Annex 16: How a QP should handle unexpected Deviations

In a recent blog of the U.K. Medicines and Healthcare products Regulatory Agency (MHRA), the inspectorate looks at one aspect of the new Annex 16 - the handling of unexpected deviations.

Before Annex 16 was revised, the handling of minor deviations from defined processes was discussed in the European Medicines Agency's "reflection paper" EMEA/INS/GMP/227075/2008. However, the status of this paper was not always clear, and its use was not consistently applied. Now section 3 of the new Annex 16 provides guidance on when a Qualified Person (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.


Before a QP releases a batch these pre-requisites need to be considered:

  • All registered specifications must be met! This includes specifications for active substances, excipients, packaging materials and medicinal products with all defined in-process, bulk and finished product specifications. If any registered specification is not met, the QP must not release the batch.
  • Only unexpected deviations fall under the scope of section 3. That does also mean that repeated deviations cannot be accepted for certification, because they no longer meet the "unexpected" criteria.
  • The deviation must be thoroughly investigated, the root cause determined and the necessary actions defined.
  • A risk management process should be used to determine the impact on quality, safety and efficacy.

Quality Management System

Quality Management System failures are not covered by this section. But the quality management system of the manufacturer should maintain a record of which batches have been certified under the respective provisions. And it should also be considered in the management review and annual product quality reviews.

Notification of the Authorities

If the handling of the deviation is in accordance with the Annex 16 restrictions, the competent authority does not need to be informed (see also Chapter 8 of the EU Guide). But manufacturers and importers are required to notify competent authorities of quality problems and non-compliance affecting the Marketing Authorisation (MA).

Please also see the MHRA Inspectorate's blog for more detailed information.

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