In 2018, N-Nitrosodimethylamine (NDMA) was identified in an active pharmaceutical ingredient (API). Since then, nitrosamines have been a pressing topic in the pharmaceutical world. With major regulatory updates introduced by the FDA and EMA, all pharmaceutical manufacturers have been instructed to conduct a risk assessment and proactively test their products for the presence of nitrosamines. It’s therefore crucial for pharmaceutical companies and manufacturers to get up to speed with these latest requirements.
Nitrosamines are known environmental contaminants found in water and foods but have recently been identified in multiple drug products. They are a concern for pharmaceutical companies because they have even been identified as part of a group of high potency mutagenic carcinogens referred to as the “cohort of concern” (as per ICH’s M7 Mutagenic Impurities guidelines). Even at low levels, these genotoxic impurities pose a significant threat to human health.
International regulatory authorities have partnered to share information and publish guidelines for market authorisation holders (MAHs), including analytical methods to detect and identify nitrosamine impurities in drug products. Under the new regulations, almost all drug products are required to undergo nitrosamine testing. Even drug products which are planned for submission or have already been submitted require a risk assessment for the potential presence of nitrosamine impurities.
Regulatory agencies have set acceptable limits for nitrosamine impurities in relation to Angiotensin II receptor blockers (ARB). The FDA has determined that nitrosamines should not be present in the ARB API or DP. They have also published interim acceptable intake limits based on the maximum daily dose for NDMA, NDEA and NMBA.
These are:
The EMA has also published the same limits for NDMA and NDEA. Manufacturers may be required to conduct voluntary recalls if laboratory testing finds nitrosamine impurity levels exceed these limits.
Both the FDA and EMA have described methods to identify the potential sources of nitrosamine contamination and formation as well as approaches to control or eliminate these sources during the manufacturing process. Accordingly, a three-step risk assessment has been proposed.
STEP 1: RISK ASSESSMENT Nitrosamines can be formed across all three stages of the manufacturing process (Figure 1). Common sources of nitrosamine formation are the solvents, reagents and catalysts used (especially amines) during API and drug manufacturing. Other sources include the presence of nitrites or nitrates in water, and contamination or cross-contamination of the equipment and starting materials used.
Manufacturers must consider the risk of nitrosamine formation at all stages of the manufacturing process from API synthesis to final product packaging.
The FDA instructed manufacturers to complete risk evaluations and report the outcome by March 31, 2021.
If a risk is identified: MAHs should submit the Step 1 response and proceed with Step 2 confirmatory testing of the drug or product.
If there is no risk: A risk evaluation of the finished product should be conducted and the outcome submitted once a final conclusion is reached.
STEP 2: CONFIRMATORY TESTING If a risk of nitrosamine impurities is identified during the risk assessment step, then MAHs must conduct confirmatory testing on the products identified to be at risk and report any confirmed presence of nitrosamines as soon as possible.
Acceptable limits to consider have been proposed, based on a product’s maximum daily dose (Table 1).
While there is no requirement to use the published testing and analytical methodologies described, any method used should be quantitative, adequately sensitive, validated and conducted at a GMP-compliant facility. Below are some key points to consider for confirmatory testing:
When developing analytical methods, MAHs should consider interferences caused by the presence of trace amounts of nitrosamines in testing materials utilised such as water, plastic or rubber products. In situ formation of nitrosamines is also possible and should be accounted for, such as in the case of ranitidine in high-temperature conditions.
If nitrosamines are detected during testing: The root cause should be identified and stated in the report before moving to Step 3.
If no nitrosamines are detected: A report should be filed with (or be available to) the appropriate regulatory authority.
STEP 3: IMPLEMENTING AND REPORTING CHANGES If the confirmatory tests in Step 2 confirm the presence of nitrosamine impurities, MAHs should implement changes to prevent or reduce nitrosamine impurities in APIs and drug products. The changes implemented should be reported to the appropriate regulatory agency.
If one or more nitrosamine impurities detected are below the interim acceptable limit, then steps should be taken to determine their origin as well as actions needed for respective batches. Root causes should be determined, and corrective and preventive actions should be implemented as well as a risk mitigation plan that ensures that levels will be consistently below interim acceptable limits at the end of the product’s shelf life.
COMPENDIAL CHAPTERS ON NITROSAMINES In addition to the guidance from regulatory authorities, compendial chapters have been proposed and/or published for publications USP Nitrosamine Impurities and EP 2.5.42. N-Nitrosamines in active substances. The compendial chapters are aligned with the guidelines in terms of the assessment and testing as well as the recommended acceptable levels. Several methods using GC-MS, GC-MSMS or LC-MSMS have been published for the detection of specific nitrosamine impurities.
SGS offers a complete range of services for Nitrosamine Testing at our campus in Navi Mumbai, India. Our cGMP compliant laboratories use stateof- the-art technologies that detect ultra-trace levels of leachables and nitrosamines at recommended LOD/LOQ levels and specifications. Our test method is based on LC-MS/MS, GC-MS/MS and LC-HRMS to detect the presence of nitrosamine traces in drug products, raw materials, process impurities and active pharmaceutical ingredients (APIs).
Sensitivity achieved for respective nitrosamine with this state-of-the-art equipment are at very low levels and depending on the specification of individual nitrosamine, number of methods can be developed and validated as per customer requirement.
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