www.canada.ca Open in urlscan Pro
2600:141b:5000:5ac::fe9  Public Scan

Form analysis
1 forms found in the DOM

Name: cse-search-box — GET /en/sr/srb.html

<form action="/en/sr/srb.html" method="get" name="cse-search-box" role="search">
  <div class="form-group wb-srch-qry">
    <label for="wb-srch-q" class="wb-inv">Search Canada.ca</label>
    <input id="wb-srch-q" list="wb-srch-q-ac" class="wb-srch-q form-control" name="q" type="search" value="" size="34" maxlength="170" placeholder="Search Canada.ca">
    <datalist id="wb-srch-q-ac">
    </datalist>
  </div>
  <div class="form-group submit">
    <button type="submit" id="wb-srch-sub" class="btn btn-primary btn-small" name="wb-srch-sub"><span class="glyphicon-search glyphicon"></span><span class="wb-inv">Search</span></button>
  </div>
</form>

Text Content

 * Skip to main content
 * Skip to "About government"
 * Switch to basic HTML version


LANGUAGE SELECTION

 * Français fr

/ Gouvernement du Canada


SEARCH

Search Canada.ca
Search

--------------------------------------------------------------------------------


MENU

Main Menu
 * Jobs and the workplace
   * Jobs: home
   * 
   * Find a job
   * Training
   * Hiring and managing employees
   * Starting a business
   * Workplace standards
   * Pensions and retirement
   * Employment Insurance benefits and leave
   * 
   * Most requested
     * View your records of employment
     * Submit a record of employment - employers
     * Apply for a Social Insurance Number (SIN)
     * Hire a temporary foreign worker
     * Immigrate as a skilled worker
 * Immigration and citizenship
   * Immigration and citizenship: home
   * 
   * My application
   * Visit
   * Immigrate
   * Work
   * Study
   * Citizenship
   * New immigrants
   * Canadians
   * Refugees and asylum
   * Enforcement and violations
   * 
   * Most requested
     * Sign in to your IRCC account
     * Check your application status
     * Check application processing times
     * Find an application form
     * Pay your fees
     * Find out if you need an eTA or a visa to visit Canada
     * Have questions? Find answers in the Help Centre
 * Travel and tourism
   * Travel and tourism: home
   * 
   * Travel advice and advisories
   * COVID-19: Travel, testing and borders
   * Visit Canada
   * Travel outside Canada
   * Air travel
   * Return to Canada
   * Canadian passports and travel documents
   * Canadian attractions, events and experiences
   * Assistance outside Canada
   * Stay connected
   * 
   * Most requested
     * Emergency assistance abroad
     * Find out if you need a visa to travel to Canada
     * Apply for an eTA
     * Apply for NEXUS
     * Register as a Canadian abroad
     * Travel insurance
 * Business and industry
   * Business and industry: home
   * 
   * Starting a business
   * Business grants and financing
   * Business taxes
   * Federal corporations
   * Hiring and managing employees
   * International trade and investment
   * Permits, licences and regulations
   * Doing business with government
   * R&D and innovation
   * Research and business intelligence
   * Intellectual property and copyright
   * Maintaining your business
   * Protecting your business
   * Insolvency for business
   * 
   * Most requested
     * Find a corporation
     * Report your imported goods
     * Search for trademarks
     * Review custom tariffs for importing goods
     * Find a patent
     * Import and export from Canada
     * Name a business
     * Make changes to your corporation (Online Filing Centre)
 * Benefits
   * Benefits: home
   * 
   * Employment Insurance benefits and leave
   * Dental coverage
   * Family and caregiving benefits
   * Public pensions
   * Grants and funding opportunities
   * Student aid and education planning
   * Housing benefits
   * Disability benefits
   * Benefits by audience
   * Benefits payment dates
   * Benefits finder
   * Notify the government of a death
   * 
   * Most requested
     * Apply for Employment Insurance
     * Apply for student loans and grants
     * Sign in to a Government of Canada online account
     * Set up or change direct deposit
     * Submit your EI report
     * Child and family benefits calculators
 * Health
   * Health: home
   * 
   * Food and nutrition
   * Diseases and conditions
   * Vaccines and immunization
   * Drug and health products
   * Product safety
   * Health risks and safety
   * Healthy living
   * Indigenous health
   * Health system and services
   * Science, research and data
   * 
   * Most requested
     * Canada's food guide
     * Recalls and safety alerts
     * Mental health support: Get help
     * Measles
 * Taxes
   * Taxes: home
   * 
   * Income tax
   * GST/HST
   * Payroll
   * Business number
   * Savings and pension plans
   * Tax credits and benefits for individuals
   * Excise taxes, duties, and levies
   * Charities and giving
   * 
   * Most requested
     * My Account
     * My Business Account
     * Represent a Client
     * File a GST/HST return (NETFILE)
     * Make a payment to the Canada Revenue Agency
     * Find the next benefit payment date
 * Environment and natural resources
   * Environment and natural resources: home
   * 
   * Weather, climate and hazards
   * Energy
   * Natural resources
   * Agriculture
   * Fisheries
   * Wildlife, plants and species
   * Pollution and waste management
   * Environmental conservation and protection
   * 
   * Most requested
     * Local weather forecast
     * Fuel-efficient vehicles
     * Home energy efficiency
     * Species at risk
     * Prepare for severe weather
 * National security and defence
   * National security and defenceDefence: home
   * 
   * National security
   * Canadian Armed Forces
   * Defence equipment purchases and upgrades
   * Transportation security
   * Securing the border
   * Cyber security
   * Jobs in national security and defence
   * Services and benefits for the military
   * 
   * Most requested
     * Jobs in the Canadian Armed Forces
     * Military ranks
     * Defence equipment
     * Current list of terrorist entities
     * Join the Cadet Program
     * Canada's Defence policy
 * Culture, history and sport
   * Culture, history and sport: home
   * 
   * Funding - Culture, history and sport
   * Events, celebrations and commemorations
   * Cultural landmarks and attractions
   * Canadian identity and society
   * Sport
   * History and heritage
   * Arts and media
   * Cultural youth programs
   * Cultural trade and investment
   * 
   * Most requested
     * Visit the Canadian Virtual War Memorial
     * Anthems and symbols of Canada
     * Find a CRTC decision
     * Research your family history
     * Search census records
     * Landmarks and attractions in Canada's capital
 * Policing, justice and emergencies
   * Policing, justice and emergencies: home
   * 
   * Policing
   * Justice
   * Emergencies
   * Corrections
   * Parole, record suspension, expungement and clemency
   * Victims of crime
   * 
   * Most requested
     * Apply/Renew a firearms licence
     * Get a criminal records check
     * Apply for a criminal record suspension
     * What to do during an emergency
     * Know the law on impaired driving
     * Help solve a crime
 * Transport and infrastructure
   * Transport and infrastructure: home
   * 
   * Aviation
   * Marine transportation
   * Road transportation
   * Rail transportation
   * Dangerous goods
   * Infrastructure
   * 
   * Most requested
     * Zero-emission vehicles
     * Drone safety
     * What you can't bring on an airplane
     * Register your vessel
     * Child car seat safety
     * Transporting dangerous goods - Regulations
     * Canadian Aviation Regulations
 * Canada and the world
   * Canada and the world: home
   * 
   * International offices and emergency contacts
   * Study, work and travel worldwide
   * Information by countries and territories
   * Stories
   * International relations
   * Global issues and international assistance
   * Funding for international initiatives
   * International trade and investment
   * 
   * Most requested
     * Find a Canadian scholarship as an international student
     * International treaties signed by Canada
     * Find international study or research opportunities in Canada
     * Contact an embassy or consulate
     * Contact a foreign representative in Canada
     * Authenticate a document
 * Money and finances
   * Money and financesFinance: home
   * 
   * Managing your money
   * Debt and borrowing
   * Savings and investments
   * Education funding
   * Pensions and retirement
   * Protection from frauds and scams
   * Financial tools and calculators
   * Financial literacy programs
   * Consumer affairs
   * Insolvency
   * Taxes
   * Government finances
   * Business grants and financing
   * Financial and money services regulation
   * 
   * Most requested
     * Find a bankruptcy or insolvency record
     * Student loans
     * Set up or change direct deposit
     * Mortgages
     * Credit report and scores
     * Make a budget
     * Rates and contribution limits
 * Science and innovation
   * Science and innovation: home
   * 
   * Research funding and awards
   * Science subjects
   * Open data, statistics and archives
   * Research institutes and facilities
   * R&D and innovation
   * Intellectual property and copyright
   * Directory of scientists and research professionals
   * Science education resources
   * 
   * Most requested
     * National building codes
     * Official times across Canada
     * Check sunrise and sunset times
     * Grants for technological innovation (IRAP)
     * Federal Science Libraries Network
     * Live view of northern lights cam


