MHRA published its GMP Inspection Deficiency Data for the year 2018.

In totality MHRA Inspectorate audited 286 facilities across the globe in the year 2018 and made total 6209 deficiencies EU GMP clause-wise all together as per its published deficiency report – 2018

Here, we have tried to do the statistical analysis of all these inspection deficiencies which you can see in the below images. Out of 286 facility audits, 228 facilities have been audited in the United Kingdom itself and 44 Indian facilities have been audited by MHRA in the year 2018 against its GMP standard.

If statistically analyze, Korea has 47 deficiencies per MHRA GMP inspection against EU-GMP standard and Japan has the lowest number of EU-GMP deficiencies which are only 17 numbers. In both Korea & Japan only one facility was audited in the year 2018 by MHRA Inspectorate.

Statistical Analysis of Year-2018 MHRA GMP Inspection Deficiencies 

Statistical Evaluation of MHRA 2018 Inspection DeficienciesStatistical Analysis of MHRA 2018 GMP Inspection Deficiencies

As per the above, the average number of deficiencies per inspection graph reveals that an average 30 nos. of deficiencies per inspection reported by MHRA inspectorate in the year 2018 GMP inspection.

Categorization of MHRA GMP Inspection Deficiencies

Further categorization (critical, major, and others) of all these deficiencies are given below. Categorization of deficiencies may be done by clubbing a few deficiencies based on these severities.

Critical Major Others
17 432 1488
Categorization of Deficiencies
Categorization of Deficiencies

Categorization of MHRA GMP Inspection Deficiencies Per Inspection

If the categorization of observed deficiencies per inspection is analyzed then it reveals that Critical Deficiencies per Inspection is 0.1, Major Deficiencies per Inspection is 1.5 & Other Deficiencies per Inspection is 5.2 nos.

Deficiencies Categorization Per Inspection
Deficiencies Categorization Per MHRA GMP Inspection

Below are the Top-10 contributors (observation against EU-GMP Chapter and annex) in the overall inspection deficiencies.

Sr. No. EU-GMP Chapter & Annex Details of Chapter/ Annex Number of Deficiencies Contribution in overall deficiencies (%)
1 Chapter 1 Pharmaceutical Quality System 1519 24%
2 Chapter 4 Documentation 757 12%
3 Chapter 5 Production 655 11%
4 Annex 15 Qualification & Validation 611 10%
5 Chapter 3 Premises & Equipment 567 9%
6 Annex 1 Manufacture of Sterile Medicinal Products 448 7%
7 Chapter 6 Quality Control 349 6%
8 Chapter 8 Complaint, Quality Defect & Product Recall 285 5%
9 Chapter 7 Outsources Activities 256 4%
10 Chapter 2 Personnel 219 4%

As per Pareto analysis, approximately 80% deficiencies reported in the above mention top-7 element i.e. EU-GMP Chapter-1, Chapter-3, Chapter-4, Chapter-5, Chapter-6, Annex-1 & Annex-15.

As EU-GMP chapter -1 related deficiencies are major contributor so further analysis of EU-GMP Chapter-1 is required to understand more. As shown in the above graph “title – Chapter-1 Related Observation” Out of above top 10, most of the deficiencies were reported by MHRA inspectorate against the EU-GMP Chapter-1 “Pharmaceutical Quality System“. 1519 deficiencies were reported against the EU-GMP chapter -1 which contributes approximately 24% in overall deficiencies (6209 nos. of deficiencies reported in the year 2018 MHRA GMP inspection across the globe).

Statistical Analysis of EU-GMP Chapter -1 Related GMP Inspection Deficiencies

On the statistical analysis of EU-GMP chapter-1 related deficiencies, out of 1519 deficiencies 241 nos. of deficiencies were made against the requirement of EU GMP chapter -1 clause no. 1.4(xiv) ” An appropriate level of root cause analysis should be applied during the investigation of deviations, suspected product defects and other problems. This can be determined using Quality Risk Management principles. In cases where the true root cause(s) of the issue cannot be determined, consideration should be given to identifying the most likely root cause(s) and to addressing those. Where human error is suspected or identified as the cause, this should be justified having taken care to ensure that process, procedural or system based errors or problems have not been overlooked, if present. Appropriate corrective actions and/or preventative actions (CAPAs) should be identified and taken in response to investigations. The effectiveness of such actions should be monitored and assessed, in line with Quality Risk Management principles”

