Nitrosamines have emerged as a significant concern in the pharmaceutical industry due to their potential carcinogenic effects. As impurities that can form during drug manufacturing, their presence in medications has prompted regulatory bodies around the world to take action. In response, Mexico’s Federal Commission for the Protection against Sanitary Risk (COFEPRIS) has introduced, in July 2024, comprehensive guidelines to assess, manage, and mitigate the risks associated with nitrosamine impurities in drugs and medicines. This blog explores these new guidelines, highlighting the steps that pharmaceutical companies must take to ensure drug safety in Mexico.
What Are Nitrosamines?
Read our blog on "Regulation of Nitrosamines in Pharmaceuticals" to understand Nitrosamines in detail.
Read about how the US FDA regulates the presence of Nitrosamines in the USA in our blog
Overview of COFEPRIS Regulation of Nitrosamines in Pharmaceuticals Mexico
The new guidelines issued by COFEPRIS are designed to provide a framework for the pharmaceutical industry to effectively manage the risks associated with nitrosamine impurities. COFEPRIS follows a three-step approach in regulating nitrosamine impurities -
Risk Assessment
Confirmatory Testing for Nitrosamine impurities in drugs and medicines
Routine Confirmatory Testing
Here are the key components of the guidelines:
Risk Assessment for presence of Nitrosamine impurities in drugs and medicines
Pharmaceutical companies are required to conduct a thorough risk assessment to identify potential sources of nitrosamine formation during the drug manufacturing process. This includes evaluating raw materials, manufacturing conditions, and the potential for degradation over the product’s shelf life.
The assessment must consider all stages of the drug’s lifecycle, from development through to patient administration, ensuring that any risk factors are identified and addressed.
Companies must collect and analyze comprehensive data on their processes and products to accurately assess the risk of nitrosamine impurities.
The risk must be re-evaluated if there are any changes in manufacturing processes or suppliers.
A risk assessment must be conducted for each individual drug, medicine, and pharmaceutical form, and it should only be performed by a qualified professional. The assessment must be authorized by the Sanitary Responsible Person and TRS/FIF on the company letterhead, accompanied by the necessary documentation.
For imported medicines, the TRS and FIF are responsible for conducting the risk assessment. They must obtain all required information from the overseas manufacturer, provided in both the original language and Spanish. A declaration from the manufacturer is not acceptable; the TRS and FIF must perform the risk assessment and subsequent testing themselves.
The assessment should identify the nitrosamines at risk of forming in each drug and pharmaceutical form, and it must include the calculation of exposure doses of nitrosamine impurities.
Confirmatory Testing for Nitrosamine impurities in drugs and medicines
If no risk of nitrosamine formation is identified during the risk assessment, confirmatory testing may be waived, provided that all supporting evidence is submitted.
Once potential risks are identified, companies must conduct confirmatory tests using validated, specific and selective analytical methods to detect nitrosamine impurities. These tests are critical in determining whether the levels of impurities are within the acceptable limits set by COFEPRIS.
The guidelines specify that testing should be representative of the production process, with a focus on high-risk scenarios where nitrosamines are more likely to form.
Factors Determining Testing Sample Size
The number of drug and medicine lots subjected to confirmatory tests depends on their risk of nitrosamine impurities. High-risk factors include:
Functional Groups: Drugs containing functional groups that can form nitrosamine impurities.
Late-Stage Formation: The introduction of impurities during the later stages of manufacturing or packaging.
Packaging and Storage Risks: Risks related to impurity formation during packaging or storage.
Recommended Sample Size for Testing
If the root cause of impurity risk is identified and consistent lot quality is expected, testing will be done on 10% of the annual lots or a minimum of 3 lots per year, whichever is greater.
If fewer than 3 lots are produced annually, all must be tested.
If the root cause or consistency is not demonstrated, all lots will be tested. Additional testing is required when multiple manufacturers, processes, or raw materials are involved.
Testing of Imported Drugs and Medicine -
For imported drugs and medicines in Mexico, TRS and FIF will require the results of confirmatory tests for nitrosamine impurities, which must be provided in both the original language and Spanish. The risk assessment will be conducted using retention samples within Mexico, and studies will be performed by an Authorized Third-Party Laboratory.
