Background

Canada is a participant in several Mutual Recognition Agreements (MRAs) covering drug/medicinal products Good Manufacturing Practices (GMP) Compliance Programmes. For Canada, the Regulatory Operations Enforcement Branch (ROEB) of Health Canada is the regulatory authority responsible for these MRAs. The ROEB Health Products Compliance Directorate (HPCD) administers the drug/medicinal products GMP Compliance Programme.

On this page:

• Introduction
• Purpose and scope of a Mutual Recognition Agreement
• Objectives of a Mutual Recognition Agreement
• Parameters for a Mutual Recognition Agreement
• Equivalence of GMP compliance programmes for drug/medicinal products
• Appendix A : Principles for a Mutual Recognition Agreement
• Appendix B: Components of a GMP Compliance Programme
• Appendix C : MRA Evaluation Guide
• Appendix D: Component of a Two-Way Alert Programme

Introduction

The Mutual Recognition Agreement (MRA) approach is an effective way for Canada to enhance international regulatory cooperation and maintain high standards of product safety and quality for its drug/medicinal products Good Manufacturing Practices (GMP) Compliance Programme, while facilitating the reduction of the regulatory burden for industries.

The MRAs provide opportunities to develop closer and stronger relationships among regulatory authorities and facilitate harmonization of practices without diminishing Canadian high standards of health and safety.

Health Canada has four established MRAs covering drug/medicinal products Good Manufacturing Practices (GMP) Compliance Programmes in place.

Bilateral with Australia and Switzerland

Multilateral with:

• European Economic Area - European Free Trade Association (EEA EFTA) countries and
• the European Union Member states under the Comprehensive Economic Trade Agreement (CETA) - Protocol between the European Union (EU) and Canada on the Mutual Recognition of the Compliance and Enforcement Programs regarding Good Manufacturing Practices (GMP) for Pharmaceuticals Products (herein referred to The CETA Protocol on Pharmaceuticals).

Purpose and Scope of a Mutual Recognition Agreement

The purpose of MRAs is the recognition of equivalency of the drug/medicinal product GMP Compliance Programme of regulatory authorities.

The MRAs cover all drug/medicinal products manufactured in both countries to which GMP requirements apply, and specifically those that are imported and exported between the countries.

In the Canadian regulatory regime, the term "drugs" includes all products regulated under the Food and Drugs Act and Regulations. This definition covers biologicals, pharmaceuticals, Active Pharmaceuticals Ingredients (API) and radiopharmaceuticals.

GMP are part of quality assurance. They ensure that drugs are consistently produced and controlled. Drugs must meet the quality standards for their intended use as outlined in the marketing authorization or product specifications.

Objectives of a Mutual Recognition Agreement

1. To foster the development of a more effective international system of drug/medicinal products GMP regulation by utilizing the resources available to both Parties' regulatory agencies in the most efficient and effective manner.
2. To foster an international trade environment for drug/medicinal products within which import/export exchanges are enhanced without diminishing the high standards of product safety and quality which exist in both jurisdictions.
3. To develop an infrastructure for on-going communications/consultations between Canada and other regulatory authorities with the same high standards of safety and quality.

Parameters for a Mutual Recognition Agreement on GMP Compliance Programmes

The MRAs are based on the following three critical parameters:

1. Equivalency of the components and mechanisms included in a GMP compliance programme (refer to Appendix B);
2. Equivalency of the components and mechanisms for a "two-way" alert programme; and
3. A confidence building period during which both Parties build confidence by:
   • evaluating and determining the equivalence of their respective GMP compliance(refer to Appendix C);
   • implement a "two-way" alert programme (refer to Appendix D); and,
   • designing a "MRA maintenance programme".

Equivalent Drug/Medicinal Products GMP Compliance Programmse

The underlying principle behind a MRA for GMP compliance is to demonstrate that Canada and the other Party have equivalent drug/medicinal product GMP compliance programmes.

The GMP compliance programme of the other Party is evaluated during a confidence building exercise preceding the implementation of the operational phase of the MRA. This evaluation consists of a thorough review of legislation, policies, guidelines and procedures, followed by an on-site evaluation to determine the equivalency of the inspection process of the participating regulatory authority.

It should be understood that equivalent does not mean identical but it does mean leading to the same result.

Once equivalency is demonstrated, the operation phase consists of an exchange of Certificates of GMP Compliance between regulators, as the only evidence required certifying that the establishment complies with GMP requirements ( GUI-0080 How to demonstrate foreign building compliance with drug good manufacturing practices). The certification with the Internationally Harmonised Requirements for Batch Certification by the manufacturer on the conformity of each batch is recognised by the other Party without re-control/re-testing at import. In addition, the operational phase includes participation in the Two Way Alert and Maintenance Programmes.

