Q3D Notice: Health Canada recommendations for implementation of the ICH Harmonised Guideline for Elemental Impurities (Q3D) for new and marketed products

Notice

July 22, 2016
Our file number: 16-108149-319

Health Canada recommendations for implementation of the International Council for Harmonisation (ICH) Harmonised Guideline for Elemental Impurities (Q3D) for new and marketed products

The ICH Harmonised Guideline for Elemental Impurities Q3D has been recommended for adoption to the regulatory bodies of the European Union, Switzerland, Japan, USA, and Canada. Canadian drug products should comply with the guideline as follows:

Implementation of elemental impurity risk assessments for new submissions for drug products (ANDS or NDS, S(A)NDS and DIN Applications):

Submissions received by Health Canada after December 31, 2016 should include a risk assessment for elemental impurities. Submissions received after December 31, 2016 that do not have a risk assessment will be requested to submit the missing information.

Risk assessments will be evaluated during the assessment process. The scope of the risk assessment to be submitted for assessment should be based on the principles outlined in the ICH Q3D guideline and related training materials being developed by the ICH Q3D Implementation Working Group. Case studies are currently under development and will be published on the ICH website, when available. Detailed risk assessments and data supporting these risk assessments should be documented and available upon request by the Regulator (e.g., at the inspection stage).

The locations where the elemental impurities-related information can be found in Module 3 should be clearly summarized in Module 2.3.P.5: Control of Drug Product of the Quality Overall Summary.  The overall risk assessment summary for elemental impurities should be placed in Module 3.2.P.5.6 Justification of Specifications. The location of the overall risk assessment summary is currently under discussion by international regulatory authorities. The risk assessment for the container closure system may be cross-referenced to a master file. If toxicology data is submitted to support limits above the ICH Q3C Permitted Daily Exposure or for routes of administration not covered by ICH Q3D, it should be placed in Module 4.2.3.7.6 Other Toxicity Studies: Impurities.

Compliance with the ICH Q3D guideline should be documented after the risk assessment has been completed and any necessary controls have been implemented. For example, a statement confirming ICH Q3D compliance should be included on the drug product specifications and reflected in the updated Certified Product Information Document (CPID). Additional evidence of compliance should be available on request.

Implementation of elemental impurity risk assessments for Canadian marketed drug products:

S(A)NDSs or Post-DIN Changes for any quality related major change to a drug product (i.e. a new formulation, new drug product manufacturing site, new dosage form) submitted after December 31, 2016 should include a risk assessment for elemental impurities to allow for review and authorisation of the S(A)NDS or Post-DIN changes by January 1, 2018. A risk assessment should be performed in accordance with the ICH Q3D guideline and any training materials published as a result of work currently being done by the ICH Q3D implementation working group. Case studies are currently under development and will be published on the ICH website, when available. The risk assessment should be documented and available for inspection and any controls should be implemented, if applicable, by January 1, 2018.

If the risk assessment indicates that previously manufactured and unexpired batches have levels of elemental impurities that could pose a potential risk to health, the appropriate Directorates in Health Canada should be notified. Where appropriate this may include notification to the Health Product Compliance Directorate (formerly known as the Inspectorate) and/or the Biologics and Genetic Therapies Directorate (BGTD) for lot releases of biologics. If necessary, appropriate corrective action should be taken, such as: conducting recalls of any affected lots in accordance with recall procedures, developing an action plan to avoid a product shortage situation and filing a drug submission with appropriate manufacturing changes to effectively address the potential safety concerns.

ICH Q3D compliance should be included on the drug product specifications and reflected in the updated Certified Product Information Document (CPID). Additional evidence of compliance should be available on request. Consult Health Canada's Guidance Documents, Post-Notice of Compliance (NOC) Changes: Quality or Post-Drug Identification Number (DIN) Changes for the appropriate type of drug submission to file respective of the proposed change(s).