YOU ARE HERE:

 1. Canada.ca
 2. Departments and agencies
 3. Health Canada
 4. Drugs and health products
 5. Compliance and enforcement: Drug and health products
 6. Information by Health Product
 7. Drugs


NITROSAMINE IMPURITIES IN MEDICATIONS: GUIDANCE

 * Overview
 * Recalls
 * Test methods and test results
 * Guidance
 * Established acceptable intake limits
 * Report a problem or concern

Download in PDF format
(1.14 MB, 61 pages)

Organization: Health Canada

Date published: 2022-04-04

Date updated: 2024-05-31

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


ON THIS PAGE

 * Background
 * General
 * Safety
 * Quality
 * Appendices
   * Appendix 1: Established Acceptable Intake (AI) limits for N-nitrosamine
     impurities
   * Appendix 2: Guidance with respect to nitrosamine impurities and risk
     assessments for Post NOC Changes of new drug products containing chemically
     synthesized and semi-synthetic APIs
   * Appendix 3: Enhanced Ames assay test conditions
   * Appendix 4: Carcinogenic Potency Categorization Approach (CPCA) for
     N-nitrosamines


BACKGROUND

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 document 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 document, 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:

 * "Information to MAHs of Human Pharmaceutical Products Regarding Nitrosamine
   Impurities: Request to evaluate the risk of the presence of nitrosamine
   impurities in human pharmaceutical products containing chemically synthesized
   active pharmaceutical ingredients" (October 2, 2019)
 * Email to bpsenquiries@hc-sc.gc.ca
 * "Information to MAHs of Human Pharmaceutical Products Regarding Nitrosamine
   Impurities: Request to evaluate the risk of the presence of nitrosamine
   impurities in biologics and radiopharmaceuticals" (December 15, 2020)
 * Email to brdd.nitrosamines.dmbr@hc-sc.gc.ca

If you have queries about this guidance document, you may send an email to
bpsenquiries@hc-sc.gc.ca.


GENERAL


SCOPE AND RESPONSIBILITIES

1. DRUG PRODUCTS THAT ARE WITHIN THE SCOPE OF HEALTH CANADA'S CALL FOR REVIEW

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.

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.

2. TIMELINES FOR COMPLETING RISK ASSESSMENTS (STEP 1), CONFIRMATORY TESTING
(STEP 2) AND CHANGES TO THE MARKET AUTHORIZATION (STEP 3)

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 August 1, 2025

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 August 1, 2025

3. OUTCOMES OF RISK ASSESSMENTS (STEP 1) AND WHAT IS PROVIDED TO HEALTH CANADA

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 of the drug product,
Health Canada must be informed if the nitrosamine impurity is detected above the
established Acceptable Intake (AI) limit (refer to Appendix 1 for a listing of
established AIs) for the nitrosamine impurity in question, or above the AI limit
established using the Carcinogenic Potency Categorization Approach (CPCA) (refer
to number 24 and Appendix 4) if an AI limit has not been established by Health
Canada. The confirmatory testing results should be submitted at the same time
that Health Canada is informed of the detection and the details of the risk
assessment should be available upon request. Refer to the information in number
15.

For nitrosamine impurities listed in Appendix 1 that are classified as
non-mutagenic, the submission of the risk assessment and confirmatory testing
results is not required, and these impurities should be controlled according to
ICH's Q3A and Q3B guidelines.

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 foreign.site-etranger@hc-sc.gc.ca.

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.

4. 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 impurities in
     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)

Appendix 1 should be consulted for APIs and drug products that may 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.

5. 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.

6. 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.

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.

7. INABILITY TO MEET SPECIFIED TIMELINES FOR RISK ASSESSMENT (STEP 1),
CONFIRMATORY TESTING (STEP 2) OR CHANGES TO THE MARKET AUTHORIZATION (STEP 3)

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:

 * for drug products containing chemically synthesized or semi-synthetic APIs:
   bpsenquiries@hc-sc.gc.ca
 * for biological and radiopharmaceutical products:
   brdd.nitrosamines.dmbr@hc-sc.gc.ca

8. 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.

9. 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).

10. APPLYING THE RESULTS OF A RISK ASSESSMENT AND CONFIRMATORY TESTING FOR A
DRUG PRODUCT MARKETED OUTSIDE CANADA TO A DRUG PRODUCT AUTHORIZED FOR SALE IN
CANADA

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 in the drug product following confirmatory
testing where the nitrosamine impurity is detected above the established AI
limit (refer to Appendix 1) for the nitrosamine impurity in question, or above
the AI limit established using the CPCA (refer to number 24 and Appendix 4) if
an AI limit has not been established by Health Canada. Refer to the information
in number 15.

11. NITROSAMINE RISK ASSESSMENT APPLICABLE TO A DRUG PRODUCT BROUGHT INTO CANADA
UNDER THE SPECIAL ACCESS PROGRAM (SAP)

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
the 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 the
SAP by email at sapd-pasm@hc-sc.gc.ca.

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 the SAP should be made available to practitioners
and the SAP.

12. CONFIRMATORY TESTING WHERE THE RISK ASSESSMENT CONCLUDES THERE IS NO
IDENTIFIED RISK FOR THE PRESENCE OF NITROSAMINES

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 (refer to number 36). Following the completion of confirmatory testing
of the drug product, Health Canada must be informed if the nitrosamine impurity
is detected above the AI limit established using the CPCA (refer to number 24
and Appendix 4) if an AI limit has not been established by Health Canada. The
reporting addresses are provided in number 15.

13. MANAGING AND SUBMITTING STEP 3 CHANGES TO THE MARKET AUTHORIZATION RELATING
TO RISK MITIGATION MEASURES

Step 3 changes to the market authorization relating to risk mitigation measures
should be submitted to Health Canada in a timely manner in eCTD or non-eCTD
format using the Common Electronic Submission Gateway (CESG).

Step 3 risk mitigation related 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, with the exception of certain minor changes (see further details
described below in this section), Step 3 risk mitigation related 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. For examples of risk mitigation related changes, refer
to number 20 and Appendix 2.

