
The FDA has been investigating the presence of nitrosamine impurities in certain drug products. Since 2018, several drug products including ARBs, ranitidine, nizatidine and metformin have been found to contain unacceptable levels of nitrosamines. Nitrosamines are classified as probable human carcinogens based on animal studies and there has been a pressing need to remove the risk to patients.
As such, the Food and Drug Administration (FDA) provided industry guidance for Control of Nitrosamine Impurities in Human Drugs (Rev 1-Feb2021) authorization holders (MAHs) on risk measures to address nitrosamine impurities. The European Medicines Agency (EMA) and other health authorities have taken a similar approach. The FDA asked MAHs to review all chemical and biological human medicines for the possible presence of nitrosamines and to test products at risk.
This guidance recommends steps manufacturers of APIs and drug products should take to detect and prevent unacceptable levels of nitrosamine impurities in pharmaceutical products. The guidance also describes conditions that may introduce nitrosamine impurities.
Following the ICH Q9 principles, the manufacturer of the drug product (DP) should base the control strategy for Nitrosamines impurities on a risk assessment which is part of an overall risk management of the potential risk for impurities to occur in the DP.
Companies are required to have appropriate control strategies to prevent or limit the presence of these impurities and, where necessary, to improve their manufacturing processes. API and drug product manufacturers should take the following steps to mitigate nitrosamine impurities in their products:
Step 1: Risk Assessment – The outcome of a risk assessment to identify active substances and finished products at risk of N-nitrosamine contamination was required to be reported by March 31, 2021 for all commercial drug products and any new drug applications.
Step 2: Confirmatory Testing – If a risk was identified in Step 1, confirmatory testing on the products should be performed and the confirmed presence of nitrosamines above the acceptable levels reported as soon as possible.
Step 3: Update of Marketing Authorization – Report changes implemented to prevent or reduce nitrosamine impurities in APIs and drug products to FDA. This includes submission of any drug master file (DMF) amendments in accordance with 21 CFR 314.420(c) and changes to approved applications as required under 21 CFR 314.70 and 314.97 and pending applications under 21 CFR 314.60 and 314.96.
DS InPharmatics can help MAHs ensure they conform with the requirements in several ways:
Step 1: Risk Assessment
Develop a risk assessment report to evaluate the drug product based on factors such as maximum daily dose, duration of treatment, therapeutic indication, and number of patients treated.
Step 2: Confirmatory Testing
Provide expertise in confirmatory testing, which is dependent on outcome of the risk assessment:
- Analytical methodology with the appropriate sensitivity for the testing of nitrosamines
- Recommendation of Contract Laboratories for the testing of nitrosamines
- Evaluation of suitable approaches when either a single new (unknown) nitrosamine is identified, or more than one nitrosamine is identified
- Interpretation of the results of confirmatory testing with reference to the limit of quantitation of the method and the acceptable limit for the nitrosamine impurity
Step 3a: Update of Approved Application – Post-Approval Supplement (PAS)
Expertise in compilation, format, content, evaluation, and review of the Step 3 report, including:
- Evaluation of a nitrosamines control strategy, including impact on product safety and quality
- Classification of the changes involved, such as an updated API or finished product specification and/or updated API or finished product manufacturing process
- Recommendation of a suitable PAS submission strategy, for example CBE-30 where post-approval is required
- Coordination between the sponsor and the API and/or drug product product manufacturer or CMO, to obtain the technical information for presentation of the change(s)
- Preparation of the post-approval submission, module 1 and Module 3, eCTD compilation and publication
- Follow-up of the PAS and integration with the Step 3 report
Step 3b: Update of Submission – FDA Meetings required
If the N-nitrosamine presence is confirmed to be intrinsic to the API, e.g. is a structural feature or a metabolic formation, and/or if additional root causes for the presence of nitrosamines are reported and require further extensive assessment, DSI can assist with FDA Type B- or C-meetings.
Contact us to find out how we can help you manage all the complexities surrounding nitrosamine contamination.