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

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Contact Information for the Drug Good Manufacturing Practices Unit

Cover Letter

Related Forms (FRM-0211, FRM-0212, FRM-0213, FRM 0214)

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Supersedes:
POL-0013 (August 27, 2003)
This  document  replaces  POL-0013 "Conditions for Acceptance of Foreign
Inspection Reports for Listing Foreign Sites on Canadian Establishment Licences"

Date issued:
August 1, 2009

Date of implementation:
August 1, 2009

Disclaimer

This document does not constitute part of the Food and Drugs Act (Act) or the Food and Drugs Regulations (Regulations) and in the event of any inconsistency or conflict between that Act or Regulations and this document, the Act or the Regulations take precedence. This document is an administrative document that is intended to facilitate compliance by the regulated party with the Act, the Regulations and the applicable administrative policies. This document is not intended to provide legal advice regarding the interpretation of the Act or Regulations. If a regulated party has questions about their legal obligations or responsibilities under the Act or Regulations, they should seek the advice of legal counsel.

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Table of contents

• 1.0 Purpose
• 2.0 Scope
• 3.0 Guidance
  • 3.1 For sites located in a MRA country, for products and activities (fabrication, packaging, labelling, testing) covered under the MRA
  • 3.2 For sites not located in a MRA country, or for sites located in a MRA country for products or activities not covered under the MRA
  • 3.3 Period of validity for Drug GMP compliance evidence of foreign sites
  • 3.4 Terms and Conditions
  • 3.5 Ownership of information
• Appendix A- Acronyms and Glossary of Terms

1.0 Purpose

The purpose of this document is to provide guidance with respect to the type of information that should be submitted in order for the Health Product and Food Branch Inspectorate (Inspectorate) to assess the compliance of foreign sites with the Canadian Good Manufacturing Practices (GMP) regulations.

This guidance refers to compliance with Division 2 (Good Manufacturing Practices) of the Food and Drug Regulations for foreign sites. The outcome of the assessment by the Inspectorate will be a Compliant (C) or Non Compliant (NC) rating for the foreign site, or a request to submit additional information.

The forms referenced in this document are only intended to facilitate the submission of GMP evidence to the Drug GMP Inspection Unit for review. Alternate means of filing may be employed, however, the information captured in these forms should be submitted.

Canadian importers may wish to seek a compliance rating for a foreign site for the purpose of adding it to their Drug Establishment License. In order for a Drug Establishment Licence (DEL) applicant/holder to add a foreign site to their establishment licence, they should submit the DEL application form (Section V) to the Establishment Licensing Unit. Additional guidance is available on the Health Canada website at: Establishment Licences.

It should be noted that the establishment licence form (Section V) and "Good Manufacturing Practices - Foreign Site Submission Form  (FRM-0212)" are not both required, for any given site. Information provided to either the Establishment Licensing Unit or the Drug GMP Inspection Unit will be shared as required.

Sponsors may wish to seek a compliance rating for a foreign site in support of a drug submission, for a product which will be manufactured, packaged, labelled or tested at the foreign site. It is recommended that sponsors consult with the relevant review Directorate in order to determine the GMP requirements for a drug submission (for screening and/or review).

2.0 Scope

This guidance covers certain types of evidence:

Evidence to demonstrate GMP compliance for a site in a Mutual Recognition Agreement (MRA) country, for products and activities covered under the MRA.

Evidence to demonstrate GMP compliance for a site not located in a MRA country, or for sites located in a MRA country for products and/or activities not covered under the MRA.

3.0 Guidance

The Inspectorate recommends that the following information be submitted in order to demonstrate GMP compliance for foreign sites. Where the original information is available in a language other than English or French, the copy of the original information must be provided with an attestation on the accuracy of the translation by the translator.

3.1 For sites located in a MRA country, for products and activities (fabrication, packaging, labelling, testing) covered under the MRA

3.1.1 Type of evidence
In accordance with section C.01A.005 (m)(i)(ii) of the Food and Drug Regulations (FDR), an importer who wishes to list a site located in a MRA country which fabricates, packages/labels or conducts tests (including, but not limited to raw material testing, packaging material testing, and/or finished product testing) under Division 2 on its establishment licence must:

1. provide the name of each fabricator, packager/labeller and tester of the drug
2. provide the address of each building at which the drug is fabricated, packaged/labelled or tested
3. specify for each building the activities and the category of drug and
   • (a)  the dosage form class and whether the drug is in a sterile dosage form, and
   • (b)  whether the drug is a bulk process intermediate,
4. provide the name of the regulatory authority that is designated under subsection C.01A.019(1) in respect of that activity conducted in the MRA country

3.1.2. Request of a Certificate of Compliance (CoC) by the Inspectorate
Upon receipt of the above information, the Inspectorate will contact the regulatory authority identified to request a CoC to support GMP compliance of the requested building, activities, and dosage forms. CoCs are exchanged between regulatory authorities only. Submission of a copy of a CoC to the Inspectorate by an importer, sponsor, or DEL holder is not sufficient to demonstrate GMP compliance for the foreign site.

