When considering a marketing authorisation application, the MEB assesses whether each of the proposed manufacturers has the required permit and comply with the requirements for Good Manufacturing Practice (GMP). If the assessment outcome is positive, the manufacturer will be accepted for the marketing authorisation application. This process is known as ‘site clearance’.
Site clearance applies to all applications for marketing authorisation for a medicinal product, and to all applications for amendment or addition of a manufacturing site.
If needed, the MEB will request advice from the Health and Youth Care Inspectorate (IGJ).
What does the MEB assess?
For the permit submitted, the MEB assesses:
- whether the manufacturer is authorised to produce the requested pharmaceutical form
- which manufacturing steps the manufacturer may perform
- whether the permit is still valid
- whether the manufacturer's GMP compliance status has been recently (less than 3 years ago) confirmed by an EEA competent authority.
Applicants can also refer in their marketing authorisation application form to the manufacturing authorisation or GMP certificate in the EudraGMDP database without actually including them in the dossier. EudraGMDP is a European database from which all valid manufacturing authorisations and GMP certificates can be retrieved.
The applicant for the marketing authorisation or variation application must include all the manufacturers involved in the production of the medicinal product in the marketing authorisation application. The term ‘production’ shall in this case be taken to mean:
- All manufacturing activities: these cover the entirety or any part of the production of a medicinal product, including the primary and secondary packaging, quality control and/or batch release.
The procedure for manufacturers of active substances is given at the end of this page.
Manufacturer within the EEA
The MEB recognises permits from countries other than the Netherlands but within the EEA (European Economic Area: the EU member states plus Norway, Iceland and Liechtenstein).
Not all countries regularly issue new versions of permits. The applicant must include a recent GMP certificate (less than 3 years old) or must refer to such a GMP certificate in the EudraGMDP database if:
- no date stating the end of validity is given on the manufacturing authorisation, and
- it was issued or renewed more than 3 years ago
If the MEB assesses the information to be insufficient, it can ask, in conjunction with the IGJ, the competent inspection authority of the country in which the factory is located for further information.
Manufacturer in an MRA country
Countries with which the EU has made agreements about mutual recognition of each other’s permits are referred to as the MRA countries (Mutual Recognition Agreement).
Information about the cooperation between the EU and the MRA countries can be found on the website of the European Medicines Agency (EMA).
Manufacturers outside the EEA and not in an MRA country
The MEB does not recognise manufacturing authorisations and GMP certificates from countries outside the EEA, other than MRA countries. In such cases, the IGJ investigates whether the manufacturer has previously been inspected by any of the EEA member states. The IGJ also investigates whether that inspection looked at the product, or at least the pharmaceutical form for which a marketing authorisation is being requested. If so, site clearance might be given, based on the summary inspection report.
In all other cases, the manufacturer has to be inspected before the marketing authorisation application can be granted.
Manufacturer has not been inspected previously
The applicant for the marketing authorisation or variation application can ask the MEB to arrange an inspection for a manufacturer that has not previously been inspected by a competent inspection authority of an EEA country. In such cases, the applicant must declare that it will cover all costs of the inspection. The MEB asks the IGJ to schedule the inspection.
Manufacturers of active substances
Active substances must be manufactured in accordance with the detailed guideline on Good Manufacturing Practice (GMP) for active substances used as starting material.
A declaration is required to be submitted with all applications for new marketing authorisations, renewals and submissions of relevant quality variations, concerning changes (addition or replacement) to the manufacturer of a starting material and/or to the registered manufacturer(s) of the active substance, finished product or batch importation/certification sites.
This declaration must confirm that the active substance has been produced in accordance with GMP. This is known as the Qualified Person’s (QP) declaration.