pharmjournalРазработка и регистрация лекарственных средствDrug development & registration2305-20662658-5049LLC «CPHA»pharmjournal-612Research ArticleАНАЛИТИЧЕСКИЕ МЕТОДИКИ И МЕТОДЫ КОНТРОЛЯANALYTICAL AND QUALITY CONTROL METHODSВАЛИДАЦИЯ ХРОМАТОГРАФИЧЕСКИХ МЕТОДИК: ИССЛЕДОВАНИЕ РОБАСТНОСТИ С ИСПОЛЬЗОВАНИЕМ МАТЕМАТИЧЕСКОГО ПЛАНИРОВАНИЯ ЭКСПЕРИМЕНТОВVALIDATION OF CHROMATOGRAPHIC METHODS: ROBUSTNESS INVESTIGATION WITH USE OF EXPERIMENTAL DESIGNЭпштейнН. А.EpshteinN. A.noemail@neicon.ruАО «ШТАДА ФармДевелопмент» АО «НИЖФАРМ»Autonomous Incorporation «STADA PharmDevelopment», SC «NIZHPHARM»2018090120190396108Copyright © 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/612

Рассмотрены теоретические и практические основы исследования робастности хроматографических методик с использованием планов Плакетта - Бермана. Пошагово, с пояснениями и примерами рассмотрено установление значимых (потенциально критических) факторов, а так же определение допустимых пределов изменения значимых факторов и откликов. Оценка этих пределов важна для обоснования требований к пригодности хроматографической системы. Даны рекомендации по выполнению необходимых вычислений в Excel и оценке робастности хроматографических методик.

This article covers the theoretical and practical basics of research of the robustness of chromatographic methods on the base of Plackett - Burman design. Step by step, with explanations and examples, the estimation of significant (potentially critical) factors as well as the estimation of permissible limits of the changes of factors and responses are considered. The assessment of the limits is important for the justification of the requirements to the suitability of a chromatographic system. Also, we suggest the recommendations for performing necessary calculations in Excel and for the assessment of robustness of chromatographic methods.

робастностьпланы Плакетта - Берманарисквалидацияхроматографические методикипригодность системыrobustnessPlackett - Burman designriskvalidationchromatographic methodssystem suitabilityReferencesЭпштейн Н. А., Севастьянова В. Л., Королева А. И. Исследование робастности при валидации методик ВЭЖХ и УЭЖХ: современный подход, включающий анализ рисков // Разработка и регистрация лекарственных средств. 2018. № 1(22). С. 140-153.Epshtein N. A., Sevast'yanova V. L., Koroleva A. I. Robustness study in the validation of HPLC and HPLC techniques: a modern approach, including risk analysis // Development and registration of drugs. 2018. № 1(22). Р. 140–153.Vander Heyden Y., Nassart D. L. Review of the use of robustness and ruggedness in analytical chemistry // Robustness of analytical chemical methods and pharmaceutical technological products / Ed. by Hendriks M.W.B., de Boer J.H., Smilde A.K. - Amsterdam: Elsevier Science B.V. 1996. P. 79-147. 2018 № 3 (24) w w w.pharmjournal.ruVander Heyden Y., Nassart D. L. Review of the use of robustness and ruggedness in analytical chemistry // Robustness of analytical chemical methods and pharmaceutical technological products / Ed. by Hendriks M.W.B., de Boer J.H., Smilde A.K.. – Amsterdam: Elsevier Science B.V. 1996. P. 79–147.Montgomery D. C. Design and analysis of 15. Ragonese R., Mulholland M., Kalman J. 27. Mašković M., Jančić-Stojanović B., experiments. 5th ed. - N.Y.: John Wiley & Full and fractional experimental designs Malenović A. et al., Assessment of Liquid Sons, Inc. 2001. 684 p. for robustness in the high-performance Chromatographic Method RobustnessMontgomery D. C. Design and analysis of experiments. 5th ed. – N.Y.: John Wiley & Sons, Inc. 2001. 684 p.Кононюк А. Е. Основы научных исследований (Общая теория эксперимента). Кн. 2. - Киев. КНТ. 2010. 