Nitrosamine impurities in medications: Guidance

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Organization: Health Canada

Date published: 2022-04-04

Date updated:2023-04-17

Evaluating and managing the risks of N-nitrosamine impurities in human pharmaceutical, biological and radiopharmaceutical products

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).

A questions-and-answers (Q&A) document on nitrosamines was issued to MAHs on November 26, 2019. This document has undergone a number of revisions and has been further updated as a guidance and to provide additional details to active pharmaceutical ingredient (API) manufacturers, drug product manufacturers, MAHs and importers of APIs and drug products.

In this guidance, changes from the previous version are identified with the descriptors "new" or "updated" (as applicable). Information on a similar theme is grouped together under general headings (for example, General, Safety and Quality).

Queries about the Health Canada letters noted below can be directed as follows:

If you have queries about this guidance, you may send an email to [email protected].

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:

Also considered to be within the scope of Health Canada's call for review are:

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.

All human plasma proteins, vaccines and cell-based fermentation products are classified as biologics. They are, therefore, within the scope of the request for risk assessment.

Please refer to Health Canada's letter dated December 15, 2020, for further details.

All non-prescription products with a DIN, such as topical antiseptic products, grooming and personal hygiene products and sunscreens, are within the scope of products for assessment if they contain a chemically synthesized or semi-synthetic API. This is irrespective of the route of administration or any cosmetic properties.

Products that are not within the scope of the October 2, 2019, and December 15, 2020, letters include cosmetics (which do not have a DIN). The following categories of drug products are also excluded at this time: antimicrobial agents, veterinary products (including veterinary health products) and natural health products. Disinfectant products for use on hard surfaces are also not within the scope of products for assessment at this time.

For drug products containing chemically synthesized and semi-synthetic APIs, the steps for actions relating to nitrosamines are expected to be completed as follows:

For biological and radiopharmaceutical products, the steps for actions relating to nitrosamines are expected to be completed as follows:

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.

Canadian importers that received terms and conditions (T&C) on their drug establishment licence (DEL) for nitrosamine testing of angiotensin II receptor blockers (known as sartans) may provide supporting information to modify or remove the terms and conditions. They should submit the API and drug product risk assessments and testing results completed as per Steps 1 and 2 for consideration. Email to [email protected].

MAHs may be requested by Canadian importers for a copy of the MAH's risk assessment and testing results to facilitate this request. Alternatively, MAHs may provide the requested risk assessment and related information to Health Canada on behalf of the Canadian importer. In this case, the MAH should specify on whose behalf the risk assessment and related information is being submitted.

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:

Health Canada's list of affected medications should be consulted for drug products known to contain nitrosamine impurities. Peer-reviewed literature (for example, M.K. Parr, J.F. Joseph, Journal of Pharmaceutical and Biomedical Analysis 164 (2019) 536–549) and other sources of information (for example, regulatory communications) should also be consulted for APIs and drug products known to contain nitrosamine impurities.

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:

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.

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.

To complete risk assessments for the potential presence of nitrosamine impurities, MAHs should complete robust risk evaluations using a holistic approach. A detailed assessment of all stages of the product's life cycle should be done and would include an evaluation of the risk factors and potential root causes for the presence of nitrosamines, including those identified in number 29.

MAHs are responsible for ensuring that personnel with acceptable qualifications and expertise (for example, relevant training, knowledge and practical experience) have conducted the risk assessments. Information should be made available to the MAH by API, excipient and drug product manufacturers.

In the context of control for nitrosamine impurities, manufacturers and importers must comply with any terms and conditions specified on their DEL. This could include restrictions or additional specific testing and investigational requirements for nitrosamine impurities.

Given the potential risks associated with nitrosamines in drug products, MAHs should take all necessary measures to complete the 3 steps as soon as possible and within the designated timelines.

