Guidance for product registrants on management of nitrosamine impurities in therapeutic products

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 drug products. All product registrants of products containing chemically synthesised drug substances (irrespective of whether the products are currently marketed) must ensure that your drug product manufacturers and drug substance manufacturers review their manufacturing processes and perform risk assessments to identify the potential of nitrosamine impurities. Reasonable steps should be taken to prevent or minimise the risk of nitrosamine impurities in all therapeutic products. Product registrants should also keep up to date with the latest information and evolving international regulatory requirements on this topic.

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

In March 2020, HSA 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 a potential risk of nitrosamine is identified, HSA is to be notified via email at HSA_ProductDefect@hsa.gov.sg or via the Product Defect Reporting Form, with submission of the risk assessment documents.

• 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.

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 HSA via email at HSA_ProductDefect@hsa.gov.sg or via the Product Defect Reporting Form if any nitrosamine impurity has been detected (irrespective of any level) in any batch of the drug substance and/or drug product tested. We should be notified immediately if the levels detected exceed the acceptable intake.

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.

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.

The deadline for Step 3 has passed. If you have not submitted the appropriate variation applications, you are strongly advised to do so promptly, prioritising products that may pose higher risk of nitrosamine impurities.

Questions and answers for product registrants on management of nitrosamine impurities in therapeutic products

We have developed a question-and-answer (Q&A) document to provide further details and clarity on HSA’s current approach, recommendations, and regulatory requirements on the management of nitrosamine impurities in therapeutic products. The document covers the following topics:

1. Risk assessment

2. Acceptable intake

3. Product testing, root cause analysis and CAPA development

4. Requirements for new and pending applications

We will continue to update the document as more information becomes available. Click here for the Q&A document.

The links to the appendices mentioned in the Q&A document can be found below:

1. Appendix 1: HSA recommended acceptable intake for certain known nitrosamines

2. Appendix 2: Assessment aid for assessing nitrosamine risk

3. Appendix 3: Guidance on submission of nitrosamine risk assessment where a risk is identified

4. Appendix 4: Carcinogenic potency categorisation approach (CPCA) for nitrosamines

5. Appendix 5: Enhanced Ames test (EAT) conditions for nitrosamines

Submission of new applications

A nitrosamine risk assessment is required for all new drug applications (NDAs) and new generic drug applications (GDAs) of products containing chemically synthesised drug substance. The risk assessment should be submitted as part of the Chemistry, Manufacturing and Controls (CMC) dossier. The level of nitrosamines present should meet the acceptable intake specified in Appendix 1: HSA recommended acceptable intake for certain known nitrosamines of the Q&A document. For novel nitrosamines not identified in this document, applicants are required to propose the acceptable intake based on the approaches described in Question 19 of the Q&A document.

Industry Training Workshop on Management of Nitrosamine Impurities in Therapeutic Products held on 30 October 2024

The objectives of the workshop were to clarify HSA’s current approach, recommendations, and regulatory requirements for managing nitrosamine impurities in therapeutic products. The presentation slides, workshop recording and supplementary materials addressing questions raised during the Q&A sessions of the workshop can be accessed here.