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 proposed changes are being submitted to address risk mitigation
for nitrosamines (Step 3 of Health Canada's call for review to evaluate the risk
of the presence of nitrosamine impurities in approved drug products).

A summary of the root cause investigations and the conclusion regarding the
confirmed root causes(s) for nitrosamine presence in the drug product should be
included under section 3.2.P.2.

Where a proposal is made to add individual or cumulative nitrosamine AI limits
to an approved drug substance or drug product specification (based on the use of
the CPCA or other approaches), MAHs should manage these changes as Level I –
Supplements.

For proposed changes unrelated to Step 3 of the call for review of approved drug
products (that is, changes unrelated to risk mitigation for approved drug
products), changes should be managed and, where applicable, submitted according
to the Post-Notice of Compliance (NOC) Quality Document and Post-Drug
Identification Number (DIN) Changes Guidance Document. Refer to number 20 and
Appendix 2.

For drug products containing chemically synthesized or semi-synthetic APIs,
where AI limits for individual nitrosamine impurities and, where relevant,
limits for cumulative levels of nitrosamine impurities, are already included in
an approved drug substance or drug product specification the following changes
can be managed according to Health Canada's Post-Notice of Compliance (NOC)
Quality Document as Level III changes (Annual Notifications):

 * tightening of individual or cumulative nitrosamine AI limits in the approved
   drug substance or drug product specifications
 * relaxation of individual or cumulative AI limits in the approved drug
   substance or drug product specifications to adopt AI limits listed in
   Appendix 1 of this guidance document
 * deletion of a test for a nitrosamine impurity from a drug substance or drug
   product specification, with appropriate scientific justification

In addition, the following changes can be managed according to Health Canada's
Post-Notice of Compliance (NOC) Quality Document as Level III changes (Annual
Notifications):

 * addition of a test and acceptance criteria to a drug substance specification
   for a nitrosamine impurity that is based on a valid Certificate of
   Suitability (CEP) issued by the European Directorate of Quality of Medicines
   and HealthCare (EDQM)
 * addition of a test and acceptance criteria to a drug substance or drug
   product specification for a nitrosamine impurity that has been classified as
   non-mutagenic in Appendix 1

Where a proposal is made to relax individual or cumulative nitrosamine AI limits
already included in an approved drug substance or drug product specification
(based on the use of the CPCA or other approaches) when an AI limit
is not listed in Appendix 1, MAHs should manage these changes as Level I –
Supplements.

14. SELLING A DRUG PRODUCT IF CHANGES (SPECIFICATIONS, CONTROLS) TO THE MARKET
AUTHORIZATION (STEP 3) SUBMITTED AS A SUPPLEMENT, NOTIFIABLE CHANGE OR POST-DIN
CHANGE SUBMISSION ARE STILL UNDER REVIEW

The ongoing marketing of a drug product depends on the impurity levels and the
risk of nitrosamine impurities that are detected upon notification to Health
Canada. Some of the outcomes of the Health Canada 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.

15. CONTACTING HEALTH CANADA IF NITROSAMINE IMPURITIES ARE DETECTED FOLLOWING
THE COMPLETION OF CONFIRMATORY TESTING

Following the completion of confirmatory testing of the drug product, MAHs must
inform Health Canada if nitrosamine impurities are detected above the
established AI limit (refer to Appendix 1) for the nitrosamine impurity in
question, or above the AI limit established using the CPCA (refer to number 24
and Appendix 4) if an AI limit has not been established by Health Canada. The
confirmatory testing results should accompany the notification to Health Canada
by the MAHs.

Health Canada recognizes the challenges faced by MAHs to decrease levels of
nitrosamine impurities in their drug products while maintaining drug supply to
Canadians. To minimize the impacts on drug supply within the Canadian market,
MAHs are requested to engage Health Canada prior to taking any market action for
a drug product due to a nitrosamine impurity issue.

Communications should be directed as follows:

Table 1. Addresses and contact information Location of firm Reporting address
New Brunswick, Newfoundland and Labrador, Nova Scotia, Prince Edward Island,
Québec

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: qoc-coq@hc-sc.gc.ca

Ontario

Health Products Compliance Unit Central
2301 Midland Ave., Toronto, ON M1P 4R7
Phone: 416-973-1600
Toll free: 1-800-267-9675
Email: insponoc-coon@hc-sc.gc.ca

Manitoba, Saskatchewan, Alberta, British Columbia, Yukon, Northwest Territories,
Nunavut

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: hpcw-cpso@hc-sc.gc.ca

If nitrosamines are not detected during confirmatory testing (for example, less
than the appropriate limit of detection of the validated test method) or are
detected below the established AI limit for the nitrosamine impurity in question
or the AI limit established using the CPCA (refer to number 24 and Appendix 4)
if an AI limit has not been established by Health Canada, MAHs do not need to
communicate this information 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. Refer to number 13
for information on communicating changes to market authorization to Health
Canada.

16. WHEN INFORMATION NECESSARY TO COMPLETE RISK ASSESSMENTS IS NOT PROVIDED BY
THE API OR DRUG PRODUCT MANUFACTURER

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:

 * has all of the required information to conduct the risk assessment from the
   manufacturer but
 * does not have staff with the necessary qualifications (for example, relevant
   training and practical experience) to conduct the risk assessment

For additional guidance on outsourced activities, consult the:

 * section C.02.012, interpretation 3 to 12 of the Good Manufacturing Practices
   Guide for Drug Products (GUI-0001)

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:

 * risk assessments have been conducted by personnel with acceptable
   qualifications (relevant training and practical experience)
 * manufacturers have considered all possible risk factors and potential root
   causes of nitrosamine impurities (including those in the December 15, 2020,
   letter concerning biological and radiopharmaceutical products, and those
   identified in number 29)

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
   * where product recalls are warranted, consult the Drugs and Natural Health
     Products Recall Guide (GUI-0039) for procedures
 * 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.

18. ASSESSING PROGRESS WITH THE REQUEST TO REVIEW THE RISK OF PRESENCE OF
NITROSAMINE IMPURITIES

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:

 * verify progress, adequacy and robustness of the risk assessments,
   confirmatory testing results and any other supporting documents related to
   this request during GMP inspections, proactive risk management projects and
   compliance verification upon receipt of a complaint and/or notification or
 * request information at such time as changes are made to either the existing
   market authorization for a product or for the drug establishment licence

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.

19. APPROACH FOR DRUG PRODUCTS THAT ARE PLANNED FOR SUBMISSION OR ARE ALREADY
FILED WITH HEALTH CANADA

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 approved 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.

