pharmjournalРазработка и регистрация лекарственных средствDrug development & registration2305-20662658-5049LLC «CPHA»10.33380/2305-2066-2019-8-2-122-130pharmjournal-692Research ArticleРЕГУЛЯТОРНЫЕ ВОПРОСЫREGULATORY ISSUESВалидация аналитических методик: графические и расчетные критерии для оценки линейности методик на практикеValidation of Analytical Procedures: Graphic and Calculated Criteria for Assessment of Methods Linearity in Practicehttps://orcid.org/0000-0001-8047-4078ЭпштейнН. А.EpshteinN. A.

Researcher ID: A-7114 -2019

 

Researcher ID: A-7114-2019

 

naumepshtein@gmail.comЦентр регистрации и разработки лекарственных средств ООО «ИРВИН 2»Center of registration and development of medicines LLC «IRVIN 2»20193005201982122130Copyright © Эпштейн Н.А., 20192019Эпштейн Н.А.Epshtein N.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmjournal.ru/jour/article/view/692Введение

Введение. При валидации аналитических методик одной из обязательных характеристик является «Линейность». Вопросы, связанные с валидацией линейности методик, до сих пор являются актуальными.

Цель

Цель. Рассмотреть основные графические и расчетные критерии для подтверждения линейности аналитических методик и их ограничения, а также дать рекомендации.

Материалы и методы

Материалы и методы. Статистические расчеты выполнены с помощью программы MS Excel. Экспериментальные данные получены методом ВЭЖХ.

Результаты и обсуждение

Результаты и обсуждение. Подробно рассмотрены основные критерии для доказательства/подтверждения линейности аналитических методик и их ограничения. Показано, что эти критерии не всегда могут дать надежную оценку линейности методики, указаны возможные причины этого и даны рекомендации.

Заключение

Заключение. При валидации методик необходимо доказывать/подтверждать их линейность с помощью двух, а надежнее – трех критериев, одним из которых обязательно должна быть линейность графика зависимости измеряемого отклика (Y) от концентрации определяемого вещества (C). С другой стороны, показано, что не следует формально подходить к оценке нелинейности методики при использовании графических и расчетных критериев, основанных на математической статистике, так как они не учитывают возможность практической незначимости небольших отклонений от линейной зависимости Y от C.

Introduction

Introduction. «Linearity» is one of the required characteristics when validating analytical procedures. The issues of the validation of linearity procedures are still relevant.

Aim

Aim. To consider the main graphical and calculated criteria for confirmation of the linearity of analytical procedures and their restrictions, as well as to give recommendations.

Materials and methods

Materials and methods. Statistical calculations were performed using MS Excel. Experimental data were obtained by HPLC.

Results and discussion

Results and discussion. The main criteria for proving/confirming the linearity of analytical procedures and their restrictions are considered in detail. It is shown that these criteria cannot always give a reliable assessment of the linearity of the procedure, the possible reasons for this are indicated and recommendations are given.

Conclusion

Conclusion. When validating the procedures, it is necessary to prove/confirm their linearity by using two, and, more reliably, three criteria, one of which must be the linearity of the plot of measured response (Y) vs concentration of the tested substance (C). On the other hand, we demonstrate here that a formal approach should not be used for the estimation of non-linearity of the procedure when using graphical and calculation criteria based on mathematical statistics, since they do not take into account the possibility of practical insignificance of small deviations from the linear dependence of Y on C.

