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Updated: Jul 14, 2022

Editorial | Open Access | Published 14th July 2022

GUEST EDITORIAL : Unplanned events and interventions within Grade A: How much do you know about what has happened?

Author : Tracy Moore - TM Pharma Group Ltd

When you read a comment regarding an unplanned intervention within the Grade A area as part of the batch review (this could be the production review or QA review), is it crystal clear what exactly has happened to the point that the activity can be reconstructed from the information as required by the GMP Data Integrity requirements?

I have seen two cases whilst as a GMP inspector, where the companies, both based in the UK, had sterility test failures of in-house manufactured batches, where there was no indication from either the batch manufacturing record or the environmental monitoring data that something was amiss with the batch concerned. In each case, only upon significant investigation was it brought to light that an unplanned event and remedial intervention had occurred. In both cases, the extent of intrusion that occurred within the Grade A environment along with any indication of what items were used was missing from the documentation. Both batches were subjected to unplanned interventions that were simply not recorded in sufficient detail for any reviewer to pick up that an invasive remedial intervention had occurred. In both instances, it was engineers that had performed these, and, in both cases, neither company had provided the engineers with the required data integrity training or a robust mechanism to record, in the required level of detail, exactly what they had done to get the line back up and running.

These types of investigations are always high on the list for inspectors to review since it combines topics that always feature highly during inspections, aseptic processing technical and organisational measures and data integrity. Unplanned interventions are not expected, inherent interventions, required as part of the process. These are usually something different altogether and consideration and discussion are needed to ensure the correct actions are taken. The problem these companies had, however, was that they didn’t know what had happened, how it was corrected or what items were used and therefore they were unable to take the appropriate corrective action.

An English author, Matthew Syed wrote the book ‘Black Box Thinking’ which was written as a leadership performance book. After reading this it got me thinking, Syed, relates the aviation industry to the healthcare industry and describes how the healthcare industry would benefit if they were not afraid of failure. Developing Syed’s concepts to apply to GXP data integrity requirements, it is clear that there is a significant correlation between the requirements for data integrity recording in GXP environments and the black box function from within an aircraft. This then led me to the reality that we all know, which is that we put our trust in aviation engineers and pilots to perform correctly as our lives depend on them being trained, having robust procedures and only using authorised componentry. Our lives as patients therefore absolutely rely on the engineers and production staff within our pharmaceutical manufacturing facilities based on the same principles and requirements.

An opportunity such as an unplanned intervention (usually because of a breakdown) can be used to learn from and understand so it doesn’t happen again but more importantly, it has to be described in significant detail for someone to be able to assess the activity and the contamination risks posed by it. It may be that the remedial work has produced a significant bioburden challenge to the validated cleaning and sterilisation/sanitisation processes or the items that were needed for the fix to be successful, using uncommon tools and consumables with unknown contamination levels. It was contamination vectors like those identified here that ultimately caused the contamination of the manufactured batches in these two cases.

During an inspection and now audit, I always ask for a full listing of every item that can enter Grade A and then ask for its sterilisation method and trace these items back to the vendor assurance and incoming cleanliness levels. Is the same information available for the control of the engineer’s tools, lubricants, and any other items they may need to ‘fix’ the machine? How do these items make their way into Grade A? We have an opportunity with the revision of Annex 1, and its imminent issue to ensure these details and requirements are captured by the Contamination Control Strategy (CCS) and ensure non-routine items are also captured and controlled to avoid any issues as seen by these two companies.


1. Black Box Thinking: Marginal Gains and the Secrets of High Performance, Matthew Syed.

2. MHRA GXP data Integrity Guidance 2018.

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