452 с.Kononyuk A. E. Fundamentals of scientific research (General theory of the experiment). Book. 2. – Kiev. CST. 2010. 452 р.Ott R. L., Longnecker M. An Introduction to Statistical Methods and Data Analysis. 6th Ed. - Belmont: Brooks/Cole, Cengage Learning. 2010. 1273 p.Ott R. L., Longnecker M. An Introduction to Statistical Methods and Data Analysis. 6th Ed. – Belmont: Brooks/Cole, Cengage Learning. 2010. 1273 p.Эрмер Й., МакБ. Миллер Д. Х. Валидация методик в фармацевтическом анализе. Примеры наилучших практик. - М.: ВИАЛЕК, 2013. 495 с.Method Validation in Pharmaceutical Analysis. A Guide to Best Practice / Ed. by Remer J., Miller J. H. – Wenham: Wiley-VT Verlag GmbH & Co. Ka. 2005. 403 p.Bartolucci A., Singh K. P., Bae S. Introduction to Statistical Analysis of Laboratory Data. Chart 8. Robustness and Ruggedness. - John Wiley & Sons, Inc, 2015. 256 p.Bartolucci A., Singh K. P., Bae S. Introduction to Statistical Analysis of Laboratory Data. Chart 8. Robustness and Ruggedness. – John Wiley & Sons, Inc, 2015. 256 p.Ganorkara S. B., Dhumal D. M., Shirkhedkar A. A. Development and validation of simple RP-HPLC-PDA analytical protocol for zileuton assisted with Design of Experiments for robustness determination // Arabian Journal of Chemistry. 2017. V. 10. P. 273-282.Ganorkara S. B., Dhumal D. M., Shirkhedkar A. A. Development and validation of simple RP-HPLC-PDA analytical protocol for zileuton assisted with Design of Experiments for robustness determination // Arabian Journal of Chemistry. 2017. V. 10. P. 273–282.Vander Heyden Y., Luypaert К., Hartmann С. et al. Ruggedness tests on the НРLС assay of the United States Pharmacopoeia XXII for tetracycline hydrochloride. А comparison of experimental design and statistical interpretations // Analytica Chimica Acta. 1995. V. 312. P. 245-262.Vander Heyden Y., Luypaert К., Hartmann С. et al. Ruggedness tests on the НРLС assay of the United States Pharmacopoeia XXII for tetracycline hydrochloride. А comparison of experimental design and statistical interpretations // Analytica Chimica Acta. 1995. V. 312. P. 245–262.Fabre H. Robustness testing in liquid chromatography and capillary electrophoresis // J. Pharm. Biomed. Anal. 1996. V. 14. P. 1125-1132.Fabre H. Robustness testing in liquid chromatography and capillary electrophoresis // J. Pharm. Biomed. Anal. 1996. V. 14. P. 1125–1132.Cuadros Rodrıguez L., Blanc Garcıa R., Garcıa Campana A. M., Bosque Sendra J.M. A new approach to a complete robustness test of experimental nominal conditions of chemical testing procedures for internal analytical quality assessment // Chemometrics and Intelligent Laboratory Systems. 1998. V. 41, P. 57-68.Cuadros Rodrıguez L., Blanc Garcıa R., Garcıa Campana A. M., Bosque Sendra J.M. A new approach to a complete robustness test of experimental nominal conditions of chemical testing procedures for internal analytical quality assessment // Chemometrics and Intelligent Laboratory Systems. 1998. V. 41, P. 57–68.Jimidar M., Niemeijer N., Peeters R., Hoogmartens J. Robustness testing of a liquid chromatography method for the determination of vorozole and its related compounds in oral tablets // J. Pharm. Biomed. Analysis. 1998. V. 18. P. 479-485.Jimidar M., Niemeijer N., Peeters R., Hoogmartens J. Robustness testing of a liquid chromatography method for the determination of vorozole and its related compounds in oral tablets // J. Pharm. Biomed. Analysis. 