Management and Mitigation
If nitrosamine impurities are detected, companies are required to implement corrective actions to reduce or eliminate these impurities. This may involve modifying manufacturing processes, improving controls, or using different raw materials.
In cases where nitrosamine levels exceed the acceptable limits, COFEPRIS mandates immediate notification and requires companies to present a detailed plan for risk management and mitigation.
Routine Monitoring and Testing for Nitrosamine impurities in Drugs and Medicines
The guidelines also emphasize the importance of routine monitoring for nitrosamine impurities throughout the product's lifecycle. Regular testing ensures that any potential risks are detected early, and appropriate actions are taken to safeguard public health.
Routine testing of drugs and medicines for nitrosamine impurities may be required to ensure they are either absent or below established limits. The need for such testing is based on risk assessment and should be conducted when:
There is a high risk of nitrosamine formation during storage, due to precursor functional groups, or late-stage manufacturing processes.
Nitrosamine introduction is identified during manufacturing, packaging, or storage.
Nitrosamines were detected in confirmatory tests, and the root cause is unknown. Testing continues until the cause is identified and controlled.
Post-marketing surveillance by COFEPRIS detects nitrosamines above permitted limits.
Market Withdrawal
If nitrosamine impurities are found to be above safety limits, the guidelines provide clear procedures for the withdrawal of affected products from the market. This measure is crucial to prevent consumers from being exposed to potentially harmful levels of nitrosamines.
COFEPRIS Compliance Timelines and Implementation Schedule
COFEPRIS has established a phased approach for compliance with regulations concerning nitrosamine impurities in drugs and medicines. TRS and FIF are expected to complete the initial risk assessment and management of nitrosamine impurities within eight months from the publication of the relevant guidelines. Confirmatory testing, where required, must be conducted within a 36-month period, ensuring that all processes are thoroughly validated and compliant with COFEPRIS standards. Routine testing and ongoing monitoring must be integrated into quality management practices to maintain compliance beyond these timelines, especially if post-marketing surveillance reveals any risks.
Other relevant guidelines -
Quality Risk Management of the Official Mexican Standard NOM-164-SSA1-2015, Good Manufacturing Practices for Drugs, and Section 6. Quality Management System of NOM-059-SSA1-2015, Good Manufacturing Practices for Medicines. Additionally, the principles of Quality Risk Management described in the ICH guideline Q9 on quality risk management should be used
the ICH guideline M7 (R2) on the assessment and control of DNA-reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk.
Implications for the Pharmaceutical Industry
The implementation of these guidelines represents a significant step forward in ensuring the safety of pharmaceutical products in Mexico. For manufacturers, this means increased responsibility in monitoring and controlling the quality of their products. While the new regulations may pose challenges, particularly in terms of cost and process adjustments, they are essential for maintaining public trust and compliance with international standards.
COFEPRIS’s guidelines for managing nitrosamine impurities in pharmaceuticals reflect Mexico’s commitment to protecting public health. By requiring thorough risk assessments, confirmatory testing, and ongoing monitoring, these guidelines help ensure that drugs and medicines in Mexico are safe for consumption. For pharmaceutical companies, adhering to these regulations is not only a legal obligation but also a vital part of their commitment to consumer safety.
As the industry adapts to these new requirements, ongoing collaboration between regulators and manufacturers will be key to successfully managing the risks associated with nitrosamine impurities.
Pharmaceutical companies operating in Mexico should closely review the new guidelines and take proactive steps to ensure compliance. By doing so, they can contribute to the global effort to enhance drug safety and protect public health.
Artixio, your trusted partner for COFEPRIS Compliance
For expert guidance and support in ensuring your pharmaceutical products meet COFEPRIS regulations on nitrosamine impurities, contact Artixio today. Our team specializes in compliance strategies, helping you navigate the complexities of regulatory requirements with confidence. Reach out to us now to ensure your products remain safe, effective, and market-ready.
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