conditions such as high temperatures, acidic or basic environments, and the presence of nitrite sources can favor the formation of nitrosamines.
  • Solvent Use: The choice of solvents and their impurities, including the presence of nitrites, can also contribute to the formation of nitrosamines during chemical reactions
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Impurities in or Reactions with Raw Materials:

  • Nitrosating Agents: The presence of nitrosating agents (e.g., nitrites) in raw materials can lead to nitrosamine formation when they react with amine-containing substances.
  • By-products: By-products from other reactions in the process can act as nitrosating agents, or amines can be inadvertently introduced.
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Use of Recovered or Recycled Materials or Other Intermediates Contaminated with Nitrosamines:

  • Recycling Contaminated Solvents: Recovered solvents or intermediates from other processes can carry nitrosamine contaminants if not adequately purified.
  • Reused Materials: Use of materials that have been previously exposed to nitrosating agents without thorough cleaning can result in contamination.

Cross-contamination in Multi-purpose Facilities:

  • Shared Equipment: Multi-purpose manufacturing facilities that do not have stringent cleaning protocols may experience cross-contamination between different products, leading to nitrosamine contamination.
  • Inadequate Segregation: Lack of proper segregation of materials and processes can result in unintentional mixing of nitrosamine precursors with other substances.
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Stability of Drug Substance or Drug Product:

  • Degradation Products: Over time, certain drug substances or products may degrade to form nitrosamines, especially if they contain susceptible amine groups.
  • Storage Conditions: Improper storage conditions such as high humidity or temperature can accelerate the degradation of drug substances into nitrosamines.

 

Excipient Compatibility:

  • Interaction with Excipients: Some excipients may react with drug substances or intermediates to form nitrosamines. For instance, excipients containing nitrate or nitrite impurities can react with amines present in the formulation.
  • Excipient Degradation: Excipients themselves may degrade over time, forming nitrosating agents which can subsequently react with drug substances to form nitrosamines.
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Regulators strategy and testing requirements

Nitrosodimethylamine (NDMA) prominently highlighted to emphasize the focus on nitrosamine testing
Ensuring Drug Safety: EMA and FDA Guidelines for Mitigating Nitrosamine Contamination through Rigorous Risk Assessment, Testing, and Regulatory Actions.

The European Medicines Agency (EMA) and US-FDA guided the review process and started collecting the most common root sources: APIs, impurities, excipients, primary packaging. They could directly carry a nitrosamine but also their precursors (nitrosatable and nitrosating agent) interacting into the final drug product through the shelf life.

Regulatory agencies such as the FDA and EMA have provided guidelines to pharmaceutical companies on how to assess and mitigate the risk of nitrosamine contamination in drug products. These guidelines include recommendations on testing methods, acceptable limits, and risk assessments for potential sources of nitrosamines. The European Medicines Agency (EMA) and US-FDA guided the review process and started collecting the most common root sources: APIs, impurities, excipients, primary packaging. They could directly carry a nitrosamine but also their precursors (nitrosatable and nitrosating agent) interacting into the final drug product through the shelf life.

The investigation process prescribed to all Marketing Authorization holders is a three-step approach: Risk Assessment, Confirmatory testing, and Remediation plan.

  • Step 1 : the nitrosamines presence/formation risk is investigated for each product by gaining more knowledge of the manufacturing process through an initial risk assessment.
  • Step 2 : nitrosamines presence/amount is identified during the risk evaluation, confirmatory testing is carried out on representative batches of drug products with a sensitive and appropriately validated analytical method.
  • Step 3 : If a risk is identified and confirmed by tests, Authorities are informed and when applicable, regulatory actions are initiated to start necessary changes to marketing authorizations to address nitrosamine risk

