GMP requirements

1. GMP verification of manufacturers of IMPs

Note that the requirements apply to all parts of the manufacturing process, including packaging and labelling. Import of investigational medicinal products into the EU is defined as manufacturing and consequently, requires manufacturing license.

a. Manufacturing sites in Sweden
A copy of the valid manufacturing authorisation or GMP certificate or reference to the manufacturing authorisation number.

b. Manufacturers/importers within EU/EEA
A copy of the valid manufacturing authorisation or GMP certificate including a translation to English or Swedish as necessary, should be provided.

 
c. Manufacturers in third countries
In cases where manufacturing is performed in a third country, the Qualified Person (QP) should certify that at least equivalent standards of EU GMP apply through knowledge of the quality system employed at the manufacturer. There are specific arrangements provided for in the Mutual Recognition Agreements between the EU and third countries.

Knowledge of the quality system is normally acquired through audit of the manufacture and the manufacturer’s quality systems (EU GMP, Annex 13).

The following documentation should be included in the application:

• A QP declaration (please see 2. below)
• Manufacturing license/GMP certificate if available
• Manufacturing license for the importing unit in the EU

Depending on the assessment of the application an inspection might be required by the MPA. Whether or not an inspection is required is decided by the MPA on a case by case basis using a risk based approach. Several circumstances are taken into account such as pharmaceutical form, the origin of the medicinal product (chemical or biological/biotechnological) and the complexity of the manufacturing process. Other factors significant for the risk assessment are GMP inspections carried out by EU/EES-, MRA-or PIC/s-member authorities. On what basis EU GMP is verified, personal audit, third party audit and/or inspection performed by a relevant competent authority (CA), is also an important factor. There is a possibility for the manufacturing unit to request an inspection (voluntary inspection).

2. What to include in a QP declaration:

The QP of the importing unit certifies in a QP declaration that the manufacturer outside the EU operates in compliance with standards at least equivalent to EU GMP.

It should be clear from the QP declaration on what basis EU GMP is verified, e.g. an audit (personal or third party) and/or an inspection performed by a relevant CA. In some cases an inspection carried out by a relevant CA might be necessary in order to certify GMP compliance for the manufacturing unit. In case the verification is based on an audit, information about when and by whom or by which organisation the audit was carried out, as well as which parts and activities were included in the audit. The audit report could be provided in the application as supportive documentation.

If reference to an inspection performed by a CA is made, it should be clear from the QP declaration that the inspection covered manufacturing activities relevant for the manufacturing of the specific investigational medicinal product/(-s). GMP certificate/manufacturing license should be provided if available.

Besides what is mentioned above a QP declaration should also contain the following information:

• The name and dosage form of the IMP.
• The name and address of the manufacturer.
• Name and address of the QP who issued the QP declaration.

A template for QP declarations concerning GMP compliance of IMPs manufactured in a third country is currently under preparation within the EU.

3. GMP requirements for manufacturers of active substances (active pharmaceutical ingredient, API) for investigational medicinal products:

a. Chemical substances
Manufacturing according to EU-GMP Part II is recommended for chemical active substances, however this is not mandatory.

 
b. Biological substances
Manufacturing according to EU-GMP Part II is usually required for biological substances, depending on the complexity of the active substance and/or the manufacturing process. GMP compliance status of manufacturers in a clinical trial application should be verified according to the same principles as described for product manufacturers above.