In the following cases, the filing of a post-NOC or post-DIN change may be appropriate:

1. Where there is a need for the replacement of the active pharmaceutical ingredient (API), API starting materials, synthesis intermediates or the excipients in order to comply with the ICH Q3D guideline and the requirements of the Post-NOC/ Post-DIN Changes guidance document.
2. Where there is a need for major changes to the manufacturing process to reduce and control the levels of elemental impurities and the changes are such that the requirements of the Post-NOC/Post-DIN Changes guidance document would deem that a S(A)NDS should be submitted.

The Post-NOC or Post-DIN change should contain a summary of the risk assessment, the conclusions drawn and appropriate data to support any changes made in order to comply with the ICH Q3D guideline and/or in accordance with the Post-NOC/Post DIN Changes guidance document. The overall risk assessment summary for elemental impurities should be placed in Module 3.2.P.5.6 Justification of Specifications. In Module 2.3.P.5 of the Quality Overall Summary, provide a summary of the Module 3 locations where the elemental impurities-related information can be found.

As an outcome of the risk assessment, rather than the need for a major chemistry and manufacturing change, one or more of the following scenarios may apply:

1. Additional controls are added to specifications to ensure levels of elemental impurities meet the ICH Q3D limits. Where a control of an elemental impurity is warranted, an elemental specific method is applied. A non-specific compendial test for heavy metals is not acceptable for control of elemental impurities. Consult Health Canada's Post-NOC Changes guidance document to determine if the filing of a Notifiable Change or an Annual Notification is necessary for any minor change(s) that are implemented.
2. No further controls or updates to the Specifications for elemental impurities are needed for materials such as the API (or the API starting material and synthesis intermediates), excipients or the finished product.
3. No replacement or change of the quality of materials such as the API, the API starting materials, synthesis intermediates, excipients or the manufacturing equipment is needed.
4. No change to the manufacturing process is needed.

Periodic re-assessments of the risks associated with elemental impurities, and corresponding compliance activity, may be appropriate throughout the lifecycle of the product.

Questions regarding this implementation should be directed to bps_enquiries@hc-sc.gc.ca.

Additional guidance regarding implementation of elemental impurity risk assessments for Over-the-Counter Drug Products (OTC) and Natural Health Products (NHPs):

OTCs that are classified under the Food and Drugs Act as drug products should comply with ICH Q3D guidance by the dates presented above. Generally risk assessments for elemental impurities do not need to be submitted for assessment unless a Chemistry and Manufacturing portion of the submission is reviewed by the Therapeutic Products Directorate (e.g., Risk Assessments should be submitted for certain OTCs which are submitted as Applications for Drug Identification Numbers (DINA)). For product submissions for which chemistry and manufacturing data is not submitted (e.g., DINF Category IV monographs), risk assessments should be held on file.

Natural Health Products have been excluded from meeting the requirements of the ICH Q3D guidance. They should meet the requirements for elemental impurities presented in the Quality of Natural Health Products guide or subsequent updates. NHPs which claim USP standards, should also meet the USP requirements by the date of implementation for USP <2232> (January 1, 2018).

Questions regarding NHPs should be directed to NNHPD_DPSNSO@hc-sc.gc.ca.

Additional guidance regarding implementation of elemental impurity risk assessments for drugs listed in Schedule C and Schedule D to the Food and Drugs Act:

Although "cold kits" (for reconstitution with a radiopharmaceutical) are regulated as Schedule C drugs, they do not meet the definition of a "radiopharmaceutical" and so are considered to be within the scope of ICH Q3D.

The risk assessment for elemental impurities should be conducted for Schedule D (biologics) drugs that are covered within the scope of the ICH Q3D guideline.

For biologics, additionally consult Section 5.7 of the ICH Q3D guideline and the biologics-specific case study (under development). Where implementation of manufacturing changes is considered, Appendix 3 (Biologics) and Appendix 4 (Schedule C drugs) of the Post-NOC Changes: Quality guidance document should be consulted.

Questions regarding this implementation should be directed to bgtd_ora@hc-sc.gc.ca.