Assessing the Correlation Between GMP Deviations and Potential Quality Defects of Medicinal Products: the Result of the Survey of Qualified Persons

Introduction. One of the key issues in the field of assessing the conformity of drug manufacturers with the requirements of good manufacturing practice (GMP) is a systematic methodology for classifying revealed deficiencies (deviations, non-conformities) by their level of criticality. Today the information included into regulatory documents regarding the definitions of critical, major and minor (other) deficiencies is not always sufficient for the use in GMP inspection practice, as well as in quality management systems of the pharmaceutical manufacturers. In terms to study approaches to the classification of GMP deviations applied in the practice of the Qualified persons of drug manufacturers in the Russian Federation, a survey was conducted in the form of a questionnaire. This work became a logical continuation of a previous study among employees of the pharmaceutical inspectorate of the Russian Federation.

Aim. To identify the correlation between the classification of critical and major GMP deviations and potential class I and II quality defects of medicinal products.

Materials and methods. The study was based on a survey of Qualified persons of drug manufacturers (56 respondents) using a questionnaire specially designed. The main hypothesis of the study is that specialists (Qualified persons) who make decisions on the classification of GMP deviations are guided by potential quality defects that may be caused by the indicated deviations. In the framework of the study, authors used the model of gradation of quality defects of the medicinal products into 3 classes (class I, II and III) according to the rate of their significance as indicated in the PIC/S and EMA guidelines. At the same time, for GMP deviations a three-level gradation system is also used: Critical, Major and Minor (Other). In designing of questionnaires for the survey, the focus was made on examples of quality defects of classes I and II and, accordingly, Critical and Major GMP deviations.

Results and discussion. The results of the processing and analysis of questionnaires summarize the opinion of the majority of respondents about the direct relationship between product quality defects of the high risk (class I) and critical GMP deviations. Respondents also expressed the opinion that deviations that could trigger the occurrence of the class II quality defects in most cases will be classified as critical. The results obtained during the study also indicate the similarity of existing approaches of the classification of GMP deviations (deficiencies) between QPs of the drug manufacturers and pharmaceutical inspectors.

Conclusion. The results of the study show that for the purpose of classifying (determining the criticality) of GMP deviations (deficiencies) , it is possible to use the rating system for the quality defects of medicinal products by the rate of their significance for the patient which is presented in EU regulatory documents and PIC/S guidelines. The results of the study also will facilitate the drawing of conclusions that today, not only from the position of regulatory authorities, but also for the pharmaceutical industry, there is a need to develop methodological guidelines with a focus on a risk-based classification of GMP deviations (deficiencies). These guidelines should take into account the potential impact of the mentioned GMPdeviations on the occurrence of the quality defects of medicinal products and, as a result, threats to the life and health of patients.

1. Orlov V. A., Shestakov V. N. Assessing the relationship between deviations from GMP requirements and potential quality defects of medicinal products: a survey of employees of the pharmaceutical inspectorate. Remedium. 2020; (1-2-3): 60–67 (in Russ.).

2. Procedure for Handling Rapid Alerts Arising from Quality Defects. European Commission. Available at: https://www.ema.europa.eu/en/documents/regulatory-proceduralguideline/compilation-community-procedures-inspections-exchange-information_en.pdf#%5B%7B%22num%22%3A39%2C%22gen%22%3A0%7D%2C%7B%22name%22%3A%22XYZ%22%7D%2C191%2C551%2C0%5D.

3. Procedure for handling rapid alerts and recalls arising from quality defects. Pharmaceutical Inspection Co-operation Scheme. Available at: https://picscheme.org/layout/document.php?id=1140.

4. Federal law «On circulation of medicines» No. 61-FZ dated by 12.04.2010. ConsultantPlus. Available at: http://www.consultant.ru/document/cons_doc_LAW_99350 (in Russ.).

5. GMP Inspection Report – Union Format. European Commission. Available at: https://www.ema.europa.eu/en/documents/regulatoryprocedural-guideline/compilation-community-proceduresinspections-exchange-information_en.pdf#%5B%7B%22num%22%3A371%2C%22gen%22%3A0%7D%2C%7B%22name%22%3A%22XYZ%22%7D%2C374%2C619%2C0%5D.

6. PIC/S Guidance on Classification of GMPDeficiencies. Pharmaceutical Inspection Co-operation Scheme. Available at: https://picscheme.org/layout/document.php?id=1609.

7. Decision of Council of the Eurasian Economic Union Commission No. 83 dated by 3.11.2016 «On approval of the rules for conducting the pharmaceutical inspections». Eurasian Economic Union. Available at: https://docs.eaeunion.org/docs/ru-ru/01411936/cncd_21112016_83 (in Russ.).

8. Orlov V. A., Shestakov V. N. Classification issues of GMP inspection deficiencies: regulatory practices. Remedium. 2019; (1-2): 48–54 (in Russ.).

9. Decree of the Ministry of Industry and Trade of Russia dated by 04.02.2016 No. 261 «On approval of application forms for issuing a conclusion on the conformity of a manufacturer (foreign manufacturer) of medicines for human use with the requirements of the rules of good manufacturing practice, an inspection report on the results of inspections of the manufacturers and foreign manufacturers of medicines for human use for compliance with the requirements of the rules of good manufacturing practice and the conclusion on the conformity of the manufacturer (foreign producer) of medicines for human use with the requirements of the rules of good manufacturing practice» (Registered in the Ministry of Justice of Russia on 09.03.2016 No. 41341). Consultant Plus. Available at: http://www.consultant.ru/document/cons_doc_LAW_195085 (in Russ.).

10. Risk classification guide for drug good manufacturing practices observations. Health Canada. Available at: https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-health-products/compliance-enforcement/good-manufacturing-practices/guidancedocuments/risk-classification-drug-gmp-observations-0023-eng.pdf.

11. PIC/S INSPECTION REPORT FORMAT. Pharmaceutical Inspection Co-operation Scheme. Available at: https://picscheme.org/layout/document.php?id=137.

12. Decision of Council of the Eurasian Economic Union Commission No. 73 dated by 3.11.2016 «On the procedure for the certification of Qualified persons of drug manufacturers». Eurasian Economic Union. Available at: http://docs.eaeunion.org/docs/ru-ru/01411909/cncd_21112016_73 (in Russ.).

13. DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 6 November 2001 on the Community code relating to medicinal products for human use. Available at: https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf.