Please check the following updated numbers 17, 24, and 34.
17. Additional expectations of MAHs if nitrosamine impurities are detected in the API and/or drug product (updated)
Where 1 or more nitrosamine impurities are detected following the completion of confirmatory testing (for multiple nitrosamines, refer to number 27), in addition to notifying Health Canada, MAHs should have completed or be completing as necessary:
- a health risk assessment posed by the presence of the nitrosamine(s) along with intentions related to any actions, as necessary, for the batches on the Canadian market
- an assessment to determine if the product is considered to be medically necessary or medically important and if any disruption to product supply is expected should market action be taken
- a detailed investigation report assessing all possible root causes of the detected nitrosamine impurity (or impurities) and describing corrective and preventive actions
- perform investigations in accordance with written procedures
- evaluate all potential changes to facilities, materials, equipment and/or process intended to reduce the levels of the nitrosamine impurities through a formal change control system
- a risk mitigation plan including the establishment of a suitable control strategy for detected nitrosamine(s) to ensure that, moving forward, nitrosamine impurity levels will be consistently below the Acceptable Intake (AI) limit at the end of the retest period for the API or the shelf-life for the drug product. Refer to Appendix 1 for a list of established AI limits. These AI limits are considered qualified for nitrosamine impurities in the drug product at the end of shelf life. In some cases, tighter limits in the API specifications and in the drug product release specifications may be warranted to ensure that the drug product shelf life specification will be met.
MAHs are reminded to submit changes to the market authorization as per Step 3 of the October 2, 2019 letter. Refer to number 13 on how changes should be submitted.
Health Canada may use such notifications to request additional actions and/or information. For example, the origin of nitrosamine impurities may be attributed to the type of process chemistry used and the risk mitigation plan may necessitate the establishment of a control strategy by manufacturers for each detected nitrosamine impurity according to ICH’s M7 guideline.
We may request additional actions by other MAHs of the same products to mitigate any risks identified and protect people’s health and safety if necessary.
For more information on the establishment of specifications and controls, refer to number 34 and number 35, respectively.
24. AI limits for nitrosamine impurities that Health Canada considers acceptable (updated)
AI limits have been derived for several nitrosamines (Appendix 1). These AI limits are considered appropriate for all routes of administration and should be applied to the maximum daily dose (MDD) of the drug product.
AI limits can be established using several approaches.
In cases where there is reliable compound-specific data for a nitrosamine impurity, MAHs and applicants may:
Establish an AI limit based on reliable compound-specific data
- Linearly extrapolate from the dose giving a 50% tumour incidence (TD50) to a 1 in 105 excess cancer risk, using the most relevant TD50 value from a sufficiently robust carcinogenicity study (refer to ICH’s M7 Addendum for guidance on selecting an appropriate carcinogenicity study).
- Provide a negative, GLP-compliant, enhanced Ames test using the enhanced Ames test conditions described in Appendix 3 to justify a limit of 1.5 µg/day.
- Provide negative in vivo mutagenicity data (for example, a negative in vivo mutagenicity assay conducted per the Organisation for Economic Co-operation and Development (OECD)'s Test Guideline No. 488 “Transgenic Rodent Somatic and Germ Cell Gene Mutation Assays”) to justify controlling a nitrosamine impurity per the recommendations in ICH’s Q3A and Q3B guidelines.
In cases where there is insufficient reliable compound-specific data available for a nitrosamine impurity, MAHs and applicants may:
Establish an AI limit based on a structure-activity relationship (SAR) assessment and read-across to a surrogate with sufficient compound-specific data
To justify an appropriate surrogate for read-across, the SAR assessment should take into consideration structural similarity (both overall and at the local site of activation), similarity of physicochemical characteristics, steric and electronic factors impacting reactivity and metabolic similarity (for example, metabolic pathway, stability/reactivity of metabolites).
If an appropriate surrogate for read-across is identified, to calculate an AI limit, the TD50 should be derived from a sufficiently robust carcinogenicity study. Parameters to consider include adequate description of the study design and appropriate histopathological analysis, number of dose groups (i.e., single-dose studies are not considered appropriate), number of animals per dose group, duration of exposure, route of administration, observed dose-response relationship. Refer to ICH’s M7 Addendum for guidance on selecting an appropriate carcinogenicity study.