In a follow-up letter issued to MAHs of drug products containing chemically synthesized active pharmaceutical ingredients on April 14, 2021, Health Canada requested that affected MAHs indicate their status for completing Step 1, risk assessments. MAHs should provide a completed Annex 1, Annex 2 or Annex 3, as applicable, as per the instructions in the April 14, 2021, follow-up letter. If risk assessments have not been completed for all marketed, approved and dormant products or have been partially completed, Annex 3 should be completed.

MAHs unable to meet the Step 2 or 3 deadlines due to exceptional circumstances may submit a request for extension to Health Canada. This should be done as soon as possible. The request should contain relevant information, including the progress to date, the reasons for not meeting the deadline(s), the remaining work and the expected timelines for completion.

To prioritize APIs and drug products for the completion of risk assessments, confirmatory testing or changes to the market authorization, MAHs are reminded to use quality risk management principles. Consult ICH's Q9 guideline, Health Canada's good manufacturing practices (GMP) guides 0001 (for drug products) and 0104 (for APIs). Also consult the information in number 4.

Requests for extensions will be considered on a case-by-case basis. Direct such requests as follows:

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.

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).

MAHs are responsible for ensuring that risk assessments and, if applicable, confirmatory testing are relevant to the drug product authorized for sale in Canada.

If a risk assessment and confirmatory testing have been completed for a drug product approved for use outside Canada, it may be possible to use that information for the risk assessment and confirmatory testing of the drug product authorized for sale in Canada. In this scenario, the 2 drug products must be identical (for example, composition, strength, manufacturing process, API and excipient sources, manufacturing sites).

MAHs should prepare a written justification when the risk assessment and confirmatory testing results of a foreign product will be relied upon. MAHs should be prepared to provide this justification to Health Canada upon request. This justification should be included in communications to Health Canada if nitrosamine impurities are detected at any level in the API, drug product or both following confirmatory testing. Refer to the information in number 15.

Companies may need to conduct nitrosamine risk assessments for drug products not authorized for sale in Canada that are being made available in Canada through SAP. Refer to the approaches described in Health Canada's October 2, 2019, and December 15, 2020, letters and in this document.

If the nitrosamine risk assessment or confirmatory testing results (if applicable) indicate the risk of presence of a nitrosamine impurity, notify SAP by email at [email protected].

To protect the health and safety of patients accessing unauthorized drug products, significant new information on the safety, efficacy and quality of drug products released under SAP should be made available to practitioners and SAP.

MAHs are expected to conduct a thorough, robust risk assessment. In Health Canada's letters dated October 2, 2019, and December 15, 2020, Health Canada shared some potential sources of nitrosamine impurities. Refer to number 29 for more information on risk factors and potential root causes for nitrosamine impurities.

MAHs should prepare a report that includes considerations, steps, conclusions and a rationale. The report should clearly identify which nitrosamine(s) is (are) at risk of formation, if applicable. If it is concluded that a risk for the presence of nitrosamines is not identified, then confirmatory testing is not expected.

If a risk of formation or presence of nitrosamines is identified, confirmatory testing should be carried out using appropriately validated and sensitive methods. Following the completion of confirmatory testing, if 1 or more nitrosamine impurities are detected at any level in an API or drug product, Health Canada must be informed immediately. The reporting addresses are provided in number 15.

For Step 3 (changes to the market authorization), changes should be submitted in a timely manner in eCTD or non-eCTD format using the Common Electronic Submission Gateway (CESG).

For information on change classification, reporting and supporting data recommendations, consult the following documents:

These changes are the result of potential safety concerns and therefore require Health Canada's critical review of scientific data and subsequent authorization prior to implementation by the manufacturer. Therefore, changes for drug products containing chemically synthesized and semi-synthetic APIs should be submitted as Level I - Supplements or Post-Drug Identification Number (DIN) Change submissions, as applicable. For biological and radiopharmaceutical products, changes should be submitted as Level I – Supplements or Level II - Notifiable Changes, or Post-Drug Identification Number (DIN) Change submissions (PDCs), as applicable.

When filing a Supplement, Notifiable Change or Post-DIN Change submission for the market authorization, applicants should clearly indicate in the covering letter that the changes are for issues associated with nitrosamines.

