The MHRA has taken a different approach this year in the publication of the GMP deficiencies for drug product issued during inspections in 2018 and published in October 2019. In 2015 and 2016, MHRA provided approximately 100 slide decks with tables, figures, and text from deficiencies against the requirements in the Chapters and Annexes. No data were published for 2017. The MHRA published a 6,200-plus line excel spreadsheet of their 2018 GMP inspection data so that individuals can parse and present the data according to their needs.
This article is data-dense and includes many figures in three sections, published here in a three-part series. (Note: clicking images will enlarge them.)
- Section I begins with a high-level overview of the 2018 data including additional trends from the two most recent MHRA reports, 2015 and 2016.
- In Section II we identify and evaluate the critical and major deficiencies from 2018. This section identifies the Chapters and Annexes associated with critical and major deficiencies. For critical deficiencies citing Chapter 1 and Annex 1, we identify the specific paragraphs and requirements with which they are associated.
- In Section III we present the ten most frequently cited paragraphs for the ten Chapters and Annexes with the most frequently cited deficiencies identified in Section I, Figure 5 (found in Part 1).
- Section IV provides conclusions.
In Part 1 of this series, we covered Sections I and II. In Part 2, we presented and analyzed five of the top ten most frequently cited paragraphs for the Chapters and Annexes identified in Part 1, Figure 5.
Here, in Part 3, we cover the remaining five paragraphs of Section III and present conclusions to all data in Section IV.
[NOTE: No need to go back and forth between blog posts—download the full, 16-page report for yourself now!]
III. Specific Deficiencies in the Top Ten Annexes/Chapters, Cont.
In the following section, we take a granular look at individual Chapters and Annexes identified in Part 1, Figure 5 and how the deficiencies are divided among the various paragraphs. We address Chapters 1, 3, 4 and 5, 6, 7, 8 and Annexes 1, 11, and 15. These are provided in decreasing order of deficiencies as in Part 1, Figure 5. Part 2 covered the top five Chapters and Annexes, and we continue here with the remaining five. We provide the top ten citations for each, or more in the two instances where there are ties for this honor. Each figure is followed by the short version of text of the top citations. The previous reports from MHRA in 2015 and 2016 include text from actual inspections as examples, but that is not provided this year.
Figure 1 and Figure 2 identify the fourteen most frequent requirements cited in Annex 1. The most frequent citation addresses precautions to avoid contamination and the second addresses environmental monitoring in the areas where aseptic operations are performed. The third most frequent requirement cited is associated with setting appropriate alert and action limits for the results of environmental monitoring. Five requirements are tied for tenth place, so we include them all.
Figure 1: Top Deficiencies Citing Annex 1
Figure 3 and Figure 4 identify the most frequently cited requirements in Chapter 6. The two most frequently cited requirements are the need to adequately control laboratory components and reagents and the need to trend data and investigate OOT and OOS events. Again, we find the importance of investigating such events similar to those identified in deficiencies cited in Chapter 5 and Chapter 1 (Part 2).
Figure 3: Top Deficiencies Citing Chapter 6
Figure 5 and Figure 6 identify the top ten deficiencies that cite Chapter 8. By far the most frequent citation addresses the need to periodically challenge and determine the effectiveness of the recall process. Generally, this exercise is expected to be conducted annually. The next two most frequent deficiencies address the need to implement appropriate corrective and preventive actions in response to quality defects, and to report qualify defects to the health authorities when this may result in a product recall.
Figure 5: Top Deficiencies Citing Chapter 8
Figure 7 and Figure 8 shows the deficiencies that cite Chapter 7. Among the two most frequent citations is the need for a Quality Agreement and the content of that agreement with regard to the outsourced activity.
Figure 7: Top Deficiencies Citing Chapter 7
The ten most frequent inspection deficiencies that identify requirements in Annex 11 are shown in Figure 9 and Figure 10. The first most frequent deficiency addresses the application of risk management throughout the lifecycle of computerized systems. The second most frequent deficiency addressed the failure to ensure integrity of that data and that it is routinely backed up.
Figure 9: Top Deficiencies Citing Annex 11
In 2018 the MHRA conducted fewer inspections than in 2015 and 2016. The percentage of inspections conducted in the UK increased slightly and those outside the UK decreased slightly over that period. It will be useful to monitor whether the MRA with the FDA results in a decrease in inspections of sites that they may both inspect. It is interesting that the MHRA only conducted five inspections in the US so it would be difficult to determine if the MRA with FDA results in a decrease of inspection in the US.
Chapter 7, Outsource Activities, was new among the top ten in 2018 but was not in the top ten in either 2015 or 2016 and Chapter 2, Personnel, was no longer in the top ten this year.
In no surprise, Quality Systems, Chapter 1, continues to be first among the areas cited in inspection deficiencies, regardless of classification, with more than double the number deficiencies of the next area, Chapter 4. Chapter 1 is first among all deficiencies regardless of classification, first in number among the critical deficiencies, and first in number among the major deficiencies.
Critical deficiencies constitute only 2 percent of the total identified in 2018 and these are associated primarily with Chapter 1 and Annex 1. Approximately 37 percent of critical deficiencies cite requirements in Chapter 1 and approximately 22 percent cite requirements in Annex 1.
Among the major deficiencies which constitute approximately 40 percent of the total of all deficiencies, Chapter 1 again leads the group with almost 800 deficiencies. The next three include Annex 15 with approximately 270, Annex 1 with approximately 260 and Chapter 5 with approximately 250. Clearly, Quality Systems is again the substantial leader as it is for critical deficiencies. Chapter 7, Chapter 8 and Annex 16 were among the top ten in major deficiencies yet not among the top ten for critical deficiencies.
Computerised Systems, Annex 11 remains in the top ten, reinforcing the importance of this area to data integrity and the regulator’s focus regarding the control and management of electronic data.
Hopefully MHRA will publish similar data in 2019 to which we can compare these data. It would be useful for MHRA to publish actual text of deficiencies from the various areas in future years as they did in the past. But in the absence of that, publication of these data are valuable and appreciated by the industry.
[NOTE: No need to go back and forth between blog posts—download the full, 16-page copy of this report for yourself now!]