What does Annex 16 of the EU GMP Guide cover?

Scope

Annex 16 applies to human and veterinary medicinal products holding a marketing authorisation or made for export. It refers to Article 51 of Directive 2001/83/EC. In German law, the corresponding duty is set out in § 19 AMG: before each batch is placed on the market, the Qualified Person must certify in a continuous register that the rules have been complied with. The principles also apply to investigational medicinal products, subject to any different legal provisions and more specific Commission guidance. Ultimate responsibility for quality, safety and efficacy remains with the marketing authorisation holder.

The release process

Batch release has three steps: checking the manufacture and testing of the batch against defined procedures, certification of the finished product by the QP, and transfer to saleable stock. Certification may only be performed by a QP of a manufacturer or importer named in the marketing authorisation. Each manufacturing site in the EU must have at least one QP. Where several QPs share responsibility, this is agreed in writing, and partial steps are documented with a confirmation in line with Appendix I.

What the QP must ensure

• The entire supply chain of the active substance and medicinal product is documented, and audit reports for the sites involved are available.
• Manufacture and testing comply with GMP and the marketing authorisation, and processes remain in a validated state.
• Deviations, OOS and OOT investigations relating to the batch are sufficiently complete, and on-going stability data continue to support certification.
• The safety features under Article 54(o) of Directive 2001/83/EC have been affixed where required.
• Certification is recorded in a register that remains available for at least five years.

Imports from third countries and deviations

For products from third countries, physical importation and certification are the final manufacturing steps. Without a mutual recognition agreement (MRA), each batch must undergo a full qualitative analysis and a quantitative analysis of at least all active substances in a Member State. Sampling in the third country is only acceptable on the basis of documented quality risk management supported by comparative data. Under section 3 of Annex 16, the QP may accept an unexpected deviation only if the registered specifications are met and the risk assessment concludes that the impact is negligible.