Nitrosamine Drug Substance Related Impurities (NDSRI) are a subcategory of nitrosamine impurities that share structural similarity to the active pharmaceutical ingredient (API) in drug products. The FDA Guidance provides a recommended methodology for acceptable intake (AI) determination that uses structural features of NDSRIs to generate a predicted carcinogenic potency categorization and corresponding AI limit. Manufacturers and applicants can apply these recommendations, in the absence of other FDA-recommended AI limits, in their evaluation of potential impurities in their drug products. APIs containing secondary amines or dimethyl tertiary amines are at risk of forming NDSRIs through the nitrosation of the amine center.
However, NDSRIs can also potentially form in APIs when nitrosating agents are present during the API manufacturing process or when APIs undergo processing steps, such as fluid bed drying at elevated temperatures and jet milling, which create conditions favourable for the reaction of nitrogen oxides with at-risk APIs.
Regulatory timelines for NDSRI reporting and risk mitigation vary across different regions. In the EU-EEA, there are no set deadlines, but MAHs must use specific templates for reporting risk assessments and test results. In the UK, the MHRA requires detailed risk evaluations to be included in regulatory dossiers during the next quality variation, even if no initial risk was identified. Japan’s PMDA mandates reporting if N-nitrosamines exceed acceptable limits, with steps 2 and 3 to be completed by 31 October 2024. Health Canada extends the Step 3 completion date to 1 August 2025 and requires timely submission of risk mitigation changes via the Common Electronic Submission Gateway (CESG), necessitating a critical review before implementation. Adhering to these guidelines ensures consistent management of NDSRI risks across different regions.
NDSRI - US specific request & timeline
For Nitrosamine Drug Substance-Related Impurities (NDSRIs) in the United States, the U.S. Food and Drug Administration (FDA) has provided specific guidance and timelines for the assessment and control of these impurities. NDSRI regulatory reporting requirements are important. The relevant FDA guidance includes the following key points and timelines:
- Identification of NDSRIs: Manufacturers are required to identify potential NDSRIs in their drug products.
- Risk Assessment: Conduct a risk assessment to evaluate the presence and levels of NDSRIs. This includes understanding the sources and mechanisms of formation of these impurities.
- Analytical Testing: Develop and validate appropriate analytical methods to detect and quantify NDSRIs.
- Control Strategies: Implement control strategies to ensure that NDSRIs are within acceptable limits. This may involve changes in manufacturing processes or formulation adjustments.
- Acceptable Limits (AL): Calculate the Acceptable Limits for NDSRIs based on safety assessments, including considerations of maximum daily dose and toxicological data.
The FDA has provided specific timelines for the evaluation and control of NDSRIs. These are as follows:
- Immediate Actions: Manufacturers should immediately assess their products for the presence of NDSRIs. This involves a preliminary risk assessment and initial testing.
- Six-Month Period: Within six months of the guidance issuance, manufacturers are expected to have completed a detailed risk assessment and developed validated analytical methods for detecting NDSRIs.
- Control strategies remidies: Within one year, manufacturers should have implemented control strategies to reduce NDSRIs to acceptable levels. This includes making necessary changes to the manufacturing process and/or formulation.
- Ongoing Monitoring: After the one-year period, ongoing monitoring and control should be in place to ensure that NDSRIs remain within acceptable limits.
Manufacturers may be required to submit specific data and documentation to the FDA, including:
- Risk Assessment Reports: Detailed reports on the risk assessment of NDSRIs, including identification, potential sources, and mechanisms of formation.
- Analytical Method Validation: Documentation of the development and validation of analytical methods for detecting NDSRIs.
- Control Strategy Documentation: Detailed plans and documentation of control strategies implemented to mitigate the risk of NDSRIs.
- Periodic Reports: Ongoing periodic reports to demonstrate continued compliance with the acceptable limits for NDSRIs.
US – FDA NDSRI Reporting Guidance
The FDA has specific NDSRI regulatory reporting requirements and actions that manufacturers need to follow concerning marketed or approved products in relation to Nitrosamine Drug Substance-Related Impurities (NDSRIs).
Reporting and Actions Based on Risk Assessment and NDSRI Levels
- Action: No further action needed.
- Reporting: No reporting to the FDA is required.
- Action: Develop and implement an appropriate control strategy to ensure that NDSRI levels remain reliably at or below the AI limit.
- Reporting
- Where applicable, report changes to an approved application.
- Submit these changes in compliance with appropriate regulatory requirements.
- If changes affect the formulation, they must be submitted through supplements or amendments to the application.
- Action:
- Do not release the affected batch.
- Consider removal of the affected batch from the market.
- Reporting
- For formulation changes, submit proposed changes through supplements or amendments. Typically, reformulation of an approved drug product is considered a major change, requiring a Prior Approval Supplement (PAS).
- Implement necessary changes in accordance with appropriate regulatory requirements.
- Contact the FDA if a recall is initiated.
EMA- NDSRI Reporting Guidance
The European Medicines Agency (EMA) has provided detailed guidance for Marketing Authorization Holders (MAHs) regarding the NDSRI regulatory reporting requirements for Nitrosamine Drug Substance-Related Impurities (NDSRIs).
MAHs should continue to use the established response templates and communication mechanisms for submitting information related to NDSRI risks. The templates ensure standardized reporting, which is crucial for regulatory compliance and effective communication with the EMA.