1998. V. 18. P. 479–485.Vander Heyden Y., Jimidarb M., Hunda E. et al. Determination of system suitability limits with a robustness test // J. Chromatography A. 1999. V. 845. P. 145-154.Vander Heyden Y., Jimidarb M., Hunda E. et al. Determination of system suitability limits with a robustness test // J. Chromatography A. 1999. V. 845. P. 145–154.Hund E., Vander Heyden Y., Haustein M. et al. Comparison of several criteria to decide on the significance of effects in a robustness test with an asymmetrical factorial design // Analytica Chimica Acta. 2000. V. 404. P. 257-271. liquid chromatographic analysis of codeine phosphate, pseudoephedrine hydrochloride and chlorpheniramine maleate in a pharmaceutical preparation // J Chromatogr A. 2000. V. 870. P. 45-51.Hund E., Vander Heyden Y., Haustein M. et al. Comparison of several criteria to decide on the significance of effects in a robustness test with an asymmetrical factorial design // Analytica Chimica Acta. 2000. V. 404. P. 257–271.Ragonese R., Mulholland M., Kalman J. Full and fractional experimental designs for robustness in the high-performance liquid chromatographic analysis of codeine phosphate, pseudoephedrine hydrochloride and chlorpheniramine maleate in a pharmaceutical preparation // J Chromatogr A. 2000. V. 870. P. 45-51.Ragonese R., Mulholland M., Kalman J. Full and fractional experimental designs for robustness in the high-performance liquid chromatographic analysis of codeine phosphate, pseudoephedrine hydrochloride and chlorpheniramine maleate in a pharmaceutical preparation // J Chromatogr A. 2000. V. 870. P. 45–51.Vander Heyden Y., Nijhuis A., Smeyers-Verbeke J. et al. Guidance for Robust-ness/ Ruggedness Tests in Method Validation // J. Pharm. and Biomed. Analysis. 2001. V. 24. № 5-6. P. 723-753.Vander Heyden Y., Nijhuis A., Smeyers-Verbeke J. et al. Guidance for Robust-ness/ Ruggedness Tests in Method Validation // J. Pharm. and Biomed. Analysis. 2001. V. 24. № 5–6. P. 723–753.Hund E., Massart D. L., Smeyers-Verbeke J. Robust regression and outlier detection in the evaluation of robustness tests with different experimental designs // Analytica Chimica Acta. 2002. V. 463, P. 53-73.Hund E., Massart D. L., Smeyers-Verbeke J. Robust regression and outlier detection in the evaluation of robustness tests with different experimental designs // Analytica Chimica Acta. 2002. V. 463, P. 53–73.Hund E., Vander Heyden Y., Massart D. L., Smeyers-Verbeke J. Derivation of system suitability test limits from a robustness test on an LC assay with complex antibiotic samples // J. Pharm. and Biomed. Analysis. 2002. V. 30. P. 1197-1206.Hund E., Vander Heyden Y., Massart D. L., Smeyers-Verbeke J.. Derivation of system suitability test limits from a robustness test on an LC assay with complex antibiotic samples // J. Pharm. and Biomed. Analysis. 2002. V. 30. P. 1197–1206.Jimidar M., Van Ael W., De Smet M., Cockaerts P. Method Validation and Robustness Testing of an Enantioselective CE Method for Chemical Quality Control, LC•GC Europe, April, 2002. P. 2-9.Jimidar M., Van Ael W., De Smet M., Cockaerts P. Method Validation and Robustness Testing of an Enantioselective CE Method for Chemical Quality Control, LC•GC Europe, April, 2002. P. 2–9.Yong-Guo Li, Hong Liu, Y. Vander Heyden et al. Robustness tests on the United States Pharmacopoeia XXVI HPLC assay for ginsenosides in Asian and American ginseng using an experimental design // Analytica Chimica Acta. 2005. V. 536. P. 29-38.Yong-Guo Li, Hong Liu, Y. Vander Heyden et al. Robustness tests on the United States Pharmacopoeia XXVI HPLC assay for ginsenosides in Asian and American ginseng using an experimental design // Analytica Chimica Acta. 2005. V. 536. P. 29–38.Dejaegher B., Smeyers-Verbeke J., Vander Heyden Y. The variance of screening and supersaturated design results as a measure for method robustness // Analytica Chimica Acta. 2005. V. 544. P. 28-279.Dejaegher B., Smeyers-Verbeke J., Vander Heyden Y. The variance of