Chapter-1 Clause Total observation (Clause-wise) Contribution in Chapter -1 related observations (%) Contribution in overall observations (%)
C1.4(xiv) 245 16.13% 3.95%
C1.8(vii) 156 10.27% 2.51%
C1.4(viii) 126 8.29% 2.03%
C1.4(xii) 102 6.71% 1.64%
C1.4(xiii) 66 4.34% 1.06%
C1.6 56 3.69% 0.90%
C1.5 47 3.09% 0.76%
C1.8(iv) 44 2.90% 0.71%
C1.8(v) 42 2.76% 0.68%
C1.8(iii) 38 2.50% 0.61%
C1.4(vii) 37 2.44% 0.60%
Chapter 1 Principle 33 2.17% 0.53%
C1.10(i-xii) 29 1.91% 0.47%
C1.12 29 1.91% 0.47%
C1.4(ix) 29 1.91% 0.47%
C1.4(vi) 29 1.91% 0.47%
C1.13(i-ii) 27 1.78% 0.43%
C1.10(i) 26 1.71% 0.42%
C1.4(xi) 25 1.65% 0.40%
C1.8(xi) 24 1.58% 0.39%
C1.3 23 1.51% 0.37%
C1.9(iv) 21 1.38% 0.34%
C1.4(iv) 20 1.32% 0.32%
C1.4(xvi) 20 1.32% 0.32%
C1.4(i) 17 1.12% 0.27%
C1.4(xvii) 16 1.05% 0.26%
C1.8(i) 16 1.05% 0.26%
C1.8(ix) 16 1.05% 0.26%
C1.8(vi) 13 0.86% 0.21%
C1.13(i) 11 0.72% 0.18%
C1.11 10 0.66% 0.16%
C1.4(xv) 10 0.66% 0.16%
C1.9(i) 9 0.59% 0.14%
C1.10(vii) 8 0.53% 0.13%
C1.8(x) 7 0.46% 0.11%
C1.1 6 0.39% 0.10%
C1.10(iv) 6 0.39% 0.10%
C1.4(iii) 6 0.39% 0.10%
C1.4(v) 6 0.39% 0.10%
C1.4(x) 6 0.39% 0.10%
C1.13(ii) 5 0.33% 0.08%
C1.8(viii) 5 0.33% 0.08%
C1.9(iii) 5 0.33% 0.08%
C1.10(viii) 4 0.26% 0.06%
C1.2 4 0.26% 0.06%
C1.4(ii) 4 0.26% 0.06%
C1.10(vi) 3 0.20% 0.05%
C1.10(xi) 3 0.20% 0.05%
C1.10(xii) 3 0.20% 0.05%
C1.7 3 0.20% 0.05%
C1.8(ii) 3 0.20% 0.05%
C1.9(vi) 3 0.20% 0.05%
C1.9(vii) 3 0.20% 0.05%
C1.10(ii) 2 0.13% 0.03%
C1.4 (xiv) 2 0.13% 0.03%
C1.9(i-viii) 2 0.13% 0.03%
C1 (xiii) 1 0.07% 0.02%
C1 Principle 1 0.07% 0.02%
C1.10(x) 1 0.07% 0.02%
C1.4 (xiiii) 1 0.07% 0.02%
C1.4(i-xvii) 1 0.07% 0.02%
C1.8(i-xi) 1 0.07% 0.02%
C1.9(ii) 1 0.07% 0.02%
C1.9(v) 1 0.07% 0.02%
Top 10 contributor in EU-GMP Chapter -1 Deficiencies & Its requirement
Top 10 contributor in EU-GMP Chapter -1 Deficiencies & Its requirement
  1. As per EU-GMP Chapter-1 C1.4(xiv) & C1.8(vii), all the deviation should be recorded in a timely manner and should be an investigation by using an appropriate tool which can help to identify the assignable root cause and if in any case the assignable root cause could not be identified then at-least all the possible or probable root cause should be identified and fixed. For any complex investigation, fishbone analysis, Fault tree analysis can be used to investigate any failure and identified the assignable root cause. Special focus is required where human error found assignable root cause then in that case further analysis of human error should be performed to find the reason behind any human failure. To understand further human error analysis see the following article “Common mistake during Investigation“. A Deviation and investigation procedure is required to report all the deviation in a timely manner which has deviation and investigation formats. To report the deviation on time, easy access of deviation form to each individual is required i.e paper-based or electronic
  2. As per EU-GMP Chapter-1 clause no. 1.4(viii), an effective monitoring and control system is required for process performance and product quality so to achieve consistent quality into products all the critical control parameters and critical quality attributes should be defined for each product and all these critical control parameters should be validated. To ensure the consistent quality, in-process quality parameters should be defined for each product and to be monitored at a defined frequency. The test specification is also required to test the raw material, packing material & finished products to ensure its quality. An out of trends procedure can also be developed to define the upper and lower out of trend limit (within specification limit) for any critical quality parameters and investigate in case of any out of trends.
  3. As per EU-GMP Chapter -1 clause no. 1.4(xii) & 1.4 (xiii), a change management procedure is required which provides a guidance document along with a change control form (paper-based or electronic) to address the requirement of any change in the GMP environment. All the changes should be properly analyzed for any impact on product quality and should be approved by regulatory before implementation wherever required.
  4. As per EU-GMP Chapter -1 clause no. 1.5 & 1.6, periodic management review with the involvement of senior management is required to identify the continuous improvement opportunity in the process, product & system. It is the responsibility of senior management to ensure the effective pharmaceutical system in-place where the responsibility and role of each individual should be defined. For the management review, the procedure should be in-place with agenda of discussion, responsibilities & management review meeting frequency (Six monthly or preferably each quarter).
  5. As per EU-GMP Chapter -1 clause no. 1.8 (iv) & 1.8(v), instruction and procedure should be written in the instructional form and if required it should be written in local regional language so that it can be easily understood by the operator and all the operator should be properly trained on all these procedures before doing any related job.
Disclaimer: We have tried to statistically evaluate all the published MHRA GMP inspection deficiencies but we are not giving any guarantee of the accuracy so please validate the same before use.

Reference:

Good manufacturing practice inspection deficiencies- MHRA GMP Inspection Deficiency Data 2018