Appendix A

Principles for a Mutual Recognition Agreement

The following principles are the foundation for the development of an MRA:

1. There can be no trade-offs between the objectives of health and safety and the objectives of trade. While all steps will be taken to reduce barriers to trade, the health and safety of the respective populations will remain paramount.
2. The MRA does not override the provisions of the legislations and regulations governing participating competent regulatory authorities but rather forms part of the framework in which regulatory decisions are made within each jurisdiction.
3. Participation by a competent regulatory authority in a MRA does not require that the regulatory authority relinquish its authority in its jurisdiction.
4. The acceptance of certification by the other Party's regulatory authorities depends on the successful completion of a confidence building exercise and on an evaluation of its results. Certification is only accepted from regulatory authorities with GMP compliance programmes (including the supporting infrastructure of regulatory requirements, standards, processes, and quality systems) mutually recognized as equivalent.
5. The relevant regulatory authorities of both Parties are kept informed of all changes in procedures related to GMP compliance, such as new inspection procedures or technical guidelines and changes in regulation. Each Party consults with the other before adopting these changes to ensure the continued equivalence of the programmes.
6. The regime of inspection/establishment licence fees is determined by the location of the manufacturer. The cost recovery programmes and the fees pertaining to the issuance of Manufacturing Authorizations/Licences in each jurisdiction remain the responsibility of that jurisdiction.
7. The continuous monitoring of the GMP compliance programmes determined to be equivalent at the conclusion of the confidence building exercise and any subsequent decisions concerning that equivalence must be made according to a mutually developed and managed "MRA maintenance programme".
8. Each Party shall guarantee that it has the necessary authority to protect from public disclosure any non-public confidential technical, commercial and scientific information, including trade secrets and proprietary information that is provided by the other Party.

   The sharing of non-public confidential technical, commercial and scientific information, including trade secrets and proprietary information, with the other Party, remains subject to the relevant laws of each Party for the purposes of assessing the conformity of the products with the regulatory requirements governing safety, effectiveness, and quality of the product covered by this agreement.

Appendix B

Components of a GMP Compliance Programme

The components of the GMP compliance programme are used to determine the equivalence of the relevant regulatory programmes and to ensure the mutual understanding of the GMP compliance programme of each Party's regulatory authorities.

Components/Criteria

1. Legislative and Regulatory Requirements and Scope

• Empowering legislation and regulations including authority to enforce laws and regulations, powers given to inspectors to conduct inspections, authority to remove violative products from the market, etc.
• Suitable controls on conflict of interest

2. Regulatory Directives and Policies

• Procedures for designating inspectors
• Enforcement policies/guidelines/procedures (inspection, re-inspection, corrective action)
• Codes of conduct/ethics
• Training/certification policies/guidelines
• Alert/crisis management policies/procedures/guidelines
• Organizational structure, including roles, responsibilities and reporting relationships

3. Good Manufacturing Practices (GMP) Standards

• Scope/details of GMPs necessary for the control of the manufacture of drug products
• Process validation requirements

4. Inspection Resources

• Staffing - initial qualifications, certification for inspectors
• Number of inspectors in relation to size of industry (in-house, contract, third party)
• Training/certification programmes/processes for inspectors (e.g. frequency of training)
• Quality assurance mechanisms to ensure effectiveness of training programmes

5. Inspection Procedures (pre-inspection, inspection, and post-inspection activities)

• Inspection strategy (type, scope, scheduling, focus of inspection, notification of inspections, risk based inspections)
• Pre-inspection preparation/requirements
• Format and content of inspection reports (including support tools e.g. hardware)
• Inspection methodology (access to and review of firm's files and databases, collection of evidence, data review, sample collection, interviews)
• Standard Operating Procedures (SOPs) for inspection
• Post-inspection activities (procedures for report issuance, follow-up, decision making)
• Storage of inspection data

6. Inspection Performance Standards

• Frequency/number of inspections, quality and timeliness of inspection reports, norms/frequency/procedures for re-inspection and corrective action

7. Enforcement Powers and Procedures

• Provision of written notices of violation to firms
• Non-compliance management procedures/mechanisms (recall, suspension, quarantine of products, licence revocation, seizure, prosecution)
• Appeal mechanisms
• Other measures to promote voluntary compliance by firm

8. Alert and Crisis Systems

• Alert mechanisms
• Crisis management mechanisms
• Alert performance standards (appropriateness and timeliness of alert)

9. Analytical Capability

• Access to laboratories with capacity to handle necessary analysis
• Standard Operating Procedures (SOPs) for analytical support
• Processes for validation of analytical method

10. Surveillance Programme/Measures (used by firm and by regulatory authority)

• Sampling and audit procedures
• Recall monitoring (including effectiveness controls and verifications of procedures)
• Consumer complaint system/procedures
• Adverse reaction reporting system/procedures
• Drug product defect reporting system/procedures

11. Quality Management Systems

• Quality management/assurance system/procedures to ensure the ongoing suitability and effectiveness of policies, procedures, guidelines and systems used to achieve the objectives of the GMP compliance programme, including establishment of standards and annual audit and review.

Appendix C

MRA Evaluation Guide

Under the Mutual Recognition Agreement (MRA) program, the equivalency of a regulatory authority's Good Manufacturing Practices (GMP) compliance programme is evaluated and determined using the " MRA Evaluation Guide ".

This Evaluation Guide covers the 11 components of a GMP compliance programme (Appendix B) such as legislation and regulatory requirements, GMP standards, processes and quality systems. These are grouped into subcomponents which are ranked in terms of importance (critical, very important and important). The guide is internationally harmonized with the Europe Medicines Agency's Joint Audit Program (EMA JAP) and the Pharmaceutical Inspection Co-operation Scheme (PIC/s) Joint Reassessment Program (JRP) assessment tools.

Appendix D

The components and mechanisms for a "two-way" alert programme includes:

1. Documentation

• Definition of a crisis/emergency and under an alert
• Standard Operating Procedures (SOPs)
• Mechanism of health hazards evaluation and classification
• Language of communication and transmission of information

2. Crisis Management System

• Crisis Analysis and communication mechanisms
• Establishment of contact points
• Reporting mechanisms

3. Enforcement Procedures

• Follow-up mechanisms
• Corrective action procedures

4. Quality Assurance System

• Pharmacoviligance programme
• Surveillance/monitoring of implementation of corrective action