EU GMP Annex 21 is the EudraLex Volume 4 annex governing the importation of medicinal products from third countries into the EU/EEA. Adopted by the European Commission on 16 February 2022 (C(2022) 843 final) and in operation since 21 August 2022, it summarises the GMP requirements applicable to Manufacturing Import Authorisation (MIA) holders and clarifies who does what between the site of physical importation and the site of QP certification. For QA, QPs and supply chain professionals it is the reference text for making every batch that crosses the Union border defensible in an audit.
Annex 21 and the importation of medicinal products: scope
Annex 21 applies to MIA holders importing human medicinal products, veterinary medicinal products and investigational medicinal products (IMPs) from outside the EU/EEA. Two exclusions are worth knowing by heart, because inspectors use them to test your understanding of the scope:
- products entering the EU/EEA with the intention of export only, neither processed nor released for the Union market, are out of scope;
- fiscal transactions (changes of ownership without physical movement of product) are not covered by the annex: "importation" means physically bringing a medicinal product in from outside the EU/EEA territory.
The other chapters and annexes of the EU GMP Guide continue to apply "as appropriate": Annex 21 does not replace Chapter 1 (PQS), Chapter 7 (outsourced activities) or Annex 16 (QP certification), but cross-references them and specialises them for the importation flow.
The two sites with importation responsibilities
The annex's core principle (§2.1) is that certification or confirmation of a batch takes place only after physical importation and customs clearance into the customs territory of an EU/EEA State. The annex identifies two sites with distinct responsibilities, both of which must be covered by an MIA:
- Site of physical importation: receives the product, stores it under quarantine after receipt until release (§4.2) and keeps, at a minimum, the transportation and receipt documentation (§5.1.2);
- Site of QP certification (or QP confirmation, for bulk and intermediate products undergoing further processing): the centre of gravity of the annex, responsible for batch certification, the Product Quality Review and qualification of the third-country manufacturer.
In practice the two roles may coincide at the same facility or be split across different entities, even in different Member States: that is the most delicate scenario, because the certifying QP must be able to reconstruct the entire chain — from the dispatching site of origin to the customs warehouse — with documented evidence, not declarations. Imported bulk and intermediate products may undergo further manufacturing before QP certification or confirmation.
Third-country manufacturing must be conducted in accordance with the EU GMP Guide or equivalent standards, in conformance with the MA (or CTA) and the relevant quality agreement, while overall responsibility for placing the product on the market remains with the MA holder (§2.2-2.3). Written agreements between sites, the MAH or the sponsor follow Chapter 7.
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Import testing and QP certification
Section 2.4 restates the key obligation: the QP must ensure that every imported medicinal product was manufactured in accordance with the EU GMP Guide or recognised equivalent standards and, for products with a marketing authorisation, tested upon importation into the Union, unless appropriate arrangements are in place between the Union and the third country, such as a Mutual Recognition Agreement (MRA) or an ACAA. Testing performed in the EU/EEA State must cover all the tests needed to demonstrate compliance with the MA specifications (§2.5).
An often underestimated point: import test results must be compared with the Certificate of Analysis generated by the third-country manufacturer. Discrepancies and out-of-trend results must be documented and investigated, and this comparison feeds into the PQR. Where sampling is performed in the third country under the conditions of Annex 16, the PQR must include an assessment of the basis for continued reliance on that practice, together with a review of deviations relating to transportation up to the point of batch certification.
PQS, Product Quality Review and documentation
Every site involved in importation must operate a PQS in accordance with Chapter 1, reflecting the scope of its activities (§3.1). The PQR is owned by the site responsible for QP certification, including for products imported for further processing and destined for export, with the exception of IMPs (§3.2). On the documentation front, the rule most often quoted in inspections is §5.1: full batch documentation must be available to the MIA holder responsible for certification at the time of certification — the draft said the softer "should have access"; the final text makes it an obligation.
| Documentation | Where it must be available | Reference |
|---|---|---|
| Details of transportation and receipt of the product | Site of physical importation | §5.1.2 |
| Full batch documentation | Site of QP certification, at the time of certification | §5.1 |
| Ordering and delivery documents, shipping route and temperature monitoring records, customs documents | Site of QP certification | §5.1.3 |
| Qualification evidence and periodic on-site audits of the third-country manufacturer | Site of QP certification | §5.4 |
| Reconciliation of batches subdivided and imported separately | Site of QP certification | §5.5 |
The certifying site must also ensure that the third-country manufacturer applies a record retention policy equivalent to EU requirements (§5.2) and that batch documentation and certificates are in a format the importer understands (§5.3).
Operations: stability, safety features and samples
The Operations chapter assigns three operational safeguards to the site of QP certification: the ongoing stability programme per Chapter 6, which may be outsourced to a third-country site only if the QP has all the information needed to assure ongoing product quality (§6.1); verification that safety features are affixed to the packaging where required (§6.2); and reference and retention samples per Annex 19 (§6.3). For complaints, quality defects and recalls, §7.1 requires adequate contractual arrangements between the importing sites, the third-country manufacturer and the MAH or sponsor, in line with Chapter 8.
GuideGxP recommendation
Three concrete actions to be ready for your next audit. First: map the importation flow batch by batch, formally identifying the site of physical importation and the site of QP certification, and verify that both MIAs cover the activities actually performed. Second: build a documentation checklist based on the table above and test it on a real batch — "can you show me the customs documents and the temperature records for this batch?" is an inspection classic. Third: formalise in your PQS the systematic comparison between import test results and the manufacturer's CoA, with explicit investigation criteria for out-of-trend results.
To go further: the GuideGxP guide Qualified Person (QP) — Operational guide to Annex 16, certification and batch release covers the entire certification process, importation included, with a toolkit of ready-to-use templates for QPs and QA.