screening and supersaturated design results as a measure for method robustness // Analytica Chimica Acta. 2005. V. 544. P. 28–279.Dejaegher B., Capron X., Smeyers-Verbeke J., Vander Heyden Y. Randomization tests to identify significant effects in experimental designs for robustness testing // Analytica Chimica Acta. 2006. V. 564. P. 184-200.Dejaegher B., Capron X., Smeyers-Verbeke J., Vander Heyden Y. Randomization tests to identify significant effects in experimental designs for robustness testing // Analytica Chimica Acta. 2006. V. 564. P. 184–200.Dejaegher B., Dumarey M., Capron X., Bloomfield M.S., Vander Heyden Y. Comparison of Plackett-Burman and supersaturated designs in robustness testing // Anal. Chim. Acta. 2007. V. 595. № 1-2. P. 59-71.Dejaegher B., Dumarey M., Capron X., Bloomfield M.S., Vander Heyden Y. Comparison of Plackett–Burman and supersaturated designs in robustness testing // Anal. Chim. Acta. 2007. V. 595. № 1–2. P. 59–71.Jimidar M. I., Heylen P., De Smet Ma. Method Validation // Separation Science and Technology. 2007. V. 8. P. 441-458.Jimidar M. I., Heylen P., De Smet Ma. Method Validation // Separation Science and Technology. 2007. V. 8. P. 441–458.Durden D. A. Using Plackett - Burman partial factorial designs for method robustness testing. By D. A. Durden. Canadian Food Inspection Agency Calgary Laboratory 3650 36 St NW Calgary, AB. http://www.traceorganic.com/2007/presentations/DaveDurden_Using%20 Plackett%20Burman%20partial%20factorial%20designs%20for%20method.pdf (accessed 09.08.2018).Durden D. A. Using Plackett – Burman partial factorial designs for method robustness testing. By D. A. Durden. Canadian Food Inspection Agency Calgary Laboratory 3650 36 St NW Calgary , AB. http://www.traceorganic.com/2007/presentations/DaveDurden_Using%20Plackett%20Burman%20partial%20factorial%20designs%20for%20method.pdf (accessed 09.08.2018).Dejaegher B., Vander Heyden Y. Robustness testing of CE methods // Capillary Electrophoresis Methods for Pharmaceutical Analysis / Ed. by Ahuja S. and Jimidar M.I. - Elsevier Inc., 2008. V. 9. by Use of Plackett - Burman Design // Acta Chromatographica. 2010. V. 22. № 2. P. 281-296.Dejaegher B., Vander Heyden Y. Robustness testing of CE methods // Capillary Electrophoresis Methods for Pharmaceutical Analysis / Ed. by Ahuja S. and Jimidar M.I. – Elsevier Inc., 2008. V. 9.Mašković M., Jančić-Stojanović B., Malenović A. et al., Assessment of Liquid Chromatographic Method Robustness by Use of Plackett - Burman Design // Acta Chromatographica. 2010. V. 22. № 2. P. 281-296.Mašković M., Jančić-Stojanović B., Malenović A. et al., Assessment of Liquid Chromatographic Method Robustness by Use of Plackett – Burman Design // Acta Chromatographica. 2010. V. 22. № 2. P. 281–296.Chakravarthy V. К., Kishore Babu G. К., Dasu R. L. et. al. The role of relative response factor in related substances method development by high performance liquid chromatography (HPLC) // Rasayan J. Chem. 2011. V. 4. № 4. P. 919-943. URL: http://www.rasayanjournal. co.in/vol-4/issue-4/37.pdf (accessed 09.08.2018).Chakravarthy V. К., Kishore Babu G. К., Dasu R. L. et. al. The role of relative response factor in related substances method development by high performance liquid chromatography (HPLC) // Rasayan J. Chem. 2011. V. 4. № 4. P. 919– 943. URL: http://www.rasayanjournal.co.in/vol-4/issue-4/37.pdf (accessed 09.08.2018).Brynn Hibbert D. Experimental design in chromatography: A tutorial review // J. Chromatography B. 2012. V. 910. P. 2-13.Brynn Hibbert D. Experimental design in chromatography: A tutorial review // J. Chromatography B. 2012. V. 910. P. 2–13.Stojanovic B. J., Rakic T., Slavkovic B. et al. Systematical approach in evaluation of LC method for Determination of raloxifene hydrochloride and its impurities employing experimental design // J. Pharm. Analysis. 