Tuesday 15 September 2020

Draft Annex 21 - Importation of Medicinal Products

New Annex with currently no deadline for implementation.


The Annex weighs heavily on referencing Annex 16 “ for further guidance on QP” although no new responsibilities have been defined. It also draws on the other Chapters of the Eudralex Vol4 in a similar manner.

Key points:

  • The Annex seeks to clarify or further detail terminology used, for example importation
  • Annex 16 – Importation is not defined as such whereas
  • Annex 21 states ” the term importation refers to the action of physically bringing medicinal product, from outside the territory of EEA/EU what implies the necessity of clearing it into the customs territory of an EU/EEA state QP certification of a batch of medicinal product takes place after physical importation and custom clearance.”
  • Or there are semantic differences in wording between Annex 21 and Annex 16 with same intent, for example
  • Annex 21 Section 2.4: “The Qualified Person certifying the batch has to ensure that all the medicinal products for human or veterinary use that are imported into the Union from a third country were manufactured in accordance with EU GMP or equivalent standard and tested in the Union, unless there are appropriate arrangement in place between the Union and the third country (e.g. Mutual Recognition Agreement or ACAA). See also Annex 16 for further guidance.
  • Annex 16 Section 1.5.4: “The QP certifying the finished product is responsible for ensuring that each finished medicinal product batch has been manufactured in accordance with GMP and the MA. Unless an MRA or similar agreement is in place between the EU and the exporting country, the QP is also responsible for ensuring that the finished medicinal product batch has undergone in a Member State a full qualitative analysis, a quantitative analysis of at least all the active substances and all the other tests or checks necessary to ensure the quality of medicinal products is in accordance with the requirements of the MA.”

Other issues:

  • (2.1) The sites which have specific responsibilities for importation in relation to the medicinal product or imported dosage form are
  • (i) Site of Physical Importation
  • (ii) Site of QP certification of Imported medicinal products.
  • The above importation responsibilities must be carried out by entities appropriately authorised under a MIA.
  • (2.5) Testing in an EU/EEA state covers all the tests needed to demonstrate that the medicinal product meets the specifications that are set out in the marketing authorization. – Annex 16 only refers to testing and does not contain this clarification.
  • (2.6) Written agreements should be in place between the site(s) performing manufacturing, importation activities and the MAH, as appropriate, in accordance with Chapter 7 of the EU GMP.
  • Chapter 7 does not contain this clarity and Annex 16 only mentions “agreements between sites”
  • 3. Pharmaceutical Quality System
  • 3.1. The site(s) conducting importation activities should have an appropriately detailed documented Pharmaceutical Quality System in accordance with Chapter 1 of the EU GMP Guide and reflecting the scope of the activities carried out.
  • 3.2. Product Quality Reviews should be performed by the site performing QP certification for the products imported, including products imported for export.
  • Written agreements should be in place to define the relative responsibilities of the MAH, the importer(s) and the third country manufacturers, as appropriate, in relation to compiling of the Product Quality Reviews as outlined in Chapter 1 of the EU GMP.
  • In addition to the PQR requirements described in Chapter 1, where sampling of the imported product is conducted in a third country in accordance to Annex 16, then the PQR should include assessment of the basis for continued reliance on this sampling practice. PQRs should also include a review of deviations relating to transportation. Specific requirements for sampling and transportation of imported products are detailed further in Annex 16.
  • As part of this review, the analytical results from importation testing should be compared with those in the Certificate of Analysis generated by the third country manufacturer. Any trends or discrepancies should be documented and investigated.
  • Transportation and Sampling are not stated within Chapter 1 (1.10)
  • (4.2) Imported medicinal products should be stored under quarantine after receipt, until their release for further processing or following QP certification or confirmation as appropriate, in accordance with Annex 16. Segregated areas should exist for quarantined products. Any system replacing the physical quarantine should give equivalent security.
  • Whereas Annex16 states - Until a batch is certified, it should remain at the site of manufacture or be shipped under quarantine to another site which has been approved for that purpose by the relevant Competent Authority.
  • (5.1.2) The site of physical importation should have, at minimum, details of transportation and receipt of the product (see also Annex 16).
  • Annex 16 does not detail this as such.
  • (5.1.3) 5.1.3.Relevant purchasing and delivery documentation should be available for inspection at MIA holder responsible for QP certification and clearly indicate:
  • The site from which the product has been dispatched (the origin of the product).
  • The site of physical importation.
  • Shipping details (including, transportation route and temperature monitoring records) and customs documentation, as applicable.
  • (5.5) Where batches have been subdivided and the individual quantities imported separately, documentation confirming reconciliation of the quantities should be made available at the site where QP certification takes place. Any discrepancy should be investigated.
  • (6.1) The manufacturing site where QP certification occurs should ensure that an ongoing stability program is in place, as required in Chapter 6. The ongoing stability program may be carried out at a third country site as an outsourced activity provided that the QP has all the necessary information to assure ongoing product quality. Details of the ongoing stability program, such as protocols, results and reports should be available for inspection at the MIA holder responsible for QP certification.
  • (6.2.) The QP certifying the batch is responsible for ensuring that, where required, the safety features have been affixed to the packaging.
  • (7.1) Adequate provisions should be in place between the site(s) performing importation activities, the third country manufacturer and the MAH for handling complaints, quality defects and product recalls as required in Chapter 8 of the EU GMP Guide. This should be defined in contractual arrangements.
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

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