20. RISK ASSESSMENTS FOR THE POTENTIAL PRESENCE OF NITROSAMINE IMPURITIES AS
PART OF THE EXPECTED CONTENT FOR NEW SUBMISSIONS

Risk assessments for the potential presence of 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:

 * Good Manufacturing Practices Guide for Drug Products (GUI-0001)
 * Good Manufacturing Practices Guidelines (GMP) for Active Pharmaceutical
   Ingredients (GUI-0104)
 * ICH's M7 guideline (PDF format)
 * ICH's Q9 guideline (PDF format)

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:

 * as of April 1, 2021, for NDSs, ANDSs, and Supplements for pharmaceutical
   products containing chemically synthesized and semi-synthetic APIs
 * as of April 1, 2021, for DINAs (with C&M data) including Post-DIN Change
   Submissions for quality changes for pharmaceutical products containing
   chemically synthesized and semi-synthetic APIs
 * as of November 30, 2021, for NDSs, Supplements and Notifiable Changes for
   biological and radiopharmaceutical products
 * as of November 30, 2021, for DINBs and Post-DIN Change (PDC) submissions for
   biological and radiopharmaceutical products

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:

 * identification of any third parties (for example, suppliers, manufacturers,
   consultants) who have been authorized to perform the risk assessment on
   behalf of the applicant
 * identification of intrinsic and extrinsic risk factors related to formation
   or introduction of nitrosamine impurities originating from all drug product
   components as well as quality/compliance considerations
 * identification of those nitrosamines potentially formed and/or introduced
 * information on the established process and/or analytical controls and how
   they may mitigate risk
 * supporting scientific data (for example, confirmatory testing results) and
   calculations
 * an overall conclusion on the risk of presence of nitrosamines in the drug
   product together with an appropriate scientific rationale/justification

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 need
only address the impact of the proposed change(s) on nitrosamine impurities
relative to the approved drug product. Examples of changes that may impact the
potential presence of nitrosamine impurities relative to an approved drug
product include, but are not limited to, changes in drug substance or drug
product manufacturing processes, changes to the drug product composition (API,
excipients), introduction of a new dosage form, and changes to the container
closure system.

Refer to Appendix 2 for additional guidance with respect to nitrosamine
impurities and risk assessments for Post NOC Changes of new drug products
containing chemically synthesized and semi-synthetic APIs.

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

 * For Phase 1 clinical trials of 14 days or less, include a description of
   efforts to mitigate risks of mutagenic impurities focused on Class 1 and
   Class 2 impurities and those in the cohort of concern (for example,
   nitrosamine impurities).
 * For Phase 1 clinical trials greater than 14 days and for Phase 2 and 3
   clinical trials, also include Class 3 impurities that require analytical
   controls.

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

21. CONTROLS FOR NITROSAMINES IN APIS PURCHASED FOR COMPOUNDING

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:

 * produced from an authorized API used in an authorized drug product for use in
   Canada or
 * listed in a recognized Pharmacopoeia (for example, USP/NF, Ph. Eur., Ph.
   Int., BP, Codex - Schedule B, Food and Drugs Act)

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 product recalls due to the presence of
nitrosamines. This page is updated regularly and also includes general
information on nitrosamine impurities, and what Health Canada is doing to
address the issues.


COMMUNICATIONS

22. ENGAGING STAKEHOLDERS AND ENSURING ONGOING COMMUNICATION WITH INDUSTRY

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:

 * summaries of drug products that have been affected or recalled due to the
   presence of nitrosamines
 * analytical testing results of several products for levels of nitrosamine
   impurities

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.

23. HEALTH CANADA WORKS WITH GLOBAL REGULATORS RELATING TO ISSUES ASSOCIATED
WITH NITROSAMINE IMPURITIES IN DRUG PRODUCTS

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.

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.


SAFETY

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

 1. 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).
 2. 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.
 3. 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

25. AI LIMITS FOR NITROSAMINE IMPURITIES IN DRUG PRODUCTS THAT FALL WITHIN THE
SCOPE OF ICH'S S9 GUIDELINE OR WHERE THE API IS GENOTOXIC

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 ICH's S9 guideline), the impurity can be controlled per
the recommendations in ICH's 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 ICH's Q3A and Q3B guidelines.

26. COMMUNICATING IF AI LIMITS ARE REVISED IN THE FUTURE

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.

27. ACCEPTABLE INTAKE LIMIT IF MULTIPLE NITROSAMINES ARE DETECTED IN AN API OR A
DRUG PRODUCT

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 a drug product contains both NDMA and NMBA, the total/cumulative daily
   exposure of the 2 nitrosamines should be limited to 96.0 ng/day.
 * If a drug product contains both NDMA and NDEA, the total/cumulative daily
   exposure of the 2 nitrosamines should be limited to 26.5 ng/day.

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.

For nitrosamine impurities that are considered non-mutagenic, the
recommendations provided in ICH's Q3A and Q3B guidelines apply and such
impurities do not need to be included in a limit for total nitrosamines.

28. APPLICATION OF A LESS-THAN-LIFETIME (LTL) LIMIT BY CONSIDERING THE
PRINCIPLES IN ICH'S M7 GUIDELINE IF A NITROSAMINE IMPURITY IS PRESENT IN A DRUG
PRODUCT THAT IS ADMINISTERED FOR LESS THAN A LIFETIME

Considering the risk profiles of nitrosamines and the possibility of an additive
biological effect, the AI limits outlined in Appendix 1 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:

 * the medical necessity or medical importance of the drug product
 * levels of impurity observed in representative batches
 * other risk management considerations (for example, the availability of
   alternative medications on the Canadian market)

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.

For nitrosamine impurities that are considered non-mutagenic, the
recommendations provided in ICH's Q3A and Q3B guidelines apply and such
impurities do not need to be included in a limit for total nitrosamines.


QUALITY

29. RISK FACTORS AND POTENTIAL ROOT CAUSES TO BE CONSIDERED FOR THE PRESENCE OF
NITROSAMINE IMPURITIES IN HUMAN PHARMACEUTICALS WHEN PERFORMING A RISK
ASSESSMENT

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. The collaboration
of the quality technical experts of the 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, 112, 1166-1182). This
publication 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.

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:

 * Nitrosation of a secondary or tertiary amine during API or drug product
   manufacturing, with insufficient downstream purge of the nitrosamine formed,
   and/or during API or drug product storage (common nitrosation conditions
   involve the combination of amines and nitrite ion under acidic conditions)
   * Sources of amines include APIs, API intermediates, starting materials,
     reagents, solvents, catalysts, reaction by-products and degradation
     products. Certain non-medicinal ingredients may also contain amines as part
     of their structure. Amines leading to stable nitrosamines include secondary
     amines and tertiary amines. Quaternary ammonium salts are also potential
     precursors to nitrosamines. Primary and tertiary amines may contain
     secondary amines as impurities. Amines may be present as impurities in
     amides or formed through the degradation of amides (for example, via
     hydrolysis). Tertiary amines may be nitrosated by a dealkylative pathway to
     produce one or more secondary amines, which may subsequently undergo
     nitrosation to produce multiple nitrosamines.
   * Nitrosating agent precursors and sources include:
     * nitrite ion intentionally used in a manufacturing process (for example,
       as used in diazotization chemistry or as a reducing agent for azide ion)
     * nitrite present as an impurity in reagents (for example, sodium azide),
       common non-medicinal ingredients (for example, microcrystalline
       cellulose, magnesium stearate)
     * nitrogen oxides (for example, NO, N2O3)
     * nitric acid
     * nitrosyl halides
     * alkyl nitrites and nitro compounds (for example, nitromethane)
     * potable and/or purified water containing nitrite
 * Using a nitrosamine as a starting material or synthetic intermediate, with
   incomplete conversion of the nitrosamine and/or insufficient downstream purge
 * Reaction of nitrite ion and an amine under process conditions with pH >7
   under catalysis by a carbonyl compound, with insufficient downstream purge
 * Oxidation of a hydrazine functional group in an API, starting material,
   intermediate or a reagent to produce a nitrosamine, with insufficient
   downstream purge
 * Using certain materials in container closure components, such as:
   * nitrocellulose, found in certain lidding foils used for blister packaging
   * certain types of vulcanisation accelerators (for example, dithiocarbamate,
     thiourea, thiruams) which are used in rubber manufacturing
 * Using recycled materials (for example, solvents, reagents, catalysts)
   contaminated with nitrosamines and/or nitrosamine precursors
 * Cross-contamination of materials with nitrosamines/nitrosamine precursors in
   multi-product facilities (for example, through the use of shared equipment)
 * Poor operation of a process step (for example, during liquid-liquid phase
   separations), which is intended to purge nitrosamines
 * Using certain manufacturing operations that could facilitate contact between
   nitrosamine precursors (for example, wet granulation) or introduce
   nitrosating agents/precursors (for example, nitrogen oxides during fluid bed
   drying)

30. COMPONENTS OF DRUG PRODUCTS TO CONSIDER IN RISK ASSESSMENTS

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. 2023, 112,
1615-1624) 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.

