Trend analysis of identified deviations in terms of GMP requirements when inspecting foreign manufacturers according to the Federal State Institution “State Institute of Drugs and Good Practices” over 2017-2019 years.
In today’s rapidly changing world, for the purposes of successful development of business, it is important to systematically conduct analysis, trends assessment and use the information for timely and effective decision-making.
Every year there has been a development and changes in the sphere of regulatory requirements for pharmaceutical manufacturing. On the one hand, we see a strong growth in the industry as a whole – the process of development and implementation of new process technologies in industrial pharmaceutical manufacturing is taking place in a steadily increasing ratio, the demands on the quality of pharmaceutical products is increasing as well. On the other hand, there is an accumulation of knowledge of the product and its manufacturing process management, which in turn comes to a high level of pharmaceutical staff competencies, including auditors and inspectors.
Deviations that were identified during GMP inspections are representing sort of “indicators” of the current situation, showing the main challenges of pharmaceutical productions. Analysis of deviations and trends in the ratio of identified deviations, allows to detect the “weakest” points, that require special attention.
This article provides an overview of data in terms of deviations identified during Russian inspections carried out from January 2017 to November 2019 by the Federal State Institution “State Institute of Drugs and Good Practices” (“SID&GP”).
The procedure for inspection established by the Decree of the Government of the Russian Federation of December 3, 2015 No. 1314 “On determining the conformity of medicines’ manufacturers to the requirements of the GMP rules” .
When the “SID&GP” conducts an inspection, it evaluates the pharmaceutical manufacturer in terms of its compliance with the requirements of GMP Rules (Order of the Ministry of Industry and Trade of the Russian Federation as of 14 June, 2013 No. 916 – hereinafter referred as GMP Rules) .
The analysis of deviations identified by inspectors is based on a risk-based approach. Classifications of deviations were validated by the Order of the Ministry of Industry and Trade of the Russian Federation as of 4 February, 2016 No. 261 . These definitions are harmonized with the relevant definitions of the deviations categories, approved regulations for the inspectorates of the Eurasian Economic Union, European countries as well as Canada, Australia and others. In detail, some of the inspection issues are laid down in the Article “Preparing manufacturers for GMP re-inspection. Relevant issues of pharmaceutical manufacturers”.
Since 2016 (the beginning when “SID&GP” started to conduct inspections of foreign manufacturers) till November 1, 2019 there were 1779 inspections carried out: in 2016 – 188, in 2017 – 521, in 2018 – 667, in 2019 (till November 1) – 403 inspections.
Analysis of the percentage of identified deviations by category (Critical, Major, Other) allows to make a positive conclusion about the decrease in the number of Critical and Major deviations from 2017 to 2019 as a whole – see Figure 1.
Figure 1. The percentage ratio as per deviation categories, identified during inspections conducted by “SID and GP” from 2017 to November 2019
Overall, it can be concluded that a growth of the preparedness level of the pharmaceutical manufacturers for inspections is observed.
Of a particular interest is the overview of the data on the changes in the ratio of critical and major deviations as per GMP sections – Table 1.
Table 1. Tendencies of a change in percentage ratio of major and critical deviations according to GMP chapters
With predictable consistency the largest number of deviations is observed in seven sections – Chapter 1, Chapter 3, Chapter 4, Chapter 5, Chapter 6, Annex 1 and Annex 15: in 2017 – 90,17%, in 2018 – 86,85%, in 2019 – 86,03%.
In Chapter 3 (Premises and Equipment), Chapter 5 (Production), Chapter 6 (Quality Control), Chapter 7 (Outsourced Activities) and Annex 19 (Reference and Retention Samples) positive tendencies of a decrease in the share of deviations are observed and this is, probably, linked with a gradual upgrading of equipment, an increase in automation in factories, and, of course, attention devoted by the manufacturers towards the strengthening of these areas.
In Chapter 1 (Pharmaceutical Quality System), Annex 1 (Manufacture of Sterile Medicinal Products), Annex 8 (Sampling of Starting and Packaging Materials), Annex 11 (Computerized Systems), Annex 15 (Qualification and Validation) we can see an increase in the share of deviations. A substantial part of deviations in Chapter 1 (Pharmaceutical Quality System) (approximately 50%) is related to deviations with registration dossier. In addition, much of deviations, pertinent to other GMP sections, are ultimately related to the pharmaceutical quality system; that is why they have related references to the corresponding points of deviations in Chapter 1.
