There’s been a lot more attention on nitrosamine impurities lately, especially after similar issues came up in different markets. COFEPRIS has responded with updated guidance in 2024, which adds more clarity but also a bit more responsibility for manufacturers.
It’s not just about checking finished products anymore. The expectation now is to understand where the risk comes from and keep it under control throughout.
In this blog, we’re mainly looking at COFEPRIS regulation of nitrosamines in pharmaceuticals in Mexico and how it affects current processes.
COFEPRIS Role in Nitrosamine Regulation in Mexico
COFEPRIS handles how nitrosamine impurities in pharmaceuticals in Mexico are reviewed and controlled. It sets what companies need to check and how the risk should be managed. The focus is not only on testing results, but also on how and where these impurities can form. If any issue is found, companies are expected to act on it and provide proper justification.
COFEPRIS Nitrosamine Impurity Regulations in Mexico
- COFEPRIS has put more focus on nitrosamine impurities in recent updates.
- The idea is to catch possible risk early, not only at the final stage.
- Raw materials and process steps are usually reviewed as part of this.
- Storage conditions are also checked where there is a chance of formation.
- The approach generally moves from risk check to testing and then follow-up.
- Testing is not the same for all products, it depends on what is seen during assessment.
- In some cases, more checks are added if the situation is not fully clear.
- Responsibility for compliance sits with the manufacturer and local authorized parties.
- For imported products, evaluation and testing are still expected to be handled within Mexico.
- If higher levels are detected, companies need to act on it and inform COFEPRIS.
- The overall approach is more continuous, not limited to one-time checks.
Risk Assessment for Nitrosamine Impurities in Pharmaceuticals
The starting point is usually a risk assessment in understanding how nitrosamine impurities in drugs and medicines could form. This is where raw materials, manufacturing steps, and product stability are looked at to see where nitrosamines could come from.
- Risk assessment review isn’t limited to one stage. It needs to cover the full process, from development to storage, so any possible source of risk is picked up early.
- Each product is assessed separately, and the findings need to be supported with actual data. If there are changes in suppliers or manufacturing, the assessment is expected to be revisited.
- For imported products, the responsibility still sits locally with the TRS and FIF. They are expected to review the information themselves rather than rely only on declarations from the manufacturer.
- In the end, the assessment should clearly point out where nitrosamines could form and give an estimate of exposure based on that risk.
Confirmatory Testing for Nitrosamine Impurities
- If the risk assessment doesn’t show any likely source of nitrosamines, testing may not always be needed, but the reasoning should be clearly supported with data.
- When a potential risk is identified, companies are expected to run confirmatory tests using suitable analytical methods. The aim here is to check if nitrosamine levels are within acceptable limits.
- Testing is usually planned around higher-risk situations, especially where process steps or materials increase the chances of impurity formation.
Factors Determining Testing Sample Size
The number of batches to be tested usually depends on how likely nitrosamines are to form. Products with higher risk tend to be checked more closely.
Some situations that raise concern include certain chemical groups in the drug, changes happening in later stages of manufacturing, or risks linked to packaging and storage.
Recommended Sample Size for Testing
- If the source of risk is understood and batches are consistent, only a portion of the yearly production is tested. In most cases, this works out to around 10% of batches, with at least a few samples each year.
- If production is limited, then all batches may need to be checked. On the other hand, if the risk isn’t clearly understood or consistency isn’t established, testing is generally done on every batch.
- Additional checks may also come in when there are multiple sites, processes, or material sources 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
- When nitrosamines are detected, companies generally need to look at what’s causing it and fix that part of the process. Sometimes small changes work, in other cases it may need bigger adjustments.
- If the levels go beyond what’s acceptable, COFEPRIS needs to be reported, along with a clear plan on how the issue will be handled.
Routine Monitoring and Testing for Nitrosamine impurities in Drugs and Medicines
After the initial checks, monitoring usually continues as part of regular quality activities. The idea is to catch any changes before they become an issue. Further testing depends on how much risk was seen earlier, especially in cases where the source isn’t fully clear. Routine testing is usually considered in situations like these:
- 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.
What happens if nitrosamine levels go too high?
When higher-than-allowed levels are found, products don’t always stay in the market. In some cases, they are withdrawn until the issue is understood and resolved.
COFEPRIS Timelines for Nitrosamine Compliance
COFEPRIS has set timelines, but they’re spread across different steps rather than one fixed deadline. The first focus is on completing the risk assessment, which is expected within about eight months from when the guidance was issued.
Confirmatory testing takes longer. Where it is required, companies are given a wider window, often going up to around three years, since method setup and validation can take time.
After that, monitoring doesn’t really stop. It becomes part of regular quality activities, especially in cases where risks are still being tracked or if something shows up later during post-market checks.
Related GMP and ICH guidelines for Nitrosamine Control
Nitrosamine control is also linked to existing GMP and risk management requirements in Mexico. In Mexico, this links to standards like NOM-164 and NOM-059, which cover manufacturing and quality practices. These are already part of how companies manage process risks.
Alongside this, ICH guidance is also used. ICH Q9 is generally followed for risk assessment, while ICH M7 comes in when there is a need to look at impurity-related safety concerns.
So in most cases, nitrosamine control fits into these existing frameworks rather than being treated as a completely new requirement.
Conclusion
Nitrosamine risks are now part of regular compliance, not something handled separately. With COFEPRIS guidance, the expectation is to understand the risk and keep it under control over time.
What usually causes delays is not the initial work, but what comes up during review or later stages.
Artixio works with pharma companies on COFEPRIS-related regulatory support, including risk assessment and compliance planning. For support, you can reach out at info@artixio.com!