валидациялинейностьметодикикритерии приемлемостиvalidationlinearityproceduresacceptance criteriaReferencesICH Harmonised Tripartite Guideline. Validation of Analytical Procedures: Text and Methodology Q2(R1). ICH, 2005; 13.ICH Harmonised Tripartite Guideline. Validation of Analytical Procedures: Text and Methodology Q2(R1). ICH, 2005; 13.United States Pharmacopoeia. <1225> Validation of compendial procedures. USP40–NF35. 2017; 1640–1646.United States Pharmacopoeia. <1225> Validation of compendial procedures. USP40–NF35. 2017; 1640–1646.Государственная фармакопея Российской Федерации. XIV издание. Москва. 2018; 1: 276–288.State Pharmacopoeia of the Russian Federation XIV edition, 2018, V.1; 276-288 (in Russ.).Green J. М. А Practical Guide to Analytical Method Validation. Analytical Chemistry News & Features. 1996; 1: 305А–309А. https://doi.org/10.1021/ac961912f.Green J. М. А Practical Guide to Analytical Method Validation. Analytical Chemistry News & Features. 1996; 1: 305А-309А. https://doi.org/10.1021/ac961912f.Эпштейн Н. А. Оценка пригодности (валидация) ВЭЖХ методик в фармацевтическом анализе (Обзор). Химико-фармацевтический журнал. 2004; 38(4): 40–56. https://doi.org/10.1023/b:phac.0000038422.27193.6cEpstein N. A. Evaluation of the suitability (validation) of HPLC techniques in pharmaceutical analysis (Review). Chemical Pharmaceutical Journal. 2004; 38 (4): 40–56. https://doi.org/10.1023/b:phac.0000038422.27193.6cЭрмер Й., Миллер Д. Х. Мак Б. Валидация методик в фармацевтическом анализе. Примеры наилучших практик. М.: ВИАЛЕК. 2013; 512.Ermer Y., Miller D.H. Mac B. Validation of methods in pharmaceutical analysis. Examples of best practices. M.: VIALEK. 2013; 512 (in Russ.).Руководство для предприятий фармацевтической промышленности. Методические рекомендации. Ч. I. Руководство по валидации методик анализа лекарственных средств / Под ред. Н. В. Юргеля, А. Л. Младенцева, А. В. Бурдейна и др. М.: Изд-во «Спорт и культура – 2000». 2007; 5–92.Guide for enterprises of the pharmaceutical industry. Guidelines. Part I. Guidelines for the validation of methods for analyzing drugs. Ed. N. V. Yurgelya, A. L. Mladentseva, A. V. Burdeina i dr. M.: Publishing house «Sport and Culture – 2000». 2007; 5–92 (In Russ.).Гризодуб А. И. Стандартизованные процедуры валидации методик контроля качества лекарственных средств. Харьков: Государственное предприятие «Украинский научный фармакопейный центр качества лекарственных средств», 2016; 396.Grizodub A. I. Standardized procedures for the validation of drug quality control methods. Khar’kov: Gosudarstvennoe predpriyatie «Ukrainskiy nauchnyy farmakopeynyy tsentr kachestva lekarstvennykh sredstv». 2016; 396 (in Russ.).Massart D. L., Vandeginste B. G. M., Buydens L. M. C., De Jong S., Lewi P. J., Smeyers-Verbeke J. Straight Line Regression and Calibration, in: Handbook of Chemometrics and Qualimetrics: Part A, volume 20A of Data Handling in Science and Technology. Amsterdam, Netherlands: Elsevier. 1998; 171–230. https://doi.org/10.1016/S0922-3487(97)80038-X.Massart D. L., Vandeginste B. G. M., Buydens L. M. C., De Jong S., Lewi P. J., Smeyers-Verbeke J. Straight Line Regression and Calibration, in: Handbook of Chemometrics and Qualimetrics: Part A, volume 20A of Data Handling in Science and Technology. Amsterdam, Netherlands: Elsevier. 1998: 171–230. https://doi.org/10.1016/S0922-3487(97)80038-X.Vial J., Jardy A. Taking into account both preparation and injection in HPLC linearity studies. J. Chromatogr. Sci. 2000; 38: 189–194.Vial J. and Jardy A. Taking into account both preparation and injection in HPLC linearity studies. J. Chromatogr. Sci.2000; 38:189–194.Burke S. Regression and Calibration. LC-GC Europe Online Supplement statistics and data analysis. 