3.1.3 Submission of information to the Inspectorate
The above information should normally be submitted to the Inspectorate in the Establishment Licence Renewal package. However, should the importer, sponsor, or DEL holder wish the Inspectorate to request a CoC at any other time, the request should be made on form entitled "Good Manufacturing Practices - Foreign Site Submission Form (FRM-0212)", available on the Inspectorate website, and faxed to 613-957-6709 or emailed to mra-arm@hc-sc.gc.ca

3.2 For sites not located in a MRA country, or for sites located in a MRA country for products or activities not covered under the MRA

3.2.1 Type of Evidence
In accordance with sections C.01A.005 (m)(iii) and (n)(o) of the Food and Drug Regulations, an importer who wishes to list a site not located in a MRA country which fabricates, packages/labels or conducts tests (including, but not limited to raw material testing, packaging material testing, and/or finished product testing) under Division 2; or sites located in a MRA country for activities other than fabrication, packaging/labelling or testing under Division 2, or for products not covered under the MRA must:

1.  
   1. provide a certificate from a Canadian inspector indicating that the fabricator's, packager/labeller's or tester's buildings, equipment, practices and procedures meet the applicable requirements of Divisions 2
   2. specify for each building the activities and the category of drug and
      • (a)   the dosage form class and whether any drugs will be in a sterile dosage form, and
      • (b)   whether the drugs will be a bulk process intermediate, or
2. 1. other evidence establishing that the fabricator's, packager/labeller's or tester's buildings, equipment, practices and procedures meet the applicable requirements of Divisions 2 to 4, and
   2. specify for each building the activities and the category of drug and
      • (a)   the dosage form class and whether any drugs will be in a sterile dosage form, and
        
      • (b)   whether the drugs will be a bulk process intermediate.

3.2.1.1 The certificate from a Canadian inspector referred to above (in A.I.) is a GMP Inspection Exit Notice with a C rating from the Inspectorate. The Inspectorate suggests that other available evidence be considered before requesting an inspection by the Inspectorate (see 3.2.1.2). However, should an importer wish to request an inspection by the Inspectorate, they may do so by completing the form entitled "Good Manufacturing Practices - Request for an Inspection of a Foreign Site Form (FRM-0213)" and fax or email it to 613-957-6709 or foreign_site_etranger@hc-sc.gc.ca respectively.

The decision to proceed with the request for a foreign inspection is made by the Inspectorate. Should the Inspectorate decide to proceed with the inspection, the requester will be asked to enter into an agreement with Health Canada and sign the form "Good Manufacturing Practices - Foreign Site Inspection Services Agreement Form (FRM-0214)", once the specifics of the foreign inspection have been agreed upon, and are fax or email it to 613-957-6709 or foreign_site_etranger@hc-sc.gc.ca respectively.

Please note that an On-Site Evaluation (OSE) alone, conducted by the Biologics and Genetic Therapeutics Directorate is not considered sufficient to demonstrate the GMP compliance of a site as it does not cover all applicable sections of the GMP (Division 2 of the Food and Drug Regulations)

3.2.1.2 With reference to 'other evidence', as stated above, the Inspectorate suggests the following information be submitted in order to assess GMP compliance. The list of documentation below is provided as a guide only, however, they should all be provided in order to ensure a more efficient and timely review by the Inspectorate. It is recognized that the relationship between a Canadian site and a foreign site may be complex and in some cases particular documentation may not exist. In such cases, a written justification explaining why the required document type cannot be submitted should be provided with the submission, and the Inspectorate may consider alternate means of obtaining the information.

The act of submission alone does not guarantee that a compliant rating will be assigned to the foreign site and additional information may be requested depending on the nature of the submission.

1. the most recent (within the last 3 years) signed inspection report issued by:
   1. a Regulatory Authority for a site outside of its jurisdiction, or
      e.g.: -an Medicines and Healthcare Regulatory Agency (MHRA) (UK) inspection report for a site in India
   2. a Qualified Authority for a site within its jurisdiction, or
      e.g.: -an Food Drug Administration (FDA) (US) Establishment Inspection Report for a site located inside the US
      -a Medicine Control Council (MCC) (South Africa) inspection report for a site in South Africa
   3. a Qualified Authority for a site outside of its jurisdiction
      e.g.: -an FDA (US) Establishment Inspection Report (EIR) for a site located outside the US
      -a Health Science Authority (HSA) (Singapore) inspection report for a site in China
2. the corrective actions taken, signed by a responsible official of the foreign site
3. a copy of the Site Master File (for additional guidance, refer to the document entitled "Explanatory Notes for Industry on the Preparation of a Site Master File")
4. a copy of the site's procedures for handling deviations and out of specification test results
5. a copy of the site's procedure for finished product release
6. a copy of the quality agreement between the foreign site and the Canadian site, including a list of the specific products for supply in Canada
7. if authorization has been given by another country, proof that the authorization is still valid and has not been cancelled

