Part I: An Analysis Of MHRA’s Latest Annual GMP Inspection Deficiencies Report

[Editor’s Note: Below is Part I of an analysis of the U.K. MHRA GMP deficiencies for 2019. Part II will look more in-depth at deficiencies related to Chapter 1, Annex 15, and Annex 1.]

The U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) has taken a different approach in the publication of the GMP deficiencies for drug product issued during inspections in 2018 and 2019.

In 2015 and 2016, the MHRA provided approximately a 100-slide deck each year with tables, figures, and text from deficiencies against the requirements in the chapters and annexes. No data were formally published for 2017.

The MHRA published a 6,200-plus line Excel spreadsheet of its 2018 GMP inspection data so that individuals could parse and present the data according to their needs. The 2019 data were provided in October 2020 in a just under 5,300-line Excel spreadsheet.

This article begins with a high-level overview of the 2019 data, including trends from the four most recent MHRA reports, from 2015, 2016, 2018, and 2019. It proceeds to identify and evaluate the critical and major deficiencies from 2019, identifying the chapters and annexes associated with 137 critical deficiencies and the chapters and annexes most frequently associated with the 1,999 major deficiencies.

[Download a PDF version of this report to have on hand for quick and easy reference.]

Similar to the results in 2018, the most frequently cited chapter and annexes in 2019 are Chapter 1, Quality Management, and Annex 1, Manufacture of Sterile Medicinal Products.  For critical deficiencies citing Chapter 1 and Annex 1, the specific paragraphs and requirements with which they are associated are identified.

Background

Here is how I parsed the data from the MHRA spreadsheet. Each row in the spreadsheet is treated as a unique deficiency, regardless of whether it is a “deficiency” or a “sub-point” as identified in the Notes and Guidance section of the MHRA publication. I cannot discern which is which in the spreadsheet, so I treat them all equally.

The summary data from 2015 and 2016 are taken directly from the MHRA 2016 report. Data were not posted for 2017. Any mistakes in this analysis and reporting of the 2018 and 2019 data are mine, not the MHRA’s.

Overall Data

The MHRA conducted a total of 258 inspections in 2019, a decrease from the 285 inspections conducted in 2018. The number of inspections has decreased since 2016.

Insufficient data are available to determine if the inspections outside the United Kingdom decreased because of the Mutual Recognition Agreement with the FDA.  For example, only five inspections were conducted in the U.S. in 2018, and the 2019 inspections outside the U.K. were not identified as to the country.

Table 1 identifies the number of drug GMP inspections, by country, performed by the MHRA in 2015, 2016, 2018, and 2019. As in past years, almost all MHRA inspections were conducted in the United Kingdom.

The percentage of inspections conducted in the United Kingdom in 2019 increased from previous years, and the percentage of overseas inspections decreased over the four years. In 2019, only 12 percent of inspections were conducted outside the United Kingdom.

Next year, when we receive the data for 2020, both inspections outside and within the United Kingdom will likely be far lower based on the travel limitations posed by the COVID-19 pandemic.

In 2018, approximately 75 percent of inspections conducted outside the United Kingdom were performed in India.  In 2019, MHRA did not provide a breakdown by country for the 12 percent of inspections that were conducted outside the United Kingdom.

Table 2 shows the top 10 areas of all deficiencies from 2015, 2016, 2018, and 2019.  Data from 2015 and 2016 are taken directly from the 2016 report published by the MHRA. Quality Systems leads the list in all four years. Notable features in 2019 include:

• The top six categories remain the same, and in the same order, as they were in 2018
• All of the chapters and annexes in the top 10 for 2019 were among that same group in 2018
• Quality System (Chapter 1) deficiencies exceed the number of deficiencies in the combination of the next two areas, Documentation (Chapter 4) and Production (Chapter 5). See the data in Figure 1
• Computerized Systems (Annex 11) moved up one notch from 10^th in 2018 to ninth in 2019 and Outsourced Activities dropped to 10^th in 2019

Figure 1 presents the total number of deficiencies identified in 2018 and 2019 for the top 10 combined chapters and annexes. These figures include all deficiency classifications—critical, major, and other.  

Figures 2 and 3 present the top groups for those, citing chapters and annexes, respectively.

