Introduction to the handling of unexpected deviations.

Theory is knowledge that doesn’t work. Practice is when everything works and you don’t know why

Hermann Hesse

Deviations should really be the opposite of this definition of practice. If it didn’t work, you should know and know why.

Primary Guidance

This article primarily relates to legislation and approaches that are EU centric.  However there are a range of GMP standards (EU, FDA, ICH etc) and each of them, requires the documentation of any deviation.

The primary EU Guidance on the handling of unexpected deviations, pertaining specifically to the Qualified Person and the ability of the QP to release a batch is outlined in Section 3, Annex 16 (Certification by a Qualified Person and Batch Release) of EudraLex Volume 4 (Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use).

There is a link to the full text of this Annex here. (EudraLex 4 – Annex 16)

What is a deviation?

Deviations (also sometimes referred to as Unplanned Deviations – however this is being supplanted by Temporary Change Controls in some regulators preferred terminology) are a state of non-compliance from implemented procedures, marketing authorisations or GMP relevant systems that might impact the manufacturing, packaging, testing, distribution or storage of drug product.

The management of deviations is not just a GMP concept, it could be used in any context relating to product quality where roles, equipment, procedures and processes will be clearly defined and stated – as in any GXP system.

There are multiple potential sources for deviations in any quality management system.  These include, but are not limited to:

• Unexpected variations in process/production yield
• Human error
• Utility malfunction or failure
• Equipment malfunction of failure
• Unexpected or unforeseen impacts of changes (Temporary or Permanent)

Primary Role of a QP?

Tripwire condition (my own term) – the QP can only assess a product batch, affected by a deviation, for release if the following condition is in place:

• The registered specifications for active substances, excipients, packaging materials and medicinal products are met.

A QP may certify the batch or confirm compliance (with GMP, the MA etc) even if the following has taken place but is not covered within the products marketing autoriastion or genral GMP pracitice.

• An unexpected deviation concerning the manufacturing process or
• An unexpected deviation concerning the analytical control methods

A QP cannot assess a batch for release if a deviation has occurred that forces the product to fall outside these base criteria – i.e. if the product is out of specification.

Obviously, batches falling outside of specification may (likely will) have deviations associated with them that will still need investigation and appropriate action taken.

The basis for this assessment by a QOP is a deviation investigation.  The QP must review the deviation investigation and may only release the affected batch on the conclusion that the impact is negligible.  Batch may also be reworked or rejected on the conclusion of an investigation.   

In a larger organisation, deviation investigations may be primarily undertaken by staff other than the QP but all deviations must be reviewed by a QP prior to a release assessment.   This puts importance on the robustness of the pharmaceutical quality management system in place in terms of deviation reporting and communication.

Investigation requirements for deviations.

Deviations must be investigated for two primary reasons.

1. To permit assignment of a root cause and/or contributory causes.   This is to permit the undertaking or corrective or preventative actions (CAPAs) to limit the impact of the deviation and to understand the extent of the deviation.  

• To assess the impact of the deviation.  The impact of the deviation should be assessed in accordance with a quality risk management process using an appropriate approach such as described in Part III of the GMP Guide (EurdraLex Part III – Q9 – Quality Risk Management).  As a minimum the impact assessment should include the following.
• Evaluation of the potential impact of the deviation on quality, safety or efficacy of the batch(es) concerned
• Consideration of the need to include the affected batch(es) in the ongoing stability programme.
• In the case of biological medicinal products, consideration that any deviations from the approved process can have an unexpected impact on safety and efficacy.

The deviation procedure implemented within a companies quality management system should permit the detection and reporting of the deviation in real time to allow for prompt investigation.   The investigation itself should be completed in a timely fashion (30 days or less is the current industry expectation) and corrective actions should be recorded and monitored for effectiveness.

Corrective actions may be immediate in nature or may require significant time and resource to resolve. Preventive actions, if required and implementable, should be taken to ensure prevent reoccurrence of the deviation. All actions should themselves be recorded and assessed in line with quality risk management principles if appropriate.  These actions may require undertaking within a change control system and could involve communication with the regulatory authority including the submission of a variation to the MA for the continued manufacture of the product.  

The recording, reporting and investigation of deviations is mandated and expected  in GMP but the deviation procedure, if implemented properly, can be a powerful components in a continuous improvement focussed quality management system.

Additional requirements for deviation are mentioned in the wider EU guidance.   

In Chapter 1 – Pharmaceutical Quality System the additional points are raised.

• In cases where the true root cause(s) of the issue cannot be determined, consideration should be given to identifying the most likely root cause(s) and to addressing those.  
• Where human error is suspected or identified as the cause, this should be justified having taken care to ensure that process, procedural or system based errors or problems have not been overlooked, if present.

Disclaimer

This document is not a legal document not should it be interpreted in any fashion as a guide.  This is a set of notes compiled as part of a personal training program.    If you find it helpful or if you want to take issue with the content please leave a comment.

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Revision History

Version	Reason for revision / Changes made	Date
01	First Draft	12/04/2020
02	Addition of detail from Chapter 1 of the EU Guidance.	13/04/2020