Canada's Food and Drug Regulations (Regulations) were amended to extend the requirements of Division 1A - Establishment Licensing and Division 2 - Good Manufacturing Practices (GMP) to active ingredients used in pharmaceutical drugs for human use only. The amended Regulations came into force on November 8, 2013.
As stated in the "Regulatory Impact Analysis Statement" accompanying the Regulations Amending the Food and Drug Regulations (1475 - Good Manufacturing Practices) and published in the Canada Gazette Part II on April 25, 2013, the API program will be implemented over a three-year period. Therefore, aligned with the stated timelines, November 8, 2016, will mark the full implementation of the Regulations.
To facilitate achievement of full implementation, Health Canada is communicating the following information to stakeholders:
This notice applies to the following establishments (persons) conducting activities related to active pharmaceutical ingredients (API) in Canada:
Important to note that importers of selected consumer health products and importers of API intended for use in those products continue to be covered under the pilot project outlined in the Notice to Stakeholders - Good Manufacturing Practices for Active Pharmaceutical Ingredients - Implementation Pilot Project for Selected Consumer Health Products.
The amended Food and Drug Regulations (Regulations) came into force on November 8, 2013. Since then, anyone in Canada importing FDF or fabricating, packaging/labelling, testing and importing APIs (including partially processed APIs and API intermediates) is required to apply for or submit an amendment to their DEL.
As stated in section C.02.003 of the Regulations, no distributor referred to in paragraph C.01A.003(b) and no importer shall sell a drug unless it has been fabricated, packaged/labelled, tested and stored in accordance withDivision 2 of the Regulations (GMP requirements). Also, as stated in section C.02.003.3, no person shall use an active ingredient in the fabrication of a drug unless it is fabricated, packaged/labelled, tested and stored in accordance with GMP requirements.
Since the amended Regulations came into force, importers of APIs and FDFs maintain GMP evidence of all foreign API buildings and send a Drug Establishment Licence Application Form (FRM-0033) in which they attest to the GMP compliance. Importers are required to maintain evidence of GMP compliance at their buildings in Canada and have it readily available upon request.
Important to note that sterile APIs and the testing of non-sterile APIs before use in the fabrication of FDFs was already regulated prior to the amendment of the Regulations. Importers of these products should continue to submit GMP evidence as per Health Canada's Guidance on Evidence to Demonstrate Drug GMP Compliance of Foreign Sites (GUI-0080).
Importers of API and finished dosage form (FDF) drugs are required to maintain and provide current, accurate and complete information related to their foreign buildings. Health Canada has amended the Table A: Foreign Buildings Conducting API-Related Licensable Activities in order to improve and facilitate the DEL application processes. In the coming months, FRM-0033 will also be improved to facilitate DEL applications.
Effective immediately, if any information in Table A changes, an up-to-date, comprehensive Table A and attestation as per Section 5.1 of the Drug Establishment Licence Application: Forms and Instructions (FRM-0033) must be submitted.
Health Canada expects one consolidated Table A per importer building, which will replace any previously submitted Table A. A revised Table A that only includes the new or modified information to the amendment is no longer acceptable and will be screened out (see Section B). In addition, the Table A submitted must be accompanied by a cover letter that clearly describes the changes made from the previous version (such as additions, deletions and any revised content). As a result of this process change, the most recently submitted version of an importer's Table A will completely replace any previously submitted API foreign building information.
Tips for completing Table A:
Health Canada screens API information entered by importers in Table A to ensure that all mandatory fields have been completed with relevant, recent and correct information. The information declared must correspond with the evidence available. Table A mandatory fields include:
In cases where any of the above mandatory fields are incomplete, Health Canada reserves the right to reject the application with or without previously contacting the applicant to obtain a revised comprehensive Table A addressing all deficiencies. If screening deficiencies for mandatory fields remain unaddressed within the indicated timeline, the application will be rejected.
Please note that Importers are not allowed to import APIs manufactured at any foreign building not listed on the most recently submitted Table A. Instances of non-compliance may be subject to compliance and enforcement actions.
Once the application is screened successfully, an "Acknowledgement of Acceptance" will be issued.
Health Canada received a high volume of DEL applications related to APIs between November 8, 2013 and February 8, 2014. During this time, if an application was submitted, it was permitted to import drugs fabricated, packaged and/or tested by foreign buildings listed in Table A without an acknowledgement indicating that screening is complete. This procedure is now changing.
Health Canada will begin issuing new DEL API Foreign Building Annexes. This Annex will refer to information supplied in the updated comprehensive Table A. Therefore it is important that importers submit a comprehensive Table A to Health Canada to ensure that the Annex accurately reflects all API foreign buildings.
Important to note that effective immediately, every Table A submitted to Health Canada must always be comprehensive. As such, importers must submit a comprehensive Table A with their next amendment or annual licence review application.
Should you have any questions or comments about establishment licencing, please contact the following:
Drug establishment licences (DEL): DEL_questions_LEPPP@hc-sc.gc.ca
An importer who wants to import from a foreign API building must satisfy the GMP compliance requirements. This can be done using an inspection certificate from a Canadian inspector, or "other evidence" establishing that the API-related activities conducted at the foreign building meet GMP requirements.
The following sections clarify Health Canada's expectations for evidence supporting GMP compliance of foreign buildings.
