Annex 21 – Are we on track and is there an impact?

Annex 21 went into effect on August 21, 2022. It’s time to check that processes and procedures have not fallen short of the actual requirements specified in this guideline and to consider whether this guideline has helped manufacturers, healthcare providers, and patients. 

So, what is Annex 21?

Annex 21 details the GMP requirements specified for human, investigational, and/or veterinary medicinal products imported to the European Union and European Economic Area (EEA) by holders of a Manufacturing Import Authorisation (MIA). The new Annex does not apply to medicinal products entering the EU/EEA for export only, as they do not undergo any process or release aimed at the internal market. Fiscal transactions are also not considered as a part of the new annex.

What does Annex 21 entail?

• Valid MIA (Manufacturing Import Authorisation): This covers both the importation site and the location where QP (Quality Person) certification is completed. Is the license current, and does it verify all sites and the QP are appropriately authorized to perform their designated activities?
• Designated Import Site: A site within the EU where the imported product is physically received and cleared by customs. This site is the crucial point for ensuring that all necessary checks and procedures are carried out in compliance with regulatory standards.
• Batch Test Results: Test results for all batches of the imported medicinal product must be available. Unless exempt through a Mutual Recognition Agreement between the country of origin and the EU, these results must be generated within the EU unless exempt. 

What else is involved in the Annex?

• Confirmation of GMP Compliance: This verifies that the products meet the required quality and safety standards within the EU.
• Conformance with Marketing Authorization (MA) or Clinical Trial Authorization (CTA): that the imported medicinal products have been manufactured in conformance with the Marketing Authorization (MA) or Clinical Trial Authorization (CTA).
• Technical Agreements: Technical agreements established between the importing site, manufacturing sites, and the Marketing Authorization Holder (MAH) or Sponsor, as appropriate.
• Sampling Instructions: Importers should have clear and documented sampling instructions for taking test and reference samples of the imported medicinal products. Sampling is a critical part of quality control and assurance.
• Certification to verify an ongoing stability program is in place at the third country site where manufacturing is performed.

At this stage, most importers have a comprehensive pharmaceutical management system in place that facilitates compliance but also ensures the integrity and quality of imported medicinal products.  However, there is a concern that the standards set by this system may be too high, leading to potential supply issues.

Recent shortages of critical medicines, including certain antibiotics, during the winter of 2023 have highlighted the vulnerability of Europe’s medicine supply chain. It is possible that the implementation of Annex 21, which aims to establish a robust compliance system, has inadvertently created additional barriers to supply that were not anticipated.

Could parts of Annex 21 create roadblocks to exporting manufacturers that make entry into the European market unobtainable? 

We understand the need for clear and unambiguous documentation – but discrepancies due to translation issues, interpretation issues, or indeed delays with third-party Regulatory agencies can all impact the smooth transfer of information facilitating the importation of medicines into Europe from third-party countries.

Changes in supply chains and material suppliers can have long-reaching impacts and can provide unexpected regulatory delays in placing products on the market due to delays with approval of changes by different markets.

Have issues with laboratory testing at the contract test laboratory been problematic, leading to delays in getting into test schedules and reporting data to support batch release?

Is adherence to written agreements being adhered to by all parties, and are all aspects practical and efficient? Is compliance with these agreements just creating administrative burdens on both parties that are competing with actual time spent on batch release?

The cornerstone of Annex 21’s requirement is ensuring that full, transparent, and understandable information is available to all parties. 

However, considering the multitude of requirements that must be met, reviewed, and assessed, it becomes evident that this process can be complex and time-consuming.

Thankfully the European Commission stepped up to take more actions to address critical shortages of medicines in late 2023. Key medicines have been identified which may pose a risk of critical shortfall e.g., antibiotics. A mechanism that allows a member state to flag shortages and request the redistribution of medicines from one member state to another from available stock was put in place. Regulatory exemptions and flexibility in regulatory change acceptance allow critical medicines to reach patients in a timely manner.  Finally, the Commission is setting up a Critical Medicines Alliance to co-ordinate public practices at the EU level, diversify global supply chains through strategic partnerships, and develop strategic approaches to stockpiling medicines. Such approaches can only support the importation of medicines approach into Europe and ensure the expectations of all parties are aligned and effective.