The ongoing marketing of a drug product depends on the impurity levels and the risk of nitrosamine impurities that are detected upon notification to the Regulatory Operations and Enforcement Branch (ROEB). Some of the outcomes of the ROEB assessment may include recalls or stop sale requests until the risks are mitigated and suitable corrective and preventive actions are in place to ensure that all lots being released to market meet the acceptance criteria for each nitrosamine impurity (and multiple nitrosamines, if relevant). Both outcomes would affect the ongoing marketing of the drug product while the Supplement, Notifiable Change, or Post-DIN Change submission is being reviewed. Refer to the information in number 13.

MAHs must inform Health Canada immediately if nitrosamine impurities are detected at any level in the API, drug product or both following the completion of confirmatory testing. MAHs must provide a copy of the risk assessment and confirmatory testing results.

Communications should be directed as follows:

Health Products Compliance Unit East 1001 Rue St-Laurent Ouest, Longueuil, QC, J4K 1C7 Phone: 450-646-1353 Toll free: 1-800-561-3350 Email: [email protected]

Health Products Compliance Unit Central 2301 Midland Ave., Toronto, ON M1P 4R7 Phone: 416-973-1600 Toll free: 1-800-267-9675 Email: [email protected]

Health Products Compliance Unit West Suite 400–4595 Canada Way, Burnaby, BC V5G 1J9 Phone: 604-666-3350 Toll free: 1-800-267-9675 Email: [email protected]

If nitrosamines are not detected during confirmatory testing (for example, less than the appropriate limit of detection of the validated test method), MAHs do not need to communicate to Health Canada. However, they should keep the risk assessment, analytical testing results and analytical method validation documentation on hand in case Health Canada requests them.

MAHs are responsible for ensuring the ongoing safety, efficacy and quality of products on the Canadian market. When manufacturers do not provide information that is essential for MAHs to complete the risk assessment due to confidentiality or other reasons, MAHs may engage a third party (such as a consultant) to work directly with the manufacturer to complete the risk assessment.

The third-party approach may also be appropriate when the MAH:

For additional guidance on outsourced activities, consult the:

Alternatively, MAHs should consider delegating the risk assessment to the API and drug product manufacturers. In this scenario, MAHs would continue to be responsible for ensuring the safety, efficacy and quality of their drug products.

MAHs should ensure through internal or third-party audit that:

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 provide:

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 the ICH 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.

On April 14, 2021, Health Canada issued a follow-up letter to the October 2, 2019, letter. In the letter, we asked MAHs with drug products containing chemically synthesized and semi-synthetic APIs to provide their progress towards completing Step 1 (risk assessments).

Health Canada may also:

We appreciate the significance of this request. We will continue to engage with stakeholders to consider all options to address the potential risks associated with nitrosamines.

Whenever possible for APIs and drug products that are under development, the formation or introduction of nitrosamine impurities should be avoided at the outset.

If the formation or introduction of nitrosamine impurities is unavoidable, manufacturing processes should demonstrate process capability to routinely reduce the levels of nitrosamine impurities below the AI limit. A control strategy, based on product and process understanding, should be established for each nitrosamine impurity present in the API and/or drug product.

For drug products that are planned for submission or have already been submitted, MAHs and applicants should proactively undertake a risk assessment for the potential presence of nitrosamine impurities in the drug product (if this has not already been undertaken) using the considerations and steps provided for marketed products in Health Canada's communications. For planned submissions, the relevant sections of the Common Technical Document (CTD) in the drug application should include information on these risk assessments.

A summary and discussion of the risk assessment for nitrosamine impurities in the drug product should be placed in section 3.2.P.2 of the CTD. This summary is expected to include sufficient detail to allow Health Canada to assess the adequacy and robustness of the risk assessment. Expectations for the content of the summary and discussion of risk assessments are found under number 20.

Confirmatory testing results and updated control strategy (where warranted) should also be included in the drug application (for example, under sections 3.2.S.2, 3.2.S.4, 3.2.S.7, 3.2.P.3, 3.2.P.4, 3.2.P.5, 3.2.P.8).