31. NITROSAMINE IMPURITIES TO CONSIDER IN THE STEP 1 RISK ASSESSMENT AND STEP 2
CONFIRMATORY TESTING

Each API and drug product manufacturing process is unique. Thus, the
nitrosamines listed in Appendix 1 of this guidance are not exhaustive and do not
represent all nitrosamines potentially present in APIs and drug products.
Conversely, the nitrosamines listed in Appendix 1 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 Appendix 1, MAHs and applicants should refer to
number 24 for guidance on how to establish an AI limit.

32. TESTING METHODOLOGIES PROVIDED BY HEALTH CANADA

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:

 * demonstration that the limit test is valid at or lower than the AI limit
 * supporting evidence that indicates there is no increase in the concentration
   of nitrosamine impurities over time

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.

33. VALIDATING THE LIMIT OF QUANTITATION (LOQ) FOR NITROSAMINE IMPURITY
ANALYTICAL PROCEDURES

The LOQ for analytical procedures that are intended for quantitation of
individual nitrosamine impurities in APIs and drug products should be equal to
or less than the established AI limit (Appendix 1), the AI limit established
using the CPCA (refer to number 24 and Appendix 4) if an AI limit has not been
established by Health Canada, or the relevant ICH Q3A or Q3B limit for a
nitrosamine impurity that has been classified as non-mutagenic in Appendix 1.

Analytical procedures should be validated with a LOQ which is less than or equal
to 10% of the acceptable limit for an individual nitrosamine, if a proposal to
not routinely test for the nitrosamine in the drug product specification is
anticipated (refer to number 34).

Analytical procedures should be validated with a LOQ which is less than or equal
to 30% of the acceptable limit for an individual nitrosamine, if a proposal for
periodic (skip) testing is anticipated.

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.

35. POTENTIAL CONTROL OPTIONS FOR NITROSAMINE IMPURITIES IN THE API

Control options for nitrosamine impurities include:

 * routine testing in the API (ICH's M7 Option 1)
 * control in upstream intermediate specifications at the AI limit (ICH M7
   option 2) (when the route cause, or causes, of nitrosamine presence have been
   established unequivocally)
 * control in upstream intermediate specifications at acceptance criteria that
   exceed the AI limit (ICH's M7 Option 3) (when the root cause, or causes, have
   been established unequivocally and justification of the proposed limit is
   supported by demonstrated process capability (for example, spike and purge
   studies))

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.

36. CONFIRMATORY TESTING EXPECTATIONS (STEP 2)

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.

If a drug product is available in multiple strengths of the same dosage form
with the same risk factors applicable to each, then testing could be
rationalized by testing only the worst-case scenario strength. The worst-case
approach should be justified by the MAH on a case-by-case basis. The
justification should be documented in the risk assessment in the MAH's
pharmaceutical quality system.

If, despite extensive efforts, it becomes apparent that a nitrosamine impurity
cannot be synthesized or isolated and purified, then this could be an indication
that the nitrosamine either does not exist, is unstable, or that there is no
risk of it being formed. In such cases, it may not be necessary to conduct
confirmatory testing. This should be justified thoroughly on a case-by-case
basis according to appropriate scientific principles. A scientific justification
including experimental data which summarizes the efforts made to synthesize
and/or isolate and purify the impurity should be included in the summary and
discussion of the risk assessment in the regulatory submission and documented in
the MAH's pharmaceutical quality system.

37. ANALYTICAL LABORATORIES CONDUCTING NITROSAMINE TESTING AND LISTING ON THE
DEL

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:

 * have been deemed GMP-compliant by Health Canada or
 * have a valid GMP inspection by a competent or qualified regulatory authority
   demonstrating compliance with current GMP standards

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:

 * How to Demonstrate Foreign Building Compliance with Drug Good Manufacturing
   Practices (GUI-0080)

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

 * nitrosamine testing used to release APIs and drug products for the Canadian
   market or
 * tests that are part of the API or drug product specification
   * includes testing imposed through the sartan terms and conditions

For guidance on Health Canada's expectations for testing facilities or for other
related questions, please send an email to foreign.site-etranger@hc-sc.gc.ca.

38. NUMBER AND TYPES OF DRUG PRODUCT BATCHES AS PART OF CONFIRMATORY TESTING FOR
MARKETED PRODUCTS AND NEW MARKET APPLICATIONS

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

 * late-stage formation/introduction of a nitrosamine impurity in a
   manufacturing process
 * presence of nitrosamine precursor functional groups in the API
 * potential for nitrosamine formation on storage

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:

 * the late-stage formation/introduction of a nitrosamine impurity
 * nitrosamine precursor functional groups in the API
 * stability concerns exist for nitrosamine formation over the retest
   period/shelf life

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

 * a risk has been identified that nitrosamine levels could increase in the API
   or drug product over time or
 * the potential for increases over time is unclear

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.


APPENDICES


APPENDIX 1: ESTABLISHED ACCEPTABLE INTAKE (AI) LIMITS FOR N-NITROSAMINE
IMPURITIES

 * See separate Appendix 1.


APPENDIX 2: GUIDANCE WITH RESPECT TO NITROSAMINE IMPURITIES AND RISK ASSESSMENTS
FOR POST NOC CHANGES OF NEW DRUG PRODUCTS CONTAINING CHEMICALLY SYNTHESIZED AND
SEMI-SYNTHETIC APIS

*For example, changes to drug substance or drug product manufacturing processes,
changes to the drug product composition (API, excipients), changes to a dosage
form, changes to the container closure system.

Appendix 2 - Text description

Appendix 2 contains a decision tree providing advice to Market Authorization
Holders about regulatory filing requirements related to nitrosamines. This
Appendix also describes some changes which may impact the possibility of
nitrosamine formation when a product has a change made.


APPENDIX 3: ENHANCED AMES ASSAY TEST CONDITIONS

The Organisation for Economic Co-operation and Development (OECD)'s Test
Guideline No. 471 "Bacterial Reverse Mutation Test" provides standard
recommendations for the conduct of the bacterial reverse mutation test (also
known as the Ames assay) to assess the mutagenic potential of a test compound.
For N-nitrosamines, enhanced testing conditions for the Ames assay are
recommended due to the reported reduced sensitivity of the assay under standard
conditions for some N-nitrosamines such as N-nitroso-dimethylamine (NDMA).
Moreover, very little is known about the sensitivity of the Ames assay to
N-nitrosamine drug substance related impurities (NDSRIs), which are a recently
recognized class of N-nitrosamine impurities structurally related to the drug
substance. NDSRIs generally have a wider variety of functional groups present
than typically found in low molecular weight N-nitrosamines (such as NDMA)
historically studied.