3.2.1.3 Should an inspection report referred to in section 3.2.1.2 not be available and depending on the nature and risk profile of the products, the Inspectorate recommends submission of a corporate or consultant audit report for sites dealing with ethical drugs (on a case by case basis based on the risk profile of the drug), over the counter Nonprescription Drugs, medical gases, and sites performing sterilization of packaging materials for products which will be aseptically filled without undergoing terminal sterilization. The information in section 3.2.1.2, subsections C to G should also be provided, and the audit report should meet the following conditions:

1. an explanation why a consultant or corporate audit report is submitted
2. the qualifications and experience of the individual(s) performing the inspection must be provided. As a minimum, the individual(s) must have sufficient experience and knowledge of GMP. Further guidance is available in the interpretation of section C.02.006 of the "Good Manufacturing Practices (GMP) Guidelines (GUI-0001)"
3. the audit is conducted, section by section, against the Canadian GMP Guidelines and all applicable sections are assessed.
4. any deficiencies noted during the audit must be classified using the document entitled "Risk Classification of GMP Observations (GUI-0023)"
   Note: Any Risk 1 or Risk 2 deficiencies that would lead to a non-compliant rating according to this guide would render the site unacceptable. The classification of deficiencies will be reviewed by the Inspectorate.
5. the audit report must be signed and dated by the auditor or audit team, and must be accompanied by a copy of the corrective actions taken, which has been signed by a responsible official of the foreign site
6. the adequacy of the corrective actions are assessed by the auditor or audit team.
   Note: The corrective actions will also be reviewed by the Inspectorate to determine if they are adequate.
7. If an inspection report more than 3 years old from a Regulatory Authority or a Qualified Authority is available, the report should accompany the consultant or corporate report.

   A form entitled "Good Manufacturing Practices - Audit Report Form (FRM-0211)" has been developed and may be used to ensure that all of the criteria outlined above are met. This form is available on the Inspectorate website. The use of this template does not guarantee that a compliant rating will be assigned to a foreign site, however it will ensure a more efficient and timely review by the Inspectorate. Additional documentation may be requested depending on the nature of the submission.

3.2.2 Submission of information to the Inspectorate
The information in sections 3.2.1.2 and/or 3.2.1.3 should be normally submitted to the Inspectorate in the DEL Renewal package. However, should the DEL holder, or sponsor wish to submit the information at any other time, the request should be made on form entitled "Good Manufacturing Practices - Foreign Site Submission Form (FRM-0212)" available on the Inspectorate website, and faxed to 613-957-6709 or emailed to foreign_site_etranger@hc-sc.gc.ca

3.2.3 Request for additional information by the Inspectorate
At any time during the assessment of the documentation submitted, additional information and/or clarification may be requested in order to fully assess the compliance of the foreign site with Division 2 of the FDR. For instance, where a site has a poor compliance history, repeat observations are noted, and/or the information is not sufficient to fully assess compliance with Division 2. The refusal to submit additional information and/or the submission of incomplete information may result in the Inspectorate being unable to assess the compliance of the foreign site, and as such, no compliance rating will be issued.

3.3 Period of validity for Drug GMP compliance evidence of foreign sites

3.3.1 For sites in a MRA country, for products and activities (fabrication, packaging, labelling, testing) covered under the MRA, for which a CoC has been received by the Inspectorate

The period of validity or expiry date of these CoC is assigned by the Regulatory Authority.

To match the end of the period of validity with the expiry date of the EL, the expiry date of the CoC will always be reassigned to December 31 using the criteria described in 3.4.2 below

3.3.2 For sites not located in a MRA country, or for sites located in a MRA country for products and activities not covered under the MRA.

To match the end of the period of validity of the information submitted with the expiry date of the DEL (which is December 31^st of each year), the expiry date is set as December 31^st and will be assigned as follows:

• generally, for reports dated June 30^th or before in a given year, the expiry date will be set as 2 years plus the remaining period of the year from the date of inspection, and;
• for reports dated July 1^st or after in a given year, the expiry date will be set as 3 years plus the remaining period of the year from the date of inspection.

e.g.:
   -if a report is dated March 1^st, 2008, the expiry date will be set as December 31^st, 2010
   -if a report is dated August 1^st, 2008, the expiry date will be set as December 31^st, 2011

In most cases, the information will be considered valid for a period not exceeding 42 months from the date of the inspection but not less than 30 months.