For submitted applications currently under review, MAHs and applicants may be asked to provide the risk assessment and confirmatory testing results as part of the assessment procedure. For further information, refer to number 20.

Risk assessments for nitrosamine impurities should be conducted routinely during API and drug product development. The outcome of the risk assessment for nitrosamine impurities in the drug product and the justification for the proposed control strategy for nitrosamine impurities should be made available for assessment in New Drug Submissions (NDSs), Abbreviated New Drug Submissions (ANDSs), applications for a Drug Identification Number for a Pharmaceutical Product (DINAs) (with Chemistry & Manufacturing (C&M) data), applications for a Drug Identification Number for a Biological Product (DINBs), Supplements, Notifiable Changes and Post-DIN Changes submissions (refer to number 13). For more information on mutagenic impurity considerations and quality risk management principles, consult the following:

All NDSs, ANDSs, DINAs (with C&M data), and DINBs and all Supplements, Notifiable Changes and Post-DIN Change submissions (for quality changes that may impact the potential presence of nitrosamine impurities in the API or drug product) should include a summary and discussion of the risk assessment for the potential formation/presence of nitrosamine impurities in the drug product. This is required as follows:

The summary and discussion of the risk assessment for the drug product is expected to include sufficient detail to allow Health Canada to assess the adequacy and robustness of the risk assessment. It should include a discussion of the risk factors and potential root causes considered in relation to specific knowledge of the drug product and its components (including the API). Checklists lacking sufficient discussion and detail should be avoided. The summary and discussion should include the following:

For Supplements, Notifiable Changes and Post-DIN Change submissions (for quality changes that may impact the potential presence of nitrosamine impurities in the API or drug product), the summary and discussion of the risk assessment should address the impact of the proposed change(s) on nitrosamine impurities relative to the approved drug product.

For Clinical Trial Applications (CTAs) (as described in section 9.1 of ICH's M7 guideline):

Failure to include this information could result in requests for additional information, delays in the review process, and potentially the issuance of negative decisions.

The Policy on Manufacturing and Compounding Drug Products in Canada (POL-0051) provides a policy framework to help distinguish between compounding and manufacturing activities of drug products in Canada. In Canada, the compounding of drugs is done mainly by pharmacists as an integral part of their profession. It's regulated by the respective regulatory authorities in each province/territory.

This policy indicates that compounded products should be either:

Health Canada recommends, therefore, that principles outlined in the October 2, 2019, letter and in this guidance should be considered when purchasing APIs and producing compounded products.

Health care professionals and compounding firms are encouraged to access the nitrosamines webpage to stay informed on affected medications and recalls due to the presence of nitrosamines. This page is updated regularly and also includes general information on nitrosamine impurities, what Health Canada is doing to address the issue and our testing results.

Health Canada is committed to sharing information with stakeholders and maintaining transparency as we continue to analyze and better understand this evolving, global situation.

To date, we have shared information openly with stakeholders, including information on the potential sources of nitrosamine impurities, root causes, risk factors and new findings. We hosted stakeholder sessions in January 2020, February 2021 and October 2021, and may host more sessions in the future if necessary.

We also established a dedicated webpage on nitrosamine impurities in medications. The webpage includes the following:

Discussions are ongoing to determine the most appropriate and effective methods to continue to engage stakeholders as new information becomes available to ensure a coordinated and consistent approach in dealing with this complex issue.

Health Canada regularly collaborates with international regulatory partners, including those in Europe, the United States, Japan, Switzerland, Singapore, Australia and Brazil, as well as the World Health Organization. Through collaboration, we hope to increase the understanding of the issues associated with nitrosamine impurities, align requirements and actions as appropriate, and share information under the terms of our confidentiality agreements.

