Under European Union (EU) law, all manufacturers and importers of medicines located in the European Economic Area (EEA) must hold a manufacturing authorisation. These authorisations are supervised by medicines regulatory authorities in Member States (the 'supervisory authorities'), which are responsible for issuing authorisations for activities taking place in their territories.
The supervisory authorities must perform inspections of manufacturing-authorisation holders to ensure that they are adhering to the principles and guidelines of good manufacturing practice (GMP).
For products imported from countries outside the EU, the supervisory authority is responsible for verifying that the manufacturer conforms to standards of GMP equivalent to those in force in the EU, unless the country has negotiated an appropriate agreement with the EU establishing mutual recognition of GMP inspections. The supervisory authority for manufacturing sites in countries outside the EU is the regulatory authority that issues the manufacturing authorisation to the importer.
The European Medicines Agency’s Manufacturing and Quality Compliance Section coordinates GMP inspections of manufacturing sites connected to centrally authorised human and veterinary medicines.
- For more information, see the standard operating procedure on co-ordination of GMP/GDP inspections.
The responsibility for carrying out inspections rests with the regulatory authority the the Member State that is responsible for supervising the manufacturer or importer.
Number of inspections performed from 1999 to 2009
GMP inspections may take place when an application for a marketing authorisation is received. This is to check the GMP compliance of the manufacturers connected to the medicine concerned or to investigate a specific matter arising from the assessment of the application.
Inspections also take place periodically after the granting of a marketing authorisation as part of the ongoing supervision of manufacturers.
This graph below shows the numbers of inspections carried out following requests by the Agency between 1999 and 2009. It covers pre- and post-authorisation for human and veterinary medicines.
Manufacturers located within the EEA are under the direct supervision of regulatory authorities in Member States. Because of this, the Agency does not specifically request inspections of manufacturers located in the EEA except when the need arises for a specific medicine. This is usually during the pre-authorisation phase of a centralised marketing-authorisation application.
This means that most inspections requested by the Agency are in countries outside the EU ('third countries').
Most inspections are carried out by teams of inspectors from two countries. The lead is usually the supervisory authority, supported by another authority. The supporting authority often shares supervisory responsibility with the lead. This occurs when a medicine from a particular manufacturing site outside the EU is directly imported into more than one Member State.
The pattern of commercial activity results in an uneven distribution of responsibility. In the interests of flexibility and better use of resources, the Agency is keen to involve all Member States in its GMP inspection programmes, even if they have no formal supervisory responsibility.
These pie charts illustrate the distribution of inspection activities at the end of 2009.
The Agency has conducted two pilot programs of inspections with international partners:
- International active-pharmaceutical-ingredient inspection programme
In 2011, EMA began an initiative on GMP inspection of active-pharmaceutical-ingredient (API) manufacturers with five EU Member States (France, Denmark, Ireland, Italy and the United Kingdom), the European Directorate of the Quality of Medicines and Healthcare (EDQM), United States Food and Drug Administration (FDA), Australian Therapeutic Goods Administration (TGA) and World Health Organization (WHO).
The programme aims to increase cooperation and mutual reliance between regulators participating in the initiative as well as to ensure the best use of inspection resources worldwide:
- Programme to rationalise international GMP inspections of active pharmaceutical ingredients/active substances manufacturers: Terms of reference and procedures for participating authorities
The programme began with a pilot from December 2008 to December 2010, involving competent authorities from Australia, Europe and the United States. Based on the positive experience, the agencies agreed to continue collaborating, taking experiences and lessons learned into account. The programme includes Health Canada since December 2015 and PMDA Japan from December 2016.
This collaboration is not linked and is without prejudice to the EU Falsified Medicines Directive, which adds specific rules on the import of active substances into the EU.
- EMA /FDA inspection programme for finished-dosage-form manufacturers
The Agency is conducting a joint inspection programme on finished-dosage-form manufacturers.
The programme began with the agencies organising joint pre-authorisation inspections. However, this required simultaneous submissions of marketing-authorisation applications to both agencies, with manufacturing sites in the US or the EU. It also required both applications to trigger pre-authorisation inspections of similar scope. Consequently, the results were limited to two joint inspections conducted in 2009.
Because of these limitations, the agencies agreed to extend the scope of this programme to routine surveillance inspections. This involves the exchange of information and planning for possible joint routine surveillance inspections. This began in October 2010. The Agency published a reminder about this collaboration in August 2010, inviting companies to participate in the pilot programme for upcoming FDA or EMA pre-authorisation or routine surveillance inspections.
The EMA and FDA also launched an initiative to share work on inspections of manufacturing sites in each other's territories in January 2012. This enables the two authorities to rely on each other's inspection outcomes rather than carrying out separate inspections in duplicate. The initiative applies to inspections of manufacturing sites of human or veterinary medicines in the EEA or USA, focusing on sites that are already known to the two authorities and have a history of compliance with GMP following previous inspections. The outcomes of the initiative will be reviewed after three years.
More detailed information about these initiatives are available in the documents below.
Table of contents
Documents of interest
|Document(s)||Language||Status||First published||Last updated||Effective Date|
|Good manufacturing practice: An analysis of regulatory inspection findings in the centralised procedure in 2006 and plasma-master-file procedure during 2004-2006 period||(English only)||2008-04-08|
|Standard operating procedure for co-ordination of GCP inspections||(English only)||adopted||2007-05-16||2012-09-27||2012-09-27|
|Good manufacturing practice: An analysis of regulatory inspection findings in the centralised procedure||(English only)||2007-01-18|