On 5th July 2013, a draft revision to Annex 16 was published
by the European Commission, in what amounted to a complete rewrite of the Good
Manufacturing Practices (GMP) document, which covers a Qualified Person (QP)
and batch release. The reason for the revision was given as the need “to
reflect the globalisation of the pharmaceutical supply chains and the
introduction of new quality control strategies.” Comments on the planned
changes were due to the Commission by 5th November 2013.
The revised Annex makes 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, EU GMP, and with local laws and those of the
destination country, lies with the QP certifying that batch as being suitable
In terms of batch release, the draft says that it must occur
after certification by the QP. But it 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 a Standard Operating Procedure (SOP) or contract.” This
is an important clarification as some European member states’ competent
authorities have insisted that batch release must be performed by the QP.
The ‘process of certification’ section clarifies that the
certification of a batch can only be performed by a QP of the manufacturing and
importation authorisation (MIA) holder that is named in the MA as a site of
manufacture for the product.
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 that they meet their
obligations through an agreed quality management system.
The new text explicitly states: “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 important as QPs
at contract manufacturers are not always provided with the necessary MA details
by the contract-giver.
The revision is consistent with the existing Annex 16 in
that, when partial manufacturing occurs in different sites within the European
Economic Area (EEA), it allows QPs at each site to take responsibility for
their operations, providing that this is covered by a written agreement. This agreement
can be in the form of an SOP where the QPs are operating as a single MIA
holder. A template for the written agreement is given as an attachment to the
Where a product is imported from outside of the EEA, the
draft 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 Committee for Medicinal
Products for Human Use Note for Guidance on Real Time Release Testing.
The draft Annex no longer contains the eight 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 of the revised Annex focuses on relying on GMP
assessments by third parties (audits, for example). 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 a 2009 Reflection Paper, in
that it states that the registered specifications must all be complied with.
However, if this is the case, “finished product may be considered to meet the
requirements of the MA and GMP when the details described below have been taken
- The deviation is unexpected, unplanned and relates to the
manufacturing process and/or the analytical control methods as described in the
- An assessment has been performed using quality risk
management and 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(es) in the ongoing 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”
Finally, Section 6 of the draft Annex 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 safeguards to be in place to ensure that uncertified batches are not
This draft revision of Annex 16 represents a significant
move to harmonise the expectations 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.