2001: 13–18.Burke S. Regression and Calibration. LC-GC Europe Online Supplement statistics and data analysis. 2001: 13–18.Kiser M. M., Dolan J. W. Selecting the Best Curve Fit. LC-GC North America. 2004; 22(2): 138–143.Kiser M. M., Dolan J. W. Selecting the Best Curve Fit. LC-GC North America. 2004; 22(2): 138–143.Mark H., Workman J. Chemometrics in Spectroscopy. How to Test for Non-linearity. Spectroscopy. 2005; 20(9): 26–35.Mark H., Workman J. Chemometrics in Spectroscopy. How to Test for Non-linearity. Spectroscopy. 2005; 20(9): 26–35.Mark H., Workman J. Linearity in calibration: Other tests for nonlinearity // Spectroscopy. 2005; 20(4): 38–39.Mark H., Workman J. Linearity in calibration: Other tests for nonlinearity // Spectroscopy. 2005; 20(4):38–39.Scheilla Vitorino Carvalho de Souza, Junqueira R. G. A procedure to assess linearity by ordinary least squares method. Analytica Chimica Acta. 2005; 552(1-2): 25–35. https://doi.org/10.1016/j.aca.2005.07.043.Scheilla Vitorino Carvalho de Souza, Junqueira R. G. A procedure to assess linearity by ordinary least squares method. Analytica Chimica Acta. 2005; 552(1-2): 25–35. https://doi.org/10.1016/j.aca.2005.07.043.Mark H., Workman J. Chemometrics in Spectroscopy. Linearity in Calibration: Quantifying Nonlinearity, Part II. Spectroscopy. 2006; 21(1): 44-54.Mark H., Workman J. Chemometrics in Spectroscopy. Linearity in Calibration: Quantifying Nonlinearity, Part II. Spectroscopy. 2006; 21(1): 44–54Bruggemann L., Quapp W., Wennrich R. Test for non-linearity concerning linear calibrated chemical measurements. Accred Qual Assur.2006; 11: 625–631. https://doi.org/10.1007/s00769-006-0205-x.Bruggemann L., Quapp W., Wennrich R. Test for non-linearity concerning linear calibrated chemical measurements. Accred Qual Assur.2006; 11: 625–631. https://doi.org/10.1007/s00769-006-0205-x.Burrows J, Watson K. Linearity of chromatographic systems in drug analysis part I: theory of nonlinearity and quantification of curvature. Bioanalysis. 2015; 7 (14): 1731–1743. https://doi.org/10.4155/bio.15.103.Burrows J, Watson K. Linearity of chromatographic systems in drug analysis part I: theory of nonlinearity and quantification of curvature. Bioanalysis. 2015; 7(14): 1731–1743. https://doi.org/10.4155/bio.15.103.Burrows J, Watson K. Linearity of chromatographic systems in drug analysis part II: a Monte Carlo justification for the use of nonlinear regressions. Bioanalysis. 2015; 7 (14): 1745–1761. https://doi.org/10.4155/bio.15.104.Burrows J, Watson K. Linearity of chromatographic systems in drug analysis part II: a Monte Carlo justification for the use of nonlinear regressions. Bioanalysis. 2015; 7(14): 1745-1761. https://doi.org/10.4155/bio.15.104.Burrows J, Watson K. Linearity of chromatographic systems in drug analysis part III: examples of nonlinear drug assays. Bioanalysis. 2015; 7 (14): 1763–1774. https://doi.org/10.4155/bio.15.105.Burrows J, Watson K. Linearity of chromatographic systems in drug analysis part III: examples of nonlinear drug assays. Bioanalysis. 2015; 7(14): 1763–1774. https://doi.org/10.4155/bio.15.105.Raposo F. Evaluation of analytical calibration based on least-squares linear regression for instrumental techniques: A tutorial review. TrAC Trends in Analytical Chemistry. 2016; 77: 167–185. https://doi.org/10.1016/j.trac.2015.12.006.Raposo F. Evaluation of analytical calibration based on least-squares linear regression for instrumental techniques: A tutorial review. TrAC Trends in Analytical Chemistry. 