Annex 21: What You Need to Know

April 21, 2022

It’s finally here, a guidance on how to handle medicinal products imported from outside EU/EEA. If you’ve ever wondered what the expectations are on these imported medicinal products, you’re in for a treat!

As many countries are developing and improving, both in terms of technology and also in terms of drug development and manufacture, the importation of medicinal products has become more of a habit rather than an exception. If you are involved in the importation of these products, here are the key areas you should be aware of from Annex 21.

Importation

Questions often arise as to who is responsible for the importation. Is a QP certification or confirmation necessary upon the importation? Is any additional paperwork needed for the QP before the imported product may be processed further? How should the product(s) be stored after importation? When can a QP certify a batch?

Annex 21 clarifies early on that the act of importation (in this annex) is when medicinal products are brought from outside an EU/EEA country into the Community, this applies to medicinal products for human use, veterinary use, and include investigational medicinal products.

Key Players

Two sites are considered to have specific importance when importing from outside the EU/EEA, these key players are;

  1. Site of Physical Importation: Must at a minimum document the details of the transportation and receipt of the products, further details are given in Annex 16 of EU GMP
  2. Site of QP certification or QP confirmation: QP confirmation is applied to bulk or intermediate products

Naturally, written agreements must be in place in accordance with Chapter 7 of EU GMP Guide to outline the responsibility and activities of each and every site.

The MAH has the overall responsibility for placing the product on the (EU/EEA) market.

GMP Requirements

There have been many discussions on the necessary level of GMP compliance when importing goods. This new annex states that the manufacturing activities carried out in third countries prior to import, must be:

  • Conducted in accordance with EU GMP Guide or equivalent standard
  • In accordance with the marketing authorization (or CTA)

To ensure that the GMP level is up to standard, the manufacturer in the third country must be qualified by the site performing QP certification or QP confirmation and there must be regular on-site audits. These audits can, as always, be outsourced in accordance with Annex 16 of EU GMP Guide. When outsourcing, the service provider needs to be qualified, have trained auditors, and the appropriate contracts need to be in place.

Testing on Importation

As many are aware, testing upon importation is required unless a MRA1 is in place. The testing must be such that it ensures that the medicinal product meets the specifications as set out in the marketing authorization.

However, Annex 21 only mentions testing upon importation specifically for products with a MA, this implies that only marketed products and excludes IMPs.

QP Certification

An important note is that the QP certification or QP confirmation may only take place after the physical importation into the EU/EEA.

The certifying QP must, as always, ensure that the manufacturing has been in accordance with the EU GMP Guide (or equivalent). Additionally, for products with a marketing authorization, ensure that the goods have been tested upon importation (unless a MRA is in place).

The QP certification or QP confirmation must be documented and should demonstrate that it has been carried out in accordance with the MA or CTA.

The frequency of full batch reviews should be justified using a risk-based approach and should be defined in the quality system.

Responsibility of the QP

The certifying QP is responsible for:

  • Ensuring that safety features are added to the packaging as required
  • Ensuring that reference and retention samples have been taken in accordance with Annex 19 of EU GMP Guide or GMP guidelines for IMPs, see Annex 13 of EU GMP Guide and Article 63 in Regulation (EU) No 536/2014 on Clinical Trials
  • Investigating reconciliation; when one batch has been divided into multiple imported deliveries, the quantities should add up and the numbers should be available for review

Information Sharing and Batch Documentation

According to this annex, information is expected to be shared between the different sites. The site of QP certification should have access to the full batch documentation and other supporting documents that would support batch certification. This information sharing also applies to other sites/MIAs involved in the importation process.

Document Retention

The site of QP certification or confirmation must ensure that the manufacturing site in the third country follows the EU requirements on record retention as described in Chapter 4 of EU GMP Guide.

Batch documents, including other supporting documentation, supplied by the third country manufacturer must be in a format that is understood by the importer, e.g. multilingual documents or translations might be needed.

Product Quality Reviews

Most manufacturers and MAHs know about Product Quality Reviews (PQRs). Annex 21 highlights three additional topics to include in PQRs for imported products (investigational medicinal products excluded) by the site of QP certification:

  • Sampling in third countries: Wherever sampling is done in third countries, it has to be evaluated as to why this sampling practice is reliable, and the assessment should be included in the PQR.
  • Transport deviations: There must be a review of deviations relating to transport up to point of certification. This review must be included in the PQR.
  • Test results: The test results from the import testing and the test results from the received CoA from third country must be compared. Any discrepancies and OOT should be documented and investigated.

Ongoing Stability Program

The site of QP certification must ensure that there is an ongoing stability program in place. These activities could be carried out at a third country, provided that the QP has all necessary information. Access to documents such as protocols, results, and reports should be available to the site of the QP certification.

Quarantine of Imported Products

As with any other products, there are requirements on the premises of the sites involved in an importation. Next to the usual business of having adequate premises and equipment, the quarantine area is highlighted with following requirements:

  • There must be a quarantine area to store the imported products until certification or confirmation
  • The quarantine area must be physically segregated or replaced by a system that ensures an equivalent level of security

Delivery Documents

The site of QP certification or QP confirmation must keep order & delivery documents which clearly indicate:

  • The site of dispatch
  • The site of physical importation
  • Shipping documents including temperature monitoring records and customs (import) documentation

Complaints, Quality Defects, and Product Recalls

There must be appropriate arrangements between the sites involved in the importation (i.e. third country manufacturer, importer, MAH, etc.) for handling complaints, quality defects, and product recalls as defined in Chapter 8 of the EU GMP Guide.

Summary

In conclusion, there is an expectation of EU GMP to be followed by all sites, the adherence to EU GMP is to be monitored and followed up by the QP certifying site. All activities and responsibilities are expected to be outlined in written agreements between the involved sites. Documents are expected to be understandable by all parties and kept in accordance with EU GMP Guide. Last but not least, as always, the MAH has the overall responsibility for the product and for placing it on the EU/EEA market(s).

1 Mutual Recognition Agreement, allows EU authorities and their counterparts (Australia, Canada, Israel, Japan, New Zealand, Switzerland, United States) to rely on each other's GMP inspection system, share information on inspections and quality defects and waive batch testing of products on import into their territories.




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