Discussions amongst the consortium of regulatory authorities continued, with the "Nitrosamines International Strategic Group" (NISG), which was formed in 2018. The NISG began meeting regularly with a focus on knowledge sharing on market and other regulatory actions. Due to a mutual interest of the participating regulatory agencies of the NISG to have greater in-depth discussions on technical issues and scientific developments, a sub-group of the same regulators, the "Nitrosamines International Technical Working Group" (NITWG), was established in late 2020.

The collaboration of the quality technical experts of these international regulatory partners of the NITWG has led to the development and publication of the paper "Regulatory Experiences with Root Causes and Risk Factors for Nitrosamine Impurities in Pharmaceuticals" (Horne et al. J. Pharm. Sci. 2023, DOI: https://doi.org/10.1016/j.xphs.2022.12.022). This manuscript is designed to share current information and experiences from a quality perspective on root causes, risk factors, and risk mitigation measures relating to nitrosamine impurities in pharmaceuticals for human use.

When determining appropriate regulatory measures to address the presence of nitrosamine impurities that exceed the AI limit in human drug products, individual jurisdictions must determine timelines and actions that will best protect patient safety and work within the relevant regulatory framework.

AI limits have been derived for 26 nitrosamines (Table 2). These AI limits are considered appropriate for all routes of administration.

Table 2 Footnotes

Limit to be applied to maximum daily dose (MDD) of the drug product

Return to table 2 footnote * referrer

For NDMA and NDEA, sufficient carcinogenicity data were available to 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 in the Carcinogenic Potency Database.

Insufficient carcinogenicity data were available to derive compound-specific limits for certain nitrosamines (for example, NMBA, NDIPA, NEIPA, NDBA and MNP). For this reason, a structure-activity relationship (SAR) assessment was performed to determine if sufficient carcinogenicity data were available for a structurally similar compound or, if not available, determine if the nitrosamine is anticipated to be chemically more or less potent than NDMA or NDEA.

For a nitrosamine impurity not included in the table, MAHs and applicants should refer to the ICH M7 guideline for recommendations on how to derive an AI limit. In cases where there is insufficient carcinogenicity data available for a nitrosamine impurity, MAHs and applicants may:

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 an analogue is selected for read-across.

MAHs and applicants should also refer to the following items for more information:

If a nitrosamine impurity is identified in a pharmaceutical, biological or radiopharmaceutical product that is intended for advanced cancer indications (defined in the scope of the ICH S9 guideline), the impurity can be controlled per the recommendations in the ICH S9 questions-and-answers document.

If a nitrosamine impurity is identified in a drug product where the API is genotoxic at therapeutic concentrations, the impurity can be controlled at limits for non-mutagenic impurities. Refer to the ICH Q3A and Q3B guidelines.

Health Canada continues to work with international regulatory agencies to determine AI limits for nitrosamine impurities. We will communicate any changes to the AI limits for nitrosamine impurities to MAHs and applicants in a timely manner.

Interim AI limits were originally communicated to MAHs for 5 nitrosamine impurities in angiotensin II receptor blockers (also known as "sartans"). These were in place until September 30, 2020, and will not be reduced to a lower level.

If an API or drug product has the risk of containing more than 1 actual or potential nitrosamine impurity, total (cumulative) daily exposure should be limited to the nitrosamine with the most conservative AI limit at the maximum daily dose of the drug product.

Examples:

If an applicant or MAH proposes to control multiple nitrosamine impurities in an API or drug product using an alternative methodology, Health Canada will assess the acceptability of the approach on a case-by-case basis. Any proposed alternative methodology should ensure that excess cancer risk does not exceed 1 in 100,000.

Considering the risk profiles of nitrosamines and the possibility of an additive biological effect, the limits outlined in Table 2 are considered appropriate for lifetime and LTL administration of a drug product.

If a nitrosamine impurity cannot be controlled at the AI limit, Health Canada may consider an interim limit higher than the AI limit. We will do so on a case-by-case basis and only in exceptional circumstances (for example, to avoid a drug shortage of a drug product that is considered medically necessary or medically important).