A "certificate" is an inspection report (Exit Notice) with a "compliant" rating issued by Health Canada.
Health Canada accepts inspection reports issued by:
It is recommended that importers use foreign API suppliers that have been inspected by a recognized regulatory authority or organization. Use the most recent inspection report as evidence of GMP compliance.
Where there are multiple inspection reports conducted by different authorities with conflicting results, Health Canada should be notified, as all available information will be taken into consideration. The importers are to take timely action, upon becoming aware of any issues that could affect the quality, safety or efficacy of an active pharmaceutical ingredient, to mitigate any potential risks to the health and safety of Canadians and to notify Health Canada.
In the absence of inspections by recognised regulatory authorities or organisations, corporate and consultant audits may continue to be used until November 2016 (refer to Next Phase). It is important to note that a report of a self-audit conducted by the foreign API fabricator is not acceptable as GMP evidence.
The audit report should clearly:
Corporate or consultant audits should be conducted regularly. The most recent audit report should be listed in Table A and maintained on-site, along with applicable corrective actions. In cases where a non-compliant rating has been issued by a regulatory authority, an independent third party audit may not be used as evidence of GMP compliance.
Where the original information is available in a language other than English or French, a copy of the original information along with a translated version in either French or English should be available, with an attestation about the accuracy of the translation by a certified translator.
Since the amended Regulations came into force, Health Canada analyzed the API foreign building data submitted by importers as part of their DEL applications. It is recognized that some importers may be limited to using foreign buildings that have not been inspected by authorities and organizations noted under Part B, Section A.1 and A.2.i of this notice. As an interim measure until November 8, 2016 (see below- Next Phase), these importers may attest to the GMP compliance status of foreign buildings based on inspections conducted by other regulatory agencies. However, the inspections conducted must be against Canadian GMP and/or ICH Q7 guidelines, with no serious concerns - including risks to health and safety identified. Inspections of API buildings against standards/guidelines/regulations outside of the scope of Canadian human drug GMP guidelines (e.g. for cosmetics, excipients, natural health products, dietary supplements, food, medical devices, veterinary, or occupational health and safety) are not acceptable as proof of GMP compliance, unless there is other information to show equivalence.
In cases where there are multiple inspection reports available on-site, from different regulatory authorities/organizations, those inspections conducted by trusted regulatory authorities or recognized organizations are preferred and should be indicated in Table A.
It is the importer's responsibility to ensure that foreign buildings from which they are importing comply with GMP, and have relevant and recent GMP compliance evidence at their buildings in Canada. Health Canada will further assess the GMP compliance evidence of foreign buildings at one or all of the following stages:
If GMP compliance evidence is not satisfactory, Health Canada will take compliance and enforcement actions as needed (see Compliance and Enforcement Policy (POL-0001)).
It is important to note that all regulated establishments may be subject to an inspection by Health Canada, unannounced or announced, whether routine or for cause. The scope of the inspections is determined by Health Canada, as deemed appropriate. Inspections may also be conducted in situations where an immediate risk to health and safety has been identified or in situations where it is anticipated that this approach will provide a more accurate compliance assessment.
As of November 8, 2016 (three years after the amended Regulations came into force), importers will be expected to have satisfactory GMP compliance evidence as outlined in Part B, Sections A.1 (inspections by Health Canada) and A.2.i (inspections by recognized regulatory authorities and organizations) of this notice.
Consultant or corporate audits should not be used as GMP evidence for buildings conducting activities related to APIs used in the manufacture of drugs listed on the Prescription Drug List.
Depending on the nature and risk profile of the products, for example APIs used in manufacture of over-the-counter drugs, Health Canada may consider evidence as noted in Part B, Section A.2.ii (consultant or corporate audits). Inspection reports or certificates issued by regulatory authorities or organizations indicated in Part B, Section A.2.iiimay be considered as supplementary information to complement the GMP evidence indicated.
Alternatively, importers may ask Health Canada to conduct an inspection. For more information on requesting inspections by Health Canada, please see Section 18.104.22.168 of the Guidance on Evidence to Demonstrate Drug GMP Compliance of Foreign Sites (GUI-0080).
Important to note, the information on Health Canada's website will be updated to align with this notice and will be in effect until further guidance is provided. Stakeholders will be informed when GUI-0080 will be amended and published.
Should you have any questions or comments regarding GMP evidence, please contact the following:
Good manufacturing practices : API_questions_IPA@hc-sc.gc.ca
API importers, FDF importers, and FDF fabricators importing API for use in manufacturing should establish written quality agreements with foreign suppliers. These agreements should clearly identify the foreign API fabricator and the GMP responsibilities of each party. The key areas to be covered for FDF importer and API importer agreements are outlined in Good Manufacturing Practices (GMP) Guidelines - 2009 Edition, Version 2 (GUI-0001) and Good Manufacturing Practices (GMP) Guidelines for Active Pharmaceutical Ingredients (API) - (GUI-0104), respectively.
Where applicable, written agreements should include (but are not limited to):
Records and documentation are required as per the Regulations and associated guidance. Distribution records must also be maintained at the importer's location as per the Regulations.
It is important to note that the integrity of data is a key expectation in the regulation of drugs and associated establishments. Any related issues have the potential to cause significant risk if not addressed. Health Canada continues to monitor these issues and take actions, as needed.