- Annex 16 of EudraLex Volume 4, titled Certification by a Qualified Person and Batch Release, outlines the Good Manufacturing Practice (GMP) requirements for the certification and release of medicinal product batches by the Qualified Person (QP) within the European Union. This annex is a cornerstone of the EU regulatory framework, ensuring that every batch of medicinal product—whether manufactured in the EU or imported—is thoroughly assessed and certified before being released to the market or used in clinical trials.
- The primary responsibility of the Qualified Person, as emphasized in Annex 16, is to certify that each batch complies with the relevant EU marketing authorization (MA) or clinical trial authorization (CTA) and has been manufactured in accordance with EU GMP standards. The QP’s certification is a legal requirement and serves as a declaration that the product is safe, effective, and of consistent quality. The QP must have unfettered access to all relevant data and documentation to carry out this responsibility independently and with full authority.
- A significant feature of Annex 16 is its focus on batch certification for imported products. Any medicinal product imported from outside the EU/EEA must undergo full QP certification within the EU, including confirmation that the product was manufactured in accordance with GMP standards at least equivalent to those of the EU. Additionally, for biological or biotechnology-derived products, the QP must also ensure that appropriate control strategies, such as testing for adventitious agents and consistent manufacturing performance, are in place.
- Annex 16 outlines the minimum criteria and supporting documentation required for batch certification, including but not limited to the batch manufacturing record (BMR), analytical results, deviation and change control reports, in-process controls, and quality control (QC) testing outcomes. The QP must also confirm that any deviations or out-of-specification (OOS) results have been properly investigated, resolved, and documented. For clinical trial products, the QP must ensure that manufacturing is consistent with the protocol and investigator brochure.
- Another key concept in Annex 16 is “confirmatory testing” for imported batches. While some exemptions apply under Mutual Recognition Agreements (MRAs) or equivalence arrangements, typically, products imported into the EU must undergo retesting in the EU/EEA unless there is a legal basis for waiving this requirement. The QP is responsible for ensuring that any such exemption is justified and documented in accordance with EU legislation.
- Annex 16 also addresses handling of deviations. It introduces the concept of “unexpected deviations”—situations where a product does not fully comply with the MA but may still be suitable for release due to a well-documented, justified, and risk-assessed decision. In such cases, the QP must consult with the marketing authorization holder (MAH) and, where applicable, with competent authorities, to determine whether batch certification is appropriate. These situations must be exceptional, thoroughly justified, and fully documented.
- The annex further stresses the importance of audit and oversight. The QP must have confidence in the entire supply chain, including contract manufacturers, testing laboratories, and distribution partners. This requires effective technical and quality agreements, documented audits, and oversight of GMP compliance across all third-party sites involved in the manufacture, testing, packaging, and labeling of the product.
- Additionally, Annex 16 highlights the concept of “continuous process verification” and ongoing product quality review, especially for products released under real-time release testing (RTRT) or advanced manufacturing processes. These approaches must be scientifically justified and form part of the QP’s overall assessment during batch certification.
- In summary, EudraLex Volume 4 – Annex 16 defines the legal and scientific framework for the QP certification and batch release of medicinal products in the EU. It reinforces the QP’s role as a final gatekeeper for product quality and patient safety, mandating a comprehensive review of the entire manufacturing and testing process. With a strong focus on compliance, documentation, and risk management, Annex 16 is critical to maintaining trust in the pharmaceutical supply chain and ensuring that only safe, effective, and high-quality products reach patients.
Further reading:
- EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines
- EudraLex – The Rules Governing Medicinal Products in the European Union, Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Annex 16: Certification by a Qualified Person and Batch Release