Where an applicant or MAH proposes an interim limit higher than the AI limit for a nitrosamine impurity, Health Canada will consider:

We will consider an interim limit higher than the AI limit for a nitrosamine impurity as a transitory measure only, until appropriate changes to reduce the level of the nitrosamine impurity to at or below the AI limit have been implemented.

Knowledge of risk factors and potential root causes for nitrosamine impurities continues to evolve. Applicants and MAHs should stay up-to-date on risk factors and potential root causes that Health Canada and other regulators have identified in their guidances and peer-reviewed publications (for example, see Horne et al. J. Pharm. Sci. 2023, DOI:https://doi.org/10.1016/j.xphs.2022.12.022).The formation or introduction of nitrosamines may occur during the API or drug product manufacturing process. It may also occur through degradation mechanisms over the retest period of the API and the shelf-life of the drug product.

Inadequate process design and/or process controls, as well as gaps in quality and compliance oversight, may contribute to the presence of nitrosamine impurities in APIs and drug products above AI limits. Applicants and MAHs should consider both intrinsic and extrinsic factors when conducting risk assessments for nitrosamine impurities.

Potential and confirmed root causes and risk factors for the presence of nitrosamines in drug products include the following:

All components of the drug product should be considered as potential sources of nitrosamine impurities, or their precursor nitrosating agents and amines, in the context of the designated process and storage conditions. For example, some excipients may contain residual levels of nitrite (see Wu, Y. et al. AAPS PharmSciTech 2011, 12(4), 1246-1263 and Boetzel et al. J. Pharm. Sci. 2022, DOI:https://doi.org/10.1016/j.xphs.2022.04.016) or reactive amines as part of their molecular structure. Under certain manufacturing process or storage conditions, this may lead to the formation of nitrosamine impurities.

Refer to number 29 for more information on risk factors and potential root causes to take into consideration.

Each API and drug product manufacturing process is unique. Thus, the nitrosamines listed in Table 2 of this guidance (refer to number 24) are not exhaustive and do not represent all nitrosamines potentially present in APIs and drug products. Conversely, the nitrosamines listed in Table 2 may not be potential impurities in all APIs and drug products.

MAHs and applicants should ensure that the risk assessments consider and identify the possibility of any nitrosamine impurity that may be formed or introduced. All nitrosamines that have been determined to be potentially formed or introduced should be included within the program for confirmatory testing (Step 2).

For nitrosamines not included Table 2, MAHs and applicants should follow the principles outlined in the ICH M7 guideline on mutagenic impurities to establish an AI limit. Refer to number 24 for more information.

Several regulators, including Health Canada, Europe's network of Official Medicines Control Laboratories (OMCLs) and the U.S. Food and Drug Administration (FDA), have published and shared testing methodologies. These methods may be used, although there is no requirement to do so.

In all cases, companies should use appropriately sensitive, validated analytical methods and conduct the testing at a GMP-compliant facility. If other methodologies are used, there is no need to verify the method with Health Canada prior to use.

Analytical methods should be quantitative in nature (as opposed to limit-based tests) and should be fully validated before confirmatory testing begins. If limit-based tests are used, ensure that the appropriate scientific justification is provided in the risk assessment documentation. For example:

Unless otherwise justified, method validation should be performed using the drug product that is authorized for use in Canada.

Where multiple strengths of a drug product exist and the validation is to cover multiple strengths, the justification for the choice of product strength used for validation should be described in the validation protocol.

The LOQ for analytical procedures that are intended for quantitation of nitrosamine impurities should be equal to or less than the most conservative AI limit of the nitrosamines detected in an API or drug product. Analytical procedures may need to be validated with LOQs well below the most conservative AI limit of the nitrosamines present, if proposals for a reduced testing program or absence of testing of the drug product are anticipated.

The API specification should include a test and acceptance criterion for each nitrosamine impurity when:

Examples where the risk for nitrosamines is considered high:

Where multiple nitrosamines are potential and/or detected in an API, a cumulative limit using the most conservative AI limit of the nitrosamines present should also be included in the specification.

