[Editor’s Note: This is Part II of an analysis of the FY2019 UK MHRA GMP deficiencies by Redica Systems Senior GMP Expert Barbara W. Unger. Part I of her analysis includes geographic data, overall trends, and top chapters and annexes cited.]

Next, we look at the deficiencies identified in Chapter 1, Annex 15, and Annex 1 in more detail than presented above.  We identify the paragraphs that were cited most frequently. For two of these, Chapter 1 and Annex 15, we provide two figures for each because a handful of the paragraphs dominate the deficiencies in those areas.

[Related: Download a PDF containing both Parts I and II of this analysis to keep on hand for quick and easy access.]

MHRA 2019 Special Report

Chapter 1

Let us start with Chapter 1, Quality System, as failure to comply with this chapter is the source of the largest number of total deficiencies, critical deficiencies, and major deficiencies.  Approximately 25 percent of all deficiencies in 2019 cite Chapter 1.

The data from all deficiencies in Chapter 1 are presented in two figures below because of the disproportionate representation of C1.4 and C1.8 in the total.  C1.4 addresses the purpose of the pharmaceutical quality system, and C1.8 addresses, at a very high level, the basic requirements of GMP.

Taken together, C1.4 and C1.8 make up 70 percent of the total number of deficiencies that cite Chapter 1.  Taking a more granular look, the five specific paragraphs representing the bars on the right side in Figure 9 make up 42 percent of all deficiencies that cite Chapter 1.  The third through 10th most frequent deficiencies that identify Chapter 1 are presented in Figure 2 [Editor’s Note: Figure 2 can be viewed in Part I]. 

Figure 9 Chapter 1, paragraphs 1.4 and 1.8
FIGURE 9 | Chapter 1, paragraphs 1.4 and 1.8

The eight paragraphs identified in Figure 10 constitute 27 percent of all deficiencies that cite Chapter 1.  Table 1 identifies the text of requirements for the 10 most frequent deficiencies citing Chapter 1 [Editor’s Note: Table 1 can be viewed in Part I].

Figure 10 Chapter 1, numbers 3 through 10 in frequency
FIGURE 10 | Chapter 1, numbers 3 through 10 in frequency

Annex 15

Annex 15, Qualification and Validation, provides an interesting story this year.  The four most frequently cited paragraphs constitute 68 percent of all citations from Annex 15.  Citations of A15.10, Cleaning Validation, constitute 24 percent of the total.  Thus, it seemed appropriate to present those data in more detail.  Figure 11 shows the 10 most frequently cited paragraphs in Annex 15. Figure 12 provides the 10 more frequent citations within A15.10, Cleaning Validation

Figure 11 Annex 15
FIGURE 11 | Annex 15
Figure 12 Annex 15, Cleaning Validation Annex 15.10
FIGURE 12 | Annex 15, Cleaning Validation Annex 15.10

Annex 1

Annex 1, Manufacture of Sterile Medicinal Products, was a close second to Annex 15 in the total number of deficiencies that cite the annexes.  It was, however, first among the annexes for the number of critical deficiencies in both 2018 and 2019.  Annex 1 was a very close second place for the number of major deficiencies, just behind Chapter 1. 

The 10 most frequently cited paragraphs from Annex 1 are shown in Figure 13.  The four most frequently cited paragraphs constitute approximately 28 percent of all deficiencies citing Annex 1, and the top 10 include 47 percent of all deficiency citations.

Looking forward to the revised Annex 1, it will be interesting to see how the deficiencies divide, though I imagine that shortcomings in the company-developed contamination control strategy and lack of fully implemented risk management principles will be near the top of the list.  We likely will not see the results of this change until 2022 or 2023, depending on when the revision is finalized and made effective.

Figure 13 Annex 1
FIGURE 13 | Annex 1

Conclusions

We have looked at differences year over year, and in 2019 we show the differences between inspections conducted in the United Kingdom and those conducted outside the United Kingdom.  Overall conclusions include:

  • In 2019, the MHRA continued to conduct fewer inspections year over year.  The percentage of inspections conducted in the U.K. increased slightly, and those outside the United Kingdom. decreased by almost half since 2015. It will be useful to monitor whether the MRA with the FDA results in a decrease in the number of inspections of sites that they may both inspect. Because the MHRA only conducted five inspections in the United States., it will be difficult to determine if the MRA with the FDA results in a decrease in inspections in the United States.
  • It is no surprise that Quality Systems, Chapter 1, continues to be first among the areas cited in inspection deficiencies, regardless of classification.  It has remained in the number one position for all four years covered in this article.
  • Critical deficiencies constitute just under 3 percent of the total deficiencies identified in 2019, 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.  It is noteworthy that among the inspections conducted outside the United Kingdom, critical deficiencies make up 5 percent of the deficiencies identified.
  • Among the major deficiencies that constitute approximately 40 percent of the total deficiencies, Chapter 1 again leads the group with just over 600 deficiencies. The next two include Annex 1 with almost 600 deficiencies and Annex 15 with approximately 200.  Clearly, Quality Systems is the clear leader as it is for critical deficiencies.
  • Computerized Systems, Annex 11, remains in the top 10 for both critical and major deficiencies, reinforcing the importance of this area to data integrity and the regulator’s focus on the control and management of electronic data.  This year the critical deficiencies citing Annex 11 were identified at sites outside of the United Kingdom.
  • In Chapter 1, Pharmaceutical Quality Systems, deficiencies cluster in two sections, C1.4 and C1.8, addressing fundamental GMP requirements for pharmaceutical firms.  We provide additional detail on each of those areas.  For Annex 15, Validation and Qualification, much of the focus was on deficiencies in cleaning validation.  We take a deep dive into this area in addition to covering the other paragraphs that are cited in Annex 15.  Annex 1 is another area where many of the deficiencies cluster in one area regarding failure to take precautions to minimize contamination.

Hopefully, the MHRA will continue to publish data in the Excel format in the future and expand the concept to include its GCP and GDP inspection findings.  It would also be useful for the MHRA to publish a selection of the actual text of critical deficiencies from the various areas in future years as it did in the past.  But in the absence of that, the publication of these data is valuable and appreciated by the industry. 

A version of this article previously appeared in BioProcess Online.

About the Author

Barbara Unger formed Unger Consulting, Inc. to provide GMP auditing and regulatory intelligence services to the pharmaceutical industry, including general GMP auditing and auditing and remediation in the area of data management and data integrity.

Her auditing experience includes leadership of the Amgen corporate GMP audit group for APIs and quality systems. She also developed, implemented, and maintained the GMP regulatory intelligence program for eight years at Amgen. This included surveillance, analysis, and communication of GMP-related legislation, regulations, guidance, and industry compliance enforcement trends.

Unger was the first chairperson of the Rx-360 Monitoring and Reporting work group that summarized and published relevant GMP and supply chain-related laws, regulations, and guidance. She was also the past co-lead of the Rx-360 Data Integrity Working Group.

You can contact her at [email protected].

[Related: Download a PDF containing both Parts I and II of this analysis to keep on hand for quick and easy access.]

MHRA 2019 Special Report
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