Unpacking The EU's Mutual Recognition Agreements For Pharma

By Sabine Paris, Ph.D., GMP Compliance Adviser

In order to lower technical trade barriers and to advance international harmonization, the European Union (EU) has signed MRAs with a number of third countries (Canada, the U.S., New Zealand, Japan, and Switzerland). The subject of these agreements is mutual recognition of the results of conformity assessment procedures that are mandatory for market access in the signatory states' territories as well as of the certificates resulting from these procedures.

As a rule, MRAs take the following subject areas into account:

• telecommunications terminals
• electromagnetic compatibility (EMC)
• electrical safety
• good manufacturing practice (GMP) for drug products
• good laboratory practice (GLP) for chemicals
• medical devices.

When the agreements were drafted, the various subject areas were intentionally tied into a framework agreement with a corresponding number of annexes. This package solution was meant to also include those subject areas for which no stand-alone agreement would have been possible.

Objective And Scope In Relation To GMP

The GMP annexes of the individual MRAs cover the mutual recognition of the following areas:

• GMP inspections by the locally responsible authorities
• manufacturing authorizations
• batch certificates of the manufacturers.

One of the advantages of MRAs lies in the saved resources both for regulatory authorities and for the pharmaceutical industry, since, firstly, the number of third-country inspections can be reduced and, secondly, the retesting procedure required after importing a drug product to Europe can be waived.

Mutual recognition fundamentally applies to drug products for human and veterinary use and to active substances, intermediate products, and pharmaceutical bulk products as well as clinical trial preparations. In addition, the national batch release (for instance, of certain blood and immunological products) is mutually recognized within the framework of the MRA with Switzerland.

Some MRAs also foresee the recognition of inspections conducted in third countries by MRA states, in countries outside the EU, EEA, and the MRA partner states. A key requirement for this is that the respective MRA explicitly allows for the inclusion of third-country inspections. Currently, this applies to the EU's MRAs with the U.S., Canada, and Switzerland, as well as to the ACAA with Israel (see below) and the EU’s agreement with the U.K. (see below).

However, active substances and other starting materials used for manufacturing can be purchased from third countries (countries other than MRA partner states).

Simultaneously, a policy of immediate mutual notification about product recalls and other actions being taken with regard to quality deficiencies in drug products was adopted within the framework of the MRAs (Two-Way Alert System). This system also includes information about drug product counterfeiting and suspension or withdrawal of manufacturing authorizations. The information system contributes to global safety of drug products.

The MRA with Canada includes a maintenance program that ensures continuing comparability of GMP regulations as well as their monitoring for both contract parties. The maintenance program includes preparation of annual reports to ensure that information is shared on subjects such as new and updated GMP regulations or the status of the supervisory authorities' quality system. In its capacity as the responsible European authority, the EMA represented the European supervisory authorities during the agreement negotiations. Presently the EMA coordinates the flow of information and the maintenance program and organizes regular meetings with the MRA partners.

Existing Agreements

At present, MRAs exist with

• Australia
• Canada
• Japan
• New Zealand
• Switzerland
• the U.S.

The sectoral annex relating to GMP is operational for all aforementioned MRAs.

Figure 1 Scope of the MRAs

Covered by the MRA's Scope	Australia	Canada	Japan	New Zealand	Switzerland	U.S.
Human chemical pharmaceuticals, including intermediate products and bulk pharmaceuticals	Yes	Yes	Yes	Yes	Yes	Yes
Medicinal gasses	Yes	Yes	No	Yes	Yes	Yes
Human biologicals including immunologicals and biotherapeutics	Yes	Yes	Yes	Yes	Yes	Yes1
Human radiopharmaceuticals	Yes	Yes	No	Yes	Yes	Yes
Advanced therapy medicinal products (ATMPs)	No	No	No	No	Yes	No
Stable medicinal products derived from human blood or human plasma	Yes	No	No	Yes	Yes	No
Veterinary chemical pharmaceuticals	Yes	Yes	No	Yes	Yes	Yes
Veterinary immunologicals	Yes	No	No	Yes	Yes	No
Vitamins, minerals, and herbal medicines2	Yes	Yes	Yes	Yes	Yes	Yes
Homeopathic medicines2	Yes	Yes	Yes	Yes	Yes	Yes
Investigational medicinal products (IMPs)	Yes	Yes	No	Yes	Yes	No
Third country inspections	No	Yes	No	No	Yes	Yes
Active pharmaceutical ingredients (APIs)	Yes	No	Yes	No	Yes	Yes
Official batch release	No	No	No	No	Yes	No

• ¹ Except vaccines
• ² For medicinal products; in the case of Canada, only if the Canadian authority confirms that the products have been manufactured in accordance with the GMP regulations applicable to medicinal products; in Canada, herbal medicinal products, homeopathic medicinal products, and vitamins and minerals are no longer covered by the Medicines Act (now Natural Health Products) as of January 2004; Canada accepts European MRA certificates for these products.

