Mutual Recognition Agreement

Pharma is a highly regulated industry. Regulatory audits are an integral part of the drug regulations. Any pharmaceutical industry having a global presence undergo numerous audits in a year by various regulatory agencies. This not only affects their productivity but also the agencies have to spend their financial resources and deploy manpower to conduct these audits. Hence, many advance regulatory agencies have developed a system of Mutual Recognition Agreement (MRA) wherein they recognize the regulatory control of each other after assessment on various parameters. This allows them to rely upon information from drug inspections conducted by each other in a particular firm and aid them in taking informed decision without actually conducting an audit.

Mutual recognition agreements (MRAs) are international agreements that specify the condition under which the participating country will accept or recognize one another’s conformity assessments, and that identify how the parties will cooperate on other activities, as specified. The primary objective of MRAs is to provide effective and efficient access throughout the territories of the MRA parties.

Benefits of MRA:

1. Strengthening use of each other’s drug inspection expertise and resources results in greater efficiencies for both regulatory systems and provide a more practical means to oversee the large number of drug manufacturing facilities.
2. Avoid duplication of inspections. Without MRA, there is a possibility that the agencies sometimes would, in the same year, inspect some of the same facilities even if the facilities had a strong record of compliance, which otherwise should have been an exception. This is to be clearly understood that the two partnering agencies may take different enforcement actions as per their laws and enforcement tools, in case of non-compliances observed during facility inspection. Although, it is expected that the impact of different enforcement actions shall be similar.
3. By utilizing each other’s inspection reports and related information, the regulatory agencies will be able to reallocate resources towards inspection of drug manufacturing facilities with potentially higher public health risks across the globe. This will benefit patients and reduce adverse public health outcomes.
4. Sharing of GMP surveillance inspection reports.
5. Waive batch testing of products on import into their territories.
6. Step toward International harmonization.

Various drug regulatory authorities like USFDA, European Union etc. have MRAs with various other agencies. The 2017 amended Sectoral Annex to the 1998 U.S.-EU MRA allows the FDA and the EU regulatory authorities to use inspection reports and other related information obtained during current Good Manufacturing Practice (GMP) surveillance inspections, whether conducted by an EU authority or by the FDA, to help determine whether a facility is manufacturing high quality drugs. Then, if necessary, the FDA or EU can require further inspections or take other action to protect the public.

Every regulatory agency has reduced their workload in their own way after getting into MRAs. For example, USFDA has continued performing inspections in foreign countries with capable inspectorates, such as product manufacturing assessment inspections to support marketing approval decisions. However, FDA expects to perform fewer routine surveillance inspections in foreign countries with a capable inspectorate. Under the MRAs in place, FDA collaborates with inspectorates in the EU and the United Kingdom and is reviewing their recent inspection reports and related information to determine a manufacturer’s suitability for the U.S. market in lieu of an FDA site inspection.

This is to be noted that entering into MRA does not mean that the partner country inspectors will never inspect in the other partner countries. They reserve the right to inspect at any time and in any country. However, surveillance inspections are expected to be the exception rather than the rule. Following capability assessments, the regulatory agencies recognize other agency as capable and thus recognize their drug manufacturing facility inspections.

As on date, most of the counties have kept pre approval inspections out of the scope of MRA. This is due to non-availability of a tool to assess each other’s capability w.r.t. pre-approval assessments.

How does the countries assess each other’s regulatory system for considering to be capable of entering into MRA?

Normally the countries perform a rigorous assessment using a pre-approved tool to recognize each other’s regulatory framework They do have a robust assessment method and decision-making tools to determine if an authority is capable of conducting drug manufacturing facility inspections according to their standards. Normally the countries should:

• have the legal and regulatory authority to conduct inspections against a standard for GMP;
• manages conflicts of interest in an ethical manner;
• evaluates risks and mitigates them;
• maintains appropriate oversight of manufacturing facilities within its territory;
• receives adequate resources and uses them;
• employs trained and qualified inspectors with the skills and knowledge to identify manufacturing practices that may lead to patient harm; and
• possesses the tools necessary to take action to protect the public from harm due to poor quality drugs or medicinal products

Does the regulatory agencies like FDA assess all the member countries in EU individually or the MRA if done with EU leads to automatic approval of all the member countries?

The European Union is made up of 27 countries each with its own regulatory authority(ies). Although the overall legal requirements and guidelines for regulatory authorities exist at the EU level, some discretion is necessarily left to the individual countries to implement the law in the best way for them. Therefore, the FDA undertook to assess each country’s regulatory authority(ies).

In September 2014, the EU invited the FDA to observe the EU’s internal audits of its regulatory authorities. These audits are meant to ensure consistency across all the EU country by assessing each regulatory authority’s processes, workforce skills and compliance with EU laws and, in particular, relevant guidelines.