2016; 77: 167–185. https://doi.org/10.1016/j.trac.2015.12.006.Rawski R. I., Sanecki P. T., Kijowska K. M., Skital P. M., Saletnik D. E. Regression Analysis in Analytical Chemistry. Determination and Validation of Linear and Quadratic Regression Dependencies. S. Afr. J. Chem. 2016; 69: 166–173. https://doi.org/10.17159/0379-4350/2016/v69a20.Rawski R. I., Sanecki P. T., Kijowska K. M., Skital P. M., Saletnik D. E. Regression Analysis in Analytical Chemistry. Determination and Validation of Linear and Quadratic Regression Dependencies. S. Afr. J. Chem. 2016; 69: 166–173. https://doi.org/10.17159/0379-4350/2016/v69a20.Мымриков Антон. Действительно ли ваша калибровка является прямой линией? Available at: https://pharm-community.com/2017/8336/ (accessed 25.12.2017).Mymrikov Anton. Is your calibration a straight line? Available at: https://pharm-community.com/2017/8336/ (accessed 25.12.2017).Chemometrics in Chromatography ed. by Komsta L., Vander Heyden Y., Sherma J. Boca Raton: CRC Press. 2018; 506. https://doi.org/10.1201/9781315154404.Chemometrics in Chromatography ed. by Komsta L., Vander Heyden Y., Sherma J. Boca Raton: CRC Press. 2018; 506. https://doi.org/10.1201/9781315154404.Доерфель К. Статистика в аналитической химии. М.: Мир. 1966; 211. https://doi.org/10.1002/bimj.19690110612.Doerffel K. Statistik in der analytischen Chemie. Leipzig: VEB Deutscher Verlag für Grundstoffindustrie. 1966; 211. https://doi.org/10.1002/bimj.19690110612.Эпштейн Н. А. О допустимых значениях порога игнорирования примесей и отношения сигнал/шум при проверке чувствительности хроматографической системы. Ведомости НЦЭСМП. 2017; 7(2): 85–91.Epshtein N.A. About admissible values of disregard limits for impurities and signal-to-noise ratio when checking chromatographic system sensitivity // The Bulletin of the Scientific Center for Expert Evaluation of Medicinal Products. 2017; 7(2): 85–91 (In Russ.).Reviewer Guidance: Validation of Chromatographic Methods. Center for Drug Evaluation and Research (CDER). Washington. 1994. Available at: https://www.fda.gov/downloads/drugs/guidances/ucm134409.pdf.Reviewer Guidance: Validation of Chromatographic Methods. Center for Drug Evaluation and Research (CDER). Washington. 1994. Available at: https://www.fda.gov/downloads/drugs/guidances/ucm134409.pdf.Rosario LoBrutto and Tarun Patel. Method Validation in HPLC for Pharmaceutical Scientists. Ed. By Kazakevich Y.V., LoBrutto R. Hoboken, New Jersey: John Wiley & Sons, Inc. 2007; 455–502. https://doi.org/10.1002/9780470087954.ch9.Rosario LoBrutto and Tarun Patel. Method Validation in HPLC for Pharmaceutical Scientists. Ed. By Kazakevich Y. V., LoBrutto R. Hoboken, New Jersey: John Wiley & Sons, Inc. 2007; 455–502. https://doi.org/10.1002/9780470087954.ch9.Gao Quanyin and Sanvordeker D.R. Analytical methods development and methods validation for oral solid dosage forms in Generic Drug Product Development: Solid Oral Dosage Forms, 2-nd Ed. Shargel, Leon: CRC Press/Taylor & Francis Group. 2014; 31–50.Gao Quanyin and Sanvordeker D.R. Analytical methods development and methods validation for oral solid dosage forms in Generic Drug Product Development: Solid Oral Dosage Forms, 2-nd Ed. Shargel, Leon: CRC Press/Taylor & Francis Group. 2014; 31–50.Дерффель К. Статистика в аналитической химии. М.: Мир, 1994; 268.Doerffel K. Statistik in der analytischen Chemie. Leipzig: Deutscher Verlag für Grundstoffindustrie GmbH: 1990; 256.Njaka N. A., Elise O. R., Herinirina N. R., Lucienne V. R., Manovantsoatsiferana H., R. A., Randrianarivony E. Dealing with Outlier in Linear Calibration Curves: A Case Study of Graphite Furnace Atomic Absorption Spectrometry. World Journal of Applied Chemistry. 2018; 3 (1): 10–16.Njaka N. A., Elise O. R., Herinirina N. R., Lucienne V. R., Manovantsoatsiferana H., R.A., Randrianarivony E. Dealing with Outlier in Linear Calibration Curves: A Case Study of Graphite Furnace Atomic Absorption Spectrometry. World Journal of Applied Chemistry. 2018; 3 (1): 10–16.

The authors declare that there are no conflicts of interest present.