 

The Japanese Ministry of Health, Labour and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA) have been entering information on GMP compliance of Japanese manufacturers into the EudraGMDP database since 2013. The Swiss regulatory authority Swissmedic has been entering its data since the beginning of 2019. This allows the authorities involved to use the information in the database instead of specially issued GMP certificates. This shortens the regulatory process.

EU Agreement With Israel

On January 19, 2013, the European Commission published an Agreement on Conformity Assessment and Acceptance of Industrial Products (ACAA) with Israel. The agreement entered into force upon publication.

An ACAA goes beyond an MRA, as the partner country must not only have comparable legislation in the area concerned but must also fully implement the European legislation – comparable to a new member of the EU.

The ACAA with Israel provides for mutual recognition in the following areas:

• inspection systems of the authorities in the pharmaceutical sector
• results of inspections
• manufacturing and import authorizations
• certification by the manufacturer or importer in the territory of the parties that each batch conforms to its specifications.

The GMP Annex to the ACAA covers medicinal products, active ingredients, excipients or mixtures thereof for human or veterinary use that are subject to GMP requirements. This applies to chemical and biological medicinal products, immunologicals, radiopharmaceuticals, and herbal medicinal products. However, medicinal products derived from human blood or plasma, advanced therapy medicinal products (ATMPs), investigational medicinal products, homeopathic medicinal products, medical gases, and veterinary immunologicals are not yet covered by the ACAA (see Figure 2).

Figure 2 Scope of the ACAA between the EU and Israel

Scope of the ACAA	Covered	Not covered
Human chemical and biological pharmaceuticals, active pharmaceutical ingredients, excipients, intermediate products, and bulk pharmaceuticals	x
Veterinary chemical and biological pharmaceuticals, active pharmaceutical ingredients, excipients, intermediate products, and bulk pharmaceuticals	x
Vitamins, minerals, and herbal medicines if classified as medicinal products	x
Excipients	x
Official batch release	x
Medicinal products derived from human blood or human plasma		x
Advanced therapy medicinal products (ATMPs)		x
Investigational medicinal products (IMP)		x
Homeopathic medicines		x
Medicinal gases		x
Veterinary immunologicals		x

 

In practice, the ACAA means that inspection reports, manufacturing and import authorizations, GMP certificates, and batch certificates are mutually recognized. There is therefore no need for retesting in the EU. The ACAA is therefore similar to the mutual recognition between MRA partners. Unlike the MRA agreements, the ACAA also recognizes inspections carried out in third countries.

EU Trade And Cooperation Agreement With The U.K.

Following the United Kingdom's withdrawal from the EU, the EU has concluded a trade and cooperation agreement with the U.K., which has been in force since January 1, 2021. The agreement contains a special annex on medicinal products (Annex TBT2 - Medicinal Products), which regulates the mutual recognition of the outcomes of GMP inspections and official GMP documents.

The agreement covers the following products for human and veterinary use:

• marketed medicinal products, including marketed biological and immunological products
• advanced therapy medicinal products (ATMPs)
• active pharmaceutical ingredients
• investigational medicinal products.

International Cooperation For Inspecting Manufacturers Of Active Substances

Between 2008 and 2010, a pilot program on international cooperation in inspecting manufacturers of active substances in third countries was implemented. Five European supervisory authorities, the European Directorate for the Quality of Medicines and Healthcare (EDQM), FDA, and the Australian Therapeutic Goods Administration (TGA) participated in the program.

Following the successful completion of the pilot phase, this cooperation has been continued with other EEA authorities and the WHO.

Inspection plans and inspection reports are exchanged within the program. Joint inspections will also be carried out in third countries (outside the countries participating in the program).

The aim of the cooperation is to support risk-based planning of inspections on the basis of the information collected, thus allowing a more efficient use of global inspection resources.

The principles of the program and the cooperation are published on the EMA website.

Editor's Note: This article is an excerpt from GMP knowledge contained in the online portal GMP Compliance Adviser, which provides in-depth information about GMP best practices and regulations with a focus on Europe but also referring to the U.S., Japan, and many more (PIC/S, ICH, WHO, etc.).

About The Author:

Sabine Paris is a senior GMP expert entrusted with safeguarding the regulatory accuracy and integrity of GMP Verlag Peither’s knowledge portals. She also serves as a specialist editor, reports on international conferences, and acts as the primary technical liaison for global partners. She is a pharmacist with a Ph.D. in pharmaceutical analytics and has held roles in marketing authorization, medical science, and medical marketing. From 2005 to 2013, she held the position of head of the pharmaceuticals division at the Central Authority of the Länder for Health Protection (ZLG). In this capacity, she represented the German federal states in the EMA’s GMP/GDP Inspectors Working Group and in the international PIC/S committee.