Dynamics of an increase in the share of deviations in Annex 8 (Sampling of Starting and Packaging Materials) and Annex 11 (Computerized Systems) are of a significant interest.
From the data presented (Table 1, Figure 2) a considerable increase in the share of deviations can be seen in Annex 8 (Sampling of Starting and Packaging Materials) in 2019 as oppose to 2017 and 2018 – practically a fivefold increase.
Figure 2. Change in a share of deviations in Annex 8 (critical + major) from 2017 to 2019
An increase in the share of deviations in Annex 8 (Sampling of Starting and Packaging Materials) is primarily related to the identified violations during the sampling of sterile materials and intermediate products. In this regard, such tendency is attributed to deviations, identified at manufacturing facilities of sterile products, which in turn, also, shows an increase in the share of deviations in Annex 1 (Manufacture of Sterile Medicinal Products). Indeed, an increase in the share of deviations in Annex 1 arises from different reasons. However, in our view, there is an interrelationship and an effect of an increase of the share of deviations in Annex 8 (at manufacturing facilities of sterile products) on an increase of the share of deviations in Annex 1, through the related points of GMP rules.
A similar interrelationship, as we see it, can be observed and in the case of an increase in the share of deviations in Annex 11 (Computerized Systems) and Annex 15 (Qualification and Validation). We would first like to draw attention towards the dynamics of an increase in deviations in Annex 11 (table 1, figure 3). In 2018, compared to 2017, share of deviaions in Annex 11 increased by more than five-fold. In 2019 – compared to 2018 – a share of deviations in Annex 11 increased by 37%.
Figure 3. Change in a share of deviations in Annex 11 (critical + major) from 2017 to 2019
At present, an active development of computerized systems and digitalization as a whole is taking place in the pharmaceutical industry. Quite often a rapid implementation of new computerized systems in combination with an insufficiently fine-tuned pharmaceutical quality system poses risks of using the system data on the first place due to the unavailability of an assurance that works are properly done. As a result, during inspections it is particularly revealed in the absence of documentation on computerized system validation beginning from the stage of installation, verification of the functioning and finishing with the unavailability of a documentary evidence of a periodic review to ensure that the system works in an appropriate manner. A separate cluster of deviations is related to the unavailability of date preservation, limited access and change control, whose confirmation is also included in the documentation on validation of computerized system. Therefore, we can highlight a certain degree of interrelationship of an increase of share of deviations in Annex 11 (Computerized Systems)) and an increase of the share of deviations in Annex 15 (Qualification and Validation).
This overview of data reflects general current trends of identifying deviations. At the same time, by using such information each manufacturer can conduct an individual comparative analysis as applicable to a particular manufacturing site.
A change in a proportion of deviations can be attributed to different factors. In so doing, the evaluation of a change dynamics and identifying interrelationships, related to an increase in deviations in certain sections of GMP Rules, are a matter of interest.
The trend assessment of identifiable deviations can act as an additional source of information and a basis for effective decision-making on development of the pharmaceutical sector.
- Decree of the Russian Government No. 1314 of 03.12.2015 “On conformity of drug manufacturers to GMP Rules requirements”;
- Order of the Ministry of Industry and Trade of Russia No. 916 of 14.06.2013 “On Approval of Good Manufacturing Practice Rules”, registered by the Ministry of Justice of Russia on 10.09.2013, registration No. 29938; as amended by the Order No. 4148 of 18.12.2015;
- Order of the Ministry of Industry and Trade of the Russian Federation No. 261 of 04.02.2016 “On approval of the application form for issuing the compliance certificate of manufacturer (foreign manufacturer) of drugs for medical use with GMP Rules requirements; the form of GMP inspection upon the results of inspection of drugs for medical use manufacturer on compliance with GMP Rules requirements and the form of GMP compliance certificate of the manufacturer (foreign manufacturer) of drugs for medical use compliance with GMP Rules requirements”;
- https://gmp-publication.net/gmp-news-autumn-2018 (pages 32-35).
- Vladislav Shestakov, Director of the Federal State Institution “State Institute of Drugs and Good Practices” of the Ministry of Industry and Trade of the Russian Federation;
- Ivan Gulyaev, Candidate of Pharmaceutical Sciences, with an input from the presentation, delivered on November 14, 2019 at the II International Scientific Anniversary Conference “Harmonization of approaches to pharmaceutical development”, Peoples’ Friendship University of Russia, Moscow. Russia.