The EMA and MHRA have reminded Marketing Authorization Holders (MAHs) that the submission dates for steps 1, 2, and 3 for both chemical and biological medicinal products have already passed. Despite the absence of new deadlines, it is critical to comply with the ongoing NDSRI regulatory reporting requirements and maintain proactive communication with the regulatory bodies.
The steps and requirements are as follows:
Scenario 1: If NDSRI risk is identified after the initial Step 1:
- Action: Submit a response using the Step 1 Risk Identified Response Template.
- Details to Include: Starting and completion dates for confirmatory testing.
- Next Steps: Begin confirmatory testing as soon as possible.
Scenario 2: If the previous Step 1 notification indicated a likely presence of NDSRIs:
- Details to Include: Starting and completion dates for confirmatory testing.
- Next Steps: Begin confirmatory testing as soon as possible.
- Action: Submit a response using the Step 2 Nitroamine Detected Response Template.
- Conduct confirmatory testing based on the identified risk. If NDSRIs are detected, use the appropriate response templates to report findings to the EMA.
- If the confirmatory testing indicates the presence of NDSRIs, follow the subsequent steps as per the EMA guidelines for mitigation and communication.
If Step 1 concludes there is no risk of the presence or formation of NDSRIs, no further action is required
UK (MHRA) NDSRI Reporting Guidance
The UK Medicines and Healthcare products Regulatory Agency (MHRA) has provided specific guidance for Marketing Authorization Holders (MAHs) regarding the NDSRI regulatory reporting requirements and the management of Nitrosamine Drug Substance-Related Impurities (NDSRIs). Here are the key points:
Global Risk Assessment:
- Inclusion in Dossier: Even if no risk was initially identified, a detailed risk evaluation should be included in the dossier at the next regulatory opportunity (e.g., during a quality variation submission).
- CTD Sequence: Ensure that the risk evaluation is documented in the Common Technical Document (CTD) sequence.
Handling Changes in Risk Assessment:
- Product Life Cycle Management: Any changes to the initial risk assessment must be managed through the product life cycle.
- Submission Requirements: Submit an appropriate procedure to MHRA, supported by a cover letter and all relevant supporting data. This should be done during the next quality variation submission.
NDSRIs Reporting Guidance for PMDA (Japan)
The Pharmaceuticals and Medical Devices Agency (PMDA) in Japan has outlined specific requirements for reporting N-nitrosamine Drug Substance-Related Impurities (NDSRIs) when the levels exceed the acceptable intake limit. Here are the key points and NDSRI regulatory reporting requirements:
Reporting Requirements: If the concentration of N-nitrosamines exceeds the acceptable intake limit, the following information must be included in the report:
Name and Content: Clearly state the name and concentration of the N-nitrosamines that exceed the limit.
Necessity: Indicate whether a product recall is necessary based on the findings.
- Evaluation Methods and Standards: Describe the specific evaluation methods and standards used.
- Lots Measured and Exceeding: Provide details of the lots measured, the ones that exceed limit values, and their distribution status.
- Distribution Status: Outline the distribution status of each affected lot.
- Distribution Status: Detail the current distribution status of the product.
- Impact Due to Shipment Suspension: Assess the impact on the market due to any suspension of shipments.
- Impact Due to Collection: Evaluate the impact on the market if collection (recall) of the product is necessary.
- Origin of Contamination: Include information on the origin of nitrosamine contamination, including any presumed sources.
- Status of Overseas Measures: Report on any measures taken overseas regarding the contamination.
- Completion Date: The steps 2 and 3 for confirmatory testing and risk evaluation should be completed by 31 October 2024 .
- Reporting Format: The PMDA does not specify a particular format for the report. However, all the aforementioned information must be included to ensure comprehensive reporting.
NDSRI Reporting Guidance for Health Canada
Here are the essential points:
Reporting Requirements: Reporting to Health Canada is required only if the concentration of N-nitrosamines exceeds the acceptable intake limit.
Completion Date: The completion date for Step 3 has been extended to 1 August 2025. The guidance document has been updated to indicate that the timeline for completing Changes to the Market Authorization (Step 3 of Health Canada’s call for review) has been extended to August 1, 2025 for drug products containing chemically synthesized and semi-synthetic active pharmaceutical ingredients and for biological and radiopharmaceutical drug products.
Submission Details/ Step 3 Risk Mitigation Changes:
- These changes are due to potential safety concerns and require Health Canada’s critical review of scientific data before the manufacturer can implement them.
- For Drug Products with Chemically Synthesized and Semi-Synthetic APIs: Submit as Level I – Supplements or Post-Drug Identification Number (DIN) Change submissions, as applicable.
- For Biological and Radiopharmaceutical Products: Submit as Level I – Supplements, Level II – Notifiable Changes, or Post-Drug Identification Number (DIN) Change submissions (PDCs), as applicable.
Sagar Pawar
Sagar Pawar, a Quality Specialist at Zamann Pharma Support, brings over 11 years of experience in Quality domain for the pharmaceutical and medical technology industries. Specializing in qualification, validation, Computer System Validation (CSV), and Nitrosamine activities, Sagar is currently focused on enhancing the Zamann Service portfolio by developing and implementing robust strategies to address Nitrosamine-related challenges. Outside of work, Sagar enjoys trekking and cooking. Connect with Sagar on LinkedIn to discuss topics related to equipment qualification, GMP Compliance and Nitrosamine-related challenges.
