Good manufacturing practice

This content applies to human and veterinary medicines.

Good manufacturing practice (GMP) describes the minimum standard that a medicines manufacturer must meet in their production processes. The European Medicines Agency (EMA) coordinates inspections to verify compliance with these standards and plays a key role in harmonising GMP activities at European Union (EU) level.

Any manufacturer of medicines intended for the EU market, no matter where in the world it is located, must comply with GMP.

GMP requires that medicines:

• are of consistent high quality;
• are appropriate for their intended use;
• meet the requirements of the marketing authorisation or clinical trial authorisation.

Guidance is available for marketing authorisation holders, manufacturers and importers of human and veterinary medicines on adaptations to the regulatory framework to address challenges of the COVID-19 pandemic, including with GMP certificates and inspections:

• Notice to stakeholders: Questions and answers on regulatory expectations for medicinal products for human use during the COVID-19 pandemic
• Notice to stakeholders: Questions and answers on regulatory expectations for medicinal products for veterinary use during the COVID-19 pandemic

This does not waive manufacturers' and importers' obligations to comply with GMP standards.

For new sites and facilities within and outside the EEA that have not been inspected or where an inspection is required, a remote inspection may be carried out. On-site inspections will resume as soon as feasible.

EU authorities may not be able to conduct inspections in some non-EU countries where travel restrictions are in force. Restrictions can include measures such as quarantines.

For such cases as described above, delays may occur in the evaluation procedure for a marketing authorisation, if this requires a pre-authorisation GMP inspection of a proposed manufacturing and / or control site.

Applicants are strongly advised to consider the potential impact of travel restrictions on inspections required for their marketing authorisation application. In such scenarios, they can mitigate them by:

• if possible, identifying and including manufacturing and / or control sites with no travel restrictions;
• liaising with the relevant national authorities where the sites are located to verify whether existing restrictions can be waived or eased.

Please consult the chapter dedicated to inspections in the document below.

• European Medicines Agency pre-authorisation procedural advice for users of the centralised procedure

The guidance was agreed by the GMP/GDP Inspectors Working Group coordinated by EMA, the European Commission, the European medicines regulatory network and endorsed by the EU Executive Steering Group on Shortages of Medicines Caused by Major Events. It is updated as the pandemic develops.

For more information, see:

• Guidance for medicine developers and companies on COVID-19: Regulatory expectations and flexibility

The Agency has a coordinating role for GMP inspections of manufacturing sites for medicines whose marketing authorisation in the EU is submitted through the centralised procedure or as part of a referral procedure.

The Agency also plays a key role in coordinating and harmonising GMP activities at an EU level. It is involved in:

• coordinating the preparation of new and revised guidance on GMP;
• ensuring common interpretation of EU GMP requirements and related technical issues;
• developing EU-wide procedures on GMP inspections and related activities;
• facilitating cooperation between Member States for inspections of manufacturers in third countries.

Marketing authorisation holders and applicants need to use EMA's IRIS system to communicate with EMA on GMP inspections requested by the Agency’s scientific committees.

Using IRIS for GMP inspections improves efficiency by harmonising and automating processes and re-using master data held by EMA. It also simplifies retrieving and reporting data.

More information on the use of EMA's IRIS system:

• IRIS system

Three legal instruments lay down the principles and guidelines of GMP in the EU:

• Regulation No. 1252/2014 and Directive 2003/94/EC, applying to active substances and medicines for human use;
• Directive 91/412/EEC applying to medicines for veterinary use.

In addition Directive 2001/83/EC and Directive 2001/82/EC lay down related provisions.

The EU GMP guidelines provide interpretation of these principles and guidelines, supplemented by a series of annexes that modify or augment the detailed guidelines for certain types of product, or provide more specific guidance on a particular topic.

The GMP / Good Distribution Practice (GDP) Inspectors Working Group provides additional interpretation of the EU GMP guidelines in the form of questions and answers (Q&As).

Annex 1: Manufacture of Sterile Medicinal Products was revised in August 2022. It comes into operation on 25 August 2023 except for point 8.123 which is postponed until 25 August 2024.

Manufacturers and importers located in the European Economic Area (EEA) must hold an authorisation issued by the national competent authority of the Member State where they carry out these activities.

