28 February 2022

Published Annex 21 to the EU-GMP Guidelines

On February 21st, European Medicines Agency (EMA) published a long-awaited Annex 21 to the EU-GMP Guidelines (“Importation of medicinal products”) in EudraLex Vol. 4. The new Annex will come into operation on 21 August 2022 and summarises the EU GMP requirements for Manufacturing Import Authorization (MIA) holders of human, investigational, and veterinary medicinal products from outside the EU/EEA.

Annex 21 can be seen as a new guidance document for importers of medicinal products since it addresses all actors in the supply chain and sets out their roles to ensure the integrity of the supply chain of medicinal products. The document defines specific requirements explaining the application of GMP principles to the import of medicinal products subject to GMP requirements in the light of Article 40(3) of Directive 2001/83/EC. Requirements from other parts of the EU GMP Guidance on activities around import activities continue to apply and are not repeated in full in the new Annex 21.

The main topics that are regulated by the new Annex are the physical transfer from the third country to the EU/EEA, certification by the QP (link with the requirements of Annex 13 and 16), requirements for equipment and facilities, required documentation GMP requirements for manufacturers and exporters in third countries, qualification, and audits under the responsibility of the importing company and the QP, import testing and contractual regulations between all companies or persons involved in the import.

Some points to underline:

  • published document (compared to Draft proposal) covers Investigational Medicinal Products (IMPs) regulated by Regulation (EU) 536/2014 as well. Advanced Therapeutic Medicinal Products (ATMPs) and medicinal products that do not have a marketing authorisation in the EU/EEA and are directly re-exported were not included;
  • “Fiscal transactions” (where the product physically remains in the EU but changes ownership to a third country or vice versa) remain explicitly excluded;
  • the complete batch documentation must be available to the MIA holder responsible for QP certification or batch confirmation at the time of certification or batch confirmation. For QP certification or batch confirmation, a packing list, freight documentation or customs import declaration, is now required. The certification of a batch can therefore only take place after physical importation and customs clearance;
  • imported bulk products and intermediate products may undergo further manufacturing activities, as appropriate, prior to certification or confirmation by the QP, provided they are in compliance with the marketing authorization or clinical trial authorization;
  • If sampling of an imported product is done in a third country, a confidence assessment of this sampling should be done as part of the quality review. Nonconformities and out of trend results should be investigated and documented.