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Guidance for product registrants

Information on actions required to manage this issue

Responsibilities of product registrants

Product registrants are responsible for the quality, safety, and efficacy of their products, including the quality of the drug substance used in the finished products. All product registrants of products containing chemically synthesised drug substances (irrespective of whether the products are currently marketed) must ensure that your finished product manufacturers and drug substance manufacturers review their manufacturing processes and perform risk assessments to identify the potential of nitrosamine impurities.

Risk assessment of nitrosamine impurities in all therapeutic products containing chemically synthesised drug substances

In March 2020, we had communicated the regulatory requirement for all product registrants to conduct risk assessments for all therapeutic products containing chemically synthesised drug substances to identify any potential risk of nitrosamine impurities. Where the potential risk is identified, confirmatory testing should be done, and the necessary changes should be made to mitigate the risk.

Below are the actions required to be taken by product registrants and their corresponding timelines.

Step 1: Risk assessment by 01 Apr 21

Perform risk assessments of all your therapeutic products containing chemically synthesised drug substances, using the quality risk management principles described in the ICH Q9 guideline.

  • If no risk of nitrosamine is identified, you do not need to submit the risk assessment documents to us but should retain the risk assessment documents and submit to us when requested.
  • If a risk of nitrosamine is identified, notify us of the identified risk and proceed to Steps 2 and 3.

You may refer to the recently published paper on ‘Regulatory Experiences with Root Causes and Risk Factors for Nitrosamine Impurities in Pharmaceuticals’ for additional information to aid in your assessment. This paper provides the current scientific information from a quality perspective on risk factors and potential root causes for nitrosamine impurities, as well as recommendations for risk mitigation and control strategies. Click here for the paper.

The deadline for Step 1 has passed. If you have not completed and submitted the risk assessment (where required), you are strongly advised to do so promptly, prioritising products that may pose higher risk of nitrosamine impurities.

Step 2: Detailed assessment, product testing and corrective action and preventive action (CAPA) plan by 30 Jun 23

The below steps are to be taken if risk of nitrosamine impurities has been identified with any of the drug substance or drug product manufacturers.

a) Conduct a detailed assessment to identify all potential sources of the nitrosamine(s).

b) Conduct testing of the drug substance and/or drug product for the at-risk nitrosamine(s) on a representative number of batches using appropriately validated and sensitive methods. Products identified as high priority should be tested as soon as possible.

c) Notify us if any nitrosamine impurity has been detected in any batch of the drug substance and/or drug product tested (as per quality defect reporting requirements). We should be notified immediately if the levels detected exceed the acceptable intake limit.

d) Develop the CAPA plan to mitigate the risk for the nitrosamine(s).

e) Submit the detailed risk assessment, test results and CAPA plan to us in a timely manner, latest by 30 Jun 2023.

We have developed test methods for the identification and determination of nitrosamine impurities in some medicines. These test methods can be adapted and used by you to detect nitrosamine impurities in your products. Click here for the test methods.

The deadline for Step 2 has passed. If you have not completed and submitted the required documents, you are strongly advised to do so promptly, prioritising products that may pose higher risk of nitrosamine impurities.

Step 3: Submission of variation application to implement CAPA to mitigate risk by 31 Dec 23

Following our review of your company’s proposed CAPA plan, you should submit the appropriate variation application(s) to implement the agreed measures to mitigate the risk of nitrosamines, such as changes to manufacturing process and/or changes to product specifications, by 31 December 2023.

For all the above steps, the timeline should be shortened if findings indicate an immediate risk to public health. We should be notified immediately if the findings indicate an immediate risk to public health.

Acceptable intake for certain known nitrosamines

The document titled "Appendix 1_HSA recommended acceptable intake for certain known nitrosamines1944 KB" lists the acceptable intakes that are recommended by us for certain known nitrosamines. We will continue to update the list as more information becomes available.

Submission of new applications

For products with identified nitrosamine risks, the risk assessment should be submitted as part of the Chemistry, Manufacturing and Controls (CMC) dossier for all new drug applications (NDAs) and generic drug applications (GDAs). The level of nitrosamines present should meet the acceptable intake specified in the document titled “Appendix 1: HSA recommended acceptable intake for certain known nitrosamines”. For novel nitrosamines not identified in this document, applicants are required to propose the acceptable intake with scientific justification. 

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