Analysis of trends in identified nonconformities to GMP requirements during inspecting of foreign manufacturers

      In today's rapidly changing world, for successful business development, it is very important to systematically analyze, evaluate trends and use the information received for timely and effective management decisions. Every year there is a development and change in regulatory requirements for pharmaceutical production. On the one hand, we see active growth in the industry as a whole. The process of developing and introducing new technologies into industrial pharmaceutical production is growing at an accelerated pace, and the quality requirements for pharmaceutical products are increasing. On the other hand, there is an accumulation of knowledges about products and the organization of their production, which is expressed in increasing the level of competencies of pharmaceutical workers, including auditors and inspectors.

       Nonconformities identified in GMP audits / inspections are a kind of “indicator” of the current  situation, showing the main problems of pharmaceutical production. Analysis of nonconformities, as well as trends in the ratio of detected nonconformities, allows us to find the most "weak" sides that require special attention.

       This publication provides an overview of data on nonconformities identified during Russian inspections conducted from January 2017 to November 2019 by the Federal State Institution «State Institute of Drugs and Good Practices» (FSI «SID & GP»).

From 2016 (the beginning of inspections of foreign manufacturers conducted by the FSI «SID & GP») to November 1, 2019, 1779 inspections were carried out: in 2016 - 188, in 2017 - 521, in 2018 - 667, in 2019 (up to 1 November) - 403 inspections.

       An analysis of the percentage of identified nonconformities by category (critical, major, others) from 2017 to 2019 as a whole allows us to make a positive conclusion about a decrease in the number of critical and major nonconformities - Figure 1.

Figure 1. Percentage by category of nonconformities identified during inspections of the FSI «SID & GP» from 2017 to November 2019.
       There are several reasons for this trend, starting from the procedure for conducting inspections by inspectors and ending with a more balanced approach to making decisions on filing applications for inspection by manufacturers. In any case, in the end we conclude that basically there is an increase in the level of preparation of pharmaceutical manufacturers for inspection.
       Of particular interest is a review of data on changes in the ratio of critical and major nonconformities in GMP chapters - table 1.

Table 1. Trends in percentages of critical and major nonconformities in GMP chapters.
     With predictable constancy, the largest number of nonconformities is observed in seven chapters - Chapters 1, 3, 4, 5, 6, Annex 1 and Annex 15: in 2017 - 90,17%, in 2018 - 86,85%, in 2019 - 86,03%.
      Chapters 3 (Premises and equipment), Chapter 5 (Production), Chapter 6 (Quality control),    Chapter 7 (Outsourced activities) and Annex 19 (Reference and Retention Samples) show positive trends in reducing the proportion of nonconformities, which probably due to the gradual upgrade of equipment from manufacturers, increased automation in production and, of course, manufacturers' attention to strengthening 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 see an increase in the proportion of nonconformities. Among the nonconformities of Chapter 1 (Pharmaceutical Quality System), a significant part (about 50%) is associated with nonconformities to the registration dossier. In addition, many nonconformities related to other GMP chapters are ultimately related to the pharmaceutical quality system of the enterprise, therefore, they have related links to the relevant points of nonconformity to Chapter 1.
       Of great interest is the dynamics of the increase in the percentage of nonconformities to Annex 8 (Sampling of Starting and Packaging Materials) and Annex 11 (Computerized systems).
From the data presented (table 1, figure 2), we see a significant increase in the proportion of nonconformities to Annex 8 (Sampling of Starting and Packaging Materials) in 2019 compared to 2017 and 2018 - an increase of almost 5 times.

The increase in the proportion of nonconformities to Annex 8 (Sampling of Starting and Packaging Materials) is primarily associated with the identification of violations during sampling of sterile materials and intermediate products. Thus, this trend is due to nonconformities identified in sterile production, which, in turn, is also reflected in the increase in the proportion of discrepancies to Annex 1 (Manufacture of Sterile Medicinal Products). Of course, the increase in the proportion of nonconformities to Annex 1 may be due to various reasons. Nevertheless, in our opinion, there is a correlation and influence of the increase in the share of nonconformities to Annex 8 (in sterile production) on the increase in the percentage of nonconformities to Annex 1, due to the related clauses of the GMP requirements.
       A similar relationship, in our opinion, can be detected in the case of an increase in the proportion of nonconformities to Annex 11 (Computerized Systems) and Annex 15 (Qualification and Validation). First of all, we would like to draw attention to the growth dynamics of nonconformities to Annex 11 (table 1, figure 3). In 2018, compared with 2017, the proportion of nonconformities to Annex 11 increased by more than 5 times. In 2019, compared with 2018, the share of nonconformities to Annex 11 increased by 37%.

Currently, there is an active development of computerized systems and digitalization in general in the pharmaceutical industry. Often, the rapid introduction of new computerized systems in combination with an insufficiently established pharmaceutical quality system creates risks for the use of these systems primarily because of the lack of guarantees of their correct operation.
       As a result, during the inspection, this is primarily revealed in the absence of documentation on the validation of computerized systems, starting from the installation, verification of operation and ending with the lack of documentary evidence of periodic verification of the proper operation of the system. A separate block of nonconformities is associated with the lack of data security, limited access and control of changes, the confirmation of which is also included in the documentation on the validation of computerized systems.
       Thus, we can mark a certain degree of correlation between the increase in the share of nonconformities to Annex 11 (Computerized Systems) and the increase in the percentage of nonconformities to Annex 15 (Qualification and Validation).
       The data review presented reflects general current trends in identifying nonconformities. At the same time, each manufacturer, using this information, can conduct an individual comparative analysis in relation to a specific manufacturing site.
       Changes in the ratio of nonconformities may be due to various factors. At the same time, it is of interest to assess the dynamics of change and identify the relationships associated with the growth of inconsistencies in certain chapters of the GMP rules.
       Assessment of trends in detected nonconformities can serve as an additional source of information and justification for making effective management decisions on the development of pharmaceutical production.
       Prepared by Ivan Guliaev, Ph. D, using the materials of the presentation presented on November 14, 2019 at the II International Scientific and Practical Anniversary Conference “Harmonization of Approaches to Pharmaceutical Development”, Peoples' Friendship University of Russia (RUDN University, Moscow, Russia.
       According to the Federal State Institution «State Institute of Drugs and Good Practices» for 2017-2019