2013. V. 3. № 1. P. 45-52.Stojanovic B. J., Rakic T., Slavkovic B. et al. Systematical approach in evaluation of LC method for Determination of raloxifene hydrochloride and its impurities employing experimental design // J. Pharm. Analysis. 2013. V. 3. № 1. P. 45–52.Luciana F. Oliveira, Soraia C. G. N. Braga, Paulo R. Filgueiras et al., Assessment of robustness on analysis using head space solid-phase microextraction and comprehensive two-dimensional gas chromatography through experimental designs // Talanta. 2014. V. 129. P. 303-308.Luciana F. Oliveira, Soraia C. G. N. Braga, Paulo R. Filgueiras et al., Assessment of robustness on analysis using head space solid-phase microextraction and comprehensive two-dimensional gas chromatography through experimental designs // Talanta. 2014. V. 129. P. 303–308.Schmidt A. H., Stanica M., Molnárc I. In silico robustness testing of a compendial HPLC purity method by using of a multidimensional design space build by chromatography modeling-Case study pramipexole // J. Pharm. and Biomed. Analysis. 2014. V. 91. P. 97-107.Schmidt A. H., Stanica M., Molnárc I. In silico robustness testing of a compendial HPLC purity method by using of a multidimensional design space build by chromatography modeling–Case study pramipexole // J. Pharm. and Biomed. Analysis. 2014. V. 91. P. 97–107.Mokhtara H. I., Abdel-Salamb R. A., Hadadb G.M. Development of a fast high performance liquid chromatographic screening system for eight antidiabetic drugs by an improved methodology of in-silico robustness simulation // J. Chromatography A. 2015. V. 1399. P. 32-44.Mokhtara H. I., Abdel-Salamb R. A., Hadadb G.M. Development of a fast high performance liquid chromatographic screening system for eight antidiabetic drugs by an improved methodology of in-silico robustness simulation // J. Chromatography A. 2015. V. 1399. P. 32–44.Prafulla Kumar Sahu. Definition of System Suitability Test Limits on the Basis of Robustness Test Results // J. Anal. Bioanal. Tech. 2017. V. 8. № 2. P. 1-6. URL:https://www.omicsonline.org/open-access/definition-of-system-suitabili-ty-test-limits-on-the-basis-of-robust-ness-testresults-2155-9872-1000363.php?aid=90748&view=mobile (accessed 08.08.2018).Prafulla Kumar Sahu. Definition of System Suitability Test Limits on the Basis of Robustness Test Results // J. Anal. Bioanal. Tech. 2017. V. 8. № 2. P. 1–6. URL: https://www.omicsonline.org/openaccess/definition-of-system-suitability-test-limits-on-the-basis-of-robustness-testresults-2155-9872-1000363.php?aid=90748&view=mobile (accessed 08.08.2018).Szerkusa O., Jacynaa J., Gibasb A. et al. Robust HPLC-MS/MS method for levofloxacin and ciprofloxacin determination in human prostate tissue // J. Pharm. and Biomed. Analysis. 2017. V. 132. P. 173-183.Szerkusa O., Jacynaa J., Gibasb A. et al. Robust HPLC–MS/MS method for levofloxacin and ciprofloxacin determination in human prostate tissue // J. Pharm. and Biomed. Analysis. 2017. V. 132. P. 173–183.How to Draw a Normal Probability Plot By Hand. Url: http://www.statisticshowto.com/normal-probability-plot/ (accessed 09.08.2018).How to Draw a Normal Probability Plot By Hand. Url: http://www.statisticshowto.com/normal-probability-plot/ (accessed 09.08.2018).Dong F. On the identification of active contrasts in unreplicated fractional factorials // Statistica Sinica. 1993. V. 3. P. 209-217.Dong F. On the identification of active contrasts in unreplicated fractional factorials // Statistica Sinica. 1993. V. 3. P. 209–217.

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