Annex 16 to the EU-GMP Guidelines (Certification by a Qualified Person and Batch Release) states in section 3 that “provided registered specifications (…) are met, 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 details contained within the MA and/or GMP has occurred“. But what exactly are “registered specifications”? And can we deviate from in-process controls?
This is answered in Q&A No 3 to Annex 16 published by EMA “Registered specifications for medicinal products include in-process, bulk and finished product specifications which have been included in the MA application.”
However, the criticality of registered in-process specifications “may vary depending on the quality attribute tested, the impact to subsequent manufacturing processes and ability to test the quality attribute in the finished product“. So depending on a risk assessment, it might be possible to accept deviations from in-process specifications. As a pre-requisite, the risk assessment performed must confirm that there is “no impact to manufacturing process or product quality“.
EMA emphasises that non-compliance with registered product specifications fall outside the scope of Annex 16 section 3. That means that a QP will not be able to certify an affected batch.
What happens, if more than one batch affected by the same unexpected deviation?
In this case, it would be acceptable to certify the batches if they have “already been manufactured and/or tested at the time of discovery of the unexpected deviation“.
For batches manufactured after the discovery, these then repeated deviations should be considered to be a change. As a consequence, “variations to the affected marketing authorisations must be submitted“. In “exceptional circumstances” and to avoid disruption to supply, it “may be possible to continue QP certification while corrective and preventive action is in progress”.