Figure 2 shows that among the chapters, Chapter 1, Quality Management, with just over 1,300 citations in 2019, has more than twice the number of deficiency citations as the next nearest chapter. Chapter 4, Documentation, with 700 deficiencies, is closely followed by Chapter 5, Production, with just under 600, and Chapter 3, Premises and Equipment, received almost 425 citations. Chapters 2, 6, 7, and 8 each had between 200 and 250 cited deficiencies. The remaining chapter, Chapter 9, Self-Inspection, had 30 citations.

The top six annexes cited in deficiencies in 2018 and 2019 are shown in Figure 3.  Annex 15, Qualification and Validation, and Annex 1, Sterility Assurance, take first and second place among the most frequently cited annexes, respectively. This is followed by Annex 11, Computerized Systems, and Annex 16, Certification by a Qualified Person and Batch Release. All other annexes are associated with double-digit or fewer deficiencies.

Critical and Major Deficiencies

Table 3 provides a tabulation of all 2018 and 2019 deficiencies by their classification. Critical deficiencies constitute the smallest category; additional specific detail on these is provided later.

Major deficiencies consistently constitute almost 40 percent of the total, and “other” deficiencies consistently constitute the majority at almost 60 percent of the total.

Most critical and major deficiencies cluster in a few chapters and annexes. Figure 4 shows the number of critical deficiencies identified in 2019 and the chapters or annexes that are referenced. Among the critical deficiencies in 2019, 34 percent are associated with Chapter 1, Quality Management, and 23 percent are associated with Annex 1, Sterility Assurance.  Annexes 1 and 11 are the only annexes that include citations for critical deficiencies; the remainder cite GMP chapters.

Figure 4 provides the specifics on the 11 most frequently cited chapters and annexes in critical deficiencies in both 2018 and 2019.  Chapter 7, Outsourced Activities, and Chapter 8, Complaints and Product Recall, were cited among critical deficiencies in 2019 but were not cited in critical deficiencies in 2018.

Figure 5 shows critical deficiency data for 2019 and presents these by location, a U.K. site, or in a site outside the United Kingdom.

Interesting this year is that the number of critical deficiencies for Chapter 5, Production, more than doubled from last year, and the vast majority of these deficiencies are cited for locations outside the United Kingdom when only approximately 12 percent of inspections were conducted outside the United Kingdom. 

In total, Chapter 1 and Annex 1 top the list for both 2018 and 2019, with Chapter 5 coming in third. Annex 1 critical deficiencies in 2019 are identified exclusively in the United Kingdom. It is worth noting that critical deficiencies citing Chapter 5, Annex 11, and Annex 15 were cited exclusively at sites outside the United Kingdom in 2019. 

Figure 6 shows the critical deficiencies identifying Chapter 1 presented by the paragraph most frequently cited.  Sections 1.4 and 1.8, taken together, comprise 77 percent of the critical deficiencies cited Chapter 1. 

Table 4 provides specific citations and more granularity on these two sections.  Section 1.4 identifies the purpose and activities to be ensured by the quality system, and section 1.8 describes the basic requirements of GMP.

Figure 7 presents the critical deficiencies citing Annex 1.  These do not cluster as closely as the deficiencies in Chapter 1 but are rather spread over the entire annex.  Most of the requirements are cited in only a single critical deficiency.  Only six paragraphs are cited more than once, and the abbreviated text for these are provided in Table 5.

Figure 8 shows 11 annexes and chapters associated with a subset of the major deficiencies and the number of times they were cited during inspections both in the United Kingdom and outside the United Kingdom (ROW). In addition to these 11 chapters and annexes shown in Figure 8, major deficiencies were also identified in Chapter 2, Chapter 7, Chapter 9, Annex 2, Annex 3, Annex 6, Annex 8, Annex 9, Annex 12, Annex 17, and Annex 19.

More GMP chapters and annexes were cited in major deficiencies than were cited in critical deficiencies. Among the major deficiencies, 31 percent are associated with Chapter 1, 29 percent are associated with Annex 1, 10 percent are associated with Annex 15, and 9 percent are associated with Chapter 4.

Shortcomings in quality systems clearly lead the list of both critical and major deficiencies, demonstrating the agency’s focus on the importance of a sound quality system to GMP compliance.  Annex 1 ranks a very close second, emphasizing the prioritization of the manufacture of sterile products during inspections.

[Editor’s Note: Part II will cover U.K. MHRA GMP deficiencies related to Chapter 1, Annex 15, and Annex 1. You can also download a PDF containing both parts of this analysis.]