Routine testing for nitrosamine impurities should be included in the drug product specification when:

Where such a risk is identified, a test and acceptance criteria for both release and shelf life specifications should be included. Where multiple nitrosamines are potential and/or detected, control for total nitrosamines using the most conservative AI limit of the nitrosamines potential and/or detected 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.

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.

Control options for nitrosamine impurities include:

Proposals for an ICH M7 option 4 control strategy for nitrosamine impurities in a new market authorization application will be evaluated on a case-by-case basis. An option 4 control strategy proposal may not be appropriate when the concentration of any nitrosamine impurity in an API is greater than 30% of the AI limit. However, such a strategy may be acceptable when process understanding has been demonstrated by fate-purge studies, identification of process parameters that impact nitrosamine impurity levels and when supported by appropriate analytical data. Predicted purge factor calculations should be supported by appropriate analytical data.

This information should be provided along with copies of analytical procedures and method validation reports in the new market authorization application.

Refer also to number 34 for information on routine testing for nitrosamine impurities in the API and/or drug product specification.

During confirmatory testing, MAHs should test the drug product to determine the levels of nitrosamine impurities.

Testing the API is also recommended if the risk assessment indicated that the API is a potential source of nitrosamine impurities in the drug product. The API testing results may be used to support root cause investigations and the development of a justified control strategy for nitrosamine impurities in the API.

The analytical lab used for nitrosamine confirmatory testing (Step 2) does not have to be listed on the DEL at this time. However, in all cases, the confirmatory testing must be conducted at a GMP-compliant facility. A foreign analytical lab, if used for conducting the nitrosamine confirmatory testing, must either:

Ethical drugs are those that do not require a prescription, but are generally prescribed by a medical practitioner as professional use products (for example, hemodialysis solutions, nitroglycerine). For testing ethical and over-the-counter drugs, if no inspection reports by regulatory/qualified authorities are available, a corporate or consultant audit report to demonstrate GMP compliance is acceptable.

For more information about acceptable GMP evidence and regulatory requirements, refer to the following guidance:

However, analytical labs must be listed on the applicable annex of the DEL if they are conducting:

For guidance on Health Canada's expectations for testing facilities or for other related questions, please send an email to [email protected].

For marketed products, the number of batches to be tested should be commensurate with the risk. Examples of high risk include:

MAHs and manufacturers should test a representative number of batches of the drug product as appropriate based on the risk assessment (for example, batches that are representative of sources of components, manufacturing processes/sites, manufacturing dates).

If the root cause for the nitrosamine presence has been identified and scientifically demonstrated, and impurity levels are expected to be consistent from batch-to-batch (for example, as demonstrated by spike-purge studies), testing should be conducted on 10% of annual batches, or 3 per year, whichever is highest. Testing should include both newly produced batches as well as retained samples of batches still within the expiry date. If fewer than 3 batches are manufactured annually, then all batches within the expiry date should be tested.

Testing plans or protocols (for example, a protocol for the number and type of batches to be tested) do not need to be submitted to Health Canada for assessment and approval before initiating confirmatory testing.

If nitrosamine impurities are detected at significant levels (approaching, at or above AI limits), additional batches of the drug product on the Canadian market and within the expiry date should undergo confirmatory testing. In such cases, MAHs may be requested to test all lots on the Canadian market that are within the expiry date.

For NDSs, ANDSs, DINAs (with C&M data), DINBs, Supplements Notifiable Changes and Post-DIN Change (PDC) submissions(for quality changes that may impact the potential presence of nitrosamines in the drug substance or drug product, refer to number 13), at least 6 pilot or 3 commercial-scale batches should undergo confirmatory testing where a risk of nitrosamines has been identified. A higher number of batch results should be submitted for assessment where the risk of nitrosamine presence is high. Examples include:

Testing of stability batches for a nitrosamine impurity should be conducted where:

Where applicable, testing for the nitrosamine impurity for a minimum of 6 months of accelerated and long-term stability data in the proposed container closure system(s) should be provided in the drug application.

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