Industry news

Draft Annex 16: QP Certification and Batch Release

The draft revision to Annex 16, Certification by a Qualified Person and Batch Release, which was published on 5 July is a complete re-writing of this annex. The reason for the revision is given as the need “to reflect the globalisation of the pharmaceutical supply chains and the introduction of new quality control strategies”. Comments are due to the Commission by the 5 November 2013.

The revised annex starts by making it clear that the ultimate responsibility for the performance of an authorised medicinal product over its lifetime lies with the marketing authorisation (MA) holder. However, the responsibility for ensuring that a particular batch has been manufactured in accordance with the MA, with EU GMP and with local laws and those of the destination country, lies with the QP certifying that batch as being suitable for release.

Regarding batch release the draft makes it clear that batch release has to occur after certification by the QP but then states that batch release “could be done by the QP as an integral part of certification or it could be done afterwards by another person. In this case, this arrangement should be delegated by the QP in an SOP or contract.” This is an important clarification as some Member State’s competent authorities have been insisting that batch release must be performed by the QP.

This section continues by stating “Any QP involved in the certification, or confirmation, of a batch must have detailed knowledge of the steps for which they are taking responsibility. The QPs should be able to demonstrate knowledge of the product type, production processes, technical advances and changes to GMP.” The QP must ensure they meet their obligations through an agreed quality management system.

The new text explicitly states that “If the QP is responsible for confirming compliance of those operations with the relevant MA then it is expected that the QP has access to the necessary details of the MA to facilitate declaration of compliance.” This clarification is again important as QPs at contract manufacturers are not always provided with the necessary MA details by the contract giver.

The revised annex is consistent with the existing annex in that when partial manufacturing occurs within different sites within the EEA it allows QPs at each site to take responsibility for their operations providing that this is covered by a written agreement. This written agreement can be in the form of an SOP where the QPs are operating at a single MIA holder. A template for the written agreement is given as an attachment to the Annex.

Where a product is imported from outside of the EEA the requirements are again essentially the same as in the current annex 16 but it adds that the product must either undergo the required re-testing within the EEA or be “in accordance with an approved Real Time Release Testing programme”. This aligns the revised annex with the CHMP NfG on Real Time Release Testing.

The new annex no longer contains the 8 ‘routine’ duties of the QP, which originally came from the UK’s Code of Practice for QPs. Instead these are replaced by 22 “operational responsibilities”. The QP must personally ensure the first three of these responsibilities but may delegate the remaining 19 to appropriately trained personnel or third parties. It is recognised that the QP will need to rely on a quality management system. The QP should have ongoing assurance that this reliance is well founded.

Section 4 deals with relying on GMP assessments by third parties e.g. audits. It states that Chapter 7 of the GMP guide should be complied with and gives detailed guidance on the content of audit reports.

Section 5 deals with unplanned deviations. This section essentially reproduces the guidance contained in the 2009 ‘Reflection Paper’ in that it states that the registered specifications must all be complied with but if this is the case “finished product it may be considered to meet the requirements of the MA and GMP when the details described below have been taken into account:

• The deviation is unexpected, unplanned and relates to the manufacturing process and/or the analytical control methods as described in the Marketing Authorisation.
• An assessment has been performed using Quality Risk Management, and which supports a conclusion that the occurrence does not have an adverse effect on quality, safety or efficacy of the product.
• The risk management has evaluated the need for inclusion of the affected batch/ batches in the on-going stability programme.
• For biological medicinal products in particular, the risk management has taken into consideration that even minor changes to the process can have an unexpected impact on safety or efficacy.”

Section 6 deals with batch release. Until it is released the batch should remain at the site of manufacture or be shipped under quarantine to another authorised site. It requires that safeguards, to ensure that uncertified batches are not released, must be in place.

This draft revision of Annex 16 represents a significant move to harmonise the expectations for the role of the QP across the EEA. It introduces the latest thinking on areas such as risk management, quality systems, supply chain controls and Real Time Release Testing.