Background

Canada is a participant to 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) is administering the drug/medicinal products GMP Compliance Programme.

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Introduction

The Mutual Recognition Agreement approach is an effective way to ensure the participation of the HPCD in enhancing international regulatory cooperation and maintaining high standards of product safety and quality, while facilitating the reduction of the regulatory burden for industries.

While the MRAs do not include harmonization of standards and drug regulations, they provide opportunities to develop closer and stronger relationships with other regulatory authorities. This should, in the long term, facilitate harmonization and ensure that this is accomplished without diminishing the high standards of health and safety.

The mutual recognition of compliance programmes presupposes the joint exercise to determine the equivalency of compliance programmes. The joint evaluation of these programmes provides opportunities to identify similar approaches and to resolve discrepancies. Once concluded, the MRAs increase communications between regulatory authorities and enable a better understanding of respective regulatory systems. In that sense, the MRAs foster the maintenance of high standards and high quality compliance programmes.

Terms of Reference for a Mutual Recognition Agreement

Purpose

Recognition of equivalency of the GMP Compliance Programme(s) of the regulatory authorities of the other Party.

Scope

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, and radiopharmaceuticals.

The provisions of a MRA should cover all drug/medicinal products manufactured in both countries to which GMP requirements apply, and specifically those that are imported into Canada from the other country and exported to the other country from Canada.

The scope of products covered by a MRA can be adjusted as a result of the negotiations with the other Party.

The Good Manufacturing Practices are that part of quality assurance which ensures that products are consistently produced and controlled to quality standards: appropriate to their intended use, and required by the Marketing Authorization (MA) or product specifications, and by assignment procedure of the Drug Identification Number (DIN) or the Licence.

Parameters for a Mutual Recognition Agreement on GMP Compliance Programmes

The MRA is built on three pillars:

  1. The components (refer to Appendix A) and mechanisms included in a GMP compliance programme;
  2. 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 and alert programmes; implement a "two-way" alert programme; and, design a "MRA maintenance programme".

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 exchange 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.

Principles for a Mutual Recognition Agreement

The underlying principle behind a MRA for GMP compliance is that, it can be demonstrated that Canada and the other Party have equivalent GMP compliance programmes. Once demonstrated through an evaluation process, then a GMP Compliance Certificate is all the evidence required to certify that the establishment is in compliance with GMP requirements. In addition, the certification to 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.

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

The following principles are offered as guidelines 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. Only certification by regulatory authorities with GMP compliance programmes (including the supporting infrastructure of regulatory requirements, standards, processes, and quality systems) mutually recognized as equivalent is accepted.
  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 continuing 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.

The GMP Compliance Programme(s) of the other Party is (are) evaluated during a confidence building exercise preceding the implementation or operational phase of the MRA. This evaluation includes a review of the legislation and quality system of each regulatory authority. The evaluation process requires joint visits to determine the equivalency of the inspection process of the participating regulatory authorities. Standard Operation Procedure for the determination of Equivalency of Inspection Methods

To learn more about the MRAs presently administered by the ROEB HPCD, please consult the MRAs Updates' document. MRA Updates

You can also consult web site of the Global Affairs Canada (GAC) for the texts of the Agreement and of the Sectoral Annexes, including the Drugs GMP Compliance Programme Sectoral Annex.

Appendix A

Components of a GMP Compliance Programme

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

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.

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 including 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.

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