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Handling of unexpected deviations

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Every batch of medicinal product must be certified by a Qualified Person (QP) of the EU manufacturer or importer before being released for sale. The certifying QP takes responsibility for ensuring that each batch has been manufactured and checked in compliance with the laws in force in the Member State where certification takes place, in accordance with the requirements of the marketing authorisation (MA) and Good Manufacturing Practice (GMP).

Annex 16 to the EU Guide to GMP provides specific guidance on certification by a QP and batch release. The Annex has recently been revised, with the updated version coming into effect from 15 April 2016.

The purpose of this post is to look in more detail at one aspect of the new Annex 16 – the handling of unexpected deviations.

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Section 3 of the new Annex 16 provides guidance on when a QP may consider confirming compliance or certifying a batch where an unexpected deviation (concerning the manufacturing process and/or the analytical control methods) from the MA and/or GMP has occurred. Previous guidance on dealing with minor deviations from the MA had been issued by the European Medicines Agency in their 2009 “reflection paper” EMEA/INS/GMP/227075/2008. However, there have been questions over the status of this paper, and its use was not consistently applied. It is important to note that the guidance in Annex 16 is new and not simply a rewrite of the EMA paper.

Criteria for assessment

For a QP to consider certifying a batch using the new Annex 16 (Section 3) approach, there are a number of pre-requisites that must be satisfied:

  • All registered specifications for active substances, excipients, packaging materials and medicinal products must be met. Note that the term medicinal product includes in–process, bulk and finished product specifications. Non-compliance with any registered specifications falls outside the scope of the Annex 16 (Section 3) approach.
  • The deviation must be unexpected. One or more batches manufactured prior to discovery may be eligible for certification, however further manufacture or testing must be in compliance with the MA. Repeated occurrences thereafter cannot continue to be accepted for certification, because they no longer meet the ‘unexpected’ criteria.

As an example of where this may (or may not) be used, let’s look at a short-term temperature excursion during the transport of a product from a third country to the EU. The label claim for the product is ‘store below 25°C’, and the excursion was up to 29°C for 3 days. Existing stability data demonstrated no issues when stored at 30°C for up to 3 months. This situation would fall within the scope of ‘unexpected deviations’, provided that the shipment process was designed to comply with the registered conditions (i.e. that the excursion could be reasonably described as ‘unexpected’). However if there were no controls over shipment conditions, then the use of stability data as a ‘routine’ means to justify such an excursion would not be acceptable.

  • The deviation must be thoroughly investigated, and the root cause determined. The root cause should then be corrected, and the process brought back into compliance with the MA. This may involve reverting to the registered process, or submission of a variation to the MA. If the root cause is not identified then the batches cannot be certified under this approach.
  • A risk management process should be used to determine the impact of the deviation on quality, safety and efficacy. To proceed with batch certification, a science and evidence based conclusion must confirm that the impact is negligible.

Quality Management System

Companies should also bear in mind that the Annex 16 approach described above is only applicable to the handling of unexpected deviations, and should not be used for a failure in the quality management system. By way of example, imagine a scenario where the registered impurity specification for a tablet is BP, with the BP TLC method detailed in the MA. The BP monograph is then revised to a HPLC method, but the MA holder fails to update the MA. Directive 2001/83/EC Art 23 requires MA holders to maintain the MA in compliance with current science; when a BP monograph changes, the expectation is that the MA is varied where necessary.

It is essential that the quality management system of the manufacturer or importer maintains a record of which batches have been certified under these provisions. This is to provide visibility to the QPs (who may be relying on the confirmation of other QPs in the supply chain), and should also feed into the management review and annual product quality review processes.

Manufacturers and importers are currently required to notify competent authorities of quality problems such as non-compliance with the MA. However Chapter 8 of the EU Guide to GMP states that there is no requirement to notify competent authorities provided the degree of non-compliance satisfies the Annex 16 restrictions regarding the handling of unplanned deviations.


The revised Annex 16 to the EU Guide to GMP provides new guidance on dealing with deviations from marketing authorisations, with the aim of ensuring consistency across the EU. As the full implementation of guideline revisions takes time to establish, including interpretation of requirements in practice by all stakeholders, MHRA is open to receiving questions or comments on the application of the revised guideline.

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Check out our guidance on good practice for information on the inspection process and staying compliant.

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