GMP certification and GMP certificate in Europe – an overview

Again and again, we receive questions about GMP certification and GMP certificates. Thinking that the procedure for a GMP certification is similar to that of an ISO certification is a common failure, i.e. misunderstanding. The term "GMP certificate" is therefore not quite correct; but what is the correct procedure?

In Europe, manufacturers of medicinal products and APIs are subject to monitoring by competent authorities with regard to compliance with the principles of Good Manufacturing Practices (GMP). Each EU Member State disposes of its own inspectorates. The location of the production is therefore crucial in order to decide which inspectorate is responsible. For example a facility located in Frankfurt (Germany) is therefore monitored by the local GMP inspectorate in Darmstadt. A facility in London (UK) will be monitored by the British authority (MHRA) and so on.

The basics of GMP inspections

Only a governmental authority is entitled to perform a GMP inspection in the pharmaceutical environment. Accredited bodies which carry out e.g. ISO audits are neither allowed to initiate official GMP inspections nor to certify GMP conformity. As a matter of fact, no GMP certification/GMP certificate can be issued by the authority, only a confirmation. The official name is: "Certificate of GMP Compliance of a manufacturer". Colloquially, one says "GMP certificate". The EU GMP Certificates are entered into the EudraGMDP Database.

The performance of such a confirmation is based on the EU GMP Directive 2001/83/EC. This directive was transposed into the laws of each member state. The competent authority of each Member State carries out its inspections based on the requirements laid down in EU Directive 2003/94. The concrete interpretation of these requirements can be found in the EU GMP Guide and its Annexes.

Manufacturing sites located outside the EU

If the manufacturing site is located outside the EU it is important to verify in which country the medicinal product will be imported (the first entry to EU market defines the competent authority e.g. if the product first enters the German territory at the Frankfurt Airport, the competent authority in Darmstadt will be competent). To import a medicinal product, a company located outside the EU needs an import authorization (which includes a permanent representative in Europe). Prior to the first importation of medicinal products (and in order to receive the import license), the site located outside the EU has to be inspected by the competent EU authority. A GMP inspection from an EU Authority will only be performed when the manufacturing site outside the EU either has a valid marketing authorisation for a medicinal product (issued by a competent EU Authority or by EMA) or if it is referenced by a EU marketing authorization holder for manufacturing.

Moreover, inspections have to be performed regularly (every 2 years according to the EU guidelines) in order to check the ongoing compliance with the GMP requirements. GMP monitoring is also intended for APIs facilities. However, the performance of a GMP inspection is not a prerequisite unlike medicinal products. The competent EU authority decides itself when an inspection has to be carried out for an API.

The WHO GMP certificate

At the request of the medicinal products manufacturer, a competent EU authority can issue a WHO GMP certificate for a company that owns a manufacturing authorisation – and therefore is monitored according to GMP. Manufacturers of medicinal products often need these certificates for the export, as the customs of non-EU countries usually require these certificates. Therefore, WHO certificates are often also called export certificates.

Other GMP certificates

Because of all the reasons named above, there exists no GMP certificate for companies that e.g. develop equipment for the pharmaceutical production or other services relating to manufacturing like engineering, IT systems etc. The pharmaceutical manufacturer is responsible for the selection of the service providers and suppliers. Within the framework of a supplier qualification, the pharmaceutical manufacturer (respectively the head of production and the head of quality control) have to demonstrate that the company did monitor the selected suppliers initially and then on a regular basis. The qualification of suppliers must rely on a risk-based approach.

For suppliers whose products have a low potential risk to patient safety, self-evaluation forms may be sufficient. On the contrary, products which pose a potential high risk to patient safety (e.g. all APIs) have to be audited by the pharmaceutical manufacturer.

GMP qualification of employees and managers

The EU GMP Guide requires a sufficient and continuous level of training for the personnel. Therefore, every pharmaceutical company must establish a comprehensive training system which plans and documents each GMP training course. As Europe’s largest advanced training and information service provider, Concept Heidelberg has developed GMP specific training courses and certification programmes. Annually, more than 300 GMP seminars/ courses, workshops and conferences are offered. In co-operation with the European Compliance Academy a GMP Certification Programme has been developed

The training courses are not only relevant for employees and executives in the pharmaceutical and API industry but also for service providers in the pharmaceutical industry (like IT providers, contract laboratories, cleaning companies etc.). Firms involved in the construction of equipment, engineering companies, etc. should also consider GMP training regarding qualification measures. GMP In-house seminars are also offered for the training of larger groups. GMP eLearning courses present an interesting alternative.

GMP Mock inspections and GMP audits

One talks about GMP Mock inspections when - before an official GMP inspection by an authority - a company decides to let an experienced GMP auditor verify its GMP compliance. The objective is to find any weak points and to eliminate them. GMP audits - in turn - are measures which are carried out by the company itself or by external specialized service providers. In addition, GMP audits are often carried out at suppliers (of raw materials, packaging, service providers, engineering etc.) or contract manufacturers within the supplier qualification. The PCA consulting offers such a service worldwide.

Special situation in Germany: GMP supervision by Bundeslaender (Federal States)

Germany counts 37 monitoring authorities, including 27 GMP inspectorates which are in charge of monitoring manufacturers and importers. There are 6 inspectorates for manufacturers of veterinary vaccines and 10 additional drug investigation authorities. According to statistics of the ZLG (only data from 2011 are available), 1,470 inspections were conducted in that year in Germany. Around 2,000 businesses possess a so-called manufacturing and/ or import authorisation for medicinal products for human use which therefore means that they manufacture in compliance with the GMP requirements. In such cases, a manufacturing authorisation according to § 13 AMG or - for the import - a certificate according to AMG §72a (1)2 is required. Monitoring is analogous to that for medicinal products.

Further information