Notice to Stakeholders - Updates to drug establishment licence applications and good manufacturing practice evidence requirements for active pharmaceutical ingredients

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:

• Updated Table A and instructions for new and amending drug establishment licence (DEL) applications related to importing drugs, including APIs.
• Updated information about the good manufacturing practice (GMP) evidence required by Health Canada to demonstrate GMP compliance of API foreign buildings.

• Who will this notice affect?
• Background
• Changes to the EL Application Package and Process
• GMP evidence for API foreign buildings
• Additional Information - Written Agreements

Who will this notice affect?

This notice applies to the following establishments (persons) conducting activities related to active pharmaceutical ingredients (API) in Canada:

1. API importers
2. Finished dosage form (FDF) fabricators who import APIs for use in manufacturing
3. FDF importers

Background

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.

PART A - Changes to the EL Application Package and Process

A. Completing Table A: Foreign Buildings Conducting API-Related Licensable Activities

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:

1. Importers must continue to submit GMP evidence for foreign buildings conducting sterile API activities or non-sterile API testing on behalf of the FDF fabricator, or bulk process intermediates (BPIs used in biologic products) - these buildings should not be included on Table A unless they also conduct other API-related activities.
2. In cases where the API and the FDF are the same, or where the manufacturing process is continuous, the foreign buildings should be included only on the DEL Foreign Building Annex, not in Table A.
3. Active ingredients used in the manufacture of drugs outside of the scope of the amendment to the Regulations (such as veterinary drugs, dilute drug premix, a medicated feed, a drug to be used only for the purpose of an experimental study, natural health products, cosmetics) should not be included in Table A, unless they are also used in a pharmaceutical drug for human use.

B. Screening the information in 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:

• API name (one per line)
• foreign building name
• complete address
• GMP compliance status
• date of last inspection
• inspection type (specify type of inspection if "other" is selected)
• activity

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.

C. Receiving an Acknowledgement of Acceptance

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.

Effective immediately:

1. Only complete applications will be screened. Service standards for screening are within 20 business days.
2. Incomplete applications will result in processing delays.
3. DEL holders who add API foreign buildings to their current Table A cannot import from those buildings until Health Canada's screening is complete and the "Acknowledgement of Acceptance" is received.

D. Receiving an API Foreign Building Annex

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.

Contact Information

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

PART B - Good manufacturing practice evidence for API foreign buildings

A. Requirements - GMP compliance evidence for foreign API buildings

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.

1. Certificate from Canadian inspector

A "certificate" is an inspection report (Exit Notice) with a "compliant" rating issued by Health Canada.

2. Other evidence to support GMP compliance of foreign API buildings

i. Recognized regulatory authorities and organizations

Health Canada accepts inspection reports issued by:

• regulatory partners with whom Health Canada has established equivalence under Mutual Recognition Agreements (MRA)
• regulatory partners whose inspection system has been assessed and found comparable under the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/s)
• organizations such as the European Directorate for the Quality of Medicines and Healthcare (EDQM) and World Health Organization (WHO), which inspect against ICH Q7 guidelines

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.

ii. Consultant or Corporate audits

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:

1. Include an explanation of why a consultant or corporate audit report is submitted.
2. Outline the qualifications and experience of the individual(s) performing the inspection. At a minimum, the individual(s) must have sufficient experience and knowledge of GMP. Further guidance on personnel qualification is available in the interpretation of section C.02.006 of the Good Manufacturing Practices (GMP) Guidelines (GUI-0001).
3. Describe the scope of the inspection (ensure that the report clearly identifies the address, APIs imported, and that the regulated activities associated to those APIs are within scope).
4. Be conducted, section by section, against the Part C, Division 2 of the Food and Drug Regulations. All applicable sections should be assessed.
5. Be signed and dated by the lead auditor.
6. Be accompanied by a copy of the corrective actions taken, which has been signed by a responsible official of the foreign building.
7. Be assessed by the auditor(s) for the adequacy of the corrective actions, and for whether the audit is considered to meet Part C, Division 2 of the Food and Drug Regulations.

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.

iii. Other GMP evidence

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.

B. Verifying evidence

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:

1. Clarification of GMP evidence
   
   At any time, Health Canada may request clarification with respect to Table A.
   
2. Inspection of an importer
   
   During domestic FDF and API importer inspections, Health Canada verifies evidence of GMP compliance of foreign API buildings for completeness, relevancy and consistency with the information provided in the DEL application. Any deviations or deficiencies will be documented in the inspection report, and may have consequences on the existing DEL or issuing of a new DEL.
   
3. Off-site paper assessment
   
   Health Canada requests information for further assessment (such as inspection reports, Site Master Files, corrective actions, and written agreements between foreign buildings and importers). Enforcement actions will be taken in accordance with the Compliance and Enforcement Policy (POL-0001) for foreign buildings that are non-compliant, or if the evidence submitted is found to be incomplete and non-satisfactory for assessment.
   
4. Foreign on-site inspections
   
   Health Canada uses a risk-based approach to select foreign buildings for on-site inspections to establish GMP compliance.

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.

Next phase - Beginning November 8, 2016

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 3.2.1.1 of the Guidance on Evidence to Demonstrate Drug GMP Compliance of Foreign Sites (GUI-0080).

Contact Information

Should you have any questions or comments regarding GMP evidence, please contact the following:

Good manufacturing practices : API_questions_IPA@hc-sc.gc.ca

Additional Information

A. Written agreements

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):

1. Provisions requiring that the Canadian importer be notified of any change to the API manufacturing process and/or supplier and/or specifications.
2. Provisions that the Canadian importer is notified of any recalls and/or other regulatory actions such as statements of non-compliance, warning letters or import alerts/bans that originate at any foreign buildings where FDF and/or API activities are conducted.
3. Provisions, where applicable, requiring that upon request, a copy of the foreign API fabricator's Annual Product Quality Review (APQR) is to be provided to the API importer, as well as the Canadian FDF importer via the foreign FDF Fabricator.
4. Provisions, where applicable, requiring that upon request the foreign API fabricator to provide on-going stability to the API importer, as well as the Canadian FDF importer via the foreign FDF Fabricator.
5. For FDF importers, provisions requiring that foreign FDF fabricators use APIs manufactured at GMP-compliant buildings.
6. For FDF importers, provisions requiring foreign FDF fabricators to ensure that the API supplier buildings are compliant with Canadian GMP or ICH Q7 guidelines. This should also enable foreign FDF fabricators to conduct GMP corporate audits on the other buildings used and/or request the relevant GMP compliance evidence.

B. Records

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.