The FDA’s capability assessment begins with observing the EU’s internal audit of an EU country to ensure that the authority is functioning properly and does not deviate in any significant way from EU law and guidance. These audits include observations of drug manufacturing facility inspections conducted by the audited authorities and utilize the 78 indicators based on the Pharmaceutical Inspection Co-operation Scheme (PIC/S) compliance assessment program with an EU addendum. PIC/S is an internationally recognized cooperative arrangement between 49 regulatory authorities, including the FDA. The goal of PIC/S is to harmonize inspection procedures worldwide and develop common standards in the field of good manufacturing practices.

After observing an audit of a country’s drug authority, the FDA conducts an independent and comprehensive assessment. This assessment includes a review of the country’s conflict-of interest policies, specific legislation related to good manufacturing practices, samples of inspection reports, inspector training records, inventory of drug manufacturing facilities, surveillance program, and numerous standard operating procedures.

Maintenance provisions are also included in the Annex to ensure each capable country continues to meet FDA requirements.

What happens if the inspection outcome of two MRA regulatory authorities is different after inspecting the same facility?

Although the regulatory agencies in MRA use essentially harmonized quality standards and the same underlying principles of current good manufacturing practices, it is important to note that inspections are a snapshot in time. It is the responsibility of the investigators/inspectors to only note what they see during the course of the inspection at a particular time. Therefore, observations made by one investigator/inspector at a given time may not be observed by another investigator/inspector at a different time. In other words, every inspection will have its own set of observations that may or may not overlap.

The MRA fosters collaborative efforts between trusted regulators to engage in discussions related to inspectional findings and outcomes. These discussions provide a platform for regulators to examine and ask questions about each other’s inspectional processes to better understand each other’s regulatory and enforcement frameworks. Open dialogue and collaboration between regulators will help determine the reasons why their inspections resulted in different outcomes. This information allows the regulators to learn from each other’s best practices and update their collective standards and inspectional processes, as appropriate.

What is Pharmaceutical Inspection Co-operation Scheme?

The Pharmaceutical Inspection Convention and the Pharmaceutical Inspection Co-operation Scheme (jointly referred to as PIC/S) provide a means for international cooperation in the field of GMP. PIC/S is a cooperation scheme. PIC/s membership does not mean that an MRA exists. PIC/S’s mission is to lead the international development, implementation, and maintenance of harmonized GMP standards and quality systems of inspectorates in the field of medicinal products. The purpose of PIC/S is to:

• Purpose and strengthen the cooperation established between the participating authorities in the field of inspection and related areas with a view to maintain mutual confidence and quality assurance of inspections
• Provides the framework for all necessary exchange of information and experience
• Coordinate mutual training for inspectors and for other technical experts in related field
• Continued common efforts toward the improvement and harmonization of technical standards and procedures regarding the inspection of the manufacturer of medicinal products the testing of medicinal products by official control laboratories
• Continue common efforts for the development, harmonization, and maintenance of GMP
• Extent cooperating to other competent authorities having the national arrangements necessary to apply equivalent standards and procedures with a view to contributing to global harmonization

Currently, there are member countries, including all EEA countries, Argentina, Australia, Canada, Israel, Malaysia, Singapore, South Africa, and Switzerland. The United States Food and Drug Administration (FDA) is also a participating authority.

Before a regulatory authority can become a member of PIC/S, a detailed assessment is undertaken to determine whether the authority has the arrangements and competence necessary to apply and inspection system comparable to that of current PIC/S member. This assessment involves an examination of the authority’s inspection and licensing system, quality system, legislative requirements, inspector training, and so on, and is followed by a visit from a PIC/S delegation to observe inspectors carrying out actual GMP inspections.

International Coalition of Medicines Regulatory Authorities (ICMRA) is a voluntary, executive-level, strategic coordinating, advocacy and leadership entity of regulatory authorities (USFDA, EMA, MHRA, ANVISA, PMDA, TGA) that work together to:

• address current and emerging human medicine regulatory and safety challenges globally, strategically and in an on- going, transparent, authoritative and institutional manner
• provide direction for areas and activities common to many regulatory authorities’ missions
• identify areas for potential synergies
• wherever possible, leverage existing initiatives/enablers and resources

List of Authority Recognized by FDA:

List of countries recognized by European Union (EU)

• Australia
• Canada
• Israel
• Japan
• New Zealand
• Switzerland
• United States

References:

1. EMA Mutual recognition agreements (MRA)
2. FDA Mutual recognition agreement (FDA)
3. Frequently Asked Questions about Mutual recognition agreement