If a standard Ames assay is conducted and produces a positive result, there is
no need to conduct an additional assay using enhanced testing conditions.

The enhanced Ames assay test conditions presented below are informed by work
conducted by FDA's National Center for Toxicological Research (NCTR) (Li et.
al., 2023), as well as other groups, and have been evaluated for a variety of
N-nitrosamines including NDSRIs. Evaluation of Ames assay test conditions for
N-nitrosamines is ongoing with a goal to identify the most robust Ames testing
conditions. The enhanced Ames assay test conditions described below will be
updated as warranted. Deviations from the recommended conditions should be
justified.

Tester strains:S. typhimurium TA98, TA100, TA1535, TA1537, and E. coli WP2 uvrA
(pKM101) tester strains should be included.

Type of assay and preincubation time: The pre-incubation, and not plate
incorporation, method should be used. The recommended pre-incubation time is 30
minutes.

Species and concentration of S9: Ames assays should be conducted in the absence
of a post-mitochondrial fraction (S9), and also in the presence of 30% rat liver
S9, as well as 30% hamster liver S9. The rat and hamster post-mitochondrial
fractions (S9s) should be prepared from rodents treated with inducers of
cytochrome P450 enzymes (for example, a combination of phenobarbital and
β-naphthoflavone).

Negative (solvent/vehicle) control: Solvents need to be compatible with the Ames
assay as per the OECD 471 guideline. Solvents can include, but are not limited
to:

 * water
 * organic solvents such as acetone, methanol and DMSO

> When an organic solvent is used, the lowest possible volume should be included
> in the pre-incubation mixture with justification to indicate that the volume
> of solvent does not interfere with metabolic activation of the N-nitrosamine.

Positive controls: Concurrent strain-specific positive controls should be
included per the OECD 471 guideline.

Two N-nitrosamines that are known to be mutagenic in the presence of S9 should
also be included as positive controls.

The choice of the N-nitrosamine positive controls needs to be justified based on
the anticipated metabolism of the N-nitrosamine and the cytochrome P450 enzymes
most likely involved. In addition, if an organic solvent is used to dissolve the
test compound, it is recommended that the volume of organic solvent employed to
dissolve the N-nitrosamine positive controls results in a similar concentration
as for the test compound in the pre-incubation mix, if possible.

N-Nitrosamine positive controls to consider include:

 1. NDMA (CAS # 62-75-9)
 2. 1-Cyclopentyl-4-nitrosopiperazine (CAS # 61379-66-6)
 3. An NDSRI

All other recommendations for the Ames assay should follow the OECD 471
guideline.

References:

OECD Test Guideline No. 471 "Bacterial Reverse Mutation Test". 2020

Li et al. Revisiting the mutagenicity and genotoxicity of N-nitroso propranolol
in bacterial and human in vitro assays. Regulatory Pharmacology and Toxicology.
2023


APPENDIX 4: CARCINOGENIC POTENCY CATEGORIZATION APPROACH (CPCA) FOR
N-NITROSAMINES

This document describes an approach for assigning an N-nitrosamine impurity
(including nitrosamine drug substance-related impurities [NDSRIs]) to a
predicted carcinogenic potency category, with a corresponding Acceptable Intake
(AI) limit, based on an assessment of activating or deactivating structural
features present in the molecule. In the context of this document, activating or
deactivating features are defined as molecular substructures that are associated
with an increase or decrease, respectively, in carcinogenic potency.

The Carcinogenic Potency Categorization Approach is based on structure-activity
relationship (SAR) concepts described in recent scientific publications for
N-nitrosamine compoundsFootnote 1 and also used a set of approximately 80
N-nitrosamines with either rat TD50 values from the Carcinogenic Potency
Database (CPDB) and/or the Lhasa Carcinogenicity Database (LCDB)Footnote 2,
relative potency classifications as defined by Rao et al. (1979)Footnote 3,
and/or AI limits based on previously-conducted surrogate analysesFootnote 4. The
approach assumes that the α-hydroxylation mechanism of metabolic
activationFootnote 5 is responsible for the mutagenic and highly potent
carcinogenic response observed for many N-nitrosamines. Structural features that
directly increase or decrease the favorability of the activation mechanism, or
that increase the clearance of the nitrosamine by other biological pathways, are
expected to have a corresponding effect on carcinogenic potency. Therefore, a
prediction of the mutagenic potential and carcinogenic potency of an
N-nitrosamine can be generated based on its structural features.

It is recognized that the science is evolving in the prediction of mutagenic
potential and carcinogenic potency based on SAR concepts. Therefore, the
predicted Carcinogenic Potency Categorization Approach described in this
document is a conservative approach that represents the best available science
at this time and is expected to be further refined and expanded as new data
become available. This may include refinement of the AI limits associated with
predicted carcinogenic potency categories and changes to the structural features
and their associated activating and deactivating feature scores.

The Carcinogenic Potency Categorization Approach applies to N-nitrosamines
bearing a carbon atom on both sides of the N-nitroso group, and where the carbon
is not directly double bonded to a heteroatom (that is, N-nitrosamides,
N-nitrosoureas, N-nitrosoguanidines and other related structures are excluded).
Additionally, the potency categorization approach does not apply to
N-nitrosamines where the N-nitroso group is within an aromatic ring (for
example, nitrosated indole). For N-nitrosamines containing two N-nitroso groups,
the group with the highest predicted carcinogenic potency (that is, the group
with the lowest numerical potency category) defines the AI for the entire
moleculeFootnote 6. The α- and β-carbons are defined relative to the N-nitroso
group, as illustrated in Figure 1.


Figure 1. Structural Representation of α- and β-carbons on an N-nitrosamine
Figure 1 - Text description

Structural representation of α- and β-carbons on an N-nitrosamine

The process for predicting the appropriate carcinogenic potency category is
described in Figure 2. Table 1 summarizes the five predicted carcinogenic
potency categories and their associated AI limits. Supporting tables to
calculate the Potency Score referenced in Figure 2 are in Appendix A and example
calculations are presented in Appendix B.

Figure 2. Flowchart to Predict the Potency Category of an N-nitrosamine Figure 2
- Text description

Figure 2 shows a step-by-step process of how to assign a potency category to an
N-nitrosamine. Each step has two options to choose from, and the steps are
followed until a potency category of 1, 2, 3, 4, or 5, is reached. The potency
category determines the acceptable intake limit that the N-nitrosamine impurity
can be controlled at.

*A tertiary α-carbon is defined as an α-carbon atom in an sp3 hybridization
state, bonded to three other carbon atoms.
** To calculate Potency Score, see Appendix A.

