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.
- 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.
- Section IV provides conclusions.
In Part 1 of this series, we cover Sections I and II. Parts 2 and 3 will cover Sections III and IV.
[NOTE: You don’t have to wait for Parts 2 and 3—download the full, 16-page report for yourself now!]
I found the “Notes and Guidance” segment of the MHRA spreadsheet a bit confusing. In light of this, here’s how I’ve parsed the data. 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 data are mine, not the MHRAs.
I. Overall Data
The MHRA conducted 285 GMP inspections, both domestic and outside of the UK, in 2018. Inspections outside the UK were conducted in Bangladesh, China, India, Japan, Singapore, South Korea, and the United States. Country specific data, other than that provided for the UK and “overseas”, was not provided in the 2015 and 2016 MHRA reports. The 285 inspections from 2018 reflect a decrease from the number of inspections conducted in both 2015 and 2016.
Figure 1 identifies the number of drug product inspections, by country, performed by the MHRA in 2018. As in past years, almost all MHRA inspections were conducted in the UK. The percentage of inspections conducted in the UK in 2018 increased slightly from 2015 and 2016 and the percentage of overseas inspection decreased slightly in 2018 to 20 percent of the total.
In 2018, the largest number of inspections conducted outside the UK were performed in India with a total of 43. The remaining 14 inspections outside the UK were conducted in six countries with China and the US each having been the subject of five inspections, and the other countries had one each.
Figure 2 shows the trends including all classification of deficiencies from 2015, 2016 and 2018 identified in the top ten Chapters and Annexes. Data from 2015 and 2016 are taken directly from the 2016 report published by the MHRA. Quality Systems leads the list in all three years. Notable changes in 2018 from the two previous years include:
- Outsourced Activities (Chapter 7) appears within the top ten in 2018 though it did not appear in either of the two other years.
- Personnel (Chapter 2) is no longer among the top ten in 2018.
- Computerized Systems (Annex 11) remains within the top ten in 2018 though it has fallen from fifth place in 2015 to seventh in 2016 to tenth place in 2018.
- Complaints and Recalls (Chapter 8) also diminishes in rank over the time period from second in 2015, to fourth in 2016 and eighth in 2018.
Figure 3 and Figure 4 present the total number of deficiencies according to the GMP Chapter or GMP Annex cited, respectively. These figures include all deficiency classifications, critical, major and other. Annex 15, Qualification and Validation, and Annex 1, Sterility Assurance, take first and second place among the most frequently cited annexes with approximately 600 and 450 deficiencies, 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 a double-digit or fewer number of deficiencies.
Chapter 1, Quality Management, with approximately 1500 citations has more than twice the number of deficiency citations as the nearest chapter. Chapter 4, Documentation, with almost 760 deficiencies is closely followed by Chapter 5, Production, with just over 650, and Chapter 3, Premises and Equipment, at just under 570 citations. Chapters 2, 6, 7 and 8 each had between 200 and 400 deficiencies and the remaining two chapters had fewer than 50 and 1 citation respectively.
Figure 3: Inspection Citations by GMP Chapter
Figure 4: Inspection Citations by GMP Annex
Figure 5 shows the top ten categories when values from Annexes and Chapters are combined, the same information provided in Figure 2 with the number of associated deficiencies. Again, this includes all categories of deficiencies. We will identify the top ten citations in each of these in Parts 2 and 3.
Figure 5: Top Ten Chapters and Annexes Cited in Deficiencies
II. Critical and Major Deficiencies
Figure 6 provides a tabulation of all 2018 deficiencies by their classification. Critical deficiencies clearly constitute the smallest category and we will provide additional detail on them later. Major deficiencies constitute almost 40 percent of the total and other deficiencies constitute the majority of the deficiencies at almost 60 percent of the total.
Figure 6: Number of Deficiencies by Classification in 2018
The majority of critical and major deficiencies among the 6,200-plus deficiencies cluster in a few Chapters and Annexes. Figure 7 shows the number of critical deficiencies and the Chapters or Annexes which are referenced. Among the critical deficiencies, 37 percent are associated with Chapter 1, Quality Systems, and 22 percent are associated with Annex 1, Sterility Assurance. Annexes 1 and 11 are the only other Annexes that include citations for critical deficiencies, the remainder cite GMP Chapters.
Figure 7: Critical Deficiencies
Figures 8 and 9 provide the specifics on the citations for Chapter 1 and Annex 1 respectively. The table includes the identifying paragraph, the number of times the deficiency was cited, and a short version of the text in the GMP guide.
Figure 10 shows twelve Annexes and Chapters associated with major deficiencies and the number of times they were cited. In addition to these twelve Chapters and Annexes, major deficiencies were identified in Chapter 9 (11), Annex 2 (4), Annex 8 (8), Annex 3 (3), Annex 13 (3) and one each in Annex 6 and Annex 19. More GMP Chapters and Annexes were cited in major deficiencies than were cited in critical deficiencies. Among the major deficiencies, 33 percent are associated with Chapter 1, 11 percent are associated with Annex 15, 11 percent are associated with Annex 1, and 10 percent are associated with Chapter 5. Shortcomings in Quality Systems clearly leads the list of both critical and major deficiencies demonstrating the agencies’ focus on the importance of a sound Quality System to GMP compliance.
Figure 10: Major Deficiencies
In Part 2, we will continue with a granular look at the individual Chapters and Annexes identified here and how the deficiencies are divided among the various paragraphs.
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