FDA Recommendations

The FDA’s final guidance on nitrosamine impurities emphasizes the need for thorough risk assessments, sensitive confirmatory testing, and robust remediation plans. This guidance recommends steps manufacturers of APIs and drug products should take to detect
and prevent unacceptable levels of nitrosamine impurities in pharmaceutical products. Key points include from understanding of carcinogenic potential of nitrosamines, the FDA advises manufacturers to thoroughly assess and mitigate their formation in Active Pharmaceutical Ingredients (APIs) and drug products. This detailed approach requires the investigation of both established and potential pathways for nitrosamine formation, underlining the need to prioritize assessments based on key factors such as the drug’s dosage, duration of treatment, and extent of patient exposure. In line with these guidelines, if nitrosamines are detected, a thorough investigation must be conducted to determine their origins. Subsequently, necessary adjustments to manufacturing protocols should be made to minimize or eliminate such risks. This process demands a collaborative effort between API (Active Pharmaceutical Ingredients) producers and drug product manufacturers to effectively identify and address risks.

  • If the risk assessment determines that there is no potential for nitrosamine impurities, there is no need to take further action -> No reporting
  • If an NDSRI falls at or below the FDA-recommended AI limit (e.g., associated with its predicted carcinogenic potency category), the manufacturer or applicant should still develop an appropriate control strategy to ensure that the nitrosamine level is reliably at or below that AI limit. Where applicable, applicants should report changes to an approved application.
  • If an NDSRI level is detected above the FDA-recommended AI limit, related batch should not be released and may warrant removal from the market. Manufacturer should contact the Agency if a recall is initiated. Manufacturers must implement changes in accordance with appropriate requirements. Applicants must submit proposed formulation changes through supplements or amendments to their applications.

Generally, FDA considers reformulation of an approved drug product a major change requiring a prior approval supplement (PAS).

EMA Recommendations

The European Medicines Agency (EMA) has issued comprehensive guidelines to manage and mitigate the risk of nitrosamine impurities in human medicines. These recommendations are intended for marketing authorisation holders (MAHs) and applicants to ensure the safety and quality of their drug products.

These recommendations by the EMA ensure that pharmaceutical companies take proactive measures to identify, prevent, and control nitrosamine impurities, thereby protecting patient safety and maintaining the integrity of medicinal products in the European market. For more detailed guidance and documentation, companies are encouraged to refer to the EMA’s official publications and resources on their website.

  • MAHs must conduct a thorough risk assessment of their products to identify the potential presence of nitrosamines. This assessment includes evaluating the entire manufacturing process, including raw materials, solvents, and packaging materials.
  • Priority should be given to products most likely to contain nitrosamines based on factors such as chemical structure and manufacturing processes​ (European Medicines Agency)​​ 
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  • If a risk is identified, MAHs must perform confirmatory testing to detect nitrosamines in their products. Analytical methods used must be validated for accuracy and reliability.
  • Any detection of nitrosamines must be reported to the relevant authorities immediately. Confirmatory testing for chemical medicines had a deadline of September 2022​ (European Medicines Agency)​​ 
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  • Companies must implement appropriate control strategies to limit the presence of nitrosamines as much as possible. This includes modifying manufacturing processes, using nitrite-free materials, and ensuring stringent controls during production.
  • Continuous monitoring and periodic re-evaluation of the risk of nitrosamine contamination are required to keep up with new scientific developments​ (European Medicines Agency)​​ 
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  • MAHs need to apply for any necessary changes to their marketing authorisations to address nitrosamine risks. This involves submitting variation applications to the regulatory authorities by specified deadlines (October 2023 for chemical medicines, and July 2023 for biological medicines).
  • Companies should complete these steps within three years, prioritizing high-risk products​ (European Medicines Agency)​​ 
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  • The EMA emphasizes the importance of transparency with healthcare professionals and patients regarding the presence of nitrosamines in medicines. Companies are urged to communicate any findings and actions taken to mitigate risks effectively.
  • Detailed information and updates for companies are available on the EMA’s nitrosamine impurities webpage, ensuring that MAHs stay informed about the latest guidelines and timelines​ (European Medicines Agency)​​ 
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References

Sagar Pawar

Sagar Pawar

Computer System Validation Specialist