If a site has a questionable compliance history, repeat observations are noted, and/or the Inspectorate requires additional information in order to fully assess compliance with Division 2, a shortened expiry date may be issued, until that additional information is received and assessed.

3.4 Terms and Conditions

Pursuant to sections C.01A.008 of the FDR, the Minister may set out in an establishment license terms and conditions respecting:

• (a)   the tests to be performed in respect of a drug, and the equipment to be used, to ensure that the drug is not unsafe for use; and
  
• (b)   any other matters necessary to prevent injury to the health of consumers, including conditions under which drugs are fabricated, packaged/labelled or tested.

And, pursuant to section C.01A.012 of the FDR, the Minister may amend the terms and conditions of an Establishment Licence if the Minister believes on reasonable grounds that an amendment is necessary to prevent injury to the health of the consumer. In such cases, the Minister shall give at least 15 days notice in writing to the holder of the Establishment Licence of the proposed amendment, the reasons for the amendment and its effective date.

Should, in the opinion of the Inspectorate, Terms and Conditions be required for a foreign site, these Terms and Conditions will be listed on the Canadian DEL.

3.5 Ownership of information

Any of the above documentation submitted to Health Canada is owned by the Crown, as duly represented by the Inspectorate and under its control, and is subject to the dispositions of any applicable Act including the Access to Information Act.

Appendix A

Acronyms

CoC: Certificate of Compliance

DEL: Drug Establishment Licence

FDR: Food and Drug Regulations

GMP: Good Manufacturing Practices

HPFB: Health Products and Food Branch

Inspectorate: Health Products and Food Branch Inspectorate

MRA: Mutual Recognition Agreement

PIC/S: Pharmaceutical Inspection Cooperation Scheme

Glossary of Terms

Certificate of Compliance (CoC) (certificat de conformité (CC)) - A certificate issued by a Regulatory Authority attesting to the GMP compliance of a recognized building in that country. In Canada, the CoC is issued by the HPFB Inspectorate.

Compliant (C) (conforme (C) ) - At the time of the inspection, the regulated party has demonstrated that the activities it conducts are in compliance with the Food and Drugs Act and its associated Regulations. A C rating does not mean that there are no observations or corrective actions required.

Drug (drogue) - In Division 1A and Division 2 of the Food and Drug Regulations, "drug" "means a drug in dosage form, or a drug that is a bulk process intermediate that can be used in the preparation of a drug listed in Schedule C to the Act or in Schedule D to the Act that is of biological origin. It does not include a dilute drug premix, a medicated feed as defined in Section 2 of the Feeds Regulations, 1983, a drug that is used only for the purposes of an experimental study in accordance with a certificate issued under Section C.08.015 or a drug listed in Schedule H to the Act." (C.01A.001(2))

Ethical Drug (spécialité médicale) - A drug that in accordance with Federal Legislation does not require a prescription, but that is generally prescribed by a medical practitioner.

Foreign Site (site étranger) - An establishment (building) that is outside of Canada that performs fabrication, packaging/labelling, or testing for drugs that are sold in Canada.

Mutual Recognition Agreement (MRA) (accord de reconnaissance mutuelle (ARM)) - "An international agreement that provides for the mutual recognition of compliance certification for Good Manufacturing Practices for drugs." (C.01A.001)

MRA Country (pays participant à un ARM) - A country that is a participant to a mutual recognition agreement with Canada. (C.01A.001).

Non-Compliant (NC) (non-conforme (NC) ) - At the time of the inspection, the regulated party has not demonstrated that the activities it conducts are in compliance with the Food and Drugs Act and its associated Regulations.

On-Site Evaluation (évaluation sur place) - An On-Site Evaluation is a product specific evaluation conducted by the Biologics and Genetic Therapies Directorate (BGTD) at the site of manufacture of a Schedule D drug (intermediate or finished product) to assess the premises in which the drug is manufactured, the process, conditions and control of manufacture and conformity with the information submitted in support of that drug

Qualified Authority (autorité qualifiée) - A member of the Pharmaceutical Inspection Cooperation/Scheme (PIC/S) or the United States Food and Drug Administration (USFDA).

Recognized Building (bâtiment reconnu) - "In respect of the fabrication, packaging/labelling or testing of a drug, a building that a regulatory authority that is designated under subsection C.01A.019(1) in respect of that activity has recognized as meeting its Good Manufacturing Practices standards in respect of that activity for that drug." (C.01A.001)

Regulatory Authority (autorité réglementaire) - "A government agency or other entity in an MRA country that has a legal right to control the use or sale of drugs within that country and that may take enforcement action to ensure that drugs marketed within its jurisdiction comply with legal requirements." (C.01A.001)