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European Pharmaceutical Contractor

Quality First

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 for release.

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.

Batch Certification

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.

Continuing Requirements

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 Annex.

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.

Operational Responsibilities

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.

Unplanned Deviations

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 into account:

  • The deviation is unexpected, unplanned and relates to the manufacturing process and/or the analytical control methods as described in the MA
  • 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 released.

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.


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Peter Gough has over 35 years of experience in pharmaceutical manufacture, and control and quality management, culminating in the role of Executive Director of NSF International’s Health Sciences Pharma Biotech Division (formerly David Begg Associates). He has broad experience, particularly with quality control laboratories, and the manufacture of solid dosage forms and active pharmaceutical ingredients. Peter is a former member of the European Federation of Pharmaceutical Industry Association’s Manufacturing and GMP ad hoc group. He is a Fellow of the Royal Society of Chemistry and of the UK Chartered Quality Institute (CQI), and is a former chairman of the CQI’s Pharmaceutical Quality Group.
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