EU GMP Annex 16: The Duty a Reliance Framework Doesn’t Replace

A manufacturing network with technical agreements, audited sites, and a documented reliance framework can look like it has solved batch release. It has solved most of the paperwork behind it. EudraLex Volume 4, Annex 16 — in operation since 15 April 2016 — is specific that one decision in that chain still belongs to one person: the Qualified Person who certifies the batch.

What Annex 16 actually assigns to the QP

The legal basis sits in Article 51 of Directive 2001/83/EC for human medicinal products, with parallel provisions for veterinary products and investigational medicinal products. Annex 16 translates that legal duty into an operational one: before a batch is released onto the EU market, a named QP has to certify that it was manufactured and checked in accordance with the law, with GMP, and with the marketing authorisation — or, for an investigational product, the relevant product specification file. That certification is the output of a great deal of work most of which the QP did not personally perform. It is not, on that account, a task the QP can hand off.

Reliance has a shape, not a blank check

Modern supply chains rarely put every manufacturing and testing step under one QP's direct view, and Annex 16 accounts for that: a QP can rely on assessments carried out by others, including QPs at other sites in the chain. That reliance is not informal. It runs behind a documented technical or quality agreement defining what each party is responsible for, and it depends on audit evidence that the other party's GxP-compliant quality system is actually functioning as the agreement describes — not a one-time confirmation at onboarding, but ongoing assurance the reliance stays well-founded as the relationship continues.

• What can be delegated. The individual assessments, tests, and reviews that feed the certification decision — performed at the QP's own site or, under a documented agreement, at another site or by another QP.
• What cannot be delegated. The certification act itself: the QP's personal decision that a specific batch meets GMP and the marketing authorisation, made on the strength of the assurances behind it.
• What reliance requires. A technical or quality agreement setting out each party's responsibilities, plus audit evidence — not just a contract — that the relied-upon quality system performs as described.
• What reliance is not. A transfer of accountability. If the underlying assurance turns out to be unfounded, the exposure sits with the certifying QP's decision, not only with the party whose work was relied upon.

A technical agreement tells you who is responsible for what. It does not tell the QP anything a certification decision can be built on unless the audit evidence behind it says the agreement is actually being kept. Why reliance is documented, not assumed

The unexpected-deviation route, and why it is conditional

Batch release rarely happens with a perfectly clean record, and Annex 16 does not pretend otherwise. It gives a QP a defined path to certify a batch even where an unexpected deviation from the manufacturing process or analytical control methods described in the marketing authorisation or GMP has occurred — provided the registered specifications bearing on the batch's quality, safety, and efficacy are still met, and provided the deviation has gone through a documented quality risk management process. That is a conditional allowance, not a waiver: it requires the same risk-based rigor a contamination control strategy or a validated process brings to any other quality decision, applied at the point of release rather than assumed away by it.

The stakes are least forgiving for products that cannot wait. A short-shelf-life autologous cell therapy batch does not give a QP the luxury of a lengthy re-review if a deviation surfaces late, which is exactly why the reliance framework and the deviation pathway need to be built — and rehearsed — before the first commercial batch, not discovered during it. Teams building out cell and gene therapy quality systems or running commissioning, qualification, and validation programs across a multi-site network are the ones for whom this distinction between documented reliance and personal certification stops being definitional and starts deciding whether a batch ships on time.