The Health Products and Food Branch (HPFB) Inspectorate is notifying stakeholders that Canada's Food and Drug Regulations (Regulations) have been 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 were published in Part II of the Canada Gazette and were announced on May 8, 2013. The amended Regulations will come into force on November 8, 2013. This delay in the coming into force of the regulatory amendment was to allow regulated parties to adjust to the new requirements.
To facilitate implementation, Health Canada will be leveraging the existing establishment licence (EL) process to establish oversight over active pharmaceutical ingredient (API) activities.
The new requirements will affect the following four categories of stakeholders in Canada:
Current EL holders that conduct more than one activity need to comply with the requirements applicable to each of those activities as described in the below sections.
Health Canada will be conducting a pilot for manufacturers of selected consumer health products and their associated APIs. A subsequent document related specifically to the pilot for selected consumer health products and their associated APIs will be available on the Health Canada website shortly.
As of November 8, 2013, all establishments in Canada that are conducting the licensable activities of fabrication, packaging/labelling, testing and importing of APIs, including dosage form fabricators that import APIs for use in manufacturing their own products, will be required to submit an Establishment Licence (EL) application form (FRM-0033) before February 08, 2014. The updated form includes:
Addresses of foreign API buildings will be listed on the ELs for API importers. At this time, no validity periods or expiry dates will be assigned to API foreign buildings listed on ELs. API importers in Canada will be required to maintain and provide current, accurate and complete information related to their foreign buildings by submitting an updated API Foreign Building Information Table (Part B section 5.1 of FRM-0033) to Health Canada before implementing the change.
Importers of finished dosage forms (who are not conducting any API activities in Canada) will be required to submit an amendment to their existing EL by signing the attestation to the GMP compliance status of the foreign buildings where fabrication, packaging/labelling and/or testing of APIs occur (Part B, section 5.1 of FRM-0033) and completing the Foreign Building Information Table referenced in Part B Section 5.1 of FRM-0033 to Health Canada. Information regarding the API contained in their imported products will be collected through this process for the purpose of planning for a phased implementation and to provide Health Canada with critical traceability information. Addresses of the foreign API buildings will not be listed on their EL at this time.
Importers of finished dosage forms that also import APIs will be required to submit an EL application to Health Canada in order to include the API importation activity on their EL.
As per the transitional provisions set out in the amended Regulations, all API stakeholders impacted by this new regulatory framework (sections 1 and 2 above) will be able to continue conducting API licensable activities provided they submit a completed EL application form (FRM-0033) with all applicable sections duly filled in to reach Health Canada before February 8, 2014.
Establishments that will be issued ELs prior to or on December 31st, 2013 will be required to submit Annual Review applications prior to April 1st, 2014. Establishments that will be issued ELs on or after January 1st, 2014 will be required to submit Annual Review applications prior to April 1st of the following year.
Distributors and Wholesalers of APIs in Canada that source APIs within Canada and that perform no other licensable activities will be subject to the applicable GMP requirements but will not be required to hold an EL for these activities.
Distributors and Wholesalers of APIs in Canada that import APIs from abroad will be required to submit an EL application to Health Canada to include the API importation activity on their EL and will be subject to the applicable GMP requirements for API importers. Please refer to section 1 "API Fabricators, Packagers/Labellers, Testers, Importers and Dosage Form Fabricators that import APIs for use in manufacturing their own products" for more information.
Distributors and Wholesalers of dosage forms and bulk process intermediates will continue to be subject to existing EL and GMP requirements.
The transitional provisions do not apply to establishments in Canada that begin to conduct API related licensable activities after the amended Regulations come into force. These establishments will be required to:
Dosage Form Fabricators that source APIs within Canada (i.e., do not conduct API licensable activities in Canada) are not required to amend their existing EL, to sign the attestation to the GMP compliance status of the foreign buildings where fabrication, packaging/labelling and/or testing of APIs occur (Part B, section 5.1 of FRM-0033) nor to complete the Foreign Building Information Table referenced in Part B Section 5.1 of FRM-0033.
The EL application form (FRM-0033) has been updated to collect API information and is expected to be made available on the Health Canada website. The package will include the following updated documents:
|ActivityTable 1 footnote 1Table 1 footnote 2||EL for APIsTable 1 footnote 3||FRM-0033||Attestation for GMP compliance of API foreign buildings||API Foreign Buildings Table||Compliance with Division 2 for APIs||Listing of API foreign buildings on the EL||Provide updated information related to API foreign buildings|
Table 1 footnotes
|Fabricator of APIsTable 1 footnote 3|
|Packager/ Labeller of APIs|
|Tester of APIs|
|Importer of APIs|
|DFTable 1 footnote 4 Fabricator importing APIs for own manufacturing|
|Importer of DFTable 1 footnote 4|
|Distributer of APIs only|
|Wholesaler of APIs only|
|DFTable 1 footnote 4 Fabricators that source APIs within Canada|
Canadian API Buildings - API GMP Guidelines (GUI-0104)
Good Manufacturing Practices (GMP) for Active Pharmaceutical Ingredients (APIs) (GUI-0104) provides interpretive guidance for Part C, Division 2, of the Regulations for the manufacturing of APIs. This guide was drafted to facilitate compliance by the regulated industry with the Regulations.
A Notice to Stakeholders was posted on Health Canada's Website on October 22, 2012 to invite them to send their comments with respect to the draft guidance document GUI-0104. The comments received were reviewed and where appropriate, were incorporated into the document. GUI-0104 is currently in the process of being finalised and the final version will be available this fall on the Health Canada website.
Foreign API Buildings - GMP Evidence (GUI-0080)
The Guidance on Evidence to Demonstrate Drug GMP Compliance of Foreign Sites (GUI-0080) was revised to encompass APIs. Due to web posting delays, the revised GUI-0080 was sent via email to stakeholders on April 8, 2013 for a 90-day public consultation period. The comments received are being reviewed and will be incorporated where appropriate. However, given the number of comments received from stakeholders, Health Canada has decided to issue a separate guidance document on evidence to demonstrate GMP compliance of API foreign buildings. The resulting guidance document will be available this fall on the Health Canada website.
In light of the concerns brought forward regarding the increased regulatory burden, Health Canada has adopted the attestation process outlined in the sections 1 and 2 of this Notice to Stakeholders entitled "API Fabricators, Packagers/Labellers, Testers, Importers and Dosage Form Fabricators that import APIs for use in the manufacturing of their own products" and "Dosage Form Importers" to confirm GMP compliance of a foreign building where fabrication, packaging/labelling and/or testing of APIs occur. This interim measure will be in place until mid-2015. During this period, Health Canada will gather and analyse data contained in the completed API Foreign Building Tables. Based on this analysis, Health Canada will determine the risk-based strategy moving forward.
API Questions and Answers
API GMP Questions and Answers (API GMP Q&As) have been created to provide additional guidance regarding inspections and GMPs and will be available this fall on the Health Canada website.
Mutual Recognition Agreements (MRAs)
Health Canada intends on working with MRA partners to include APIs within MRAs. For the time being, Canadian API importers, including dosage form fabricators who import APIs for use in their own manufacturing, and dosage form importers are required to follow the aforementioned process for API foreign buildings.