2016 MHRA GMP Inspections yields 50% more deficiencies in key areas

MHRA Identified GMP Inspection Deficiencies,  2016

by Barbara Unger, GMP Quality Expert and GMP Regulatory Intelligence Editor-in-Chief

The MHRA published a large slide deck that addressed GMP deficiencies identified during inspections in 2016.  They published a slide deck of similar information for 2015 a few months ago.  In this blog, we look at some of the similarities and differences between the two years. The data only represent deficiencies noted for dosage forms and do not include those identified at inspections of API manufacturers.  We previously compared the FDA inspection observations for 2016 with the 2015 MHRA Deficiencies.  

The MHRA performed just under 10% more inspections in 2016 than in 2015. This included an increase in both local UK inspections and overseas inspections.  Even with a similar number of GMP inspections, the number of critical observations almost tripled in number from 51 in 2015 to 143 in 2016.  The critical deficiencies represent those identified for the ten most cited deficiency groups (see slide 5 for 2016 and slide 5 for 2015 at the links in the first paragraph).  It is not clear whether there were additional groups in 2016 with fewer than 2 critical observations.  The data are shown in Figure 1.

Figure 1:  Inspection Number and Critical Observations by Year

Considering the critical deficiencies identified in each of the two years, the rankings differ though the number of critical deficiencies may actually be smaller for some groups with a higher ranking.  For example, Computerized Systems ranked number 5 in 2015 with one critical observation, and number 7 in 2016 with 9 critical observations.  Figure 2 below presents the groups that had critical deficiencies in 2016 and compares data with the number of critical deficiencies identified in 2015.

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Figure 2:  Critical Observation Groups by Year

Critical deficiencies were identified in only five areas in 2015, and expanded to 10 areas in 2016.  Several categories saw significant increases, for example:

  • Sterility Assurance had no critical observations identified in 2015 and 34 were identified in 2016
  • Personnel had no critical observations identified in 2015 and 8 were identified in 2016
  • Premises and Equipment had no critical observations identified in 2015 and 9 were identified in 2016
  • Computerized Systems had 1 critical observation identified in 2015 and 9 were identified in 2016.

Two groups were not included in both years:  Sterility Assurance appeared in the 2016 group only and Materials Management was in the 2015 group only.

For the top 10 most cited deficiencies in 2015 and 2016 the total number of deficiencies, critical / major / other, also increased. The Table 2 and Figure 3 present data for the nine groups that were in the top 10 for both of the two years.  In all cases, 2016 saw an increase for all nine groups that were common to both years.  The increases averaged approximately 50% except for computerized systems which saw an increase between the two years of more than 400%.

Table 2:  Total Number of Deficiencies Per Group for 2015 and 2016

2015 2016
Quality Systems 875 1259
Production 518 754
Complaints and Recalls 129 201
Qualification / Validation 221 365
Premises and Equipment 418 586
Computerized Systems 41 173
Personnel 136 200
Documentation 519 814
Quality Control 166 236
TOTAL 3,023 4,588

Figure 3:  Total Numbers of Deficiencies Per Group, 2015 and 2016

 

The MHRA slide deck continues with a presentation of Figures presenting the number and criticality of findings per Chapter per section followed by narrative examples of the findings.  Table 3 identifies the chapters, the sections with the most findings and the slides associated with them. The information provided clearly focuses most emphasis on Chapters 1, 3, 5, and 6, and then on Annexes 1, 11, and 16.

Table 3:  EU GMP Chapters, Annexes and Sections

Chapter / Annex Sections with Most Findings Slide #s
Chapter 1: Pharmaceutical Quality System 1.4, 1.8 7-18
Chapter 2:  Personnel 2.9, 2.10, 2.11 19 – 21
Chapter 3: Premises and Equipment 3.2, 3.19, 3.34, 3.41 22 – 28
Chapter 4:  Documentation 4.2, 4.3, 4.4, 4.9 29 – 32
Chapter 5: Production 5.10, 5.19, 5.27, 5.29 33 – 40
Chapter 6: Quality Control 7.9, 7.12, 7.15, 7.17 41 – 48
Chapter 7:  Outsourced Activities Principle, 7.1, 7.14, 7.15 49 – 51
Chapter 8:  Complaints and Product Recall Principle, 8.6, 8.9 52 – 55
Chapter 9: Self Inspection Principle, 9.1 56 – 57
Annex 1:  Manufacture of Sterile Medicinal Products 64, 68 58 – 63
Annex 2:  Manufacture of Biological Active Substances and Medicinal Products for Human Use 6, 61 64 – 66
Annex 3: Manufacture of Radiopharmaceuticals 4 67 – 69
Annex 4:  Manufacture of Veterinary Medicinal Products Other than Immunological Veterinary Medicinal Products None identified 70
Annex 5: Manufacture of Immunological Veterinary Medicinal Products None identified 71
Annex 6: Manufacture of Medicinal Gases 19, 23, 30 72 – 74
Annex 7: Manufacture of Herbal Medicinal Products None identified 75
Annex 8:  Sampling of starting and packaging Materials 2,3,4,5 76 – 77
Annex 9: Manufacture of Liquids, Creams and Ointments 8 78 – 79
Annex 10: Manufacture of Pressurized Metered Dose Aerosol Preparations for Inhalation None identified 80
Annex 11: Computerized Systems 4, 7, 9, 12 81 –  84
Annex 12: Use of Ionizing Radiation in the Manufacture of Medicinal Products 7, 28, 34 85 –  86
Annex 13: Manufacture of Investigational Medicinal Products Principle, 33, 40 87 – 89
Annex 14: Manufacture of Products Derived from Human Blood or Human Plasma None identified 90
Annex 15: Qualification and Validation 1, 2, 3, 5 91 – 93
Annex 16:  Certification by a Quality Person and Batch Release 1 94 -97
Annex 17: Parametric Release None identified 98
Annex 19:  Reference and Retention Samples Principle 99 – 100

CONCLUSIONS:

MHRA minimally increased their number of GMP inspections in 2016 over 2015, but the number of findings / deficiencies (they seem to use the terms interchangeably) increased by an average of 50% with the number of deficiencies identified in computerized systems increasing over 400%. The increase occurs across all levels of criticality including critical, major and other.

The change for Chapter 11 certainly represent a continued focus on data integrity and data governance, particularly when coupled with documentation deficiencies identified for Chapter 4.

Sterility Assurance didn’t make the top 10 last year, but it ranks second this year, with 34 critical deficiencies.  Only five groups had critical observations last year, and that doubled to 10 groups this year.  In all cases, 2016 saw an increase in identified deficiencies for the nine groups that were common to both years.  The increases averaged approximately 50% except for computerized systems which saw an increase between the two years of more than 400%.  In addition to the total number of deficiencies identified increasing, the number of critical deficiencies identified almost tripled from 2015 to 2016.

MHRA has always enjoyed a reputation as one of the most rigorous health authority inspectorates.  They seem to have upped their game this year, however, as demonstrated by an increase in both the number of critical deficiencies and an increase in the total number of deficiencies identified for essentially the same number of inspections based on information in their summary slide deck. I expect 2017 to continue in a similar fashion, with a  focus on sterility assurance and data integrity / data governance.  The Mutual Recognition Agreement (MRA) between FDA and the EMA will likely not impact the number of inspections for 2017, though it may be possible to see changes in 2018 with MHRA conducting fewer inspections in the US.  This may allow them to focus their resources outside the UK in areas that have less developed regulatory and GMP systems.

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