They must comply with EU GMP to obtain a manufacturing or import authorisation. They can ensure that they meet all their legal obligations by following the EU GMP guidelines.

Importers are responsible to ensure that the third country manufacturer they are importing from comply with GMP.

Marketing authorisation applicants are responsible to ensure that the proposed manufacturing sites included in the marketing authorisation application comply with GMP. For more information, see section 5.2 Inspections of the Pre-authorisation guidance.

Manufacturers of active substances intended for the manufacture of human medicines for the EU market must register with the national competent authority of the Member State where they are located.

Active substance manufacturers must comply with GMP. In addition, the manufacturer of the finished product is obliged to ensure that the active substances they use have been manufactured in compliance with GMP.

Importers of active substances intended for the EU market are also required to register. In addition, each consignment needs to be accompanied by a confirmation by the competent authority of the country where it is produced that it conforms to GMP standards equivalent to those in the EU, unless a waiver applies.

In the EU, national competent authorities are responsible for inspecting manufacturing sites located within their own territories.

Manufacturing sites outside the EU are inspected by the national competent authority of the Member State where the EU importer is located, unless a mutual recognition agreement (MRA) is in place between the EU and the country concerned. If an MRA applies, the authorities mutually rely on each other's inspections.

If products are imported directly into more than one Member State from a manufacturing site outside the EU, there may be more than one national competent authority responsible for inspecting it. EMA facilitates cooperation between the authorities concerned in supervising the site.

EU competent authorities plan routine inspections following a risk-based approach, or if there is suspicion of non-compliance.

EudraGMDP is a publicly accessible EU database which contains manufacturing and import authorisations, registration of active substance manufacturers, GMP certificates and non-compliance statements.

After inspecting a manufacturing site, EU competent authorities issue a GMP certificate or a non-compliance statement, which is entered in the EudraGMDP database.

EMA chairs and provides the secretariat for the GMP/GDP Inspectors Working Group of senior inspectors appointed by all the EEA competent authorities. It meets at EMA four times a year.

The European Commission and observers from EU accession countries, mutual recognition partner authorities, the European Directorate for the Quality of Medicines and HealthCare and the World Health Organization also attend the working group's meetings.

The group provides a forum for harmonisation and discussion of common issues, such as:

• updates or amendments to the EU GMP guidelines;
• the compilation of Union procedures;
• harmonised interpretation of GMP and related requirements.

EMA maintains a compilation of GMP and good distribution practice (GDP) inspection-related procedures and forms agreed by all Member States. This facilitates cooperation between EU Member States and supports harmonisation and exchange of inspection-related information.

It covers the basis for national procedures that form part of the national inspectorates' quality systems:

EMA published the Word and PDF versions of some of the templates for the convenience of inspectorates

Important
The forms and templates should be downloaded and saved first before being completed, using for example “Save target as” function. To report any technical issues with the form, please use the EMA Service Desk portal.

• Rapid alert notification of a quality defect / recall
• Follow-up and non-urgent information for quality defects
• Good-manufacturing-practice inspection report - Community format

Revision of template for serious GMP non-compliance

EMA's GMP/GDP Inspectors Working Group is discussing actions required after an inspection concludes that a manufacturing site does not comply with GMP, specifically where this can lead to a shortage of critical medicines. EMA has held a public consultation on an updated template for GMP non-compliance statement in 2018:

• Public consultation concerning the EU template for GMP non-compliance statement

Plasma master file (PMF) inspections

For products derived from blood or blood plasma, EMA is responsible for coordinating inspections of the blood establishments in which collection, testing, processing, storage and distribution is carried out under the PMF certification procedure.

For more information on the PMF certification procedure, see Plasma master files.

Vaccine antigen master file (VAMF) inspections

EMA is responsible for coordinating inspections of vaccine antigen manufacturing sites under the VAMF certification procedure.

For more information on the VAMF certification procedure, see Vaccine antigens.

The EU has signed mutual recognition agreements on GMP inspections with regulatory authorities outside the EU. This allows EU authorities and their counterparts to:

• rely on each other's GMP inspections;
• waive batch testing of products on entry into their territories;
• share information on inspections and quality defects.
• The scope of each agreement differs.