Table 1. The Five Predicted Potency Categories and Associated AI Limits for
N-Nitrosamines Potency Category

Recommended AI Limit
(ng/day)

Comments 1 18 The recommended AI limit of 18 ng/day is equal to the
class-specific TTC for N-nitrosamine impurities.Footnote * N-nitrosamines
assigned to Category 1 are predicted to have high carcinogenic potency; however,
the class-specific TTC for N-nitrosamine impurities is considered sufficiently
protective to patients. 2 100 The recommended AI limit of 100 ng/day is
representative of two potent, robustly tested N-nitrosamines,
N-nitrosodimethylamine (NDMA) and
4-(methylnitrosamino)-1-(3-pyridyl)-1-(butanone) (NNK), which have recommended
AI limits of 96 ng/day and 100 ng/day, respectively. N-nitrosamines assigned to
Category 2 are predicted to have carcinogenic potency no higher than NDMA and
NNK. 3 400 Compared to Potency Category 2, N-nitrosamines in this category have
lower carcinogenic potency due to, for example, the presence of a weakly
deactivating structural feature. The recommended AI limit was set to reflect a
4-fold decrease in carcinogenic potency from Category 2. 4 1500 N-Nitrosamines
assigned to Category 4 may be metabolically activated through an α-hydroxylation
pathway but are predicted to be of low carcinogenic potency, for example,
because the pathway is disfavored due to steric or electronic influences, or
because clearance pathways are favored. The recommended AI limit of 1500 ng/day
is set at the TTC per ICH M7.Footnote ** 5 1500 N-Nitrosamines assigned to
Category 5 are not predicted to be metabolically activated via an
α-hydroxylation pathway due to steric hindrance or the absence of α-hydrogens,
or are predicted to form unstable species that will not react with DNA. The
recommended AI limit of 1500 ng/day is set at the TTC per ICH M7.Footnote **
Footnote *

Assessment report Procedure under Article 5(3) of Regulation EC (No) 726/2004
Nitrosamine impurities in human medicinal products Procedure number:
EMEA/H/A-5(3)/1490

Return to footnote * referrer

Footnote **

See the International Council for Harmonisation guidance for industry M7
Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals
To Limit Potential Carcinogenic Risk. Threshold of Toxicological Concern (TTC)
of 1.5 µg/day (1500 ng/day) as explained in ICH M7, represents an AI for any
unstudied chemical that poses a negligible risk of carcinogenicity or other
toxic effect.

Return to footnote ** referrer


APPENDIX A. CALCULATION OF POTENCY SCORE

For N-nitrosamines not assigned to Potency Category 5, the Potency Score is
calculated as the sum of the α-Hydrogen Score (Table 2), Deactivating Feature
Score (Table 3) and Activating Feature Score (Table 4) based on selected
structural features present in the N-nitrosamine. The N-nitrosamine structure is
expected to match exactly one of the α-hydrogen definitions in Table 2, but it
may contain multiple or no structural features identified in Tables 3 and 4. In
cases where one or more features from Tables 3 and 4 are contained in the
N-nitrosamine, the Potency Score should be calculated as outlined in the box
below. In cases where the N-nitrosamine contains no features from Tables 3 and
4, the Potency Score will be equal to the α-Hydrogen Score.

Potency Score = α-Hydrogen Score + Deactivating Feature Score (sum all scores
for features present in the N-nitrosamine) + Activating Feature Score (sum all
scores for features present in the N-nitrosamine)

Table 2. Count of hydrogen atoms on each α-carbon (lowest count first) and
corresponding α-Hydrogen Score. Examples are intended to be illustrative only
and are not intended to be exhaustive.

Count of Hydrogen Atoms on Each
α-Carbon, Lowest First

Example α-Hydrogen Score 0,2 3Footnote * 0,3 2 1,2 3 1,3 3 2,2 1 2,3 1
Footnote *

A score of 3 applies when the methylene α-carbon is not part of an ethyl group.
If the methylene α-carbon is part of an ethyl group, a score of 2 should be
applied.

Return to footnote * referrer

Table 3. List of deactivating features and associated scores. To calculate
Deactivating Feature Score, sum the individual scores for all listed features
present in the N-nitrosamine structure. Each deactivating feature row in the
table may only be counted once. For N-nitrosamines where the N-nitroso group is
within more than one ring, the feature score for only the smallest matching ring
should be applied. Examples are intended to be illustrative only and are not
intended to be exhaustive. Deactivating Feature Example Individual Deactivating
Feature Score Carboxylic acid group anywhere on molecule +3 N-nitroso group in a
pyrrolidine ring +3 N-nitroso group in a 6-membered ring containing at least one
sulfur atom +3 N-nitroso group in a 5- or 6-membered ringFootnote * +2 N-nitroso
group in a morpholine ring +1 N-nitroso group in a 7-membered ring +1 Chains of
≥5 consecutive non-hydrogen atoms (cyclic or acyclic) on both side of acyclic
N-nitroso group. Not more than 4 atoms in each chain may be in the same ring.
+1 Electron-withdrawing groupFootnote ** bonded to α-carbon on only one side of
N-nitroso group (cyclic or acyclic) +1 Electron-withdrawing groupsFootnote **
bonded to α-carbons on both sides of N-nitroso group (cyclic or acyclic) +2
Hydroxyl group bonded to β-carbonFootnote *** on only one side of N-nitroso
group (cyclic or acyclic) +1 Hydroxyl group bonded to β-carbon on both sides of
N-nitroso group (cyclic or acyclic) +2
Footnote *

Excludes examples where N-nitroso group is in a pyrrolidine ring, a 6-membered
ring containing at least one sulfur atom or a morpholine ring (all counted
separately).

Return to footnote * referrer

Footnote **

Excludes carboxylic acid and aryl (counted separately), and ketone (conflicting
data). Additional electron withdrawing group examples are limited to those
described in Cross KP and Ponting DJ, 2021, Developing Structure-Activity
Relationships for N-Nitrosamine Activity, Comput Toxicol, 20:100186, where they
are referred to as "β-carbon electron withdrawing groups."

Return to footnote ** referrer

Footnote ***

β-Carbon must be in an sp3 hybridization state for this feature to apply

Return to footnote *** referrer

Table 4. List of activating features and associated scores. To calculate
Activating Feature Score, sum the individual scores for all listed features
present in the N-nitrosamine structure. Each activating feature row in the table
may only be counted once. Examples are intended to be illustrative only and are
not intended to be exhaustive.

Activating Feature Example Individual Activating Feature Score Aryl group bonded
to α-carbon (i.e., benzylic or pseudo-benzylic substituent on N-nitroso group)
-1 Methyl group bonded to β-carbon (cyclic or acyclic) -1


APPENDIX B. EXAMPLE CARCINOGENIC POTENCY CATEGORIZATION APPROACH CALCULATIONS
BASED ON FLOW CHART

Example 1 shows how the potency categorization approach flow chart (Figure 2)
can be applied to the N-nitrosamine, N-nitroso-felodipine. N-Nitroso-felodipine
is placed in Potency Category 5 with an associated AI limit of 1500 ng/day.

Example 1 – N-Nitroso-felodipine Example 1 - Text description

The example 1 figure shows a step-by-step process of how to assign a potency
category for N-nitroso-felodipine. The example shows how the steps have led to a
potency category 5.

Example 2 shows how the potency categorization approach flow chart (Figure 2)
can be applied to the N-nitrosamine, N-nitroso-enalapril. N-Nitroso-enalapril is
placed in Potency Category 5 with an associated AI limit of 1500 ng/day.

Example 2 – N-Nitroso-enalapril Example 2 - Text description

The example 2 figure shows a step-by-step process of how to assign a potency
category for N-nitroso-enalapril. The example shows how the steps have led to a
potency category 5.

Example 3 shows how the potency categorization approach flow chart (Figure 2)
can be applied to the N-nitrosamine, N-nitroso-ketamine. N-Nitroso-ketamine is
placed in Potency Category 5 with an associated AI limit of 1500 ng/day.

