Notice to Stakeholders - Amended Food and Drug Regulations for Active Ingredients - Coming into force on November 8, 2013

Contact Information

Active pharmaceutical ingredients (API): API_questions_IPA@hc-sc.gc.ca
Drug establishment licences (DEL): DEL_questions_LEPPP@hc-sc.gc.ca

November 2013

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.

Who will these changes affect?
Dosage Form Fabricator
The EL Application Package
Additional Information

Who will these changes affect?

The new requirements will affect the following four categories of stakeholders in Canada:

API Fabricators, Packagers/Labellers, Testers, Importers and Dosage Form Fabricators that import APIs for use in manufacturing their own products;
Dosage Form Importers;
API Distributors and Wholesalers; and
Establishments that begin to conduct licensable activities related to APIs starting on or after November 8, 2013.

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.

1. API Fabricators, Packagers/Labellers, Testers, Importers and Dosage Form Fabricators that import APIs for use in manufacturing their own products

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:

Domestic activity, category and final API Form Class Information (Part B Section 3.1 of FRM-0033);
If applicable, 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). For the initial phase of coming into force of the amended Regulations, Health Canada will use these attestations as proof of GMP compliance for non-sterile APIs and it will not be necessary for establishments to submit additional GMP evidence at this time. However, information must be readily available within 48 hours upon request by Health Canada. As and when necessary, Health Canada may also assess foreign buildings for compliance with the applicable GMP requirements in Division 2 of the Regulations. For sterile APIs and for testing of non-sterile APIs prior to its use in the fabrication of finished products that are already being regulated prior to November 8, 2013, importers will be required to continue to submit GMP evidence as per the Guidance on Evidence to Demonstrate Drug GMP Compliance of Foreign Sites (GUI-0080) in addition to the attestation and the table and,
If applicable, the Foreign Building Information Table referenced in Part B Section 5.1 of FRM-0033, a standardized table listing foreign buildings where fabrication, packaging/labeling, and testing of APIs occur.

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.

2. Dosage Form Importers

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.

3. API Distributors and Wholesalers in Canada

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.

4. Establishments in Canada that begin to conduct licensable activities related to APIs on or after November 8, 2013

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:

submit an EL application form (FRM-0033) and, if applicable, the attestation as well as the completed API Foreign Building Information Table;
be inspected and found to be compliant with the applicable Division 2 requirements of the Regulations; and
have a EL issued by Health Canada prior to starting licensable activities.

Dosage Form Fabricators

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 Package

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:

EL Application Form (FRM-0033). New sections in the form are:
- Application information tables
- Part B, Section 3.1 Activity, category and final API Form Class Information
- Part B, Section 5.1 API Foreign Building Information (table and attestation)
FRM-0033 instructions
Frequently Asked Questions (FAQs) for ELs

Table 1: Summary Table of Requirements for an Application by Activity
Activity^{Table 1 Footnote 1},^{Table 1 Footnote 2}	Attestation for GMP compliance of API foreign buildings	API Foreign Buildings Table	Listing of API foreign buildings on the EL	Provide updated information related to API foreign buildings
Fabricator of APIs^{Table 1 Footnote 3}	^{Table 1 Footnote 5}	^{Table 1 Footnote 5}	^{Table 1 Footnote 5}	^{Table 1 Footnote 5}
Packager/ Labeller of APIs	^{Table 1 Footnote 5}	^{Table 1 Footnote 5}	^{Table 1 Footnote 5}	^{Table 1 Footnote 5}
Tester of APIs	^{Table 1 Footnote 5}	^{Table 1 Footnote 5}	^{Table 1 Footnote 5}	^{Table 1 Footnote 5}
Importer of APIs
DF^{Table 1 Footnote 4} Fabricator importing APIs for own manufacturing
Importer of DF^{Table 1 Footnote 4}
Distributer of APIs only
Wholesaler of APIs only
DF^{Table 1 Footnote 4} Fabricators that source APIs within Canada
Table 1 Footnotes Table 1 Footnote 1 Current EL holders that conduct more than one activity listed in Table 1 need to comply with the requirements applicable to each of those activities. Return to footnote 1 referrer Table 1 Footnote 2 For sterile APIs and for testing of non-sterile APIs prior to its use in the fabrication of finished products that are already being regulated under the current framework, importers will be required to continue to submit GMP evidence as per the Guidance on Evidence to Demonstrate Drug GMP Compliance of Foreign Sites (GUI-0080) in addition to the attestation and the API Foreign Building Information Table. Return to footnote 2 referrer Table 1 Footnote 3 API: Active pharmaceutical ingredients Return to footnote 3 referrer Table 1 Footnote 4 DF: Dosage forms Return to footnote 4 referrer Table 1 Footnote 5 Applicable if activities are performed in whole or in part by a foreign building Return to footnote 5 referrer

Additional Information

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.

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Date modified:: 2013-11-08

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