Documentation relating to compliance with Good Manufacturing Practice (GMP) for Investigational Medicinal Product and Auxiliary Medicinal Product | The Central Committee on Research Involving Human Subjects

Requirements for the documentation of investigational medicinal products and auxiliary medicinal products.

Investigational medicinal product

The manufacturing and importation of investigational medicinal products (IMPs) and auxiliary medicinal products (AxMPs) are subject to Good Manufacturing Practice (GMP) requirements or equivalent standards. The documentation required to demonstrate GMP compliance is described in Section F of Annex 1 to the Clinical Trials Regulation (CTR):

For products authorised in the EU/EEA (European Economic Area) no documentation is required;
For products with no EU/EEA authorisation, or no authorisation from a third country that is a party to ICH, and not manufactured in the EU, a manufacturing and import authorisation (MIA) and a QP declaration of GMP equivalence is required. If a Mutual Recognition Agreement (MRA) is in place with the particular country which already provides for this equivalence the latter declaration is not required;
In all other cases, a manufacturing and import authorisation (MIA) is required.

Exemptions under Article 61(5) of the Clinical Trials Regulation (CTR)

A manufacturing authorisation is not required for the following processes, where any of them are conducted in hospitals, health centres or clinics participating in the same clinical trial in the same Member State, regardless of whether the investigational medicinal product is dispensed in these same institutions or to study participants elsewhere, e.g. for use at home (art 61, CTR):

The preparation of an investigational medicinal product in a pharmacy in accordance with a medical prescription for an individual patient, as referred to in Article 3(1) of Directive 2001/83/EG (magistral formula);
The preparation of an investigational medicinal product in a pharmacy in accordance with the prescriptions of a pharmacopoeia and is intended to be supplied directly to the patients by the pharmacy concerned, as referred to in Article 3(2) of Directive 2001/83/EG (officinal formula);
The preparation of radiopharmaceuticals used as diagnostic investigational medicinal products;
Re-labelling or re-packaging of investigational medicinal products.

All above mentioned processes must be performed by hospital pharmacists or other individuals legally authorised in the Member State concerned to conduct such processes.

The processes must always be carried out in accordance with the GMP-Z Guideline (Good Manufacturing Practice for Hospital Pharmacies). This guideline provides the quality framework for the safe and appropriate preparation, packaging, and labelling of medicinal products within hospital pharmacies. In addition, Member States shall make the processes subject to appropriate and proportionate requirements to ensure subject safety and reliability and robustness of the data generated in the clinical trial. They shall subject the processes to regular inspections.

During an inspection of a hospital pharmacy performing activities under the exemption under Article 61(5), CTR without a manufacturer's authorization, the Dutch Health and Youth Care Inspectorate (IGJ) evaluates whether these activities are carried out in accordance with the GMP-Z Guideline.

The inspected site will then receive a CTR declaration (CTR-verklaring), confirming that the activities have been carried out in accordance with the GMP-Z Guideline and specifying which activities covered by the exemption under Article 61(5) CTR have been assessed.

Hospital pharmacies may also apply for a CTR-verklaring by contacting the IGJ.

From 1 October onwards, a valid CTR-verklaring must be included with the submission of clinical trial applications that are conducted under the exemption provided in Article 61(5), CTR. If the CTR-verklaring could not be submitted yet, the assessing ethics committee may contact the IGJ to verify GMP-Z compliance of the relevant site. In this case, the site may not perform the proposed activities under Article 61(5), CTR until the CTR-verklaring has been submitted as Non-Substantial Modification (NSM) in accordance with Article 81(9) of the CTR.