Alternatively, in cases where an acceptable surrogate for read-across may be controlled to a limit as per the recommendations in ICH’s Q3A and Q3B guidelines (when indicated in Appendix 1), this limit can be applied to the nitrosamine impurity.
Consistent with international regulatory practices, Health Canada will continue to use, and expect applicants and MAHs to use, mass-based calculations (rather than molar-based) to derive AI limits for nitrosamine impurities when a surrogate is selected for read-across.
Establish an AI limit using the Carcinogenic Potency Categorization Approach (CPCA)
The Carcinogenicity Potency Categorization Approach (CPCA) is an approach for assigning a nitrosamine to a predicted carcinogenic potency category.
A total of five carcinogenic potency categories are available, each with a corresponding AI limit that ranges from 18 ng/day to 1500 ng/day.
A nitrosamine is assigned to a predicted carcinogenic potency category based on an assessment of alpha hydrogen atoms and activating or deactivating structural features present in the nitrosamine. Refer to Appendix 4 for a description of the approach which also includes case examples to illustrate application of the CPCA.
MAHs and applicants should also refer to the following items for more information:
- number 27 on the presence of multiple nitrosamines
- number 28 on applying a less-than-lifetime limit
- number 31 on which nitrosamines should be included in risk assessments and confirmatory testing
34. Including routine testing for nitrosamine impurities in the API and/or drug product specification (updated)
The API specification should include a test and acceptance criterion for each nitrosamine impurity when:
- the risk for nitrosamine presence is considered to be high and/or
- the concentration of any nitrosamine is found to be at significant levels (for example, greater than 30% of the AI limit) during confirmatory testing
Examples where the risk for nitrosamines is considered high:
- potential for nitrosamine formation on storage
- presence of nitrosamine precursor functional groups in the API
- late-stage formation/introduction of a nitrosamine impurity in the manufacturing process
Where multiple nitrosamines are detected in an API, a cumulative limit should also be included in the specification using one of the approaches outlined in number 27.
Routine testing for nitrosamine impurities should be included in the drug product specification when:
- the potential for nitrosamine introduction during drug product manufacturing, packaging and storage is identified and/or
- a nitrosamine impurity is detected in the drug product during confirmatory testing and the root cause is unknown
Where such a risk is identified, a test and acceptance criteria for both release and shelf life specifications should be included. Refer to Appendix 1 for a list of established AI limits. These AI limits are considered qualified for nitrosamine impurities in the drug product at the end of shelf life. In some cases, tighter limits in the API specifications and in the drug product release specifications may be warranted to ensure that the drug product shelf life specification will be met.
Where multiple nitrosamines are detected, control for total nitrosamines using one of the approaches outlined in number 27 should be included in the specification. Alternatively, control limits expressed on an individual impurity basis (for example, a limit for each nitrosamine set at a percentage of its AI limit such that the sum of the % AI limits for each specified nitrosamine does not exceed 100%) may be proposed with appropriate justification. Other approaches for establishing a suitable specification when multiple nitrosamines are concerned may be acceptable if appropriately justified.
The presence of one or more nitrosamines at <10% of their individual AI limits in a drug product constitutes a negligible toxicological risk; if the root cause for the presence of such nitrosamine impurities is understood and appropriate controls have been established to ensure such impurities will consistently be <10% of their individual AI limits, then such impurities do not need to be specified in the drug product specifications. Nitrosamines present below 10% of their respective AI limit do not need to be factored into the calculation of limits for total nitrosamines.
MAHs should test all new lots of drug product for nitrosamines and only release lots that meet the acceptance criteria for individual (and multiple nitrosamines, if relevant). Continue routine testing of all drug product lots until the root cause is identified and alternative controls/risk mitigation measures (such as process controls, raw material specifications) have been implemented. Ensure that nitrosamine impurities will be routinely below the AI limit in the future.
