This guidance represents Health Canada’s current thinking and recommendations on issues related to N-nitrosamine impurities (nitrosamine impurities or nitrosamines). This guidance may be subject to change as new information becomes available and if further guidance is needed for applicants and market authorization holders (MAHs).
The request in Health Canada’s call for review to evaluate the risk of the presence of nitrosamine impurities outlined in the October 2, 2019, letter applies to human pharmaceutical products with a drug identification number (DIN) containing chemically synthesized and semi-synthetic APIs. This includes:
- prescription and non-prescription (over-the-counter) drug products
- chemically synthesized excipients and raw materials used in the manufacturing of drug products
Also considered to be within the scope of Health Canada’s call for review are:
- drug products that have been approved but are not yet marketed
- approved drug products with a DIN status reported as “dormant”
The request for conducting risk assessments for the potential presence of nitrosamine impurities was extended to all biological and radiopharmaceutical products for human use. This was outlined in Health Canada’s letter dated December 15, 2020.
Timelines for Risk Assessment
For drug products containing chemically synthesized and semi-synthetic APIs, the steps for actions relating to nitrosamines are expected to be completed as follows:
- Step 1: risk assessments by March 31, 2021
- Step 2: confirmatory testing by October 1, 2022
- Step 3: changes to the market authorization by October 1, 2023
For biological and radiopharmaceutical products, the steps for actions relating to nitrosamines are expected to be completed as follows:
- Step 1: risk assessments by November 30, 2021
- Step 2: confirmatory testing by November 30, 2023
- Step 3: changes to the market authorization by November 30, 2023
Outcomes of risk assessments (Step 1) and what is provided to Health Canada (updated)
Risk assessment documentation should be retained by the MAH, unless nitrosamine impurities are detected in the API, drug product or both during confirmatory testing. Following the completion of confirmatory testing, if any nitrosamine impurity is detected at any level, Health Canada must be informed immediately.
The available details of the risk assessment should be submitted at the same time that Health Canada is informed of the detection.
Please note that Health Canada may request to review the MAH’s risk assessment for all products and will request this information directly from the MAH, as necessary.
Determining the priorities and order in which products should be reviewed
MAHs should use a risk-based approach to determine the order in which their drug products are reviewed. In order to prioritize the sequence in which products should be reviewed, MAHs should consider a number of factors, including the following:
- principles set out in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q9 guideline on quality risk management
- maximum daily dose of the drug product
- route of administration
- duration of use
- indication and consideration of special populations, such as pregnant women and children
- toxicological profile of the API. For example, evaluating the risk of presence of nitrosamine impuritiesNin cancer therapies in which the API is a potent mutagen could be considered lower priority and sequenced for review after higher priority APIs.
- market considerations such as the availability of product for sale on the Canadian market and number of patients being treated with the drug product
- emerging international or domestic information that 1 or more nitrosamine impurities has been identified in an API (or a structurally similar API) or drug product
- the presence of structural elements in the API or conditions in the manufacturing and packaging processes for the API or drug product, which are conducive to nitrosamine formation (for example, presence of secondary or tertiary amine groups in the API).
MAHs co-operating with API and drug product manufacturers to perform risk assessments
After receiving authorization to market in Canada, MAHs are responsible for the safety, efficacy and quality of their drug products and for carrying out the risk assessments. They should:
- work with API and drug product manufacturers to review their API and drug product manufacturing processes to conduct risk assessments
- take into account the API and drug product manufacturers’ knowledge of the manufacturing processes, potential sources of contamination and other root causes of the formation and presence of nitrosamine impurities
API and drug product manufacturers should make available to the MAHs the information necessary for conducting the risk assessments.
If the risk of nitrosamine impurity formation has been assessed during the development phase of the API or drug product manufacturing processes, the information from the assessment can be used to support the evaluation.
Responsibilities of API manufacturers, excipient manufacturers, drug product manufacturers, MAHs and importers
After receiving authorization, MAHs are responsible for ensuring the ongoing safety, efficacy and quality of drug products on the Canadian market. This would include implementing an ongoing monitoring program to detect trends in quality. Such a program should be based on appropriate controls for raw materials, all processing steps, critical process parameters and critical quality attributes.
Statements or declarations by manufacturers and suppliers in lieu of completing risk assessments
Statements and declarations provided by manufacturers and/or suppliers are not a substitute for an overall robust risk assessment by the MAH. While the knowledge and expertise offered by manufacturers is valuable and is encouraged to support the risk assessment process, manufacturer/supplier statements or declarations do not replace a documented risk assessment by the MAH.
Skipping the risk assessment step (Step 1) and proceeding directly to confirmatory testing (Step 2)
The risk assessment step (Step 1) is necessary to identify risk factors, possible root causes and the scope of nitrosamine impurities that have the potential to be formed or introduced into the API or drug product. If a risk of 1 or more nitrosamine impurities is identified, this knowledge is used to guide the development and validation of appropriate test methods required for the confirmatory testing stage
(Step 2).
This knowledge may also be useful for the establishment of a suitable control strategy and changes introduced to prevent the presence of nitrosamines.
As such, it is not appropriate to proceed directly to confirmatory testing (Step 2) without completing the risk assessment step (Step 1).
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