Good Manufacturing Practices (GMP)
The manufacture or import of medicinal products is subject to manufacturing or import authorisation. The authorisation holder must comply with the principles and guidelines of good manufacturing practice and use active substances (active pharmaceutical ingredients) which were manufactured in compliance with GMP. The relevant legal requirements are outlined below.
For human medicinal products and investigational medicinal products:
- Directive 2001/83/EC (Title IV Manufacture and Importation)
- Directive 2001/20/EC (Article 13 Manufacture and import of investigational medicinal products)
- Directive 2003/94/EC (GMP)
For veterinary medicinal products:
Eudralex Volume 4 of "The rules governing medicinal products in the European Union" contains guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human and veterinary use laid down in Commission Directives 2003/94/EC and 91/412/EEC, respectively. Further information can be found on the website of the EMA.
Mutual Recognition Agreements (MRAs) and related agreements on GMP with third countries
The EU has MRAs on GMP with Australia, Canada, Israel, Japan, New Zealand, Switzerland and the United States. All these agreements cover human/veterinary medicines; however the detailed product scope varies. For more details please see:
EU-US FDA mutual recognition of inspections of medicines manufacturers milestone reached
On 11 July 2019, the FDA confirmed the capability of Slovakia. The EU and the US have now fully implemented the Mutual Recognition Agreement (MRA) for inspections of manufacturing sites for human medicines in their respective territories.
Both in the EU and the US, the authorities in charge of medicines can now rely on inspections results to replace their own inspections.
Earlier the following countries were recognized as capable by US FDA:
- Germany, The Netherlands and Luxembourg in June 2019;
- Cyprus and Bulgaria in April 2019;
- Poland and Slovenia in February 2019;
- Belgium, Denmark, Estonia, Finland and Latvia in November 2018;
- Portugal in September 2018;
- Ireland and Lithuania in June 2018;
- Czechia, Greece, Hungary, and Romania in March 2018;
- Austria, Croatia, France, Italy, Malta, Spain, Sweden (and United Kingdom, a former EU country since 1 February 2020), in November 2017.
This means that the FDA can now rely on a total of 27 Member States to replace their own inspections.
From now on, the batch testing waiver will also start to apply. This means that the qualified persons in the EU pharmaceutical company will be relieved of their task for carrying out the quality controls when carried out already in the United States.
The US Food and Drug Administration (FDA) completed the capability assessments of drug manufacturing regulatory authorities in all EU countries, recognising them as capable to carry out good manufacturing practice (GMP) inspections.
For its part, the European Commission confirmed that the US FDA has the capability, capacity and procedures in place to carry out good manufacturing practice (GMP) inspections at a level equivalent to the EU, earlier in 2017.
This important agreement, which updates the mutual recognition agreement from 1998, strengthens reliance upon each other’s inspection expertise and resources. Mutual benefits for EU authorities and the FDA include:
- The ability to focus inspection resources on other parts of the world where active pharmaceutical ingredients and medicines for the EU or US markets are manufactured
- Prioritising inspections of medicines manufacturing sites for higher risk cases
- Reassuring patients that they can rely on the quality, safety and efficacy of all medicines, no matter where they have been manufactured
- Improving the ability to identify and address problems at manufacturing sites before they become a public health risk
- Reducing the administrative burdens and costs facing pharmaceutical manufacturers, including smaller producers.
To make this agreement operational, teams from the EU national competent authorities, European Commission, European Medicines Agency and the US FDA have been working intensively on auditing and assessing the respective supervisory system.
Mutual recognition currently covers medicinal products for human use with the exception of vaccines, plasma derived medicinal products, and investigational medicinal products (clinical trial material).
The Mutual Recognition Agreement implementation work will continue with view to expanding the operational scope to veterinary medicines, human vaccines and plasma derived medicinal products.
- Press release (11 July 2019)
- List of recognised authorities (February 2020) - 3a – revised list of recognised authorities
- Bilateral relations on pharmaceutical cooperation – USA
EU and Japan reinforce their collaboration on inspections of medicine manufacturers
On 18 July 2018, The EU and Japan agreed to broaden the range of medicines for which they recognise each other’s inspections of manufacturing sites. The full scope of the MRA covers chemical pharmaceuticals, homeopathic medicinal products (as long as treated as medicinal products and subject to the GMP requirements in Japan), vitamins, minerals and herbal medicines (if considered as medicinal products in both parties); certain biological pharmaceuticals including immunologicals and vaccines, active pharmaceutical ingredients (APIs) for any of the above categories and sterile products belonging to any of the above categories.
The former mutual recognition agreement (MRA) was operational since 29 May 2004. It allowed regulators to rely on Good Manufacturing Practice (GMP) inspections in each other’s territories, to waive batch testing of medicines that enter Japan from EU countries and vice versa and to share information on inspections and quality defects.
Import of active substances
Directive 2011/62/EU amending Directive 2001/83/EC introduces EU-wide rules for the import of active substances (active pharmaceutical ingredients APIs). Article 46b(2) specifies that APIs can only be imported if, they are accompanied by written confirmation from the competent authority of the exporting third country confirming similar standards of GMP and control to those of the EU.
- Questions and Answers document (version 7.0 June 2016)
- Information leaflet
- Information on listed third countries and how to apply for listing
- Evaluation guide for GMP Regulatory Compliance Programme
Good Distribution Practice (GDP)
The wholesale distribution of medicinal products and active substances is an important activity. The quality and the integrity of medicinal products can be affected by a lack of adequate control. To this end, the Commission published:
- Commission guideline 2013/C 343/01 on Good Distribution Practice of medicinal products for human use
- Commission guideline 2015/C 95/01 on principles of Good Distribution Practice for active substances for medicinal products for human use
- Questions and Answers document
Further information can be found on the website of the EMA.