Avoid surprises with Annex 21

Good Manufacturing Practices (GMP) does not stop at the borders, which is why in Annex 21 the requirements for Manufacturing Importation Authorisation (MIA) holders regarding physical imports from outside the EU/EEA has been elaborated.


Do you import medicines from outside the EU/EEA? Then you’re normally already familiar with Annex 21, which came into force in August 2022. The rules apply to human, veterinary and investigational medicines, unless these are immediately re-exported. Although the annex may seem pretty straightforward, there are several surprises that we are keen to highlight. Read on, and make sure that you are fully compliant.

Annex 21 in a nutshell


Annex 21 is the latest legislation from Eudralex, enforced on 21 August 2022 and it summarises the GMP requirements for MIA holders when physically importing medicinal products from outside the EU/EEA for further processing or resale within the same region.


The Annex comes on top of other chapters and annexes concerning Good Manufacturing Practice for Medicinal Products and emphasises the particular responsibility and role of importers in respecting GMP throughout the cycle of manufacture and importation.


What to watch out for


Despite being relatively simply, there are certain points that you may have missed. We have listed seven of them for you in order to prevent any surprises.


  1. Site of QP certification? Site of physical import? Bulk? Intermediate products? Yes, you too!


Something that is easily missed in the GMP guidelines, but has now been made clear in the new annex. As an importer (site of QP certification) or even a site of physical importation you need a MIA. Yes, even if you are not involved in the actual manufacturing process. Also, did you know that the rules apply not only to packaged goods, but also to bulk and intermediate products?


This means it is your responsibility to ensure that all stages of manufacture of imported medicinal products that are carried out in third countries respect the EU GMP or equivalent standards and are in conformance with the Marketing Authorisation (MA), the clinical trial authorisation (in case of investigation medicinal products) and the relevant quality agreement.


  1. Don’t forget MAH


Written agreements are required with the sites performing manufacturing and importation activities. What you may not realise is that the written agreement applies to the MAH (Marketing Authorisation Holder) as well. While you probably think to establish contracts with other manufacturing sites and importers this aspect is easily forgotten.


  1. New requirements regarding Product Quality Review (PQR)



The Product Quality Review is nothing new, but did you spot the additions? For those not familiar with the term: PQR is conducted with the objective of verifying the consistency of the existing process, the appropriateness of current specifications for both starting materials and finished product, to highlight any trends and to identify product and process improvements. The minimum requirements of the content of the PQR was already outlined in Chapter 1 of the EU GMP Guide.


However, from now on and what you might have missed is to include an assessment of the basis for continued reliance on the sampling practice (in case performed outside EU/EEA). What else? Well, new PQRs are also expected to include a review of deviations relating to transportation up to the point of batch certification. Another new and very time-consuming requirement is that the analytical testing in EU/EEA should be compared with those in the Certificate of Analysis generated by the third country manufacturer. Any discrepancies or out of trends must be documented and investigated. Is there a Mutual Recognition Agreement in place? Then you’re off the hook!


  1. Put your reasoning in writing


According to Annex 21, full batch documentation must be available to the MIA holder responsible for QP certification or confirmation of the batch, as appropriate, at the time of certification or confirmation of the batch. The frequency at which full batch documentation is reviewed at the site responsible for QP certification or confirmation of the product should be justified on a risk assessment basis and defined in the Pharmaceutical Quality System. In other words, as a QP, you need to review full batch documentation in order to release, or you will need to have your reasons for not doing so, and the frequency with which such information must be reviewed based on the specific risk. No surprises there, and it is likely that you were already doing this with your subcontractors. However, did you put your reasoning in writing (risk assessment)? Even where trusted partners, including other divisions in your own company, are concerned? Then, if lots of deviations appear, you know it’s time to increase the frequency. Safety first!


  1. Get your hands on the documents


There should be documentary evidence that the site performing QP certification has qualified the third country manufacturer and regularly monitors its performance by periodic on-site audits, either by the site performing QP certification or by a third party on its behalf. However, by simply trusting that the Supplier Quality Department have done their work, is not the same as demonstrating oversight. Therefore, we advise that audit reports must also be physically available and assessed by you, if your site is in charge of performing QP certification. In other words, it’s up to you to access information and act upon it.


Have batches been subdivided and the individual quantities imported separately? Then documentation confirming reconciliation of the quantities should be made available at the site responsible for QP certification. Any discrepancy should be investigated under the responsibility of the certifying QP.


  1. Permanent product quality


As the site responsible for QP certification you must ensure that an ongoing stability programme is in place. This may be conducted at a third party site provided that you, as QP, have all the necessary information to ensure ongoing product quality. As a reminder, it is also your responsibility to ensure that the safety features have been affixed to the packaging, if this is required.


  1. Keep a local stock of samples


Lastly, here’s a handy tip relating to samples to ensure that you stay on top of the regulations. 2 types of samples are required in GMP:

  • Reference samples for the purpose of future analysis.
  • Retention samples representing the batch of finished product as distributed.


Unless you have a mutual recognition agreement (MRA), reference samples of the finished medicinal product should be taken and stored at an authorised manufacturer located within the EEA. These samples should be taken in accordance with written agreement(s) between all of the parties concerned. The samples should, preferably, be stored at the location where testing on importation has been performed.


A retention sample should represent a batch of finished products as distributed in the EEA and may need to be examined in order to confirm non-technical attributes for compliance with the marketing authorisation or EU legislation. Therefore, retention samples should in all cases be located within the EEA. These should preferably be stored at the site where the Qualified Person (QP) certifying the finished product batch is located.

Do you need support in implementing the requirements of the new Annex 21? Would you like some help in updating your contracts and product quality reviews? Q-support offers a complete service and is there to help you. Get in touch and let’s discuss how we can make your life easier.

Do you want to receive our interesting blogs directly into your email? Subscribe to our newsletter!