Example 3 – N-Nitroso-ketamine Example 3.2 - Text description

The example 3 figure shows a step-by-step process of how to assign a potency
category for N-nitroso-ketamine. The example shows how the steps have led to a
potency category 5.

Example 4 – N-Nitroso-nebivolol

Example 4 shows how the potency categorization approach flow chart (Figure 2)
can be applied to the N-nitrosamine, N-nitroso-nebivolol. A Potency Score of 4
is calculated for N-nitroso-nebivolol, resulting in its placement in Potency
Category 4 with an associated AI limit of 1500 ng/day.

Count of α-Hydrogens

Score

Feature highlighted in red

2,2 1

Deactivating features

Score

Feature highlighted in red

Hydroxyl group bonded to β-carbons on both sides of N-nitroso group (cyclic or
acyclic) +2 Chains of ≥5 consecutive non-hydrogen atoms (cyclic or acyclic) on
both sides of acyclic N-nitroso group. Not more than 4 atoms in each chain may
be in the same ring. +1

No Activating Features Present

   

Potency score = 1 + 2 + 1 = 4

Potency category 4

AI = 1500 ng/day

Example 4 Chart - Text description

The example 4 figure shows a step-by-step process of how to assign a potency
category for N-nitroso-nebivolol. The example shows how the steps have led to a
potency category 4.

Example 5 – N-Nitroso-meropenem

Example 5 shows how the potency categorization approach flow chart (Figure 2)
can be applied to the N-nitrosamine, N-nitroso-meropenem. A Potency Score of 4
is calculated for N-nitroso-meropenem, resulting in its placement in Potency
Category 4 with an associated AI limit of 1500 ng/day.

Count of α-Hydrogens

Score

Feature highlighted in red

1,2 3

Deactivating features

Score

Feature highlighted in red

Carboxylic acid group anywhere on molecule +3 N-nitroso group in a pyrrolidine
ring +3 Electron-withdrawing group bonded to α-carbon on only one side of
N-nitroso group (cyclic or acyclic) +1

No Activating Features Present

   

Potency score = 3 + 3 + 3 + 1 = 10

Potency category 4

AI = 1500 ng/day

Example 5 Chart - Text description

The example 5 figure shows a step-by-step process of how to assign a potency
category for N-nitroso-meropenem. The example shows how the steps have led to a
potency category 4.

Example 6 – N-Nitroso-desloratadine

Example 6 shows how the potency categorization approach flow chart (Figure 2)
can be applied to the N-nitrosamine, N-nitroso-desloratadine. A Potency Score of
3 is calculated for N-nitroso-desloratadine, resulting in its placement in
Potency Category 3 with an associated AI limit of 400 ng/day.

Count of α-Hydrogens

Score

Feature highlighted in red

2,2 1

Deactivating features

Score

Feature highlighted in red

N-nitroso group in a 5- or 6-membered ring +2

No Activating Features Present

   

Potency score = 1 + 2 = 3 Potency category 3 AI = 400 ng/day

Example 6 Chart - Text description

The example 6 figure shows a step-by-step process of how to assign a potency
category for N-nitroso-desloratadine. The example shows how the steps have led
to a potency category 3.

Example 7 – N-Nitroso-sertraline

Example 7 shows how the potency categorization approach flow chart (Figure 2)
can be applied to the N-nitrosamine, N-nitroso-sertraline. A Potency Score of 2
is calculated for N-nitroso- sertraline, resulting in its placement in Potency
Category 2 with an associated AI limit of 100 ng/day.

Count of α-Hydrogens

Score

Feature highlighted in red

1,3 3

No Deactivating Features Present

   

Activating features

Score

Feature highlighted in red

Aryl group bonded to α-carbon (i.e., benzylic or pseudo-benzylic substituent on
N-nitroso group) -1

Potency score = 3 - 1 = 2

Potency category 2

AI = 100 ng/day

Example 7 Chart - Text description

The example 7 figure shows a step-by-step process of how to assign a potency
category for N-nitroso- sertraline. The example shows how the steps have led to
a potency category 2.

Example 8 – N-Nitroso-lorcaserin

Example 8 shows how the potency categorization approach flow chart (Figure 2)
can be applied to the N-nitrosamine, N-nitroso-lorcaserin. A Potency Score of 1
is calculated for N-nitroso-lorcaserin, resulting in its placement in Potency
Category 1 with an associated AI limit of 18 ng/day.

Count of α-Hydrogens

Score

Feature highlighted in red

2,2 1

Deactivating features

Score

Feature highlighted in red

N-nitroso group in a 7-membered ring +1

Activating Features

Score

Feature highlighted in red

Methyl group bonded to β-carbon (cyclic or acyclic) -1

Potency score =1 + 1 - 1 = 1

Potency category 1

AI = 18 ng/day

Example 8 Chart - Text description

The example 8 figure shows a step-by-step process of how to assign a potency
category for N-nitroso-lorcaserin. The example shows how the steps have led to a
potency category 1.


FOOTNOTES

Footnote 1

For example, see Cross KP and Ponting DJ, 2021. Developing Structure-Activity
Relationships for N-Nitrosamine Activity, Comput Toxicol, 20:100186; Thomas R,
Tennant RE, Oliveira AAF, and Ponting DJ, 2022. What Makes a Potent Nitrosamine?
Statistical Validation of Expert-Derived Structure-Activity Relationships, Chem
Res Toxicol, 35:1997–2013; and Ponting DJ, Dobo KL, Kenyon MO, and Kalgutkar AS,
2022. Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines
Derived From Active Pharmaceutical Ingredients, J Med Chem, 65:15584–15607.

Return to footnote 1 referrer

Footnote 2

See Lhasa Carcinogenicity Database at https://carcdb.lhasalimited.org/.

Return to footnote 2 referrer

Footnote 3

Rao TK, Young JA, Lijinsky W and Epler JL, 1979. Mutagenicity of Aliphatic
Nitrosamines in Salmonella typhimurium, Mutat Res, 66:1-7.

Return to footnote 3 referrer

Footnote 4

Questions and answers for marketing authorisation holders / applicants on the
CHMP opinion for the Article 5(3) referral.

Return to footnote 4 referrer

Footnote 5

Li Y, Hecht SS, 2022. Metabolic Activation and DNA Interactions of Carcinogenic
N-Nitrosamines to Which Humans Are Commonly Exposed, Int J Mol Sci, 23:4559.

Return to footnote 5 referrer

Footnote 6

For N-nitrosamines containing more than two N-nitroso groups, the applicant or
manufacturer should contact the applicable drug regulatory authority for further
guidance.

Return to footnote 6 referrer


PAGE DETAILS

Date modified: 2024-05-31





ABOUT THIS SITE


HEALTH CANADA

 * Contact us


GOVERNMENT OF CANADA

 * All contacts
 * Departments and agencies
 * About government

THEMES AND TOPICS

 * Jobs
 * Immigration and citizenship
 * Travel and tourism
 * Business
 * Benefits
 * Health
 * Taxes
 * Environment and natural resources
 * National security and defence
 * Culture, history and sport
 * Policing, justice and emergencies
 * Transport and infrastructure
 * Canada and the world
 * Money and finance
 * Science and innovation
 * Indigenous peoples
 * Veterans and military
 * Youth


GOVERNMENT OF CANADA CORPORATE

 * Social media
 * Mobile applications
 * About Canada.ca
 * Terms and conditions
 * Privacy